Mechanical ventilation strategies in the management of congenital diaphragmatic hernia

Seminars in Pediatric Surgery (2007) 16, 115-125

Mechanical ventilation strategies in the management of congenital diaphragmatic hernia J. Wells Logan, MD,a C. Michael Cotten, MD, MHS,a Ronald N. Goldberg, MD,a Reese H. Clark, MDb From the aDivision of Neonatology, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina; and the b Clinical Research and Education, Pediatrix Medical Group, Sunrise, Florida. KEYWORDS Congenital diaphragmatic hernia; Mechanical ventilation; Lung hypoplasia; Pulmonary hypertension; Ventilator-induced lung injury; Permissive hypercapnia

Most infants with congenital diaphragmatic hernia (CDH) require respiratory support. The goal of this report is to present an overview of mechanical ventilation strategies in the management of infants with CDH. The anatomic and physiologic limitations in the lungs of infants with diaphragmatic hernia make decisions on the best strategy and use of mechanical ventilation challenging. We will briefly review lung development in infants with CDH, identifying factors that provide a basis for lung protection strategies. Background on the use of specific mechanical ventilation modes and the rationale for each are provided. Finally, we review mechanical ventilation practices described in published case series of successful CDH management, with a brief review of additional treatments, including inhaled nitric oxide and extracorporeal membrane oxygenation. Although details of a single specific best strategy for mechanical ventilation for CDH infants cannot be identified from current literature, a lung protection ventilation approach, regardless of the device used, appears to reduce mortality risk. © 2007 Elsevier Inc. All rights reserved.

Most infants with congenital diaphragmatic hernia (CDH) require respiratory support.1,2 Anatomic and physiologic limitations in the lung parenchyma and vasculature make the decision of how best to use mechanical ventilation in these fragile infants a challenge. Although single-center reports have described significant improvements in survival with lung-protective ventilation strategies, the details of these approaches are actually quite varied. In this report, we will briefly review lung development in infants with CDH, identifying factors that provide a basis for these strategies. We will review the ventilatory practices presented in the multiple published case series of successful CDH management, and provide information on decisions to use addiAddress reprint requests and correspondence: C. Michael Cotten, MD, MHS, Duke University Medical Center, Division of Neonatology/Dept. of Pediatrics, DUMC 3179, 204 Bell Bldg. Svc Drive, Durham, NC 27710. E-mail: [email protected].

1055-8586/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.sempedsurg.2007.01.006

tional treatments including use of surfactant, inhaled nitric oxide, and extracorporeal membrane oxygenation (ECMO).

Cardiopulmonary development in CDH Lung hypoplasia, dysmaturity, and abnormalities of the pulmonary vasculature contribute to the risk of poor outcome. Human and animal studies demonstrate that lung function and health outcome correlate well with the degree of pulmonary hypoplasia. Survival is very unlikely if lung volumes are lower than 30% of predicted.3-7 Volumes of both ipsilateral and contralateral lungs are lower than normal,8,9 and airway smooth muscle dysregulation may contribute to airway obstruction.10 Lung hypoplasia in CDH, characterized by both a decreased number of airways and smaller airspaces, is also accompanied by a decreased number of vascular branches with

116 increased adventitia and medial thickness.11 This combination results in varying degrees of pulmonary hypertension and right heart failure in many CDH infants.12 Postmortem lung studies, that include information about the pulmonary vasculature, conclude that CDH infants with moderate hypoplasia (ⱖ50% predicted volume for gestational age) and impaired, but adequate, pulmonary blood flow can survive in the absence of pulmonary injury caused by various well-intentioned ventilatory therapies. Clinicians can also be encouraged by the fact that pulmonary airway and vascular development does continue after birth.13,14 Taking a less aggressive ventilatory approach, one that avoids lung injury while allowing for growth of lung parenchyma and vasculature, may be the optimal management strategy.

Lung injury and CDH: optimizing blood gases or survival odds? Best practice in the past: CDH-PPHN treated with chemical and ventilator-induced alkalosis Induced alkalosis significantly attenuates right-to-left ductal and atrial shunting by decreasing pulmonary vascular resistance and pulmonary artery pressure. Because most infants with CDH have some component of pulmonary hypertension, this approach was commonly used by clinicians before the mid-1990s.15,16 Best postductal PaO2, best PaCO2, and various ventilation indices were frequently used as “targets” for prognostication. Eventually, induced alkalosis became a standard treatment regimen for postnatal pulmonary hypertension. Higher peak inspiratory pressures and higher mean airway pressures were used routinely to reach these “targets” (PaCO2 ⬍40 and PaO2⬎ 100), and failing to meet the targets despite maximal therapy implied low chances for survival. Outcome reports such as those described by Azarow and coworkers (ie, “Bohn’s box”) reflected the results of this targeted “best practice” for infants with CDH. Infants with reassuring blood gases (PaCO2 ⬍ 40 mm Hg) often survived, whereas babies unable to achieve these results died despite use of maximal mechanical ventilatory support.17,18 Use of high ventilatory pressures to achieve PaCO2 ⬍ 40 mm Hg, which seemed an appropriate goal to test potential survival, may have exacerbated lung injury to the less than optimal lung anatomy and contributed to high pulmonary morbidity and mortality among CDH infants.7,19-23 There is also evidence in animal models and in preterm infants that hypocarbia and alkalosis are associated with neurodevelopmental impairment, and a recent observational study from NICHD Neonatal Network data suggests that chemical-induced alkalosis may be associated with increased risk for ECMO.24-27

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Permissive hypercapnia: a better approach? The benefits of minimizing ventilatory-induced lung injury (VILI) likely derive from avoiding potential lung and pulmonary vascular injuries related to over-distension of terminal lung units.28-30 The concept of permissive hypercapnia with “gentle ventilation,” introduced by Wung and coworkers in 1985, was slow to be adopted due to reports that associated improvement in outcomes with the ability to achieve PaCO2 in the 40s with mechanical ventilation.15,16,23 Eventually, the concept of permissive hypercapnia as part of multi-faceted (ventilation, sedation, surgery timing, etc) approach to CDH caught on with reports of increased survival using higher tolerance limits for ventilation.31-42 Currently, more than 90% of International CDH Registry centers cite the use of permissive hypercapnia, accepting higher PaCO2 during the early course, rather than targeting low PaCO2 to estimate viability and lower pulmonary vascular resistance, as a primary therapeutic guideline.43 Although this strategy is only one aspect of a larger therapeutic package, such as that recently described by Bohn, we will focus primarily on mechanical ventilation.41

Ventilator-induced lung injury: clinicopathologic correlation Although differences in reporting patterns and lack of randomized controlled trials make it difficult to analyze ventilation strategies for CDH infants, there is accumulating evidence that ventilator-induced lung injury may have significantly impacted survival statistics for infants with CDH. Reports from the 1990s suggest that as much as 25% of the observed CDH mortality in liveborn infants is due to potentially preventable complications of care.7,21,22 Analysis of records from 100 CDH infants from 29 centers which contributed to the Extracorporeal Life Support Organization (ELSO) databank revealed that only 17% died primarily from pulmonary hypoplasia.21 A postmortem analyses in which pathological findings were correlated with measures of cardiopulmonary function in 18 high-risk CDH infants demonstrated that a subset of infants that die from CDH had wet lung weights, quantitative DNA, and morphometric lung measurements that would predict survival (⬎45% of control measures), suggesting the potential negative impact of postnatal treatment on outcome.7 In a large single-center retrospective series, which included autopsy and clinical data from 68 of 101 nonsurvivors of CDH, the predominant treatment strategy included high peak airway pressures, ranging from 32.5 to 48.3 cm H2O. Sixty-two of 68 autopsied CDH infants (91%) had evidence of diffuse alveolar damage, 44/68 (65%) had evidence of air-leak, and 34/68 (50%) had evidence of pulmonary hemorrhage, with destruction of the alveolar– capillary interface. The authors suggested that a significant degree of lung injury was related to high peak inspiratory pressures and that these changes were present at 3 days.22 These reports suggest that the primary cause of death in many neonates with CDH may be VILI and that a relatively

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small number of CDH infants who die have severe pulmonary hypoplasia incompatible with survival.7,21,22

What causes VILI? Excessive distending pressure, volutrauma, and atelectotrauma The deleterious effects of mechanical ventilation likely originate from multiple factors, including the level of pressure applied to the airway (MAP, PIP), the resulting tidal volume (VT), the duration of mechanical ventilation, the developmental state of the airway, and exposure to oxidative stress or other biological mediators of injury.28,29,44-49 Animal studies have shown that mechanical ventilation at high peak inflation pressures impairs lung function.28 However, the effects of tidal ventilation (volutrauma) appear to be more profound than the pressure-related effects.50,51 The best clinical evidence that limiting tidal volume improves outcome is from the ARDS network trial, which evaluated whether ventilation at lower target tidal volumes (6 mL/kg versus 12 mL/kg) would improve the outcomes. The trial was stopped after enrollment of 861 patients because the mortality rate was lower in the group treated with lower tidal volumes (31.0% versus 39.8%, P ⫽ 0.007).52 Atelectotrauma, tidal ventilation below the critical opening pressure, is also believed to contribute to VILI. Repetitive collapse and re-expansion of terminal lung units result in shear stress and injury.51 This suggests that high positive end-expiratory pressure (PEEP) would aide in the preservation of lung volume during exhalation, and therefore reduce atelectotrauma. However, high levels of PEEP at constant VT may exacerbate lung injury as well.53 In the end, the overall degree of lung inflation (distension) is believed to be responsible for the VILI noted in human and animal models. The goal of determining and establishing optimal end-expiratory lung volume in neonates with CDH remains frustratingly elusive.

Ventilatory pressures and pulmonary blood flow High mean airway pressure (MAP) adversely affects transpulmonary vascular efficiency in animal models. Pulmonary vascular resistance (PVR) correlates with the level of PEEP (higher PEEP, higher resistance), but changes in PVR are also related to pulmonary vascular tone.54,55 In an animal model used to study the effects of increasing levels of tidal volume and overdistension on pulmonary blood flow and cardiac output, increasing the tidal volume at constant PEEP was accompanied by increased PVR and significant decreases in both cardiac output and the lung’s dynamic compliance. Furthermore, the adverse effects of excessive tidal volume were exacerbated by increasing the level of PEEP.56 Creamer and coworkers demonstrated that ventilation below the closing lung volume, where atelectasis occurs, was associated with increased PVR, whereas the adverse effects on

117 PVR disappeared with each ventilatory cycle above the closing lung volume.57 Keeping the lung aerated (but not overdistended) will optimize pulmonary blood flow. Subsequently, Venkataraman and coworkers confirmed these findings and showed further that these effects are independent of the baseline level of pulmonary vascular tone.58

Biotrauma and systemic effects of VILI Injury to the lungs can have downstream effects on multiple organ systems.45 The pulmonary vasculature harbors a large reservoir of marginated neutrophils (up to a third of all neutrophils outside the bone marrow). Thus, significant potential exists for the lungs to interact with, and contribute to, the circulating pool of inflammatory cells. Mechanical ventilation affects the numbers of inflammatory cells and the expression of soluble mediators within the lungs. In saline-lavaged rabbits, manifestations of lung injury (ie, hyaline membranes, neutrophil infiltration, and impaired gas exchange), originally attributed to barotrauma/volutrauma, were almost completely abrogated in granulocyte-depleted rabbits.59 In addition to initiating an inflammatory cascade within the lungs, mechanical support can injure the alveolar– capillary barrier and allow the efflux of inflammatory mediators from the alveolar space into the general circulation.60,61 A systemic inflammatory response can also be promoted by translocation of bacteria62 and endotoxin63 from the air spaces into the circulation, somewhat analogous to the gut bacterial translocation hypothesis of multiple organ failure.64 Human studies in adults with respiratory failure have also shown that ventilatory strategy has an impact on pulmonary and systemic cytokines and that these changes are associated with multisystem organ failure.65,66

Mechanical ventilation strategies aimed at minimizing lung injury Several “benchmark” centers have reported significant improvements in survival using various lung-sparing mechanical ventilation strategies. Literature review reveals 11 case series from centers reporting survival greater than 75% for at least 25 infants with isolated CDH. Ten of these centers specifically mention avoiding lung injury as a primary goal of therapy.31-40,42 This section reviews aspects of mechanical ventilation practice that are credited with improvements in survival in these successful centers.

Minimizing lung injury Although there is surprisingly wide practice variation among the 11 reports, a consistent theme among successful centers is

118 Table 1

Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 Pressure limits and decision points

Author (Year)

Initial settings or limits

Decision points

HFV limits/settings

Boloker (1992-1999)

PIP up to 25, PEEP 5, I-time 0.3 seconds, IMV 20-40. Occasionally PIP to 30 cm H2O. Avoid precipitous changes in ventilator.

SaO2 ⬍ 90% switch to HFCV: PIP 20-25 cm H2O. IMV 100, PEEP ⫽ 0 with conventional ventilator. HFOV for persistent hypoxemia.

Wung(1983-1995)

PIP up to 25, PEEP 5, IMV 20-40. Permissive hypercapnia.

Wilson*(1991-1994)

PIP up to 30, PEEP 5, MAP 12 Minimize barotraumas by ignoring right to left shunt. Post-ductal SaO2 ignored. Permissive hypercapnia

Finer (1989-1995)

PIP up to 24 (usually 20-22)

Frenckner (19901995) Reyes(1993- 1995)

PIP up to 35

Ideal: Pre-ductal SaO2 ⬎90%. Acceptable: SaO2 80% to 90%. For severe hypoxia or hypercarbia, switch to HFCV, then HFOV. SaO2 ⬍ 80%, PCO2 ⬎ 65 torr Ideal: Preductal SaO2 ⬎ 90%. For severe or labile hypoxia (SaO2 ⬍ 80%) or hypercarbia (PCO2 ⬎ 60 torr) switch to HFCV. PIP 30 cm H2O, MAP 12 Preductal SaO2 ⬍ 90% with no evolving metabolic acidosis.For severe hypoxia/ hypercarbia, if unable to attain, or PaCO2 ⬎ 60, switch to HFCV PaCO2 ⬍ 60, if can’t attain with conventional, switch to HFOV. SaO2 ⬎ 70 in 1st 2 hours. SaO2 75-85% 2-4 hours. Postductal SaO2 ⬎ 90%. Avoid PCO2 ⬎ 65 torr “Normal range” PaCO2. Nitric oxide as rescue.

Kays (1992-1998)

Somaschini (19941998)

Bagolan (19962001)

Early HFOV. HFOV range of MAP 5-25 (only two required ⬎ 20, mean ⫽ 12). Adequate chest movement (usually 20-24 cm H2O PIP; PEEP 4 to 5 cm H2O; IMV for patient comfort; FiO2 started at 1.0. Occasional brief use of PIP ⫽ 28 if poor chest rise.

Initial HFOV. FiO2 ⫽ 1, MAP 13- 15 cm H2O, Amp 3035 cm H2O freq ⫽ 10 Hz, insp:expiratory ratio ⫽ 0.33 itime 0.35, etime 0.65, Peep 3-4 cm H2O

Ideal: PaCO2 of 40-65 torr; postductal SpO2 ⬎ 97%, And PaO2 80-100 Non-ideal patients: Pre-ductal SaO2 ⬍ 85% Post-ductal SaO2 ⬍ 60% PCO2 ⬎ 65 torr Unsatisfactory perfusion. pH 7.4-7.5 PaO2 80-120 torr SaO2 ⬎ 95%, PaCO2 25-35 Torr Max PIP 24. Max Rate 65. If PIP ⬎ 24¡HFOV pH ⬎ 7.25, PCO2 ⬎ 40, ⬍ 60 torr. 1st 2 hours: Pre-ductal SaO2 ⬎ 70% was tolerated, then 75-85% between 2 and 4 hours of life.

HFCV: PIP 20 cm H2O IMV 100, PEEP ⫽ 0 with conventional vent Maintain pre-ductal SaO2 ⬎ 80%. HFOV used rarely

HFOV, rescue PaCO2 ⬎ 60 torr MAP similar to CMV.

HFOV, rescue ECMO for OI ⬎ 40, failure CMV. HFOV, within first 3 hours.

HFCV for severe hypoxia or hypercarbia. IMV 100, PEEP ⫽ 0 with conventional vent. Trial of nitric oxide. PIP ⬎ 28 cm H2O: bridge to ECMO. Refractory hypoxemia or rising lactates ¡ ECMO. HFOV, initial

Freq 10 Hz, itime 0.33 MAP 2 cm ⬎ CMV

OI, oxygenation index; PaCO2, partial pressure CO2; PIP, peak inspiratory press; PEEP, positive end expir press; MAP, mean airway pressure; FiO2, fraction of inspired O2; PaO2, partial pressure of O2; HFCV, High freq conv ventilation. *Downard, et al. (see Wilson for early treatment strategies).

use of well-defined treatment guidelines that include mechanical ventilation strategies aimed at minimizing lung injury (Tables 1 and 2). In the initial report of a “protect the lung” strategy, Wung and coworkers attributed improvements in survival largely to minimizing overdistension of the lung, suggesting that strategies from previous eras (ie, alkalinization,

hyperventilation, and paralysis) served only to induce barotrauma and exacerbate pulmonary hypertension (PPHN).40 Kays and coworkers attributed improvements in survival to limiting peak inspiratory pressures along with a strategy of permissive hypercapnia.36 Finer credited success to adoption of a consistent protocol of care and limiting peak inspiratory

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Mechanical Ventilation Strategies

119

Measures of cardiopulmonary function and decision points

Pressure limits

Blood gas parameters

Tissue perfusion and tolerance limits for acidosis, hypercarbia, or hypoxia

Boloker (1992-1999)

PIP max 25, PEEP 5, I-time 0.3 seconds, IMV 20-40. Occasionally PIP to 30 cm H2O. Avoid precipitous changes in ventilator.

Pre-ductal SaO2 ⬍ 90%. For severe hypoxia ⫹ hypercarbia switch to HFCV, then HFOV.

Dopamine, dobutamine and volume boluses used [rarely] for maintenance of “adequate” perfusion. NaHCO3 used [rarely] for metabolic acidosis only.

Wung (1983-1995)

PIP ⱕ 25, PEEP 5, IMV 20-40. Permissive hypercapnia.

Specifics parameters not mentioned. Avoidance of hyperventilation or induced alkalosis, overdistension.

Ssemakula (1985-1996)

Specifics not reported

Goal: Preductal SaO2 ⬎ 90% For severe or labile hypoxia (SaO2 ⬍ 80%) or hypercarbia (PCO2 ⬎ 60 torr) switch to HFCV. Sedation and hyperventilation were mainstay of therapy for most patients in the report.

Wilson* (1991-1994)

PIP ⬍ 30, PEEP 5, MAP 12. Minimize barotrauma by ignoring right to left shunt. Post-ductal SaO2 ignored. Permissive hypercapnia

PIP 30 cm H2O, MAP 12. Preductal SaO2 ⬍ 90% with no evolving met acidosis If unable to attain, or PaCO2 ⬎ 60, switch to HFCV.

Metabolic acidosis as indirect measure of tissue perfusion. No post-ductal lines.

Finer (1989-1995)

PIP up to 24 (usually 20-22).

PaCO2 ⬍ 60, if can’t attain with conventional, switch to HFOV. Accept SaO2 ⬎ 70 in 1st 2 hours. SaO2 75-85% in 2-4 hours.

Frenckner (1990-1995)

PIP up to 35

Postductal SaO2 ⬎ 90%. Avoid PCO2 ⬎ 65 torr.

Meticulous attention to maintenance of BP, tissue perfusion and sedation: MBP 45-50 mm Hg with good UOP. To overcome Right-Left shunt: Dopamine, albumin boluses, epinephrine (refractory cases). Maintain “adequate” blood gases

Reyes (1993-1995)

HFOV range of MAP 5-25

Pre-ductal blood gases: maintained PCO2 in the “normal range.” Acceptable PO2 defined as ⬎60 mm Hg.

Report (Year)

Specific details not reported. Intractable hypotension was a criteria for ECMO. Inotropes were used.

N/A

Decision points: High frequency and ECMO criteria HFCV for severe respiratory distress, labile oxygenation or preductal hypoxemia. SaO2 ⬎ 80%. HFOV for persistent hypoxemia or labile oxygenation: SaO2 ⬍ 80%, PCO2 ⬎ 65 torr. ECMO initiated for high lung distending pressures or progressive hypoxemia, acidosis, or organ failure. Aa-DO2 ⬎ 600 for ⬎4 hrs was indication for ECMO. ECMO for acute deterioration of PaO2 ⬍ 40 mm Hg for 2 hours, pH ⬍ 7.25 for 2 hours, intractably hypotension, or OI ⬎ 40 on two measurements 30 minutes apart, or severe pulmonary airleak. Preductal SaO2 ⬍ 90% with no evolving metabolic acidosis. For severe hypoxia/hypercarbia If unable to attain, or PaCO2 ⬎ 60, switch to HFV; oxygenation index ⬎ 40 was indication for ECMO. No ventilator weaning until PaO2 ⬎150 mm Hg.

Postductal SaO2 ⬎ 90%. Avoid PCO2 ⬎ 65 torr HFOV rescue. ECMO for OI ⬎ 40, failure CMV. MAP weaned after adequate lung volume and “acceptable” blood gases achieved. Pulmonary to systemic BP ratio ⬎ 0.75 suggested pulm hypertension. Nitric oxide rescue.

120 Table 2

Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 (continued.)

Report (Year)

Pressure limits

Blood gas parameters

Kays (1992-1998)

Adequate chest movement (usually 20-24 cm H2O PIP; PEEP 4 to 5 cm H2O; IMV for patient comfort; FiO2 started at 1.0. Occasional brief use of PIP ⫽ 28 if poor chest rise.

Weber (1988-1997)

N/A. ECMO only.

Somaschini (1994-1998)

Inicial HFOV. FiO2 ⫽ 1, MAP 13- 15 cm H2O, Amp 30 - 35 cm H2O. freq ⫽ 10 Hz, insp:expiratory ratio ⫽ 0.33.

Ideal patients: Preductal blood gases: PaCO2 40 to 65 torr; postductal SaO2 ⬎ 97%, with PaO2 80100. Non-ideal patients: Pre-ductal SaO2 ⬎ 85%. Postductal SaO2 ⬎ 60%. PCO2 ⬎ 65 torr tolerated if patient otherwise stable. pH ⬎ 7.20. Analysis of report suggests goal of the regimen: pH ⬎ 7.20, PO2 ⬎ 60 mm Hg PCO2 50-69 mm Hg. pH 7.4-7.5 PaO2 80-120 torr SaO2 ⬎ 95%, PaCO2 25-35 Torr. NaHCO3 and THAM for mild induced alkalosis.

Bagolan (1996-2001)

Max PIP 24. Max Rate 65. itime 0.35, etime 0.65, Peep 3-4 cm H2O.

pH ⬎7.25, PCO2 ⬎40 and PCO2 ⬍ 60 torr. 1st 2 hours: Pre-ductal SaO2 ⬎ 70% was tolerated, then 7585% between 2 and 4 hours of life.

Tissue perfusion and tolerance limits for acidosis, hypercarbia, or hypoxia

Decision points: High frequency and ECMO criteria

Dopamine maintained at 3 mcg/Kg/min, and titrated to keep MBP ⬎ gestational age (weeks), and to maintain “satisfactory perfusion.” Normal serum lactates. NaHCO3 for pH ⬍ 7.20 even if hypercarbic.

Pre-ductal SaO2 ⬍ 85%, or pre-ductal PaO2 ⬍ 30 mm Hg, or rising serum lactates suggest need for ECMO or inhaled nitric oxide. Nitric oxide for hypoxemia in the hemodynamically stable patient.

N/A

Unable to surmise exact decision points: PreECMO: Aa-DO2 540 ⫾ 95 and OI 35.5 ⫾ 10.1.

Modest fluid restriction. Dopamine, dobutamine, and crystalloid for “hemodynamic support”.

Early HFOV. Surgical repair on HFOV. Nitric oxide for OI ⬎ 30 and pulmonary hypertension (by echo). ECMO was offered for OI ⬎ 40 or PaO2 ⬍40 mmHg. Transitioned to CMV when FiO2 ⬍ 30%. If PIP ⬎ 24 ¡ HFOV. Nitric oxide for refractory pre-ductal hypoxemia (PaO2 60 mm Hg, SaO2 ⬍ 85% on ⬎80% FiO2). No ventilator weaning until: pH ⬎ 7.25, PCO2 ⬍ 60 mm Hg, and FiO2 ⬍ 70%.

Dopamine 3-5 mcg/kg/min for MBP ⬍ 45 mm Hg, especially in presence of oliguria.

OI, oxygenation index; PaCO2, partial pressure CO2; PIP, peak inspiratory press; PEEP, positive end expir press; MAP, mean airway pressure; FiO2, fraction of inspired O2; PaO2, partial pressure of O2; HFCV, high freq conv ventilation. *Downard et al. (see Wilson for early treatment strategies).

pressures.34 In a report of 100 survivors of CDH, Wilson’s group attributed a 25% increase in survival to a strategy of permissive hypercapnia.20

Pressure limits Despite uniform goals, the range of acceptable peak inspiratory pressures with conventional mechanical ventilation was wide, ranging from 2532,36,40 to 35 cm H2O.35,39 Acceptable MAPs, more applicable to high frequency oscillatory ventilation, were not always reported, but ranged from 12 to 15 cm H2O.37,39,67 Some centers set PIP limits for conventional ventilation and transitioned to alternate forms of cardiore-

spiratory support, either high frequency ventilation or ECMO, once predetermined tolerance limits were reached.31,32,34,40 In most cases, decision points were based on preductal oximetry, PCO2 measurements, and predetermined limits for ventilator settings. Pressure limits and decision points are detailed in Table 1.

Blood gas parameters, end-organ perfusion, and oximetry Along with pressure guidelines, some centers set “ideal” and “acceptable” blood gas parameters. If initial ventilator settings within established limits failed to achieve ideal blood gases,

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“acceptable” blood gas results were targeted.31,32,34-36,40 If “acceptable” results were still not achieved using conventional ventilation (with pressure limits), patients were switched to high frequency ventilation, and if this failed, sent to ECMO.31,32,34-36,39,40 The limitations set on ventilator pressures distinguish this strategy from earlier targeting strategies where blood gas results were targeted and ventilator settings increased until the ideal blood gas targets were reached. The “acceptable” blood gas approach has definite limitations due to the inability to accurately measure oxygen acquisition and delivery at the cellular level. Within the context of these limitations, several centers have recommended guidelines based on clinical data that are commonly available. Most agree that both pre- and postductal measurements of oxygen saturation and blood gases are important. Preductal measurements offer an estimate of oxygenation of blood that enters the lungs and contributes to preductal circulation including the brain, whereas postductal gases provide a measure of systemic oxygen delivery. Tolerance of “acceptable” blood gases is dependent on signs suggesting adequate systemic perfusion, which for most centers includes combinations of pH, serum lactate levels, urine output, and clinical measures of peripheral perfusion. Clinicians can all agree that these signs are only estimates of real-time oxygen delivery or utilization, but they do permit the clinician to tolerate “adequate” blood gases while minimizing VILI with some degree of confidence that there is sufficient cardiac output and end-organ perfusion. Decision points and correlation of respiratory support with estimated measures of cardiopulmonary function are listed by center report in Table 2. Although there are no human data demonstrating the safety of this approach, survival seems to be more likely in centers reporting use of this general approach. Long-term follow up is important for evaluation of this strategy.68

Specific mechanical ventilation techniques High frequency ventilation (HFV) The physiologic rationale for use of HFV derives from its ability to preserve end-expiratory lung volume while avoiding overdistension, and therefore injury, at end-inspiration. To date only one mode of HFV has been studied in the care of infants with CDH: high frequency oscillatory ventilation (HFOV). Several studies suggest the use of HFOV as a protective strategy in minimizing VILI. Some authors took a more proactive approach using HFOV early in the postnatal course,37,67,69,70 whereas others employed HFOV as a rescue tool once certain peak pressure limits were reached.31,34,35,41 Most successful centers used predefined decision points, with some combination of pressure limits, blood gas parameters, and/or measures of perfusion as detailed in Table 2.31,32,34-36,39,40

121 A key component of the treatment regimen for HFOV is the achievement of optimal lung volume, which is perhaps more difficult to estimate and attain in the CDH infant given the anatomic malformation. However, eight-rib expansion, particularly on the side contralateral to the defect, seems an appropriate starting point.37,71 Using the oscillator, the clinician must be aware that tidal volume is directly related to amplitude, and inversely related to frequency. Increases in tidal volume are usually noted at frequencies less than 10 Hz.72 The impact of changes in HFOV settings must be monitored carefully, as high airway pressures may cause lung hyperinflation, with adverse effects on venous return, pulmonary vascular resistance, and ultimately in cardiac output.73,74 In patients with marginal cardio-respiratory reserve, as in many CDH cases, the constant distending airway pressure associated with use of HFOV may be more detrimental than helpful. Assessments of signs of end-organ perfusion such as pH, serum lactate levels, and urine output are imperative, particularly when pressures are increased, with lung compliance changes over time, or with therapeutic interventions such as surgical repair of the diaphragmatic defect.75,76

Surfactant Animal studies and human clinical trials suggest that term infants with CDH have surfactant deficiency and that surfactant composition may be altered.77-83 These studies and the presence of the endotracheal tube may tempt the clinician caring for a term CDH infant to offer empirical surfactant therapy. A recent report by Van Meurs and coworkers suggests that surfactant therapy in the management of CDH is associated with increased risk of mortality, even after correcting for use of ECMO, iNO, and postnatal steroids.84 The only randomized clinical trial using surfactant in CDH tested 17 infants ⬎34 weeks gestation who were already on ECMO.85 The results suggest that postnatal surfactant deficiency may be more persistent in CDH infants than non-CDH infants on ECMO; but, the study showed no improvement with surfactant treatment. Whereas some centers reporting low mortality rates used surfactant therapy in the first few hours of life, others used surfactant only as a rescue therapy for the most severely affected infants (Table 2).34,37,67 This composite information raises concerns over the routine use of surfactant in term infants with CDH, as its administration may not be without risk and the benefits remain unclear.32,34,37,67

Pulmonary hypertension Pulmonary hypertension and CDH The literature suggests that a subset of severely ill CDH infants can be adequately ventilated but are difficult to

122 oxygenate, suggesting restriction of pulmonary blood flow. Severe restriction of pulmonary blood flow leads to hypercapnia. Furthermore, cardiovascular function, which has been associated with severity of illness and mortality in CDH, appears to be related to the degree of pulmonary hypertension.20,86 Dillon and coworkers reported 47 CDH infants with 3 categories of PPHN. In the first category, while varying degrees of support were required (including ECMO), pulmonary arterial (PA) pressures decreased to less than half of systemic blood pressure within 3 weeks, with 100% survival.87 Despite all efforts, including nitric oxide and ECMO, all 8 infants in the second category demonstrating persistence of PA pressure ratios ⬎1.0 died. The 16 infants in the third category had moderately elevated PA pressure ratios (range 0.5 to 0.9) which persisted for a median of 49 days. More that 50% of this group required ECMO, and the survival for this group was 75%. This report suggests that respiratory support which minimizes iatrogenic injury while awaiting resolution of reversible pulmonary hypertension may lead to improved survival in highrisk CDH infants with prolonged pulmonary hypertension.87

Is there a place for inhaled nitric oxide in the management of CDH? Ventilator parameters alone should not be an indication for inhaled nitric oxide (iNO) therapy in CDH infants. Although the use of iNO has become standard for infants with PPHN, the current literature suggests that iNO may not reduce mortality risk or the need for ECMO in CDH infants with pulmonary hypertension.88 Among the CDH subgroup of subjects treated with nitric oxide in the Neonatal Inhaled Nitric Oxide Study Group trial (NINOS), there was a trend toward higher likelihood of ECMO or death.89 Recent studies have demonstrated that, although iNO may have benefit in the postacute management of pulmonary hypertension, the early use of iNO may have only transient benefits and may not decrease the need for ECMO support.86,87 We agree with the current recommendations that iNO therapy should not be routinely used in patients with CDH. Inhaled nitric oxide may have a role in CDH patients with suprasystemic pulmonary vascular resistance after establishing optimal lung inflation and demonstrating adequate left ventricular performance (ie, without ductal-dependent systemic blood flow).86 Complete resolution of PPHN should not be expected; rather, the goal of this therapy should be some incremental reduction in right ventricular pressure.41

Is there a place for ductal patency in the management of CDH? In a cohort study of 19 antenatally diagnosed CDH infants, infants with predominantly right-to-left shunting through the ductus arteriosus were given prostaglandin (PGE1) and iNO to maintain ductal patency and improve pulmonary blood flow. The authors postulated that the cardiac dysfunc-

Seminars in Pediatric Surgery, Vol 16, No 2, May 2007 tion may be alleviated by maintaining ductal patency to improve cardiac output. The authors reported gradual improvement in pulmonary blood flow and left ventricular preload.90 The results suggested that left ventricular diastolic function is impaired in many CDH infants shortly after birth, and maintaining whole-body circulation with prostaglandin while awaiting pulmonary vascular and LV remodeling may improve outcomes. Additional studies are needed to verify the safety and efficacy of this approach.

Are there ventilatory criteria for Institution of ECMO? A recent Cochrane Review looked at randomized controlled trials of ECMO use in infants with respiratory failure. Two of the 4 cited trials included subgroup analyses examining ECMO in CDH infants, with no apparent survival benefit.91,92 Additionally, the CDH study group has observed higher than predicted mortality when ECMO was used in a low-mortality risk group, and higher than expected survival for ECMO-treated CDH neonates in a high-mortality risk (⬎80%) group.93 The literature suggests that ECMO-treated CDH infants may require longer ECMO courses compared with non-CDH patients with respiratory failure. Although it is clear that there is a subpopulation of CDH infants which have irreversible pulmonary hypertension superimposed on severe lung hypoplasia, determining which patients fit into different risk groups remains one of the larger unanswered questions for physicians caring for babies with CDH.94 Neonates with an oxygenation index ⬎40, occasionally cited as an indication for ECMO, combined with a diagnosis of congenital diaphragmatic hernia often do not respond to high-frequency ventilation rescue.95,96 In these cases, ECMO may improve survival. Delayed referral to an ECMO center may increase the risks of morbidity and mortality. Increasing hypoxia despite adequate ventilation or other signs of poor cardiac performance unresponsive to therapy may be a sign of impending heart failure and should be an indication for ECMO. If the CDH infant is in a non-ECMO center and high-frequency ventilation and/or nitric oxide are in use, the clinician must remember that such transfers can be complicated by the unavailability of high-frequency ventilation or nitric oxide transport systems. In these cases, referral to an ECMO center should occur before initiating these modalities.

Conclusion Mechanical ventilation in most CDH infants is unavoidable. Ventilation strategies must be adapted to various combinations of airway, pulmonary vasculature and cardiovascular anatomic limitations. Furthermore, there are variable cardiovascular and pulmonary adaptations to extrauterine life. Successful centers with better than expected CDH survival report the combination of establishing clinical care guidelines that set limits on ven-

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tilatory pressures to avoid lung overdistention and accepting blood gas results with adequate rather than optimal PaCO2 and PaO2 as long as there is evidence for adequate cardiac output and organ function.31-34,36,37,39,40,67 Careful use of HFV, either empirically or as rescue in infants requiring higher PIP’s with CMV, also appears to reduce mortality, but HFV strategies have not been compared head to head with conventional ventilation,23,28,30,40,55 The most significant clinical dilemma continues to be the appropriate approach to pulmonary hypertension in CDH infants. Remaining questions include when and if iNO helps these infants, when to use ECMO, or whether or not maintaining patency of the ductus arteriosus will improve CDH outcome. In the absence of randomized clinical trials of the lung protective strategies that tolerate adequate rather than optimal blood gases, evaluation of long-term outcomes is imperative.

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