Recent Advances in Paediatric Ventilation
`
`W. BUTT
`Paediatric Intensive Care Unit, Royal Children’s Hospital, VICTORIA
`
`
`
`ABSTRACT
` Background: To review the recent advances in ventilatory therapy for acute respiratory failure in
`children.
` Data sources: Recent published peer-review articles on mechanical ventilation for acute respiratory
`failure in children.
`
`Summary of review: Advances in conventional treatment for acute respiratory failure (e.g. mechanical
`ventilation) have not increased survival in children. However, recent therapies including high frequency
`ventilation, extracorporeal membrane oxygenation, nitric oxide and liquid ventilation have reported
`improved outcomes. The rationale and use of each are presented.
` Conclusions: High frequency ventilation exists in three forms, although only high frequency oscillation
`appears to show any benefit in the management of acute respiratory failure refractory to conventional
`mechanical ventilation. Extracorporeal oxygenation has halved mortality in neonates with acute
`respiratory failure, and has been used successfully in non-neonate patients. Inhaled nitric oxide from 6 to
`20 parts per million improves oxygenation in paediatric patients with acute respiratory failure and
`congenital heart disease (particularly in the presence of pulmonary arterial hypertension). Liquid
`ventilation or perfluorocarbon-associated gas exchange has also been used to treat acute respiratory
`failure in paediatric patients, with partial liquid ventilation particularly appearing to show promise.
`(Critical Care and Resuscitation 1999; 1: 85-92)
`
` Key words: Paediatric ventilation, high frequency ventilation, ECMO, liquid ventilation
`
`
`
`organ failure. Secondly, most therapies fail to treat the
`underlying cause of ARDS and the abnormalities of the
`surfactant system with accompanying derangements in
`lung compliance, pulmonary arterial hypertension
`(PAH), and ventilation-perfusion (V/Q) mismatch.
`
`CONVENTIONAL MECHANICAL VENTILATION
`(CMV)
` All modes of positive pressure ventilation used in
`adult intensive care units are also used in children,
`although paralysis or spontaneous breathing with
`triggered breaths, pressure and volume limited modes
`are most widely used. Cuffed endotracheal tubes are
`uncommonly used because of the smaller size of the
`endotracheal tube (no cuff allows a tube with a larger
`internal diameter), and the lower bronchial perfusion
`pressure of children which makes bronchial mucosal
`injury more likely. Humidification is essential to
`
`
`
` Acute respiratory failure (ARF) continues to be a
`major problem in paediatric critical care. In a recent
`report from a large paediatric intensive care unit,1
`patients with ARF comprised nearly 3% of all
`admissions and 8% of total patient days. Mortality in
`this group was 62% and accounted for 33% of all deaths
`in the intensive care unit during the 24-month study
`period. Others report similar findings with mortalities
`ranging from 40% to 75%.2-5 Freund and Jorch reviewed
`four
`recent
`reports of acute
`respiratory distress
`syndrome (ARDS) in children, reporting an overall
`mortality of 52%.6
` Recent advances in conventional therapy for the
`treatment of ARF and ARDS have not had a major
`impact on survival. Firstly, the refinements of existing
`care have had complications, including volutrauma,
`barotrauma, oxygen toxicity, impairment of cardiac
`output and nosocomial infections with multiple system
`
`
` Correspondence to: Dr. W. Butt, Paediatric Intensive Care Unit, Royal Children’s Hospital, Victoria 3052
`
`
`
`
`85
`
`Ex. 2038-0001
`
`

`
`Critical Care and Resuscitation 1999; 1: 85-92
`
`ventilation (HFPPV), high frequency jet ventilation
`(HFJV), and high
`frequency oscillation
`(HFO).
`Important differences between the latter two modes of
`HFV
`are
`summarised
`in Table 1
`and
`are
`comprehensively reviewed by Froese and Bryan.7 Figure
`1 illustrates an HFO device. All types of HFV effect
`elimination of carbon dioxide by the delivery of a very
`cycled
`at
`supraphysiologic
`small
`tidal volume
`respiratory rates.
` HFPPV is similar to CMV and accomplishes gas
`exchange largely through bulk convection, although
`some bulk convection occurs with the other modes of
`HFV as well. The tidal volume generated with HFJV
`and HFV, however, is smaller than the anatomic dead-
`space volume itself, and thus, other mechanisms must be
`invoked to explain their effectiveness in ventilation.8
`These mechanisms
`include pendelluft, asymmetric
`velocity profiles, Taylor dispersion, and molecular
`diffusion.
`
`Pendelluft refers to peripheral mixing of gas between
`alveolar units with variable time constants. During HFV,
`the respiratory cycle is shorter than the shorter alveolar
`time constant, and ventilation is considerably augmented
`as units with longer and shorter time constants empty
`into one another. Lung diseases in which there is
`considerable
`inequality
`in
`time constants between
`alveolar units, such as ARDS, theoretically amplify this
`effect by 300%.
` Asymmetric velocity profiles refer to air flow that
`has, during inspiration, a parabolic velocity profile;
`whereas during expiration, it has a flat profile.
`
`
`
`
`Figure 1. Schematic of a high frequency oscillator.
` Piston
`displacement, a function of rate and amplitude, determine “tidal
`volume”. (From Wetzel RC, Gioia FR. High frequency ventilation.
`Pediatr Clin North Am 1987;34:15.)
`
`
`
`W. BUTT
`
`prevent endotracheal tube blockage with inspissated
`mucous.
` Diaphragmatic splinting by a distended
`stomach must be prevented
`in
`the spontaneously
`breathing child because of the dependence of the small
`child on diaphragmatic function.
`
`Objectives of Mechanical Ventilation
`Improve pulmonary gas exchange
`- Relieve acute respiratory acidosis or ventilatory failure
`- Reverse hypoxemia or hypoxemic respiratory failure
`Change pressure-volume relations in lung
`- Optimise pulmonary compliance
`- Prevent or reverse atelectasis
`Reduce or otherwise modulate work of breathing
`- Decrease oxygen cost of breathing
`- Reverse respiratory muscle fatigue
`- Use anaesthesia, sedation, or neuromuscular blockade
`Avoid complications
`- Decrease or prevent anoxic-hypoxic events
`- Prevent barotrauma, volutrauma, and oxygen toxicity
`Support lung and airway healing
`- Allow time for therapeutic intervention to succeed
`- Allow time for lung repair to evolve
`Promote independent breathing or independent lifestyle
`- Facilitate ventilatory independence
`- Provide partial, complete, ambulatory, permanent, or
`temporary assisted ventilation to support chronic
`debilitating illness or lung disease
`
`
`Direct Goals
` Oxygenation: Oxygen delivery (DO2) and oxygen
`uptake (VO2) are more important than arterial blood
`thus an arterial blood
`(PaO2),
`oxygen
`tension
`haemoglobin oxygen saturation (SaO2) of greater than
`80% (with no metabolic acidosis) is adequate. Mean
`airway pressure and inspired oxygen concentration
`to
`limit volutrauma,
`(FiO2) may be minimised
`barotrauma and oxygen toxicity.
` Ventilation: respiratory acidosis (in the absence of
`metabolic acidosis) is rarely lethal, thus pH not carbon
`dioxide is the goal of ventilation (> 7.15). If reactive
`pulmonary hypertension is present then it may be
`necessary to have a pH > 7.4.
`
`OTHER THERAPIES FOR ACUTE RESPIRATORY
`FAILURE
`
`High Frequency Ventilation
`a
`is
`(HFV)
` High
`frequency
`ventilation
`nonconventional mode of mechanical ventilation that
`has been used clinically for almost 15 years in the
`management of refractory ARF. There are three distinct
`types of HFV: High
`frequency positive-pressure
`
`
`86
`
`
`
`Ex. 2038-0002
`
`

`
`
`
`W. BUTT
`
`benefit from ECMO and effectively stopped the use of
`that therapy in ARF for a time. However, interest in
`ECMO
`resurfaced
`in
`the early 1980s,
`led by
`pediatricians and neonatologists in search of modality
`that would provide temporising support to premature
`infants with hyaline membrane disease and persistent
`pulmonary hypertension of the newborn (PPHN).
`
`
`
`Critical Care and Resuscitation 1998; 1: 7-14
`
`Table 1. Differences between high frequency jet ventilation (HFJV) and high frequency oscillation (HFO)
`
`HFJV
`HFO
`Rate (HZ)
`1.5-3.0
`3.0-15.0
`Expiration
`Passive
`Active
`Special ETT/reintubation
`Yes
`No
`Gas exchange
`
`
`++
`++
`↓ PaCO2
`+
`↑PaO2
`±
`Cardiac output
`↑↓
`↓
`Tracheal injury
`++
`?
`
` Accordingly, net convective transport of gas occurs
`with each respiratory cycle. This mechanism of gas
`transport is particularly important at points of airway
`division, where velocity profiles are normally even more
`skewed.
` Taylor dispersion refers to the dispersion of gas
`within the airway that results from the interaction
`between the axial velocity profile of the breath and the
`forces of radial diffusion that act on bases in motion;
`this effect is enhanced by the turbulent flow encountered
`at airway branch points and by the high flow velocities
`seen with HFV. This mechanism
`contributes
`significantly to gas mixing during HFV.
`
`Finally, molecular diffusion is no less a factor in gas
`exchange with HFV than it is with CMV. Figure 2
`illustrates those locations within the lung where these
`various mechanisms of gas exchange are thought to
`predominate.
` HFO appears to be a therapy with great promise for
`the treatment of ARF refractory to management with
`CMV. It may also have a role in the prevention of
`iatrogenic lung injury and in the promotion of lung
`healing. A strategy that opens alveoli with a sustained
`inflation maneuver, maintains
`them open for gas
`exchange with sufficiently high airway pressure is most
`likely to achieve improved oxygenation and compliance,
`and decrease in lung injury.9
`frequent chest
`Proper monitoring of PaO2,
`
`radiographs, and serial determination of indices of
`pulmonary and cardiac function will decrease the
`potential for barotrauma and low cardiac output that is
`inherent with this therapy.
`
`Extracorporeal membrane oxygenation (ECMO)
`
` During the early 1970s, numerous cases and small
`series were reported which led to a multi-institutional
`ECMO trial in 1975.10 This study, involving 9 centers
`over 2.5 years, randomised 90 adults patients with
`severe ARF to receive ECMO or CMV therapy.
`and
`Subsequently
`criticised
`for
`design
`
`methodological flaws, this study failed to demonstrate
`
`
`Figure 2. A representation of mechanisms of gas transport that
`predominate in given lung regions. 1 = bulk convection; 2 = Taylor
`dispersion; 3 = asymmetric velocity profiles; 4 = pendelluft; 5 =
`molecular diffusion. (From Wetzel RC, Gioia FR. High frequency
`ventilation. Pediatr Clin North Am 1987;34:15.)
`
`
`
`Indications for neonatal ECMO became more refined
`its complications became better understood
`as
`(particularly bleeding in the more premature patients). A
`prospective, randomised study was undertaken in 1985
`by O’Rourke et al in which neonates with ARF who fell
`into an 80% mortality group, as defined by
`historically derived predictor data, were randomised to
`therapy.11
`receive either ECMO or conventional
`Although the mortality in the control group was only
`half of that predicted, it was twice that in the ECMO
`
`
`
`88
`
`Ex. 2038-0003
`
`

`
`
`
`W. BUTT
`
`reached statistical
`that
`figure
`group, a survival
`significance and established ECMO as a standard
`therapy for selected groups of neonates, especially those
`with associated pulmonary arterial hypertension (PAH).
` The success of ECMO in the neonatal population
`inspired renewed interest in applications of this therapy
`in the non-neonate, and once again, reports of successes
`in single cases and small series have begun to appear in
`the literature.12-15
`
`Technical aspects
` The advantages of veno-arterial compared with
`veno-venous ECMO include, maintaining a normal
`pulmonary blood flow, as an aid in lung healing,
`providing a better coronary blood pH and PaO2, and
`maintaining a pulsatile flow. Cerebral embolism is also
`less likely to occur as the normal pattern of cerebral
`arterial flow is maintained.
`
`Nitric oxide
` Multiple physical and chemical stimuli acting on
`receptors located on the endothelial cell membrane,
`activate the intracellular enzyme, nitric oxide synthetase,
`which catalyses the conversion of L-arginine to nitric
`oxide (NO). This reaction appears to be dependent on
`the
`presence
`of
`cofactors,
`including
`reduced
`nicotinamide
`adenine
`dinucleotide
`phosphate
`(NADPH)16 and sufficient substate17 and can be blocked
`by various arginine analogues.18 It may also involve
`active notrosothiol intermediates.19 The NO so formed
`diffuses easily and rapidly from the endothelial cells into
`subjacent vascular smooth muscle cells, where
`it
`stimulates
`guanylate
`cyclase
`to
`increase
`the
`concentration of cyclic guanosine monophosphate,
`which in turn causes smooth muscle relaxtion.20
` Nitrovasodilators currently
`in clinical use are
`thought to act via mechanisms that result in NO
`release.21 Any NO that reaches the vascular space is
`quickly inactivated by binding to the heme ring of
`haemoglobin, which ultimately
`is metabolised
`to
`methaemoglobin.22 Guanylate cyclase can also be
`inactivated by methylene blue,23 also limiting the effect
`of NO.
`
`Inhaled NO distributes to aerated lung only, where
`its localised vasodilating effect improves V/Q matching.
`Thereafter, any NO that diffuses into the vascular space
`is quickly inactivated by haemoglobin, so its systemic
`vasodilatory effects are minimal; thus inhaled NO acts
`as a selective pulmonary vasodilator.
` Laboratory studies prepared the way for trials of
`inhaled NO
`in a variety of disease processes
`characterised by PAH or severe V/Q mismatching.
`Roberts et al used inhaled NO at 80 parts per million
`(ppm) to treat six infants with PPHN, which increased
`
`88
`
`
`
`Critical Care and Resuscitation 1999; 1: 85-92
`
`preductal SaO2 in all six patients (88% to 97%) and
`postductal SaO2 in five of six patients (82% to 90%),
`without
`systemic
`hypotension
`or
`significant
`methaemoglobinaema.24 Little response was seen with a
`lower dose of NO and five of six patients manifested
`rebound PAH when the NO was discontinued after 30
`minutes. One patient continued to respond to NO for 23
`days.
` Kinsella et al, reported their experience treating nine
`neonates with PPHN using NO at 10 to 20 ppm.25
`Within 15 minutes of initiating NO at 10 ppm, the PaO2
`increased from 55 mmHg to 136 mmHg and the
`oxygenation index (i.e. mean airway pressure x FiO2 x
`100 ÷ PaO2) decreased from 60 to 26. No patient
`developed
`systemic
`hypotension
`or meth-
`aemoglobinaemia. Their first three of nine patients were
`treated with NO for less than 4 hours and, though they
`responded, they were referred for ECMO because the
`PAH persisted when the NO was discontinued. The last
`six of nine patients were treated for 24 hours with NO,
`the dose reduced progressively to 6 ppm; all continued
`to respond to NO administration, and none required
`ECMO.
`In a subsequent report, Kinsella et al, again noted a
`
`marked improvement in oxygenation with NO for
`neonates with PPHN.26 NO was initiated at 20 ppm for
`4 hours, then maintained at 6 ppm for 20 hours. Only 1
`out of 9 of these ECMO-eligible patients ultimately
`required ECMO; that patient received primarily left
`heart support for sepsis-induced low cardiac output and
`multiple organ system dysfunction. No patients had any
`haemodynamic compromise because of NO. The blood
`pressure was well maintained and heart rate fell,
`indicating a rising cardiac output, even in 2 of 3 of the
`patients with sepsis. Echocardiographic indices of PAH
`improved. Methaemoglobin levels peaked at 1.44 ±
`0.09% with the “loading dose” of NO but, at 24 hours,
`were no different than the pretreatment values.
`Finer et al studied 23 ECMO-eligible neonates
`
`treated with conventional medical
`therapy and
`surfactant, who continued to have an oxygenation index
`greater than 20.27 Fourteen of the 23 patients showed
`some improvement in oxygenation with NO at 5 to 80
`ppm, 1 in 14 responding hours later to NO having not
`responded initially, but 11 of 23 ultimately required
`ECMO. Eleven of 13 patients with echocardiographic
`signs of PAH responded to NO, whereas 7 of 10 with
`normal pulmonary artery pressures did not.
` Abman et al, reported a 28-week gestation neonate
`with PAH secondary to sepsis, who demonstrated
`improved oxygenation and decreased pulmonary artery
`pressure (PAP) when treated with low-dose NO.28 They
`speculated that NO might prove particularly helpful in
`the treatment of some preterm patients who were at great
`
`Ex. 2038-0004
`
`

`
`Critical Care and Resuscitation 1999; 1: 85-92
`
`
`
`W. BUTT
`
`patients for up to 53 days. Methaemoglobin levels
`remained less than 1.3%.
` Considerable potential exists with NO to reduce the
`short-term mortality and the long-term morbidity of
`severe cardiopulmonary failure in children. It appears
`that the long-sought selective pulmonary vasodilator
`may finally be here.
`
`Liquid ventilation
` The concept of liquid ventilation (LV) seems almost
`anti-evolutionary, yet, as a therapy for ARF, it offers
`several theoretic advantages compared with CMV for
`the safe, effective gas exchange in the surfactant-
`deficient lung.
`
`Forces
`that determine surface tension may be
`predicted by considering the Laplace equation;
`
`
`
`
`
`risk for injury with conventional therapy for ARF and
`PAH, but who were not ECMO-eligible, because of their
`age and size.
`
`Patients with PAH secondary to congenital heart
`disease may also benefit, both diagnostically and
`therapeutically, from NO. Roberts et al reported 10
`patients, aged from 3 months to 6.5 years, with
`structural congenital heart disease and PAH; 6 had
`septal defects with left-to-right shunts, and 5 had
`trisomy 21.29 Inhaled NO at 80 ppm was more effective
`at reducing pulmonary vascular resistance than oxygen
`at an FiO2 of 0.9. Pulmonary vascular resistance fell
`20% with oxygen, 26% with NO at 80 ppm, and 54%
`with a combination of the two. Patients with the highest
`pulmonary vascular resistance had the greatest response
`to NO. A decrease in the systemic vascular resistance
`did not occur. The authors suggested that, in addition to
`being a short-term treatment for patients with PAH, NO
`might be useful in the cardiac catheterisation laboratory
`to determine which patients have reactive rather than
`fixed pulmonary vascular disease.
` Wessel et al, determined
`to an
`the response
`acetylcholine infusion and NO in patients with structural
`congenital
`heart
`disease
`and PAH
`following
`cardiopulmonary bypass and repair.30 They noted that
`NO at 80 ppm was a potent and selective pulmonary
`vasodilator both before and after cardiopulmonary
`bypass, but
`that
`the vasodilatory
`response
`to
`acetylcholine was diminished (37% reduction versus a
`9% reduction) after cardiopulmonary bypass. They
`attributed
`this finding to cardiopulmonary bypass-
`induced pulmonary vascular endothelial dysfunction,
`with failure to release endogenous NO.
`
`Following relief of chronic mitral stenosis with PAH,
`Girard et al31 (in adults), and Atz et al32 (in children),
`showed a pulmonary vasodilatory response to NO
`without a decrease in systemic arterial pressure. Atz et
`al, speculated that in children, where mitral stenosis
`commonly coexists with
`important
`left ventricular
`outflow tract obstruction, NO might be of particular
`benefit because systemic diastolic pressure, and
`therefore coronary artery perfusion, might be better
`maintained using a selective pulmonary dilator without
`system vascular effects.
` A decrease in endothelium-dependent pulmonary
`vasodilation has been demonstrated with experimental
`syndrome,34
`shunts,33 Eisenmenger’s
`left-to-right
`idiopathic PAH,35 and COPD.36 Rossaint et al, treated
`10 adults with ARDS using NO at 18 ppm and observed
`a 19% decrease in mean PAP, a 14% decrease in
`intrapulmonary shunt, and a 31% increase in PaO2/FiO2,
`the cardiac output and mean arterial blood pressure
`remained unchanged.37 Inhaled NO remained effective
`even when administered continuously in one of these
`
`
`
`
`
`P = 2T/r
`
`
`Where,
`
`P = alveolar distending pressure
` T = surface tension
`
`r = radius of the alveolus
`
` This predicts that if surface tension is decreased,
`lung expansion can be accomplished more easily, and
`even small alveoli can be maintained open for gas
`exchange at low distending pressures. The risk of
`pressure-induced lung injury is also decreased.
`
`It has been reasoned that by using liquid functional
`residual capacity (FRC) and tidal gas breathing by
`CMV, oxygenation and carbon dioxide removal may be
`facilitated and one may improve pulmonary mechanics
`in the surfactant-deficient lung. Liquid-filled alveoli
`have a much diminished air-fluid interface, and thus, the
`surface tension forces that favor alveolar collapse are
`minimised. Other physical properties of fluid favor its
`more homogeneous distribution compared with gas, and
`therefore a more complete expansion of the lung.
`Oxygenation and ventilation will be directly enhanced if
`oxygen and carbon dioxide are highly soluble in the
`fluid used to inflate the alveoli, as the fluid itself will act
`as a gas exchange reservoir. Finally, the liquid can act
`mechanically
`to
`lavage particulate matter
`and
`inflammatory or infectious material from the lung, as
`well as delivering pharmacological agents to it.
`
`Theoretic advantages of liquid ventilation
`• Reduces lung distending pressures;
`• Facilitates homogeneous lung expansion;
`• Maintains functional residual capacity; and
`• Acts as a vehicle for pulmonary administration of
`drugs to the lung.
`
`
`
`89
`
`Ex. 2038-0005
`
`

`
`W. BUTT
`
` Two forms of LV are currently used: total (tidal)
`liquid ventilation (TLV), and partial liquid (PLV) or
`perfluorocarbon-associated gas exchange
`(PAGE).
`With TLV, a volume of perfluorocarbon equal to the
`lung’s functional residual capacity (FRC) is instilled via
`an endotracheal tube, and tidal volume (VT) aliquots of
`liquid are subsequently cycled to effect gas exchange,
`often utilising highly specialised apparatus. With PLV
`or PAGE, a volume of perfluorocarbon equal to the
`lung’s FRC is instilled into the trachea, but unlike TLV
`the subsequent tidal ventilation is performed with
`respiratory gas administered via a standard mechanical
`ventilator at conventional settings.
` An extensive
`experimental literature has accumulated over the last 25
`years for each form of LV, with animal studies
`documenting its efficacy and safety in mature and
`immature animals, both with and without a variety of
`respiratory disease processes. Succinct reviews of this
`topic have recently been published.38,39
` Liquid ventilation, especially the technically simpler
`PLV or PAGE, is a promising therapy, the applications
`for which are increasing in number. Studies to date have
`focused on its use to improve gas exchange and increase
`respiratory compliance in surfactant deficiency states,
`especially in immature animals. Experimental evidence
`reported by Fuhrman’s group supports its application in
`lung injury secondary to gastric aspiration40 and in oleic
`acid-induced ARDS.41 PAGE decreases protein loss into
`the alveoli if initiated prior to inducing ARDS with oleic
`acid.42 Perfluorocarbon will also decrease free radical
`in vitro,43
`production by alveolar macrophages
`supporting another lung-protective role. Hirschl et al,
`determined that a combination of TLV and PLV
`improves lung compliance and gas exchange in animals
`supported with ECMO following oleic-acid-induced
`lung injury, with LV decreasing the ECMO blood flow
`
`Table 2. Gas exchange and compliance in conventional mechanical ventilation versus perfluorocarbon-
`associated gas exchange
`
`
`
`Critical Care and Resuscitation 1999; 1: 85-92
`
`requirements.44 A recent report of gas exchange and
`compliance change in surfactant deficiency highlights
`the improvements in this group with PAGE and is
`summarised in Table 2.
`
`Investigations are also ongoing utilising LV
`techniques to improve delivery of a wide variety of
`medications to the lung, for example, antimicrobial
`agents, surfactants, and NO. “Dose-response” curves
`for various applications of LV need to be determined
`and new perfluorocarbons need to be developed, the
`physical properties of which will hopefully facilitate
`particular therapies.
`
`CONCLUSION
` CMV of patients with ARF has undergone many
`changes over the past quarter century, with ever more
`sophisticated strategies and technology being used.
`Despite these advances, mobidity and mortality have
`been improved only modestly, at best. Further advances
`with modification of conventional therapies are likely to
`be limited by their failure to address the underlying
`physiologic disturbances which lead to the clinical
`syndrome of ARF, and their poor success rate in
`minimising complications associated with the therapy.
` New approaches to treatment of ARF usually address
`some fundamental physiologic principle, for example,
`surface tension, heart-lung interaction,
`normalisation of lung function in the diseased state, or
`V/Q mismatch, in ways which minimise iatrogenic lung
`injury.
` A number of recently investigated novel therapies,
`including
`pressure-controlled
`ventilation
`with
`permissive hypercapnia, high-frequency ventilation,
`ECMO,
`inhaled nitric oxide
`therapy, and per-
`fluorocarbon liquid ventilation, show promise.
`
`
`
`Time (min)
`
`
`
`CMV
`-5
`
`-30
`
`5
`
`PAGE
`30
`
`60
`
`PaO2 (mm Hg)
`PaCO2 (mm Hg)
`pH
`CDyn (ml/cm H2O/kg)
`
`CMV = conventional mechanical ventilation; CDyn = dynamic compliance; PAGE = perfluorocarbon-associated gas exchange; PaCO2 = partial
`pressure of carbon dioxide, arterial; PaO2 = partial pressure of oxygen, arterial. From Leach CL, Fuhrman BP. Perfluorocarbon-associated gas
`exchange (PAGE) in surfactant deficiency. Am Rev Respir Dis 1992;145:A454.
`
`61 ± 6
`62 ± 6
`7.19 ± .05
`0.33 ± .03
`
`59 ± 6
`62 ± 4
`7.20 ± .04
`0.37 ± .04
`
`250 ± 28
`50 ± 4
`7.27 ± .03
`0.85 ± .09
`
`251 ± 18
`41 ± 3
`7.34 ± .04
`0.87 ± .08
`
`268 ± 38
`38 ± 3
`7.36 ± .04
`0.88 ± .10
`
`
`
`
`
`
`
`90
`
`Ex. 2038-0006
`
`

`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`Received: 27 March 1998
`Accepted: 20 August 1998
`
`REFERENCES
`1. Davis SL, Furman DP, Costarino AT Jr. Adult
`respiratory distress syndrome in children: Associated
`disease, clinical course, and predictors of death. J
`Pediatr 1993;123:35-45.
`Lyrne RK, Truog WE. Adult respiratory distress
`syndrome in a pediatric intensive care unit: Predisposing
`conditions, clinical course, and outcome. Pediatrics
`1981;67:790-795.
`Rivera RA, Butt W, Shann F. Predictors of mortality in
`children with respiratory failure: Possible indications for
`ECMO. Anaesth Intensive Care 1990;18:385-389.
`Tamburro RF, Bugnitz MC, Stidham GL. Alveolar-
`arterial oxygen gradient as predictor of outcome in
`patients with non-neonatal pediatric respiratory failure. J
`Pediatr 1991;119:935-938
`Timmons OD, Dean JM, Vernon DD. Mortality rates
`and prognostic variables
`in children with adult
`respiratory distress syndrome. J Pediatr 1991;119:896-
`899.
`Freund A, Jorch G. Pediatric characteristics of adult
`respiratory distress syndrome: A meta-analysis. Klin
`Padiatr 1993;205:411-415.
`Froese AB, Bryan AC. High-frequency ventilation. Am
`Rev Respir Dis 1987;135:1363-1374.
`8. Wetzel RC, Gioia FR. High frequency ventilation.
`Pediatr Clin North Am 1987;34:15-38.
`9. Gerstmann DR, DeLemos RA, Clark RH. High-
`frequency ventilation: Issues of strategy. Clin Perinatol
`1991;18:563-580.
`10. Zapol WM, Snider MT, Hill JD, et al. Extracorporeal
`membrane oxygenation in severe acute respiratory
`failure. JAMA 1979;242:2193-2196.
`JP, et al.
`11. O'Rourke PP, Crone RK, Vacanti
`Extracorporeal membrane oxygenation and conventional
`medical therapy in neonates with persistent pulmonary
`hypertension of the newborn: a prospective randomized
`study. Pediatrics 1989;84:957-963.
`12. Adolph V, Heaton J, Steiner R, Bonis S, Falterman K,
`Arensman R. Extracorporeal membrane oxygenation for
`non-neonatal
`respiratory
`failure.
`J Pediatr Surg
`1991;26:326-330.
`13. Butt W, Karl T, Horton A, Shann F, Mullaly R.
`Experience with extracorporeal membrane oxygenation
`in children more than one month old. Anaesth Intensive
`Care 1992;20:308-310.
`14. Steiner RB, Adolph VR, Heaton JF, Bonis SL,
`Falterman KW, Arensman RM. Pediatric extracorporeal
`membrane oxygenation in posttraumatic respiratory
`failure. J Pediatr Surg 1991;26:1011-1014.
`15. Weber TR, Tracy TF Jr, Connors R, Kountzman B,
`Pennington DG. Prolonged extracorporeal support for
`nonneonatal
`respiratory
`failure.
`J Pediatr Surg
`1992;27:1100-1104.
`16. Palmer RM, Moncada S. A novel citrulline-forming
`enzyme implicated in the formation of nitric oxide by
`
`Critical Care and Resuscitation 1999; 1: 85-92
`
`
`
`W. BUTT
`
`2.
`
`19.
`
`vascular endothelial cells. Biochem Biophys Res
`Commun 1989;158:348-352.
`17. Mitchell JA, Hecker M, Vane JR. The generation of L-
`arginine in endothelial cells is linked to the release of
`endothelim-derived relaxing factor. Eur J Pharmacol
`1990;176:253-254.
`18. Vargas HM, Cuevas JM, Ignarro LJ, Chaudhuri G.
`Comparison of the inhibitory potencies of N-methyl-, N-
`nitro and n-amino-L-arginine on EDRF function in the
`rat: Evidence for continuous basal EDRF release. J
`Pharmacol Exp Ther 1991;257:1208-1215.
`Ignarro LJ, Lippton H, Edwards JC, et al. Mechanism of
`vascular smooth muscle relaxation by organic nitrates,
`nitrites, nitroprusside, and nitric oxide: Evidence for the
`involvement of S-nitrosothiols as active intermediates. J
`Pharmacol Exp Ther 1981;218:739-749.
`20. Griffith TM, Edwards DH, Lewis MJ, Henderson AH.
`Evidence that cyclic guanosine monophosphate (cGMP)
`mediates endothelium-dependent
`relaxation. Eur J
`Pharmacol 1985;112:195-202.
`21. Gruetter DY, Gruetter CA, Barry BK, et al. Activation
`of coronary artery guanylate cyclase by nitric oxide,
`nitroprusside, and nitrosoguanidine:
`Inhibition by
`calcium, lanthanum, and other cations; enhancement by
`thiols. Biochem Pharmacol 1980;29:2943-2950.
`22. Doyle MP, Hoekstra JW. Oxidation of nitrogen oxides
`by bound dioxygen in hemoproteins. J Inorg Biochem
`1981;14:351-358.
`23. Gruetter CA, Gruetter DY, Lyon JE, Kadowitz PJ,
`Ignarro LJ. Relationship between cyclic guanosine 3’-
`5’monophosphate formation and relaxation of coronary
`arterial
`smooth muscle
`by
`glyceryl
`trinitrate,
`nitroprusside, nitrite, and nitric oxide: effects of
`methylene blue and methemoglobin. J Pharmacol Exp
`Ther 1981;219:181-186.
`24. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled
`nitric oxide in persistent pulmonary hypertension of the
`newborn. Lancet 1992;340:818-819.
`25. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose
`inhalational nitric oxide
`in persistent pulmonary
`hypertension of the newborn. Lancet 1992;340:819-820
`26. Kinsella JP, Neish SR, Ivy DD, Shaffer E, Abman SH.
`Clinical responses to prolonged treatment of persistent
`pulmonary hypertension of the newborn with low doses
`of inhaled nitric oxide. J Pediatr 1993;123:103-108.
`27. Finer NN, Etches PC, Kamstra B, Tierney AJ, Peliowski
`A, Ryan CA. Inhaled nitric oxide in infants referred for
`extracorporeal membrane oxygenation: dose response. J
`Pediatr 1994;124:302-308.
`28. Abman SH, Kinsella JP, Schaffer MS, Wilkening RB.
`Inhaled nitric oxide in the management of a premature
`newborn with severe respiratory distress and pulmonary
`hypertension. Pediatrics 1993;92:606-609.
`29. Roberts JD Jr, Lang P, Bigatello LM, Vlahakes GJ,
`Zapol WM. Inhaled nitric oxide in congenital heart
`disease. Circulation 1993;87:447-453.
`30. Wessel DL, Adatia I, Giglia TM, Thompson JE, Kulik
`TJ. Use of inhaled nitric oxide and acetylcholine in the
`evaluation of pulmonary hypertension and endothelial
`
`
`
`91
`
`Ex. 2038-0007
`
`

`
`W. BUTT
`
`
`
`
`Critical Care and Resuscitation 1999; 1: 85-92
`
`function after cardiopulmonary bypass. Circulation
`1993;88:2128-2138.
`31. Girard C, Lehot JJ, Pannetier JC, Filley S, Ffrench P,
`Estanove S. Inhaled nitric oxide after mitral valve
`replacement in patients with chronic pulmonary artery
`hypertension. Anesthesiology 1992;77:880-883.
`32. Atz AM, Adatia I, Jonas RA, Wessel DL. Inhaled nitric
`oxide in children with p