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Pharmaceutical Services DivisionMinistry of Health Malaysia


Lot 36, Jalan University,46350 Petaling Jaya,Selangor Darul Ehsan.

Tel : +603 7841 3200 Fax : +603 7968 2222Website : www.pharmacy.gov.my

Paediatric Pharmacy Services Guideline2

First Edition 2015Pharmaceutical Services DivisionMinistry of Health, Malaysia

©ALL RIGHTS RESERVED

This is a publication of the Pharmaceutical Services Division, Ministry of Health Malaysia. Enquiries are to be directed to the address below. Permission is hereby granted to reproduce information contained herein provided that such reproduction be given due acknowledgement and shall not modify the text.


Lot 36, Jalan Universiti, 46350 Petaling Jaya, Selangor, Malaysia

Tel: 603 - 7841 3200 | Fax: 603 - 7968 2222Website: www.pharmacy.gov.my

Paediatric Pharmacy Services Guideline 3

Mes

sage

MESSAGE

Paediatric pharmacists are in prime position to maximize the safe and effective use of medicines and influence the management of medicines for children and adolescents. Children are a special population which require detailed attention on the management and medications as their physiological function is still developing and yet to mature.

Paediatric pharmacy is a specialized clinical pharmacy service that is currently increasing in significance in Malaysia. We aim to have paediatric pharmacy service in all major hospitals and at least one paediatric pharmacist in secondary hospitals.

Therefore Clinical Pharmacy Working Committee ( Paediatric subspecialty ) Pharmaceutical Services Division, Ministry of Health has initiated to produce this guideline. I am optimistic that this guideline will assist paediatric pharmacist in their practices especially for those who will set up paediatric pharmacy services in their setting.

I would like to commend the Clinical Pharmacy Working Committee (Paediatric subspecialty) Pharmaceutical Services Division, Ministry of Health for their contribution and commitment to the development of this guideline.

Thank you.

Puan Abida Haq bt Syed M. HaqDirector of Pharmacy Practice and Development Division


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ADVISORS

Main Editorial Committees

Madam Abida Haq Syed M.HaqDirector of Pharmacy Practice & Development DivisionPharmaceutical Services Division, Ministry of Health, Malaysia

Madam Rosminah Mohd DinDeputy Director (Clinical Pharmacy & Technical)Pharmaceutical Services Division, Ministry of Health, Malaysia

Madam Noraini MohamadSenior Principal Assistant Director PharmacyPharmaceutical Services Division, Ministry of Health, Malaysia

Noor Haslina OthmanSenior Clinical PharmacistHospital Raja Perempuan Zainab II

Subasyini SivasupramaniamSenior Clinical PharmacistHospital Kuala Lumpur

Khoo Sze NiSenior Clinical PharmacistHospital Raja Permaisuri Bainun

Ng Boon YahSenior PharmacistHospital Pulau Pinang

Ng See YeeSenior Clinical PharmacistHospital Sultanah Bahiyah

Stella Chuo Sing HongSenior PharmacistHospital Sibu

Won Zi YunPharmacistHospital Putrajaya

Wong Pui MunSenior PharmacistHospital Serdang

Nurul Hidayah SallehPharmacistHospital Tengku Ampuan Afzan

Khairunnisa Mohamad PharmacistHospital Kemaman


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Wong Shien WoanPharmacistHospital Melaka

Sharini Sha’ariSenior PharmacistHospital Tuanku Ja’afar

Tea Ming HuiPharmacistHospital Sultanah Nora Ismail

Irwinder Kaur ChhabraPharmacistHospital Wanita dan Kanak - kanak Likas

Low Yong ChiaPharmacistHospital Wanita dan Kanak-kanak Likas

Tan Jing WenPharmacistHospital Kuala Lumpur

Angeline Tan Meng Wah Principal Assistant Director Pharmaceutical Services Division, MOH


Table of Content

1.0 Introduction To The Guideline 8

2.0 Job Description Of A Paediatric Pharmacist 9

3.0 General Pediatrics 11

Respiratory Illness 12

Viral Bronchiolitis 12

Asthma 14

Neurology 24

Status Epilepticus 24

Epilepsy 28

Infantile Spasm 37

Nephrology 43

Acute Glomerulonephritis 43

Nephrotic Syndrome 45

Acute Renal Failure 49

Infectious diseases 52

Tuberculosis 52

Malaria 60

Meningitis 71

Urinary Tract Infection 77

Viral Croup 80

Pneumonia 84

Cardiovascular 92

Kawasaki Disease 92

Rheumatic Heart Disease 95


4.0 Paediatric ICU 98

Fluid & Electrolyte Management 99

Nutrition In Critically Ill Patients 107

Shock Management 113

Neuromuscular Blockade 119

Stress Ulcer Prophylaxis 127

Sedation & Pain Management 131

5.0 Neonatal ICU 141

Neonatal Jaundice (NNJ) 142

Sedation & Pain Management 147

Total Parenteral Nutrition In Neonates 161

Fluid & Electrolyte Management 168

Necrotizing Enterocolitis 170

6.0 Dosing Considerations in Special Populations 181

7.0 Appendix 189

Corticosteroid Equipotency Chart 189

Nutrition Reference 190

Immediate-release Opioid Analgesics Comparison Chart 191

TDM Sampling Time 192

Growth Charts 193

Stability and Storage of Oral Medications 203

Drugs To Avoid In G6PD Deficiency 211


1.0 Introduction To The Guideline

Neonates and paediatrics are vulnerable groups who require extra careful handling, and hence the role of paediatric pharmacists is crucial to ensure medication safety. With this insight, paediatric pharmacy service was introduced under the pharmacy program of Ministry of Health (MOH), Malaysia in 2006, and subsequently the first paediatric pharmacists working group committee was formed in 2009.

The role of paediatric pharmacists has gained recognition throughout the years. Despite the increasing demand for paediatric pharmacists, this remains as one of the most challenging clinical pharmacy field to venture in. The lack of evidence and standardized dosing in paediatrics and neonates can be a hurdle to practice evidence based medicine in this field. Also, the lack of standardized guidelines on the conduct of paediatric pharmacy services under facilities of MOH, Malaysia may lead to great differences in the expected roles and responsibilities as a paediatric pharmacist. The aim of this service guideline is to serve as a baseline reference and information for paediatric pharmacists who are new to this field on the conduct and practice of paediatric pharmacy. It can also be a basic reference for provisionally registered pharmacists (PRP) who will be doing paediatric clinical clerkship during clinical attachment. It is of great hope that with the introduction of this service guideline, paediatric pharmacy services under MOH, Malaysia can be further expanded and established.


2.0 Job Description of a Paediatric Pharmacist

Paediatric pharmacy consists of general paediatric, paediatric intensive care and neonatal intensive care. The ultimate goal of paediatric pharmacy service is to assist in the best possible way to achieve safe and effective treatment. Hence, evidence-based practice should be the mainstay in the management of all patients at all time.

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2.0 Job Description Of A Paediatric Pharmacist Paediatric pharmacy consists of general paediatric, paediatric intensive care and neonatal intensive care. The ultimate goal of paediatric pharmacy service is to assist in the best possible way to achieve safe and effective treatment. Hence, evidence-based practice should be the mainstay in the management of all patients at all time.

Table 2.1: Job Description of Paediatric Pharmacist Job Scope Description

Admission clerking

• Medication history clerking, which includes non-prescription

drugs e.g. herbal remedies and over the counter drugs (OTC) • Compliance assessment (CP1 form) – if applicable • Medication reconciliation

Pharmacotherapy Rounds

• Active participation in ward rounds with doctors • Collaborate with other healthcare providers in developing

pharmaceutical care plans for the patients • Provide medication therapy evaluations and

recommendations to healthcare providers supported by evidence-based medicines

Monitor and review patients’ medication

• Case clerking and review (CP2 form) • Checking patient’s medication chart • Ensure medications are served • Ensure prescription is completely filled • Ensure safe and rational drug use • Ensure approppriate dilution and administration of injectable

drugs • Ascertain proper extemporaneous preparation • Therapeutic Drug Monitoring (TDM) / Total Parenteral

Nutrition (TPN) services

Identify Pharmaceutical Care Issues

• Dosing adjustment based on patient’s body weight, age

group, body surface area, renal and liver function. • Medication errors e.g. drug, dose, frequency, duration,

administration, etc • Drug- drug interactions • Drug incompatibilities and contraindications • Polypharmacy


Adverse Drug Reaction Report

• Identifies and report any suspected adverse drug reaction (ADR) or drug allergy

• Provision of allergy card

Provision of Drug Information

• Drug availability • Safety and toxicology • Cost-effectiveness of medications • Maintains current drug references

Education

• Continuous Professional Development • Continuous Nursing Education • Provides drug therapy related to team members

Patient /caregiver counselling

• Bedside/Discharge counselling • Specialised drug delivery devices e.g. Insulin pen, inhalers,

spacers • Oral drug preparation (e.g. freshly prepared syrup, drug

reconstitution)

Research and Development

• Participate in research work/project pertaining to paediatric

pharmacy practice • Contributes to the pharmacy and medical literature for

examples case reports, pharmacokinetics and pharmacoeconomics reports


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3.0 General Paediatric


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Respiratory Illness

Viral Bronchiolitis

Introduction

Viral bronchiolitits is a common respiratory illness especially in infants aged 1 to 6 months old. Respiratory Syncytial Virus (RSV) remains the commonest cause of acute bronchiolitis in Malaysia. Although it is endemic throughout the year, cyclical periodicity with annual peaks occuring in the months of November December and January1. It is characterized by acute inflammation, edema and necrosis of epithelial cells lining small airways, increased mucus production, and bronchospasm2.

Clinical Features

Patients typically presents with a mild coryza, low grade fever and cough. Tachypnoea, chest wall recession, wheeze and respiratory distress subsequently develop. The chest may be hyperinflated and auscultation usually reveals fine crepitations and sometimes rhonchi. A majority of children with viral bronchiolitis has mild illness and about 1% of these children require hospital admission1.

Management

Pharmacotherapy

• 3% saline solution via nebulizer Shown to increase mucus clearance and significantly reduce hospital stay among non-severe acute bronchiolits. It improves clinical severity score in both outpatients and inpatients populations1.

• Inhaled ß2-agonists Pooled data have indicated a modest clinical improvement with the use of ß2 - agonist. A trial of nebulised ß2-agonist, given in oxygen, may be considered in infants with viral bronchiolitis. Vigilant and regular assessment of the child should be carried out1.Parameters to measure its effectiveness include improvements in wheezing, respiratory rate, respiratory effort, and oxygen saturation1.


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• Inhaled steroids Randomised controlled trials of the use of inhaled or oral steroids for treatment of viral bronchiolitis show no meaningful benefit1.

• Antibiotics Recommended for all infants with recurrent apnoea and circulatory impairment, possibility of septicaemia, acute clinical deterioration, high white cell count., progressive infiltrative changes on chest radiograph1.

Supportive Management

Arterial oxygenation by pulse oximetry (SPO2) should be performed at presentation and maintained above 93%. Administer supplemental humidified oxygen if necessary. Routine full blood count and bacteriological testing (of blood and urine) is not indicated in the assessment and management of infants with typical acute bronchiolitis1.

Special consideration

• Palivizumab Injection Clinicians may administer palivizumab prophylaxis to selected infants and children with chronic lung disease or a history of prematurity ( less than 35 weeks’ gestation ) or with congenital heart disease2. When given, prophylaxis should be given monthly for a total of 5 doses at a dose of 15mg/kg/dose administered intramuscularly2.

References:

1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 31, Viral Bronchiolitis; p.161-2.

2. Lieberthal AS, Bauchner H, Hall CB, Johnson DW, Kotagal U,Light MJ, et al. Diagnosis and Management of bronchiolitis. American Academy of Pediatrics 2006;118:1774-1793.


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ASTHMA

Introduction

Asthma is defined as a chronic airway inflammation leading to increase airway responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or early morning. It is often associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. There is reversible and variable airflow limitation as evidenced by >15% improvement in PEFR (Peak Expiratory Flow Rate), in response to administration of a bronchodilator1.

Pre-school wheezing can be divided into two main categories, episodic (viral wheeze) and multiple trigger wheeze. Children who only wheeze with viral infections and are well between episodes can be classified as viral wheeze. Multiple trigger wheezers are children who have discrete exacerbations and symptoms in between these episodes. Triggers are smoke, allergens, crying, laughing and exercise1. The presence of atopy (eczema, allergic rhinitis and conjunctivitis) in the child or family supports the diagnosis of asthma. However, the absence of these conditions does not exclude the diagnosis1.

Management of Chronic Asthma

The management of chronic asthma can be based on either the severity of asthma or the degree of asthma control. Newly diagnosed patients will be categorized into different degrees of asthma severity by the physicians as in Table 11. Patients who are already on treatment should be assessed at every clinic visit on their control of asthma as in Table 22.

Respiratory Illness


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Asthma

Introduction

Asthma is defined as a chronic airway inflammation leading to increase airway responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or early morning. It is often associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. There is reversible and variable airflow limitation as evidenced by >15% improvement in PEFR (Peak Expiratory Flow Rate), in response to administration of a bronchodilator1.

Pre-school wheezing can be divided into two main categories, episodic (viral wheeze) and multiple trigger wheeze. Children who only wheeze with viral infections and are well between episodes can be classified as viral wheeze. Multiple trigger wheezers are children who have discrete exacerbations and symptoms in between these episodes. Triggers are smoke, allergens, crying, laughing and exercise1. The presence of atopy (eczema, allergic rhinitis and conjunctivitis) in the child or family supports the diagnosis of asthma. However, the absence of these conditions does not exclude the diagnosis1

.

Management of Chronic Asthma

The management of chronic asthma can be based on either the severity of asthma or the degree of asthma control. Newly diagnosed patients will be categorized into different degrees of asthma severity by the physicians as in Table 11. Patients who are already on treatment should be assessed at every clinic visit on their control of asthma as in Table 22.

Table 1: Evaluation of Newly Diagnosed Asthma

Clinical Parameters

Category

Intermittent Persistent

Mild Moderate Severe

Daytime symptoms Less than once a week More than once a week Daily Daily

Nocturnal symptoms Less than once a month More than twice a month More than once a week Daily

Exercise induced symptoms No Yes Yes Daily

Exacerbations Brief exacerbations not

affecting sleep and activity

> 1x/month affecting sleep, activity

> 2x/month affecting sleep, activity

Frequent >2x/month affecting sleep,activity

Lung function Normal PEFR / FEV1:> 80% PEFR / FEV1: 60 - 80%

PEFR / FEV1: < 60

• This division is arbitrary and the groupings may merge. An individual patient’s classification may change from time to time.

• There are a few patients who have very infrequent but severe or life threatening attacks with completely normal lung function and no symptoms between episodes. This type of patient remains very difficult to manage.

• PEFR = Peak Expiratory Flow Rate; FEV1 = Forced Expiratory Volume in One Second.

Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition

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Table 2: Evaluation of Asthma Control

Characteristics

Controlled

All of the following:

Partly Controlled

Any measure present in any week

Uncontrolled

Daytime Symptoms None >2 per week

≥ 3 features of

partly controlled

asthma present

in any week

Limitations of activities None Any

Nocturnal symptoms or awakenings None Any

Need for reliever None >2 per week

Lung function test Normal < 80% predicted or

personal best

Exacerbations None ≥ 1 per year One in any week


Pharmacotherapy

The treatment of asthma consists of 2 components which consist of preventor therapy for reducing airway inflammation and reliever therapy for relieving the respiratory symptoms. Patients who have persistent asthma should be started on daily preventor medication. The initial medication and dosages depends on the severity and necessity to attain quick control of asthma2. A comprehensive treatment plan for asthma includes asthma education, avoidance of trigger factors and strategies to optimize pharmacotherapy. The management plan for each patient should be individualized because each patient has different trigger factors, asthma phenotypes and different responses to the medication2. Asthma management based on levels of control is a step up and step down approach as shown in Table 4. Before progressing to the next step, pharmacists can assist physicians in deciding the management of asthma by assessing the compliance and inhaler technique as well as any exposure to trigger factors and relaying the information to the physicians. It is important that the delivery system is appropriate to the child’s age2. Metered dose inhaler therapy via spacer with facemask is as efficacious as nebulizer therapy2.

Role of pharmacists:

• Provide medication education by providing information on the indication of the medications, dose, frequency and duration of the medications.

• Suggest the most suitable inhaler devices based on the patient's ability to understand the instructions and ability to use the inhalers correctly

• Counseling of proper inhaler techniques (metered dose inhalers [MDI], spacers with face mask, dry powder inhalers) and proper way of administrating medications (ie Montelukast Granules) to patients, parents or care givers

• Counsel patients on common side effects of each medications and how to prevent them (eg: Gargle after using inhaled corticosteroids to avoid oral thrush, sore throat and hoarse voice )

• Educate on the proper care of drug delivery devices for example spacers with face mask (refer to individual product care) as a properly functioning delivery device is essential to


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Pharmacotherapy

The treatment of asthma consists of 2 components which consist of preventor therapy for reducing airway inflammation and reliever therapy for relieving the respiratory symptoms. Patients who have persistent asthma should be started on daily preventor medication. The initial medication and dosages depends on the severity and necessity to attain quick control of asthma2. A comprehensive treatment plan for asthma includes asthma education, avoidance of trigger factors and strategies to optimize pharmacotherapy. The management plan for each patient should be individualized because each patient has different trigger factors, asthma phenotypes and different responses to the medication2. Asthma management based on levels of control is a step up and step down approach as shown in Table 4. Before progressing to the next step, pharmacists can assist physicians in deciding the management of asthma by assessing the compliance and inhaler technique as well as any exposure to trigger factors and relaying the information to the physicians. It is important that the delivery system is appropriate to the child’s age2. Metered dose inhaler therapy via spacer with facemask is as efficacious as nebulizer therapy2.

Role of pharmacists:

• Provide medication education by providing information on the indication of the medications, dose, frequency and duration of the medications.

• Suggest the most suitable inhaler devices based on the patient’s ability to understand the instructions and ability to use the inhalers correctly

• Counseling of proper inhaler techniques (metered dose inhalers [MDI], spacers with face mask, dry powder inhalers) and proper way of administrating medications ( ie Montelukast Granules ) to patients, parents or care givers

• Counsel patients on common side effects of each medications and how to prevent them (eg: Gargle after using inhaled corticosteroids to avoid oral thrush, sore throat and hoarse voice )

• Educate on the proper care of drug delivery devices for example spacers with face mask (refer to individual product care) as a properly functioning delivery device is essential to ensure optimum delivery of medication to patients.

• Encourage adherence to medications and find ways to overcome if any issues of nonadherence (eg: noncompliance to inhaled corticosteroid due to fear of dependence to steroids)


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ensure optimum delivery of medication to patients. • Encourage adherence to medications and find ways to overcome if any issues of

nonadherence (eg: noncompliance to inhaled corticosteroid due to fear of dependence to steroids)

Table 3: Inhaler Devices Recommended For Different Age

Children aged 0-6 years Metered dose inhaler + spacer with facemask

Children aged > 6 years

Metered dose inhaler + spacer with facemask Metered dose inhaler + spacer with mouthpiece Dry powder inhaler (may be suitable)

Source: Adapted from Clinical Practice Guidelines for the Management of Childhood Asthma 2014

Table 4: Management of Asthma

REDUCE ← → INCREASE

STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

Intermittent Mild Persistent

Moderate Persistent

Severe Persistent

Severe Persistent

As needed rapid acting β2-agonist

Controller Options Select one Select one Add one / more Add one / more

Low dose inhaled

steroids

Low dose ICS + long acting β2-

agonist

Medium / High dose ICS

+ long acting β2-agonist

Oral Glucocorticoids

lowest dose

Leukotriene

receptor antagonist


Leukotriene receptor antagonist

Anti-IgE

Low dose ICS +


SR Theophylline

Low dose ICS + SR Theophylline

ICS: Inhaled corticosteroid; SR: Sustained relase Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition

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ensure optimum delivery of medication to patients. • Encourage adherence to medications and find ways to overcome if any issues of

nonadherence (eg: noncompliance to inhaled corticosteroid due to fear of dependence to steroids)

Table 3: Inhaler Devices Recommended For Different Age

Children aged 0-6 years Metered dose inhaler + spacer with facemask

Children aged > 6 years

Metered dose inhaler + spacer with facemask Metered dose inhaler + spacer with mouthpiece Dry powder inhaler (may be suitable)


Table 4: Management of Asthma

REDUCE ← → INCREASE

STEP 1 STEP 2 STEP 3 STEP 4 STEP 5

Intermittent Mild Persistent

Moderate Persistent

Severe Persistent

Severe Persistent

As needed rapid acting β2-agonist

Controller Options Select one Select one Add one / more Add one / more

Low dose inhaled

steroids

Low dose ICS + long acting β2-

agonist


+ long acting β2-agonist

Oral Glucocorticoids

lowest dose

Leukotriene

receptor antagonist



Anti-IgE

Low dose ICS +


SR Theophylline

Low dose ICS + SR Theophylline

ICS: Inhaled corticosteroid; SR: Sustained relase Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition


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Table 5: Drug Doses Of Common Medications Used in Asthma

Drug Formulation Dose1.2.3.4.5.6 Additional information4,5,7

Salbutamol

Oral

0.15 mg/kg/dose 6-8H/ PRN

Metered dose inhaler

100-200 mcg/dose 4-6H/ PRN

Dry powder inhaler 100-200 mcg/dose 6H/ PRN

Intravenous

Bolus: 5-10 mcg/kg over 10 min

Infusion: Start 0.5-1 mcg/kg/min, increase by 1 mcg/kg/min every 15 min to a max of 20 mcg/kg/min

For continuous intravenous infusion,

dilute to a concentration of 200 micrograms/mL

with Glucose 5%, Sodium Chloride 0.9% ; if fluid-restricted,can be

given undiluted through central venous catheter

Nebuliser

0.15 mg/kg/dose (max 5 mg) or < 2 years old : 2.5 mg/dose > 2 years old : 5.0 mg/dose Continuous : 500 mcg/kg/hr

Terbutaline Subcutaneous 5-10mcg/kg (Maximum 0.5mg/dose)

Prednisolone Oral 0.5-1mg/kg/day x 3-5 days (Maximum: 60mg/day)

Hydrocortisone Intravenous 4 mg/kg/dose 6H (max 100mg/dose)

Methylprednisolone Intravenous

0.5-1 mg/kg 6H day 1, 12H day 2, then 1mg/kg daily, reducing to minimum effective dose

Beclomethasone Diproprionate /

Budesonide

Metered dose inhaler Dry powder inhaler

<400 mcg/day : low dose 400-800 mcg/day : Moderate 800- 1200 mcg/day: High

Fluticasone Propionate

Metered dose inhaler Dry powder inhaler

<200 mcg/day : Low 200-400 mcg/day : Moderate 400-600 mcg/day : High


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Ciclesonide


160 microgram daily 320 microgram daily

Licensed for children over 6 years old

Salmeterol + Fluticasone


Children 4 years and older:

2 inhalations of 25mcg/50mcg BD

12 years and older:

2 inhalations of 25mcg/50mcg BD or

2 inhalations of 25mcg/125mcg BD

There are no data available for use in children below 4 years old

Dry powder inhaler

12 years and older:

1 inhalation of 50mcg/250mcg BD or

1 inhalation of 50mcg/500mcg BD

Montelukast

Oral

1-5 years old: 4 mg granules ON

6-14 years old:

5mg/tablet chewable ON

>14 years old:

10mg/tablet ON

Theophylline

Oral Syrup Slow Release

5 mg/kg/dose TDS/QID 10 mg/kg/dose BD

Therapeutic drug monitoring: 10-20mg/L

Aminophylline Intravenous (IV)

6 mg/kg slow bolus (if not previously on theophylline) followed by infusion 0.5 -1mg/kg/hr

Ipratropium bromide

Nebuliser solution (250 mcg/ml)

< 5 years old : 250 mcg 4-6 hourly > 5 years old : 500 mcg 4-6 hourly


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Prevention

Identifying and avoiding the following common triggers may be useful1

• Environmental allergens These include house dust mites, animal dander, insects like cockroach, mould and pollen. Useful measures include damp dusting, frequent laundering of bedding with hot water, encasing pillow and mattresses with plastic / vinyl covers, removal of carpets from bedrooms, frequent vacuuming and removal of pets from the household

• Cigarette smoke

• Respiratory tract infections - commonest trigger in children

• Food allergy - uncommon trigger, occurring in 1-2% of children

• Exercise- Although it is a recognized trigger, activity should not be limited. Taking short acting 2-agonist prior to strenuous exercise ( 10-20 minutes before exercise )2 as well as optimizing treatment is usually helpful.

Asthma Action Plan

An asthma action plan is a written instruction by the physician for the patient, parents or care giver on the daily management of asthma and how to identify and manage asthma exacerbations. The asthma action plan may differ for different institutions. An example of asthma action plan is available in the Clinical Practice Guidelines for the Management of Childhood Asthma 2014, Malaysia.

Special Considerations :

Ciclesonide is the most recent inhaled corticosteroid available for use in children. It is a prodrug activated locally in the lung by pulmonary esterase to des-ciclesonide, which ensures high local concentration8.


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Management Of Acute Asthma

The management of acute asthma depends on the severity at presentation, the response to therapy, the availability of drugs and facilities at the particular clinic/ hospital and the experience of the attending doctor. Before children can receive appropriate treatment for the acute asthma in any setting, it is essential to assess accurately the severity of their attack2.

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Management Of Acute Asthma

The management of acute asthma depends on the severity at presentation, the response to therapy, the availability of drugs and facilities at the particular clinic/ hospital and the experience of the attending doctor. Before children can receive appropriate treatment for the acute asthma in any setting, it is essential to assess accurately the severity of their attack2.

Table 7: Assessment of Severity of Acute Asthma Exacerbation in Children

Parameters Mild Moderate Severe Life Threatening

Breathless When walking When talking Infant: When

feeding

At rest Infant: Stops

Feeding

Talks in Sentences Phrases Words Unable to speak

Alertness Maybe agitated Usually agitated

Usually agitated

Drowsy / confused/ coma

Respiratory Rate Normal to Mildly increased Increased Markedly

increased Poor Respiratory

Effort

Accessory Muscle Usage / retractions Absent Present –

Moderate Present –

Severe Paradoxical thoraco-abdominal movement

Wheeze Moderate, often

only end expiratory

Loud Usually loud Silent chest

SpO2 (on air) >95% 92-95% <92% Cyanosis & <92%

Pulse / min <100 100-120

>120 (>5 yrs)

>160 (infants)

Bradycardia

PEFR* >80% 60-80% <60% Unable to perform

*Peak Expiratory Flow Rate (PEFR) after initial bronchodilator, % predicted or of personal best



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Algorithm 1: Management of Acute Exacerbation of Bronchial Asthma in Children



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References :

1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 30, Asthma; p.149-60

2. Clinical Practice Guidelines for the Management of Childhood Asthma. A Consensus statement prepared for the Academy of Medicine of Malaysia, Malaysian Thoracic Society and Lung Foundation of Malaysia. 2014.

3. Shann F. Drug Doses.16th Edition. Australia:Royal Children’s Hospital Parkville, Victoria; 2014.

4. BMA, Royal Pharmaceutical Society, Royal College and Pediatric of Child Health. BNF for Children 2012-2013.

5. Seretide Evohaler [Package insert].Burgos, Spain: Glaxo Wellcome S.A; 2010

6. Seretide Accuhaler [Package insert].Ware,UK: Glaxo Wellcome Operations; 2010

7. Alvesco [Package insert].Leicester,England: Takeda GmbH; 2013

8. Rizzo MC, Solé D. Inhaled corticosteroids in the treatment of respiratory allergy: safety vs. efficacy. J Pediatr (Rio J). 2006;82(5 Suppl):S198-205.


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NEUROLOGY

Status Epilepticus

Introduction

Status epilepticus (SE) is defined as any seizure lasted > 30 minutes which can be continuous or intermittent with incomplete recovery of consciousness in between seizures. However, any seizure > 5 minutes warrants pharmacological intervention as it is unlikely to terminate rapidly or spontaneously by itself. Based on the electroclinical features, SE may be classified broadly as convulsive SE and non-convulsive SE1, 2.

Convulsive SE is defined as convulsions associated with rhythmic jerking of extremities and mental status impairment. It can be further classified as tonic-clonic SE, tonic SE, clonic SE and myoclonic SE. Generalised tonic-clonic SE is the most common form of SE1.

Non-Convulsive SE is defined as seizure activity seen on electroencephalogram (EEG) without physical convulsions. It is characterized by abnormal mental status, unresponsiveness, ocular motor abnormalities, persistent electrographic seizures and possible response to anticonvulsants1.

Seizure which is continuous or repetitive lasting longer than 60 minutes despite treatment with benzodiazepine and one standard anticonvulsant (usually phenytoin or phenobartbitone) in adequate loading dose is defined as refractory status epilepticus1.


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Management

Pharmacotherapy

Refer to Algorithm 1.

Algorithm 1: Management of Status Epilepticus


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Special Consideration

1. Benzodiazepine should be the agent of choice for emergent initial treatment of SE3.

2. If the patient is currently treated with antiepileptic drugs, a drug level (TDM) should be checked and history obtained regarding compliance3.

3. If < 2 years old, pyridoxine ( IV 100mg if available, oral dose up to 30mg / kg / day ) will be helpful especially for suspected pyridoxine dependent seizures2,4.

4. Avoid sodium valproate in metabolic encephalopathy ( patient with metabolic or mitochondrial disease)2.

5. Be aware of the severe complication associated with propofol- ‘propofol infusion syndrome’ especially on dose exceeds 5mg/kg/hr for more than 48 hours. It is a potentially fatal condition characterized by severe metabolic acidosis, hyperlipidemia, rhabdomyolysis and cardiovascular collapsed1.

6. Phenobarbitone has no anticonvulsant ceiling effect, titrate to achieve burst suppression pattern on EEG. High dose phenobarbitone up to 80mg/kg/ day, with serum level more than 1000 micromol/L (232 microgram/ml) has been shown to be effective in achieving seizure control children with refractory SE (eg. FIRES- Febrile Infection Related Epilepsy Syndrome). Major adverse effects of high dose phenobarbitone are sedation and respiratory depression which are usually subject to tolerance over a relatively short time1.

7. Therapeutic Drug Monitoring (TDM) sampling time and indication are important; always relate TDM results with clinical condition of patient2.


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References :

1. Cherian A, Thomas SV. Status Epilepticus. Annals of Indian Academy of Neurology 2009 Jul-Sep; 12(3): 140-53.

2. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia;2013. Chapter 44, Status Epilepticus; p.207-12

3. Gretchen MB, Rodney B, Jan C, et al. Guideline for the Evaluation and Management of Status Epilepticus. Neurocritical Society 2012 April 24.

4. Gospe SM. Pyridoxine- dependent Epilepsy. NCBI Bookshelf; 2001.

5. Pediatric Dosage Handbook (Lexi-comp) 16th Edition

6. Product Insert Parental Dilantin Pfizer

7. Drug Doses Frank Shann 15th Edition 2010

8. Abend NS, Gutierrez-Colina AM, Monk HM, et al. Levetiracetam for Treatment of Neonatal Seizure. Child Neurol. 2011 April 26(4): 465-470.

9. University Collge London Hosputals NHS Fpundation Trust. Neonatal Unit Drug Monography - Phenobarbital; 2012 [cited 4 Nov 2014]. Available from www.uclhguide.com / fragr_image / media / phenobarbital

10.RPA Newborn Care Drug Database [cited 4 Nov 2014]. Available from www.sswahs.nsw.gov.au / rpa / neonatal / html / listview.asp ? DrugID=35

11.Taylor LM, Farzam F, Cook AM, Lewis DA, Baumann RJ, Kuhn RJ. Clinical Utility of a Continuous Intravenous Infusion of Valproic Acid in Pediatric Patients. Pharmacotherapy. 2007;27(4):519-25.


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Epilepsy

Introduction

Epilepsy is a neurological condition characterized by recurrent unprovoked epileptic seizures. According to The International League Against Epilepsy (ILAE) classification of seizure type revised in 2010, seizures are broadly classified as generalized, focal and unknown1.

19

Epilepsy Introduction

Epilepsy is a neurological condition characterized by recurrent unprovoked epileptic seizures. According to The International League Against Epilepsy (ILAE) classification of seizure type revised in 2010, seizures are broadly classified as generalized, focal and unknown1.

Chart 1: Category of Seizures

Tonic-clonic Absence Clonic Tonic Atonic Myoclonic - myoclonic - myclonic-atonic - myclonic-tonic

Typical

Absence with special features

- Myoclonic absence - Eyelid myoclonia

Atypical

Characterized according to one or more features:

Aura Motor

Autonomic Awareness/ responsiveness:

Altered (dyscognitive) or retained

Bilateral convulsive seizure (Old term: secondarily tonic clonic seizure)

May evolve to

- Epileptic spasms - Other

1. Generalised seizures (arising within and rapidly engaging bilaterally

distributed networks- involves whole brain)

2. Focal seizure Originating within networks limited

to one hemisphere

3. Unknown Insufficient evidence to characterize as focal, generalized or both)

NEUROLOGY


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Pharmacotherapy2

• Treatment recommended if ≥ 2 episodes ( recurrent risk up to 80% ).

• Monotherapy is preferred, choose most appropriate drug according to types of seizure and epileptic syndromes. Increase dose gradually until seizure controlled or maximum dose reached or side effects occur.

• Add on second AED if the first drug failed, then optimize 2nd AED and try to withdraw first AED ( alternative monotherapy ).

• Rational combination therapy (usually 2 or maximum 3 drugs) i.e. combines drugs with different mechanism of action, and consider their spectrum of efficacy, drug interactions and adverse effects

• TDM monitoring is not routinely required ( except for phenytoin ) unless noncompliance, toxicity or drug interaction suspected.

• When withdrawal of medication is planned ( generally after being seizure free for 2 years ), consideration should be given to epilepsy syndrome, likely prognosis and individual circumstances before attempting slow withdrawal of medicat ion over 3-6months ( maybe longer for clonazepam and phenobarbitone ). If seizures recur, the last dose reduction is reversed and medical advice sought.

20

Types of seizure Characteristic signs Tonic clonic (grand-mal)

Tonic stiffening (extension) followed by clonic flexion motions (muscle jerking). Seizure followed by postictal confusion May produce labored respirations, cyanosis, incontinence, involuntary tongue biting.

Absence (petit-mal) Staring, loss of expression, unresponsiveness, stopping from ongoing activity No convulsions or postictal symptoms Usually recovers immediately and resumes previous activity with no memory of the seizure.

Clonic Rapid, repetitive motor activity Tonic Sudden, brief stiffening of the muscles of whole body Atonic Sudden, brief loss of muscle tone of the body Myoclonic Brief but intense muscle jerks

Pharmacotherapy2

• Treatment recommended if ≥ 2 episodes (recurrent risk up to 80%).

• Monotherapy is preferred, choose most appropriate drug according to types of seizure and epileptic syndromes. Increase dose gradually until seizure controlled or maximum dose reached or side effects occur.

• Add on second AED if the first drug failed, then optimize 2nd AED and try to withdraw first

AED (alternative monotherapy).

• Rational combination therapy (usually 2 or maximum 3 drugs) i.e. combines drugs with different mechanism of action, and consider their spectrum of efficacy, drug interactions and adverse effects

• TDM monitoring is not routinely required (except for phenytoin) unless non-compliance, toxicity or drug interaction suspected.

• When withdrawal of medication is planned (generally after being seizure free for 2 years), consideration should be given to epilepsy syndrome, likely prognosis and individual circumstances before attempting slow withdrawal of medication over 3-6months ( maybe longer for clonazepam and phenobarbitone). If seizures recur, the last dose reduction is reversed and medical advice sought.


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21

Table 2: Choice of Antiepileptics

Selecting antiepileptic drugs according to seizure type Seizure type First line Second line

Focal Seizure

Carbamazepine Valproate

Lamotrigine, Topiramate, Lavetiracetam, Clobazam, Phenytoin, Phenobarbitone

Generalised Seizure Tonic-clonic/ clonic Valproate

Lamotrigine, Topiramate, Clonazepam, Carbamazepine1, Phenytoin1, Phenobarbitone

Absence Valproate Lamotrigine, Levetiracetam Atypical absences, Atonic, Tonic

Valproate Lamotrigine, Topiramate, Clonazepam, Phenytoin

Myoclonic Valproate Clonazepam

Topiramate, Levetiracetam, Clonazepam, Lamotrigine2, Phenobarbitone

Infantile Spasm Prednisolone4 ,Vigabatrin3, ACTH

Nitrazepam, Clonazepam, Valproate, Topiramate

Footnote: 1. May aggravate myoclonus/ absence seizure in Idiopathic Generalized Epilepsy. 2. May cause seizure aggravation in Dravet syndrome and Juvenile Myoclonic Epilepsy 3. Especially for patient with Tuberous Sclerosis (TS). 4. United Kingdom Infantile Spasms Study (UKISS) protocol

Antiepileptic Drugs That Aggravate Selected Seizure Type Phenobarbitone Absence seizure Clonazepam Causes Tonic Status in Lennox-Gastaut syndrome Lamotrigine Dravet syndrome

Myoclonic seizures in Juvenile Myoclonic Epilepsy Phenytoin Absence, Myoclonic seizure Vigabatrin Myclonic, Absence seizure Source: Adapted from Paediatric Protocols For Malaysian Hospitals 3rd edition


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References :

1. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, Boas WE, Engel J, French J, Glauser TA, Mathern GW, Moshe SL, Nordli D, Plouin P, Sheffer IE. Revised Terminology and Concepts for Organization of Seizures and Epilepsies: Reports of the ILAE Commision on Classification and Terminology, 2005-2009. Epilepsia 2010, 51 (4):676-685.

2. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 44, Epilepsy; p.207-12

3. Kammerman S, Wasserman L. Seizure disorders: Part 1. Classification and Diagnosis. WJM 2001 August; 175.

4. Seizure SMART Classification of Seizures. Epilepsy Austria; March 2012. Available from: http://www.epilepsy.org.au/sites/default/files/Seizure%20 Smart%20-%20Classification%20of%20Seizures%20%28focal%29_0.pdf


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22

PH

AR

MA

CO

KIN

ETIC

S A

ND

SID

E EF

FEC

TS O

F C

OM

MO

N A

NTI

EPIL

EPTI

C D

RU

GS

DR

UG

PHA

RM

AC

OK

INET

IC

SU

BST

RA

TE

OF

CYP

IN

DU

CER

/ IN

HIB

IT C

YP

SI

DE

EFFE

CTS

CO

MM

ENTS

Car

bam

azep

ine1

t ½ 8

-14h

rs

Met

abol

ised

by

CY

P 3

A4

to

CB

Z-ep

oxid

e an

d ot

hers

Pro

tein

bin

ding

CB

Z 75

-90%

, ep

oxid

e 50

%

2C8

(min

or)

3A4

(maj

or)

Indu

ces

1A2

(stro

ng)

2B6

(stro

ng)

2C8

(stro

ng)

2C9

(stro

ng)

2C19

(stro

ng)

3A4

(stro

ng)

Pot

entia

lly fa

tal b

lood

cel

l ab

norm

aliti

es (a

plas

tic

anem

ia, a

gran

uloc

ytos

is),

seve

re d

erm

atol

ogic

re

actio

n: S

JS, t

oxic

ep

ider

mal

nec

rosi

s (h

ighe

r ris

k w

ith v

aria

nt H

LA-

B*1

502

alle

le),

elev

ated

liv

er e

nzym

e, ja

undi

ce.

AD

M: w

ith fo

od to

dec

reas

e G

I up

set.

Do

not c

rush

CR

tab.

A

dvic

e pt

to re

port

if de

velo

ps s

kin

rash

or a

ny s

ign/

sym

ptom

bon

e m

arro

w d

epre

ssio

n eg

. Fev

er, s

ore

thro

at, e

asy

brui

sing

, inf

ectio

ns.

Leve

l dec

reas

e ~3

wee

ks a

fter

initi

atio

n du

e to

sel

f -ind

uced

m

etab

olis

m.

Clo

baza

m4

t ½ 3

6-42

hrs

M

etab

olis

ed p

rimar

ily v

ia

3A4

to a

ctiv

e N

-de

smet

ylcl

obaz

am.

Exc

retio

n: re

nal 8

2% (9

4%

as m

etab

olite

) P

rote

in b

indi

ng 8

0-90

%

2C19

In

duce

3A

4 In

hibi

t 2D

6

Con

stip

atio

n (2

-10%

) D

rool

ing

(up

to 1

4%)

AD

M: w

ith o

r with

out f

ood

Tab

can

be c

rush

ed.

Clo

naze

pam

1 t ½

22-3

3hrs

M

etab

olis

ed in

live

r P

rote

in b

indi

ng 8

5%

3A4

-

Hyp

oten

sion

, res

pira

tory

de

pres

sion

, bro

nchi

al

hype

rsec

retio

n,

hype

ract

ivity

and

ag

gres

sion

.

AD

M: w

ith fo

od to

dec

reas

e G

I di

stre

ss

With

draw

gra

dual

ly w

hen

disc

ontin

uing

ther

apy.

Lam

otrig

ine1

With

enz

yme-

indu

cer

t ½

6-11

hrs

(age

10

mo-

5.3

yr) 7

-31h

rs

W

ith V

PA

: 30-

52hr

s (1

0 m

o-5.

3 yr

) 50

-74h

rs (5

-11y

o)

W

ith b

oth:

7-1

3 hr

s P

rote

in b

indi

ng 5

5%

- -

Ski

n ra

sh 1

0% (h

ighe

r in

cide

nce

in c

hild

ren

and

thos

e re

ceiv

ing

valp

roat

e,

high

initi

al d

ose

or w

ith

rapi

d do

se in

crem

ent).

S

ever

e sk

in ra

sh e

g.S

JS

0.8%

P

oten

tial f

atal

hy

pers

ensi

tivity

(wat

ch fo

r ea

rly s

igns

: ly

mph

aden

opat

hy, f

ever

)

AD

M: w

ithou

t reg

ard

to fo

od

Reg

ular

tab:

Do

not c

hew

, as

a bi

tter t

aste

may

resu

lt.

Dis

pers

ible

/ che

wab

le ta

b: O

nly

who

le ta

blet

s sh

ould

be

adm

inis

tere

d; m

ay s

wal

low

who

le,

chew

, or d

ispe

rse

in w

ater

or

dilu

ted

fruit

juic

e (~

5ml).

W

hen

disc

ontin

ue th

erap

y, ta

pper

do

se b

y 50

%/w

eek

over

at l

east

2

wee

ks u

nles

s sa

fety

con

cern

s.


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23

Dru

g Ph

arm

acok

inet

ic

Subs

trat

e of

C

YP

Indu

cer

/Inhi

bit

CYP

Si

de e

ffect

s C

omm

ents

Leve

tirac

etam

1

t ½ 5h

rs

enzy

mat

ic h

ydro

lysi

s, n

ot

cyto

chro

me

P45

0 de

pend

ent.

Exc

rete

d re

nally

as

unc

hang

ed d

rug

66%

and

in

activ

e m

etab

olite

s 27

%.

Cle

aran

ce d

ecre

ased

in

rena

l dys

func

tion.

P

rote

in b

indi

ng <

10%

- -

Neu

rops

ychi

atric

s/e

: be

havi

oura

l sym

ptom

s 38

%

(agi

tatio

n, a

ggre

ssio

n,

ange

r), s

omno

lenc

e 23

% ,

dizz

ines

s 7%

. hea

dach

e G

I: vo

miti

ng 1

5%, a

nore

xia

13%

, dia

rrhe

a 8%

H

emat

olog

ic: d

ecre

ased

in

RB

C, H

b, H

ct, W

BC

, and

ne

utro

phil.

AD

M: w

ithou

t reg

ard

to m

eals

. S

wal

low

who

le, d

o no

t bre

ak, c

rush

or

che

w if

pos

sibl

e.

Phe

noba

rbito

ne1

t ½ 20

-133

hrs

(inf

ant),

37-

73

hrs

(chi

ldre

n).

20-5

0% e

xcre

ted

unch

ange

d in

urin

e, c

lear

ance

can

be

incr

ease

d w

ith u

rine

alka

lizat

ion

or o

ral m

ultip

le-

dose

act

ivat

ed c

harc

oal.

Pro

tein

bin

ding

35-

50%

2C9

(min

or)

2E1

(min

or)

2C19

(maj

or)

Indu

ces

1A2

(stro

ng)

2A6

(stro

ng)

2B6

(stro

ng)

2C8

(stro

ng)

2C9

(stro

ng)

3A4

(stro

ng)

CV

S: h

ypot

ensi

on,

brad

ycar

dia

CN

S: d

row

sinw

ss,

CN

S

depr

essi

on, p

arad

oxic

al

exci

tem

ent,

hype

rkin

etic

ac

tivity

D

ER

M: s

kin

erup

tion,

rash

, ex

folia

tive

derm

atiti

s R

ES

PI:

depr

essi

on, a

pnea

H

epat

ic: h

epat

itis

AD

M: o

ral w

ith w

ater

, milk

or j

uice

R

apid

IV a

dmin

istra

tion

may

cau

se

resp

irato

ry d

istre

ss, a

pnea

, la

ryng

ospa

sm, o

r hyp

oten

sion

(do

not i

njec

t fas

ter t

han

1mg/

kg/m

in).

Phe

nyto

in1

t ½ 14

- 22h

rs

Maj

or m

etab

olite

(via

ox

idat

ion)

und

ergo

es

ente

rohe

patic

recy

clin

g an

d el

imin

ate

in u

rine

as

gluc

uron

ides

. P

rote

in b

indi

ng 9

0-95

%

2C9

(maj

or)

2C19

(maj

or)

3A4

(min

or)

Indu

ces

2B6

(stro

ng)

2C8

(stro

ng)

2C9

(stro

ng)

2C19

(stro

ng)

3A4

(stro

ng)

Ocu

lar:

nyst

agm

us,

dipl

opia

, blu

rred

vis

ion

CN

S: s

lurr

ed s

peec

h,

dizz

ines

s D

erm

: hirs

utis

m,

coar

seni

ng o

f fac

ial

feat

ures

, ras

h S

JS

GI:

ging

ival

hyp

erpl

asia

, gu

m te

nder

ness

, nau

sea,

vo

miti

ng

Oth

ers:

folic

aci

d de

plet

ion,

bl

ood

dysc

rasi

as

AD

M: M

ay a

dmin

iste

r with

food

or

milk

to re

duce

GI u

pset

. Hig

h fa

t m

eal r

educ

es b

ioav

aila

bilit

y of

ge

neric

pro

duct

s. S

witc

hing

bra

nd

may

affe

ct s

erum

con

cent

ratio

n.

Bio

avai

labi

lity

decr

ease

with

NG

tu

be a

nd a

ntac

id. H

old

feed

ings

/ an

taci

d fo

r 2 h

rs p

rior t

o an

d 2h

rs

afte

r phe

nyto

in a

dmin

istra

tion.


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DR

UG

PH

AR

MA

CO

KIN

ETIC

SU

BST

RA

TE

OF

CYP

IN

DU

CER

/IN

HIB

IT C

YP

SID

E EF

FEC

TS

CO

MM

ENTS

Ruf

inam

ide2

t ½

6-10

hrs

Ext

ensi

vely

via

ca

rbox

yles

tera

se-m

edia

ted

hydr

olys

is o

f the

ca

rbox

ylam

ide

grou

p P

rote

in b

indi

ng 3

4%

-

Inhi

bit

2E1

(wea

k)

In

duce

3A

4 (w

eak)

Som

nole

nce,

fatig

ue, g

ait

dist

urba

nces

, ata

xia,

sh

orte

ning

of Q

T in

terv

al,

mul

tiorg

an h

yper

sens

itivi

ty

reac

tions

(inc

ludi

ng s

ever

e he

patit

is).

AD

M: t

ake

with

food

(inc

reas

ed

abso

rptio

n)

Tabl

et m

ay b

e sw

allo

wed

who

le,

split

in h

alf,

or c

rush

ed.

Topi

ram

ate1

t ½ 7.

7-12

.8hr

s M

inor

am

ount

met

abol

ized

in

liver

. 70%

exc

rete

d un

chan

ged

in u

rine

Pro

tein

bin

ding

15-

41%

-

Inhi

bit 2

C19

(w

eak)

Indu

ce 3

A4

(wea

k)

Hyp

erch

lore

mic

met

abol

ic

acid

osis

may

occ

ur (i

nhib

its

carb

onic

anh

ydra

se,

incr

ease

s re

nal b

icar

bona

te

loss

cau

sing

dec

reas

ed

seru

m b

icar

bona

te).

Ocu

lar s

ympt

oms

(sec

onda

ry a

cute

ang

le

clos

ure

glau

com

a an

d ac

ute

myo

pia)

. O

ligoh

ydro

sis

(dec

reas

ed

swea

ting)

and

hyp

erth

erm

ia

Con

curr

ent u

se o

f val

proi

c ac

id m

ay re

sult

in

hype

ram

mon

emia

with

or

with

out e

ncep

halo

path

y S

omno

lenc

e, fa

tigue

al

opec

ia, r

ash,

pa

raes

thes

ia, t

rem

or e

tc.

Mon

itor s

ympt

oms

of m

etab

olic

ac

idos

is (h

yper

vent

ilatio

n, fa

tigue

, an

orex

ia, s

tupo

r, ca

rdia

c ar

rhyt

hmia

) and

pot

entia

l co

mpl

icat

ions

of c

hron

ic a

cido

sis

(nep

hrol

ithia

sis,

rick

ets,

redu

ced

grow

th ra

te).

Cou

nsel

pat

ient

s to

repo

rt an

y bl

urre

d vi

sion

and

/or e

ye p

ain.

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ouns

el p

atie

nts

for p

reve

ntiv

e st

rate

gies

(hyd

ratio

n be

fore

and

du

ring

exer

cise

or e

xpos

ure

to h

ot

tem

pera

ture

). U

se w

ith c

autio

n in

pat

ient

s w

ith

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rn m

etab

olic

err

ors

of

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abol

ism

or d

ecre

ased

hep

atic

m

itoch

ondr

ial a

ctiv

ity.

AD

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ithou

t reg

ards

to fo

od.

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et c

an b

e cr

ushe

d; b

roke

n ta

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s m

ay h

ave

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r tas

te.

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e ca

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e ca

n be

ope

ned

and

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ent w

ith s

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l am

ount

of s

oft f

ood

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aspo

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l of

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l, pu

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g, c

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rd,

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esau

ce, y

ogur

t or i

ce c

ream

), sw

allo

w w

hole

and

do

not c

hew

.


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25

DR

UG

PH

AR

MA

CO

KIN

ETIC

SU

BST

RA

TE

OF

CYP

IN

DU

CER

/IN

HIB

IT C

YP

SID

E EF

FEC

TS

CO

MM

ENTS

Val

proi

c ac

id 1,

2

t ½ 7-

12 h

rs, p

rolo

nged

with

liv

er d

isea

se

M

etab

olis

ed e

xten

sive

ly in

liv

er v

ia g

lucu

roni

de

conj

ugat

ion

30 -

50%

and

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% v

ia m

itoch

ondr

ial b

eta-

oxid

atio

n.

Pro

tein

bin

ding

80-

90%

2A6

(min

or)

2B6

(min

or)

2C19

(min

or)

2C9

(min

or)

2E1

(min

or)

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bit

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(wea

k)

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(wea

k)

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(wea

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(wea

k)

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duce

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6 (w

eak/

m

oder

ate)

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ere:

hep

atiti

s fa

ilure

, lif

e-th

reat

enin

g pa

ncre

atiti

s hy

pera

mm

onem

ic

ence

phal

opat

hy.

Ris

k of

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mbo

cyto

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a w

ith h

ighe

r dos

e.

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ness

, irr

itabi

lity,

ra

sh, e

ryth

ema

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ion

etc.

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itor p

atie

nt c

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ly fo

r ap

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ance

of m

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se, v

omiti

ng,

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dice

, abd

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al p

ain,

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aine

d le

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r cha

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tal s

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s.

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ient

to re

port

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sy

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, yel

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ss o

f ap

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e, n

ause

a, v

omiti

ng o

r un

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aine

d le

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gy o

ccur

s.

AD

M: m

ay ta

ke w

ith fo

od to

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ce

GI e

ffect

s. A

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car

bohy

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e dr

ink

and

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. Do

not c

rush

or

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ent

eric

coa

ted

tabl

et.

Vig

abat

rin2

t ½ 5.

7-9.

5 hr

s, p

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nged

w

ith re

nal i

mpa

irmen

t

Min

imal

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ism

80

% e

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ted

unch

ange

d in

ur

ine

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ind

to p

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a pr

otei

n

- In

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oder

ate)

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man

ent b

ilate

ral

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c vi

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us.

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ain,

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nce,

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, exc

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tion,

na

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, abd

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al p

ain

etc.

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thal

mol

ogic

exa

min

atio

n sh

ould

be

per

form

ed a

t bas

elin

e, 3

m

onth

ly (o

n th

erap

y) a

nd 3

-6m

onth

s af

ter d

isco

ntin

uatio

n.

Use

with

cau

tion

in p

atie

nts

with

re

nal i

mpa

irmen

t; do

sage

ad

just

men

t if

CrC

l <80

mL/

min

ute

AD

M:

with

out r

egar

d to

food

. Fi

lm c

oate

d ta

blet

: sw

allo

w w

hole

or

bre

ak in

to h

alf,

do n

ot c

rush

(m

anuf

actu

rer’s

reco

mm

enda

tion)

. If

tabl

et a

dmin

istra

tion

not f

easi

ble,

m

ay c

rush

tabl

et a

nd m

ix w

ith s

oft

food

eg.

yog

urt,

hone

y or

jam

, sw

allo

w w

hole

with

out c

hew

ing3 .

REF

EREN

CES

: 1.

P

edia

tric

Dos

age

Han

dboo

k (L

exi-c

omp)

16th

Edi

tion

2.

Onl

ine

Lexi

com

p 3.

M

edic

ines

for C

hild

ren

[Inte

rnet

]. In

form

atio

n fo

r car

eer a

nd p

aren

ts:v

igab

atrin

for p

reve

ntin

g se

izur

es; 2

014

[u

pdat

ed J

an, 2

014]

. Ava

ilabl

e fro

m w

ww

.med

icin

esfo

rchi

ldre

n.or

g.uk

4.

M

icro

med

ex v

1622


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References:

1. Pediatric Dosage Handbook (Lexi-comp) 16th Edition

2. Online Lexicomp

3. Medicines for Children [Internet]. Information for career and parents:vigabatrin for preventing seizures; 2014 [updated Jan, 2014]. Available from www. medicinesforchildren.org.uk

4. Micromedex v1622


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Infantile Spasm

Introduction

Infantile spasm (West syndrome) is a severe form of epilepsy of early infancy, onset during the first year of life with peak age between 3 and 7 month1. The 3 main features are a history of epileptic spasms, hypsarrhythmia (or modified hypsarrhythmia) on EEG and often development arrest or regression2.

Spasms maybe subtle, brief, and sudden, the most subtle being a head nod or tonic eye rolling, shown great variability in frequency which may be easily missed. Typically the spasms involve brief symmetrical contraction of musculature of neck, trunk and extremities lasting up to 5 seconds and occurring in clusters, occur before or on awaking or just before sleep. The number of spasms can vary from a few to more than hundreds per cluster with every cluster lasted from less than a minute to more than 10 minutes3. Early detection and prompt effective treatment is important to improve neurodevelopmental outcomes.

Management Pharmacotherapy 1. United Kingdom Infantile Spasm Study (UKISS) Protocol4

Hormone treatment: Prednisolone 10mg QID (not weight based) for 2 weeks, increasing to 20mg TDS after 1 week if spasm continued. After 2 weeks of treatment, tapper off Prednisolone slowly with reduction of 10mg every 5 days (over 2-3 weeks).

Ranitidine, omeprazole or esomeprazole should be considered to help prevent gastric ulcer that may be caused by high dose prednisolone3.

NEUROLOGY


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Special consideration5

• Prednisolone should be tapered off slowly to avoid acute adrenocortical insufficiency.

• Steroid may cause a level of immunosuppression, causing increased susceptibility of infection. Parents should be counseled to avoid contact with infectious person, in particular those with varicella infection.

• No live vaccines (e.g. MMR, MMR-V, varicella, BCG) should be given during therapy, and for 1 month after cessation of therapy.

• Similar efficacy between IM Tetracosactide (adrenocorticotrophic hormone ACTH) and oral prednisolone4. Oral prednisolone is easily available, cost effective, and having fewer side effects. It is recommended as an alternative to intramuscular ACTH in the treatment of non-TS infantile spasms8. 2. Vigabatrin

Vigabatrin is recommended as first line treatment for children with infantile spasm associated with tuberous sclerosis (TS) and also as second line treatment after 2-4 weeks of no response to corticosteroid in non-TS settings2.

Start with 50mg / kg / day in 2 divided doses, may titrate upwards by 25 to 50 mg / kg / day increments every 3 days based on response and tolerability ( max 150 mg / kg / day )6.

26

Infantile Spasm Introduction

Infantile spasm (West syndrome) is a severe form of epilepsy of early infancy, onset during the first year of life with peak age between 3 and 7 month1. The 3 main features are a history of epileptic spasms, hypsarrhythmia (or modified hypsarrhythmia) on EEG and often development arrest or regression2. Spasms maybe subtle, brief, and sudden, the most subtle being a head nod or tonic eye rolling, shown great variability in frequency which may be easily missed. Typically the spasms involve brief symmetrical contraction of musculature of neck, trunk and extremities lasting up to 5 seconds and occurring in clusters, occur before or on awaking or just before sleep. The number of spasms can vary from a few to more than hundreds per cluster with every cluster lasted from less than a minute to more than 10 minutes3. Early detection and prompt effective treatment is important to improve neurodevelopmental outcomes.

Management

Pharmacotherapy

1. United Kingdom Infantile Spasm Study (UKISS) Protocol4

Hormone treatment: Prednisolone 10mg QID (not weight based) for 2 weeks, increasing to 20mg TDS after 1 week if spasm continued. After 2 weeks of treatment, tapper off Prednisolone slowly with reduction of 10mg every 5 days (over 2-3 weeks). Ranitidine, omeprazole or esomeprazole should be considered to help prevent gastric ulcer that may be caused by high dose prednisolone3.

Tab Prednisolone 10mg QID Day 1- Day 7

D7 Spasm continued? Yes No

Day 8 - Day 14 Continue 10mg QID

Increase 20mg TDS

Tapper off Prednisolone with reduction of 10mg every 5 days

Over 2-3 weeks

With ranitidine, omeprazole or esomeprazole.

Monitor side effects:

§ Hypertension § Electrolytes

imbalance, particularly hypoK+

§ Immunosuppression § Irritability, restlessness § Increased appetite § Weight gain § Facial puffiness § Acne § Glucosuria § UTI


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Special considerations

• Side effects: hypotonia, somnolence or insomnia along with permanent vision field constriction (tunnel vision)7.

• Vigabatrin has also been associated with reversible signal changes at brain MRI localized at thalamus, basal ganglia, corpus callosum and mid brain7.

• Use with caution in patients with renal impairment; dosage modification may be necessary if CrCl <80 mL/minute6.

Non Pharmacotherapy

3. Ketogenic diet

Ketogenic diet is a strict diet which is high in fat, with adequate protein and low in carbohydrate used as a treatment in refractory seizure. It may be considered for children with infantile spasm who do not respond to hormone treatment and/or vigabatrin3. The exact mechanism still unknown, metabolic changes likely related to the its anticonvulsant properties include - but are not limited to - ketosis, reduced glucose, elevated fatty acid levels, and enhanced bioenergetic reserves9.

Pharmacist’s role in managing patient on ketogenic diet

Pharmacist plays important role in optimize patient’s treatment outcomes by restricting the use of concurrent medications with high carbohydrate content. A general rule of thumb is that carbohydrate content is the highest in suspensions and solutions, lower in chewable and disintegrating tablets, and lowest in tablets and capsules10.

General principles • No syrup medications, change to tablet or IV formulation. • Freshly prepared with water only.• No dextrose in IV drip, including diluents used for IV infusion.• Medications using saccharin as the sweetener are suitable.• Medications in suppository form are suitable for use on the ketogenic diet.• Medication labeled as ‘sugar free’ does not mean the product is carbohydrate free. Hidden carbohydrate source can be contributed by excipients.


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• Sugar ( dextrose, fructose, glucose, lactose, sucrose, sugar )

• Starches ( cornstarch, pregelatinized starch, sodium starch glycolate, sodium starch glycolate )

• Sorbitol

• Mannitol

• Xylitol

• Maltitol

• Isomalt

• Erythritol

• Alcohol

• Glycerin

• Hydrogenated Starch Hydrolysates (HSH)

• Ascorbic acid

• Su Cellulose

• Carboxymethylcellulose

• Hydroxymethylcellulose

• Microcrystalline cellulose

• Polyethylene glycol

• Magnesium stearate

• Aspartame

• Saccharine

• Asulfamine potassium (K)

Excipients which are source of carbohydrate11

Excipients which are not source of carbohydrate11


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Information on carbohydrate content in medications :

• www.matthewsfriends.org/Keto_Friendly_Medicine_List.doc

• Denis Lebel et al. (2001) The Carbohydrate and Caloric Content of Concomitant Medications for Children with Epilepsy on the Ketogenic Diet. Can. J. Neurol. Sci. 2001; 28: 322-340.

• Contact pharmaceutical companies for generic products

4. Other treatment options for infantile spasm

• Sodium valproate

• Topiramate etc.

References:

1. Hrachovy RA, Frost JD. Severe encephalopathic epilepsy in infants: infantile spasm (West syndrome). In Pediatric Epilepsy: Diagnosis and Therapy. Edited by Pellock JM, Bourgeois BF, Dodson WE, Nordli DR Jr,Sankar R. New York, NY: Demos Medical Publishing 2008:249–268.

2. Children’s Neuroscience Centre Management Guideline: Management of Infantile spasm (IS)/ West syndrome final 14-6-07

3. James WW, Patricia AG, Kari LR, Maria H, Christine OD, Vicky W, John MP. Infantile spasms (West syndrome): update and resource for pediatricians and providers to share with parents. BMC Pediatrics. 2012, 12:108.

4. Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, Callaghan FJK, Verity CM, Osborne JP. The United Kingdom Infantile Spasm Study comparing vigabatrin with prednisolone or tetracosactide st 14 days: a multicentre, randomized controlled study. Lancet 2004 Nov 13: 364: 1773- 1778.

5. Guideline for Investigation and Management of Children with Infantile Spasms and West Syndrome. Nottingham University Hospital Trust; 2008 [cited 2014 Nov 4]. Available from: https://www.nuh.nhs.uk/handlers/downloads. ashx?id=52197

6. Lexicomp Online


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7. Piero P, Pasquale S, Raffaele F, Lorenzo P, Martino R. Infantile spasm syndrome, West syndrome and related phenotypes: what we know in 2013. Brain & Development. 2014, 739-751.

8. BH Ching, JW Tan, HS Heng, S Terumalay, TB Khoo, AR Mohamed. Paper presented at: Paediatric Neurology Update; 2013 Sept 28; Ipoh General Hospital, Perak, Malaysia.

9. Masino SA, Rho JM. Mechanisms of Ketogenic Diet Action. Jasper’s Basic Mechanisms of Epilepsies. 4th Edition. NCBI Bookshelf Online Book Version.

10. Runyon Am, So TY. Review Article The Useof Ketogenic Diet in Pediatric Patients with Epilepsy. International Scholarly Research Network ISRN Pediatrics volume 2012.

11. Minimising the carbohydrate content of medications on the ketogenic diet [cited 2014Nov 4]. Available from: http://www.gosh.nhs.uk/EasySiteWeb/ GatewayLink.aspx?alId=105274.


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NEPHROLOGY

Acute Glomerulonephritis

Introduction

Acute Glomerulonephritis (AGN) is an abrupt onset of one or more features of an Acute Nephritic Syndrome.Glomerular lesions are the results of glomerular deposition or insitu formation of immune complexes. Commonest cause of AGN in children (6-10 years old) is post-streptococcal infection of upper respiratory tract or skin1 due to group A Beta-Hemolytic Streptococcus2. Non-infectious causes of AGN are Henoch-Schoenlein purpura, IgA nephropathy, hereditary nephritis, systemic lupus erythematosus or systemic vasculitidis.

Clinical Features

The onset is usually abrupt and nephritis may follow 7–15 days after streptococcal tonsillitis and 4–6 weeks after impetigo2.

• Oedema (peripheral or periorbital). • Microscopic /macroscopic haematuria (urine: tea-coloured or smoky) • Decreased urine output (oliguria). • Hypertension.• Azotemia

Management

Fluid intake, urine output, daily weight and blood pressure (nephrotic chart) must be strictly monitor. Patient must be bed rested and put on salt-free diet. Fluid restriction if necessary until child diuresis and blood pressure (BP) is controlled.

Pharmacotherapy

• Penicillin V : Start oral Penicillin (7.5-15mg/kg 6 hourly) for 10 days to eliminate - haemolytic streptococcal infection (may use Erythromycin if allergic to Penicillin).


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Management of Severe Complications1

Hypertension

• For the management of hypertension use the following antihypertensives: oral Nifedipine 0.25 - 0.5 mg / kg up to 4 hourly if needed, Frusemide 1mg / kg / dose, Captopril 0.1-0.5mg / kg 8 hourly or Metoprolol 1-4mg / kg 12 hourly.

• Monitor closely for signs and symptoms of severe hypertension or hypertensive emergency / encephalopathy such as headache, vomiting, loss of vision, convulsions, papilloedema.

• Target of BP control is to reduce BP to <90th percentile of BP for age, gender and height percentile. Reduce BP by 25% of target BP over 3 - 12 hours and the next 75% reduction is achieved over 48 hours. Total BP to be reduced = Observed mean BP - Desired mean BP

Pulmonary Oedema

• IV Frusemide 2 mg/kg/dose stat; double this dose 4 hours later if poor response.

• Fluid restriction for 24 hours if possible.

• Consider dialysis if no response to diuretics.

Acute Kidney Injury

• Mild renal impairment is common.

References:

1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 58, Post-Infectious Glomerulonephritis; p.275-78

2. Garabed E, Norbert L, Kai-Uwe E, et.al. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney International Supplements 2012 June; 2(2):200-8.


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Nephrotic Syndrome

Introduction

Primary or idiopathic nephrotic syndrome (NS) is the commonest type of nephrotic syndrome in children. Secondary NS include post-streptococcal glomerulonephritis, systemic lupus nephritis1.

Definition2: • Relapses: Urine protein to creatinine ratio (uPCR) ≥2000mg/g (≥200mg/ mmol) or ≥ 3+ protein on urine dipstick for 3 consecutive days.

• Frequent relapses: ≥ 2 relapses within 6 months of initial response, or ≥ 4 relapses within any 12 month period.

• Steroid dependent: ≥ 2 consecutive relapses occurring during steroid taper or within 14 days of the cessation of steroids.

• Steroid resistant: failure to achieve response to an initial 4 weeks treatment with prednisolone at 60mg/m2/day.

Clinical Features

• Edema

• Hypoalbuminaemia of < 25g/l

• Proteinuria > 40 mg/m²/hour (> 1g/m²/day) or an early morning urine protein creatinine index of >200 mg/mmol (> 3.5 mg/mg)

• Hypercholesterolaemia

NEPHROLOGY


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Management

Pharmacotheraphy

• Oral Penicillin V For prevention of primary bacterial peritonitis, 125 mg Oral BD (1-5 years age), 250 mg BD (6-12 years), 500 mg BD (> 12 years)

• In patient with reduced urine output Human Albumin (20-25%) at 0.5 - 1.0 g / kg may be use with IV Frusemide at 1-2 mg/kg to produce a diuresis.

• Corticosteroid therapy, cyclophosphamide (refer algorithm).

Management of Complications1

• Hypovolaemia. Clinical features: abdominal pain, cold peripheries, poor pulse volume, hypotension, and haemoconcentration. Treatment is to infuse Human Albumin at 0.5 to 1.0 g/kg/dose fast. If human albumin is not available, other volume expanders like human plasma can be used. Do not give Frusemide.

• Primary Peritonitis Clinical features: fever, abdominal pain and tenderness in children with newly diagnosed or relapse nephrotic syndrome. Peritonitis is treated with parenteral penicillin and a third generation cephalosporin

• Thrombosis Thorough investigation and adequate treatment with anticoagulation is usually needed. Please consult a Paediatric Nephrologist.


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34

• Thrombosis Thorough investigation and adequate treatment with anticoagulation is usually needed. Please consult a Paediatric Nephrologist.

Algorithm 1: Management of Nephrotic Syndrome

1. INITIAL EPISODE OF NEPHROTIC SYNDROME Prednisolone 60 mg/m²/day for 4 weeks

6. RELAPSES POST CYCLOPHOSPHAMIDE • As for (2) and (3) if not steroid toxic • If steroid toxic, refer paediatric nephrologist to consider therapy with cyclosporin or levamisole

2. RELAPSE • Prednisolone 60 mg/m²/day till remission • 40 mg/m²/alternate day for 4 weeks then stop

3. FREQUENT RELAPSES • Reinduce as (2), then taper and keep low dose alternate day Prednisolone 0.1 -‐ 0.5 mg/kg/dose for 6 months

4. RELAPSES WHILE ON PREDNISOLONE • Treat as for (3) if not steroid toxic • Consider cyclophosphamide if steroid toxic.

5. ORAL CYCLOPHOSPHAMIDE • 2-‐3 mg/kg/day for 8-‐12 weeks Cumulative dose 168 mg/kg

Prednisolone 40 mg/m²/alternate day for 4 weeks. then taper at 25% monthly over 4 months

Response No Response

RENAL BIOPSY



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• If exposed to chickenpox and measles during corticosteroid therapy, it should be treated like any immunocompromised child who has come into contact with these diseases.

• Live vaccines should be deferred until prednisolone dose is <20mg/day or 2mg / kg on a l ternate days (<40mg on a l ternate days) and/or immunosuppressive agents have been stopped for at least 1-3 months2.

References:

1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 59, Nephrotic Syndrome; p.279-84

2. Garabed E, Norbert L, Kai-Uwe E, et.al. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney International Supplements 2012 June; 2(2):156-76


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Acute Renal Failure

Introduction

Acute renal failure (ARF) also known as acute kidney injury. It is an abrupt onset of rising in serum creatinine (SCr) level and decreased glomerular filtration rate (GFR) and inability of kidney to regulate electrolytes and fluid hemostasis. ARF is divided into pre-renal injury, intrinsic renal disease, or post-renal obstruction. ARF since childhood due to haemolytic-uremic syndrome, post-infectious acute glomerulonephritis or dehydration are reversible, but a small percentage may progress to chronic renal failure (CRF)1.

Clinical Features

• Oliguria (< 300 ml/m²/day in children; < 1 ml/kg/hour in neonates) or • Non-oliguria (Nephrotoxic injury, Interstitial Nephritis, or Neonatal Asphyxia)

Management

Pharmacotherapy

Fluid BalanceIn hypovolaemia, fluid resuscitation must be initiated regardless of oliguric / anuric state by crystalloids e.g. isotonic 0.9% saline / Ringer’s lactate 20 ml/kg fast (in < 20 minutes) after obtaining vascular access. Transfuse blood if haemorrhage is the cause of shock. If urine output increases, continue fluid replacemen homever if there is no urine output after 4 hours (confirm with urinary catheterization), monitor central venous pressure to assess fluid status3.

In hypervolaemia / fluid if necessary to give fluid, restrict to insensible loss (400 ml/m²/day or 30ml/kg in neonates depending on ambient conditions). Treat with IV Frusemide 2 mg/kg/dose (over 10-15 minutes), maximum of 5 mg/kg/dose or IV Frusemide infusion 0.5 mg/kg/hour. Dialysis if no response or if volume overload is life-threatening. Once normal volume status is achieved, give insensible loss plus obvious losses (urine / extrarenal) 3.

NEPHROLOGY


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Hypertension Usually related to fluid overload and/or alteration in vascular tone. Treatment with anti-hypertensive drugs depends on degree of BP elevation, presence of central nervous system symptoms of hypertension and cause of renal failure. A diuretic is usually needed.

Metabolic acidosis It is treated if pH < 7.2 or symptomatic or contributing to hyperkalaemia. Ensure that patient’s serum calcium is > 1.8 mmol/L to prevent hypocalcaemic seizures with Sodium bicarbonate therapy. Replace half the deficit with IV 8.4% Sodium bicarbonate (1:1 dilution) if indicated.

Bicarbonate deficit = 0.3 x body weight (kg) x base excess (BE)

Electrolytes abnormalities

• Hyperkalemia (K+> 6.0 mmol/l in neonates and > 5.5 mmol/l in children):

37

Electrolytes abnormalities • Hyperkalemia (K⁺> 6.0 mmol/l in neonates and > 5.5 mmol/l in children):

Table 1: Treatment of Hyperkalemia in Acute Kidney Injury

TREATMENT OF HYPERKALEMIA IN AKI PATIENTS Do 12-‐lead ECG and look for hyperkalaemic changes If ECG is abnormal or plasma K+ > 7 mmol/l, connect patient to a cardiac monitor and give the following in sequence: 1 IV 10% Calcium gluconate 0.5 -‐ 1.0 ml/kg (1:1 dilution) over 5 -‐15 mins (Immediate onset of action) 2 IV Dextrose 0.5 g/kg (2 ml/kg of 25%) over 15 – 30 mins. 3 ± IV Insulin 0.1 unit/kg (onset of action 30 mins). 4 IV 8.4% sodium bicarbonate 1 ml/kg (1:1 dilution) over 10 -‐ 30 mins (Onset of action 15 -‐ 30 mins) 5 Nebulized 0.5% salbutamol 2.5 -‐ 5 mg (0.5 -‐ 1 ml : 3 ml 0.9% Saline) (Onset of action 30 mins)

6 Calcium polystyrene sulphonate 0.25g/kg oral or rectally 4 times/day (Max 10g/dose) (Calcium Resonium / Kalimate) [Give rectally (NOT orally) in neonates 0.125 – 0.25g/kg 4 times/day]

OR 6 Sodium polystyrene sulphonate 1g/kg oral or rectally 4 times/day (Max15g/dose) (Resonium) In patients with serum potassium between 5.5 -‐ 7 mmol/L without ECG changes, give calcium or sodium polystyrene sulphonate

If insulin is given after dextrose, monitor RBS / Dextrostix for hypoglycaemia. Dialyse if poor or no response to the above measures


• Hyponatremia: fluid restriction if dilutional; if symptomatic or level Na+ <120 mmol/L give Sodium Chloride. [Sodium deficit: (desired sodium – actual sodium) x 0.6 x body weight] Give 50% of sodium deficit then reassess, avoid rapid correction.1

• Hyperphosphatemia: oral phosphate binder. • Hypocalcemia: Treat if symptomatic (usually serum Ca²⁺ < 1.8 mmol/L), and if Sodium

bicarbonate is required for hyperkalaemia, with IV 10% Calcium gluconate 0.5 ml/kg, given over 10 – 20 minutes, with ECG monitoring3.

Dialysis Indicated if there are severe complication. Special consideration

• Medications: dose adjustment, avoidance of nephrotoxic agents, dilutions of medications.3


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• Hyponatremia: fluid restriction if dilutional; if symptomatic or level Na+ <120 mmol/L give Sodium Chloride. [Sodium deficit: (desired sodium – actual sodium) x 0.6 x body weight] Give 50% of sodium deficit then reassess, avoid rapid correction.1

• Hyperphosphatemia: oral phosphate binder.

• Hypocalcemia: Treat if symptomatic (usually serum Ca² < 1.8 mmol/L), and if Sodium bicarbonate is required for hyperkalaemia, with IV 10% Calcium gluconate 0.5 ml/kg, given over 10 - 20 minutes, with ECG monitoring3.

Dialysis

Indicated if there are severe complication.


• Medications: dose adjustment, avoidance of nephrotoxic agents, dilutions of medications.3

References:

1. Chan, J.C.M, Williams, D.M., Roth, K.S. Pediarics in Review. Feb 2002; 23(2): 47-60.

2. Guideline on management and investigation of acute renal failure. Renal Unit Royal Hospital for Sick Children. November 2005. [cited on: 2014 Oct 20 ] Available from: http://www.clinicalguidelines.scot.nhs.uk

3. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 60, Acute Renal Failure; p.285-91


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INFECTIOUS DISEASES

Tuberculosis

Introduction

Tuberculosis (TB) is the most common cause of infection-related death worldwide1.

TB occurs when individuals inhale bacteria aerosolized by infected persons. The organism is slow growing and tolerates the intracellular environment, where it may remain metabolically inert for years before reactivation and disease. The main determinant of the pathogenicity of TB is its ability to escape host defense mechanisms, including macrophages and delayed hypersensitivity responses2.

Disease may be pulmonary (PTB) or extrapulmonary (EPTB), (i.e. central nervous system (CNS), disseminated (miliary), lymph node, bone & joint) or both2.

Clinical features

Common clinical features suggestive of TB in children are prolonged fever, failure to thrive, unresolving pneumonia, loss of weight and persistent lymphadenopathy. TB should be suspected in a symptomatic child having history of contact with active TB2.

Any patient with pneumonia, pleural effusion, or a cavitary or mass lesion in the lung that does not improve with standard antibacterial therapy should be evaluated for TB2.

Management

Pharmacotherapy

Corticosteroids3

• Indicated for children with TB meningitis

• May be considered for children with pleural and pericardial effusion (to hasten reabsorption of fluid), severe miliary disease (if hypoxic) and endobronchial disease

• Steroids should be given only when accompanied by appropriate antituberculous therapy

• Dosage: prednisolone 1-2mg/kg per day (max. 40 mg daily) for first 3-4 week, then taper over 3-4 weeks


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40

Table 1: Recommended Doses of AntiTB Drugs in Children2

DRUG

DAILY DOSE INTERMITTENT DOSE

SIDE EFFECTS4,5 DOSE (RANGE) IN MG/KG/DAY

MAXIMUM DOSE (MG) MG/KG/DAY MAXIMUM

DOSE (MG)

Isoniazid 10 (10-15) 300 10 900

Skin rash, jaundice, hepatitis,

anorexia, nausea, abdominal pain,

burning, numbness or

tingling sensation in the hands or

feet

Rifampicin 15 (10-20) 600 10 600


anorexia, nausea, abdominal pain, orange or red

urine, flu syndrome (fever, chills, malaise,

headache, bone pain)

Pyrazinamide 35 (30-40) 2000 - -


anorexia, nausea, abdominal pain &

joint pains Ethambutol 20 (15-25) 1000 30-50 2500 Visual impairment

Pyridoxine 5 - 10 mg daily needs to be added if isoniazid is prescribed


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Table 2: Suggested second line AntiTB Drugs in Children, Dosages and Side effects2

DRUG DAILY DOSE

SIDE EFFECTS4,5 DOSE (RANGE) IN MG/KG/DAY

MAXIMUM DOSE (MG) FREQUENCY

Kanamycin 15-30 1000 Daily Nephrotoxicity, peripheral neuropathy, rash, auditory damage Amikacin 15-22.5 1000 Daily

Capreomycin 15-30 1000 Daily

Nephrotoxicity, tubular dysfunction, azotaemia, proteinuria, urticaria or

maculopapular rash

Cyloserine* 10-20 1000 Daily/Twice daily

Neurological and psychiatric disturbances

Including headaches, irritability, sleep disturbances,

aggression and tremors, gum inflammation, pale

skin, depression, confusion, dizziness, restlessness, anxiety, nightmares, severe

headache, drowsiness

Ethionamide 15-20 1000 Twice daily

Severe gastrointestinal intolerance, psychotic

disturbances, neurotoxicity, gynecomastia

p-aminosalicylic acid (PAS)

200-300 12000 3-4 times equally divided dose

Gastrointestinal intolerance, careful use

in patients with glucose6-phosphate

dehydrogenase (G6PD) deficiency.

Clofazimine Safety and efficacy not estalished

Chthyosis,dry skin; pink to brownish-black

discolouration of skin, cornea, retina and urine; anorexia,

abdominal pain Ofloxacin

15-20 800 Twice daily

Gastrointestinal intolerance, headache,

malaise, insomnia, restlessness, dizziness,

allergic reactions, diarrhoea,

photosensitivity

Levofloxacin

7.5-10 750 Daily

Moxifloxacin 7.5-10 400 Daily


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* All patients receiving cycloserine should be given 50 mg pyridoxine for every 250 mg of cycloserine.

Monitoring of Drug Toxicity2

• Indications for baseline and routine monitoring of serum transaminases and bilirubin are recommended for: * Severe TB disease. * Clinical symptoms of hepatotoxicity. * Underlying hepatic disease. * Use of other hepatotoxic drugs (especially anticonvulsants). * HIV infection.

• Routine testing of serum transaminases in healthy children with none of the above risk factors is not necessary.

• Children on Ethambutol should be monitored for visual acuity and colour discrimination.


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Table 3: Recommended Treatment Regimens for Children in Different TB Diagnostic Categories2

TB cases

Regimen*

Remarks Intensive phase

Continuation phase

New smear positive PTB New smear negative PTB Less severe EPTB

2HRZ 4HR

Ethambutol can be added in the intensive phase of suspected isoniazid-resistance or extensive pulmonary disease cases

Severe concomitant HIV disease

2HRZE 4HR

Severe form of EPTB TB meningitis/ spine/bone

2HRZE 10HR

Previously treated smear positive PTB including relapse and treatment after interruption

3HRZE 5HRE

All attempt should be made to obtain culture and sensitivity result. In those highly suspicious of Multidrug resistant (MDR-TB), refer to paediatrician with experience in TB management.

Treatment failure TB

Refer to paediatrician with experience in TB management.

MDR-TB Individualised regimen

Refer to paediatrician with experience in TB management.

*Direct observation of drug ingestion is recommended especially during the initial phase of treatment and whenever possible during the continuation phase. Source: Adapted from Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH Latent Tb Infection (LTBI)2

Young children living in close contact with a case of smear-positive PTB are at risk of TB infection and disease. The risk of developing disease after infection is much greater for infants and young children under five years. Active TB usually develops within two years of infection but the time-lag can be as short as a few weeks in infants.

H=isoniazid, R=rifampicin, Z=pyrazinamide, E=ethambutol

Source: Adapted from Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH Latent Tb Infection (LTBI)2


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Young children living in close contact with a case of smear-positive PTB are at risk of TB infection and disease. The risk of developing disease after infection is much greater for infants and young children under five years. Active TB usually develops within two years of infection but the time-lag can be as short as a few weeks in infants.

Children younger than 5 years of age with LTBI have a 10 - 20% risk of developing TB disease

Management

Pharmacotherapy

Non-HIV infected children with latent tuberculosis infection should be treated with 6-month of isoniazid or 3-month of isoniazid plus rifampicin2.

There is no retrievable evidence of treatment for LTBI in HIV-infected children. However, WHO recommends 6-months isoniazid therapy2.

43

Source: Adapted from Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH Latent Tb Infection (LTBI)2

Young children living in close contact with a case of smear-positive PTB are at risk of TB infection and disease. The risk of developing disease after infection is much greater for infants and young children under five years. Active TB usually develops within two years of infection but the time-lag can be as short as a few weeks in infants. Children younger than 5 years of age with LTBI have a 10 - 20% risk of developing TB disease Management Pharmacotherapy Table 4: Anti-TB Regimens for LTBI in Children

Drug Duration Interval Isoniazid 6 months Daily

Isoniazid + Rifampicin 3 months Daily Non-HIV infected children with latent tuberculosis infection should be treated with 6-month of isoniazid or 3-month of isoniazid plus rifampicin2. There is no retrievable evidence of treatment for LTBI in HIV-infected children. However, WHO recommends 6-months isoniazid therapy2. Congenital & Perinatal TB Congenital TB is defined as a direct spread through the umbilical cord, by aspiration or swallowing of infected amniotic fluid, or by direct contact with maternal genital lesions during delivery. Perinatal TB includes early postnatal transmission of the disease and is a more inclusive term2. After active TB is ruled out, babies at risk of infection from their mothers should be given six months of isoniazid preventive therapy, followed by BCG vaccination2. Alternatively, if three months of isoniazid is given, tuberculin skin test (TST) should be done on completion of treatment:- •If TST is negative (<5 mm), BCG vaccine should be administered and treatment stopped2

•If TST is positive (=5 mm), treatment should continue for six months, followed by the BCG at the end of treatment2.


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Congenital & Perinatal TB

Congenital TB is defined as a direct spread through the umbilical cord, by aspiration or swallowing of infected amniotic fluid, or by direct contact with maternal genital lesions during delivery. Perinatal TB includes early postnatal transmission of the disease and is a more inclusive term2.

After active TB is ruled out, babies at risk of infection from their mothers should be given six months of isoniazid preventive therapy, followed by BCG vaccination2.

Alternatively, if three months of isoniazid is given, tuberculin skin test (TST) should be done on completion of treatment:-

• If TST is negative (<5 mm), BCG vaccine should be administered and treatment stopped2

• If TST is positive (=5 mm), treatment should continue for six months, followed by the BCG at the end of treatment2

44

Table 5: Prophylaxis for Infants with Maternal TB2

Active PTB diagnosed before delivery

Active PTB diagnosed after delivery

>2 months before

<2 months before

<2 months after

>2 months after

Smear negative just

before delivery

Smear positive

just before delivery

- - -

No prophylaxis for infant

Give prophylaxis: Isoniazid for six months OR isoniazid for three

months followed by TST

Give prophylaxis: Isoniazid for six months

OR isoniazid + rifampicin for three months

BCG at birth Defer BCG at birth, give after stopping isoniazid

Reimmunise with BCG after

stopping isoniazid

If BCG given at birth, no need to reimmunise

Source: Adapted from Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH Special Consideration Breast-feeding and mother with PTB3

TB treatment in lactating mothers is safe as the amount of drug ingested by the baby is minimal. Hence if the mother is already on treatment and is non-infective, the baby can be breastfed. Women who are receiving isoniazid and are breastfeeding should receive pyridoxine. If the mother is diagnosed to have active PTB and is still infective:

• The newborn should be separated from the mother for at least 1 week while the mother is being treated.

• Mother should wear a surgical mask subsequently while breast feeding until she is

asymptomatic and her sputum is AFB-smear negative.

• Breast feeding is best avoided during this period but expressed breast milk can be given.

• The infant should be evaluated for congenital TB. If this is excluded, BCG is deferred and the baby should receive isoniazid for 3 months and then tuberculin tested. If tuberculin negative and mother has been adherent to treatment and non-infectious, isoniazid can be discontinued and BCG given. If tuberculin positive, the infant should be


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Breast-feeding and mother with PTB3

TB treatment in lactating mothers is safe as the amount of drug ingested by the baby is minimal. Hence if the mother is already on treatment and is non-infective, the baby can be breastfed.

Women who are receiving isoniazid and are breastfeeding should receive pyridoxine.

If the mother is diagnosed to have active PTB and is still infective:

• The newborn should be separated from the mother for at least 1 week while the mother is being treated.

• Mother should wear a surgical mask subsequently while breast feeding until she is asymptomatic and her sputum is AFB-smear negative.

• Breast feeding is best avoided during this period but expressed breast milk can be given.

• The infant should be evaluated for congenital TB. If this is excluded, BCG is deferred and the baby should receive isoniazid for 3 months and then tuberculin tested. If tuberculin negative and mother has been adherent to treatment and non-infectious, isoniazid can be discontinued and BCG given. If tuberculin positive, the infant should be reassessed for TB disease and if disease is not present, isoniazid is continued for total of 6 months and BCG given at the end of treatment.

References

1. Pediatric Tuberculosis.Vandana Batra, MD; Chief Editor: Russell W Steele, MD http://emedicine.medscape.com/article/969401-overview#aw2aab6b4

2. Malaysian CPG- Management of Tuberculosis, 3rd Edition, MOH, 2012.

3. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 80, Tuberculosis; p.419-24.

4. World Health Organization. Treatment of tuberculosis Guidelines Fourth Edition. Geneva: WHO; 2010

5. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis 2011 Update. Geneva: WHO; 2011


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Malaria

Introduction

Malaria is a tropical infection caused by members of protozoan genus called Plasmodium that parasitize human red blood cells and liver. It is transmitted by anopheline mosquitoes and the most common Plasmodium species that caused malaria infection in human included P. falciparum, P.vivax, P.ovale, P. malariae and P.knowlesi1. According to WHO world report 2013, endemic area in Malaysia included Sabah, Sarawak and central Peninsular Malaysia, with majority infection caused by P.vivax (24%) and P. falciparum (18%). P.falciparum is associated with highest mortality and morbidity. Symptoms of malaria included fever, malaise, weakness, gastrointestinal complaints (nausea, vomiting, diarrhea), neurologic complaints (dizziness, confusion, disorientation, coma), headache, back pain, myalgia, chills, and / or cough2.

Management

Pharmacotherapy Disease management depends on the type of Plasmodium infection and the severity of infection3-5.

INFECTIOUS DISEASES


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46

Malaria

Introduction Malaria is a tropical infection caused by members of protozoan genus called Plasmodium that parasitize human red blood cells and liver. It is transmitted by anopheline mosquitoes and the most common Plasmodium species that caused malaria infection in human included P. falciparum, P.vivax, P.ovale, P. malariae and P.knowlesi1.

According to WHO world report 2013, endemic area in Malaysia included Sabah, Sarawak and central Peninsular Malaysia, with majority infection caused by P.vivax (24%) and P. falciparum (18%). P.falciparum is associated with highest mortality and morbidity. Symptoms of malaria included fever, malaise, weakness, gastrointestinal complaints (nausea, vomiting, diarrhea), neurologic complaints (dizziness, confusion, disorientation, coma), headache, back pain, myalgia, chills, and/or cough2.

Management Pharmacotherapy Disease management depends on the type of Plasmodium infection and the severity of infection3-5. (i) Uncomplicated P. falciparum infection3

Table 1: First line treatment for uncomplicated P. falciparum infection

First line : Artemisinin-based Combination Therapy (ACT)

Preferred treatment Alternative treatment Artesunate/Mefloquine (Artequine)* Dosage: 10-20kg: Artesunate 50mg OD x 3/7 Mefloquine 125mg OD x 3/7 Artequine 50/125mg (fixed dose pellets) OD x 3/7 20-40kg: Artesunate 100mg OD x 3/7 Mefloquine 250mg OD x 3/7 (Artequine 300/750) >40kg: Artesunate 200mg OD x 3/7 Mefloquine 500mg OD x 3/7 (Artequine 600/1500)

Artemether/Lumefantrine (Riamet) Dosage: 5-14kg: D1: 1 tab stat then 1 tab again after 8 hours, D2-D3: 1 tab BD 15-24kg: D1: 2 tabs stat then 2 tabs again after 8 hours D2-D3: 2 tabs BD 25-35kg: D1: 3 tabs stat then 3 tabs again after 8 hours D2-D3: 3 tabs BD >35kg: D1: 4 tabs stat then 4 tabs again after 8 hours D2-D3: 4 tabs BD

Riamet should NOT be used in young infant less than 5kg or less than 4 months. Treatment recommendation for these group of patients :

D1: IM Artesunate 1.2mg / kg or IM Arthemether 1.6mg / kg D2-D7: Oral Artesunate 2mg / kg / day OR

D1-7: Oral Quinine 10mg/kg TDS for 4 days, then 15-20mg/kg TDS for 4 days.

(Ref: Malaria in children, Department of tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University)

(i) Uncomplicated P. falciparum infection3


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‘Add primaquine 0.75mg base/kg single dose OD if gametocyte is present at any time during treatment.

47

Riamet should NOT be used in young infant less than 5kg or less than 4 months. Treatment recommendation for these group of patients : D1: IM Artesunate 1.2mg/kg or IM Arthemether 1.6mg/kg D2-D7: Oral Artesunate 2mg/kg/day

OR D1-7: Oral Quinine 10mg/kg TDS for 4 days, then 15-20mg/kg TDS for 4 days. (Ref: Malaria in children, Department of tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University) (ii) Second line P. falciparum infection3

• An alternative ACT is used (if Riamet was used in the first regimen, use Artequine for

treatment failure and vice-versa). • Artesunate 4mg/kg OD plus Clindamycin 10mg/kg/dose bd for a total of 7 days. • Quinine 10mg salt/kg 8 hourly plus Clindamycin 10mg/kg/dose bd for a total of 7 days.

Add primaquine 0.75mg base/kg single dose OD if gametocyte is present at any time during treatment. (iii) Severe P. falciparum infection3

Table 2: Treatment for severe P. falciparum infection

Preferred Treatment Alternative treatment

IV Artesunate: 2.4mg/kg at 0,12 and 24 hours, then daily until patient is able to tolerate orally. The use of IV Artesunate should continue for minimum of 24 hours or as soon as patient can tolerate orally.

IV Quinine loading 7mg salt/kg over 1 hour followed by 10mg salt/kg over 4 hours then 10mg salt/kg every 8 hour OR IV Quinine loading 20mg salt/kg over 4 hours, then 10mg salt/kg every 8 hour, for 7 days. PLUS Children > 8 yrs old: Doxycycline 3.5mg/kg OD x 7 days OR Children < 8 yrs old: Clindamycin 10mg/kg BD x 7 days.

(iii) Severe P. falciparum infection3

(ii) Second line P. falciparum infection3

• An alternative ACT is used (if Riamet was used in the first regimen, use Artequine for treatment failure and vice-versa).

• Artesunate 4mg/kg OD plus Clindamycin 10mg/kg/dose bd for a total of 7 days.

• Quinine 10mg salt/kg 8 hourly plus Clindamycin 10mg/kg/dose bd for a total of 7 days.


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(iv) Treatment of P.vivax*, malariae or knowlesi3

Table 3: Treatment for P.vivax, malariae or knowlesi

Preferred Treatment

Chloroquine sensitive: Chloroquine (150mg base/tab) D1: 10mg base/kg stat then 5mg base/kg 6 hours later D2: 5mg base/kg OD D3: 5mg base/kg OD * Calculation of chloroquine dose should be based on the base, not salt form.

Primaquine (7.5mg base/tab)

§ Add on Primaquine 0.5mg base/kg

daily for 14 days to ensure radical cure of hypnozoites for P.vivax infection.

§ Check G6PD before giving Primaquine.

§ For mild to moderate G6PD deficiency, an intermittent Primaquine regimen of 0.75mg base/kg weekly for 8 weeks can be given under medical supervision.

§ In severe G6PD deficiency Primaquine is contraindicated.

Chloroquine resistant: § To use ACT in relapse or chloroquine

resistant P.vivax, OR § Quinine 10mg salt/kg three times a day for

7 days OR § Mefloquine 15mg/kg single dose

Severe and complicated P.vivax, malariae and knowlesi should be managed as severe falciparum malaria.

PLUS

S

(iv) Treatment of P.vivax*, malariae or knowlesi3

Severe and complicated P.vivax, malariae and knowlesi should be managed as severe falciparum malaria.


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49

(v) Chemoprophylaxis6-7

Table 4: Chemoprophylaxis for travelling to malaria endemic areas

Drug Duration of Prophylaxis Dosage

Atovaquone/Proguanil (Malarone) Pediatric tablet: (Atovaquone 62.5mg/Proguanil 25mg) Adult tablet: (Atovaquone 250mg/Proguanil 100mg)

Start 2 days before journey, continue daily during exposure and up to 7 days thereafter.

Pediatric tablet of 62.5mg Atovaquone and 25mg Proguanil: 5-8kg: ½ tablet daily >8-10kg: ¾ tablets daily >10-20kg: 1 tablet daily >20-30kg: 2 tablets daily >30-40kg: 3 tablets daily >40kg: 1 adult tablet daily

Mefloquine (250mg base, 275mg salt per tablet)

Start 2-3 weeks before, continue weekly during exposure and for 4 weeks thereafter

<15kg: 5mg salt/kg 15-19kg: ¼ tab/week 20-30kg: ½ tab/week 31-45kg: ¾ tab/week >45kg: 1 tab/week

Doxycycline Start 2 days before journey, continue daily during exposure and for 4 weeks thereafter. Maximum duration of prophylaxis: 4 months

2.2mg base/kg once daily (max 100mg) (ref: Lexi comp) <25kg or < 8 years old: Do not use 25-35kg or 8-10 yrs old: 50mg 36-50kg or 11-13 yrs old: 75mg >50kg or >14 yrs old: 100mg

Chloroquine phosphate 250mg (equivalent to Chloroquine base 155mg)

Begin 1–2 weeks before travel to malarious areas. Take weekly on the same day of the week while in the malarious area and for 4 weeks after leaving such areas.

5mg/kg base orally once/week, up to maximum of 300mg base

Primaquine (i) Prophylaxis for short- duration travel to areas with principally P.vivax (ii) Used for presumptive antirelapse therapy (terminal prophylaxis) to decrease the risk for relapses of P. vivax and P. ovale

(i) 0.5mg/kg base up to 30mg base (adult dose) orally, daily (ii) 0.5 mg/kg base up to adult dose orally, daily for 14 days after departure from the malarious area

(v) Chemoprophylaxis6-7


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an b

e cr

ushe

d an

d m

ixed

with

liqu

ids.

-Do

not g

ive

Ria

met

for c

hild

ren

less

th

an 5

kg o

r les

s th

an 4

mon

ths

of li

fe

-No

dosa

ge a

djus

tmen

t for

live

r and

re

nal i

mpa

irmen

t.

-QT

inve

rval

pro

long

atio

n -F

atig

ue

-Diz

zine

ss

3 C

hlor

oqui

ne

sulp

hate

Adm

inis

ter w

ith m

eal t

o de

crea

se G

I up

set.

May

mix

with

cho

cola

te s

yrup

or

bana

na to

mas

k th

e bi

tter t

aste

. If

the

child

vom

its w

ithin

firs

t 30

min

utes

, fu

ll do

se to

be

repe

ated

, hal

f dos

e if

vom

ited

betw

een

30

min

utes

and

1 h

our)

-Ren

al a

djus

tmen

t dos

e ne

eded

. -U

se w

ith c

autio

n in

pat

ient

s w

ith li

ver

dise

ase,

G6P

D d

efic

ienc

y, s

eizu

re

diso

rder

, sev

ere

bloo

d di

sord

er a

nd

pre-

exis

ting

audi

tory

dam

age.

-U

se in

pre

gnan

cy s

houl

d be

avo

ided

un

less

ben

efit

outw

eigh

s th

e ris

k to

the

fetu

s.

-May

exa

cerb

ate

psor

iasi

s an

d po

rphy

ria.

-Irre

vers

ible

retin

al d

aman

ge

was

repo

rted

in p

atie

nts

with

lo

ng te

rm o

r hig

h do

se

ther

apy.

- A

gran

uloc

ytos

is, n

eutro

peni

a,

panc

ytop

enia

, th

rom

bocy

tope

nia

- Myo

path

y -A

lope

cia,

blu

e gr

ay s

kin

pigm

enta

tion


3.0

G

ener

al P

edia

tric

s

Sp

ecia

l Con

sid

erat

ion6

-9

50

Ta

ble

6: S

peci

al c

onsi

dera

tions

in a

nti-m

alar

ials

No

A

ntim

alar

ial

A

dmin

istr

atio

n

Prec

autio

n/C

ontr

aind

icat

ions

Side

Effe

cts/

Rem

arks

1

Arte

suna

te/

Mef

loqu

ine

(Arte

quin

e)

Ped

iatri

c pe

llets

can

be

adm

inis

tere

d di

rect

ly o

n pa

tient

’s to

ngue

, or p

lace

d on

th

e sp

oon

and

mix

ed w

ith li

ttle

amou

nt o

f liq

uid.

The

n rin

se th

e m

outh

with

sm

all

amou

nt o

f liq

uid

to e

nsur

e al

l rem

aini

ng

pelle

ts a

re s

wal

low

ed.

If pa

tient

vom

ited

with

in 1

hou

r of

adm

inis

tratio

n, o

ne re

plac

emen

t dos

e is

re

quire

d

-Not

to b

e us

ed in

chi

ldre

n <1

0kg.

- A

void

in c

hild

ren

with

epi

leps

y as

it

may

incr

ease

the

risk

of s

eizu

re (i

t may

lo

wer

the

plas

ma

conc

entra

tion

of

Val

proi

c ac

id, C

arba

maz

epin

e,

Phe

noba

rbita

l or P

heny

toin

). -N

o do

sage

adj

ustm

ent f

or li

ver a

nd

rena

l im

pairm

ent.

-Do

not a

dmin

iste

r Hal

ofan

trine

with

A

rtequ

ine

as it

may

cau

se p

oten

tially

fa

tal p

rolo

ngat

ion

of Q

T in

terv

al.

- Diz

zine

ss

- Dis

turb

ed s

ense

of b

alan

ce

- Neu

ro- p

sych

iatri

c re

actio

ns

-Abd

omin

al p

ain

-Nau

sea

- V

omiti

ng

- Dia

rrho

ea

-Ast

heni

a - A

nore

xia

-Hyp

okal

aem

ia

2 A

rtem

ethe

r/Lum

efan

trine

(R

iam

et)

Adm

inis

ter w

ith h

igh

fat d

iet.

In y

oung

chi

ldre

n, R

iam

et c

an b

e cr

ushe

d an

d m

ixed

with

liqu

ids.

-Do

not g

ive

Ria

met

for c

hild

ren

less

th

an 5

kg o

r les

s th

an 4

mon

ths

of li

fe

-No

dosa

ge a

djus

tmen

t for

live

r and

re

nal i

mpa

irmen

t.

-QT

inve

rval

pro

long

atio

n -F

atig

ue

-Diz

zine

ss

3 C

hlor

oqui

ne

sulp

hate

Adm

inis

ter w

ith m

eal t

o de

crea

se G

I up

set.

May

mix

with

cho

cola

te s

yrup

or

bana

na to

mas

k th

e bi

tter t

aste

. If

the

child

vom

its w

ithin

firs

t 30

min

utes

, fu

ll do

se to

be

repe

ated

, hal

f dos

e if

vom

ited

betw

een

30

min

utes

and

1 h

our)

-Ren

al a

djus

tmen

t dos

e ne

eded

. -U

se w

ith c

autio

n in

pat

ient

s w

ith li

ver

dise

ase,

G6P

D d

efic

ienc

y, s

eizu

re

diso

rder

, sev

ere

bloo

d di

sord

er a

nd

pre-

exis

ting

audi

tory

dam

age.

-U

se in

pre

gnan

cy s

houl

d be

avo

ided

un

less

ben

efit

outw

eigh

s th

e ris

k to

the

fetu

s.

-May

exa

cerb

ate

psor

iasi

s an

d po

rphy

ria.

-Irre

vers

ible

retin

al d

aman

ge

was

repo

rted

in p

atie

nts

with

lo

ng te

rm o

r hig

h do

se

ther

apy.

- A

gran

uloc

ytos

is, n

eutro

peni

a,

panc

ytop

enia

, th

rom

bocy

tope

nia

- Myo

path

y -A

lope

cia,

blu

e gr

ay s

kin

pigm

enta

tion

51

4 P

rimaq

uine

A

dmin

iste

r with

mea

ls to

dec

reas

e G

I ef

fect

s; d

rug

has

a bi

tter t

aste

. E

xtem

pora

neou

s pr

epar

atio

ns fo

rmul

a av

aila

ble.

- Scr

een

for G

6PD

sta

tus

befo

re

initi

atin

g tre

atm

ent

- Can

not b

e us

ed b

y pr

egna

nt w

omen

- C

anno

t be

used

by

wom

en w

ho a

re

brea

stfe

edin

g un

less

the

infa

nt h

as a

lso

been

test

ed fo

r G6P

D d

efic

ienc

y

- Ane

mia

- M

ethe

mog

lobi

nem

ia (

in

NA

DH

-met

hem

oglo

bin

redu

ctas

e de

ficie

nt in

divi

dual

s)

- Leu

kope

nia

5 Q

uini

ne

Infu

sion

rate

sho

uld

be <

5 m

g sa

lt /k

g/hr

M

axim

um Q

uini

ne p

er d

ose

= 60

0mg

-May

pro

long

QT

inte

rval

or c

ause

ca

rdia

c ar

rhyt

hmia

s -r

educ

e do

se in

pat

ient

s w

ith im

paire

d liv

er fu

nctio

n.

-Con

train

dica

ted

in p

atie

nts

with

pre

-ex

istin

g Q

T pr

olon

gatio

n, m

yast

heni

a gr

avis

, opt

ic n

eurit

is, G

6PD

def

icie

ncy.

-U

se o

f Qui

nine

in p

regn

ancy

at

ther

apeu

tic d

ose

is g

ener

ally

co

nsid

ered

saf

e. (L

exi C

omp)

-May

cau

se s

igni

fican

t hy

pogl

ycae

mia

in p

regn

ancy

. -S

teve

ns J

ohns

on s

yndr

ome

and

toxi

c ep

ider

mal

nec

roly

sis

has

been

repo

rted.

- A

gran

uloc

ytos

is, a

plas

tic

anem

ia, I

TP, h

emol

ytic

ane

mia

- C

olou

r vis

ion

dist

urba

nce,

di

min

ishe

d vi

sual

fiel

ds, o

ptic

ne

uriti

s

6.

Arte

suna

te

-Inje

ct (1

ml)

5% N

aHC

O3 s

olut

ion

prov

ided

into

the

Arte

suna

te v

ial,

shak

e 2-

3 m

inut

es u

ntil

clea

r sol

utio

n is

ob

tain

ed.

-For

IV in

ject

ion,

add

5m

l of N

S o

r D5%

to

mak

e fin

al c

once

ntra

tion

of 1

0mg/

ml o

f A

rtesu

nate

. A

dmin

iste

r at t

he ra

te o

f 3-4

ml/m

in.

-For

IM in

ject

ion,

add

2m

l NS

or D

5% to

m

ake

final

con

cent

ratio

n of

20m

g/m

l (to

tal 3

ml)

-Inje

ct im

med

iate

ly a

fter r

econ

stitu

tion.

-Ani

mal

exp

erim

ents

hav

e sh

own

som

e em

bryo

toxi

c ef

fect

. Sho

uld

be u

sed

with

ext

rem

e ca

utio

n in

pre

gnan

cy

with

in fi

rst t

hree

mon

ths.

- N

o do

sage

adj

ustm

ent f

or li

ver a

nd

rena

l im

pairm

ent.

-Tra

nsie

nt re

ticul

ocyt

open

ia

may

occ

ur w

hen

>3.7

5mg/

kg is

us

ed.


3.0

G

ener

al P

edia

tric

s

Sp

ecia

l Con

sid

erat

ion6

-9

50

Ta

ble

6: S

peci

al c

onsi

dera

tions

in a

nti-m

alar

ials

No

A

ntim

alar

ial

A

dmin

istr

atio

n

Prec

autio

n/C

ontr

aind

icat

ions

Side

Effe

cts/

Rem

arks

1

Arte

suna

te/

Mef

loqu

ine

(Arte

quin

e)

Ped

iatri

c pe

llets

can

be

adm

inis

tere

d di

rect

ly o

n pa

tient

’s to

ngue

, or p

lace

d on

th

e sp

oon

and

mix

ed w

ith li

ttle

amou

nt o

f liq

uid.

The

n rin

se th

e m

outh

with

sm

all

amou

nt o

f liq

uid

to e

nsur

e al

l rem

aini

ng

pelle

ts a

re s

wal

low

ed.

If pa

tient

vom

ited

with

in 1

hou

r of

adm

inis

tratio

n, o

ne re

plac

emen

t dos

e is

re

quire

d

-Not

to b

e us

ed in

chi

ldre

n <1

0kg.

- A

void

in c

hild

ren

with

epi

leps

y as

it

may

incr

ease

the

risk

of s

eizu

re (i

t may

lo

wer

the

plas

ma

conc

entra

tion

of

Val

proi

c ac

id, C

arba

maz

epin

e,

Phe

noba

rbita

l or P

heny

toin

). -N

o do

sage

adj

ustm

ent f

or li

ver a

nd

rena

l im

pairm

ent.

-Do

not a

dmin

iste

r Hal

ofan

trine

with

A

rtequ

ine

as it

may

cau

se p

oten

tially

fa

tal p

rolo

ngat

ion

of Q

T in

terv

al.

- Diz

zine

ss

- Dis

turb

ed s

ense

of b

alan

ce

- Neu

ro- p

sych

iatri

c re

actio

ns

-Abd

omin

al p

ain

-Nau

sea

- V

omiti

ng

- Dia

rrho

ea

-Ast

heni

a - A

nore

xia

-Hyp

okal

aem

ia

2 A

rtem

ethe

r/Lum

efan

trine

(R

iam

et)

Adm

inis

ter w

ith h

igh

fat d

iet.

In y

oung

chi

ldre

n, R

iam

et c

an b

e cr

ushe

d an

d m

ixed

with

liqu

ids.

-Do

not g

ive

Ria

met

for c

hild

ren

less

th

an 5

kg o

r les

s th

an 4

mon

ths

of li

fe

-No

dosa

ge a

djus

tmen

t for

live

r and

re

nal i

mpa

irmen

t.

-QT

inve

rval

pro

long

atio

n -F

atig

ue

-Diz

zine

ss

3 C

hlor

oqui

ne

sulp

hate

Adm

inis

ter w

ith m

eal t

o de

crea

se G

I up

set.

May

mix

with

cho

cola

te s

yrup

or

bana

na to

mas

k th

e bi

tter t

aste

. If

the

child

vom

its w

ithin

firs

t 30

min

utes

, fu

ll do

se to

be

repe

ated

, hal

f dos

e if

vom

ited

betw

een

30

min

utes

and

1 h

our)

-Ren

al a

djus

tmen

t dos

e ne

eded

. -U

se w

ith c

autio

n in

pat

ient

s w

ith li

ver

dise

ase,

G6P

D d

efic

ienc

y, s

eizu

re

diso

rder

, sev

ere

bloo

d di

sord

er a

nd

pre-

exis

ting

audi

tory

dam

age.

-U

se in

pre

gnan

cy s

houl

d be

avo

ided

un

less

ben

efit

outw

eigh

s th

e ris

k to

the

fetu

s.

-May

exa

cerb

ate

psor

iasi

s an

d po

rphy

ria.

-Irre

vers

ible

retin

al d

aman

ge

was

repo

rted

in p

atie

nts

with

lo

ng te

rm o

r hig

h do

se

ther

apy.

- A

gran

uloc

ytos

is, n

eutro

peni

a,

panc

ytop

enia

, th

rom

bocy

tope

nia

- Myo

path

y -A

lope

cia,

blu

e gr

ay s

kin

pigm

enta

tion

52

7 A

tova

quon

e/P

rogu

anil

(Mal

aron

e)

Tabl

ets

are

not p

alat

able

due

to b

itter

ta

ste.

May

cru

sh th

e ta

blet

s an

d m

ix w

ith

cond

ense

d m

ilk in

chi

ldre

n w

ith d

iffic

ulty

sw

allo

win

g ta

blet

s.

Take

with

food

or a

milk

y dr

ink

(incr

ease

th

e ra

te a

nd e

xten

d of

abs

orpt

ion)

. Ta

ke d

aily

at t

he s

ame

time

each

day

w

hile

in th

e m

alar

ious

are

a an

d fo

r 7

days

afte

r lea

ving

suc

h ar

eas.

-Con

train

dica

ted

in p

eopl

e w

ith s

ever

e re

nal i

mpa

irmen

t (C

rCl <

30 m

l/min

) -N

ot re

com

men

ded

for c

hild

ren

wei

ghin

g <5

kg,

pre

gnan

t wom

en, a

nd

wom

en b

reas

tfeed

ing

infa

nts

wei

ghin

g <5

kg

-Abs

orpt

ion

of A

tova

quon

e m

ay b

e de

crea

sed

in p

atie

nts

who

hav

e di

arrh

oea

or v

omiti

ng.

- Tra

nsam

inas

e in

crea

ses

- Mus

cle

wea

knes

s - D

izzi

ness

and

hea

dach

e - A

bdom

inal

pai

n, a

nore

xia,

di

arrh

oea,

nau

sea,

vom

iting

. G

ood

for l

ast-m

inut

e tra

vele

rs

beca

use

the

drug

is s

tarte

d 1-

2 da

ys b

efor

e tra

velin

g to

an

area

whe

re m

alar

ia

trans

mis

sion

occ

urs

8 M

eflo

quin

e A

dmin

iste

r with

food

. B

itter

tast

e.

Tabl

ets

can

be c

rush

ed a

nd m

ixed

with

sm

all a

mou

nt o

f wat

er, m

ilk, a

pple

sauc

e,

choc

olat

e sy

rup,

jelly

or f

ood.

R

epea

t ful

l dos

e if

vom

iting

occ

urs

with

in

30 m

inut

es a

fter a

dmin

istra

tion.

R

epea

t add

ition

al h

alf d

ose

if vo

miti

ng

occu

rs w

ithin

30-

60 m

inut

es a

fter

adm

inis

tratio

n.

- Can

not b

e us

ed in

: •

area

s w

ith m

eflo

quin

e re

sist

ance

•

patie

nts

with

cer

tain

psy

chia

tric

cond

ition

s •

patie

nts

with

a s

eizu

re d

isor

der

• pa

tient

s w

ith c

ardi

ac c

ondu

ctio

n ab

norm

aliti

es

- Can

be

used

in p

regn

ancy

-A

void

con

curr

ent u

se o

f dru

gs k

now

n to

cau

se Q

T-in

terv

al p

rolo

ngat

ion

(eg.

ha

lofa

ntrin

e, q

uini

ne, q

uini

dine

) or

CY

P3A

4 in

hibi

tors

(eg.

ket

ocon

azol

e)

-Con

curr

ent u

se w

ith c

hlor

oqui

ne m

ay

incr

ease

risk

of s

eizu

re.

- Not

a g

ood

choi

ce fo

r las

t-min

ute

trave

lers

bec

ause

dru

g ne

eds

to b

e st

arte

d at

leas

t 2 w

eeks

prio

r to

trave

l

-Diz

zine

ss, v

ertig

o, ti

nnitu

s,

loss

of b

alan

ce

-Anx

iety

, dep

ress

ion,

re

stle

ssne

ss, c

onfu

sion

-A

gran

uloc

ytos

is, a

plas

tic

anem

ia

-Sin

us b

rady

card

ia, s

inus

ar

rhyt

hmia

, fis

t deg

ree

AV

bl

ock,

QT-

inte

rval

pr

olon

gatio

n, a

bnor

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Non Pharmacotherapy

Malaria Protective Measures10-11

Mosquito avoidance methods:

• Minimize outdoors activities during its feeding time from dusk to dawn, and protect living quarters from mosquitoes to reduce exposure to the female Anopheles mosquito

• Avoid dark clothing, aftershaves, perfumes which can attract mosquitoes

• Covering exposed skin areas with long sleeve clothes and long pants

• Use mosquito repellents, eg. diethyltoluamide (DEET)-containing repellents (use DEET <35% in children) indoor and outdoor.

• Use mosquito nets, insecticidal (Deltamethrin, Permethrin, Alpha- cypermethrin) impregnated clothes and nets.

Mosquito repellents:

CDC recommends the use of products containing DEET, picaridin, IR3535, and some oil of lemon eucalyptus and para-menthane-diol products that provide longer-lasting protection. Most products can be used on children. The American Academy of Pediatrics recommended that insect repellents containing DEET should not be used on children under 2 months of age and ≤30% DEET should be used on children aged >2 months. Products containing oil of lemon eucalyptus should not to be used on children under the age of three years. (CDC, FDA)

References:

1. Centers for Disease Control and Prevention (CDC). CDC Health Information for International Travel. New York: Oxford University Press; 2014; Chapter 3. Available from http://wwwnc.cdc.gov/travel/page/yellowbook- home-2014. Accessed 26 Oct 2014.

2. World Health Organization. World Malaria Report 2013; 2013:147.ISBN: 9789241564694. Available from http://www.who.int/malaria/publications/ world_malaria_report_2013/en/. Accessed 26 Oct 2014.

3. Muhammad Ismail HI, Ng HP, Thomas T. Paediatric Protocols for Malaysian Hospitals. 3rd Ed. Ministry of Health;2013


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4. Stauffer W, Fischer PR. Diagnosis and treatment of malaria in children. Clinical Infectious Diseases. 2003;37:1340-1348.

5. Centers for Disease Control and Prevention (CDC). Treatment of Malaria (Guidelines For Clinicians). July 2013. Available from http://www.cdc.gov/ malaria/resources/pdf/clinicalguidance.pdf. Accessed 26 Oct 2014.

6. Centers for Disease Control and Prevention (CDC). Choosing a drug to prevent Malaria. Updated November 9, 2012. Available from http://www. cdc.gov/malaria/travelers/drugs.html. Accessed 26 Oct 2014.\

7. World Health Organization. Guidelines for the treatment of malaria, 2nd ed i t ion. March 2010. Ava i lab le f rom ht tp://whql ibdoc.who. in t / publications/2010/9789241547925_eng.pdf?ua=1. Accessed 16 Oct 2014. 8. Lexi-Comp Inc. Pediatric & Neonatal Lexi-Drugs. Lexi-Comp Inc.; Version 2.2.1 26 Oct 2014.

9. World Health Organization. Status report on artemisinin resistance. September 2014. Available from http://www.who.int/malaria/publications/ atoz/status-rep-artemisinin-resistance-sep2014.pdf?ua=1. Accessed 26 Oct 2014.

10. World Health Organization. WHO recommended long lasting insecticidal nets. February 2014. Available from http://www.who.int/whopes/Long_ lasting_insecticidal_nets_Jul_2012.pdf. Accessed 26 Oct 2014.

11. Centers for Disease Control and Prevention (CDC). Fight the bite for protection from malaria. Guidelines for DEET insect repellent use. Department of health and human services centers for disease control and prevention. Available from http://www.cdc.gov/malaria/toolkit/DEET. pdf. Accessed 26 Oct 2014.


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Meningitis

Introduction

Meningitis is still a major and sometimes fatal problem in Paediatrics1.

Bacterial meningitis, an inflammation of the meninges affecting the pia, arachnoid, and subarachnoid space that happens in response to bacteria and bacterial products, continues to be an important cause of mortality and morbidity in neonates and children2.

Morbidity is also high. A third of survivors have sequelae of their disease. However, these complications can be reduced if meningitis is treated early1.

Approach to a Child With Fever and Signs/symptoms of Miningitis

Fever & Symptoms/Signsof Bacterial Meningitis

• Do Blood, urline C&S• Start Anitibiotics + Dexamethasone

Lumbar Puncture (LP)Contra indicated

No Yes

Do LP

Abnormal CSF

Improvement No improvement

Change antibiotics

Positive Negetive

Continue antibiotics

Normal CSF, wait forCSF cuture and Latex agglutination

With Hold LP

-

Re-evaluate, Consider discontinue Antibiotics

Complate Treatment ( See Next Page )

Consider TB, Fungus or Encephalitis Complate course of antibiotics

Persistent Fever > 72 Hours andNeurological de�cit

(rule out various causes)

Consider Ultrasound / CT BrainRepeat LP if no evidence of

raised ICP

When NOT to do a Lumbar Puncture

• Glasgow coma Scale < 8

• Abnormal ‘dolls eye’ re�ex or unequal pupils

• Lateralized signs or abnormal posturing

• Immediately after a recent seizure

• Papilloedema

Management

INFECTIOUS DISEASES


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Table 1.0 Investigation of Cerebrospinal fluid (CSF) values in neurological disorders with fever1:

Cerebrospinal fluid (CSF) values in neurological disorders with fever

Condition Leukocytes

(mm³)

Protein (g/l) Glucose (mmol/l)

Comments

Acute Bacterial Meningitis

100 - >50,000 Usually 1- 5 <0.5 - 1.5 Gram stain may be positive

Partially-treated Bacterial Meningitis

1 - 10,000 Usually high

PMN, but may have lymphocytes

>1 low

CSF may be sterile in Pneumococcal, Meningococcal meningitis

Tuberculous (TB) Meningitis

10 - 500 Early PMN, later

high lymphocytes

1- 5 0 - 2.0

Smear for acid fast bacilli (AFB), TB Polymerase chain reaction (PCR) + in CSF; High Erythrocyte sedimentation rate (ESR)

Fungal Meningitis

50 – 500 Lymphocytes

0.5 - 2

Normal or low

CSF for Cryptococcal Ag

Encephalitis 10 - 1,000 Normal /

0.5-1

Normal CSF virology and HSV DNA PCR

Table 2.0: Gram Stain results of common bacteria causing community acquired bacteria meningitis3

ORGANISM CSF GRAM STAIN

Group B streptococcus Gram positive cocci resembling streptococci

Streptococcus pneumoniae Gram positive diplococci or GPC resembling streptococci

Neisseria meningitidis Gram negative diplococci or gram negative cocci

Haemophilus influenzae Gram negative cocco-bacilli

Enterobacteriaceae e.g. E coli Gram negative rods

Listeria monocytogenes Gram positive or Gram variable rods


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Pharmacotherapy

Table 3.0: Recommended antibiotic therapy according to likely pathogen1

Age Group Initial

Antibiotic

Likely Organism Duration

(if uncomplicated)

< 1 month

C Penicillin + Cefotaxime

Grp B Streptococcus E. coli

21 days

1 - 3 months C Penicillin + Cefotaxime

Group B Streptococcus

E. coli H. influenzae

Strep. pneumoniae

10 – 21 days

> 3 months

C Penicillin + Cefotaxime, OR

Ceftriaxone

H. influenzae Strep. pneumoniae

N. meningitides

7 – 10 days 10 – 14 days

7 days

Note: 1. Review antibiotic choice when infective organism has been identified. 2. Ceftriaxone gives more rapid CSF sterilisation as compared to Cefotaxime or Cefuroxime. 3. Ceftazidime has poor activity against pneumococci and should not be substituted for cefotaxime or ceftriaxone4. 4. If Streptococcal meningitis, request for MIC values of antibiotics MIC level Drug of choice: • MIC < 0.1 mg/L (sensitive strain) C Penicillin • MIC 0.1-< 2 mg/L (relatively resistant) Ceftriaxone or Cefotaxime • MIC > 2 mg/L (resistant strain) Vancomycin + Ceftriaxone or Cefotaxime 5.Extend duration of treatment if complications e.g. subdural empyema, brain abscess.

Table 4.0: Duration of therapy for uncomplicated cases of meningitis

Common organism Duration of therapy Group B streptococcus 21 days1

Gram negative rods 21 days3

Listeria monocytogenes 21 days3

Neisseria meningitidis 7 days3

Haemophilus influenzae type b 10 days3

Streptococcus pneumoniae 14 days3

‘Culture negative’ but significant CSF pleocytosis present, minimum of 7 days recommended3.


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Table 5.0 Estimates of CSF penetration of antibiotics used for the treatment of bacterial meningitis5-7

Antibiotics

CSF penetration

(Drug in CSF:plasma) in

uninflamed meninges

CSF penetration

(Drug in CSF:plasma) in inflamed meninges

Comments on use of antibiotic class for meningitis treatment

ß-lactams Benzylpenicillin Amoxicillin/ampicillin Cefotaxime Ceftriaxone Meropenem

0.02 0·01 0.1 0.007 0.1

0.1 0·05 0.2 0.1 0.3

Poor CSF penetration, but high systemic doses are well tolerated and attain CSF concentrations that greatly exceed the MIC of susceptible bacteria. 40% of cefotaxime vs 90% of ceftriaxone is protein bound. Avoid imipenem because it could lower the seizure threshold. Continuous infusions could enhance bacterial killing.

Aminoglycosides Gentamicin Amikacin

0.01 No data

0.1 0.1

Poor CSF penetration and toxicity limits increases in systemic doses. Consider intraventricular/intrathecal delivery if needed

Glycopeptides Vancomycin Teicoplanin

0.01 0.01

0.2 0.1

Poor CSF penetration and toxicity limits increases in systemic doses. Continuous infusions could enhance bacterial killing. Limited data for intraventricular/intrathecal delivery

Fluoroquinolones Ciprofloxacin Moxifloxacin Levofloxacin

0.3 0.5 0.7

0.4 0.8 0.8

Good CSF penetration. Moxifloxacin is an alternative agent for the treatment of penicillin-resistant pneumococcal meningitis

Others Chloramphenicol Rifampicin

0.6 0.2

0.7 0.3

Excellent CSF penetration, although toxicity concerns limit its use. 80% protein bound; CSF concentrations greatly exceed MIC of susceptible bacteria.

Newer agents Cefepime Linezolid Daptomycin Tigecycline

0.1 0.5 No data No data

0.2 0.7 0.05 0.5

Effective against penicillin-resistant pneumococcal meningitis Case report/series suggest eff ectiveness for pneumococcal, staphylococcal, and enterococcal meningitis, although high interindividual variability in CSF pharmacokinetics suggests therapeutic drug measurements could be needed Poor penetration, but CSF concentrations exceed MIC of susceptible bacteria; case reports/series suggest efficacy in staphylococcal and enterococcal meningitis Good CSF penetration, but concentrations achieved at current standard doses could be insufficient to ensure bacterial killing


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Corticosteroids in meningitis:

Corticosteroids are drugs that can reduce the inflammation caused by infection8.Dose: IV Dexamethasone 0.15 mg/kg 6 hly for 4 days or 0.4 mg/kg 12 hly for 2 days1

Do not use corticosteroids in children younger than 3 months with suspected or confirmed bacterial meningitis9.

If dexamethasone was not given before or with the first dose of antibiotics, but was indicated, try to administer the first dose within 4 hours of starting antibiotics, but do not start dexamethasone more than 12 hours after starting antibiotics9.

The corticosteroid dexamethasone leads to a reduction in hearing loss and other neurological sequelae in participants in high-income countries who have bacterial meningitis, but is not effective in low-income countries8.

An analysis for different bacteria causing meningitis showed that patients with meningitis due to Streptococcus pneumoniae treated with corticosteroids had a lower death rate, while no effect on mortality was seen in patients with Haemophilus influenzae and Neisseria meningitidis meningitis8.

Corticosteroids decreased the rate of hearing loss in children with meningitis due to H. influenzae, but not in children with meningitis due to other bacteria8.

Dexamethasone increased the rate of recurrent fever but was not associated with other adverse events8.


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References:

1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 46, Meningitis; p.215-8.

2. Kim KS. Acute bacterial meningitis in infants and children. The Lancet infectious diseases. 2010;10(1):32-42.

3. NSW Health. Infants and Children: Acute Management of Bacterial Meningitis: Clinical Practice Guideline. 2014

4. Muller ML. Pediatric bacteria meningitis treatment and management. [Online]. 2014 Nov 03 [cited 2015 Aug 4]; Available from: http://emedicine.medscape. com/article/961497-treatment#d10

5. Van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. The Lancet. 2012;380(9854):1693-702.

6. Nau R, Sorgel F, Eiff ert H. Penetration of drugs through the blood- cerebrospinal fluid/blood–brain barrier for treatment of central nervous system infections. Clin Microbiol Rev 2010; 23: 858–83.

7. Andes DR, Craig WA. Pharmacokinetics and pharmacodynamics of antibiotics in meningitis. Infect Dis Clin North Am 1999; 13: 595–618.

8. Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev. 2013;6.

9. NICE clinical guideline. Bacterial meningitis andmeningococcal septicaemia Management of bacterial meningitis and meningococcal septicaemia in children and young people younger than 16 years in primary and secondary care. 2015


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Urinary Tract Infection

Introduction

UTI comprises 5% of febrile ilnesses in childhood. Around 2% of children will have had a UTI before the age of 2 years. UTI is an important risk factor for the development of hypertension, renal failure and end-stage renal disease1.

Management1

Pharmacotherapy

All infants with febrile UTI should be admitted and IV antibiotics started as for acute pyelonephritis. In patients with high risk of serious illness, it’s preferable to obtain a urine sample first; however treatment should be started if urine sample is unobtainable.

• Antibiotic Prophylaxis Antibiotic prophylaxis should not be routinely recommended in infants and children following first time UTI, as antimicrobial prophylaxis does not seem to reduce significantly the rates of recurrence of pyelonephritis, regardless of age or degree of reflux. However, antibiotic prophylaxis may be considered in the following:

- Infants and children with recurrent symptomatic UTI. - Infants and children with vesico-ureteric reflux grades of at least grade III.

INFECTIOUS DISEASES


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-

Antibiotic treatment for UTI Type of Infection Preferred Treatment Alternative Treatment

UTI (Acute cystitis) E. coli

PO Trimethoprim 4mg/kg/dose BD (max 300mg daily) for 1 week

PO Trimethoprim/ Sulphamethoxazole 4mg/kg/dose (TMP) BD for 1 week

Proteus spp.

• Cephalexin, cefuroxime can be ued especially in children who had prior antibiotics. • Single dose of antibiotic therapy is not recommended.

Upper Tract UTI (Acute pyelonephritis)

E. coli

IV Cefotaxime 100mg/kg/day q8h for 10-14 days

IV Cefuroxime 100mg/kg/day q8h OR IV Gentamicin 5-7mg/kg/day daily

Proteus spp.

• Repeat culture within 48 hours if poor response. • Antibiotics may need to be changed according to sensivity.

Suggest to continue IV antibiotic until a child is afebrile for 2-3 days and then switch to appropriate oral therapy after culture results. Eg. Cefuroxime for total 10-14 days.

Asymptomatic bacteriuria No treatment recommended

Antibiotic prophylaxis for UTI UTI prophylaxis

PO Trimethoprim 1-2mg/kg ON

PO Nitrofurantoin 1-2mg/kg ON OR PO Cephalexin 5mg/kg ON

• Antibiotic prophylaxus is not to be routinely recommended in children with UTI. • Prophylactic antibiotics should be given for 3 days with MCUG done on second day. • A child who develops an infection while on prophylactic medication, treatment should be

with a different antibiotic and not a higher dose of the same prophylactic antibiotic.

Normal Renal Tracts

• Prophylactic antibiotic not required.

• Urine culture during any febrile illness or if the child is unwell.

No vesicoureteric reflux but renal scarring present

• Repeat urine culture only if symptomatic.

• Assessment includes height, weight, blood pressure and routine tests for proteinuria.


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Vesicoureteric Reflux

Management

• Antibiotic prophylaxis

• Surgical management or endoscopic treatment is considered if the child has recurrent breakthrough febrile UTI.

Non Pharmacotherapy1

Measures to reduce risk of infections

• Dysfunctional elimination syndrome (DES) or dysfunctional voiding is defined a an abnormal pattern of voiding of unknown etiology characterised by fecal and/or urinary incontinence and witholding of both urine and feces.

• Treatment of DES includes high fibre diet, use of laxatives, timed frequent voiding, and regular bowel movement.

• If condition persists, referral to a pediatric urologist/nephrologist is needed.

Summary

• All children less than 2 years of age with unexplained fever should have urine tested for UTI.

• Antibiotic prophylaxis should not be routinely recommended following first time UTI.

Reference:

1. Hussain Imam MI, Ng HP, Thomas T. Urinary Tract Infection. Paediatric Protocols For Malaysian Hospitals 3rd Edition. 63:305-312.

• Children with a minor, unilateral scarring do not need long-term follow up unless recurrent UTI/family history/lifestyle risk factors for hypertension.

• Children with bilateral abnormalities, impaired renal function, raised blood pressure and/or proteinuria should be managed by a nephrologist.

• Close follow up during pregnancy.


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Viral Croup

Introduction

Viral Croup is a clinical syndrome that is characterized by barking cough, inspiratory stridor, hoarse voice and respiratory distress of varying severity. It is also known as laryngotracheobronchitis, as it involved the inflammation of larynx, trachea and bronchi. Virus that commonly caused croup included Parainfluenza 1 and 2 and Respiratory Syncytial Virus (RSV), Adenovirus, Enterovirus, Influenza virus type A & B, and it mostly affects children between 6 and 36 months of age, although may occur on older children. Croup may cause various degrees of airway obstruction. However, several structural and infective conditions may also cause airway obstruction (eg. laryngomalacia, foreign body, epiglottitis, subglottic hemangioma). Hence, other causes need to be ruled out as the management may differ.

MANAGEMENT

Management of croup depends on the severity upon presentation. Mild croup can be managed as outpatient but moderate and severe croup will warrant hospital admission for further management (treatment algorithm as below-paeds protocol).

Assessment of severity Clinical Assessment of Croup (Wagener) • Mild : Stridor with excitement or at rest, with no respiratory distress. • Moderate : Stridor at rest with intercostal, subcostal or sternal recession. • Severe : Stridor at rest with marked recession, decreased air entry and altered level of consciousness.

INFECTIOUS DISEASES


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63

Viral Croup Introduction1

Viral Croup is a clinical syndrome that is characterized by barking cough, inspiratory stridor, hoarse voice and respiratory distress of varying severity. It is also known as laryngotracheobronchitis, as it involved the inflammation of larynx, trachea and bronchi. Virus that commonly caused croup included Parainfluenza 1 and 2 and Respiratory Syncytial Virus (RSV), Adenovirus, Enterovirus, Influenza virus type A & B, and it mostly affects children between 6 and 36 months of age, although may occur on older children. Croup may cause various degrees of airway obstruction. However, several structural and infective conditions may also cause airway obstruction (eg. laryngomalacia, foreign body, epiglottitis, subglottic hemangioma). Hence, other causes need to be ruled out as the management may differ. MANAGEMENT Management of croup depends on the severity upon presentation. Mild croup can be managed as outpatient but moderate and severe croup will warrant hospital admission for further management (treatment algorithm as below-paeds protocol). Assessment of severity Clinical Assessment of Croup (Wagener)

• Mild: Stridor with excitement or at rest, with no respiratory distress. • Moderate: Stridor at rest with intercostal, subcostal or sternal recession. • Severe: Stridor at rest with marked recession, decreased air entry and

altered level of consciousness.

Pharmacological treatment

• Corticosteroid2-6

The mechanism of action of systemic corticosteroid is believed to be due to its rapid anti-inflammatory effects or rapid vasoconstriction actions on the upper airways. The use of systemic steroids is associated with significant reduction of the number of adrenaline nebulization needed and reduced the average length of stay in Emergency Department9,10.

Dexamethasone and prednisolone has been shown to have equivalent initial clinical response7 but there is a higher representation rate with prednisolone8 is no superiority in the choice of route of administration for the steroids (IV, IM or oral), however oral route maybe preferable if the child can tolerate orally as it is the least expensive and least traumatic way for the child (Feyzullah 2004).The anti-inflammatory effect of Dexamethasone can last for 2-4 days.

The use of inhaled corticosteroid (eg. inhaled Budesonide) is also effective in treating moderate croup. The onset of action is within 30 minutes5, which is comparable to the systemic steroid, which the onset of action is 1 hour1,2,6.

• Nebulised Adrenaline

Nebulised Adrenaline should be used if the patient present with severe croup, or no improvement or stridor worsened after the use of corticosteroid. It has been suggested that inhaled adrenaline reduce bronchial and tracheal epithelial vascular permeability to help decrease airway edema, which results in increase in airway radius and improved airflow1,2. The onset of action is clinically rapid (30 minutes), and the duration of effect is 2 hours3,4. However, in severe croup, the dose maybe repeated every 15-20 minutes. if the child required repeated doses of Adrenaline nebulization, it may indicate that the child required intubation4.


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Non pharmacological treatment4

• Oxygen

Oxygen is considered as the standard treatment for any patient with severe croup, SpO2 <93% or with any significant respiratory distress. It can be given concurrently with other pharmacological treatment such as corticosteroid and adrenaline nebulization.

• Steam

Cold mist, steam and humidified air was once the mainstay of treatment in croup during the 19th and 20th century, but there is no evidence that this strategy can speed recovery, yet it may be associated with burns and scalds, hence the use is not recommended in most of the treatment guidelines.

• Heliox

Heliox is a mixture of Helium and Oxygen (with not less than 20% oxygen). Despite the conflicting findings from several clinical trials on the efficacy of Heliox compared to other conventional modalities, there is still insufficient evidence to establish the beneficial effect of the role of Heliox in the management of croup


The use of adrenaline should be cautioned in patients with ventricular outflow obstruction such as TOF.


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References:

1. Klassen TP. Croup: A Current Perspective in Emergency Medicine. Pediatric Clinic of North America. 1999;46(6):1167-1178

2. Fitzgerald DA, Mellis CM, Johnson M, Copper PC, Allen HA, Van Asperren PP, Nebulised Budesonide as Effective as Nebulised Adrenaline in moderately severe croup. Pediatrics. 1996;97:722-725.

3. Waissman Y, Klein BL, Boenning DA et al. Prospective randomised double blind study comparing L-epinephrine and racemic epinephrine aerosols in the treatment of laryngotracheitis (croup). Pediatrics.1992;89:302-306.

4. Fitzgerald DA, Mellis CM. Management of acute upper airways obstruction in children. Mod. Med Aust. 1995; 38:80-88

5. Husby S, Agertoft L, Mortensen S, Pedersen S. Treatment of croup with nebulised steroid (Budesonide): a double blind, placebo controlled study. Arch Dis Child.1993;68:352-355.

6. Geelhoed GC, MacDonald WB. Oral and inhaled steroid in croup: A randomized, placebo-controlled trial. Pediatr Pulmonol.1995; 20:362-368.

7. Fifoot and Ting. EMA 2007;19:51-58.

8. Sparrow and Geelhoed GC. Arch Dis Child 2006:91;580-583.

9. Cruz MN, Stewart G, Rosenberg N. Use of Dexamethasone in the outpatient management of acute laryngotracheitis. Pediatrics. 1995; 96:220-223

10. Jaffe D. The treatment of croup with glucocorticoids. N Eng J Med. 1998; 339:498-503.

11. Super DM, Cartelli NA, Brooks LJ et al. A prospective randomised double blind study to evaluate the effect of dexamethasone in acute laryngotracheitis. J Pediatr .1989;115:323-329.

12. Cetinkaya F, Tufekci BS, Kutluk G. A comparison of nebulised budesonide, and intramuscular, and oral dexamethasone for treatment of croup. International Journal of Pediatric Otorhinolaryngology. 2004 April; 68(4): 453-456.


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Pneumonia

Introduction

There are two clinical definitions of pneumonia:

• Bronchopneumonia: a febrile illness with cough, respiratory distress with evidence of localised or generalised patchy infiltrates1.

• Lobar pneumonia: similar to bronchopneumonia except that the physical findings and radiographs indicate lobar consolidation1.

Clinical features

Criteria for Respiratory Distress in Children With Pneumonia2

Signs of Respiratory Distress

1. Tachypnea, respiratory rate, breaths/min

Age 0–2 months: > 60/min

Age 2–12 months: >50/min

Age 1–5 Years: >40/min

Age >5 Years: >20/min

2. Dyspnea

3. Retractions (suprasternal, intercostals, or subcostal)

4. Grunting

5. Nasal flaring

6. Apnea

7. Altered mental status

8. Pulse oximetry measurement ,90% on room air

INFECTIOUS DISEASES


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Criteria for hospitalization1

• Community acquired pneumonia can be treated at home

• Identify indicators of severity in children who need admission, as pneumonia can be fatal. The following indicators can be used as a guide for admission:

• Children aged 3 months and below, whatever the severity of pneumonia.

• Fever ( more than 38.5 °C ), refusal to feed and vomiting

• Fast breathing with or without cyanosis

• Associated systemic manifestation

• Failure of previous antibiotic therapy

• Recurrent pneumonia

• Severe underlying disorder, e.g. Immunodeficiency

66

Pneumonia

Introduction There are two clinical definitions of pneumonia: • Bronchopneumonia: a febrile illness with cough, respiratory distress with evidence of localised or generalised patchy infiltrates1. • Lobar pneumonia: similar to bronchopneumonia except that the physical findings and radiographs indicate lobar consolidation1. Clinical features Criteria for Respiratory Distress in Children With Pneumonia2

Signs of Respiratory Distress 1. Tachypnea, respiratory rate, breaths/min

Age 0–2 months: > 60/min Age 2–12 months: >50/min Age 1–5 Years: >40/min Age >5 Years: >20/min

2. Dyspnea 3. Retractions (suprasternal, intercostals, or subcostal) 4. Grunting 5. Nasal flaring 6. Apnea 7. Altered mental status 8. Pulse oximetry measurement ,90% on room air

Table 1.0 Severity assessment3

Mild to moderate Severe Infants Temperature <38.5˚C

Respiratory rate <50 breaths/min Mild recession Taking full feeds

Temperature >38.5˚C Respiratory rate >70 breaths/min Moderate to severe recession Nasal flaring Cyanosis Intermittent apnoea Grunting respiration Not feeding Tachycardia Capillary refill time >2 s

Older children

Temperature <38.5˚C Respiratory rate <50 breaths/min Mild breathlessness No vomiting

Temperature >38.5˚C Respiratory rate >50 breaths/min Severe difficulty in breathing Nasal flaring Cyanosis Grunting respiration Signs of dehydration Tachycardia Capillary refill time >2 s


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Management

Pharmacotherapy

Specific aetiological agents are not identified in 40% to 60% of cases1. It is often difficult to distinguish viral from bacterial disease. The majority of lower respiratory tract infections are viral in origin, e.g. Respiratory syncytial virus, Influenza A or B, Adenovirus, Parainfluenza virus.

A helpful indicator in predicting aetiological agents is the age group.

Table 2.0 Predominant bacterial pathogens of pneumonia according to age group

When treating pneumonia, consider clinical, laboratory, radiographic findings, as well as age of the child, and the local epidemiology of respiratory pathogens and resistance/sensitivity patterns to microbial agents1.

Majority of infections are caused by viruses and do not require antibiotics1.

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Criteria for hospitalization1

• Community acquired pneumonia can be treated at home • Identify indicators of severity in children who need admission, as pneumonia

can be fatal. The following indicators can be used as a guide for admission: • Children aged 3 months and below, whatever the severity of pneumonia. • Fever ( more than 38.5 °C ), refusal to feed and vomiting • Fast breathing with or without cyanosis • Associated systemic manifestation • Failure of previous antibiotic therapy • Recurrent pneumonia • Severe underlying disorder, e.g. Immunodeficiency

Key features that suggest a child requires transfer to intensive care3

• failure to maintain oxygen saturation >92% in fractional inspired oxygen of >0.6; • shock; • rising respiratory and pulse rate with clinical evidence of severe respiratory distress

and exhaustion, with or without a raised arterial carbon dioxide tension; • recurrent apnoea or slow irregular breathing

Management

Pharmacotherapy

Specific aetiological agents are not identified in 40% to 60% of cases1. It is often difficult to distinguish viral from bacterial disease. The majority of lower respiratory tract infections are viral in origin, e.g. Respiratory syncytial virus, Influenza A or B, Adenovirus, Parainfluenza virus. A helpful indicator in predicting aetiological agents is the age group. Table 2.0 Predominant bacterial pathogens of pneumonia according to age group Pathogens for Pneumonia Age Bacterial Pathogens Newborns Group B streptococcus, Escherichia coli,

Klebsiella species, Enterobacteriaceae Infants 1- 3 months Chlamydia trachomatis Preschool age Streptococcus pneumoniae, Haemophilus

influenzae type b, Staphylococcal aureus Less common: Group A Streptococcus, Moraxella catarrhalis, Pseudomonas aeruginosa

School age Mycoplasma pneumoniae, Chlamydia pneumoniae

When treating pneumonia, consider clinical, laboratory, radiographic findings, as well as age of the child, and the local epidemiology of respiratory pathogens and resistance/sensitivity patterns to microbial agents1. Majority of infections are caused by viruses and do not require antibiotics1.

Key features that suggest a child requires transfer to intensive care3

• failure to maintain oxygen saturation >92% in fractional inspired oxygen of >0.6;

• shock;

• rising respiratory and pulse rate with clinical evidence of severe respiratory distress and exhaustion, with or without a raised arterial carbon dioxide tension;

• recurrent apnoea or slow irregular breathing


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Table 3.0 Bacterial pathogens and Recommended antimicrobial agents1

Pathogens Antimicrobial Agents Beta-lactam susceptible Streptococcus pneumonia Penicillin, cephalosporins Haemophilus influenzae type b Ampicillin, chloramphenicol, cephalosporins Staphylococcus aureus Cloxacillin Group A Streptococcus Penicillin, cephalosporin Mycoplasma pneumoniae Macrolides, e.g. erythromycin, azithromycin Chlamydia pneumoniae Macrolides, e.g. erythromycin, azithromycin Bordetella pertussis Macrolides, e.g. erythromycin, azithromycin Table 4.0 Bacterial pathogens and recommended antimicrobial agents2. Pathogen Parenteral therapy Oral therapy (step-down therapy

or mild infection) Streptococcus pneumoniae with MICs for penicillin ≤ 2.0 mcg/mL

Preferred: ampicillin (150–200 mg/kg/day every 6 hours) or penicillin (200 000–250 000 U/kg/day every 4–6 h); Alternatives: ceftriaxone (50–100 mg/kg/day every 12–24 hours) (preferred for parenteral outpatient therapy) or cefotaxime (150 mg/kg/day every 8 hours); may also be effective: clindamycin (40 mg/kg/day every 6–8 hours) or vancomycin (40–60 mg/kg/day every 6–8 hours)

Preferred: amoxicillin (90 mg/kg/day in 2 doses or 45 mg/kg/day in 3 doses); Alternatives: second- or third-generation cephalosporin (cefpodoxime, cefuroxime, cefprozil); oral levofloxacin, if susceptible (16–20 mg/kg/day in 2 doses for children 6 months to 5 years old and 8–10 mg/kg/day once daily for children 5 to 16 years old; maximum daily dose, 750 mg) or oral linezolid (30 mg/kg/day in 3 doses for children <12 years old and 20 mg/kg/day in 2 doses for children ≥12 years old)

S. pneumoniae resistant to penicillin, with MICs ≥4.0 mcg/mL

Preferred: ceftriaxone (100mg/kg/day every 12–24 hours); Alternatives: ampicillin (300–400 mg/kg/day every 6 hours), levofloxacin (16–20 mg/kg/day every 12 hours for children 6 months to 5 years old and 8–10 mg/kg/day once daily for children 5–16 years old; maximum daily dose, 750 mg), or linezolid (30 mg/kg/day every 8 hours for children <12 years old and 20 mg/kg/day every 12 hours for children >12 years old); may also be effective: clindamycin (40 mg/kg/day every 6–8 hours) or vancomycin (40–60 mg/kg/day every 6–8 hours)

Preferred: oral levofloxacin (16–20 mg/kg/day in 2 doses for children 6 months to 5 years and 8–10 mg/kg/day once daily for children 5–16 years, maximum daily dose, 750 mg), if susceptible, or oral linezolid (30 mg/kg/day in 3 doses for children <12 years and 20 mg/kg/day in 2 doses for children ≥12 years); Alternative: oral clindamycin (30–40 mg/kg/day in 3 doses)


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Group A Streptococcus

Preferred: intravenous penicillin (100 000–250 000 U/kg/day every 4–6 hours) or ampicillin (200 mg/kg/day every 6 hours); Alternatives: ceftriaxone (50–100 mg/kg/day every 12–24 hours) or cefotaxime (150 mg/kg/day every 8 hours); may also be effective: clindamycin, if susceptible (40 mg/kg/day every 6–8 hours) or Vancomycin (40–60 mg/kg/day every 6–8 hours)

Preferred: amoxicillin (50–75 mg/kg/day in 2 doses), or penicillin V (50–75 mg/kg/day in 3 or 4 doses); Alternative: oral clindamycin (40 mg/kg/day in 3 doses)

Stapyhylococcus aureus, methicillin susceptible (combination therapy not well studied)

Preferred: cefazolin (150 mg/kg/day every 8 hours) or semisynthetic penicillin, eg oxacillin (150–200 mg/kg/day every 6–8 hours); Alternatives: clindamycin (40 mg/kg/day every 6–8 hours) or vancomycin (40–60 mg/kg/day every 6–8 hours)

Preferred: oral cephalexin (75–100 mg/kg/day in 3 or 4 doses); Alternative: oral clindamycin (30–40 mg/kg/day in 3 or 4 doses)

S. aureus, methicillin resistant, susceptible to clindamycin (combination therapy not well-studied)

Preferred: vancomycin (40–60 mg/kg/day every 6–8 hours or dosing to achieve an AUC/MIC ratio of >400) or clindamycin (40m g/kg/day every 6–8 hours); Alternatives: linezolid (30 mg/kg/day every 8 hours for children <12 years old and 20 mg/kg/day every 12 hours for children ≥12 years old)

Preferred: oral clindamycin (30–40 mg/kg/day in 3 or 4 doses); Alternatives: oral linezolid (30 mg/kg/day in 3 doses for children <12 years and 20 mg/kg/day in 2 doses for children ≥12 years)

S. aureus, methicillin resistant,resistant to clindamycin (combination therapy not well studied)

Preferred: vancomycin (40–60 mg/kg/day every 6-8 hours or dosing to achieve an AUC/MIC ratio of >400); Alternatives: linezolid (30 mg/kg/day every 8 hours for children <12 years old and 20 mg/kg/day every 12 hours for children ≥12 years old)

Preferred: oral linezolid (30 mg/kg/day in 3 doses for children <12 years and 20 mg/kg/day in 2 doses for children ≥12 years old); Alternatives: none; entire treatment course with parenteral therapy may be required

Haemophilus influenza, typeable (A-F) or nontypeable

Preferred: intravenous ampicillin (150-200 mg/kg/day every 6 hours) if b-lactamase negative, ceftriaxone (50–100 mg/kg/day every 12-24 hours) if b-lactamase producing, or cefotaxime (150 mg/kg/day every 8 hours);

Preferred: amoxicillin (75-100 mg/kg/day in 3 doses) if b-lactamase negative) or amoxicillin clavulanate (amoxicillin component, 45 mg/kg/day in 3 doses or 90 mg/kg/day in 2 doses) if b-lactamase producing;


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Alternatives: intravenous ciprofloxacin (30 mg/kg/day every 12 hours) or intravenous levofloxacin (16-20 mg/kg/day every 12 hours for children 6 months to 5 years old and 8-10 mg/kg/day once daily for children 5 to 16 years old; maximum daily dose, 750 mg)

Alternatives: cefdinir, cefixime, cefpodoxime, or ceftibuten

Mycoplasma pneumoniae

Preferred: intravenous azithromycin (10 mg/kg on days 1 and 2 of therapy; transition to oral therapy if possible); Alternatives: intravenous erythromycin lactobionate (20 mg/kg/day every 6 hours) or levofloxacin (16-20 mg/kg/day every 12 hours; maximum daily dose, 750 mg)

Preferred: azithromycin (10 mg/kg on day 1,followed by 5 mg/kg/day once daily on days 2–5); Alternatives: clarithromycin (15 mg/kg/day in 2 doses) or oral erythromycin (40 mg/kg/day in 4 doses); for children >7 years old, doxycycline (2–4 mg/kg/day in 2 doses; for adolescents with skeletal maturity, levofloxacin (500 mg once daily) or oxifloxacin (400 mg once daily)

Chlamydia trachomatis or Chlamydophila pneumoniae

Preferred: intravenous azithromycin (10 mg/kg on days 1 and 2 of therapy; transition to oral therapy if possible); Alternatives: intravenous erythromycin lactobionate (20 mg/kg/day every 6 hours) or levofloxacin (16-20 mg/kg/day in 2 doses for children 6 months to 5 years old and 8-10 mg/kg/day once daily for children 5 to 16 years old; maximum daily dose, 750 mg)

Preferred: azithromycin (10 mg/kg on day 1,followed by 5 mg/kg/day once daily days 2–5); Alternatives: clarithromycin (15 mg/kg/day in 2 doses) or oral erythromycin (40 mg/kg/day in 4 doses); for children >7 years old, doxycycline (2-4 mg/kg/day in 2 doses); for adolescents with skeletal maturity, levofloxacin (500 mg once daily) or oxifloxacin (400 mg once daily)

Doses for oral therapy should not exceed adult doses. Supportive treatment1

i. Fluids

• Withhold oral intake when a child is in severe respiratory distress. • In severe pneumonia, secretion of anti-diuretic hormone is increased as such

dehydration is uncommon. Avoid overhydrating the child. ii. Oxygen

• Oxygen reduces mortality associated with severe pneumonia. • It should be given especially to children who are restless, and tachypnoeic with

severe chest indrawing, cyanosis, or is not tolerating feeds. • Maintain the SpO2 > 95%.

Supportive treatment1

i. Fluids

• Withhold oral intake when a child is in severe respiratory distress.

• In severe pneumonia, secretion of anti-diuretic hormone is increased as such dehydration is uncommon. Avoid overhydrating the child.

ii. Oxygen

• Oxygen reduces mortality associated with severe pneumonia.

• It should be given especially to children who are restless, and tachypnoeic with severe chest indrawing, cyanosis, or is not tolerating feeds.

• Maintain the SpO2 > 95%.


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iii. Cough medication

• Not recommended as it causes suppression of cough and may interfere with airway clearance. Adverse effects and overdosage have been reported.

iv. Temperature control

• Reduces discomfort from symptoms, as paracetamol will not abolish fever

v. Chest physiotherapy

• This assists in the removal of tracheobronchial secretions: removes airway obstruction, increase gas exchange and reduce the work of breathing.

• No evidence that chest physiotherapy should be routinely done.

Scientific basis of WHO recommendations for treatment of pneumonia4

• Children with fast breathing pneumonia with no chest indrawing or general danger sign should be treated with oral amoxicillin: at least 40mg/kg/dose twice daily (80mg/kg/day) for five days. In areas with low HIV prevalence, give amoxicillin for three days.

• Children with fast-breathing pneumonia who fail on first-line treatment with amoxicillin should have the option of referral to a facility where there is appropriate second-line treatment.

• Children age 2–59 months with chest indrawing pneumonia should be treated with oral amoxicillin: at least 40mg/kg/dose twice daily for five days.

• Children aged 2–59 months with severe pneumonia should be treated with parenteral ampicillin (or penicillin) and gentamicin as a first-line treatment. - Ampicillin: 50 mg/kg, or benzyl penicillin: 50 000 units per kg IM/IV every 6 hours for at least five days - Gentamicin: 7.5 mg/kg IM/IV once a day for at least five days

• Ceftriaxone should be used as a second-line treatment in children with severe pneumonia having failed on the first-line treatment.

• Ampicillin (or penicillin when ampicillin is not available) plus gentamicin or ceftriaxone are recommended as a first-line antibiotic regimen for HIV-infected and -exposed infants and for children under 5 years of age with chest indrawing pneumonia or severe pneumonia.

• For HIV-infected and -exposed infants and for children with chest indrawing pneumonia or severe pneumonia, who do not respond to treatment with ampicillin or penicillin plus gentamicin, ceftriaxone alone is recommended for use as second-line treatment.


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• Empiric cotrimoxazole treatment for suspected Pneumocystis jirovecii (previously Pneumocystis carinii) pneumonia (PCP) is recommended as an additional treatment for HIV-infected and -exposed infants aged from 2 months up to 1 year with chest indrawing or severe pneumonia.

• Empirical cotrimoxazole treatment for Pneumocystis jirovecii pneumonia (PCP) is not recommended for HIV-infected and - exposed children over 1 year of age with chest indrawing or severe pneumonia.

References:

1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 33, Pneumonia; p.165-8.

2. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, et al. The management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clinical Infectious Diseases. 2011;53(7):e25-e76.

3. Harris M, Clark J, Coote N, Fletcher P, Harnden A, McKean M, et al. British Thoracic Society guidelines for the management of community acquired pneumonia in children: update 2011. Thorax. 2011;66(Suppl 2):ii1-ii23.

4. Organization WH. Revised WHO classification and treatment of pneumonia in children at health facilities: evidence summaries. 2014.


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CARDIOVASCULAR

Kawasaki Disease

Introduction

Kawasaki disease (KD) is an acute, self-limited febrile illness mainly affecting small- to medium-sized vessels and occurs in early childhood. The etiology is currently unknown, however it likely results from an immunologic response triggered by microbial agents, with documented genetic susceptibility. KD typically presents in children younger than 5 years as a febrile illness with mucocutaneous changes. If untreated, KD can result in coronary aneurisms in 25% patients1,2.

In 1990 the American Heart Association(AHA) committee on rheumatic fever, endocarditis, and Kawasaki disease gave the case definition that has been generally accepted—ie, a febrile illness of at least five days with at least four of the five following signs and no other reasonable cause for the findings1:

a) Bilateral conjunctival injection – (there is no corneal ulceration but there may be a concomitant anterior uveitis on slit lamp examination)

b) Oral changes (erythema of lips or oropharynx, strawberry tongue due to prominent papillae, or fissuring of the lips)

c) Peripheral extremity changes (oedema, erythema, or generalised or periungal desquamation); erythema is seen in the first week whereas desquamation begins about 14–21 days after the onset of the illness

d) Rash – this starts in the first few days; it is often diffuse and polymorphic and lasts a week before fading. Vesicles are rarely seen; however, the rash can appear macular, maculopapular, urticarial, scarlettina or even morbilliform

e) Cervical lymphadenopathy is found in about 50% of cases; most often there is a painful solitary enlarged lymph gland, >1.5 cm in diameter


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Fever is an essential feature; it is most often sudden in onset and swinging, going above 40°C. It must last at least for five days but can persist for up to a month. If coronary arterial aneurysms (CAA) are present, one of the most important complications of Kawasaki disease, then only three of the clinical features are required to clinch the diagnosis.

There are ‘incomplete cases’ when not all of the four (three with CAA) diagnostic clinical features are present; some of these cases may evolve into complete cases. Some incomplete cases are diagnosed by CAA on echocardiography or at necropsy and the benefit of hindsight of the preceding clinical features.

For most children there is a subacute phase that lasts up to 30 days and a full recovery by day 50 following the onset of the illness.

Management2

Pharmacotherapy

74

Management2

Pharmacotherapy

Table 1. Treatment dose for Kawasaki Disease Drug Dose Suggested

monitoring Additional information

Primary treatment

IV Immunoglobulins 2 Gm/kg infusion over 10 - 12 hours

WBC (4500-11000 cell/µL)

If white blood cell increases from the normal range 4500-11000 cell/µL

then infusion rate has to be slowed down until it falls

within the range

Oral Aspirin

30 mg/kg/day for 2 wks or until patient is afebrile for 2-3

days

Bleeding Creatinine :

0.2 to 1.0 mg/dL PT:10-13.5 Sec APTT:26-42 Sec

INR:<1.5

Lower the dose if aspirin levels: >300 mcg/ml (toxic)

Maintainence

Aspirin

3-5 mg/kg daily for 6 - 8 weeks

or until ESR and platelet count

normalise.

Bleeding Creatinine :

0.2 to 1.0 mg/dL PT:10-13.5 Sec APTT:26-42 Sec

INR:<1.5

If coronary aneurysm present, then continue aspirin until resolves

Dipyridamole (Alternative for

Aspirin) 3- 5 mg/kg daily. Blood Pressure

Heart Rate

Additional treatment (Not responding to primary treatment. Persistent or recrudescent fever ≥ 36hrs after

completion of initial dose of IV Immunoglobulins) IV Immunoglobulins 2 Gm/kg infusion over 10 - 12 hours

Special Consideration regarding vaccinations : The use of Immunoglobulins may impair efficacy of live-attenuated virus vaccines. Delay these vaccinations for at least 11 months.

REFERENCES

1. Best Practice - Kawasaki Disease, Ian K Maconochie, Arch Dis Child Educ Pract Ed 2004;89:ep3–ep8. doi: 10.1136/adc.2004.053728

2. Paediatric Protocol for Malaysian Hospitals, 3rd Edition

3. Risk factors for refractory Kawasaki disease, Maria Cristina Maggio*, Eugenia Prinzi, Giovanni Corsello, 21st European Pediatric Rheumatology (PReS) Congress, Belgrade, Serbia Pediatric Rheumatology 2014, 12(Suppl 1):P359 http://www.ped-rheum.com/content/12/S1/P359


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Special Consideration regarding vaccinations : The use of Immunoglobulins may impair efficacy of live-attenuated virus vaccines. Delay these vaccinations for at least 11 months.

References :

1. Best Practice - Kawasaki Disease, Ian K Maconochie, Arch Dis Child Educ Pract Ed 2004;89:ep3–ep8. doi: 10.1136/adc.2004.053728

2. Paediatric Protocol for Malaysian Hospitals, 3rd Edition

3. Risk factors for refractory Kawasaki disease, Maria Cristina Maggio*, Eugenia Prinzi, Giovanni Corsello, 21st European Pediatric Rheumatology (PReS) Congress, Belgrade, Serbia Pediatric Rheumatology 2014, 12(Suppl 1):P359 http://www.ped-rheum.com/content/12/S1/P359


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Rheumatic Heart Disease

Introduction

Acute Rheumatic Fever

• Acute Rheumatic Fever (ARF) is an illness caused by a reaction to a bacterial infection with group A streptococcus (Streptococcus pyogenes)1.

• It causes an acute, generalised inflammatory response and an illness that targets specific parts of the body, including the heart, joints, brain and skin2.

• Individuals with ARF are often unwell, have significant joint pain and require hospitalisation. Despite the dramatic nature of the acute episode, ARF typically leaves no lasting damage to the brain, joints or skin, but can cause persisting heart damage, termed ‘rheumatic heart disease’ (RHD)2.

Rheumatic Heart Disease

• Rheumatic Heart Disease(RHD) is damage to the heart that remains after the acute ARF episode has resolved. It is caused by an episode or recurrent episodes of ARF, where the heart has become inflamed; the heart valves remain stretched and/or scarred, and normal blood flow is interrupted.

• Recurrences of ARF may cause further valve damage, leading to worsening of RHD.

• Preventing recurrences of ARF by using prophylactic treatment with penicillin is therefore of great importance in controlling RHD.

• Peak incidence 5 to 15 years old; more common in females1.

CARDIOVASCULAR


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Management1

Aim to suppress inflammatory response so as to minimize cardiac damage, provide symptomatic relief and eradicate pharyngeal streptococcal damage, provide symptomatic relief and eradicate pharyngeal streptococcal infection.

• Bed rest. Restrict activity until acute phase reactants return to normal.

• Anti-streptococcal therapy: IV C.Penicilline 50 000iu/kg/dose 6H or Oral Penicillin V 250mg 6H (<30kg), 500mg 6H (>30kg) x 10/7. Oral Erythromycin x 10/7 if allergic to penicillin.

• Anti-inflammatory therapy: Mild/no carditis: Oral aspirin 80-100mg/kg/day in 4 doses fr 2-4 weeks, tapering over 4 weeks.

Pericarditis, or moderate to severe carditis :

Oral Prednisolone 2mg/kg/day in 2 divided doses for 2-4 weeks, taper with addition of aspirin as above.

• Anti-failure medications: Diuretics, ACE inhibitors, digoxin (to be used with caution).

Secondary Prophylaxis of Rheumatic Fever1

• IM Benzathine Penicillin 6 MU (<30 kg) or 1.2 MU (>30kg) every 3 to 4 weeks.

OR

• Oral Penicillin V 250mg BD

OR

• Oral Erythromycin 250mg BD if allergic to penicillin.

Duration of Prophylaxis1

• Until age 21 years or 5 years after last attack of ARF whichever was longer.

• Lifelong for patients with carditis and valvular involvement.


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References:

1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 38, Acute Rheumatic Failure; p.185-6.

2. RHDAustralia. Management of Rheumatic Heart Disease. Ch.5. 2nd Ed.


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FLUID & ELECTROLYTE MANAGEMENT

Fluid Management

Introduction

Fluid can be administered through parenteral or enteral (oral) route; however, enteral route should be used wherever possible. Fluids are given through parenteral route for resuscitation, maintenance of daily requirement, and replacement of fluid deficit or abnormal losses such as severe dehydration due to excessive vomiting.

Resuscitation

Fluid boluses of 10-20ml/kg should be used during resuscitation to restore circulation. Repeated fluid boluses may be necessary to correct the hypovolemia after re-assessment. Crystalloids (normal saline, Ringer’s Lactate, Hartmann’s solution) and colloids (albumin, gelatin, and blood) can be used during fluid resuscitation. The volume and choice of fluid should be appropriate to patient’s cause of circulatory collapse. If patient’s blood glucose is low, 2ml/kg of 10% dextrose solution can be given1.

Maintenance

Maintenance fluid is the volume of fluid required daily to replace the ongoing losses, including both sensible (urine and stool) and insensible losses (evaporative and respiratory). Children experience greater fluid loss because children have larger body surface area and higher metabolic and respiratory rate compared to adult; thus requiring higher maintenance fluid2. Clinical conditions and illnesses (eg. meningitis, pneumonia. fever, burn or diarrhea) may affect the fluid loss; therefore the requirement should be individualized. Holliday-Segar method is very commonly used for calculating maintenance fluid requirement and estimating the infusion rate (ml/hour) in children. It is however, only applicable to children above 2 weeks old3.


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Ideal body weight should be used for calculating maintenance fluid requirement for obese or overweight patients.

Deficit

Deficit fluid is the volume of fluid that is loss before medical intervention, for instance the fluid loss in patient with diarrhea, vomiting and significant blood loss. Deficit fluid is usually administered over a period of time depending on clinical condition; however, generally the total volume is administered over the first 24 hours of hospitalization. Isotonic solution (eg. 0.9% normal saline) should be given in replacement of deficit.

Total deficit volume to be replaced (ml) = Weight (kg) x degree of dehydration (%) x 10

Infusion rate/hour = Total deficit volume to be replaced / hour of infusion

Monitor daily electrolytes, fluid input and output and weight (if feasible) for all children on IV fluids.

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FLUID & ELECTROLYTE MANAGEMENT Fluid Management

Introduction

Fluid can be administered through parenteral or enteral (oral) route; however, enteral route should be used wherever possible. Fluids are given through parenteral route for resuscitation, maintenance of daily requirement, and replacement of fluid deficit or abnormal losses such as severe dehydration due to excessive vomiting.

Resuscitation

Fluid boluses of 10-20ml/kg should be used during resuscitation to restore circulation. Repeated fluid boluses may be necessary to correct the hypovolemia after re-assessment. Crystalloids (normal saline, Ringer’s Lactate, Hartmann’s solution) and colloids (albumin, gelatin, and blood) can be used during fluid resuscitation. The volume and choice of fluid should be appropriate to patient’s cause of circulatory collapse. If patient’s blood glucose is low, 2ml/kg of 10% dextrose solution can be given1.

Maintenance

Maintenance fluid is the volume of fluid required daily to replace the ongoing losses, including both sensible (urine and stool) and insensible losses (evaporative and respiratory). Children experience greater fluid loss because children have larger body surface area and higher metabolic and respiratory rate compared to adult; thus requiring higher maintenance fluid2. Clinical conditions and illnesses (eg. meningitis, pneumonia. fever, burn or diarrhea) may affect the fluid loss; therefore the requirement should be individualized.

Holliday-Segar method is very commonly used for calculating maintenance fluid requirement and estimating the infusion rate (ml/hour) in children. It is however, only applicable to children above 2 weeks old3.

Table 1: Calculation of maintenance fluid requirement and infusion rate, Holliday-Segar method3.

Weight Total fluids requirement Infusion rate First 10kg 100 ml/kg 4 ml/kg/hour Subsequent 10kg 50 ml/kg 2 ml/kg/hour All additional kg 20 ml/kg 1 ml/kg/hour

Ideal body weight should be used for calculating maintenance fluid requirement for obese or overweight patients.

Deficit

Deficit fluid is the volume of fluid that is loss before medical intervention, for instance the fluid loss in patient with diarrhea, vomiting and significant blood loss. Deficit fluid is usually administered over a period of time depending on clinical condition; however, generally the


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total volume is administered over the first 24 hours of hospitalization. Isotonic solution (eg. 0.9% normal saline) should be given in replacement of deficit.

Total deficit volume to be replaced (ml) = Weight (kg) x degree of dehydration (%) x 10

Infusion rate/hour = Total deficit volume to be replaced / hour of infusion

Monitor daily electrolytes, fluid input and output and weight (if feasible) for all children on IV fluids.

Table 2: Commonly used intravenous fluids4,5

Fluid Na+ (mmol/l)

Cl- (mmol/l) kcal/l Osmolality

(mOsm/l)

Tonicity (with

reference to cell

membrane)

Uses

Dextrose 5% - - 200 278 Hypotonic Maintenance

Dextrose 10% - - 400 555 Hypotonic Hypoglycemia correction

Hartmann’s solution 131 111 0 278 Isotonic

Initial resuscitation

and used intra- and

post-operatively

0.45% NaCl 77 77 0 154 Hypotonic Maintenance

0.9% NaCl 150 150 0 308 Isotonic

Initial resuscitation

and maintenance

3% NaCl 513 513 0 1026 Hypertonic Sodium replacement

0.18% NaCl with 4.23% Glucose

31 31 170 296 Hypotonic Maintenance

0.18% NaCl with 10% Glucose





150 150 200 585 Isotonic Maintenance

Electrolyte Management

Table 3: Normal range and daily requirement of electrolytes6.

Electrolytes Normal range Daily requirement Sodium 135-145 mmol/l 2-5 mmol/kg/day

Potassium 3.5-5.0 mmol/ l 2-4 mmol/kg/day Calcium 2.1-2.6 mmol/l 0.25-2 mmol/kg/day


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Management of Common Electrolyte Abnormalities

• Hyponatremia

Hyponatremia is defined as serum sodium < 135mmol/l, which can be due to severe dehydration or dilutional from fluid overload. Signs and symptoms of hyponatremia include headache, nausea/vomiting, lethargy, and neurological involvement such as altered consciousness and seizure. Encephalopathy is a very serious complication of hyponatremia, which can cause poor neurological outcome and even death if not detected early and treated promptly and adequately. A bolus of 4 ml/kg of 3% sodium chloride administered over 15-30 minutes will raise the serum sodium by 3 mmol/l and usually could cease the hyponatremic seizure. Subsequent 3% saline boluses may be required if there are ongoing seizures or persistent hyponatremia7. Thereafter, sodium should be corrected gradually at a rate of not more than 8 mmol/l over 24 hours because rapid correction may cause irreversible cerebral demyelination8.

Sodium required for correction in acute hyponatremia (mmol)9

= (Desired serum Na – present Na level) x 0.6 x weight(kg)

Depending on the hydration status of the child, 0.9% sodium chloride and 3% sodium chloride solutions can be used for sodium correction. Hyponatremia without symptom can be treated with enteral fluids or 0.9% sodium chloride. Frequent serum sodium should be checked (every 1-2 hours) until patient is stable, subsequently every 4-6 hours until serum sodium normalize.

Electrolyte Management

Table 3: Normal range and daily requirement of electrolytes6.

Electrolytes Normal range Daily requirement

Sodium 135-145 mmol/l 2-5 mmol/kg/day

Potassium 3.5-5.0 mmol/ l 2-4 mmol/kg/day

Calcium 2.1-2.6 mmol/l 0.25-2 mmol/kg/day

Magnesium 0.75-1.1 mmol/l 0.15-0.25 mmol/kg/day

Phosphate 1.3-2.3 mmol/l 0.5-2 mmol/kg/day


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• Hypernatremia

Hypernatremia is defined as serum sodium > 145 mmol/l, which can be due to water loss in excess of sodium, water deficit or excess sodium gain. Symptoms usually occur when there is severe hypernatremia, that is when the serum Na+ > 160 mmol/l. Signs and symptoms include nausea/vomiting, irritability, restlessness, lethargy, anorexia, tremor, and may also lead to subarachnoid hemorrhage and coma. Management will depend on severity and the cause of hypernatremia. Lowering sodium slowly at a rate not more than 0.5 mmol/l/hr because rapid correction can cause cerebral edema, convulsion, and death. However, for patient in shock, resuscitation with 20ml/kg of 0.9% sodium chloride boluses is required7. In contrast, if the hypernatremia is caused by water deficit due to central diabetes insipidus, vasopressin can be used. Monitor the serum sodium every 6 hours until patient stabilize.

• Hypokalemia

Hypokalemia is defined as serum potassium < 3.5mmol/l. Signs and symptoms of hypokalemia include generalized muscle weakness, paralytic ileus, cardiac arrhythmias, ECG changes, confusion, and impaired respiratory function. The common causes of hypokalemia are excess loss from renal or gastrointestinal tract; other causes include diabetic ketoacidosis, sepsis, and iatrogenic. Identify and treat the underlying cause, and correct hypokalemia in patient with serum potassium < 3.0mmol/l or clinically symptomatic patient with potassium < 3.4 mmol/l, either using potassium chloride (oral or IV infusion) or IV potassium dihydrogen phosphate

Table 4: Potassium chloride administration10,11

Preferred Maximum

Concentration ofinfusion

40mmol/l 60-80 mmol/l (peripheral)*200mmol/l (central)*

Rate of infusion< 0.2 mmol/kg/hr

(peripheral)< 0.4 mmol/kg/hr (central)

1 mmol/kg/hr*

Footnote - * Infusion at concentration and rate higher than the preferred range should be used only after discussion with specialist / senior medical staff and in intensive care setting


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• Hyperkalemia

Hyperkalemia is defined as serum potassium > 5.5mmol/l. Hyperkalemia may be presented with muscles weakness, ileus, paresthesia or palpitation. Causes are dehydration, acute renal failure, diabetic ketoacidosis, hypoaldosteronism, tumour lysis syndrome and atrogenic. Underlying cause need to be identified and treated accordingly.

Table 5: Drugs used in treatment of hyperkalemia1,7,12

Drugs Dosage Onset Duration

Nebulizedsalbutamol

≤ 2.5 yrs : 2.5mg;2.5-7.5 yrs: 5mg;>7.5 yrs: 10mg

30 mins 2-3 hrs

IV calciumgluconate

0.5-1.0 ml/kg (max 20 ml)(1:1 dilution) over 5-15 mins <3 mins ~30 mins

IV 8.4% sodiumbicarbonate

1ml/kg (1:1 dilution) over10-30 mins 30-60 mins 2-3 hrs

PO/PR calciumpolystyrenesulphonate

0.25g/kg (max 10g/dose) 4times /day

4-6 hrs (PO),1hr (PR)

variable

IV dextrose 0.5g/kg (2mls/kg of 25%)over 15-30 mins

IV insulin shortaction

0.1 unit/kg

15 minspeak 60 mins,

2-3 hrs


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Algorithm 1: Hyperkalemia treatment1

Hyperkalemia (K+.5.5 mmol/l)

Stop all K+ Supplementation

Stop medications causing hyperkalemia

Exclude pseudo hyperkalemia

Recheck with venous sample

Child unstableor symptomatic

Discuss for dialysis

IV Calcium (0.1 mmol/kg)

IV Bicarbonate (1-2mmol/kg)

Neb Salbutamol( <2.5 yrs; 2.5-7.5 yrs:5mg; >7.5yrs: 10mg)

+ IV Bicarbonate if acidosis

+ PR/PO Resonium

IV Insulin with glucose + Neb Salbutamol

Discuss for dialysis Discuss for dialysis

Abnormal

K+> 7 mmol/l K+> 6, < 7 mmol/l

Normal ECG Normal ECG

Child stable asymptomatic

Child stable asymptomatic

Cardiac monitoring

K+> 5.5, < 6 mmol/l

+ PR/PO Resonium

+ IV Bicarbonate if acidosis

References:

1. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 3, Paediatric Fluid and Electrolyte Guidelines; p.19-26.

2. Muhammad Ismail HI, Ng HP, Thomas T, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia; 2013. Chapter 60, Acute Kidney Injury; p.285-291.

3. Meyers R. Pediatric fluid and electrolyte therapy. The Journal of Pediatric Pharmacology and Therapeutics 2009 Oct-Dec; 14(4):204-211


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4. Holliday MA, Segar WE. The maintenance need for water in parenteral fluid therapy. Pediatrics 1957;19:823-832

5. Terris M, Crean P. Fluid and electrolyte balance in children. Anaesthesia and intensive care medicine. Elsevier. 2011; 13(1): 15-19

6. Product labels:

a) INFUSOL® D5. Ain Medicare Sdn. Bhd.

b) INFUSOL® D10. Ain Medicare Sdn. Bhd

c) INFUSOL® HM. Ain Medicare Sdn. Bhd.

d) INFUSOL® HS. Ain Medicare Sdn. Bhd.

e) INFUSOL® NS. Ain Medicare Sdn. Bhd.

f) INFUSOL® S3. Ain Medicare Sdn. Bhd.

g) INFUSOL® QSD10. Ain Medicare Sdn. Bhd.

h) INFUSOL® QSD10. Ain Medicare Sdn. Bhd.

i) 0.45% Sodium Chloride And 5% Glucose Intravenous Infusion

B.P. B. Braun Medical Industries S/B.

j) INFUSOL® NSD5. Ain Medicare Sdn. Bhd.

7. The ASPEN Nutrition Support Manual, 2nd Edition, American Society for Parenteral and Enteral Nutrition; 2005.

8. Clinical practice guidelines: Intravenous fluids. The Royal Children’s Hospital Melbourne, Australia.

9. Sterns RH, Nigwekar SU, Hix JK. The treatment of hyponatremia. Seminars in Nephrology. 2009; 29:282–299

10. Farrell C, Del Rio M. Hyponatremia. Pediatrics in Review. 2007; 28:426-428.

11. Micromedex Healthcare Series. DRUGDEX System. Truven Health Analytics Inc. Vol. 163

12. Paediatric Formulary Committee. British National Formulary for Children 2011-2012. London and Chicago: BMJ Pub. Group, RPS Pub., RCPCH Pub.; 2011.


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Introduction

Critically ill children have a high risk of malnutrition because of stress-induced changes in intermediary metabolism; these changes are characterized by an increased basal metabolic rate and intensive protein catabolism. In general, the development or perpetuation of malnutrition during hospitalization in the paediatric intensive care unit (PICU) is due to illness, unknown nutrition condition, and an inadequate supply of nutrients. In these patients, malnutrition is associated with physiological instability. As a result, more intensive clinical care is required, and the mortality rate is high4.

Nutrition therapy is indicated when a patient is unable to receive calories and nutrients orally for a long period of time. Enteral nutrition (EN) is preferred because it is more physiologic, promotes intestinal trophism, stimulates the immune system, and reduces the incidence of bacterial translocation and sepsis. However, when it is impossible to use the digestive tract, parenteral nutrition (PN) is the only alternative for ensuring an adequate supply of nutrients during hospitalization. The combination of EN and PN may be useful for the first 72 hours of intensive clinical car or when EN alone is not sufficient to meet the nutrition demands of the patient4.

Recommendation from ASPEN for nutrition support of the critically ill child is list in Table 1. While Table 2 – 9 are the total daily requirement for paediatric.

Complications of PN

Complications may be considered in 3 groups: central venous catheter (CVC) related stability of the PN solutions and interactions with added drugs, metabolic or nutritional and other organ systems.

CVC related complications include infection, occlusion, central venous thrombosis, pulmonary embolism and accidental removal or damage1. Metabolic or nutritional complications include deficiency or excess of individual PN components including electrolytes, mineral, glucose, essential fatty acids, vitamin, trace element and the presence of contaminants1.

NUTRITION IN CRITICALLY ILL PATIENTS


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Other organ systems may be affected by the PN solutions, the underlying disease process or both. Complications include hepatobiliary disease, metabolic bone disease and growth impairment, some of which may be life threatening and raise the need for other therapeutic interventions such as non-transplant surgery or small bowel and liver transplantation1.

Monitoring of PNSevere investigations are required such as full blood count, renal profile, dextrostix, liver function test and lipid profile to monitor the complications of PN.


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Table 1: ASPEN guidelines: Nutrition Support of the Critically Ill Child 20092.

Aspect Guideline recommendations Grade

Nutrition assessment

Children admitted with critical illness should undergo nutrition screening to identify those with existing malnutrition and those who are nutritionally-at-risk

D

A formal nutrition assessment with the development of a nutrition care plan should be required, especially in those children with premorbid malnutrition

E

Energy requirement

Energy expenditure should be assessed throughout the course of illness to determine the energy needs of critically ill children. Estimates of energy expenditure using available standard equations are often unreliable.

D

IN a subgroup of patients with suspected metabolic alterations or malnutrition, accurate measurement of energy expenditure using indirect calorimetry (IC) is desirable. If IC is not feasible or not available, initial energy provision may be based on published formulas or namograms. Attention to imbalance between energy intake and expenditure will help to prevent overfeeding and underfeeding in this population.

E

Macronutrient intake during critical illness

There are insufficient data o make evidence-based recommendations for macronutrient intake in critically ill children. After determination of energy needs for critically ill child, the rational partitioning of the major substrates should be based upon understanding of protein metabolism and carbohydrate- and lipid- handling during critical illness

E

Route of nutrient intake (enteral

nutrition)

In critically ill children with a functioning gastrointestinal tract, enteral nutrition (EN) should be the preferred mode of nutrient provision, if tolerated.

C

A variety of barriers to EN exist in the paediatric intensive care unit (PICU), clinicians must identify and prevent avoidable interruptions to EN in critically ill children.

D

There are insufficient data to recommend the appropriate site (gastric vs post-pyloric/transpyloric) for enteral feeding in critically ill children. Post-pyloric or transpyloric feeding may improve caloric intake when compared to gastric feeds. Post-pyloric feeding may be considered in children at high risk of aspiration or those who have failed a trail of gastric feeding.

C

Immunonutrition in the PICU

Based on the available paediatric data, the routine use of immunonutrition or immune-enhancing diets/nutrients in critically ill children is not recommended.

D

Nutrition support team and feeding

protocols

A specialized nutrition support team in the PICU and aggressive feeding protocols may enhance the overall delivery of nutrition, with shorter time to goal nutrition, increased delivery of EN, and decreased use of parenteral nutrition. The effect of these strategies on patient outcomes has not been demonstrated.

E


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Table 2: Total Daily Fluid Requirement1,3.

Weight Total daily fluid required (ml/kg/day) ASPEN ESPEN

< 1.5kg 130 – 150 100 1.5-2kg 110 – 130

2-10kg 100 Subsequent 10kgs 50 50 All subsequent additional kgs 20 20

Table 3: Total Daily Energy Requirement1,3.

Age Total daily energy required (kcal/kg/day) ASPEN ESPEN

<6 months old 85 - 105 90 - 100 6-12 months old 80 - 100 1-7 years old 75 – 90 75 - 90 7-12 years old 50 – 75 60 - 75 > 12-18 years old 30 – 50 30 - 60

Table 4: Total Daily Protein Requirement1,3.

Age Total daily protein required (g/kg/day) ASPEN ESPEN

Infants 2 – 3 1 - 2.5 Child 1-3 years old 1 – 2 Child 3-10 years old 1 - 2 Adolescent 11-17 years old 0.8 - 1.5

Table 5: Total Daily Lipid Requirement1.

Age Total daily lipid required

(g/kg/day) ESPEN

Infants 3 Child 1-10 years old 2 – 3 Child >10 years old 1 - 2.5

Table 6: Total Daily Carbohydrate Requirement1.

Age Total daily carbohydrate

required (mg/kg/min) ESPEN

Infants 10 – 12 Child 1-10 years old 8 – 10 Child >10 years old 5 – 6


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Table 7: Total Daily Electrolyte and Mineral Requirement1,3.

Electrolyte ASPEN (mmol/kg/day) ESPEN (mmol/kg/day)

Infants/children Adolescent / child >50kg Infants Child >1

years old Sodium 2 - 5 1 – 2 2 – 3 1 - 3

Potassium 2 - 4 1 – 2 1 – 3 1 - 3

Calcium 0.25 - 2 5 - 10 0-6

months old: 0.8

7-12 months old: 0.5

0.2

Phosphorus 0.5 - 2 10 - 40 0.5 0.2 Magnesium 0.15 - 0.25 5 - 15 0.2 0.1

Acetate As needed to maintain acid-base balance

As needed to maintain acid-base balance

Chloride As needed to maintain acid-base balance

As needed to maintain acid-base balance

Table 8: Total Daily Trace Elemental Requirement1,3.

Trace elemental

ASPEN ESPEN

Infants (mcg/kg/day)

Children (mcg/kg/day)

Adolescent or child >40kg

(per day)

Infants (mcg/kg/day)

Children (mcg/kg/day)

Zinc 50 - 250 50 - 125 2 - 5mg

<3 months

old: 250

>3 months

old: 100

50 (maximum 5mg/day)

Copper 20 5 - 20 200 - 500mcg 20 20

Manganese 1 1 40 - 100mcg 1

1 (maximum

50mcg/day)

Chromium 0.2 0.14 - 0.2 5 - 15mcg 0.2 0.2

(Maximum 5mcg/kg/day)

Selenium 2 1 - 2 40 - 60mcg 2 – 3 2 - 3


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Table 9: Total Daily Vitamin Requirement1,3.

Vitamin

ASPEN ESPEN

1-3 kg (dose/day)

> 3kg (dose/day)

Infants (dose/body weight/day)

Children (dose/day)

Vitamin A (mcg)*

450 690 150 – 300 150

Vitamin D (IU) 260 (6.5mcg) 400 (10mcg) 32 (0.8mcg) 400 (10mcg)

Vitamin E (mg)

4.1 (4.5IU) 6.3 (7IU) 2.8 - 3.5 (3.1-3.9IU)

7 (7.7IU)

Vitamin K (mcg)

130 200 10 200

Ascorbic acid (mg)

52 80 15 – 25 80

Thiamine (mg)

0.78 1.2 0.35 - 0.5 1.2

Riboflavin (mg)

0.91 1.4 0.15 - 0.2 1.4

Niacin (mg) 11.05 17 4 - 6.8 17 Pantothenic acid (mg)

3.25 5 1 – 2 5

Pyridoxine (mg)

0.65 1 0.15 – 2 1

B12 mcg) 0.65 1 0.3 1

Biotin (mcg) 13 20 5 – 8 20

Folic acid (mcg)

91 140 56 140

*1 mcg RE (retinol equivalent) = 1 mcg all-trans retinol =3.33 IU Vitamin A

REFERENCES:

1) Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. Guideline on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr. 2005;41(2):S1-S87

2) Mehta NM, Compher C, A.S.P.E.N Board of Directors. A.S.P.E.N. Clinical Guidelines: Nutrition Support of the Critically Ill Child. Journal of Parenteral and Enteral Nutrition. 2009;33(3):260-276.

3) Mirtallo J, Canada T, Johnson D, Kumpf V, Petersen C, Sacks G, Seres D, Guenter P. Safe Practices for Parenteral Nutrition. JPEN J Parenter Enteral Nutr. 2004;28(6):S39-S70.

4) Zamberlan P, Delgado AF, Leone C, Feferbaum R, Okay TS. Nutrition Therapy in a Pedaitric Intensive Care Unit: Indications, Monitoring and Complications. Journal of Parenteral and Enteral Nutrition. 2011;35(4):523-529

References :

1) Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R. Guideline on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). J Pediatr Gastroenterol Nutr. 2005;41(2):S1-S87

2) Mehta NM, Compher C, A.S.P.E.N Board of Directors. A.S.P.E.N. Clinical Guidelines: Nutrition Support of the Critically Ill Child. Journal of Parenteral and Enteral Nutrition. 2009;33(3):260-276.

3) Mirtallo J, Canada T, Johnson D, Kumpf V, Petersen C, Sacks G, Seres D, Guenter P. Safe Practices for Parenteral Nutrition. JPEN J Parenter Enteral Nutr. 2004;28(6):S39-S70.

4) Zamberlan P, Delgado AF, Leone C, Feferbaum R, Okay TS. Nutrition Therapy in a Pedaitric Intensive Care Unit: Indications, Monitoring and Complications. Journal of Parenteral and Enteral Nutrition. 2011;35(4):523-529


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Introduction

Shock is a physiologic state characterized by a significant, systemic reduction in tissue perfusion; resulting in decreased tissue oxygen delivery and diminished removal of harmful by-products of metabolism (eg, lactate). Children with compromised circulation must be identified promptly. Successful management requires rapid initiation of treatment (often before the cause of shock is apparent) and careful assessment of the response to each intervention. Specific therapy must be initiated as soon as the evaluation suggests a cause of shock. Most children will improve with fluid resuscitation. Those who do not must quickly receive more aggressive treatment. According to Paediatric Advanced Life Support (PALS) course, shock is further classified into the following stages: • Compensated shock – During compensated shock, the body’s homeostatic mechanisms rapidly compensate for diminished perfusion and systolic blood pressure is maintained within the normal range. Heart rate is initially increased. Signs of peripheral vasoconstriction (such as cool skin, decreased peripheral pulses, and oliguria) can be noted as perfusion becomes further compromised5. • Decompensated shock – During this stage, compensatory mechanisms are overwhelmed. Heart rate is markedly elevated and hypotension develops. Signs and symptoms of organ dysfunction (such as altered mental status as the result of poor brain perfusion) appear. Systolic blood pressure falls, although children who have lost as much as 30 to 35 percent of circulating blood volume can typically maintain normal systolic blood pressures. Once hypotension develops, the child’s condition usually deteriorates rapidly to cardiovascular collapse and cardiac arrest5. • Irreversible shock – During this stage, progressive end-organ dysfunction leads to irreversible organ damage and death. Tachycardia may be replaced by bradycardia and blood pressure becomes very low. The process is often irreversible, despite resuscitative efforts5. In addition to these stages of shock, three broad mechanisms of shock are recognized: hypovolemic, distributive, and cardiogenic. Each type is characterized

Shock Management


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Disease management

Initial management should focus on fluid resuscitation with isotonic crystalloid solution and specific pharmacologic therapies as indicated once the aetiology of shock is identified. The following algorithm for initiating and re-evaluating therapy once shock is recognized has been adapted from consensus recommendations for the management of septic shock in children which were based primarily upon evidence extrapolated from adult studies5.

by one primary physiologic derangement in table 1.

However, a patient may have more than one type of shock (such as an infant with cardiogenic shock from supraventricular tachycardia who is also hypovolemic because he has been unable to drink or a child with underlying cardiomyopathy who is septic)5.

90

Table 1: Hemodynamic profiles of the types of shock5. Physiologic

variable Preload Pump function Afterload Tissue

perfusion

Examples Clinical measurement

Pulmonary capillary wedge

pressure

Cardiac Output

Systemic vascular

resistance

Mixed venous oxygen

saturation

Hypovolemic ↓ ↓ ↑ ↓

haemorrhage, gastrointestinal losses, insensible losses (e.g., burns), or third spacing

Cardiogenic ↑ ↓ ↑ ↓ sepsis, anaphylaxis, or acute injury to the spinal cord or brain

Distributive ↓ or ↔ ↑ ↓ ↑

primary myocardial injury, arrhythmias, congenital heart disease, or acquired obstructive conditions (eg, pneumothorax, cardiac tamponade, or pulmonary embolism)

Disease management

Initial management should focus on fluid resuscitation with isotonic crystalloid solution and specific pharmacologic therapies as indicated once the aetiology of shock is identified. The following algorithm for initiating and re-evaluating therapy once shock is recognized has been adapted from consensus recommendations for the management of septic shock in children which were based primarily upon evidence extrapolated from adult studies5.

Vasoactive agents may be useful for children with shock (other than hypovolemic shock) who have not improved with initial fluid resuscitation. These agents have effects on myocardial contractility, heart rate, and vasculature that can improve cardiac output. Initiation of vasoactive agents prior to or in place of adequately fluid resuscitating the patient, regardless of the etiology of shock, may lead to end-organ ischemia. Furthermore, these agents should be avoided in children with hypovolemic shock5.

Drugs that are typically used during the initial management of children with shock include dopamine , epinephrine , norepinephrine, dobutamine , and phosphodiesterase enzyme inhibitors. The choice of agent depends on the pathophysiologic parameters that must be manipulated5.


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Vasoactive agents may be useful for children with shock (other than hypovolemic shock) who have not improved with initial fluid resuscitation. These agents have effects on myocardial contractility, heart rate, and vasculature that can improve cardiac output. Initiation of vasoactive agents prior to or in place of adequately fluid resuscitating the patient, regardless of the etiology of shock, may lead to end-organ ischemia. Furthermore, these agents should be avoided in children with hypovolemic shock5.

Drugs that are typically used during the initial management of children with shock include dopamine , epinephrine , norepinephrine, dobutamine , and phosphodiesterase enzyme inhibitors. The choice of agent depends on the pathophysiologic parameters that must be manipulated5.

FIGURE 1: Algorithm for time sensitive, goal-directed stepwise management of hemodynamic support in infants and children. Proceed to next step if shock persists. 1) First hour goals—Restore and maintain heart rate thresholds, capillary refill ≤ 2 sec, and normal blood pressure in the first hour/emergency department. Support oxygenation and ventilation as appropriate. 2) Subsequent intensive care unit goals—If shock is not reversed, intervene to restore and maintain normal perfusion pressure (mean arterial pressure [MAP]-central venous pressure [CVP]) for age, central venous O2 saturation >70%, and CI >3.3, <6.0 L/min/m2 in pediatric intensive care unit (PICU). Hgb, hemoglobin; PICCO, pulse contour cardiac output; FATD, femoral arterial thermodilution; ECMO, extracorporeal membrane oxygenation; CI, cardiac index; CRRT, continuous renal replacement therapy; IV, intravenous; IO, interosseous; IM, intramuscular1.


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92

Tabl

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Inot

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s &

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opre

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espo

nd to

dop

amin

e, p

artic

ular

ly th

ose

with

sep

tic s

hock

and

incr

ease

d S

VR

(col

d

sho

ck).

Nor

epin

ephr

ine

0.01

-1m

cg/k

g/m

in

β1 a

goni

st <

α

agon

ist

Incr

ease

S

ome

incr

ease

N

o ef

fect

In

crea

se

Sig

nific

ant

incr

ease

M

inim

al

incr

ease

N

otes

: Lik

e ep

inep

hrin

e, n

orep

inep

hrin

e st

imul

ates

the

hear

t and

cau

ses

vaso

cons

trict

ion.

Vas

ocon

stric

tive

effe

cts

are

usua

lly g

reat

er

th

an th

e ef

fect

s on

con

tract

ility

and

hea

rt ra

te. I

t can

be

used

for c

hild

ren

who

do

not r

espo

nd to

dop

amin

e an

d is

pre

ferr

ed o

ver

epin

ephr

ine

by s

ome

expe

rts fo

r tho

se p

atie

nts

with

sep

sis

and

decr

ease

d S

VR

(war

m s

hock

).

Milr

inon

e 0.

1-1m

cg/k

g/m

in

Pho

spho

dies

tera

se

inhi

bito

r N

o ch

ange

In

crea

se

Impr

oves

M

inic

al In

crea

se

Dec

reas

e D

ecre

ase

Not

es: P

hosp

hodi

este

rase

enz

yme

inhi

bito

rs (i

e, m

ilrin

one

) im

prov

e ca

rdia

c co

ntra

ctili

ty a

nd re

duce

afte

rload

. The

y m

ay b

e us

ed to

trea

t

card

ioge

nic

shoc

k.

Vaso

pres

sors

N

eosy

neph

rine

0.1-

2 m

cg/k

g/m

in

Pur

e α

agon

ist

No

effe

ct

No

effe

ct

No

effe

ct

No

effe

ct

Sig

nific

ant

incr

ease

N

o ef

fect

Vas

opre

ssin

0.

0003

-0.0

08

mcg

/kg/

min

V

rece

ptor

ago

nist

N

o ef

fect

N

o ef

fect

N

o ef

fect

N

o ef

fect

S

igni

fican

t in

crea

se

Effe

ct

unkn

own


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Children can effectively compensate for circulatory dysfunction (primarily by increasing heart rate, systemic vascular resistance, and venous tone), maintaining normal blood pressures despite significantly compromised tissue perfusion. Consequently, hypotension is a very late and ominous finding. The challenge for the clinician is to recognize children in shock early (before they develop hypotension), when they are more likely to respond favorably to treatment5.

Paediatric inotropic therapy has been furnished with some new understanding of older agents, and new ways of using them. Some agents are gaining an evidence base, whilst even newer agents need such a base. Guidelines are emerging to facilitate their use2.

Table 3: Shock & Inotropes3

Shock Infusions to consider Comments

Septic

Early or warm • Dopamine • Norepinephrine

• Decreased SVR • Increase CO

Late or cold • Dopamine • Epinephrine • Vasopressin

• Increased SVR • Decrease CO • ? Decrease in

vasopressin levels Cardiogenic

Normotensive • Milrinone • Dobutamine

• Increased SVR • Decerase CO

Hypotensive • Epinehrine • Slow addition of Milrinone

once BPs improved

• Increased SVR • Decrease CO

Hypovolemic • Dopamine • Epinephrine

• Increased SVR • Decreased CO

Obstructive • Dopamine • Epinephrine • Milrinone

• Increased SVR • Decreased CO

Distributive • Neosynephrine • Decreased SVR • Normal CO


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References:

1. Brierley J, Carcillo J.A., Choong K, Cornell T, DeCaen A, Deymann A, et al. Clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the American College of Critical Care Medicine. Crit Care Med, 2009: Vol. 37, No. 2: 666-688.

2. Clifford M. Inotropes in Children. Australasian Anaesthesia. 2005;pg 129-134

3. Kache S. Sanford PICU Rotation Guide. [Internet]. Stanford School of Medicine.

Available from: http://peds.stanford.edu/Rotations/picu/pdfs/15_inotropes_ tables.pdf accessed 08/09/2014

4. Waltzman M. Initial management of shock in children. Up to date, 2013 [updated 2013 Apr 4]. Available from http://www.uptodate.com/contents/ initial-management-of-shock-in-children

5. Waltzman M. Initial evaluation of shock in children. Up to date, 2013 [updated: 2013 Jan 7]. Available from http://www.uptodate.com/contents/initial- evaluation-of--shock-in-children.`


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Introduction

Neuromuscular blocking agents (NMBAs) are used in critically ill children for a variety of reasons. The main indications for the use of NMBAs are based on the optimization of immobility of the patient for procedures like:

• Short term (less than 6 hours)

1. Tracheal intubation

2. High-risk invasive procedures

• Long term (more than 6 hours)

1. Synchrony with mechanical ventilation (dyssynchrony, excessive hyperventilation or hypoventilation, nonconventional ventilation)

2. Reduction of metabolic demand or work of breathing

3. Treatment of intense agitation unresponsive to higher doses of analgesia and sedation

4. Therapeutic hypothermia (decreased shivering)

5. Protection of surgical repairs

It is important to remember that in all these indications, the use of NMBAs should be considered in patients that deep sedation & analgesia have failed to reach the desired effect1,2,5. The choice of the best NMBA becomes very difficult and dependent on the degree and necessity of the muscular relaxation desired. Neuromuscular blocking agents

Neuromuscular Blockade


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1) Depolarizing NMBAs

a. Succinylcholine

Succinylcholine is the only depolarizing NMBA in clinical use. It produces the most rapid onset and ultra-short duration of neuromuscular block. Succinylcholine can cause tachycardia, bradycardia, increase in intraocular pressure, hyperkalaemia, myoglobinaemia, malignant hyperthermia, and even fatal hyperkalaemia cardiac arrests. Therefore, succinylcholine is restricted to emergency endotracheal intubation and instances where immediate securing of the airway such as laryngospasm, difficult airway and full stomach1,2,4,5.

2) Non-depolarizing NMBAs

a. Benzylquinolium e.g. atracurium & cisatracurium

• Atracurium

Atracurium is a bisquaternary benzylquinolinium diester with an intermediate duration of clinical action. The adverse effect associated with atracurium relate mainly to histamine release such as macular rash, erythema, hypotension, tachycardia or bronchospasm. Another adverse effect of atracurium is dose-related cardiovascular changes. Long term infusions have been associated with the development of tolerance, necessitating dose increment1,2,5.

• Cisatracurium

Cisatracurium is an isomer of atracurium. Like atracurium, it is an intermediate duration NMBAs. The potency of cisatracurium is about 3 times that of atracurium. Increase potency is associated with slower onset of action which necessitates a relative high dose to achieve reliable intubating conditions at 2 minutes. Cisatracurium has less propensity for histamine release and provides greater cardiovascular stability compared to atracurium2.


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b. Aminosteroidal compounds e.g. pancuronium, vecuronium & rocuronium

• Pancuronium

Pancuronium is a potent, long-acting, bisquaternary aminosteroid NMBAs which has vagolytic effect (increase in heart rate of 30-40% and systolic blood pressure of 10-15%). This vagolytic effect may be an advantage in infants, in whom bradycardia is highly undesirable, or patients undergoing anaesthesia with high-dose opiods, which tend to decrease heart rate and blood pressure. Patients with renal and liver impairment will have prolonged neuromuscular blockade due to accumulation of pancuronium and its active metabolite5.

• Vecuronium

Vecuronium is a monoquaternary derivative of pancuronium with greater selectivity of pharmacological profile, a shorter duration of action, less vagolytic effect and less cumulative properties compared to pancuronium. Same as pancuronium, vecuronium will prolong the neuromuscular blockade in patients with renal or liver impairment. Vecuronium is clearly a long-acting NMBA in newborns and infants, in agreement with its increased residence time in younger patients1,2.

• Rocuronium

Rocuronium is a desacetoxy analogue of vecuronium with a more rapid onset of action. Rapid onset is the result of reduced potency, which necessitates an increase in dose. Rocuronium has minimal cardiovascular effect (tachycardia at high dose). Like vecuronium, rocuronium is longer acting in infants than in children; however, rocuronium still retains the characteristics of an intermediate-acting NMBA in infants. Same as vecuronium, rocuronium will prolong the neuromuscular blockade in patients with renal or liver impairment Rocuronium would be an acceptable alternative to succinylcholine for rapid sequence induction2.

The pharmacological properties and drug-drug interaction of the NMBAs are listed in Table 1 and Table 2.


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98

Tabl

e 1:

Sum

mar

y of

Pha

rmac

olog

ical

pro

pert

ies

of N

MB

As1,

2,5,

6,7 .

NM

BA

Su

ccin

ylch

olin

e A

trac

uriu

m

Cis

atra

curiu

m

Panc

uron

ium

Ve

curo

nium

R

ocur

oniu

m

Dos

e

Infa

nts

IM: 3

-4m

g/kg

/dos

e IV

: 2m

g/kg

/dos

e th

en m

aint

ain

by

0.3-

0.6m

g/kg

/dos

e ev

ery

5-10

min

as

need

ed

Chi

ldre

n >

1 ye

ar

old

& a

dole

scen

ts

IM: 3

-4m

g/kg

/dos

e IV

: 1m

g/kg

/dos

e th

en m

aint

ain

by

0.3-

0.6m

g/kg

/dos

e ev

ery

5-10

min

as

need

ed

Infa

nts

& c

hild

< 2

ye

ars

old

IV: 0

.3-0

.4

mg/

kg/d

ose

then

m

aint

ain

by 0

.3-

0.4m

g/kg

/dos

e;

repe

at d

oses

as

need

ed

Con

tinuo

us

infu

sion

: 10-

20m

cg/k

g/m

in

Chi

ld >

2 y

ears

old

&

ado

lesc

ents

IV

: 0.4

-0.

5mg/

kg/d

ose

then

0.0

8-0.

1 m

g/kg

/dos

e 20

-45

min

afte

r ini

tial

dose

; rep

eat a

s

need

ed a

t 15-

25

min

ute

inte

rval

s C

ontin

uous

in

fusi

on: I

nitia

l 9-

10m

cg/k

g/m

in th

en

mai

ntai

n by

5-

9mcg

/kg/

min

Infa

nts

& c

hild

<

2 ye

ars

old

IV:

0.15

mg/

kg/d

ose

C

ontin

uous

in

fusi

on: 1

-4m

cg/k

g/m

in

Chi

ld >

2 y

ears

ol

d &

ad

oles

cent

s IV

: 0.1

-0.

5mg/

kg/d

ose

Con

tinuo

us

infu

sion

: 1-

4mcg

/kg/

min

Infa

nts

IV: 0

.1m

g/kg

/dos

e ev

ery

30-6

0 m

in a

s ne

eded

C

ontin

uous

infu

sion

: 0.

4-0.

6mcg

/kg/

min

C

hild

ren

IV: 0

.15m

g/kg

/dos

e ev

ery

30-6

0 m

in a

s ne

eded

C

ontin

uous

infu

sion

: 0.

5-1.

7mcg

/kg/

min

A

dole

scen

ts &

adu

lts

IV: 0

.15m

g/kg

/dos

e ev

ery

30-6

0 m

in

Con

tinuo

us in

fusi

on:

0.4-

0.6m

cg/k

g/m

in

Infa

nts

IV:

0.1m

g/kg

/dos

e;

repe

at e

very

ho

ur a

s ne

eded

C

ontin

uous

in

fusi

on: 1

-1.

5mcg

/kg/

min

C

hild

> 1

yea

r ol

d &

ad

oles

cent

s IV

: 0.

1mg/

kg/d

ose;

re

peat

eve

ry

hour

as

need

ed

Con

tinuo

us

infu

sion

: 1.5

-2.

5mcg

/kg/

min

Rap

id

sequ

ence

in

tuba

tion

Chi

ldre

n &

ad

oles

cent

s 0.

6-1.

2mg/

kg/d

ose

Trac

heal

in

tuba

tion,

su

rgic

al

Infa

nts,

chi

ld,

adol

esce

nts

IV: 0

.45-

0.6m

g/kg

/dos

e in

itial

ly th

en

mai

ntai

n by

0.

075-

0.15

mg/

kg/d

ose;

re

peat

as

need

ed

Con

tinuo

us

infu

sion

: 7-

12m

cg/k

g/m

in,

use

the

low

er

end

of d

osin

g ra

nge

for i

nfan

ts

and

uppe

r end

fo

r chi

ldre

n >2

ye

ars

old.

O

nset

30

-60

sec

1-3

min

2-

3 m

in

2-4

min

1-

3 m

in

30-6

0 se

c


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99

NM

BA

Su

ccin

ylch

olin

e A

trac

uriu

m

Cis

atra

curiu

m

Panc

uron

ium

Ve

curo

nium

R

ocur

oniu

m

Dur

atio

n 4-

6 m

in

25-3

5 m

in

35-4

5 m

in

90-1

00 m

in

35-4

5 m

in

25-4

0 m

in

Met

abol

ism

Rap

idly

hyd

roly

sed

by p

lasm

a ch

olin

este

rase

Hof

man

n el

imin

atio

n (p

H &

te

mpe

ratu

re) i

nto

laud

anos

ine

&

acry

late

Hof

man

n el

imin

atio

n (p

H &

te

mpe

ratu

re) i

nto

laud

anos

ine

&

acry

late

30-4

0% m

etab

oliz

ed

by li

ver i

nto

activ

e m

etab

olite

3-

hydr

oxyp

ancu

roni

um

40-5

0%

met

abol

ized

by

liver

into

3

activ

e m

etab

olite

s

50-6

0%

met

abol

ized

by

liver

Elim

inat

ion

10%

exc

rete

d as

un

chan

ged

drug

in

urin

e

<10%

exc

rete

d as

un

chan

ged

drug

in

urin

e

<10%

exc

rete

d as

unc

hang

ed

drug

in u

rine

40%

exc

rete

d as

un

chan

ged

drug

in

urin

e &

11%

exc

rete

d in

bile

50%

exc

rete

d in

bile

& 2

5%

excr

eted

as

unch

ange

d dr

ug in

urin

e

70%

exc

rete

d in

bi

le &

up

to 3

0%

excr

eted

as

unch

ange

d dr

ug

in u

rine

His

tam

ine

rele

ase

No

Yes

M

inim

um

No

No

No


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Table 2: Drug Interactions affecting NMBAs.3,5,7.

Drug potentiating the action of NMBAs Drug antagonising the action of NMBAs

Aminoglycosides Calcium channel blocker

Clindamycin Colistimethate sodium Corticosteroid (prolonged coadministration)N

CyclophosphamideS

Cyclosporine Frusemide (0.1-10mcg/kg)B

Lignocaine Lithium carbonate Magnesium MetoclopramideS

Polymyxin B Procainamide Quinidine Quinine SpironolactoneN Tetracycline Vancomycin

Frusemide (1-4mg/kg)B

CarbamazepineN

CorticosteroidN PhenytoinN TheophyllineA

S Succinylcholine only N Non-depolarizing NMBAs only A Aminosteroid NMBAs only (eg rocuronium, pancuronium & vecuronium) B Succinylcholine & aminosteroid NMBAs only

Monitoring of NMBAs

Many factors can influence the depth of neuromuscular blockade such as acid-base derangement, electrolytes imbalance and drug-drug interaction. Therefore, all patients receiving NMBAs should be monitored both clinically and by train-of-four (TOF) monitoring to assess the degree of neuromuscular blockade.

The use of TOF monitoring in attempts to optimise the degree of neuromuscular blockade has been shown to reduce the total dose requirements of patients for NMBAs and allow faster recovery of neuromuscular function and spontaneous ventilation and allow cost savings5.

Complications of NMBAs

The major described complication is the prolonged muscle weakness after its discontinuation. This complication is well documented in children, generally with the use longer than 48 hours. This effect could last for up to 6 months. There are 2 patterns of neuromuscular dysfunction: the persistent block of the NM junction (PBNMJ) and the acute myopathy.

PBNMJ is probably due to accumulation of drugs or its active metabolites mainly in patients with renal or hepatic failure. Co-administration of aminosteroid NMBA and corticosteroid is significantly associated with PBNMJ. This drug-drug interaction is very important since one of the major indications of NMBAs in paediatric is the child with status asthmaticus with

S Succinylcholine onlyN Non-depolarizing NMBAs onlyA Aminosteroid NMBAs only (eg rocuronium, pancuronium & vecuronium)B Succinylcholine & aminosteroid NMBAs only


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Monitoring of NMBAs

Many factors can influence the depth of neuromuscular blockade such as acid-base derangement, electrolytes imbalance and drug-drug interaction. Therefore, all patients receiving NMBAs should be monitored both clinically and by train-of-four (TOF) monitoring to assess the degree of neuromuscular blockade.

The use of TOF monitoring in attempts to optimise the degree of neuromuscular blockade has been shown to reduce the total dose requirements of patients for NMBAs and allow faster recovery of neuromuscular function and spontaneous ventilation and allow cost savings5.

Complications of NMBAs The major described complication is the prolonged muscle weakness after its discontinuation. This complication is well documented in children, generally with the use longer than 48 hours. This effect could last for up to 6 months. There are 2 patterns of neuromuscular dysfunction: the persistent block of the NM junction (PBNMJ) and the acute myopathy.

PBNMJ is probably due to accumulation of drugs or its active metabolites mainly in patients with renal or hepatic failure. Co-administration of aminosteroid NMBA and corticosteroid is significantly associated with PBNMJ. This drug-drug interaction is very important since one of the major indications of NMBAs in paediatric is the child with status asthmaticus with dyssynchrony with mechanical ventilation (and who uses short or long term corticosteroids). The acute myopathy also leads to prolonged paralysis, but is not caused by delayed recuperation of the neuromuscular junction1.

Muscular atrophy, joint contractures, thrombotic or embolic events, ulcers of the skin, atelectasis, pneumonia and corneal drying are other possible complications. Special attention should be given to the neurological assessment of patient with status epilepticus and receiving NMBAs as NMBAs can completely obscure many of the clinical manifestations of seizure activity1,5.


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Antagonism of NMBAs

Any residual neuromuscular block due to non-depolarizing NMBAs should be antagonised by an anticholinesterase. This is especially important in neonates and small infants because of their reduced respiratory reserve. The most commonly used anticholinesterases are neostigmine and edrophonium5. Sugammadex, a cyclodextrine which can reverse neuromuscular blockade that induced by aminosteroid NMBAs and its mechanism of action is differently than cholinesterase inhibitors4.

References :

1) Almeida JFL de, Filho WJK, Troster EJ. Neuromuscular Blockade in Children. Rev. Hosp. Clin. Fac. Med. S. Paulo.2000;55(3):105-110

2) Meakin GH. Neuromuscular blocking drugs in infants andchildren. Continuing Education in Anaesthesia. Critical Care & Pain. 2007;7(5):143-147

3) Micromedex® Healthcare Series. [Internet database]. Available from: Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc ; 2011. [cited 20/11/2014]

4) Owczarek M, Bultowicz R, Kazmirczuk R, Owczarek KS, Paciorek P, Jakubczyk M, Kupczyk K, Kusza K. Is suxamethonium still useful for paediatric anaesthesia? Anestezjol Intents Ter. 2011;44(3):181-185.

5) Playfor S. Nueromuscular Blocking Agents in Critically Ill Children. Paediatric and Perinatal Drug Therapy.2002; 5(1):35-46.

6) Shann F. Drug Doses, 16th Edition, Royal Children’s Hospital, Australia. 2014

7) Taketomo CK, Hodding JH, Kraus DM (Eds). Pediatric Dosage Handbook with International Trade Names Index. 17th ed. Ohio. Lexi-Comp Inc; 2010


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Introduction

Stress-related mucosal damage (SRMD) is the board term used to describe the spectrum of pathology attributed to the acute, erosive, inflammatory insult to the upper gastrointestinal tract associated with critical illness. SRMD represents a continuum from asymptomatic superficial lesions found incidentally during endoscopy, occult gastrointestinal bleeding causing anemia, overt gastrointestinal bleeding and clinically significant gastrointestinal bleeding.

Risk factors including:1,5

1) Coagulopathy2) Shock3) Surgery lasting for longer than 3 hours4) Trauma5) Pneumonia6) Peadiatric Risk of Mortality Score ≥ 107) Thermal injury

Prophylaxis agent for SRMD

Prophylaxis is recommended for SRMD, but there is insufficient evidence to recommend prophylaxis based on current trials on critically ill child1,5.

1) Sucralfate

Sucralfate acts by adhering to epithelial cells forming a physical cytoprotective barrier at the ulcer site, thereby protecting the gastric mucosa from the effects of acid and pepsin4.

Stress Ulcer Prophylaxis


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2) Histamine-2 receptor blockers (H2RBs)

H2RBs competitively inhibit histamine binding to its G-protein coupled receptor on the basolateral membrane of gastric parietal cells, which results in a reduction in acid production and an overall decrease in gastric secretions4.

3) Proton Pump Inhibitors (PPIs)

PPIs inactivate the H+/K+ ATPase enzyme at the secretory surface of the parietal cell, inhibiting the secretion of H+ ions and thereby increasing the pH of the gastric contents4.

The pharmacological properties and drug-drug interaction of the prophylaxis agents for SRMD are listed in Table 1.


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104

Tabl

e 1:

Sum

mar

y of

Pha

rmac

olog

ical

pro

pert

ies

of p

roph

ylax

is a

gent

s fo

r SR

MD

6,7 .

Age

nt

Sucr

alfa

te

His

tam

ine-

2 R

ecep

tor B

lock

ers

Prot

on P

ump

Inhi

bito

rs (P

PIs)

Ran

itidi

ne

Esom

epra

zole

La

nsop

razo

le

Om

epra

zole

Pa

ntop

razo

le

Dos

e

PO

: 0-

2 ye

ars

old:

25

0mg

q6h

3-12

yea

rs o

ld:

500m

g q6

h >1

2 ye

ars

old:

1g

q6h

PO

: 2-5

mg/

kg/d

ose

q8-1

2h

IV: 1

mg/

kg/d

ose

q6-8

h C

ontin

uous

infu

sion

: 2m

cg/k

g/m

in

PO

: 0.4

-0.

8mg/

kg/d

ose

daily

IV

: 0.4

-0.

8mg/

kg/d

ose

q24h

PO

: 1

year

s ol

d –

30kg

: 15m

g da

ily

>30k

g: 3

0mg

daily

PO

: 0.4

-0.

8mg/

kg/d

ose

q12-

24h

PO

: 1m

g/kg

q12

-24

h IV

: 1m

g/kg

q12

-24

h

Ons

et

1-2

hr

1 hr

-

- P

O: 1

hr

PO

: 2.5

hr

IV: 1

5-30

min

Dur

atio

n U

p to

6 h

r P

O: 4

-12

hr

- P

O: ≥

24

hr

PO

: 72

hr

PO

: 24

hr

IV: 2

4 hr

Met

abol

ism

Not

met

abol

ized

M

etab

oliz

ed b

y liv

er

Ext

ensi

vely

by

CY

P2C

19,

CY

P3A

3 &

C

YP

3A4

Ext

ensi

vely

by

CY

P2C

19 a

nd

CY

P3A

4

Ext

ensi

vely

by

CY

P2C

19 a

nd

CY

P3A

4

Ext

ensi

vely

by

CY

P2C

19 a

nd

CY

P3A

4

Elim

inat

ion

90%

exc

rete

d in

st

ool

Exc

rete

d 30

% (P

O) &

70

% (I

V) a

s un

chan

ged

drug

in

urin

e; fe

ces

as

met

abol

ite

80%

exc

rete

d as

in

activ

e m

etab

olite

in

urin

e; 2

0%

excr

eted

in fe

ces

67%

exc

rete

d in

fe

ces;

33%

ex

cret

ed in

urin

e

77%

exc

rete

d as

m

etab

olite

in u

rine

71%

exc

rete

d as

m

etab

olite

in u

rine;

18

% e

xcre

ted

in

fece

s

Dru

g In

tera

ctio

n

Dig

oxin

, fru

sem

ide,

ph

osph

ate

supp

lem

ent,

quin

idin

e,

quin

olon

e,

vita

min

D

anal

ogs,

vita

min

K

ant

agon

ists

,

Cef

urox

ime

Itrac

onaz

ole

Ket

ocon

azol

e P

rote

ase

inhi

bito

r

Fluc

onaz

ole

Itrac

onaz

ole

Ket

ocon

azol

e M

etho

trexa

te

Pro

teas

e In

hibi

tor

Vor

icon

azol

e

Fluc

onaz

ole

Itrac

onaz

ole

Ket

ocon

azol

e M

etho

trexa

te

Pro

teas

e In

hibi

tor

Vor

icon

azol

e

Fluc

onaz

ole

Itrac

onaz

ole

Ket

ocon

azol

e M

etho

trexa

te

Pro

teas

e In

hibi

tor

Vor

icon

azol

e

Fluc

onaz

ole

Itrac

onaz

ole

Ket

ocon

azol

e M

etho

trexa

te

Pro

teas

e In

hibi

tor

Vor

icon

azol

e


4.0

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Long-term and Serious Safety Concern with PPIs Use

Long-term inhibition of gastric acid secretion secretion leads to prolonged hypergastrinemia and concerns for enterochromaffin-like cell hyperplasia, carcinoid formation, vitamin B12 deficiency, hypomagnesemia, necrotizing enterocolitis, osteoporosis, atrophic gastritis, and increased infections. These concerns have been raised in adults, but paediatric studies are limited8.

Suppression of gastric acid secretion may predispose patients to certain infections (Clostridium difficile infections, other enteric infections and respiratory infections, including community-acquired pneumonias). The mechanism for this may be that acid suppression eliminates a defense against pathogens2.

References:

1. ASHP Board of Directors. ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. America: Am J Health-Syst Pharm; 1999. 33 p.

2. Chen LL, Gao WY, Johnson AP, Niak A, Troiani J, Korvick J, Snow N, Estes K, Taylor A, Griebel D. Proton Pump Inhibitors Use in Infants: FDA Reviewer Experience. JPGN. 2012;54(1):8-14

3. Micromedex® Heal thcare Ser ies. [ In ternet database] . Ava i lab le from:Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc ; 2011. [cited 25/3/2015]

4. Pummer MP, Blaser AR, Deane AM. Stress Ulceration: Prevalence, Pathology and Association with Adverse Outcomes. Critical Care. 2014;18:213

5. Reveiz L, Lozano RG, Camacho A, Yara L, Mosquera PA. Stress Ulcer, Gastritis, and Gastrointestinal Bleeding Prophylaxis in Criticlly Ill Pediatric: A Systematic Review. Pediatr Crit Care Med. 2010;11(1):124-132

6. Shann F. Drug Doses, 16th Edition, Royal Children’s Hospital, Australia. 2014

7. Taketomo CK, Hodding JH, Kraus DM (Eds). Pediatric Dosage Handbook with International Trade Names Index. 17th ed. Ohio. Lexi-Comp Inc; 2010

8. Ward RM, Kearns GL. Proton Pump Inhibitors in Pediatrics. Pediatr Drugs. 2013;15:119-131


4.0

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Introduction

The indications for sedation in the paediatric intensive care unit (PICU) patient are varied ranging from short term use for various procedures to prolonged administration to provide comfort during mechanical ventilation11.

Due to diversity among patients and the varied indications for sedative and analgesic drugs, it is not possible to provide a ‘cookbook’ of definite guidelines for sedation and analgesia. Sedative and analgesia agents should not be administered strictly on a per kilogram basis like other medications such as antibiotics. Dosage recommendations are meant as guidelines for starting doses. The actual amount administered should be titrated up or down to achieve the desired level of sedation or analgesia11.

Undersedation and oversedation are both harmful. Agitation and inadequate sedation have been correlated with adverse short- and longer-term outcomes. Recent data have highlighted the intensive care and surgery are associated with long-term dysregulation of nociceptive mechanisms, which may change behaviour and responses to future sensory and pain stimuli. By contrast, oversedation delays recovery promotes tolerance to the drugs and leads to distressing symptoms on withdrawal (agitation, seizures, hallucinations, psychosis, fever and tachycardia)12.

Opioids, in particular, are associated with dose-dependent immunosuppression of both humoral and cell-mediated immunity, which acts on promote infection and sepsis during a longer PICU stay12. Sedative Agents

• Benzodiazepine

Mechanism of action of benzodiazepine is through the facilitations in the CNS of the activity of the inhibitory neurotransmitter, Y-aminobutyric acid (GABA).Midazolam are the most commonly used benzodiazepine in PICUs8. Midazolam is a water-based acidic preparation; at plasma pH, it converts into an un-ionised form that crosses the blood-brain barrier rapidly. It has the shortest elimination half-life of the benzodiazepine group8.

SEDATION & PAIN MANAGEMENT


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Generally, midazolam is a safe and effective sedative agent if given as short- term infusion and it tends to accumulate if given as continuous infusion due to its high volume distribution and high lipophilicity4. Dose reduction is necessitating in patients with hepatic and/or renal dysfunction8,11.

The main adverse events associated with midazolam are tolerance, dependence and withdrawal following discontinuation7.

• Dexmedetomidine

Dexmedetomidine is a selective 2-adrenergic agonist and is structurally related to clonidine, but has a much greater affinity for æ2-receptors over æ2-receptors. It is extensively metabolized through the cytochrome P450 enzyme system, therefore dose reduction is recommended for patient with hepatic dysfunction2.

The most significant adverse reasons are hypotension and bradycardia, resulting from its sympatholytic activity. Both are rarely clinically significant or required intervention to correct. Transient hypertension has been reported with the administration of the loading dose due to initial vasoconstriction caused by stimulation of peripheral postsynaptic 2-adrenergic receptors. Management consists of slowing the infusion rate, but rarely is discontinuation of treatment necessary. Dexmedetomidine is recommended to be used with caution in patients with history of atrioventricular nodal block or severe ventricular dysfunction, as well as in hypovolemic patients or those with chronic hypertension2.

Although not well studied, abrupt cessation of dexmedetomidine may produce withdrawal symptoms. Slowly taper off the dose of dexmedetomidine may be useful to minimize the risk for withdrawal2.

• Ketamine

Ketamine is a dissociative anaesthetic agent, structurally similar to phencyclidine, which produces a cataleptic trance-like state by apparently producing an electrophysiological dissociation between the limbic and thalamoneocortical systems7.


4.0

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ICU

Ketamine produces a dose-related acceleration of heart rate and blood pressure thought to be caused by the release of endogenous catecholamines through its stimulatory effect on the sympathetic nervous system. The indirect sympathomometic effect of ketamine is assumed to dominate over its direct negative inotropic properties, therefore resulting in reduced risk of hypotension. In addition, respiratory function is well maintained with ketamine. Functional residual capacity, minute ventilation and tidal volume are unchanged, pulmonary compliance is improved and bronchospasms are relieved due to release of catecholamines6.

Although ketamine generally preserves airway patency, rare cases of pulmonary aspiration, apnea, arterial hypoxemia and laryngospasm have been reported. Ketamine is a potent sialagogue. It increases salivary and bronchial mucous gland secretions through stimulation of cholinergic receptors. Ketamine also increases intracranial pressure (ICP) and pulmonary vascular resistance. Therefore, is contraindicated for patients with pulmonary hypertension or at risk for elevated intracranial pressure6.

Emergency phenomena are a hallmark event for ketamine and have been described as vivid dream, hallucinations, floating sensations, delirium, recovery agitation and dysphoria. Benzodiazepines have been co- administrated with ketamine to reduce the frequency of emergency phenomena, however, it is controversial3,6.

• Propofol

Propofol is a unique sedative-hypnotic agent with a rapid onset and offset of action. Propofol also acts on the GABA receptor like benzodiazepine although the side of action on this receptor is different4. It offers the advantages of a quick onset of action, quick recovery once discontinued and lacks of active metabolites11.

In addition to its sedative and amnesia effects, propofol also decreases cerebral oxygen consumption and reduces intracranial pressure. It also shows excellent antiepileptic activities with proven efficacy in treating patients with refractory seizures11.

Propofol is a highly lipophilic compound and is essentially insoluble in water or other aqueous medium. Therefore, it is formulated as an intravenous emulsion with 10% lipid11. Propofol-related infusion syndrome is a rare but frequently fatal complication characterised by acidosis, bradyarrhythmia and rhabdomyolysis. It has been demonstrated that transient elevations in malonylcarnitine and C5-acylcarnitine occur during propofol-related infusion syndrome, suggesting that propofol impairs fatty acid oxidation and mitochondrial activity at the subcellular level8.


4.0

Pae

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110

Tabl

e 1:

Sum

mar

y of

pha

rmac

olog

ical

pro

pert

ies

of s

edat

ive

agen

ts5,

9,10

.

Age

nt

Mid

azol

am

Dex

med

etom

idin

e K

etam

ine

Prop

ofol

Dos

e

Sed

atio

n:

IV b

olus

/ IM

: 0.1

-0.

2mg/

kg/d

ose

(max

imum

dos

e: 0

.5m

g/kg

) In

fusi

on: 1

-4m

cg/k

g/m

in

ICU

: In

fusi

on: 0

.4m

cg/k

g/hr

P

roce

dure

: In

fusi

on: 0

.5-1

mcg

/kg/

min

ov

er 1

0-20

min

, the

n 0.

6 m

cg/k

g/hr

Ana

esth

esia

: IV

: 1-2

mg/

kg/d

ose

IM: 5

-10m

g/kg

/dos

e In

fusi

on: 1

0-40

mcg

/kg/

min

A

nalg

esia

: IV

: 1-1

.5m

g/kg

IM

: 3-4

mg/

kg

Infu

sion

: 2-6

mcg

/kg/

min

Ana

esth

esia

: IV

: 2.5

-3.5

mg/

kg s

tat,

then

7.

5-15

mg/

kg/h

r S

edat

ion:

IV

: 1-3

mg/

kg/h

r

Ons

et

IV: 1

-5 m

in

IM: <

5 m

in

IV: 3

0 m

in

Ana

esth

esia

: IV

: <30

sec

IM

: 3-4

min

A

nalg

esia

: IM

: 10-

15 m

in

IV: 1

0-50

sec

Max

imum

ef

fect

IV

: 5-7

min

IM

: 15-

30 m

in

- IM

: 15-

30 m

in

-

Dur

atio

n IV

: 20-

30 m

in

IM: 2

-6 h

r IV

: 4 h

r IM

: 2.5

hr

Ana

esth

esia

: IV

: 5-1

0 m

in

IM: 1

2-25

min

A

nalg

esia

: IM

: 15-

30 m

in

IV: 3

-10

min

Full

reco

very

M

ay ta

ke >

24 h

ours

-

IV: 1

-2 h

r IM

: 3-4

hr

-

Met

abol

ism

Ext

ensi

ve m

etab

oliz

e in

live

r vi

a C

YP

3A4.

P

rimar

y m

etab

olite

(á-

hydr

oxy-

mid

azol

am) i

s ac

tive

and

equi

pote

nt to

mid

azol

am

Met

abol

ize

in li

ver v

ia

CY

P2A

6 in

to in

activ

e m

etab

olite

s

Met

abol

ize

in li

ver v

ia

CY

P2B

6, C

YP

2C9

& C

YP

3A4

into

nor

keta

min

e (a

ctiv

e m

etab

olite

) and

its

pote

ncy

is

one

third

of t

he p

aren

t co

mpo

und.

Ext

ensi

ve in

live

r via

CY

P2B

6 in

to in

activ

e m

etab

olite

s

Elim

inat

ion

Urin

e:

63-8

0% e

xcre

ted

as á

-hy

drox

y-m

idaz

olam

; <1

% e

xcre

ted

as u

ncha

nged

dr

ug

Fece

s:

2-10

% a

s un

chan

ged

drug

Urin

e:

95%

Fe

ces:

4%

Urin

e:

Maj

ority

exc

rete

d as

inac

tive

met

abol

ite; 4

% e

xcre

ted

as

unch

ange

d dr

ug o

r no

rket

amin

e Fe

ces:

<5

%

Urin

e:

88%

exc

rete

d as

met

abol

ites;

<3

% e

xcre

d as

unc

hang

ed

drug

Fe

ces:

<2

%


4.0

P

AE

DIA

TRIC

ICU

111

Age

nt

Mid

azol

am

Dex

med

etom

idin

e K

etam

ine

Prop

ofol

A

mne

sia

Yes

Y

es

Yes

Y

es

Ana

lges

ia

No

Yes

Y

es

No

Dru

g in

tera

ctio

n

Con

train

dica

ted:

E

favi

renz

; Pro

teas

e in

hibi

tors

; In

crea

sed

effe

ct /

toxi

city

M

idaz

olam

may

incr

ease

the

leve

ls/e

ffect

s of

: C

loza

pine

, CN

S d

epre

ssan

t; m

etho

trim

epra

zine

; ph

enyt

oin;

pro

pofo

l Th

e le

vels

/effe

cts

of

mid

azol

am in

crea

sed

by:

Ant

ifung

al a

gent

s (A

zole

de

rivat

ives

, sys

tem

ic);

Apr

epita

nt; a

torv

asta

tin;

CC

B (n

on-d

ihyd

ropy

ridin

e);

cim

etid

ine;

con

trace

ptiv

es

(est

roge

ns &

pro

gest

ins)

; C

YP

3A4

inhi

bito

rs;

Efa

vire

nz; I

soni

azid

; M

acro

lide

antib

iotic

s;

Pro

pofo

l; P

rote

ase

inhi

bito

rs;

PP

I; S

SR

I D

ecre

ased

effe

ct

The

leve

ls/e

ffect

s of

m

idaz

olam

may

be

decr

ease

d by

: C

arba

maz

epin

e; C

YP

3A4

indu

cers

; def

eras

irox,

rif

ampi

cin

deriv

ativ

es;

theo

phyl

line

deriv

ativ

es

Incr

ease

d ef

fect

/ to

xici

ty

Mid

azol

am m

ay in

crea

se th

e le

vels

/effe

cts

of:

Hyp

oten

sive

age

nts

The

leve

ls/e

ffect

s of

m

idaz

olam

incr

ease

d by

: B

eta-

bloc

keer

s; C

YP

2A6

inhi

bito

rs; M

AO

inhi

bito

rs

Dec

reas

ed e

ffect

Th

e le

vels

/effe

cts

of

mid

azol

am m

ay b

e de

crea

sed

by:

Ant

idep

ress

ants

(α2-

anta

goni

st);

SS

RI;

tricy

clic

an

tidep

ress

ants

Incr

ease

d ef

fect

/ to

xici

ty

The

leve

ls/e

ffect

s of

ket

amin

e in

crea

sed

by:

CY

P2B

6 in

hibi

tors

; CY

P2C

9 in

hibi

tors

; CY

P3A

4 in

hibi

tors

; de

satin

ib; q

uaze

pam

D

ecre

ased

effe

ct

The

leve

ls/e

ffect

s of

ket

amin

e m

ay b

e de

crea

sed

by:

CY

P2C

9 in

duce

rs;

Peg

inte

rfero

n α-

2b

Incr

ease

d ef

fect

/ to

xici

ty

Pro

pofo

l may

incr

ease

the

leve

ls/e

ffect

s of

: M

idaz

olam

; rop

ivac

aine

Th

e le

vels

/effe

cts

of p

ropo

fol

incr

ease

d by

: A

lfent

anil;

CY

P2B

6 in

hibi

tors

; m

idaz

olam

; qua

zepa

m

Dec

reas

ed e

ffect

Th

e le

vels

/effe

cts

of p

ropo

fol

may

be

decr

ease

d by

: P

egin

terfe

ron α

-2b


4.0

Pae

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Icu

Analgesic Agents

Opioids produce analgesia via a variety of central and peripheral opioids receptors, particularly μ- and k-receptors. To varying degrees the opioids tend to produce hypotension and respiratory depression7.

• Morphine

Morphine has the lowest lipid solubility of all the opioids, which accounts for its delayed onset of clinical effect. Dose reduction of morphine is necessity for patients with hepatic and/or renal dysfunction. Morphine stimulates the release of significant amounts of histamine and inhibits compensatory sympathetic responses; the resultant vasodilatation may result in hypotension. Discontinuation of morphine is associated with withdrawal syndrome7.

• Fentanyl

Fentanyl is a potent synthetic opioid with a rapid onset of action, which is associated with less histamine release than morphine, and therefore, produces less hypotension; although it may reduce cardiac output by decreasing the heart rate. Fentanyl is 100 times more potent compared to morphine. When given intravenously there is rapid redistribution to peripheral compartments, giving fentanyl a relatively short half-life of 30-60 minutes7. An infrequenct adverse effect is chest wall rigidity, which is related to the dose used, rate of infusion and age < 6 months1. Prolonged administration of fentanyl is associated with tolerance7.

• Remifentanil

Remifentanil is a synthetic opioid with cardio-respiratiory effects similar to other opioids and which is equipotent to fentanyl. Remifentanil has a half-life of 3 minutes in all age groups because it is metabolised by plasma and tissue esterases. No dosage adjustment is needed for patients with liver and/or renal dysfunction. Prolonged administration of remifentanil is associated with tolerance7.


4.0

P

AE

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ICU

115

Tabl

e 2:

Sum

mar

y of

pha

rmac

olog

ical

pro

pert

ies

of a

nalg

esic

age

nts.

5,9,

10

Age

nt

Mor

phin

e Fe

ntan

yl

Rem

ifent

anil

Dos

e

Ven

tilat

ed p

atie

nt:

IV: 0

.1-0

.2m

g/kg

/dos

e In

fusi

on: 2

0-80

1mcg

/kg/

hr

Ven

tilat

ed p

atie

nt:

IV: 5

-10m

cg/k

g/do

se

Infu

sion

: 5-1

0mcg

/kg/

hr

Ven

tilat

ed p

atie

nt:

Infu

sion

: 0.5

-1m

cg/k

g/m

in

Ons

et

IV: 5

min

IM

: 10-

30 m

in

IV: A

lmos

t im

med

iate

IM

: 7-1

5 m

in

IV: 1

-3 m

in

Max

imum

ef

fect

IV: 2

0 m

in

IM: 3

0-60

min

-

IV: 3

-5 m

in

Dur

atio

n

IV/IM

: 3-5

hr

IV: 3

0-60

min

IM

: 1-2

hr

IV: 3

-10

min

Met

abol

ism

Met

abol

ize

in li

ver v

ia g

lucu

roni

de

conj

ugat

ion

to m

orph

ine-

6-gl

ucur

onid

e (a

ctiv

e) &

mor

phin

e-3-

gluc

uron

ide

(inac

tive)

Met

abol

ize

in li

ver v

ia C

YP

3A4

into

in

activ

e m

etab

olite

s

Met

abol

ized

rapi

dly

by b

lood

and

tis

sue

este

rase

s in

to in

activ

e m

etab

olite

s

Elim

inat

ion

Urin

e:

90%

exc

rete

d in

urin

e; 2

-12%

exc

rete

d as

unc

hang

ed d

rug

Fece

s:

7-10

%

Urin

e:

75%

exc

rete

d as

met

abol

ites;

7-

10%

exc

rete

d as

unc

hang

ed d

rug

Fece

s:

1-9%

as

met

abol

ites

Urin

e:

90%

exc

rete

d as

inac

tive

met

abol

ites

His

tam

ine

rele

ase

Yes

N

o N

o


4.0

Pae

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Icu

116

Age

nt

Mor

phin

e Fe

ntan

yl

Rem

ifent

anil

Dru

g in

tera

ctio

n

Incr

ease

d ef

fect

/ to

xici

ty

Mor

phin

e m

ay in

crea

se th

e le

vels

/effe

cts

of:

CN

S d

epre

ssan

t; de

smop

ress

in;

SS

RI;

thia

zide

diu

retic

s Th

e le

vels

/effe

cts

of m

orph

ine

may

be

incr

ease

d by

: A

mph

etam

ines

; ant

ipsy

chot

ic a

gent

s;

succ

inyl

chol

ine

Dec

reas

ed e

ffect

Th

e le

vels

/effe

cts

of m

orph

ine

may

be

decr

ease

d by

: A

mm

oniu

m c

hlor

ide;

mix

ed a

goin

ist /

an

tago

nist

opi

oids

; peg

inte

rfero

n α

-2b

; rifa

mpi

cin

deriv

ativ

es

Con

train

dica

ted:

P

rote

ase

inhi

bito

rs, M

AO

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DIA

TRIC

ICU

Withdrawal syndrome

Withdrawal syndrome may occur following the discontinuation of sedative agents, particularly benzodiazepines and opioids, and is thought to be related to the total drug doses received. The withdrawal syndrome occurs in 50% of the cases with a cumulative fentanyl dose greater than 1.5mg/kg or administration longer than 5 days, rising to 100% when the cumulative dose is greater than 2.5mg/kg or with an administration longer than 9 days. The incidence of this syndrome increases significantly with an cumulative midazolam dose greater than 60mg/kg1.

Different methods are used to prevent the development of the withdrawal syndrome, such as gradual reduction in doses, enteral sedative agents and subcutaneous use of fentanyl and midazolam and avoidance of continuous intravenous sedation1. References:

1) Bartolomé SM, Cid JLH, Freddi N. Analgesia and Sedation in Children: Practical Approach for the Most Frequent Situations. Jornal de Pediatria. 2007;83(2):S71-S82.

2) Buck ML. Dexmedetomidine Use in Pediatric Intensive Care and Procedural Sedation. J Pediatr Pharmacol Ther. 2010;15(1):17-29

3) Dolansky G, Shah A, Mosdossy G, Rieder MJ. What is the Evidence for the Safety and Efficacy of Using Ketamine in Children? Paediatr Child Health. 2008;13(4):307-308

4) Gommers D, Bakker J. Medications for Analgesia and Sedation in the Intensive Care Unit: An Overview. Critical Care. 2008;12(3):S1-S5.

5) Micromedex® Healthcare Series. [Internet database]. Available from: Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc; 2011. [cited 20/11/2014]

6) Mistry RB, Nahata MC. Ketamine for Conscious Sedation in Pediatric Emergency Care. Pharmacotherapy. 2005;25(8):1104-1111

7) Playfor SD. Analgesia and Sedation in Critically Ill Children. Arch. Dis. Child Ed. Pract. 2008;93:87-92.


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8) Playfor S, Jenkins I, Boyles C, Choonara I, Davies G, Haywood T et al. Consensus Guidelines on Sedation and Analgesia in Critically Ill Children. Intensive Care Med. 2006;32:1125-1136

9) Shann F. Drug Doses. 16th ed. Victoria. Royal Children’s Hospital; 2014

10) Taketomo CK, Hodding JH, Kraus DM (Eds). Pediatric Dosage Handbook with International Trade Names Index. 17th ed. Ohio. Lexi-Comp Inc; 2010

11) Tobias JD. Sedation and Analgesia in Paediatric Intensive Care Units Paediatr Drugs. 1999;1(2):109-126

12) Wolf AR. Analgesia and Sedation in Pediatric Intensive Care. South Afr J Anaesth Analg. 2012;18(5):258-261


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5.0 Neonatal ICU


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Introduction

Neonatal Jaundice (NNJ) is one of the most common medical conditions in newborns. All newborn babies have a transient rise in serum bilirubin but only about 75% are visibly jaundiced. There are other risk factors that may be associated with significant hyperbilirubinemia including prematurity, G6PD deficiency and ABO incompatibility.

Jaundice or hyperbilirubinaemia is either unconjugated or conjugated. Without treatment, high levels of unconjugated bilirubin may lead to acute and chronic bilirubin encephalopathy. This causes neurodevelopmental problems including athetoid cerebral palsy, hearing loss and, visual and dental problems.

Risk factors for severe NNJ: • Prematurity • Low birth weight

• Jaundice in the • Mother with Blood first 24 hours of life Group O or Rhesus Negative

• G6PD deficiency • Sepsis

• Rapid rise of total serum bilirubin • Exclusive breastfeeding

• Excessive weight loss • High predischarge bilirubin level

• Cephalhaematoma or bruises • Family history of severe NNJ in• Baby of diabetic mothers siblings

Pharmacotherapy

There is limited good evidence on pharmacotherapy in NNJ and no conclusive evidence to support the use of IVIG, human albumin and phenobarbitone in the management of NNJ.

Non-Pharmacotherapy

• Phototherapy

Phototherapy is the mainstay of treatment in NNJ. There are many types of devices that can be used to provide phototherapy such as fluorescent tubes, Light Emitting Diode (LED), fibreoptic and halogen bulbs

NEONATAL JAUNDICE (NNJ)


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• Exchange Transfusion

-> Exchange transfusion (ET) should be considered when total serum bilirubin reaches the threshold levels in neonatal jaundice (NNJ).

-> ET procedure should follow a standardized protocol and supervised by experienced personnel. Babies undergoing ET should be closely monitored.

-> Reconstituted blood products may be used if citrated fresh whole blood is not available for ET in NNJ.

-> Blood product used most commonly for ET is citrated fresh whole blood.However, some centres use reconstituted blood products when it is not available.Both citrated fresh whole blood and reconstituted blood products are comparable in terms of efficacy and safety

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4.0 NEONATAL ICU

Neonatal Jaundice (NNJ) Introduction

Neonatal Jaundice (NNJ) is one of the most common medical conditions in newborns. All newborn babies have a transient rise in serum bilirubin but only about 75% are visibly jaundiced. There are other risk factors that may be associated with significant hyperbilirubinemia including prematurity, G6PD deficiency and ABO incompatibility.

Jaundice or hyperbilirubinaemia is either unconjugated or conjugated. Without treatment, high levels of unconjugated bilirubin may lead to acute and chronic bilirubin encephalopathy. This causes neurodevelopmental problems including athetoid cerebral palsy, hearing loss and, visual and dental problems.

Risk factors for severe NNJ:

• Prematurity • Low birth weight • Jaundice in the first 24 hours of life • Mother with Blood Group O or

Rhesus Negative • G6PD deficiency • Rapid rise of total serum bilirubin • Sepsis

• Excessive weight loss • Exclusive breastfeeding • High predischarge bilirubin level • Cephalhaematoma or bruises • Baby of diabetic mothers • Family history of severe NNJ in

siblings

Pharmacotherapy

There is limited good evidence on pharmacotherapy in NNJ and no conclusive evidence to support the use of IVIG, human albumin and phenobarbitone in the management of NNJ.

Non-Pharmacotherapy

• Phototherapy

Phototherapy is the mainstay of treatment in NNJ. There are many types of devices that can be used to provide phototherapy such as fluorescent tubes, Light Emitting Diode (LED), fibreoptic and halogen bulbs.

Care of babies during phototherapy

• Babies should be regularly monitored for vital signs including temperature and hydration status.

• Babies should be adequately exposed. • Babies’ eyes should be covered to prevent retinal damage. • Breastfeeding should be continued.

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• Exchange Transfusion • Exchange transfusion (ET) should be considered when total serum bilirubin

reaches the threshold levels in neonatal jaundice (NNJ). • ET procedure should follow a standardized protocol and supervised by

experienced personnel. Babies undergoing ET should be closely monitored. • Reconstituted blood products may be used if citrated fresh whole blood is not

available for ET in NNJ. • Blood product used most commonly for ET is citrated fresh whole blood.

However, some centres use reconstituted blood products when it is not available. Both citrated fresh whole blood and reconstituted blood products are comparable in terms of efficacy and safety.

TABLE 1: TSB levels for phototherapy & ET in babies ≥35 weeks gestation

Age LOW RISK >38 weeks & well

MEDIUM RISK >38 weeks with risk factors or 35 - 37 weeks + 6 days & well

HIGH RISK 35 - 37 weeks + 6 days with risk factors

Hours of life

Conventional Phototherapy - TSB in mg/dL (µmol/L)

ET - TSB in mg/dL (µmol/L)





<24* 24 9 (154) 19 (325) 7 (120) 17 (291) 5 (86) 15 (257) 48 12 (205) 22 (376) 10 (171) 19 (325) 8 (137) 17 (291) 72 15 (257) 24 (410) 12 (205) 21 (359) 10 (171) 18.5

(316) 96 17 (291) 25 (428) 14 (239) 22.5 (385) 11 (188) 19 (325) >96 18 (308) 25 (428) 15 (257) 22.5 (385) 12 (205) 19 (325)

a. Start intensive phototherapy at TSB 3 mg/dL (51 µmol/L) above the level for conventional phototherapy or when TSB increasing at >0.5 mg/dL (8.5 µmol/L) per hour

b. Risk factors are isoimmune haemolytic disease, G6PD deficiency, neonatal encephalopathy & sepsis.

*Jaundice appearing within 24 hours of life is abnormal & needs further evaluation.

• Complementary/Alternative Medicine/Practices

There is no good quality evidence to support the use of complementary/alternative medicine/practices in the management of babies with NNJ.

Impact of Breastfeeding

• Breastfeeding, because of its benefits, should be continued in the jaundiced babies. • Adequate lactation/breastfeeding support should be provided to all mothers, particularly

those with preterm babies. In breastfed babies with jaundice associated with inadequate intake, excessive weight loss or dehydration, supplementation with expressed breast milk or formula may be considered

*Jaundice appearing within 24 hours of life is abnormal & needs further evaluation.

• Complementary/Alternative Medicine/Practices

There is no good quality evidence to support the use of complementary/ alternative medicine/practices in the management of babies with NNJ.


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Impact of Breastfeeding

• Breastfeeding, because of its benefits, should be continued in the jaundiced babies.

• Adequate lactation/breastfeeding support should be provided to all mothers, particularly those with preterm babies. In breastfed babies with jaundice associated with inadequate intake, excessive weight loss or dehydration, supplementation with expressed breast milk or formula may be considered


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References:

1. Clinical Practice Guidelines Management of Neonatal Jaundice 2nd Edition December 2014 Ministro of Health Malaysia

2. Huang MS, Lin MC, Chen HH, et al. Risk factor analysis for late-onset neonatal hyperbilirubinemia in Taiwanese infants. Pediatr Neonatol 2009 Dec;50(6):261-265.

3. Jangaard KA, Fell DB, Dodds L, et al. Outcomes in a population of healthy term and near-term infants with serum bilirubin levels of >or=325 micromol/L (>or=19 mg/dL) who were born in Nova Scotia, Canada, between 1994 and 2000. Pediatrics. 2008 Jul;122(1):119-124.

4. Kuzniewicz MW, Escobar GJ, Wi S, et al. Risk factors for severe hyperbilirubinemia among infants with borderline bilirubin levels: a nested case-control study. J Pediatr. 2008 Aug;153(2):234-240.

5. National Collaborating Centre for Women’s and Children’s Health. Neonatal jaundice. London: NCC-WCH; 2010.

6. Maisels MJ, Bhutani VK, Bogen D, et al. Hyperbilirubinemia in the newborn infant > or =35 weeks’ gestation: an update with clarifications. Pediatrics. 2009 Oct;124(4 ):1193-1198.

7. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul;114(1):297-316.

8. Boo NY, Gan CY, Gian YW, et al. Malaysian mothers’ knowledge & practices on care of neonatal jaundice. Med J Malaysia. 2011 Aug;66(3):239-243.

9. Salas AA, Mazzi E. Exchange transfusion in infants with extreme hyperbilirubinemia: an experience from a developing country. Acta Paediatr. 2008 Jun;97(6):754-758.

10.Weng YH, Chiu YW. Comparison of efficacy and safety of exchange transfusion through different catheterizations: Femoral vein versus umbilical vein versus umbilical artery/vein. Pediatr Crit Care Med. 2011 Jan;12(1):6 64.

11. Chen HN, Lee ML, Tsao LY. Exchange transfusion using peripheral vessels is safe and effective in newborn infants. Pediatrics. 2008 Oct;122(4):e905-910.

12. Gharehbaghi MM, Hosseinpour SS. Exchange transfusion in neonatal hyperbilirubinaemia: a comparison between citrated whole blood and reconstituted blood. Singapore Med J. 2010 Aug;51(8):641-644.


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13. amidi M, Zamanzad B, Mesripour A. Comparing the effect of clofibrate and phenobarbital on the newborns with hyperbilirubinemia. EXCLI Journal. 2013;12:75-78.

14. Xiong T, Chen D, Duan Z, et al. Clofibrate for unconjugated hyperbilirubinemia in neonates: a systematic review. Indian Pediatr. 2012 Jan;49(1):35-41.

15. Ashkan MM, Narges P. The effect of low and moderate doses of clofibrate on serum bilirubin level in jaundiced term neonates. Paediatric and Perinatal Drug Therapy. 2007;8(2):51-54.

16. Louis D, More K, Oberoi S, et al. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: an updated systematic review and meta- analysis. Arch Dis Child Fetal Neonatal Ed. 2014 Jul;99(4):F325-331.

17. Ismael AS, Alrabaty AA. Role of Intravenous Human Albumin in Management of Neonatal Hyperbilirubinemia. JSMC. 2013;3(1).

18. Shahian M, Moslehi MA. Effect of albumin administration prior to exchange transfusion in term neonates with hyperbilirubinemia-a randomized controlled trial. Indian Pediatr. 2010 Mar;47(3):241-244. 19. Suresh G, Martin CL, Soll R. Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane Database of Systematic Reviews. 2003;Issue 1. Art. No.: CD004207.

20. Chawla D, Parmar V. Phenobarbitone for prevention and treatment of unconjugated hyperbilirubinemia in preterm neonates: a systematic review and meta-analysis. Indian Pediatr. 2010 May;47(5):401-407.

21. Hussain Imam MI, Ng HP, Thomas T, et al. Malaysian Paediatric Protocol for Malaysian Hospitals 3rd Edition. Putrajaya: MoH; c2012.


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Sedation & Pain Management

Table 1: Responses of Neonates to Pain

Physiological changes

Behavioral changes

Hormonal changes

Autonomic changes

Body movements

Increase in: Heart rate Blood pressure Respiratory rate Oxygen consumption Mean airway pressure Muscle tone Intracranial pressure

Grimacing Pain Definition An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage 8 Responses of Neonates to Pain Prolonged or severe pain may cause short- or long term physiological, behavioral, hormonal and metabolic changes. These changes may result in higher morbidity and mortality as well as alter subsequent responses to pain 4 Screwing up eyes Nasal flaring Curving of the tongue Quivering of the chin

Increased release of: Cortisol Catecholamine Glucagon Growth hormone Renin Aldosterone Antidiuretic hormone Decreased secretion of: Insulin

Mydriasis Sweating Flushing Pallor

Finger clenching Trashing of limbs Writhing Arching of back Head hanging

SEDATION & PAIN MANAGEMENT


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Pain Assessment Pain assessment in neonatal patients is mainly via self-reporting by staffs and indirect measurement including behavioral, physiological and hormonal changes 10.

Sedation

Definition

Sedation means reduced state of awareness but does not relieve pain. Procedural sedation and analgesia is defined as the use of anxiolytic, sedative, analgesic or dissociative drugs to attenuate pain, anxiety and motion to facilitate the performance of a necessary diagnostic or therapeutic procedure, provide an appropriate degree of amnesia or decreased awareness, and ensure patient safety2.

Level of Sedation / Depth of Sedation

Depth of sedation is defined as a continuum, progressing from mild through moderate to deep sedation and to general anesthesia. Shown below are the definitions of levels of sedation as defined and adopted by American Society of Anesthesiologists1.

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Table 2: Commonly used Pain Assessment Tools in Neonatal Patients

Assessment Tools

Premature Infant Pain

Profile (PIPP)

Neonatal Facial Coding Scale

(NFCS)

Neonatal Infant Pain

Scale (NIPS) CRIES Score

Variables assessed

Gestational age Behavioural state Heart Rate Oxygen saturation Brow bulge Eye squeeze Nasolabial furrow

Brow bulge Eye squeeze Nasolabial furrow Open lips Stretch mouth Lip purse Taut tongue Chin quiver Tongue protrusion

Facial expression Cry Breathing patterns Arms Legs State of arousal

Crying Requires increase Oxygen administration Increased vital signs Expression Sleeplessness

Sedation Definition Sedation means reduced state of awareness but does not relieve pain. Procedural sedation and analgesia is defined as the use of anxiolytic, sedative, analgesic or dissociative drugs to attenuate pain, anxiety and motion to facilitate the performance of a necessary diagnostic or therapeutic procedure, provide an appropriate degree of amnesia or decreased awareness, and ensure patient safety 2. Level of Sedation / Depth of Sedation Depth of sedation is defined as a continuum, progressing from mild through moderate to deep sedation and to general anesthesia. Shown below are the definitions of levels of sedation as defined and adopted by American Society of Anesthesiologists1.

Table 3: Continuum of Depth of Sedation adopted by American Society of Anaesthesiologists

Level of Sedation

Minimal sedation / Anxiolysis

Moderate sedation/

Conscious sedation

Deep sedation General anaesthesia

Responsiveness

Normal response to

verbal stimulation

Purposeful response to verbal

or tactile stimulation

Purposeful response following repeated or painful

stimulation

Unarousable even with painful

stimulus

Airway Unaffected No intervention required

Intervention may be required

Intervention often required


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Table 2: Commonly used Pain Assessment Tools in Neonatal Patients

Assessment Tools

Premature Infant Pain

Profile (PIPP)

Neonatal Facial Coding Scale

(NFCS)

Neonatal Infant Pain

Scale (NIPS) CRIES Score

Variables assessed

Gestational age Behavioural state Heart Rate Oxygen saturation Brow bulge Eye squeeze Nasolabial furrow

Brow bulge Eye squeeze Nasolabial furrow Open lips Stretch mouth Lip purse Taut tongue Chin quiver Tongue protrusion

Facial expression Cry Breathing patterns Arms Legs State of arousal

Crying Requires increase Oxygen administration Increased vital signs Expression Sleeplessness

Sedation Definition Sedation means reduced state of awareness but does not relieve pain. Procedural sedation and analgesia is defined as the use of anxiolytic, sedative, analgesic or dissociative drugs to attenuate pain, anxiety and motion to facilitate the performance of a necessary diagnostic or therapeutic procedure, provide an appropriate degree of amnesia or decreased awareness, and ensure patient safety 2. Level of Sedation / Depth of Sedation Depth of sedation is defined as a continuum, progressing from mild through moderate to deep sedation and to general anesthesia. Shown below are the definitions of levels of sedation as defined and adopted by American Society of Anesthesiologists1.

Table 3: Continuum of Depth of Sedation adopted by American Society of Anaesthesiologists

Level of Sedation

Minimal sedation / Anxiolysis

Moderate sedation/

Conscious sedation

Deep sedation General anaesthesia

Responsiveness

Normal response to

verbal stimulation

Purposeful response to verbal

or tactile stimulation

Purposeful response following repeated or painful

stimulation

Unarousable even with painful

stimulus

Airway Unaffected No intervention required

Intervention may be required

Intervention often required

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Spontaneous ventilation Unaffected Adequate May be inadequate Frequently

inadequate Cardiovascular

function Unaffected Usually maintained Usually maintained Maybe impaired

General Principles of Pain Management & Sedation

• In both preterm and term neonates, neuroanatomical components and neuroendocrine systems are developed sufficiently to allow transmission of painful stimuli 10.

• Newborns may be more sensitive to pain and may be more susceptible to long term effects of pain. However, pain in newborns are often not recognized and undertreated10

• Sedation does not provide pain relief and may mask the patient’s response to pain • Approach to pain prevention and management: 10

- Avoiding and limiting noxious stimuli - Minimizing painful procedure

Eg: placement of peripheral lines to reduce repeated IV punctures - Applying non-invasive measurement

Eg: oximeter - Assessment of neonatal pain - Behavioral methods / non-pharmacological therapy

Eg: sucrose, swaddling, non-nutritive sucking, skin to skin contact - Pharmacological therapy as pre-emptive analgesic - Pharmacological therapy for on-going pain

Pain & Sedation Management in Ventilated Patient 4,9.

• Analgesia/sedation should be used in neonates receiving continued ventilation. • Morphine

Continuous morphine infusion may improve neurological outcome and reduce adverse responses during endotracheal suctioning. Titrate up the morphine infusion according to response. If a patient is ventilated for ≥ 1 week and on full enteral feed without needing the intravenous access, switching to oral morphine can be considered.

• Midazolam Intermittent during intubation and continuous infusion of midazolam can be used as sedation

Pain & Sedation Management in Procedures 6,11

• Behavioral methods / Non-pharmacological therapy - Hypnosis & distraction - Music - Non-nutritive sucking - Breast-feeding during procedure - Sucrose

Sucrose can be used for short term pain prior to minor procedures eg: venipuncture, cannulation, heel prick, IM/SC injection, dressing change and eye examination. It is not for continuing pain.

General Principles of Pain Management & Sedation

• In both preterm and term neonates, neuroanatomical components and neuroendocrine systems are developed sufficiently to allow transmission of painful stimuli10.

• Newborns may be more sensitive to pain and may be more susceptible to long term effects of pain. However, pain in newborns are often not recognized and undertreated10

• Sedation does not provide pain relief and may mask the patient’s response to pain

• Approach to pain prevention and management: 10

- Avoiding and limiting noxious stimuli

- Minimizing painful procedure Eg: placement of peripheral lines to reduce repeated IV punctures

- Applying non-invasive measurement Eg: oximeter

- Assessment of neonatal pain

- Behavioral methods / non-pharmacological therapy Eg: sucrose, swaddling, non-nutritive sucking, skin to skin contact

- Pharmacological therapy as pre-emptive analgesic

- Pharmacological therapy for on-going pain


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Pain & Sedation Management in Ventilated Patient4,9.

• Analgesia/sedation should be used in neonates receiving continued ventilation.

• Morphine

Continuous morphine infusion may improve neurological outcome and reduce adverse responses during endotracheal suctioning. Titrate up the morphine infusion according to response. If a patient is ventilated for ≥ 1 week and on full enteral feed without needing the intravenous access, switching to oral morphine can be considered.

• Midazolam

Intermittent during intubation and continuous infusion of midazolam can be used as sedation

Pain & Sedation Management in Procedures 6,11

• Behavioral methods / Non-pharmacological therapy

- Hypnosis & distraction - Music - Non-nutritive sucking - Breast-feeding during procedure

- Sucrose

Sucrose can be used for short term pain prior to minor procedures eg: venipuncture, cannulation, heel prick, IM/SC injection, dressing change and eye examination. It is not for continuing pain.


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Table 4: Mechanism of action, Dosing, Age group, Administration, Adverse Effects, Cautions and Contraindications of Sucrose

Mechanism of action Elusive, maybe behavioral effect 13 Age group 1st month – 18months of life 11 Dosing 11 Maximum volume sucrose

24-33% solution per procedure

Maximum volume sucrose 24-33% solution within 24hours

Gestational Age / Birthweight Nil orally 0.2ml 1ml < 1500gm 0.5ml 2.5mls < 1 month of age 1ml 5mls 1-18months of age 2mls 5mls Administration method 11,13

I) Prepare the total amount of sucrose to be given for a procedure using a syringe Ii) Give a quarter of the total amount of sucrose 2minutes prior to procedure Iii) Administer on to the anterior of the tongue / by dip of pacifier (0.2ml per dip) Iv) Give the rest of the sucrose incrementally throughout the procedure

Adverse effects5 Safe for one-off use Repeated and frequent use in preterm neonate may cause possible adverse neurobiological effect

Caution13 Coughing, choking and desaturation with oral administration Contraindications4 Necrotizing enterocolitis, paralysed, absent of gag reflex

Pharmacological Therapy Topical anesthesia Methods that provide topical anesthesia including:

• Local Anesthesia Lubricant Gel 7,13

Examples of local anesthesia lubricant gel include Lidocaine 1% and 2%( not available in MOH formulary). They can be used prior to urinary catheterization, nasogastric tube insertion and circumcision.

• Vapo-coolant Sprays 7,13

Examples of vapo-coolant sprays include Ethyl Chloride Spray which is available in MOH formulary. Vapo-coolant sprays cause evaporative cooling thus provide transient numbness. It is suitable for procedures lasting ≤ 60 seconds eg: venipuncture and immunisations. Ethyl Chloride Spray should be sprayed at a distance of about 30cm until a fine white film is produced.

Pharmacological Therapy

Topical anesthesiaMethods that provide topical anesthesia including:

• Local Anesthesia Lubricant Gel 7,13

Examples of local anesthesia lubricant gel include Lidocaine 1% and 2%( not available in MOH formulary). They can be used prior to urinary catheterization, nasogastric tube insertion and circumcision.

• Vapo-coolant Sprays 7,13

Examples of vapo-coolant sprays include Ethyl Chloride Spray which is available in MOH formulary. Vapo-coolant sprays cause evaporative cooling thus provide transient numbness. It is suitable for procedures lasting ≤ 60 seconds eg: venipuncture and immunisations. Ethyl Chloride Spray should be sprayed at a distance of about 30cm until a fine white film is produced.

• Topical Local Anesthesia Cream

Topical anesthesia is obtained by passive diffusion of cream through skin surface to inhibit sensory neurons transmission in the dermis and epidermis. Examples of topical anesthesia cream include EMLA Cream and Ametop Gel (Tetracaine 4% Gel). Ametop Cream is not available in MOH formulary as well as not in Malaysia market.


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• Topical Local Anesthesia Cream Topical anesthesia is obtained by passive diffusion of cream through skin surface to inhibit sensory neurons transmission in the dermis and epidermis. Examples of topical anesthesia cream include EMLA Cream and Ametop Gel (Tetracaine 4% Gel). Ametop Cream is not available in MOH formulary as well as not in Malaysia market.

Table 5: Mechanism of action, Age Limit, Dosing, Adverse Effects, Cautions and

Contraindications of EMLA cream

Active ingredients Lignocaine 2.5% and Prilocaine 2.5%

Mechanism of action 9

Decrease the neuronal membrane’s permeability to sodium ions, resulting in inhibition of depolarization, blocking the initiation and conduction of nerve impulses, thus cause local anesthesia action

Onset of action for dermal analgesia 9

60minutes

Duration of action after removal 9

1-2hours

Age limit 3 Not licensed for < 1 year old

Adverse effects 9

Hypotension, angioedema Shock Burning, erythema, itching, rash Bronchospasm

Caution 9

G6PD deficiency (EMLA cream will predispose the patient to methaemoglobinemia) Anemia Methaemoglobinemia

Contraindications 9

Open wound Mucous membrane Atopic dermatitis

Dosing 9

Age and weight Max total dose Max application area Max application time

GA < 37weeks 0.5g No data 1 hour GA ≥ 37weeks 1g 10cm2 1 hour 1 to <3mo or <5kg 1g 10cm2 1 hour 3 to <12mo and >5kg 2g 20cm2 4hour 1-6yo and >10kg 10g 100cm2 4hour

Non-opioid Analgesics

Non-opioid analgesics do not cause respiratory depression, do not impair gastrointestinal motility and do not cause dependence. Insufficient analgesic potency for procedural analgesia, thus mainly used for the relief of post-operative pain3,13


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Non

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ics

Non

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anal

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epre

ssio

n, d

o no

t im

pair

gas

troin

test

inal

mot

ility

and

do

not

caus

e de

pend

ence

. In

suffi

cien

t ana

lges

ic p

oten

cy fo

r pro

cedu

ral a

nalg

esia

, thu

s m

ainl

y us

ed fo

r the

relie

f of p

ost-o

pera

tive

pain

3 &

13

Tabl

e 6:

Mec

hani

sm o

f ac

tion,

indi

catio

ns,

rout

es a

vaila

ble,

tim

e of

ons

et,

dura

tion,

dos

age,

adv

erse

effe

cts

and

cont

rain

dica

tion

of n

on-

opio

id a

nalg

esic

s 3,

9, 1

2 &

13

Non

-opi

oid

Ana

lges

ics

Para

ceta

mol

N

on-s

tero

idal

Ant

i-inf

lam

mat

ory

Dru

gs

Dic

lofe

nac

Ibup

rofe

n

Mec

hani

sm o

f ac

tion

Inhi

bit t

he s

ynth

esis

of p

rost

agla

ndin

in

CN

S a

nd p

erip

hera

lly b

lock

pai

n im

puls

e ge

nera

tion

Inhi

bit p

rost

agla

ndin

syn

thes

is b

y de

crea

sing

the

activ

ity o

f cy

cloo

xyge

nase

Inhi

bit p

rost

agla

ndin

syn

thes

is b

y de

crea

sing

th

e ac

tivity

of c

yclo

oxyg

enas

e

Indi

catio

n ap

prov

ed in

M

OH

fo

rmul

ary

1) M

ild-M

oder

ate

Pai

n

2) P

ost-O

pera

tive

Pai

n 3)

Pai

n

1) P

ain

And

Infla

mm

atio

n In

Rhe

umat

ic

Dis

ease

& J

uven

ile A

rthrit

is

1) P

ain

And

Infla

mm

atio

n In

Rhe

umat

ic

Dis

ease

FDA

-app

rove

d in

dica

tion

1) M

ild-M

oder

ate

Pai

n

2) M

oder

ate-

Sev

ere

Pai

n (A

djun

ct)

3) F

ever

1) M

ild-M

oder

ate

Pai

n

1) P

ain

2)

Rhe

umat

oid

Arth

ritis

3)

Fev

er

Rou

te o

f ad

min

istra

tion

PO

, IV

, PR

P

O ,

IV, P

R

PO

Tim

e of

ons

et

PO

: < 1

hour

IV

: 5-1

0min

utes

P

R: a

bsor

ptio

n is

var

iabl

e &

pro

long

ed

PO

: 1 h

our

PR

: ≤ 1

hour

30

- 60m

inut

es

Ana

lges

ic

dura

tion

PO

; IV

: 4-6

hour

s

No

data

4-

6 ho

ur

Dos

age

Dos

age

for P

O &

PR

12 :

RO

A

LD

MD

Fr

eq.

PO

20

-25

mg/

kg

12-1

5 m

g/kg

Te

rm:

QID

PR

30

m

g/kg

12

-18

mg/

kg

Pre

m P

MA

≥

32w

eek:

TD

S

Pre

m P

MA

<

32w

eek:

BD

D

osag

e fo

r IV

: N

eona

te: L

imite

d da

ta

Infa

nt/C

hild

ren

< 2y

o:

7.5-

15m

g/kg

QID

(Max

: 60m

g/kg

/day

9)

Dos

age

for m

ild-m

oder

ate

pain

, for

≥6

mo,

PO

or P

R:

0.

3-1m

g/kg

(Max

: 50m

g) T

DS

3 D

osag

e fo

r pos

t-op

pain

for ≥

6yo,

PR

: 1-

2mg/

kg/d

ay in

BD

-TD

S (M

ax:

150m

g/da

y, 4

days

) 3 D

osag

e fo

r pos

t-op

pain

for ≥

2yo,

IM:

0.3-

1mg/

kg O

D-B

D, (

Max

: 2da

ys) 3

Dos

age

for i

nfan

ts:

4-10

mg/

kg/d

ose

TDS

-QID

M

ax: 4

0mg/

kg/d

ay 9


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132

Non

-opi

oid

Ana

lges

ics

Para

ceta

mol

N

on-s

tero

idal

Ant

i-inf

lam

mat

ory

Dru

gs

Dic

lofe

nac

Ibup

rofe

n

Adv

erse

ef

fect

s

Live

r to

xici

ty

(exc

essi

ve

dose

or

pr

olon

ged

use/

>

48ho

urs

of

ther

apeu

tic d

ose)

R

ash

Feve

r Th

rom

bocy

open

ia,

leuk

open

ia,

neut

rope

nia

12

Nau

sea

(7%

) D

iarr

hea

(6%

) LF

T ra

ised

(15%

) C

onst

ipat

ion

(8%

) U

RTI

(8%

) A

cute

rena

l fai

lure

G

IT h

aem

orrh

age

GIT

per

fora

tion

Ras

h (3

-9%

)

Nau

sea

(3-9

%)

Vom

iting

(1-3

%)

G

IT h

aem

orrh

age

(<1%

) G

IT p

erfo

ratio

n (<

1%)

H

epat

itis

(<1%

) A

cute

rena

l fai

lure

(rar

e)

Con

train

di-

catio

n

Hyp

erse

nsiti

vity

S

ever

e he

patic

impa

irmen

t H

yper

sens

itivi

ty

Ast

hma

H

isto

ry o

f alle

rgic

-rea

ctio

n to

asp

irin

Hyp

erse

nsiti

vity

A

sthm

a

His

tory

of a

llerg

ic-r

eact

ion

to a

spiri

n

Pro

duct

s av

aila

ble

in

MO

H

form

ular

y

1.P

arac

etam

ol s

yrup

125

mg/

5ml

2.P

arac

etam

ol

supp

osito

ry

125m

g;

250m

g

1.D

iclo

fena

c ta

blet

50m

g

2.D

iclo

fena

c su

ppos

itory

12.

5mg;

25m

g &

50m

g

3.D

iclo

fena

c in

ject

ion

75m

g

1.Ib

upro

fen

tabl

et 2

00m

g

Opi

oids

Ana

lges

ics

Opi

oid

anal

gesi

cs h

ad b

een

used

for a

nalg

esia

and

sed

atio

n. E

g: M

orph

ine,

tram

adol

, fen

tany

l. Tr

amad

ol is

not

lice

nsed

for t

he u

se in

chi

ldre

n <

12yo

.

Ta

ble

7: M

echa

nism

of a

ctio

n, ro

utes

ava

ilabl

e, ti

me

of o

nset

, dur

atio

n, d

osag

e an

d ad

vers

e ef

fect

s of

opi

oid

anal

gesi

cs3,

9, 2

&13

Opi

oid

Ana

lges

ics

Mor

phin

e Fe

ntan

yl

Mec

hani

sm o

f ac

tion

Ana

lges

ic:

Bin

d to

opi

oid

rece

ptor

s in

CN

S c

ausi

ng in

hibi

tion

of

desc

endi

ng p

ain

path

way

S

edat

ion:

B

ind

to o

pioi

d re

cept

ors

in C

NS

, cau

sing

gen

eral

ized

C

NS

dep

ress

ion

Act

on

opio

id m

u re

cept

or in

CN

S

Pro

perti

es

1) a

nalg

esic

2)

sed

ativ

e 1)

ana

lges

ic

2) s

edat

ive

3)

ane

sthe

sia


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Opioids Analgesics

Opioid analgesics had been used for analgesia and sedation. Eg: Morphine, tramadol, fentanyl. Tramadol is not licensed for the use in children < 12yo.

Table 7: Mechanism of action, routes available, time of onset, duration,dosage and adverse effects of opioid analgesics3,9, 2 &13

Opioid Analgesics Morphine Fentanyl

Mechanism of action Analgesic:

Bind to opioid receptors in CNS causing inhibition of descending pain pathway

Sedation:

Bind to opioid receptors in CNS, causing generalized CNS depression

Act on opioid mu receptor in CNS

Properties 1) analgesic 2) sedative

1) analgesic 2) sedative 3) anesthesia

Uses 1) Pain 2) Post-Op Pain

1) Pain2) Intra-Op Pain3) Immediate Post-Op Pain 4) Adjunct In Maintenance Of General/Regional Anesthesia

Route of administration PO IV; IM; SC (IV is preferred)

IVIM (for> 1yo)

Time of onset IV: 5-10minsPO: 30mins

IV: almost immediate IM: 8mins

Duration of action 4 hours IV: 0.5-1 hour IM: 1-2 hours

Dosage PO: 0.08mg/kg Q4-6hr

IV over 5mins, IM, SC: 0.05-0.2mg/kg/dose, repeat PRN (Q4hr)

IVI: LD 0.1-0.15mg/kg then MD 10-30mcg/kg/hour (Max: 30mcg/kg/hour) 9 & 12

Sedation/analgesia (IV slow push): 0.5-4mcg/kg, repeat PRN (Q2-4hr)

Sedation/analgesia (IVI):1-5mcg/kg/hour

Anesthesia (IV): 5-50mcg/k/dose 12

Adverse effects 1) Respiratory depression 2) Sedation 3) Nausea & vomiting 4) Reduced GIT motility: constipation, ileus 5) Urinary retention 6) Tolerance 7) Withdrawal symptoms 8) Hypotension, bradycardia

Sedation/analgesia (IV slow push): 0.5-4mcg/kg, repeat PRN (Q2-4hr)

Sedation/analgesia (IVI):1-5mcg/kg/hour

Anesthesia (IV): 5-50mcg/k/dose 12

Notes • reliable & predictable effects •easily reversed by naloxone

• synthetic opioid analgesic • 50-100times more potent than morphine • < hypotensive effect & safer in hyperactive airway disease• easily reversed by naloxone


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Benzodiazepine

• Benzodiazepine have anxiolytic, amnestic and skeletal muscle relaxant properties, but not analgesic effects. (Eg: Midazolam, diazepam, lorazepam.)

• Lorazepam has long duration of action, not used for procedural sedation. Midazolam is commonly used due to its short half-life and fast onset. Diazepam is used too but it has long half-life, active metabolites and erratic absorption.

Table 8: Mechanism of action, routes available, time of onset, duration,dosage and adverse effects of benzodiazepines3,9, 2 &13

Benzodiazepine Midazolam Diazepam

Mechanism of action Bind receptor at several sites within CNS, increase inhibitory effect of GABA

Modulate postsynaptic effect of GABA-A transmission, resulting in increase in presynaptic effect Act on limbic system as well as thalamus & hypothalamus, inducing a calming effect

Uses 1) procedural sedation2) sedation

1) sedation/muscle relaxant (for children)

Route of administration PO; IV; IM Intranasal (use 5mg/ml injection) Sublingual (5mg/ml injection, mixed with syrup)Buccal (for ≥ 6mo)PR (for ≥ 6mo)

POIV/IM

Time of onset IV: 3-5mins IM: ≤ 5mins

IV: 2-3mins

Duration IV: 20-30mins IM: 2-6hoursFull recovery maybe ≥ 24hours

IV: 30-90mins

Dosage PO0.25mg/kg/dose

Intranasal0.2mg/kg/dose

Sublingual0.2mg/kg/dose

IV (over 5mins); IM 0.05-0.15mg/kg, repeat PRN, Q2-4hr

IVI 1-4mcg/kg/min 12

For procedures: PO: 0.2-0.3mg/kg (Max: 10mg) pre-procedureIV over 5mins:0.05-0.1mg/kg, titrate slowly (Max: 0.25mg/kg total dose)

For sedation/muscle relaxant: PO:0.12-0.8mg/kg/day in TDS-QID IV/IM: 0.04-0.3mg/kg/dose Q2-4hour (Max: 0.6mg/kg/within 8hour) 9

Adverse effects Decreased respiratory effect (23%) Apnea (15%) Drowsiness (1-5%) Nausea-vomiting (3%) Cough (1%) SomnolenceHeadache Hiccoughs Respiratory arrest Hypotension

Common (frequency unknown): Hypotension Respiratory depression Fatigue Muscle weakness Urinary retention


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Barbiturates

Barbiturates act on GABA receptors and hyperpolarize the nerve cell membrane via chlor ide channels. Barbiturates have sedation andamnesia properties but not analgesic effect. Barbiturates have neuro-protective effect as they can lower intracranial pressure and they haveanticonvulsant effect.

Eg: Pentobarbital & ThiopentalPentobarbital is not available in MOH formulary.

135

Apnea (15%) Drowsiness (1-5%) Nausea-vomiting (3%) Cough (1%) Somnolence Headache Hiccoughs Respiratory arrest Hypotension

Hypotension Respiratory depression Fatigue Muscle weakness Urinary retention

Barbiturates Barbiturates act on GABA receptors and hyperpolarize the nerve cell membrane via chloride channels. Barbiturates have sedation and amnesia properties but not analgesic effect. Barbiturates have neuro-protective effect as they can lower intracranial pressure and they have anticonvulsant effect. Eg: Pentobarbital & Thiopental Pentobarbital is not available in MOH formulary. Table 9: Mechanism of action, routes available, time of onset, duration, dosage and adverse effects of thiopental

Uses Induction of anesthesia (non-FDA approved for pediatric use)

Route of administration IV

Dosage 2-6mg/kg IV slow push

Adverse effects Respiratory depression

Tolerance, dependence, cardiovascular depression

(prolonged use)

Products available in

MoH formulary

Thiopental sodium injection 500mg

Table 9: Mechanism of action, routes available, time of onset, duration, dosage and adverse effects of thiopental


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Age

nt

Ket

amin

e

Prop

ofol

D

exm

edet

omid

ine

N

itrou

s ox

ide

Mec

hani

sm o

f ac

tion

Non

com

petit

ive

NM

DA

re

cept

or a

ntag

onis

t A

ct o

n G

AB

A-A

rece

ptor

an

d bl

ock

NM

DA

rece

ptor

S

elec

tive

alph

a-2

adre

nerg

ic

agon

ist w

ith s

edat

ive

effe

cts

-

Pro

perti

es

1) S

edat

ive

2)

Ana

lges

ic

3) A

mne

stic

1)

Sed

ativ

e

1) S

edat

ive

1) A

nxio

lytic

s 2)

Am

nest

ic

3) m

ild-m

oder

ate

anal

gesi

c

Use

s in

pe

diat

ric

patie

nts

1) s

edat

ion

pre-

proc

edur

e (

1m

o)

2) In

duct

ion

& m

aint

enan

ce

of a

nest

hesi

a

1) s

edat

ion

( 1

mo)

2)

Indu

ctio

n &

m

aint

enan

ce o

f ane

sthe

sia

( 1

mo)

Saf

ety

and

effic

acy

is n

ot

esta

blis

hed

in p

edia

tric

patie

nts

1) m

aint

enan

ce o

f ane

sthe

sia

with

oth

er a

nest

hest

ic a

gent

2)

ana

lges

ia

Rou

te o

f ad

min

istra

tion

IV

IM

IV

IV

Inha

latio

n

Dos

age

3

Indu

ctio

n &

mai

nten

ance

of

anes

thes

ia (s

hort

proc

edur

e)

IV o

ver

1m

in:

1-2m

g/kg

IM

4m

g/kg

In

duct

ion

& m

aint

enan

ce o

f an

esth

esia

(lon

g pr

oced

ure)

8-

30m

g/kg

/min

- -

Mai

nten

ance

of a

nest

hesi

a:

50-6

% in

oxy

gen

A

nalg

esia

U

p to

50%

in o

xyge

n

Adv

erse

effe

cts

1) H

yper

tens

ion,

tach

ycar

dia

2)

Psc

ychi

atric

sig

n &

sy

mpt

oms

-

- 1)

hyp

oxia

2)

meg

alob

last

ic a

nem

ia

3) n

euro

logi

cal t

oxic

effe

ct

Pro

duct

s av

aila

ble

in

MoH

form

ular

y

Ket

amin

e In

ject

ion

10m

g/m

l; 50

mg/

ml

Pro

pofo

l Inj

ectio

n 10

mg/

ml;

20m

g/m

l D

exm

edet

omid

ine

Inje

ctio

n 10

0mcg

/ml

-

Mis

ce

llan

eo

us

ag

en

tsE

g:

Ke

tam

ine

, p

rop

ofo

l, d

exm

ed

eto

mid

ine

, n

itro

us

oxi

de

Tab

le 1

0:

Me

ch

an

ism

of

ac

tio

n,

rou

tes

ava

ilab

le,

tim

e o

f o

nse

t, d

ura

tio

n,

do

sag

e a

nd

ad

vers

e e

ffe

cts

of

mis

ce

llan

eo

us

ag

en

t.3

,9,1

2,1

3


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References:

1. American Society of Anesthesiologists Home of Delegates. Continuum of Depth of Sedation: Definition of General Anesthesia and Levels of Sedation / Analgesia, 2009 October

2. Bhatt M, Kennedy RM, Osmond MH, McAllister JD, Ansermino JM, Evered LM, Roback MG. Consensus-Based Recommendations for Standardizing Terminology and Reporting Adverse Events for Emergency Department Procedural Sedation and Analgesia in Children. 2009 Apr; 53(4): 426-435.

3. BMA, Royal Pharmaceutical Society, Royal College and Pediatric of Child Health. BNF for Children 2011-2012.

4. Brighton and Sussex University Hospital, NHS. Pain Management Guideline, July 2010

5. Holsti L, Grunau RE. Considerations for Using Sucrose to Reduce Procedural Pain in Preterm Infants. Pediatrics. 2010 April; 125(5): 1042-1047.

6. Lefrak L, Burch K, Caraventes R, Knoerlein Kim, DeNolf N, Duncan J, Hampton F, Johnston C, Lockey D, Martin-Walters C, McLendon D, Porter M, Richardson C , Robinson C, Toczylowski K. Sucrose Analgesia: Identifying Potentially Better Practices. Pediatrics. 2006 Nov; 118 (S2): S197-S202.

7. My Pharmacist House. My Blue Book version 2.3.1

8. Pain Terms: A Current List with Definitions and Notes on Usage. International Association for the Study of Pain Taxonomy Working Group; 2011. [cited 06 October 2014]. Available from: http://iasp.files.cms-plus.com/Content/ ContentFolders/Publications2/ClassificationofChronicPain/Part_III- PainTerms.pdf

9. Pediatric & Neonatal Lexi Drugs, Lexicomp version 2.7.2

10. The Royal Australasian College of Physicians, Pediatrics & Child Health Divisions. Guideline Statement: Management of Procedure- related Pain in Neonates, 2005


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11. The Royal Children’s Hospital Melbourne. Sucrose (Oral) for Procedural Pain Management in Infants, 14 Dec 2012.

12. Thomson Reuters. Neofax 24th edition 2011.

13. Wilson-Smith, EM. Procedural Pain Management in Neonates, Infants and Children. Reviews in Pain. 2011 Sept; 5(3): 4-12.


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Indications for Total Perenteral Nutrition (TPN)

• Birth weight < 1000 gm

• Birth weight 1000-1500 gm and anticipated to be not on significant feeds for 3 or more days.

• Birth weight > 1500 gm and anticipated to be not on significant feeds for 5 or more days.

• Surgical conditions in neonates: necrotizing enterocolitis, gastroschisis, omphalocoele, tracheo-esophageal fistula, intestinal atresia, malrotation, short bowel syndrome, meconium ileus and diaphragmatic hernia.

Components Of Parenteral Nutrition

1. Macronutrients

• Proteins

• Carbohydrates • Lipid

2. Micronutrients

• Electrolytes

• Trace elements

• Vitamins

3. Fluids

• Water for injection

138

Total Parenteral Nutrition In Neonates Indications for Total Perenteral Nutrition (TPN)

• Birth weight < 1000 gm • Birth weight 1000-1500 gm and anticipated to be not on significant feeds for 3 or more

days. • Birth weight > 1500 gm and anticipated to be not on significant feeds for 5 or more days. • Surgical conditions in neonates: necrotizing enterocolitis, gastroschisis, omphalocoele,

tracheo-esophageal fistula, intestinal atresia, malrotation, short bowel syndrome, meconium ileus and diaphragmatic hernia.

Energy Requirement

Table 1 : Parenteral Energy Requirement

Age (Year) Energy Requirements (Kcal/kg/day) Pre-term 110 - 120

0-1 90 - 100 1-7 75 - 90

7-12 60 - 75 12-18 30 - 60

Components Of Parenteral Nutrition

1. Macronutrients

• Proteins

• Carbohydrates

• Lipid

2. Micronutrients

• Electrolytes

• Trace elements

• Vitamins

3. Fluids

• Water for injection

TOTAL PARENTERAL NUTRITION IN NEONATES

Energy Requirement


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1.Macronutrients

Proteins

• Mult iple studies have demonstrated that earl ier parenteral amino acid administration at amounts of 1.0–3.5 g/(kg·day) can reverse a negative nitrogen or stable isotope balance, which is indicative of protein accretion and thus growth, even at low caloric intake

• It decreases frequency and severity of neonatal hyperglycaemia by stimulating endogenous insulin secretion and stimulates growth by enhancing the secretion of insulin and insulin-like growth factors.

• Reduction in dosage may be needed in critically ill, significant hypoxaemia, suspected or proven infection and high dose steroids.

• Adverse effects of excess protein include a rise in urea and ammonia and high levels of potentially toxic amino acids such as phenylalanine.

1g amino acids provide 4kcal energy

The preferred nitrogen/ non-protein calorie is 1 g/100~200 kcal Product used is Vaminolact 6.53%

Lipids

• Lipids prevent essential fatty acid deficiency, provide energy substrates and improve delivery of fat soluble vitamins.

• LBW infants may have immature mechanisms for fat metabolism. Some conditions inhibit lipid clearance e.g. infection, stress, malnutrition.

• Avoid concentrations >2g/kg/day if infant has jaundice requiring phototherapy.

139

1. Macronutrients

Proteins

• Multiple studies have demonstrated that earlier parenteral amino acid administration at amounts of 1.0–3.5 g/(kg·day) can reverse a negative nitrogen or stable isotope balance, which is indicative of protein accretion and thus growth, even at low caloric intake




Proteins requirement

Table 2 : Parenteral amino acid supply Age (Year) Protein Requirement (g/kg/day)

Preterm Infants 1.5 - 4.0 Term Neonates 1.5 - 3.0

2nd Month to 3rd Year 1.0 - 2.5 3rd to 18th Year 1.0 - 2.0

(Critically ill patients may require upto 3.0) 1g amino acids provide 4kcal energy The preferred nitrogen/ non-protein calorie is 1 g/100~200 kcal Product used is Vaminolact 6.53% Lipids



• Avoid concentrations >2g/kg/day if infant has jaundice requiring phototherapy. Lipids requirement

Table 3 : Lipid Requirement

Age Initiate, g/kg/day Increase by, g/kg/day Maximum, g/kg/day Preterm Neonates 0.5 - 1.0 0.5 - 1.0 3.0 - 4.0

Term Neonates 1.0 0.5 - 1.0 3.0 - 4.0 • Lipid is crucial in avoiding essential fatty acids deficiency (EFAD). EFAD can be avoided

with as little as 0.5-1g/kg/day of fat emulsion. • 1g of lipid provide 9 kcal of energy. • Product available are lipofundin 20% and SMOFlipid. MCT/LCT lipid emulsions have an

advantage over LCT lipid emulsions.

139

1. Macronutrients

Proteins

• Multiple studies have demonstrated that earlier parenteral amino acid administration at amounts of 1.0–3.5 g/(kg·day) can reverse a negative nitrogen or stable isotope balance, which is indicative of protein accretion and thus growth, even at low caloric intake




Proteins requirement

Table 2 : Parenteral amino acid supply Age (Year) Protein Requirement (g/kg/day)

Preterm Infants 1.5 - 4.0 Term Neonates 1.5 - 3.0

2nd Month to 3rd Year 1.0 - 2.5 3rd to 18th Year 1.0 - 2.0

(Critically ill patients may require upto 3.0) 1g amino acids provide 4kcal energy The preferred nitrogen/ non-protein calorie is 1 g/100~200 kcal Product used is Vaminolact 6.53% Lipids



• Avoid concentrations >2g/kg/day if infant has jaundice requiring phototherapy. Lipids requirement

Table 3 : Lipid Requirement

Age Initiate, g/kg/day Increase by, g/kg/day Maximum, g/kg/day Preterm Neonates 0.5 - 1.0 0.5 - 1.0 3.0 - 4.0

Term Neonates 1.0 0.5 - 1.0 3.0 - 4.0 • Lipid is crucial in avoiding essential fatty acids deficiency (EFAD). EFAD can be avoided

with as little as 0.5-1g/kg/day of fat emulsion. • 1g of lipid provide 9 kcal of energy. • Product available are lipofundin 20% and SMOFlipid. MCT/LCT lipid emulsions have an

advantage over LCT lipid emulsions.

Lipids Requirement

Proteins Requirement


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• Lipid is crucial in avoiding essential fatty acids deficiency (EFAD). EFAD can be avoided with as little as 0.5-1g/kg/day of fat emulsion.

• 1g of lipid provide 9 kcal of energy.

• Product available are lipofundin 20% and SMOFlipid. MCT/LCT lipid emulsions have an advantage over LCT lipid emulsions.

Carbohydrate

• For ELBW neonates, continuous glucose infusion is needed to cater relatively high energy requirement in maintaining cerebral function.

• Maximum rate: 12 - 13 mg/kg/min (lower if lipid also administered) but in practice often limited by hyperglycaemia.

• Hyperglycaemia occurs in 20-80% of ELBW as a result of decreased insulin secret ion and insul in resistance, presumably due to to glucagon, catecholamine and cortisol release. Hyperglycaemia in the ELBW managed by decreasing glucose administration, administering intravenous amino acids and/or infusing exogenous insulin.

Carbohydrate requirement

• Source of carbohydrate is Dextrose 50%

• 1g of carbohydrate provides 4kcal energy.

*The use of early insulin therapy to prevent hyperglycemia is not recommended. The glucose infusion rate should be reduced by 1-2 mg/kg/min and insulin should be administered (0.05 IU/kg/h) when hyperglycemia is uncontrollable with glucose infusion rate being 4 mg/kg/min .

Fluids

• Fluids usually started at 60-80 ml/kg/day (if newborn), or at whatever stable fluid intake the baby is already receiving. • Postnatal weight loss of 5 - 15 % per day in the ELBW is acceptable. • Volumes are increased over the first 7 days in line with the aim to deliver 120- 150ml/kg/day by day 7.

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Carbohydrate



• Hyperglycaemia occurs in 20-80% of ELBW as a result of decreased insulin secretion and insulin resistance, presumably due to to glucagon, catecholamine and cortisol release. Hyperglycaemia in the ELBW managed by decreasing glucose administration, administering intravenous amino acids and/or infusing exogenous insulin.


Table 4 : Rate of administration of dextrose in pediatric patients on PN

Age Initiate, mg/kg/day

Increase by, mg/kg/day

Maximum rate, mg/kg/day

Preterm Neonates 4 - 6 1 - 2 12 - 13 Term Neonates 6 - 8 2 - 4 -

Infant 6 - 8 2 - 4 13 - 14 Children 6 - 8 2 - 4 6 - 9




Fluids

• Fluids usually started at 60-80 ml/kg/day (if newborn), or at whatever stable fluid intake the baby is already receiving.

• Postnatal weight loss of 5 - 15 % per day in the ELBW is acceptable. • Volumes are increased over the first 7 days in line with the aim to deliver 120-150

ml/kg/day by day 7.

Fluids requirements

Table 5 : Parenteral fluid intake during first postnatal week

Days After Birth

Recommended fluid intake (ml/kg/day)

1st Day 2nd Day 3rd Day 4th Day 5th Day 6th Day Term

Neonate 60 -‐ 120 80 -‐ 120 100 -‐ 130 120 -‐ 150 140 -‐ 160 140 -‐ 180

Preterm Neonate 60 -‐ 80 80 -‐ 100 100 -‐120 120 -‐150 140 -‐ 160 140 -‐ 160


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>1500g Preterm Neonate <1500g

80 -‐ 90 100 -‐ 110 120 -‐130 130 -‐150 140 -‐ 160 160 -‐ 180

Factors affecting fluids requirement

2. Micronutrients

Electrolytes

• Sodium supplementation should be started after initial diuresis (usually after the 48 hours), when serum sodium starts to drop or at least at 5-6% weight loss.

• Failure to provide sufficient sodium may be associated with poor weight gain.

• Potassium needs are 2-3 mEq/kg/day in both term and preterm infants. Start when urine output improves after the first 2-3 days of life.

• In extrauterine conditions, intrauterine calcium accretion rates is difficult to attain. Considering long-term appropriate mineralization and the fact that calcium retention between 60 to 90 mg/kg/d suppresses the risk of fracture and clinical symptoms of osteopenia, a mineral intake between 100 to 160 mg/kg/d of highly-absorbed calcium and 60 to 75 mg/kg/d of phosphorus could be recommended.

• Monitoring for osteopaenia of prematurity is important especially if prolonged PN.

• A normal magnesium level is a prerequisite for a normal calcaemia. In well balanced formulations, however, magnesium level does not give rise to major problems.

2. Micronutrients

Electrolytes

• Sodium supplementation should be started after initial diuresis (usually after the 48 hours), when serum sodium starts to drop or at least at 5-6% weight loss.

• Failure to provide sufficient sodium may be associated with poor weight gain.

• Potassium needs are 2-3 mEq/kg/day in both term and preterm infants. Start when urine output improves after the first 2-3 days of life.

• In extrauterine conditions, intrauterine calcium accretion rates is difficult to attain. Considering long-term appropriate mineralization and the fact that calcium retention between 60 to 90 mg/kg/d suppresses the risk of fracture and clinical symptoms of osteopenia, a mineral intake between 100 to 160 mg/kg/d of highly-absorbed calcium and 60 to 75 mg/kg/d of phosphorus could be recommended.

Fluids Requirement

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Carbohydrate



• Hyperglycaemia occurs in 20-80% of ELBW as a result of decreased insulin secretion and insulin resistance, presumably due to to glucagon, catecholamine and cortisol release. Hyperglycaemia in the ELBW managed by decreasing glucose administration, administering intravenous amino acids and/or infusing exogenous insulin.


Table 4 : Rate of administration of dextrose in pediatric patients on PN

Age Initiate, mg/kg/day

Increase by, mg/kg/day

Maximum rate, mg/kg/day

Preterm Neonates 4 - 6 1 - 2 12 - 13 Term Neonates 6 - 8 2 - 4 -

Infant 6 - 8 2 - 4 13 - 14 Children 6 - 8 2 - 4 6 - 9




Table 5 : Parenteral fluid intake during first postnatal week

Days After Birth

Recommended fluid intake (ml/kg/day)

1st Day 2nd Day 3rd Day 4th Day 5th Day 6th Day Term

Neonate 60 -‐ 120 80 -‐ 120 100 -‐ 130 120 -‐ 150 140 -‐ 160 140 -‐ 180

Preterm Neonate >1500g

60 -‐ 80 80 -‐ 100 100 -‐120 120 -‐150 140 -‐ 160 140 -‐ 160

Preterm Neonate <1500g

80 -‐ 90 100 -‐ 110 120 -‐130 130 -‐150 140 -‐ 160 160 -‐ 180

Factors affecting fluids requirement Factors affect ing f luids requirement


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Electrolytes requirement

Table 6 : Daily electrolyte requirements for pediatric patients

Electrolytes Preterm Neonates Infants/Children Sodium 2 - 5 mEq/kg 2 - 5 mEq/kg

Potassium 2 - 4 mEq/kg 2 - 4 mEq/kg Calcium 2 - 4 mEq/kg 0.5 - 4 mEq/kg

Phosphorus 1 - 2 mmol/kg 0.5 - 2 mmol/kg Magnesium 0.3 - 0.5 mEq/kg 0.3 - 0.5 mEq/kg

Acetate As needed to mantain acid base balance

As needed to mantain acid base balance

Table 7 : Recommendations on the daily intake of Ca, P, Mg and vitamin D for preterm VLBW infants issued by different bodies & authors

Intake Reccomenda

tion

ESPGAN 1987

ESPGHAN 2010

LSRO 2002

Atkinson & Tsang 2005

RIGO 2007

AAP 2013

Current authors

Proposal 2013

Ca, mg/kg/day 70 -140 120-140 150-220 120-200 100-160 150-220 120-200

P, mg/kg/day 50-90 60-90 100-130 70-120 60-90 75-140 60-140 Mg,

mg/kg/day 4.85-9.7 8-15 6.8-17mg/ 100kCal 7.2-9.6 Not

provided Not

provided 8-15

Vitamin D, IU/day 800-1600 800-1000 90-225 200-1000 800-

1000 200-400 400-1000

• Monitoring for osteopaenia of prematurity is important especially if prolonged PN.

• A normal magnesium level is a prerequisite for a normal calcaemia. In well balanced formulations, however, magnesium level does not give rise to major problems.

Electrolytes Requirement


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Tab

le 8

: A

ccep

tab

le r

ange

of v

itam

in in

take

s fo

r V

LBW

& E

LBW

infa

nts


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Table 8 : Acceptable range of vitamin intakes for VLBW & ELBW infants

Trace elements requirement

Trace Elements

Product Dosage Peditrace

Neonates < 15kg : 1ml/kg/day Infants & Children >15kg : 15ml/day Max : 15mL / day

Water soluble vitamins requirement

Water Soluble Vitamin

Product Dosage Soluvit N


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Table 8 : Acceptable range of vitamin intakes for VLBW & ELBW infants


Trace Elements

Product Dosage Peditrace



Water Soluble Vitamin

Product Dosage Soluvit N


References :

1. Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Societyof Paediatric Research (ESPR) 2005; Berthold Koletzko, Olivier Goulet, oanne Hunt, Kathrin Krohn, and Raanan Shamir

2. Paediatric Protocols For Malaysian Hospitals 3rd Edition ; Hussain Imam Hj Muhammad Ismail; Ng Hoong Phak; Terrence Thomas

3. Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 49–63 ( DOI: 10.1159/000358458




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Fluid, electrolyte, and nutrition management is important because most infants in a neonatal intensive care unit (NICU) require intravenous fluids (IVFs) and have shifts of fluids between intracellular, extracellular, and vascular compartments. Therefore, careful attention to fluid and electrolyte balance is essential. If inappropriate fluids are administered, serious morbidity may result from fluid and electrolyte imbalances. Inadequate attention to nutrition in the neonatal period leads to growth failure, osteopenia of prematurity, and other complications.

Total fluid requirements

Total fluid requirement includes the maintenance requirement to replace measure losses (urine, stool) and insensible water loss (IWL) and the fluid requirement for growth.

• Total fluids = Maintenance + Growth

• Maintenance = SWL (sensible water lost) + IWL (Insensible water lost)

• Start with D10W (10% dextrose in water) Sodium and Potassium added on the second/third day

• Slower rates of increment for preterm infants, i.e. of 20 mls/kg/day.

• More increments may be needed if evidence of dehydration, i.e. excessive weight loss and hypernatraemia >145 mmol/l.

FLUID & ELECTROLYTE MANAGEMENT

145

Fluid & Electrolyte Management Fluid, electrolyte, and nutrition management is important because most infants in a neonatal intensive care unit (NICU) require intravenous fluids (IVFs) and have shifts of fluids between intracellular, extracellular, and vascular compartments. Therefore, careful attention to fluid and electrolyte balance is essential. If inappropriate fluids are administered, serious morbidity may result from fluid and electrolyte imbalances. Inadequate attention to nutrition in the neonatal period leads to growth failure, osteopenia of prematurity, and other complications.

Fluid and Electrolyte Management

Total fluid requirements

Total Fluid requirement includes the maintenance requirement to replace measure losses (urine, stool) and insensible water loss (IWL) and the fluid requirement for growth.

• Total fluids = Maintenance + Growth • Maintenance = SWL (sensible water lost) + IWL (Insensible water lost) • Start with D10W (10% dextrose in water) Sodium and Potassium added on the

second/third day • Slower rates of increment for preterm infants, i.e. of 20 mls/kg/day. • More increments may be needed if evidence of dehydration,

i.e. excessive weight loss and hypernatraemia >145 mmol/l.

Table 1: Empiric Fluid Therapy for newborns

0-24 hours 60 ml/kg/day 24-48 hours 90 ml/kg/day 48-72 hours 120 ml/kg/day > 72 hours 150 ml/kg/day

Fluid Issues Associated With Common Neonatal Conditions:

Issues requiring fluid restriction:

� RDS: Excessive fluid can lead to fluid overload and increased risk of BPD � BPD: Excessive fluid can worsen therefore treated with diuretics to reduce

pulmonary edema � PDA: Volume overload can open ductus and worsen respiratory status � HIE: Associated with ATN and/or SIADH and can lead to subsequent volume

overload

Electrolyte Requirements

Table 1 : Empiric Fluid Therapy for Newborns


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Fluid Issues Associated With Common Neonatal Conditions:

Issues requiring fluid restriction:

• RDS: Excessive fluid can lead to fluid overload and increased risk of BPD • BPD: Excessive fluid can worsen therefore treated with diuretics to reduce pulmonary edema • PDA: Volume overload can open ductus and worsen respiratory status • HIE: Associated with ATN and/or SIADH and can lead to subsequent volume overload

Electrolyte Requirements

First 24h of life: No electrolytes (except Ca)

• Ca especially important for preterm infants After 24h of life: • Na : 2-3 mmol/kg/day • K : 1-2 mmmol/kg/day

Supplemetation of elctrolytes will need to be fine-tuned according to measurement of electrolytes and urine output and disease status.

* Extremely pre-term infants with metabolic acidosis (loss of bicarb in urine) may benefit from sodium acetate

After the first week of life, during active groth the requirement of sodium and potassium increases;

• Na: 3-5 mmol/kg/day• K: 2-3 mmmol/kg/day

Many preterm may require 6-8mmol/kg/day of sodium and up to 12mmol/kg/day. This is partly due to inability to retain sodium and secondary use of diuretics

References:

1. Hussain Imam Hj Muhammad Ismail, Ng Hoong Phak, Terrence Thomas. Paediatric Protocols for Malaysian Hospitals, 3rd ed. : Kementerian Kesihatan Malaysia; 2012

2. O’Brien, F., Walker, I. A. (2014), Fluid homeostasis in the neonate. Pediatric Anesthesia, 24: 49–59. doi: 10.1111/pan.12326

3. B. Koletzko, C. Agostoni, P. Ball et al. ESPGHAN Guidelines on paediatric parenteral nutrition.Journal of Pediatric Gastroenterology and Nutrition 2005;41:S1-S87


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Introduction

As mentioned by Morgan JA et al, necrotising enterocolitis (NEC) is the commonest neonatal gastrointestinal emergency.7 NEC is an inflammatory disease of the intestine which is often associated with sepsis and frequently complicated by perforation, peritonitis and death12

Spontaneous intestinal perforation (SIP) among preterm infants had been categorized as necrotizing enterocolits. However it has different disease entity and different pathogenesis. SIP usually occurs in the 1st several days after birth and is not associated with enteral feeding. SIP is associated with minimal intestinal inflammation and necrosis with low level of serum inflammatory markers8

Risk Factors7,9 (1) Prematurity (<28weeks)

(2) Enteral feeding

(3) Growth restricted neonate

(4) Maternal hypertensive disease of pregnancy

(5) Placental abruption

(6) Absent or reversed end diastolic flow velocity

(7) Use of umbilical catheters

(8) Low Apgar scores

(9) Packed cell transfusions Pathogenesis6,8,9,12

The pathogenesis of NEC is not completely understood, it is considered to be multifactorial. It is a combination of the following causes:

(1) Immature epithelial barrier

(2) Abnormal microbial colonization in the intestine

(3) Hypoxia-ischemia

(4) Genetic predisposition

NECROTIZING ENTEROCOLITIS


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• Immature epithelial barrier 12

The intestinal mucosa presents a persistent equilibrium state between injury and repair. Intestinal mucosa injury can be due to various factors including hypoxia, infection, and starvation. In physiological conditions, healing of epithelium starts with migration of matured enterocytes from health to the injured area. Subsequently, new enterocytes will mature and migrate to the surface epithelium. In NEC, there is a marked inhibition in both the enterocyte migration and proliferation, resulting more intestinal mucosa injury.

Toll-like receptors (TLRs) are innate immunity components located on the epithelial surface which play a major role in tissue repair. TLR type 4 (TLR4) are crucial in NEC development. The activation of TLR4 inhibits the enterocyte migration and maturation thus.

• Abnormal microbial colonization in the intestine9,12

Mechanism by which infection contribute to NEC remain unknown. The suggested mechanism is the decreased microbial diversity and alteration in the microbial species that may happen in prolonged antibiotic therapy, which may reduce the colonization resistance. The usual rich diversity of intestinal microflora which protect the host against hospital-acquired pathogens is lacking. Studies suggest that NEC is not due to a single species but is more likely from an undefined dysbiosis, that may cause TLR4 activation and pathogens translocation across the epithelium.

• Hypoxia-ischemia8

Hypoxia and ischemia modulate the balance in microvascular tone related to the production of vascular regulator eg nitric oxide and endothelin which may cause NEC


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Complications6,9

(1) higher incidence of nosocomial infection(2) lower level of nutrient intake(3) slower growth development(4) longer duration of intensive care and hospital stay(5) higher incidence of bronchopulmonary dysplasia(6) higher incidence of retinopathy of prematurity(7) growth restriction in long term(8) neurodisability(9) adverse neurodevelopment in long term

148

Studies suggest that NEC is not due to a single species but is more likely from an undefined dysbiosis, that may cause TLR4 activation and pathogens translocation across the epithelium.

• Hypoxia-ischemia 8

Hypoxia and ischemia modulate the balance in microvascular tone related to the production of vascular regulator eg nitric oxide and endothelin which may cause NEC

Fig 1: Pathogenesis of NEC (Adapted from Terrin G) 12

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Table 1: Clinical presentation of NEC (Modified Bell Classification) (Adapted from Patel BK)9

Complications6,9 (1) higher incidence of nosocomial infection (2) lower level of nutrient intake (3) slower growth development (4) longer duration of intensive care and hospital stay (5) higher incidence of bronchopulmonary dysplasia (6) higher incidence of retinopathy of prematurity (7) growth restriction in long term (8) neurodisability (9) adverse neurodevelopment in long term Management

Table 2: Management of NEC based on Modified Bell Classification (Adopted from Neu J)8

Modified Bell Classification

Management

“Suspected” NEC

(1) Clinical observation of increased abdominal distension and feeding intolerance (2) Brief discontinuation of feeding eg: 24hr-NBM (3) Abdominal radiograph (if have yet done) (4) Monitor FBC (5) Blood C&S (6) Short course of IV antibiotics

“Defined” NEC

(1) Enteral feeding discontinuation for 7-10days (2) Monitor FBC (3) Blood C&S (4) IV antibiotics 7-10days (5) Refer surgical team

“Advanced” NEC (1) Exploratory laparotomy with resection if necessary


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Table 1: Clinical presentation of NEC (Modified Bell Classification) (Adapted from Patel BK)9

Complications6,9 (1) higher incidence of nosocomial infection (2) lower level of nutrient intake (3) slower growth development (4) longer duration of intensive care and hospital stay (5) higher incidence of bronchopulmonary dysplasia (6) higher incidence of retinopathy of prematurity (7) growth restriction in long term (8) neurodisability (9) adverse neurodevelopment in long term Management

Table 2: Management of NEC based on Modified Bell Classification (Adopted from Neu J)8

Modified Bell Classification

Management

“Suspected” NEC

(1) Clinical observation of increased abdominal distension and feeding intolerance (2) Brief discontinuation of feeding eg: 24hr-NBM (3) Abdominal radiograph (if have yet done) (4) Monitor FBC (5) Blood C&S (6) Short course of IV antibiotics

“Defined” NEC

(1) Enteral feeding discontinuation for 7-10days (2) Monitor FBC (3) Blood C&S (4) IV antibiotics 7-10days (5) Refer surgical team

“Advanced” NEC (1) Exploratory laparotomy with resection if necessary

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(2) Primary peritoneal drainage without laparotomy

Indications for surgery9 (1) clinical deterioration despite maximal medical intervention (2) presence of pneumoperitoneum (3) abdominal mass with intestinal obstruction (4) development of intestinal stricture Prevention Numerous approaches have been proposed to prevent NEC:

Table 3: Strategies to Prevent NEC (Adapted from Neu J & Walker WA)8

Evidence of Efficacy & Safety

Evidence of Efficacy but Questionable

Safety

Evidence of Efficacy in Animal Models but Not in Human

Proposed Efficacy but Lack of Evidence

Breast-milk feeding Probiotics Growth factors Prebiotics Non-aggressive enteral feeding

Arginine Anticytokines TLR4 modulation

Enteral antibiotics Glutamine Glucocorticoids n-3 fatty acids

• Arginine

Nitric oxide (NO) plays an important role in mediating intestinal vasomotor tone. It is an inhibitory neurotransmitter in the gastrointestinal system inducing gut smooth muscle relaxation, regulate mucosal blood flow, maintain mucosal integrity and intestinal barrier function. Arginine is involved in NO production. A relative deficiency of arginine results in inadequate NO, causing vasoconstriction, ischemic reperfusion injury and development of NEC. A systemic review included 2 studies ie. Amin et al 2002 and Polycarpou et al 2013 had been carried out.

Table 4: A study of Arginine Supplementation in Prevention of NEC in Preterm Infants

Study Population Study design

Results Conclusion

Mitchell K et al. (2014)6

2 RCT Systematic review

59% NEC reduction in L-arginine group

L-arginine can prevent NEC in preterm infants. However large RCTs are needed.

• Epidermal Growth Factor (EGF)

EGF have shown protective role in animal model. EGF in amniotic fluid can inhibit TLR4 signal and subsequently enhance epithelial repair. As quoted by Patel BK & Shah JS, a small study by Sullivan et al. in 2007 showed positive effect. Further investigation is needed9

• Feeding Strategies - Cautious Advancement of Feeds

Observational studies showed that NEC incidence is higher in patients with early enteral feed introduction and faster advancement. Nonetheless recent data are insufficient to determine which specific feeding strategies have the highest risk of patients developing NEC6

150






Safety






• Arginine




Results Conclusion









Indications for surgery9

(1) clinical deterioration despite maximal medical intervention(2) presence of pneumoperitoneum(3) abdominal mass with intestinal obstruction(4) development of intestinal stricture

PreventionNumerous approaches have been proposed to prevent NEC:

• Arginine


Management


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Safety






• Arginine




Results Conclusion










- EGF have shown protective role in animal model. EGF in amniotic fluid can inhibit TLR4 signal and subsequently enhance epithelial repair. As quoted by Patel BK & Shah JS, a small study by Sullivan et al. in 2007 showed positive effect. Further investigation is needed9

• Feeding Strategies - Cautious Advancement of Feeds Observational studies showed that NEC incidence is higher in patients with early enteral feed introduction and faster advancement. Nonetheless recent data are insufficient to determine which specific feeding strategies have the highest risk of patients developing NEC6

- Trophic Feeding

As quoted by Patel BK & Shah JS, Cochrane review of 8 studies concluded that trophic feeding has no significant effect on NEC9

• Gastric Acid Suppression - As quoted by Morgan JA et al., Guillet R & colleagues showed that the use of H2-blocker which suppress gastric acidity in preterm infants is associated with higher risk of NEC. Gastic acid may play crucial role in preventing the infection and inflammation that will cause NEC development. As quoted by Morgan JA et al., Anderson P & Guillet R recommended that use of H2- blocker should be restricted until further evidence that benefits outweigh the harm is available7

• Glutamine - Experimental studies have shown that glutamine serve as fuel for enterocytes, stimulate the mucosal cell proliferation and differentiation and maintain the integrity of tight junctions thus reduce mucosal damage and lower the risk of invasive infection7,9 However, as quoted by Morgan JA etal., a Cochrane review of good quality randomized controlled trial, by Tubman TR published in 2008 indicated that glutamine supplementation does not confer benefits for preterm infants7


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Table 6: Studies on Prolonged Empirical Antibiotics Increase the Incidence of NEC or Death

Study Population Study design Results Cotton MC et al. (2009) 1

(1) N= 5693 (2) ≤ 1.0kg

Retrospective cohort study

NEC or death is higher in the group of prolonged empirical antibiotics (≥5days) (61%, p<.001)

Kuppala V et al. (2011) 3

(1) N= 365 (2) ≤ 32weeks gestational age & ≤1.5kg


Late-onset-sepsis, NEC or death is significantly higher in the group of prolonged empirical antibiotics (≥5 days) (41% vs 18%, p<.0001)

Based on the findings of these studies, Morgan JA et al reinforce that empirical antibiotics for preterm infants should be started early when sepsis is suspected and to be discontinued early once sepsis is excluded7

• Lactoferrin Lactoferrin is an antimicrobial glycoprotein which present in colostrum and breast milk. Lactoferrin has broad activity against Gram-positive cocci, Gram-negative bacilli and Candida sp. There is low level of Lactoferrin in VLBW infants and this is worsened by delay establishment of enteral feeding7,9. An Italian randomized controlled trial showed positive effect of Lactoferrin supplementation4

Table 7: RCT of Lactoferrin Supplementation in Prevention NEC in VLBW Infants

Study Population Study design Results Manzoni P et al. (2009)4

472 VLBW infants Multicenter, double blind, RCT

Nil NEC in Lactoferrin + probiotic group; 6% NEC in control group (p=.002)

• Modulation of TLR4 Signal

Only animal model has been tested, more human clinical trials are needed

• Oral Immunoglobulins (Ig) Ig is a possible factors in human milk which is responsible for NEC protective effect. However, as quoted by Patel BK & Shah JS, Cochrane review published in 2004 showed that oral IgG as well as combination of IgG with IgA did not result in significant reduction of NEC incidence9

• Prebiotics Prebiotics are non-digestible food components that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon thereby improving host health9. Examples of prebiotics include oligosaccharides inulin, galactose, fructose and lactulose. Oligosaccharides that are contained in human milk have been shown to enhance

• Human milk

- It is suggested that human milk may reduce the risk of NEC by reducing pathogenic bacterial colonization, promote the growth of non-pathogenic microflora, enhance the maturation of gastrointestinal tract and regulate the pro-inflammatory response in preterm neonates. The positive effects of human milk may be due to several factors eg: macrophages, lymphocytes, lysozyme, lactoferrin, oligosaccharides, nucleotides, cytokines, growth factors and enzymes. Studies have demonstrated positive effect of human milk in lowering incidence of NEC8,9,12

• Judicious Restriction of Prolonged Empirical Antibiotics

Studies have shown that prolonged empirical antibiotics lead to higher NEC risk in premature infants.


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- Trophic Feeding As quoted by Patel BK & Shah JS, Cochrane review of 8 studies concluded that trophic feeding has no significant effect on NEC9

• Gastric Acid Suppression As quoted by Morgan JA et al., Guillet R & colleagues showed that the use of H2-blocker which suppress gastric acidity in preterm infants is associated with higher risk of NEC. Gastic acid may play crucial role in preventing the infection and inflammation that will cause NEC development. As quoted by Morgan JA et al., Anderson P & Guillet R recommended that use of H2-blocker should be restricted until further evidence that benefits outweigh the harm is available7

• Glutamine Experimental studies have shown that glutamine serve as fuel for enterocytes, stimulate the mucosal cell proliferation and differentiation and maintain the integrity of tight junctions thus reduce mucosal damage and lower the risk of invasive infection7,9 However, as quoted by Morgan JA et al., a Cochrane review of good quality randomized controlled trial, by Tubman TR published in 2008 indicated that glutamine supplementation does not confer benefits for preterm infants7

• Human milk It is suggested that human milk may reduce the risk of NEC by reducing pathogenic bacterial colonization, promote the growth of non-pathogenic microflora, enhance the maturation of gastrointestinal tract and regulate the pro-inflammatory response in preterm neonates. The positive effects of human milk may be due to several factors eg: macrophages, lymphocytes, lysozyme, lactoferrin, oligosaccharides, nucleotides, cytokines, growth factors and enzymes. Studies have demonstrated positive effect of human milk in lowering incidence of NEC8,9 & 12

Table 5: Studies on Effect of Human Milk on NEC Development

Study Population/Subjects Study

Design Results

McGuire &

Anthony,

20035

4 clinical trials Meta-analysis Infants on human milk were 4

times less likely to have confirmed

NEC

Sullivan et

al, 201010

207 preterm infants Randomized

Controlled

Trial

Exclusive human milk result in

lower incidence of NEC

• Judicious Restriction of Prolonged Empirical Antibiotics

Studies have shown that prolonged empirical antibiotics lead to higher NEC risk in premature infants.


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(1) N= 5693 (2) ≤ 1.0kg

















• Lactoferrin

- Lactoferrin is an antimicrobial glycoprotein which present in colostrum and breast milk. Lactoferrin has broad activity against Gram-positive cocci, Gram- negative bacilli and Candida sp. There is low level of Lactoferrin in VLBW infants and this is worsened by delay establishment of enteral feeding7.9. An Italian randomized controlled trial showed positive effect of Lactoferrin supplementation4


- Only animal model has been tested, more human clinical trials are needed

• Oral Immunoglobulins (Ig)

- Ig is a possible factors in human milk which is responsible for NEC protective effect. However, as quoted by Patel BK & Shah JS, Cochrane review published in 2004 showed that oral IgG as well as combination of IgG with IgA did not result in significant reduction of NEC incidence9

• Prebiotics

- Prebiotics are non-digestible food components that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon thereby improving host health9. Examples of prebiotics include oligosaccharides inulin, galactose, fructose and lactulose. Oligosaccharides that are contained in human milk have been shown to enhance the proliferation of bifidobacteria and lactobacilli in the colon9. However, up to date, the evidence regarding the effectiveness of prebiotics use in preterm infants is still limited.

• Probiotics

- Probiotics are live microorganisms such as lactobacilli and bifidobacteria which when administered in adequate amount confer a health benefit on the host. Potential benefits of probiotics including:

(1) inhibition of pathogenic colonization and produce anti-inflammatory effects

(2) secretion of lactic acid that lower local pH thus inhibit the growth of pathogenic bacteria


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(1) N= 5693 (2) ≤ 1.0kg

















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the proliferation of bifidobacteria and lactobacilli in the colon9. However, up to date, the evidence regarding the effectiveness of prebiotics use in preterm infants is still limited.

• Probiotics Probiotics are live microorganisms such as lactobacilli and bifidobacteria which when administered in adequate amount confer a health benefit on the host. Potential benefits of probiotics including: (1) inhibition of pathogenic colonization and produce anti-inflammatory effects (2) secretion of lactic acid that lower local pH thus inhibit the growth of pathogenic bacteria (3) communicate directly with pathogenic bacteria thus modulating their gene expression, reducing the binding to the host epithelial cells (4) stimulation of production of secretory immunoglobulins and cause positive effect to immunity response Some clinical trials have demonstrated that supplementing the diet of preterm infants with probiotics is beneficial.

Table 8: Clinical Trials of Probiotics Supplementation Decrease the Incidence of Neonatal NEC

Study Population / Subjects Study

Design Results

Lin et al. (quoted by Patel BK)9

Multicenter, 434 infants Masked randomized controlled trial

1.8% probiotics group developed NEC; 6.5% non-probiotics group developed NEC

Deshpande et al.2

15 randomized controlled trial

Meta analysis 30% reduction in NEC (p<.00001)

Wang et al.13

20 randomized controlled trial

Meta analysis 3% probiotics group developed NEC; 7.4% placebo-group developed NEC (p<.00001)

A recent commentary by Tarnow-Modi WO and colleagues also suggest the routine use of probiotics11 However, a systematic review by Milhatsch et al, published in 2012 concluded that there is still no conclusive evidence to recommend routine use of probiotics in preterm infants. In settings with high incidence of NEC, clinicians may consider off-label use of specific probiotics. There are still limitations of routine probiotics use14: (1) unknown optimal strain and dosing (2) no evidence showing whether single or multiple strain are more effective (3) safety and efficacy of each probiotic strain has to be studied (4) non convincing data that probiotics prevent sepsis (5) possibility of infections caused by probiotics (6) long term effects on fecal flora and immune system

(3) communicate directly with pathogenic bacteria thus modulating their gene expression, reducing the binding to the host epithelial cells

(4) stimulation of production of secretory immunoglobulins and cause positive effect to immunity response some clinical trials have demonstrated that supplementing the diet of preterm infants with probiotics is beneficial.

A recent commentary by Tarnow-Modi WO and colleagues also suggest the routine use of probiotics11

However, a systematic review by Milhatsch et al, published in 2012 concluded that there is still no conclusive evidence to recommend routine use of probiotics in preterm infants.

In settings with high incidence of NEC, clinicians may consider off-label use of specific probiotics.

There are still limitations of routine probiotics use14:

(1) unknown optimal strain and dosing (2) no evidence showing whether single or multiple strain are more effective (3) safety and efficacy of each probiotic strain has to be studied (4) non convincing data that probiotics prevent sepsis (5) possibility of infections caused by probiotics (6) long term effects on fecal flora and immune system

• Prophylatic Enteral Antibiotics

- As quoted by Patel BK & Shah JS and also Neu J & Walker WA, several small studies suggest that oral antibiotics can reduce incidence of NEC8,9


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• Prophylatic Enteral Antibiotics As quoted by Patel BK & Shah JS and also Neu J & Walker WA, several small studies suggest that oral antibiotics can reduce incidence of NEC8,9

Table 9: Studies of Enteral Antibiotics Reduce the Incidence of NEC

Study Enteral antibiotics

Quoted by Patel BK & Shah JS 9 Egan et al. (1977) Kanamycin Siu YK et al. (1998) Vancomycin Bury RG (2000) Systemic review Quoted by Neu J & Walker WA Grylack LJ et al (1978) Gentamicin

Nonetheless, as being quoted by Patel BK, Cochrane review by Bury RG showed concern on resistant bacteria thus routine use of prophylactic enteral antibiotics is not recommended9

• Polyunsaturated Fatty Acids (PUFA) PUFA have been proposed to modulate inflammation and immunity. As quoted by Patel BK & Shah JS, Carlson et al (1998) demonstrated lower incidence of NEC9

• Synbiotics Synbiotic is a product contain both probiotics and prebiotics. As quoted by Patel BK & Shah JS, RCT done by Underwood MA & friends in 2009 demonstrated positive result in synbiotics-group9

• Zinc Zinc participates in many metabolic pathway. As quoted by Patel BK & Shah JS, Terrin R et al. demonstrated that zinc plays important role in maintenance of epithelial barrier function and induction of adequate immune response. Terrin R & colleagues (2013) showed that high dose zinc is also effective in reducing NEC in preterm infants9

Nonetheless, as being quoted by Patel BK, Cochrane review by Bury RG showed concern on resistant bacteria thus routine use of prophylactic enteral antibiotics is not recommended9

• Polyunsaturated Fatty Acids (PUFA)

- PUFA have been proposed to modulate inflammation and immunity. As quoted by Patel BK & Shah JS, Carlson et al (1998) demonstrated lower incidence of NEC9

• Synbiotics

- Synbiotic is a product contain both probiotics and prebiotics. As quoted by Patel BK & Shah JS, RCT done by Underwood MA & friends in 2009 demonstrated positive result in synbiotics-group9

• Zinc

- Zinc participates in many metabolic pathway. As quoted by Patel BK & Shah JS, Terrin R et al. demonstrated that zinc plays important role in maintenance of epithelial barrier function and induction of adequate immune response. Terrin R & colleagues (2013) showed that high dose zinc is also effective in reducing NEC in preterm infants9


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References:

1. Cotten MC, Taylor S, Stoll B, Goldberg R, Hansen NI, Sanchez PJ, Ambalavanan N, Benjamin DK. Prolonged Duration of Initial Empirical Antibiotic Treatment Is Associated with Increased Rates of Necrotising Enterocol i t is and Death for Extremely Low Birth Weight Infants. Pediatrics. 2009; 123(1): 58-66.

2. Deshpande G, Rao S, Patole S, Bulsara M. Updated Meta-analysis of Probiotics for Preventing Necrotising Enterocolitis in Preterm Neonates. Pediatrics. 2010;125: 921-30.

3. Kuppala VS, Meinzen-Derr J, Morrow AL, Schibbler KR. Prolonged Initial Empirical Antibiotic Treatment is Associated with Adverse Outcomes in Premature Infants. Journal of Pediatric. 2011: 159(5): 720-25.

4. Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MC, Messner H, Stolfi I, Decembrino L, Laforgia N, Vagnarelli F, Memo L, Bordignon L, Saia OS,Maule M, Gallo E, Mostert M, Magnani C, Quercia M, Bollani L, Pedicino R, Renzullo L, Betta P, Mosca P, Ferrari F, Magaldi R, Stronati M, Farina D. Bovine Lactoferrin Supplementation for Prevention of Late-Onset Sepsis in Very Low-Birth-Weight Neonates: A Randomised Trial.JAMA. 2009; 302(13): 1421-28.

5. McGuire W, Anthony AY. Donor Human Milk versus Formula for Preventing Necrotising Enterocolitis in Preterm Infants: Systemic Review. Arch Dis Child Fetal Neonatal, 2003; 88: F11-14.

6. Mitchell K, Lyttle A, Amin H, Shaireen H, Robertson HL, Lodha A. Arginine Supplementat ion in the Prevention of Necrot ising Enterocol i t is in the Premature Infant: An Updated Systemic Review. BMC Pediatrics. 2014; 14 (226): 1-10.

7. Morgan JA, Young L, McGuire W. Pathogenesis and Prevention of Necrotising Enterocolitis. Current Opinion in Infectious Diseases. 2011; 24: 183-189. doi: 10.1097

8. Neu J, Walker WA. Necrotising Enterocolitis. The New England Journal of Medicine. 2011 Jan 20; 36(43): 255-263.


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9. Patel BK, Shah JS. Necrotizing Enterocolitis in Very Low Birth Weight Infants: A Systemic Review. International Scholarly Research Network, 2012 June 19: 1-7. doi: 10.5402

10. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawoger R, Kohlendorfer UK, Chan GM, Blanco CL, Abrams S, Cotton M, Laroia N, Ehrenkranz R, Dudell G, Cristofalo E, Meier P, Lee ML, Retchman DJ, Lucas A. An Exclusively Human-milk Based Diet is Associated with a Lower rate of Necrotising Enterocolitis than A Diet of Human Milk and Bovine Milk-Based Products. The Journal of Pediatrics. 2010; 156: 562-67.

11. Tarnow-Modi WO, Wilkinson D, Trivedi A, Brok J. Probiotics Reduce All- Cause Mortality and Necrotising Enterocolitis: It Is Time to Change Practice. Pediatrics. 2009; 125: 1068-70.

12. Terrin G, Scipione A, Curtis MD. Update in the Pathogenesis and Prospective in Treatment of Necrotisong Enterocolitis. BioMed Research International. 2014 July 17: 1-9. doi: 10.1155

13. Wang Q, Dong J, Zhu Y. Probiotic Supplement Reduces Risk of Necrotizing Enterocolitis and Mortality in Preterm Very Low-Birth Weight Infants: An Updated Meta-Analysis of 20 Randomized, Controlled Trials. Journal of Pediatric Surgery. 2012; 47: 241-48.

14. Mihatsch WA, Braegger CP, Decsi T, Kolacek S, Lanzinger H, Mayer B, Moreno LA, Pohlandt F, Puntis J, Shamir R, Stadtmuller U, Szajewska H, Turck D, Gondoever JB. Crit ical Systemic Review of the Level of Evidence for Routine Use of Probiotics For Reduction of Mortality and Prevention of Necrotising Enterocolitis and Sepsis in Preterm Infants. Clinical Nutrition. 2012; 31: 6-15


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Dosing considerations in underweight, overweight & obese children

When initiating drug therapy for children, the patient’s total body weight or body surface area is used to calculate the dose required. However, special consideration must be given to patients whose weight does not fall within the accepted healthy weight range. Definition of Healthy Weight: Children > 2 years or older : BMI-for-age is above the 5th percentile and below the 85th percentile compared with children of the same age and sex which reflects the desirable body weight for a particular age and height that is optimal for nutrition status.

Dosing in Underweight Patients :

Definition of Underweight: Children > 2 years or older : BMI-for-age is below the 5th percentile compared with children of the same age and sex.

Dosing utilizes the actual total body weight while taking into consideration general nutritional status and precautions regarding possible altered drug clearance e.g. renal and hepatic function.

Dosing in overweight & obese children :

Definition of Overweight:

Children < 2 years of age: Normal BMI not available, hence weight-for-height values above the 95th percentile in this age group can be categorized as overweight.

Children >2 years or older : BMI-for-age at or above the 85th and below the 95th percentile compared with children of the same age and sex

6.0 DOSING CONSIDERATIONS INSPECIAL POPULATIONS


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Definition of Obese:

Children 2 years to adolescence: BMI-for-age at or above the 95th percentile on the BMI for age charts compared with children of the same age and sex.

Adolescents: Obesity may be defined as BMI at or greater than the 95th percentile OR 30kg/m2, whichever is lower.

There is limited data on the impact of obesity on the pharmacokinetics and pharmacodynamics of drugs. Obese patients have significantly higher total body water, body volume, lean mass, fat mass and bone mineral content. They also have an increased hydration of lean mass, which is attributed to increased extracellular water. The increases in fat mass are substantially more than that of lean mass.1

Fat mass in the body will alter a drug’s volume of distribution whereby obese patients will generally have a higher volume of distribution for lipophilic medications due to its distribution into adipose tissue. Hydrophilic drugs will also have an altered volume of distribution due to increased lean body mass, blood volume & a decreased percentage of total body water. This may affect the loading dose, dosing intervals, plasma half-life and the time to reach the steady-state concentration. Obesity may also alter the metabolism and elimination of drugs.1-3

Loading doses are based on the volume of distribution (VD), body composition, blood flow and plasma protein binding.

• Hydrophilic drugs are generally loaded based on ideal body weight (IBW)

• Partially lipophilic drugs are loaded based on an adjusted body metric with consideration of the variability in distribution.

• Lipophilic drugs distribute freely into fat tissue resulting in greater distribution. A larger dose may be needed for adequate response. Some recommend dosing lipophilic medications on TBW. (However this should be assessed on a case by case basis where the risks of toxicity are considered. For example, propofol and thiopentone are lipophilic and are recommended for IBW dosing).

Maintenance doses depend on the clearance rate for drugs, which is determined by renal and hepatic function. The effect of obesity on metabolic activities in children is not known and measures of renal function in children are not validated in obesity.


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Utilizing an obese patient’s body weight or body surface area to calculate the dose may result in doses exceeding the recommended adult doses, which are used as a threshold for maximum doses in paediatric patients. Conversely, using the maximum dose recommended may result in a sub therapeutic dose as compared to the recommended weight-based dose if the drug is lipophilic.2

There is little evidence supporting the use of adjusted body weight to calculate safe and efficacious doses in obese children as it assumes that the body composition and functions are similar in obese and non obese children. Using adjusted body weights may lead to subtherapeutic doses in obese children.1,2

Weight -based dosing should be utilized in patient’s <18 years of age who are < 40kg.

For children who are >40kg, weight based dosing should be used, unless the patient’s dose or dose per day exceeds the recommended adult dose. If available, pharmacokinetics analysis for adjusting medications can be used to ensure safe and effective regimen.

Consideration of other patient factors such as renal and hepatic function, drug interactions and co-morbid states should also be considered when applying the recommendations.1

References:

1. Johnson PN, Miller JL, Boucher EA, et al; PPAG Advocacy Committee. Medication dosing in overweight and obese children. http://www.ppag.org/ obesedose/ Accessed April 30th, 2015.

2. Jessica C. Stovel. How Should Medicat ions Be Dosed in Obese Children? Medscape, Updates Sep 03, 2013. http://www.medscape.com/ viewarticle/81037/ Accessed May 2nd, 2015.

3. Mulla H, Johnson TN. Dosing dilemmas in obese children. Arch Dis Child Educ Prac Ed. 2010;95:112-117


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Children with renal impairment

Renal excretion of drugs depend on glomerular filtration, renal tubular secretion/absorption mechanism, molecular size of the drug involved and the extent of protein binding of the drug. When renal function is impaired, glomerular filtration becomes impaired and elimination of drugs will be decreased, resulting in a prolonged plasma half-life of drugs.1

The rate of drug elimination excreted by the kidneys is proportional to the glomerular filtration rate. The Schwartz equation, Traub Equation or a nomogram based on serum creatinine clearance and height are the generally accepted methods of estimating Glomerular Filtration Rate(GFR) in children <18 years of age.1

The gold standard for calculating endogenous creatinine clearance is still a timed collection of urine.

The Traditional Schwartz Equation:1,2

CrCl = Creatinine clearance, mL/min/1.73m2Scr = Serum Creatinine expressed as mg/dL (1 µmol/L = 0.0113mg/dL).K = Constant proportionality that is age specific

158

3. Mulla H, Johnson TN. Dosing dilemmas in obese children. Arch Dis Child Educ Prac Ed. 2010;95:112-117

Children with renal impairment

Renal excretion of drugs depend on glomerular filtration, renal tubular secretion/absorption mechanism, molecular size of the drug involved and the extent of protein binding of the drug. When renal function is impaired, glomerular filtration becomes impaired and elimination of drugs will be decreased, resulting in a prolonged plasma half-life of drugs.1

The rate of drug elimination excreted by the kidneys is proportional to the glomerular filtration rate. The Schwartz equation, Traub Equation or a nomogram based on serum creatinine clearance and height are the generally accepted methods of estimating Glomerular Filtration Rate(GFR) in children <18 years of age.1

The gold standard for calculating endogenous creatinine clearance is still a timed collection of urine.

The Traditional Schwartz Equation:1,2

CrCl = Creatinine clearance, mL/min/1.73m2

Scr = Serum Creatinine expressed as mg/dL (1 µmol/L = 0.0113mg/dL).

K = Constant proportionality that is age specific

Age K Low birth weight 0.33

Full term ≤ 1 year old 0.45 1-12 years 0.55

13-21 years (Female) 0.55 13-21 years (Male) 0.70

However, this formula should not be used with SCr measurements calibrated to reference measurements by IDMS(Isotope dilution mass spectroscopy). Using IDMS creatinine values in the traditional Schwartz equation will result in an overestimation of GFR by 18%–39%, depending on the patient’s age. The overestimation is highest in children younger than 3 years.

In 2009, the equation was updated to account for more modern creatinine calculations done by laboratories. The modified Schwartz no longer uses a variable K value and instead uses a set K of 0.413.

The modified Schwartz equation :1,2

CrCl (mL/min/1.73m2) = 0.413 x L(cm) / SCr(mg/dL)*

*1 µmol/L = 0.0113mg/dL.


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However, this formula should not be used with SCr measurements calibrated to reference measurements by IDMS(Isotope dilution mass spectroscopy). Using IDMS creatinine values in the traditional Schwartz equation will result in an overestimation of GFR by 18%–39%, depending on the patient’s age. The overestimation is highest in children younger than 3 years.

In 2009, the equation was updated to account for more modern creatinine calculations done by laboratories. The modified Schwartz no longer uses a variable K value and instead uses a set K of 0.413.

The modified Schwartz equation :1,2

CrCl (mL/min/1.73m2) = 0.413 x L(cm) / SCr(mg/dL)*

*1 µmol/L = 0.0113mg/dL.

However, the Schwartz equation has its limitations. It can potentially overestimate GFR, especially in moderate to severe renal insufficiency as serum creatinine is a crude marker of GFR . Alternative methods based on additional factors such as cystatin C or blood urea nitrogen have been proposed to estimate GFR in children with renal insufficiency such as chronic kidney disease.2

The Paediatric Protocol for Malaysian Hospitals (3rd Edition) recommends the following equation for estimating the GFR once the serum creatinine level remains constant for at least 2 days :3

Creatinine Clearance (ml/min/1.73m2) =

References:

1. Michael E. Brier, PhD and George R. Aronoff, MD. Drug Prescribing in Renal Failure, 5th Edition: American College of Physicians; 2007

2. Sandra Benavides, Milap C. Nahata,Michael Chicella, Michelle Condren, et al. Paediatric Pharmacotherapy, 1st Edition. Kansas: American College of Clinical Pharmacy; 2013. p. 23-25.

3. Hussain Imam B. Hj. Muhammad Ismail, Ng Hoong Phak, Terrence Thomas, et.al. Paediatric Protocols for Malaysian Hospitals, 3rd Edition. Malaysia: Kementerian Kesihatan Malaysia;p.290-1.


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Tpn In Special Populations

Total energy needs of a healthy individual are the sum of the basal metabolic rate (BMR), diet induced thermogenesis (DIT), physical activity (PA) and growth. Nutritional status, underlying diseases, energy intake, energy losses, age and gender may affect the energy needs. Goran et al (1991) found that fat free mass, gender and fat mass are important determinants of total energy expenditure (TEE) in prepubertal children. On the other hand, gender, body composition and season affects energy expenditure during puberty and adolescence.

Since body composition is an important factor in determining total energy expenditure, patients who are obese or malnourished may have different energy requirements. Prediction of energy needs should be based on fat free mass, to account for differences in body composition.

Energy needs can be either measured or calculated based on acceptable equations. The best way to assess energy needs in children is to measure total energy expenditure or alternatively REE.1

TPN In Obese Paediatric Patients2

The American Academy of Pediatrics (AAP) defines obesity as children aged between 2–20 years with a body mass index ≥ 95th percentile. Body mass index is the preferred practical method to screen children for obesity.

(Grade D Evidence)

Pediatric obese inpatients may be at increased nutrition risk. Potential laboratory abnormalities should be tested for safety reasons. Examples include fasting blood sample, including lipid profile, glucose, phosphorus, and complete blood count. This may aid in the development of a formal nutrition care plan as obese paediatric patients are at risk for anemia, low concentrations of fat-soluble vitamin levels, low vitamin B status, hyperlipidemia, insulin resistance and hyperglycemia.

(Grade E Evidence)

Whenever possible, energy requirements of obese hospitalized children should be assessed using indirect calorimetry rather than predictive equations as the Resting Energy Expenditure (REE) varies with obesity status. Using the excess weight to estimate the ideal body weight using predictive equations leads to imprecise estimations. This is because for every kilogram of weight above the ideal weight, the percentage of lean body mass varies, which will result in varying REE.


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Indirect calorimetry is considered the gold standard for determining energy expenditure, enabling feeding to be adapted to the measured energy expenditure.

(Grade D Evidence)

Evidence is lacking regarding the clinical outcomes of the use of hypocaloric or hypercaloric feeding during hospitalization in obese children. Therefore, until more evidence is available, the goals for the provision of energy to pediatric obese inpatients should be similar to the goals for their non obese counterparts.

(Grade E Evidence)

TPN in Malnourished Children1

During the first 2 years of life and later on during adolescence, changes in organ maturation and higher growth velocity requires extra caloric needs as compared to adults. The energy needed to maintain accelerated growth represents 30–35% of the energy requirements in term neonates and is greater in preterm infants.

Children recovering from malnutrition need extra calories to correct their growth deficits (weight, height). Thus, energy needs may be calculated based on the 50th percentile of weight and height for the actual age, rather than the present weight. This difference will provide extra calories (above daily needs) to achieve catch-up growth.

Alternatively, calculation may be based on the actual weight multiplied by 1.2–1.5, or even by 1.5 to 2 times in severe cases of failure to thrive, to provide the extra calories needed for catch up growth. Further caloric needs should be adjusted according to weight and height gain.

ESPGHAN 2005 Guidelines for Paediatric Parenteral Nutrition quotes the Schofield -WH equation to be the best predicting equation for calculating estimated daily energy needs in cases of failure to thrive.

Schofield (WH) Equations for calculating REE and BMR (kcal/day) in children from 0-3 years

Male BMR = 0.167 x Wt(kg) + 1517.4 x Ht(m) - 617.6 Female BMR = 16.25 x Wt(kg) + 1023.2 x Ht(m) - 413.5


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Schofield-(WH) Equations for calculating REE and BMR (kcal/day) in children from 3–10 years

Male BMR = 19.6 x Wt(kg) + 130.3 x Ht(m) + 414.9 Female BMR = 16.97 x Wt(kg) + 161.8 x Ht(m) + 371.2

Schofield (WH) Equations for calculating REE and BMR (kcal/day) in children from 10-18 years

Male BMR = 16.25 x Wt(kg) + 137.2 x Ht(m) + 515.5 Female BMR = 8.365 x Wt(kg) + 465 x Ht(m) + 200

A caveat to refeeding the malnourished child is the risk of refeeding syndrome, due to the sudden disruption to the adaptative state of semi-starvation. These rapid changes in metabolic status can create life-threatening complications, so the nutritional regimen must be chosen wisely and monitored closely. Kindly refer to the ESPGHAN 2005 Guidelines on Paediatric Parenteral Nutrition for strategies to reduce the risk of developing complications of refeeding syndrome.

References:

1. Berthold Koletzko, Olivier Goulet, Joanne Hunt, Kathrin Krohn,Raanan Shamir . Guidelines on Paediatric Parenteral Nutrition of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Society for Clinical Nutrition and Metabolism (ESPEN), Supported by the European Society of Paediatric Research (ESPR). Journal of Pediatric Gastroenterology and Nutrition 2005; Volume 41(Sup 2): p. S5- 8, S79.

2. Cheryl Jesuit, Cristin Dillon, Charlene Compher, Carine M. Lenders. A.S.P.E.N. Clinical Guidelines: Nutrition Support of Hospitalized Pediatric Patients With Obesity. Journal of Parenteral and Enteral Nutrition 2010; 34(1): p.13-20.


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Corticosteroid Equipotency Chart

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Appendix

Corticosteroid Equipotency Chart

Corticosteroid

Potency relative to Hydrocortisone Half-Life

Equivalent Glucocorticoid

Dose (mg)

Anti-Inflammatory Mineralocorticoid Plasma

(minutes) Biological

(hours)

Short Acting

Hydrocortisone 20 1 1 90 8-12

Cortisone Acetate 25 0.8 0.8 30 8-12

Intermediate Acting

Prednisone 5 4 0.8 60 12-36

Prednisolone 5 4 0.8 200 12-36

Triamcinolone 4 5 0 300 12-36

Methylprednisolone 4 5 0.5 180 12-36

Long Acting

Dexamethasone 0.75 30 0 200 36-54

Betamethasone 0.6 30 0 300 36-54

Mineralocorticoid

Fludrocortisone 0 15 150 240 24-36

Aldosterone 0 0 400+ 20 -

REFERENCE:

1) Steven K. H. Adrenal cortical steroids. In: Drug facts and comparisons. 5th ed. St. Louis: Facts and Comparisons, Inc.; 122–128 (1997).

References:

1) Steven K. H. Adrenal cortical steroids. In: Drug facts and comparisons. 5th ed. St. Louis: Facts and Comparisons, Inc.; 122–128 (1997).

7.0 APPENDIX


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Nutrition Reference

165

Nutrition Reference Supplement Nutrient Content Calories Indications And Contraindications

Carbohydrate Polycose Infant rice cereal

Glucose polymers from hydrolyzed cornstarch Rice

3.8kcal/g powder; 2kcal/mL liquid 15 cal/tbsp

Calorie supplemetation (lactose and gluten free) Contains Na, K, Ca, Cl and P (Limiting formula intake while increasing calories may compromise protein, vitamin, and mineral intake, which may also lead to hyperglycemia and diarrhea) Thickens feedings

Fat Medium-chain triglyceride Vegetable oil Microlipid

Lipid fraction of coconut oil Soy, corn oil Safflower oil, Soy lecithin, ascorbic acid, linoleic acid

8.3 kcal/g, 7.7 cal/mL 9.0 cal/g (120 cal/tbsp) 4.5 cal/mL, 5.9 g/tbsp

Limit to 50% calories from fat to prevent ketosis; may cause diarrhea; do not use in bronchopulmonary dysplasia (BPD) because risk of aspiration pneumonia To increase calories if fat absorption is normal To increase caloric density, fluid restriction

Protein Beneprotein

Whey protein isolate/soy lecithin

4.1 cal/g (6 g of protein/packet) Calcium = 30mg/scoop Sodium = 15mg/scoop Potassium = 35mg/scoop Phosphorus = 15mg/scoop Calories = 25/scoop

Useful for protein and calorie supplementation

Adapted from: Gomella TL, Cunningham MD, Eyal FG, et al, editor. Neonatology management, procedures, on-call problems, diseases and drugs. 6th ed. New York: Mc Graw Hil


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Immediate-Release Opioid Analgesics Comparison Chart

166

IMMEDIATE-RELEASE OPIOID ANALGESICS COMPARISON CHART

Drug

Equianalgesic doses

Usual starting IV doses and Intervals Parenteral

/ oral ratio

Usual starting oral doses and intervals

Parenteral Oral Child <50kg Child > 50kg

Child <50kg

Child > 50kg

Codeine 120mg 200mg - - 1:2 0.5-1 mg/kg q 3-4 hr

30-60 mg q 3-4 hr

Morphine 10mg 30mg (long term)

Bolus: 0.1 mg/kg q 2-4 hr Infusion: 0.02-0.03 mg/kg/hr

Bolus: 5-8 mg q 2-4 hr Infusion: 1.5mg/kg/hr

1:3

Immediate release: 0.3mg/kg q 3-4 hr

Immediate release: 15-20mg q 3-4 hr Sustained release: 30-45 mg q 8-12 hr

Oxycodone - 15-20 mg - - -

0.1-0.2 mg/kg q 3-4 hr

5-10 mg q 3-4 hr

Methadone 10mg 10-20mg 0.1mg/kg 5-8 mg q 4-

8 hr 1:2 0.1mg/kg q 8-12 hr

2.5-10 mg q 8-12 hr

Fentanyl 100mcg (0.1mg) -

Bolus: 0.5-1 mcg/kg q 1-2 hr Infusion: 0.5-2mcg/kg/hr

Bolus: 25-50 mcg q 1-2 hr Infusion: 25-100 mcg/hr

- - -

Hydromorphone 1.5-2 mg 6-8 mg

Bolus: 0.02 mg q 2-4 hr Infusion: 0.006mg/kg/hr

Bolus: 1 mg q 2-4 hr Infusion: 0.3 mg/hr

1:4 0.04-0.08 mg/kg q 3-4 hr

2-4 mg q 3-4 hr

Meperdine (Pethidine) 75-100 mg 300

mg

Bolus: 0.8-1 mg/kg q 2-3 hr

Bolus: 50-75mg q 2-3 hr

1:4 2-3 mg/kg q 3-4 hr

100-150 mg q 3-4 hr

REFERENCE:

1) Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Eng J Med. 2002;347:1094-1103

References:

1) Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Eng J Med. 2002;347:1094-1103


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TDM Sampling Time


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Growth Charts

168

GROWTH CHARTS


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169


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170


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171


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172


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173


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174


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175


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176


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Stability And Storage Of Oral Medications

The following information was adapted from Hospital Kuala Lumpur’s Pharmacy Department Guidelines of Compilation of Medication Management (2013) :

DEFINITION

Stability The extent to which a product retains, within specified limits, and throughout its period of storage and use (i.e., shelf-life/BUD/etc), the same properties and characteristics that it possessed at the time of its manufacture/compounding/repackaging. There are five (5) types of stability which are generally recognized i.e. Chemical, Physical, Microbiological, Therapeutic and Toxicological stability.

Stability studies conducted by the manufacturer are used determine shelf life and thus the expiry date of a product.

Expiration Date

Expiration date is the identified time up to which the product is expected to meet the requirements of the Pharmacopeial monograph, provided it is kept under the prescribed storage conditions. Expiration date limits the time during which the product may be dispensed or used. It is determined using stability studies and is not the same as Beyond-Use Date (BUD)/ DiscardAfter Date.

In the event where stability studies are unavailable as in the case of extemporaneous products, BUD will be assigned to the product.

Beyond-Use Date (BUD)/ Discard-After Date/ Shelf Life

Beyond-Use Date (BUD)/Discard-After Date/Shelf Life are equivalent and it is the time/date after which a product (usually compounded/repackaged) must not be used. It is assigned, using the criteria stated in the relevant sections below. In the absence of appropriate stability studies to support expiration dates used and the assigned BUD must be less than the expiration date of any of the initial product/raw material/s.


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Extemporaneous/Compounded Preparation

A medicinal product (internal and external) where its use (prescribing, dispensing and/or administration), involves some element of recipe or formula preparation. This recipe or formulation must be present in at least one step in prescribing, dispensing and/or administration but does not have to be present in all steps.

Repackaging/Pre-packing

An act of removing a preparation/drug from its original primary container and placing it into another primary container (may be called secondary if Unit-Dose packaging), usually of smaller size.

Storage

Procedures to maintain a proper storage environment for pharmaceutical products, and to ensure product integrity, including its appearance, until it reaches the user. Children >2 years or older : BMI-for-age at or above the 85th and below the 95th percentile compared with children of the same age and sex


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178

Sto

rage

Pro

cedu

res

to m

aint

ain

a pr

oper

sto

rage

env

ironm

ent f

or p

harm

aceu

tical

pro

duct

s, a

nd to

en

sure

pro

duct

inte

grity

, inc

ludi

ng it

s ap

pear

ance

, unt

il it

reac

hes

the

user

.

Equ

ival

ent C

onta

iner

-Clo

sure

Sys

tem

Ref

ers

to a

con

tain

er-c

losu

re s

yste

m th

at y

ield

s th

e sa

me,

or b

ette

r, m

oist

ure

vapo

ur

trans

mis

sion

rate

(MV

TR),

oxyg

en a

nd li

ght t

rans

mis

sion

as

the

orig

inal

mar

ket c

onta

iner

.

Mul

tidos

e P

acka

ging

Mul

tidos

e pa

ckag

ing

is th

e pa

ckag

ing

of m

ore

than

one

sin

gle-

dosa

ge u

nit i

n a

reus

able

co

ntai

ner.

Uni

t-Dos

e P

acka

ging

Uni

t-dos

e pa

ckag

ing

is th

e pa

ckag

ing

of a

sin

gle

dose

in a

non

-reu

sabl

e co

ntai

ner.

Med

icat

ions

in

uni

t-dos

e pa

ckag

ing

are

easi

ly id

entif

iabl

e an

d ca

n be

retu

rned

to th

e ph

arm

acy

if th

e m

edic

atio

n is

dis

cont

inue

d/w

ithho

ld.

Stor

age

& S

tabi

lity

For E

xtem

pora

neou

s / N

on-S

teril

e C

ompo

unde

d Pr

epar

atio

ns

The

assi

gnm

ent o

f sta

bilit

y, o

f an

exte

mpo

rane

ous/

non-

ster

ile c

ompo

unde

d pr

epar

atio

n sh

ould

be

don

e w

ith p

rude

nt p

harm

aceu

tical

judg

men

t by

atte

ndin

g ph

arm

acis

t bas

ed o

n lit

erat

ures

/ pu

blic

atio

ns/ r

efer

ence

s on

form

ulas

with

sta

bilit

y da

ta.


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Equivalent Container-Closure System

Refers to a container-closure system that yields the same, or better, moisture vapour transmission rate (MVTR), oxygen and light transmission as the original market container.

Multidose Packaging

Multidose packaging is the packaging of more than one single-dosage unit in a reusable container.

Unit-Dose Packaging

Unit-dose packaging is the packaging of a single dose in a non-reusable container. Medications in unit-dose packaging are easily identifiable and can be returned to the pharmacy if the medication is discontinued/withhold.

Storage & Stability For Extemporaneous / Non-Sterile Compounded Preparations

The assignment of stability, of an extemporaneous/non-sterile compounded preparation should be done with prudent pharmaceutical judgment by attending pharmacist based on literatures/ publications/ references on formulas with stability data.

In the absence of stability information or if only anecdotal data is available; the following maximum BUD are recommended for extemporaneous/non-sterile compounded preparations, that are packed in tight, light resistant (if applicable) containers and stored at Controlled-Room Temperature (CRT), unless otherwise indicated:-


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179

In th

e ab

senc

e of

sta

bilit

y in

form

atio

n or

if o

nly

anec

dota

l dat

a is

ava

ilabl

e; th

e fo

llow

ing

max

imum

BU

D a

re re

com

men

ded

for e

xtem

pora

neou

s/no

n-st

erile

com

poun

ded

prep

arat

ions

, th

at a

re p

acke

d in

tigh

t, lig

ht re

sist

ant (

if ap

plic

able

) con

tain

ers

and

stor

ed a

t Con

trolle

d-R

oom

Te

mpe

ratu

re (C

RT)

, unl

ess

othe

rwis

e in

dica

ted:

-

Inte

rnal

a)

All

exte

mpo

rane

ous/

com

poun

ded

prep

arat

ion

mus

t util

ize

form

ulas

with

refe

renc

es w

hene

ver

poss

ible

. Pre

para

tions

with

out s

uch

form

ulas

or w

ith a

necd

otal

refe

renc

e on

ly, s

houl

d be

use

d w

ith p

rude

nt p

harm

aceu

tical

judg

men

t by

the

atte

ndin

g ph

arm

acis

t. b)

Sta

bilit

y of

pre

para

tion

shou

ld b

e la

bele

d ap

prop

riate

ly w

here

by, t

he te

rm ‘E

xpiry

Dat

e’

shou

ld b

e us

ed fo

r for

mul

as w

ith s

tabi

lity

stud

ies

and

‘BU

D’ s

houl

d be

use

d fo

r for

mul

as w

ithou

t re

fere

nces

on

stab

ility

stu

dies

or f

or fo

rmul

as w

ith o

nly

anec

dota

l ref

eren

ces.

c)

If a

form

ula

is n

ot a

vaila

ble,

‘fre

shly

pre

pare

d’ (‘

just

prio

r to

adm

inis

tratio

n’) o

r tab

let

disp

ersi

on m

etho

d (s

tabl

e fo

r 24

hour

s) is

reco

mm

ende

d.

d) A

ll pr

epar

atio

ns s

houl

d be

refri

gera

ted

(Col

d te

mpe

ratu

res

[2°C

to 8

°C])

unle

ss s

tate

d ot

herw

ise.

Syr

ups,

Sus

pens

ions

, Sol

utio

ns m

ade

from

Pow

der;

are

to b

e st

ored

at C

ontro

lled-

Roo

m T

empe

ratu

re u

nles

s ot

herw

ise

indi

cate

d.

e) H

owev

er, A

ntib

iotic

sus

pens

ion/

solu

tion

(pre

pare

d fro

m in

gred

ient

s in

sol

id fo

rm) i

s st

able

for

14 d

ays

if st

ored

in C

old

Tem

pera

ture

, unl

ess

stat

ed o

ther

wis

e on

pac

kage

. f)

All

othe

r for

mul

atio

ns: o

nce

used

, mus

t be

disc

arde

d up

on c

ompl

etio

n of

ther

apy

OR

not

mor

e th

an 3

0 da

ys, w

hich

ever

is e

arlie

r.


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Internal

a) All extemporaneous/compounded preparation must utilize formulas with references whenever possible. Preparations without such formulas or with anecdotal reference only, should be used with prudent pharmaceutical judgment by the attending pharmacist.

b) Stability of preparation should be labeled appropriately whereby, the term ‘Expiry Date’ should be used for formulas with stability studies and ‘BUD’ should be used for formulas without references on stability studies or for formulas with only anecdotal references.

c) If a formula is not available, ‘freshly prepared’ (‘just prior to administration’) or tablet dispersion method (stable for 24 hours) is recommended.

d) All preparations should be refrigerated (Cold temperatures [2°C to 8°C]) unless stated otherwise. Syrups, Suspensions, Solutions made from Powder; are to be stored at Controlled-Room Temperature unless otherwise indicated.

e) However, Antibiotic suspension/solution (prepared from ingredients in solid form) is stable for 14 days if stored in Cold Temperature, unless stated otherwise on package.

f) All other formulations: once used, must be discarded upon completion of therapy OR not more than 30 days, whichever is earlier.


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External

a) Refer Internal a) – b).

b) Material Safety Data Sheet (MSDS) should be readily available, for easy retrieval and interpretation, in particular the safety hazard information; to all staff preparing drug substances or bulk chemical on the compounding premise.

c) Stability of preparation should be assigned using the recommended expiry date or BUD (refer above).

Repackaging/Prepacking Storage & Stability

Repackaging/prepacking operations should be conducted under conditions that meet requirements; including specific storage temperature, i.e. maintenance of CRT. Written procedures must be maintained for traceability of end product. Repackaged/prepacked containers must be labeled with: 1. Generic name 2. Manufacturer name 3. Manufacturers batch number4. Expiry date (new)/BUD

Package inserts (PI) or other appropriate literature of the item being repackaged/prepacked should be readily available, for easy reference, in order to properly select an equivalent container-closure system.

Manufacturer’s original expiration date may be used without additional stability testing if the drug product is repackaged/prepacked into an equivalent container-closure system.

If an equivalent container-closure system is not available, a stability data for the new containerclosure system must be generated to justify the expiry date assigned. In the absence of stability information or only anecdotal data is available; the following maximum BUD are recommended for repackaged/prepacked products in an equivalent container-closure system and stored at Controlled-Room Temperature (CRT) (if applicable), unless otherwise indicated:-


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181


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182

Drugs To Avoid In G6PD Deficiency

Definite Risk Of Hemolysis Pharmacological Class Drugs

Anthelmintics • ß-Naphthol • Niridazole • Stibophen

Antibiotics

• Nitrofurans - Nitrofurantoin - Nitrofurazone

• Quinolones - Ciprofloxacin - Moxifloxacin - Nalidixic acid - Norfloxacin - Ofloxacin

• Chloramphenicol • Sulfonamides

- Co-trimoxazole (Sulfamethoxazole + Trimethoprim)

- Sulfacetamide - Sulfadiazine - Sulfadimidine - Sulfamethoxazole - Sulfanilamide - Sulfapyridine - Sulfasalazine

(Salazosulfapyridine) - Sulfisoxazole

(Sulfafurazole)

Antimalarials

• Mepacrine • Pamaquine • Pentaquine • Primaquine

Antimethemoglobinaemic Agents • Methylene blue

Antimycobacterials

• Dapsone • Para-aminosalicylic

acid • Sulfones - Aldesulfone sodium

(Sulfoxone) - Glucosulfone - Thiazosulfone

Antineoplastic Adjuncts • Doxorubicin • Rasburicase

Genitourinary Analgesics • Phenazopyridine (Pyridium)

Others • Acetylphenylhydrazine • Phenylhydrazine

Source : Adapted from MIIMS 2006 For further information, Kindly refer : www.g6pd.org

Possible Risk Of Hemolysis Pharmacological Class Drugs

Analgesics

• Acetylsalicylic acid (Aspirin)

• Acetanilide • Paracetamol

(Acetaminophen) • Aminophenazone

(Aminopyrine) • Dipyrone (Metamizole) • Phenacetin • Phenazone (Antipyrine) • Phenylbutazone • Tiaprofenic acid

Antibiotics

• Furazolidone • Streptomycin • Sulfonamides • Sulfacytine • Sulfaguanidine • Sulfamerazine • Sulfamethoxypyridazole

Anticonvulsants • Phenytoin Antidiabetics • Glibenclamide Antidotes • Dimercaprol (BAL)

Antihistamines • Antazoline (Antistine) • Diphenhydramine • Tripelennamine

Antihypertensives • Hydralazine • Methyldopa

Antimalarials

• Chloroquine & derivatives

• Proguanil • Pyrimethamine • Quinidine • Quinine

Antimycobacterials • Isoniazid

Antiparkinsonism • Trihexyphenidyl (Benzhexol)

Cardiovascular Drugs • Dopamine (L-dopa) • Procainamide • Quinidine

Diagnostic Agent for Cancer Detection • Toluidine blue

Gout Preparations • Colchicine • Probenecid

Hormonal Contraceptives • Mestranol

Nitrates • Isobutyl nitrite

Vitamin K Substances

• Menadiol Na sulfate • Menadione • Menadione Na bisulfite • Phytomenadione

Vitamins • Ascorbic acid (Vit C) (rare)

Others

• Arsine • Berberine (in Coptis

chinensis) • Fava beans • Naphthalene (in

mothballs) • Para-aminobenzoic acid

For further information, Kindly refer : www.g6pd.org

Drugs To Avoid In G6PD Deficiency

Lot 36, Jalan University,46350 Petaling Jaya,Selangor Darul Ehsan.

Tel : +603 7841 3200 Fax : +603 7968 2222Website : www.pharmacy.gov.my

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