Practical Approach
`to
`
`Pediatric Intensive Care
`
`Editor
`
`A
`
`Praveen Khilnani
`MD FAAP FCCM (USA)
`Senior Consultant
`
`Pediatric lntensivist and Pulmonologist
`Apollo Centre for Advanced Pediatrics
`lP Apollo Hospitals, New Delhi
`
`Associate Editor
`
`Rajiv Uttam
`MRCP (UK)
`Senior Consultant
`
`Pediatric Intensivlst and Pulmonologist
`IP Apollo Hospitals, New Delhi
`
`Editorial Board
`
`Vinay K Aggarwal
`Sandeep Chopra
`RK Mani
`
`Rajesh Chawla
`Yogesh Gautam
`
`Editorial Assistant
`Kavita Sharma
`
`Hodder Arnold
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`
`First published in India in 2004 by Jaypee Brothers, Medical Publishers (P) Ltd,
`EMCA House, 23/23B Ansari Road, Daryaganj, New Delhi 110 002, India
`
`First published in the United Kingdom in 2005 by Hodder Arnold,
`an imprint of Hodder Education and a member of the Hodder Headline Group,
`338 Euston Road, London NW1 3BH
`
`http:lIwww.hoddereducation.com
`
`This UK edition distributed in the United States of America by
`Oxford University Press |nc.,
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`
`© 2005 Praveen Khilnani
`
`All rights reserved. Apart from any use permitted under UK copyright law, this publication may
`only be reproduced, stored or transmitted, in any form, or by any means with prior permission in
`writing of the publishers or in the case of reprographic production in accordance with the terms
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`
`Whilst the advice and information in this book are believed to be true and accurate at the date of
`going to press, neither the author[s] nor the publisher can accept any legal responsibility or
`liability for any errors or omissions that may be made.
`In particular (but without
`limiting the
`generality of the preceding disclaimer) every effort has been made to check drug dosages;
`however it is still possible that errors have been missed. Furthermore, dosage schedules are
`constantly being revised and new side-effects recognized. For these reasons the reader is
`strongly urged to consult the drug companies’ printed instructions before administering any of
`the drugs recommended in this book.
`
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`Ex. 2031-0002
`
`

`
`Raiiv Uttam, Reeta Singh
`
`Inhaled Nitric Oxide (IN0)
`
`Since the discovery of endothelium derived relaxing
`factor and its subsequent identification as nitric oxide,‘
`recognition of its potent vasodilator properties and its
`unique ability to be delivered as a gas to the lung, inhaled
`nitric oxide (INO) has become an exciting new treatment
`for several disorders, characterized by pulmonary hyper-
`tension and pulmonary vasoregulation.
`
`Endogenous NO
`
`NO is produced by L- argine by a family of enzymes
`called nitric oxide synthase (NOS) which exist in
`constitutive and inducible forms? Constitutive NOS is
`
`always present, is calcium dependent and produce low
`levels ofNO intermittently, which is a major endogenous
`regulator of vascular tone. In contrast the inducible NOS
`is activated by cytokines and endotoxins, once induced it
`produces large amounts of NO. The pathophysiological
`role of this nitric oxide is evident in a variety of disease
`including septic shock, asthma, and reperfusion endo-
`genous injury, etc. (Fig. 43.2).
`
`Clinical Pharmacology of INO
`
`NO binds rapidly to iron in haern moiety ofproteins such
`as guanyl cyclase, hemoglobin and electron transport
`chain. Activation of guanyl cyclase results in production
`of cyclic guanosine monophosphate (CGMP) which leads
`to vasodilation, and relaxation of smooth muscles of
`cardiovascular, respiratory, gastrointestinal and genito—
`urinary system. Because it binds to haem, it gets inacti-
`vated in blood and does not enter systemic circulation.
`
`This accounts for selective effect of INO on pulmonary
`circulation}
`
`IN 0 appears to increase the partial pressure of arterial
`oxygen (PaO3) by dilating pulmonary vessels in better
`ventilated areas of the lung, redistributing pulmonary
`blood flow away from lung regions with low ventilation/
`perfusion (V/Q) ratios towards regions with normal ratios.
`Persistent pulmonary hypertension of newborns
`(PPHN).
`At birth, the pulmonary circulation changes dramati-
`cally. Pulmonary blood flow increases 8-10 fold and
`pulmonary arterial pressure decrease to less than half
`systemic levels in the first 24 hours of life.4' 5 Although
`release of vasoactive mediators, increased oxygenation,
`establishment of an airliquid interface have been shown
`to play a central role in transition of pulmonary circu-
`lation,6 if postnatal adaption of pulmonary circulation
`does not occur, a clinical syndrome, PPHN results.
`It is characterized by extrapulmonary right to left
`shunting across the foramen ovale and ductus arteriosus,
`pulmonary hypertension and severe central hypoxemia,
`that is not responsive to high concentrations of inspired
`oxygen. PPHN is often complicated by parenchymal lung
`injury, such as meconium aspiration, pneumonia and
`surfactant deficiency, further compromising efforts to
`improve oxygenation.
`When other therapies fail neonates are treated with
`extracorporeal membrane oxygenation.7 This theraPY
`improves survival in neonates with respiratory failure,
`but its administration is labor-intensive and costly and to
`
`Ex. 2031-0003
`
`

`
`necessitates large amounts of blood products. The morta-
`lity rate in neonates treated with exlracorporeal membrane
`oxygenation is 15-20 percent and 10-20 percent of the
`neonates, Whose survive have substantial developmental
`delay.8 Effective treatment has been limited by the
`absence of a selective pulmonary vasodilators. Intra-
`venous Vasodilator agents can cause non—selective Vasodi-
`lation, resulting in worsening of intrapulmonary shunting
`and systemic Hypotension.9 Neonates with PPI-IN might
`be hypoxemic from a combination of intrapulrnonary
`shunting secondary to parenchymal lung disease and
`extrapulmonary shunting secondary to increased pulmo-
`nary vascular resistance with or without myocardial
`dysfunction. INO (Fig. 43.1) acutely improves
`oxygenation in most- term and near term neonates by
`reversal of extrapulmonary right to left shunting ofblood
`secondary to pulmonary vasodilation and also improves
`VQ matching secondary to redistribution of pulmonary
`blood flow to well ventilated lung regions.“
`Clinical trials indicate that need for ECMO is dimini-
`
`shed by INO") (Fig. 43.4). Responsiveness to INO in these
`patients is dependent on the primary disease or
`physiologic cause of hypoxemia, with the best response
`rates observed in patients with idiopathic PPHN.” In
`neonates with severe parenchymal lung disease,
`responsiveness to INO can be improved by therapies that
`enhance lung recruitment, especially during high
`frequency oscillatory ventilation (HFOV). The combi-
`nation of HFOV and INO can be efficacious in patients
`who fail to respond to either therapy alone.”
`
`DOSES
`
`Experimental data support the notion that the minimally
`effective doses of INO should be used. At high concen-
`trations INO can react with oxygen to form dioxygen
`nitrite (N00), which has been shown to cause surfactant
`destruction.
`
`The recommended dose is 10 to 20 part per million
`(pp1n).m"3 When dose is increased to 80 ppm, if the
`improvement in PaO2 was less than 20 mmHg, increased
`incidence of methemoglobinemia occurs without any
`increase in PaO2.‘4 At the same time administration of a
`subtherapeutic (2 ppm) dose ofINO may adversely affect
`the clinical response to a subsequent therapeutic doses
`of INO.” Clark et al used INO at 20 ppm for 24 hours
`followed by 5 ppm for next 96 hours and requirement for
`subsequent ECMO was reduced. 16 Figure 43.1 shows the
`Nitric oxide delivery setup with dial regulator of PPM
`dose of INO.
`
`Inhaled Nitric Oxide (mo) 307
`
`Fig. 43.1: Nitric oxide delivery system
`
`Duration ofTreatment
`
`No controlled data are available to determine the maximal
`
`safe duration of INO therapy. In multicenterclinical trials
`of INO, the typical duration of INO has been less than
`5 days, which parallels the clinical resolution of PPHN,
`16 If INO is required for longer than 5 days, other causes
`like pulmonary hypoplasia must be excluded. INO can
`be discontinued if the fraction of inspired oxygen is less
`than 0.6 and PaO2 is more than 60 without evidence of
`rebound pulmonary hypertension or an increase in FiO2
`more than 15 percent after INO withdrawal.”
`
`Weaning
`
`Sudden withdrawal can be associated with life-threatening
`elevation of pulmonary vascular resistance, profound
`desaturation and systemic hypotension caused by
`decreased cardiac output. Exogenous NO may down-
`regulate endogenous NO production, which contribute
`to severity of pulmonary hypertension after INO
`withdrawal. To avoid these rebound effects numerous
`
`approaches have been used and INO should be reduced
`in a step wise fashion.”
`
`Ex. 2031-0004
`
`

`
`308 Practical Approach to Pediatric Intensive Care
`
`'Cytoprotective"
`— Vasodiation
`— Antiproliferative
`— Antioxidant
`— Anti-inflammatory
`— Antithrombotic
`
`“Cytotoxic”
`— Nitrosative stress
`- Proinflammatory
`— Mutagenic
`— Metabolic effects
`
`Fig. 43.2: Inhaled nitric oxide therapy: a balance between
`cytoprotective and cytotoxic effects
`
`Unresponsiveness to INOTherapy in PPHN
`
`Many neonates have only partial or transient improvement
`in oxygenation during INO therapy. INO tends to increase
`PaO2 more readily in idiopathic PPHN than in patients
`with congenital diaphragmatic hernia.” It’s use in
`hypoxemic neonates without pulmonary hypertension.
`Unresponsiveness to INO is commonly seen in
`following situations:
`1. IN0 use in hypoxemic neonates without pulmonary
`hypertension.
`2. Inability to deliver NO due to poor lung inflation.
`3. Unsuspected or missed anatomic cardiovascular
`lesions
`
`. Alveolar capillary dysplasia is a very rare cause for
`PPHN and is characterized by a developmental abnor-
`mality in the pulmonary vasculature. Despite aggres-
`sive therapy with NO and ECMO survival is rare.”
`. Advanced vascular remodeling or severe lung
`hypoplasia.
`In some cases, IN0 therapy reverses right to left
`shunting but hypoxemia may persist due to intrapulmo-
`nary shunt, suggesting underlying disease. In these
`situations changes in conventional ventilator management
`or HFOV can filrther improve PaO2 by improving lung
`inflation and may decrease the need for ECMO. “ In many
`cases greater improvement is achieved with INO in
`combination with either therapy alone.”
`
`Monitoring
`
`Methemoglobinernia occurs after exposure to high
`concentration of INO. This complication has not been
`reported at lower doses. However, because methemo-
`globin reductase deficiency may occur unpredictably, it
`is reasonable to measure methemoglobin level by co-
`
`oximetry within four hours of starting INO therapy and
`subsequently at 24 hour intervals.
`
`Transport with INO
`
`Although INO therapy is often effective, 30-40 percent
`of sick newborns do not have sustained improvement in
`oxygenation and hemodynamics after the initiation of
`therapy often require transport to ECMO center. Abrupt
`discontinuation may be dangerous and availability ofNO
`during transport is vital.2°
`Long term outcomes of neonates treated by INO has
`been studied widely, preliminary studies show no excess
`adverse health or neurodevelopmental outcome among
`PPHN survivors treated with NO compared with those
`treated with conventional therapies.“
`The premature newborns-uncertainities about use of
`INO.
`
`In the preterm neonate, severe respiratory failure is, in
`large part, the result of surfactant deficiency. Although
`treatment with exogenous surfactant can cause dramatic
`improvements in oxygenation. Some have suboptimal
`responses. Low dose INO causes immediate improvement
`in oxygenation in preterms.” It may be effective as a lung
`specific anti-inflammatory therapy to decrease lung
`neutrophil accumulation and the associated inflammatory
`injury and subsequent decreased incidence ofchronic lung
`disease. INO is shown to impair platelet function in vitro,
`but clinical trials have not shown increased incidence of
`
`ICH,” and a trend in the reduced risk and severity of
`chronic lung disease among INO treated prematures is the
`main working hypothesis for most ofthe ongoing trials.“
`
`INO in Chronic Lung Disease
`
`Long term ambulatory use ofNO via nasal canula causes
`decrease in PVR and improved oxygenation in adults with
`stable chronic obstructive puhnonary disease. It’s efficacy
`is not proved in interstitial pulmonary fibrosis, although
`transient improvement occurs. It can cause bronch0-
`dilation, but not as effectively as beta agonists.25
`
`|NOTherapy in Children with AFIDS
`
`The management of ARDS continues to be a challenge.
`Clinically ARDS is characterized by pulmonary hyper-
`tension and profound hypoxemia, abnormal vasoreactivity
`and increased permeability. Unlike PPHN extrapulmo-
`nary shunt does not occur in ARDS and hypoxemia is
`primarily due to intrapulmonary shunt (perfusion oflung
`
`Ex. 2031-0005
`
`

`
`~l« Lung Inflammation
`Oxidant stress
`
`~11 Pulmonary Artery Pressure
`Pulmonary Vein Pressure
`
`Redistribution of blood
`flow within lung
`
`Inhaled Nitric Oxide (INC) 309
`
`dz Lung Injury
`Pulmonary Edema
`
`4* Right Ventricular Function
`
`~l«
`
`lntrapulmonary Shunt
`
`l
`
`4‘ Cardiac Output
`
`l
`4‘ Systemic Oxygen Delivery 1
`
`»
`
`i
`
`i
`
`It PaO2
`
`Fig. 43.3: Physiological targets of inhaled nitric oxide therapy in acute respiratory distress
`
`units that lack ventilation). When pulmonary hypertension
`in ARDS is profound, right ventricular contractility may
`be depressed and its subsequent dilation may interfere
`with left ventricular fimction which further aggravates
`gas exchange.”
`
`Physiological Effects of
`INO in ARDS (Fig. 43.3)
`
`1.
`
`INO lowers pulmonary artery pressure and pulmonary
`vascular resistance.
`
`2. Decreases V/Q mismatch—The low dose INO redirects
`blood flow from poorly aerated, atelectatic or diseased
`lung regions to better aerated distal air spaces. This is
`known as “microselective effects”. This response is
`dose related, lower doses achieving greater oxygena-
`tion. At higher doses this microselective effect is lost
`and NO may reach poorly ventilated lung areas.“
`. INO decreases lung inflammation, vascular perme-
`ability and thrombosis, thus reduces permeability
`edema formation, although some studies suggest that
`it can inactivate surfactant.“ 2”
`
`. Permissive hypercapnea (a strategy used in manage-
`ment of ARDS as an attempt to decrease ventilator
`induced lung injury caused by barotrauma or volu-
`trauma. Tidal Volume and minute ventilation are
`
`decreased and PaCO2 allowed to rise. Hypercapnea
`exacerbates pulmonary vasoconstriction. INO atten-
`uates this and allows use ofpermissive hypercapnea.”
`
`simply cosmetic or actually beneficial in terms of
`mortality.29 Various studies report acute improvement in
`oxygenation but fail to alter mortality, ventilator days
`and other critical end points. Actually ARDS is a clinical
`syndrome with multiple complicating factors, such as
`sepsis and multiorgan dysfunction. Moses prospective
`controlled studies using large patient population are
`needed to document any outcome benefits ofINO therapy
`in ARDS.”
`
`INO in Cardiology
`
`Pulmonary hypertension with associated right ventricular
`dysfunction may complicate postoperative cardiac patients
`despite maximal pharmacologic and ventilatory support.
`By reducing mean pulmonary artery pressure, INO may
`protect the right ventricle, while maintaining left ventri-
`cular filling by increasing pulmonary arterial bloodflow.“
`
`Congenital Heart Disease
`
`The use of INO has been shown to be helpful for the
`assessment of pulmonary vascular reactivity in selecting
`patients for surgery and postoperative management.”
`Post—cardiac surgery pulmonary has been successfully
`treated with INO in patients with significant prospective
`pulmonary hypertension.
`
`Primary Pulmonary Hypertension
`
`ARDS, Controversies with lNOTherapy
`
`Despite wonderful physiologic effects, it remains
`unproven, whether improved oxygenation in ARDS are
`
`INO is used to test pulmonary vascular reactivity. A posi-
`tive response with decrease in pulmonary artery pressure
`suggests a favourable response to long term vasodilator
`therapy with prostacyclin or calcium channel blockers.
`
`Ex. 2031-0006
`
`

`
`310 Practical Approach to Pediatric Intensive Care
`
`activation, interest has arisen in developing technique
`for increasing NO donors in the setting of AMI.”
`
`. Neonatal chronic lung disease Defined as the
`continuing need in preterm infants for supplemental
`inspired oxygen at 36 weeks postconceptional age.
`INO improves oxygenation in most infants with early
`chronic lung disease, without inducing changes in
`markers of inflammatory or oxidative injury.“
`
`Pneumonia
`
`1.
`
`Fig. 43.4: Percent survival without ECMO by disease category
`in a controlled trial of INO occurred in newborns with PPHN or
`pneumonia FlDS—Flesplratory distress syndrome. MAS-
`Meconium aspiration syndrome, PPHN—Primary pulmonary
`hypertension
`Data from Neonatal inhaled Nitric Oxide study group.
`
`Miscellaneous Uses and OngoingTrials
`
`1. Life-threatening status asthmaticus In children
`with life—threatening asthma, hypercapnea increases
`pulmonary vascular tone, thus increasing right
`ventricular afterload, which is already compromised
`by positive pressure ventilation and air trapping. NO
`plays an important role in regulating bronchial smooth
`muscle tone. Selective vasodilation ofventilated lung
`units may improve oxygenation and carbon dioxide
`elimination and unload the right ventricle, improving
`cardiac output.”
`
`. Cerebral malaria Some researchers have used it,
`but prospective multicentre trials and are needed to
`document beneficial effects.“
`
`. Heart transplantation INO is a useful adjunct to
`the postoperative treatment protocol of heart trans-
`plant patients with pulmonary hypertension. It selec-
`tively reduces PVR and enhances right ventricular
`stroke work.”
`
`. Lung transplantation Reperfusion injury is a major
`cause of mortality and morbidity among lung trans-
`plant recipients. Prophylactic INO does not prevent
`reperfusion injury in human lung transplantation
`however, if started at reperfusion, improves gas
`exchange and reduces pulmonary artery pressure in
`those patients who develop reperfusion injury.”
`
`. Acute myocardial infarction(AMl) Given the
`important role that NO plays in regulatory platelet
`
`Rebound effects Abrupt withdrawal of nitric oxide
`can cause rebound pulmonary hypertension, right
`ventricular failure and severe hypoxemia.”
`
`. Prolonged bleeding time INO increases platelet
`cyclic GMP and by inhibiting platelet aggregation
`can increase bleeding time. Although clinically signi-
`ficant bleeding is fortunately not observed.“
`
`. Paradoxical worsening of oxygenation in chronic
`lung disease.“
`
`4.
`
`Elevated pulmonary capillary wedge pressure In
`patients with left ventricular dysfunction and poor
`ventricular compliance, an increase in pulmonary
`flow can increase left ventricular filing pressure,
`leading to ventricular failure and pulmonary edema.“
`
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