Research Article26th New Horizons Symposium: ARDS Update

Pediatric Acute Respiratory Distress Syndrome

Ira M Cheifetz
Respiratory Care October 2011, 56 (10) 1589-1599; DOI: https://doi.org/10.4187/respcare.01515

Abstract

The data available to guide clinical management of acute lung injury and acute respiratory distress syndrome are much more limited for infants and children than for adult patients. This paper reviews the available medical data and the pertinent physiology on the management of pediatric patients with acute lung injury. With the collaboration of multicenter investigation networks, definitive pediatric data may be on the horizon to better guide our clinical practice.

Introduction

Although representing a small percentage of the total number of pediatric intensive care unit (PICU) admissions, acute respiratory distress syndrome (ARDS) is one of the most challenging patient populations for a clinician to manage. Even more challenging to the pediatric practitioner is the lack of definitive data to guide clinical management. As data are more readily available in the adult population, one must ask whether children are really different than adults in regard to treatment strategies for acute lung injury (ALI) and ARDS? The answer to this question could be debated for quite some time and really depends on the individual patient, the etiology of the lung disease, underlying comorbidities, and patient age and weight.

As a starting point, it is important to note that the definitions of ALI and ARDS for infants (older than one month of life), children, and adolescents are essentially identical to those for adults.1–3 However, there are intrinsic differences between pediatric patients and adults, which often can affect management strategies. Infants and young children, as compared to older children, adolescents, and adults, have more compliant chest walls, higher sedation requirements, lower hematocrit (which may affect global oxygen delivery), higher baseline airways resistance, and lower functional residual capacity. Additionally, the still developing and growing lung may be at greater risk for ventilator-induced lung injury at a lower airway pressure than the developed lung of an adult.

Although one may debate how, or even whether, adult data are applicable to children,4 the answer is somewhat arbitrary without knowing the specific clinical details. Clearly, a 14-year-old adolescent with ARDS resembles an adult patient in terms of anatomy, physiology, and pathophysiology much more closely than an 8-month-old infant. Additionally, adult data are more likely to be applicable to a previously healthy child with viral-induced ARDS than a child with underlying complex congenital heart disease.

Epidemiology of Pediatric ALI and ARDS

The first step in discussing pediatric ALI and ARDS requires an understanding of the epidemiology of this important clinical entity. The Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) network described the incidence of ALI and ARDS.5,6 Of note, the focus of this report was to describe the characteristics of those patients eligible for a mechanical ventilation weaning study and, thus, it likely underestimated the true incidence of ALI/ARDS in the total PICU population. Of the total 6,403 admissions, 1,096 (17.1%) required mechanical ventilation for more than 24 hours, and 395 (6.2%) were eligible for the weaning study.6 Of the 303 (4.7%) enrolled patients, only 23 had ARDS, representing 7.6% of the eligible patients and 0.4% of the total population screened. Although that report likely underestimates the true incidence of pediatric ARDS, it met its primary goal of describing why definitive clinical trials for pediatric ALI/ARDS have been very limited.

Santschi et al, in collaboration with the PALISI Network and the European Society of Pediatric and Neonatal Intensive Care,7 reported the incidence of the broader clinical entity of pediatric ALI (ie, not just ARDS) in a more global population. This larger-scale study included 59 PICUs in 12 North American and European countries. Of 3,823 pediatric patients screened, 414 (10.8%) were diagnosed with ALI by the clinical care teams at the individual centers. Of interest, only 165 (4.3%) of the total screened met pre-established inclusion/exclusion criteria for a clinical trial: a number that closely matches the data from the PALISI Network.2

Erickson et al2 described the Australia/New Zealand experience with pediatric ALI in a prospective 12-month observational study. Overall, there were 117 cases of ALI in the total PICU population of 5,252 children, which is an incidence of only 2.95 per 100,000 population < 16 years of age. ALI accounted for 2.2% of all PICU admissions during that one-year period.

Overall, the risk factors and pathophysiology of ALI/ARDS are similar for children and adults.8 In a comprehensive description of pediatric ALI/ARDS,9 the primary diagnoses were pneumonia (35%), aspiration (15%), sepsis (13%), near-drowning (9%), concomitant cardiac disease (7%), and other clinical entities (21%). Infectious causes, including sepsis and pneumonia, represented approximately half of all clinical disorders associated with ALI.

Although the overall incidence of pediatric ALI is low,2,5–7 the mortality in this population remains high, ranging from 22% to 35%.2,9 Erickson2 reported that mortality from ALI/ARDS accounted for 30% of all PICU deaths. The highest mortality rates are with near-drowning (54%), associated cardiac disease (39%), and sepsis (31%).9 Lower mortality rates are associated with pneumonia (11%) and aspiration (12%).9 Using reported population estimates, between 500 and 2,000 children die from ALI/ARDS in the United States annually. The exact mortality rate is difficult to determine, as ALI/ARDS is not a reportable disorder. It should be noted that the reported mortality from pediatric ALI/ARDS has been as low as 8% in some studies.10 However, one must be cautious in generalizing mortality data from randomized controlled trials, as such clinical investigations have strict inclusion/exclusion criteria that are likely to eliminate patients with more severe lung injury and/or important high-risk comorbidities, such as bone marrow transplantation.

Important pre-admission mortality risk factors include pre-existing comorbidities and substantial immunosuppression.2 Higher ventilation requirements and the development of multiple-organ system failure are associated with a higher mortality rate.2 The literature differs on whether patient age is a factor in predicting mortality. Erickson et al found higher mortality with older age,2 whereas Flori et al found no age-mortality relationship.9 Other predictors of outcome for pediatric ALI/ARDS include multi-organ system dysfunction/failure, severity of illness, and degree of impairment in oxygenation.9,11–13

It is also important to mention some recent work in attempting to identify infants and children with ALI/ARDS earlier in their presentation, often prior to obtaining arterial blood gas samples.14–16 These studies have favorably compared the SpO2/FIO2 ratio and the PaO2/FIO2 ratio to formulate a useful noninvasive diagnostic tool for helping to define ALI/ARDS.

Where Are the Pediatric Data?

A search of the PubMed database (on July 1, 2011) yielded 25,829 entries related to ALI and/or ARDS. However, only 1,495 articles remained when this search was limited to pediatric patients. Although that is still a substantial number of publications, only a very small number of them describe multicenter randomized controlled clinical trials.

As described in the previous section, data from the PALISI Network5–7 have helped to explain the lack of definitive pediatric ALI/ARDS studies. Based on the small number of patients in the pediatric ALI descriptive reports,6,7 one can conclude that a study of pediatric ALI/ARDS would require the cooperation of multiple centers, most likely within a larger network such as PALISI,5–7,17,18 the Collaborative Pediatric Critical Care Research Network,19–22 or the Australian and New Zealand Intensive Care Society Clinical Trials Group.2,23,24 The funding and institutional cooperation that such a study would require are quite substantial.

Once an appropriate number of international centers is identified, clear and concise ventilator-management protocols must be accepted by those involved in the study. Khemani et al25 described potential difficulties with any pediatric ALI/ARDS study by characterizing mechanical ventilation practices for intubated children in 16 North American PICUs. The substantial variability in ventilation strategies they described would have clear implications when choosing PICUs for a clinical investigation. In that report the vast majority of the infants and children were ventilated with PEEP of 5 cm H2O, and few infants or children were ventilated with PEEP settings outside of the 4–8 cm H2O range.

Many adult ALI/ARDS studies were designed with mortality as an end point. However, when considering a primary end point for a pediatric ALI/ARDS investigation, debate occurs as to the optimal end point, since a mortality difference is an unrealistic goal for most such studies. If severely immunosupressed patients (eg, bone marrow transplant patients) and other high-risk patients are excluded, mortality for a pediatric ALI/ARDS clinical trial would be estimated at 8–15%. Given that low mortality rate, it would require approximately 2,000 pediatric subjects per study group to detect a moderate (25%) decrease in mortality.26 An even greater number of patients would be required to detect smaller, but still clinically important, improvements in mortality. This is obviously not feasible because of the low occurrence of pediatric ALI/ARDS.

Khemani and Newth described the hurdles involved in pediatric ALI/ARDS clinical trials and made suggestions for the future.27 Specific concerns included heterogeneous management strategies, a lack of explicit ventilation protocols for pediatric patients, an unpredictable relationship between lung injury severity and outcome, and the reliance on potentially biased surrogate outcome measures such as ventilator-free days. Given the hurdles in studying pediatric ALI/ARDS, clinicians involved with the care of critically ill infants and children are left with extrapolation of data from the adult population, reliance on the limited available pediatric data, careful assessment of applicable principles of physiology and pathophysiology, and/or reliance on clinical experience.

Clinical Management Strategies

Clinical management strategies for ALI/ARDS are targeted at improving mortality and morbidity, hastening recovery with shorter duration of ventilation, and optimizing long-term pulmonary and neurologic function. Although mechanical ventilation is often life-saving, decreased lung compliance and elevated airway pressure can lead to ventilator-induced lung injury from volutrauma (ie, alveolar overdistention), atelectrauma (ie, repeated alveolar collapse and re-expansion), and oxygen toxicity. The overall management approach to the adult patient with ALI/ARDS focuses on lung-protective ventilation with low tidal volume (VT)28–33 and moderate to high PEEP.34–37 Although this approach has become the standard of care for adult ALI/ARDS, definitive data for infants and children are lacking.

Tidal Volume

Despite the generally accepted VT of 6 mL/kg (based on ideal body weight) to improve survival in adult ALI/ARDS patients,28 the reported mean VT for pediatric ALI in various studies include 8.3 mL/kg by Santshci et al,7 8.0 mL/kg by Erickson et al,2 and 8.1 mL/kg by Albuali et al.38 It is important to note that these pediatric VT are reported per actual body weight. So, given the incidence of pediatric obesity, we should speculate that the VT per ideal body weight was significantly greater.

It should be noted that although most standard textbooks include ideal body weight calculations only for older children, adolescents, and adults, several Internet programs provide interactive calculators to determine the ideal body weight for pediatric patients as young as one year of age. Required inputs are sex, age, and height/length. Alternatively, one may estimate the ideal body weight for a child by using the available sex and age growth charts (eg, http://www.cdc.gov/growthcharts/clinical_charts.htm). On the appropriate chart, graph the patient's height/length. Once the height/length percentile is known based on sex and age, simply determine the predicted weight that corresponds to that percentile.

It is unclear why not all pediatric clinicians are routinely limiting VT delivery to 6 mL/kg ideal body weight for infants and children with ALI/ARDS. Various possibilities exist. Some pediatric practitioners may simply not believe that the adult-based VT data are applicable to infants and children. Other providers may believe in limiting VT to 6 mL/kg, but the extrapolation to “real life” bedside practice may be lacking. While another possibility is that pediatric practitioners may believe a delivered VT of 6 mL/kg is appropriate, but the VT set on the ventilator is intentionally increased to compensate for the VT lost due to the distensibility of the ventilator circuit.

For older children and adults it is reasonable to measure VT at the expiratory valve of the ventilator, since the volume of gas lost due to circuit distensibility is minimal when expressed as a percent of the total VT delivered. However, for infants and smaller children, a substantial proportion of the delivered VT may be lost due to circuit distensibility. Cannon et al39 found that for neonatal circuits the expiratory VT measured at the endotracheal tube was on average only 56% of that measured at the expiratory valve. Somewhat improved correlation was found with pediatric circuits: the average measured VT at the endotracheal tube was 73% of that measured at the ventilator. Similar findings have been reported by Castle et al,40 Chow et al,41 and Heulitt et al.42

Thus, when determining the actual delivered VT for smaller pediatric patients, the use of a pneumotachometer placed at the endotracheal tube would seem to be the optimal approach. Most newer-generation ventilators include software that is supposed to account for the circuit compliance in calculating the actual delivered VT,42 but those algorithms have not been systematically studied in the “real life” clinical situation.

PEEP

As noted above, Khemani et al25 reported relatively low PEEP settings for pediatric ALI/ARDS patients. Explanations for this finding may include a general “PEEP phobia,” the frequent conversion to high-frequency oscillatory ventilation (HFOV) as an alternative to a “higher” PEEP strategy, and/or an inaccurate representation of actual management, given the small number of centers (n = 16) in the study.

Several large-scale adult PEEP trials have found no survival benefit with more aggressive PEEP strategies. Brower et al,34 in the ARDS Network's ALVEOLI trial, found no mortality difference with a more aggressive PEEP strategy despite improved arterial oxygenation and improved pulmonary compliance. It is important to note that the “lower” PEEP group in that study was not a “low” PEEP approach, but rather an “adequate” PEEP approach. A follow-up study in adults with ALI/ARDS, Meade et al35 also found no survival benefit from a high-PEEP strategy with recruitment maneuvers, although oxygenation improved. Mercat et al36 also found no mortality difference, but did find improved lung function, shorter duration of ventilation, and lower incidence of multi-organ failure with a more aggressive PEEP strategy.

Thus, one is left explaining the findings from the various PEEP studies in the adult population. It is likely that individual patients respond differently to different PEEP levels, and the difference might be even greater for infants and children, given the heterogeneity of the pediatric population. Patients with recruitable lung may benefit from a more aggressive PEEP strategy. In that subset of patients, increased PEEP might improve pulmonary compliance and, thus, the ability to provide higher PEEP without significantly elevating the peak or plateau pressure. On the other hand, in patients without recruitable lung, higher PEEP would not translate to improved pulmonary compliance, so the peak and plateau pressures would be expected to increase with higher PEEP.

Thus, it seems reasonable to speculate that in patients with recruitable lung a more aggressive PEEP strategy might improve outcomes, whereas in patients with non-recruitable lung a more aggressive PEEP strategy might worsen outcomes. Thus, in a heterogeneous patient population the published studies31–33 would be expected to show a neutral mortality effect from higher PEEP, because the contrary effects in the 2 subgroups (recruitable vs non-recruitable lung) would cancel each other (Fig. 1).43

Fig. 1.
Fig. 1.

Potential effects of PEEP increase. If the potential for alveolar recruitment is low, increasing the PEEP increases the plateau pressure (Pplat) to an unsafe level, and the risk of over-distention probably outweighs any benefit from alveolar recruitment. If the potential for alveolar recruitment is high, increasing the PEEP results in little increase in Pplat, and the potential benefit of increased PEEP probably outweighs the risk from the small Pplat increase. (From Reference 43, with permission.)

One may then propose a PEEP management algorithm as shown in Figure 2. The bedside clinician could determine lung recruitability by assessing whether pulmonary compliance, oxygenation, and/or dead space substantially improves with increased PEEP. If so, a more aggressive PEEP strategy should be considered. If not, then a less aggressive PEEP strategy would seem more reasonable.

Fig. 2.
Fig. 2.

PEEP titration based on lung recruitability.

Of interest, when Briel et al37 extracted data from the Brower,34 Meade35 and Mercat36 studies, it became apparent that a higher PEEP approach benefited those patients who met the standard accepted criteria for ARDS—a group that may be speculated to have more recruitable lung. Briel et al concluded that higher PEEP may be associated with shorter duration of ventilation and lower hospital mortality in adults with ARDS. In contrast, this benefit was not seen in non-ARDS patients. The applicability of these findings to pediatric patients is worth careful consideration.

Although the data for adult patients are quite helpful, the pediatric critical care clinician is again left wondering about the best approach for infants and children with ALI/ARDS. Are the adult PEEP data applicable to infants and children due to their differences in chest-wall compliance, cardiac reserve, and generally higher sedation requirements needed to tolerate mechanical ventilation at increased mean peak airway pressure? Unfortunately, answers to this question as well as definitive data on PEEP management for pediatric ARDS simply do not exist. Practitioners must carefully consider the pathophysiology of an individual patient before determining the applicability of the available data from adult ARDS to infants and children.

High-Frequency Oscillatory Ventilation

A common management strategy for pediatric ALI/ARDS is HFOV. It should be noted that only one randomized controlled trial has compared HFOV to conventional ventilation in pediatric patients, but the control group received a high-VT approach, as the study was reported in 1994.44 More recently, Sud et al,45 in a meta-analysis that included both pediatric and adult studies, concluded that HFOV “might improve survival and is unlikely to cause harm.” Unfortunately, that may be the best available summary on HFOV in pediatric or adult ALI/ARDS for some time to come. Despite the lack of a definitive, randomized controlled trial in pediatric patients demonstrating an advantage of HFOV over a lung-protective (ie, low-VT) conventional ventilation strategy, the use of HFOV for infants and children has become commonplace.46–48

It remains uncertain whether we will obtain definitive data on HFOV versus lung-protective conventional ventilation in pediatric ALI/ARDS. With the current widespread use of HFOV, it seems unlikely that such a clinical study will be performed, because equipoise may be lacking, especially in centers that routinely employ HFOV. Without those, generally larger, centers there may be an inadequate sample size available within a reasonable time frame and within funding constraints. In the meantime, the available data support at least equivalency between HFOV and lung-protective conventional ventilation. One may speculate that HFOV would be found superior if studied in a sufficiently powered, randomized controlled trial, because it takes the concept of low-VT ventilation to the extreme.

Exogenous Surfactant

Although exogenous surfactant administration is the standard of care for infants with neonatal respiratory distress syndrome,49–53 its use for pediatric ALI remains uncertain. The preliminary results54–56 of surfactant administration for pediatric ALI were promising, but more recent studies have been disappointing.17,57,58 Many had hoped that the Calfactant Therapy for Direct Acute Respiratory Distress Syndrome and Direct Acute Lung Injury in Children (CARDS) trial, which involved 30 international centers, would provide definitive guidance for the surfactant management of pediatric patients with direct lung injury; however, the study was recently closed for futility.59

At this point the clinician is left with his or her own interpretation of the data by Willson et al.17,54,59 Calfactant improved oxygenation and significantly decreased mortality in a heterogeneous group of pediatric patients with ALI.17 However, there were no significant differences in the duration of ventilation, intensive care unit stay, or hospital stay. Additionally, the placebo group contained a higher proportion of high-risk, immunosuppressed patients and, thus, might be expected to have a higher mortality rate. At this point the administration of exogenous surfactant for a pediatric patient with ALI/ARDS must be left to the discretion of the bedside clinician. But it is important to note that if a clinician administers surfactant based on the data by Willson et al,17 then it should be done early in the course of lung injury, generally within 48 hours of ALI/ARDS onset.

Inhaled Pulmonary Vasodilators

For almost 2 decades, inhaled nitric oxide (INO) has played an essential role in the management of persistent pulmonary hypertension of the newborn. However, its use for pediatric ALI/ARDS remains controversial. Despite both pediatric and adult studies finding clear oxygenation improvement with INO,60–63 no outcome improvements were found.62,64,65 Many researchers have hypothesized that INO should benefit patients with ALI, by improving oxygenation and thus allowing lower ventilator settings, which decreases the risk of ventilator-induced lung injury. Unfortunately, this hypothesis has never proven to be correct.

In a meta-analysis of 14 randomized controlled trials, which included 1,303 patients, INO had no statistically significant effect on mortality, duration of ventilation, ventilator-free days, ICU stay, or hospital stay.64,65 Afshari et al concluded that INO cannot be recommended for patients with acute hypoxemic respiratory failure, because INO transiently improves oxygenation but does not decrease mortality.64,65 Based on the currently available data, this conclusion seems applicable to children with ALI/ARDS in the absence of clinically important pulmonary hypertension. A possible exception to this recommendation are patients with congenital heart disease and passive pulmonary blood flow (eg, after Fontan or Glenn procedure).

Another pulmonary vasodilator that has received attention recently is aerosolized prostacyclin. Similar to INO, aerosolized prostacyclin improves oxygenation in children with ALI.66 Unfortunately, clinical outcome data are lacking.

Non-respiratory Management Strategies

Beyond the respiratory management of the pediatric ALI/ARDS patient, the clinician must consider fluid management, glucose titration, and transfusion criteria. The care of the pediatric ALI/ARDS patient clearly goes beyond pulmonary support.

Diuretics are frequently administered to pediatric ALI/ARDS patients to manage fluid status. Although no survival difference was found between conservative and liberal fluid-management strategies in adult ALI/ARDS, a conservative fluid approach increased the number of ventilator-free days and ICU-free days, without more adverse effects.67

Although definitive fluid-management data do not currently exist for pediatric ALI/ARDS patients, a general approach to the infant or child with ALI is to similarly use diuretics with a conservative fluid-management strategy in mind. The PALISI Network5,6,18 is currently considering such a study. Key issues for a clinical fluid-management investigation include the optimal fluid targets (eg, in/out fluid balance, central venous pressure, and daily weight). In preliminary work, the PALISI Network found18 that cumulative fluid balance in pediatric ICU patients with ALI did not appear to have clinical utility.

The key to success of such a ALI/ARDS fluid-management study will be clear agreement among the investigators on the liberal and conservative management fluid algorithms, the types of invasive monitoring lines, fluid titration end points, and outcome measures. Until pediatric data become available, it seems reasonable to extrapolate the ARDS Network fluid management concept to pediatric ALI/ARDS patients and use a fluid-conservative approach. Unfortunately, the ARDS Network algorithms67 are not applicable to most infants and children.

Glucose/insulin-management strategies remain very controversial, and recommendations have fluctuated over the past several years.68–72 Despite multiple studies, it remains uncertain whether strict glycemic control improves outcomes for ALI/ARDS patients. This uncertainty is even greater in the pediatric population, especially infants, as the neurologic risk of hypoglycemia may greatly outweigh any potential benefit of tight glycemic control.68 The PALISI Network is about to embark on a glucose-control study in critically ill pediatric patients. Hopefully, a definitive answer is on the horizon.

Although the data on transfusion criteria for critically ill children are more clear than those on glucose/insulin management, their applicability to ALI/ARDS may be questioned. Lacroix et al73 found that in stable, critically ill children a hemoglobin threshold of 7 g/dL for red-cell transfusion can decrease the transfusion requirement without increasing adverse effects. However, a conservative approach to transfusion thresholds for pediatric ARDS has not been studied in combination with permissive hypoxemia,74 which is gaining acceptance. Furthermore, it must be noted that profound hypoxia was a study exclusion in the Lacroix study.73

Extracorporeal Membrane Oxygenation

Extracorporeal life support, most often in the form of extracorporeal membrane oxygenation (ECMO), can be life-saving for infants and children with refractory hypoxemia due to ARDS. The currently reported overall survival rate for ECMO for pediatric ARDS is 54%.75 However, recent publications have reported survival rates over 70% in relation to ECMO for pediatric and adult patients with H1N1-influenza-induced ARDS.76–78

Much has been learned from the over 45,000 patients in the Extracorporeal Life Support Organization registry.75 Over the past decade, the technological advances in extracorporeal life support rival any other in the management of ARDS. The most important of these advances include the introduction of centrifugal pumps, hollow-fiber oxygenators, and improved double-lumen venous cannulas. Centrifugal pumps and hollow-fiber oxygenators allow for smaller priming volume and shorter pump setup time. The Avalon double-lumen cannula (Avalon Laboratories, Rancho Dominguez, California) decreases the degree of recirculation, improves the possibility of single-site cannulation in venovenous ECMO, and improves the possibility of ambulation and physical rehabilitation in patients on ECMO.79,80

The typical pediatric ECMO patient is changing. Traditionally, ECMO criteria included less than 7–10 days of substantial ventilator support prior to cannulation. However, recent data indicate similar survival with pre-ECMO duration of ventilation up to 14 days.81 Also of note is increasing ECMO use in patients with comorbidities.81

The recent increased use of ECMO in pediatric patients with ARDS75 is likely to continue (Fig. 3). With simplification of ECMO technology we may no longer need 1:1 nurse/ECMO-specialist-to-patient ratio, which would improve resource allocation.78 ECMO should no longer be considered a therapy of desperation, but instead part of our standard armamentarium for severe ARDS.79

Fig. 3.
Fig. 3.

Recent trends in the utilization of extracorporeal membrane oxygenation (ECMO) for refractory pediatric respiratory failure. (Adapted from Reference 75, with permission.)

The decision to initiate ECMO in a patient with severe lung injury is difficult because we have limited data available to make a risk/benefit assessment, and the published data do not always reflect current clinical practice. Unfortunately, there are no data to guide the timing of ECMO cannulation in a patient with refractory hypoxemia, and such data are unlikely to become available in the foreseeable future. Thus, the bedside clinical care team must make a careful risk/benefit assessment for each individual patient.

Management Algorithm

Until definitive randomized controlled trial data become available, it seems reasonable to ventilate infants and children with ALI/ARDS with a VT of 6 mL/kg predicted body weight. This recommendation is supported by retrospective pediatric data from Albuali et al,38 which indicated 40% lower mortality in pediatric ALI/ARDS patients with lower VT.

Additional recommendations based on a composite of pediatric and adult data include maintaining the plateau pressure less than 30 cm H2O. Because many pediatric patients are still ventilated with uncuffed endotracheal tubes, measuring the plateau pressure is not always possible. Thus, it would seem reasonable to take an even more conservative approach and maintain the peak airway pressure less than 30 cm H2O.

Unfortunately, definitive data do not exist to guide PEEP management for the pediatric ALI/ARDS patient. One must, therefore, balance the cardiorespiratory effects of higher PEEP by determining the optimal relationship between increased pulmonary compliance, reduced dead-space ventilation, and acceptable hemodynamics, while maintaining adequate, but not maximal, oxygenation.74 It must be remembered that optimal oxygen delivery may not occur at the point of maximal arterial oxygen content, because this may correspond to excessive mean intrathoracic pressure and, thus, lower cardiac output. The key for optimal global oxygen delivery is determining the best possible balance between cardiac output (as clinically determined, given the lack of available cardiac output monitors for infants and small children) and arterial oxygen content. It must be stressed that close cardiorespiratory monitoring is essential when titrating PEEP, especially in younger pediatric patients and those with underlying cardiac structural anomalies and/or dysfunction.

In terms of determining appropriate gas-exchange goals, it should be stressed that oxygenation and ventilation should have “adequate” rather than “optimal” targets. Permissive hypercapnia and permissive hypoxemia should be employed when clinically indicated, to minimize exposure to toxic ventilatory support.74,82–86 The target PaO2, SpO2, and PaCO2 are likely to differ between patients and within an individual patient over time, based on the degree of ventilatory support the patient requires (ie, risk of ventilator-induced lung injury).

In summary, Figure 4 shows a general suggested approach to the management of pediatric ALI/ARDS. Initial management should include low-VT ventilation, optimization of PEEP (preferably utilizing a decremental titration strategy), and consideration of exogenous surfactant. If “adequate” oxygenation and ventilation can be obtained with a peak inspiratory pressure less than 30 cm H2O, a mean airway pressure less than 17 cm H2O, and an oxygenation index less than 15, then a suggested approach is to continue with periodic optimization of the delivered VT and PEEP, along with close cardiorespiratory monitoring. If those ventilation goals cannot be met, consider recruitment maneuvers and/or transitioning to HFOV or airway pressure-release ventilation.

Fig. 4.
Fig. 4.

Proposed algorithm for pediatric acute lung injury and acute respiratory distress syndrome. PImax = maximum inspiratory pressure. APRV = airway pressure-release ventilation. HFOV = high-frequency oscillatory ventilation. ECMO = extracorporeal membrane oxygenation.

In general, INO should not be included in the general management of the pediatric ARDS patient; however, INO should be considered if substantial pulmonary hypertension exists, and as a potential bridge to ECMO, to maintain oxygenation and clinical stability while preparing for ECMO cannulation. If hypoxemia can be appropriately managed without “toxic” ventilatory support, then optimization of ventilatory settings should continue with frequent reassessment.

If refractory hypoxemia or “toxic” ventilatory support persists/develops, consider the appropriate timing for ECMO. As previously stated, the bedside clinical care team must make a careful risk/benefit assessment for each individual patient.

From a non-respiratory perspective, it seems reasonable to use diuretics to strive for a conservative fluid-management approach, keeping in mind that the appropriate target for “dry lungs” in pediatric patients remains unknown. Persistent hyperglycemia should probably be avoided; however, data are lacking to support the need for strict glycemic control. Hypoglycemia should be avoided as much as possible, especially in younger patients. Transfusion thresholds remain at the discretion of the bedside clinician while attempting to balance a lower hematocrit (ie, avoid transfusions) while providing adequate (but not necessarily supranormal) global oxygen delivery. Striving for a supranormal oxygen delivery is more likely to lead to increased toxicity from the interventions than to improve outcome.74 No data support the need for supranormal oxygen delivery. The key point is to avoid oxygen debt at the cellular level of the organs and tissues throughout the body. Serial monitoring of blood gases and serum lactate levels are generally required. The use of cerebral oximetry (as a surrogate to mixed venous oxygen saturation monitoring) should be considered.

Summary and Thoughts for the Future

Unfortunately, definitive pediatric data are lacking to guide clinical ALI/ARDS management. So pediatric critical care clinicians must extrapolate data from other populations (ie, neonates and adults), rely on their own and their colleagues' clinical experience, and apply the pertinent physiology and pathophysiology with each individual patient. When applying the available data, one must also carefully consider the numerous uncontrolled variables in the individual “real life” critical care setting, including the knowledge and experience of the respiratory therapists, physicians, nurse practitioners, bedside nurses, ECMO specialists, pharmacists, and other personnel.

At the conclusion of this paper, the reader should be left with the view that additional prospective, randomized controlled trials for pediatric ALI and ARDS are clearly needed. One should remain hopeful that more definitive pediatric data are forthcoming, especially with the cooperative efforts and recent growth of the various pediatric clinical research networks. Hopefully, more definitive data to guide pediatric critical care clinicians in their management of infants and children with ALI and ARDS are on the horizon.

Footnotes

  • Correspondence: Ira M Cheifetz MD FAARC, Pediatric Critical Care Medicine, Duke Children's Hospital, Duke University Medical Center, Box 3046, Durham NC 27710. E-mail: ira.cheifetz{at}duke.edu.

  • Dr Cheifetz presented a version of this paper at the 26th New Horizons Symposium, “ARDS Update,” at the 56th International Respiratory Congress of the American Association for Respiratory Care, held December 6–9, 2010, in Las Vegas, Nevada.

  • Dr Cheifetz has disclosed relationships with Philips-Respironics, Covidien, Discovery Laboratories, and Teleflex.

References

  1. 1.↵
    1. Bernard GR,
    2. Artigas A,
    3. Brigham KL,
    4. Carlet J,
    5. Falke K,
    6. Hudson L,
    7. et al
    . The North American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149(3):818–824.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Erickson S,
    2. Schibler A,
    3. Numa A,
    4. Nuthall G,
    5. Yung M,
    6. Pascoe E,
    7. et al
    . Acute lung injury in pediatric intensive care in Australia and New Zealand: a prospective, multicenter, observational study. Pediatr Crit Care Med 2007;8(4):317–323.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Zimmerman JJ,
    2. Akhtar SR,
    3. Caldwell E,
    4. Rubenfeld GD
    . Incidence and outcomes of pediatric acute lung injury. Pediatrics 2009;124(1):87–95.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Cheifetz IM
    . Management of acute lung injury: Sharing data between adults and children. Respir Care 2011;56(9):1258–1268; discussion 1268-1272.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Randolph AG,
    2. Meert KL,
    3. O'Neil ME,
    4. Hanson JH,
    5. Luckett PM,
    6. Arnold JH,
    7. et al
    . on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators Network. The feasibility of conducting clinical trials in infants and children with acute respiratory failure. Am J Respir Crit Care Med 2003;167(10):1334–1340.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Randolph AG,
    2. Wypij D,
    3. Venkataraman ST,
    4. Hanson JH,
    5. Gedeit RG,
    6. Meert KL,
    7. et al
    ; on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children: a randomized controlled trial. JAMA 2002;288(20):2561–2568.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Santschi M,
    2. Jouvet P,
    3. Leclerc F,
    4. Gauvin F,
    5. Newth CJ,
    6. Carroll CL,
    7. et al
    ; on behalf of the PALIVE Investigators; Pediatric Acute Lung Injury and Sepsis Investigators Network (PALISI) and the European Society of Pediatric and Neonatal Intensive Care (ESPNIC). Acute lung injury in children: therapeutic practice and feasibility of international clinical trials. Pediatr Crit Care Med 2010;11(6):681–689.
    OpenUrlPubMed
  8. 8.↵
    1. Timmons OD,
    2. Havens PL,
    3. Fackler JC
    . Predicting death in pediatric patients with acute respiratory failure. Pediatric Critical Care Study Group. Extracorporeal Life Support Organization. Chest 1995;108(3):789–797.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Flori HR,
    2. Glidden EV,
    3. Rutherford GW,
    4. Matthay MA
    . Pediatric acute lung injury: Prospective evaluation of risk factors associated with mortality. Am J Respir Crit Care Med 2005;171(9):995–1001.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Curley MA,
    2. Hibberd PL,
    3. Fineman LD,
    4. Wypij D,
    5. Shih MC,
    6. Thompson JE,
    7. et al
    . Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA 2005;294(2):229–237.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Costil J,
    2. Cloup M,
    3. Leclerc F,
    4. Devictor D,
    5. Beaufils F,
    6. Simeoni U,
    7. et al
    . Acute respiratory distress syndrome (ARDS) in children: Multicenter Collaborative Study of the French Group of Pediatric Intensive Care. Pediatr Pulmonol 1995;11(Suppl.):106–107.
    OpenUrl
  12. 12.
    1. Goh AY,
    2. Chan PW,
    3. Lum LC,
    4. Roziah M
    . Incidence of acute respiratory distress syndrome: a comparison of two definitions. Arch Dis Child 1998;79(3):256–259.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Dahlem P,
    2. van Aalderen WM,
    3. Bos AP
    . Pediatric acute lung injury. Pediatr Respir Rev 2007;8(4):348–362.
    OpenUrl
  14. 14.↵
    1. Khemani RG,
    2. Patel NR,
    3. Bart RD 3rd.,
    4. Newth CJ
    . Comparison of the pulse oximetric saturation/fraction of inspired oxygen ratio and the PaO2/fraction of inspired oxygen ratio in children. Chest 2009;135(3):662–668.
    OpenUrlCrossRefPubMed
  15. 15.
    1. Rice TW,
    2. Wheeler AP,
    3. Bernard GR,
    4. Hayden DL,
    5. Schoenfeld DA,
    6. Ware LB
    ; on behalf of the National Institutes of Health, National Heart, Lung, and Blood Institute ARDS Network. Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest 2007;132(2):410–417.
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Thomas NJ,
    2. Shaffer ML,
    3. Willson DF,
    4. Shih MC,
    5. Curley MA
    . Defining acute lung disease in children with the oxygenation saturation index. Pediatr Crit Care Med 2010;11(1):12–17.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Willson DF,
    2. Thomas NJ,
    3. Markovitz BP,
    4. Bauman LA,
    5. DiCarlo JV,
    6. Pon S,
    7. et al
    ; on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury: a randomized controlled trial. JAMA 2005;293(4):470–476.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Randolph AG,
    2. Forbes PW,
    3. Gedeit RG,
    4. Arnold JH,
    5. Wetzel RC,
    6. Luckett PM,
    7. et al
    . on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. Cumulative fluid intake minus output is not associated with ventilator weaning duration or extubation outcomes in children. Pediatr Crit Care Med 2005;6(6):642–647.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Burr JS,
    2. Jenkins TL,
    3. Harrison R,
    4. Meert K,
    5. Anand KJ,
    6. Berger JT,
    7. et al
    ; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Collaborative Pediatric Critical Care Research Network (CPCCRN). The Collaborative Pediatric Critical Care Research Network (CPCCRN) Critical Pertussis Study: collaborative research in pediatric critical care medicine. Pediatr Crit Care Med 2011;12(4):387–392.
    OpenUrlPubMed
  20. 20.
    1. Meert KL,
    2. Eggly S,
    3. Dean JM,
    4. Pollack M,
    5. Zimmerman J,
    6. Anand KJ,
    7. et al
    . Ethical and logistical considerations of multicenter parental bereavement research. J Palliat Med 2008;11(3):444–450.
    OpenUrlCrossRefPubMed
  21. 21.
    1. Meert KL,
    2. Eggly S,
    3. Pollack M,
    4. Anand KJ,
    5. Zimmerman J,
    6. Carcillo J,
    7. et al
    ; on behalf of the National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Parents' perspectives regarding a physician-parent conference after their child's death in the pediatric intensive care unit. J Pediatr 2007;151(1):50–55, e1-e2.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Willson DF,
    2. Dean JM,
    3. Newth C,
    4. Pollack M,
    5. Anand KJ,
    6. Meert K,
    7. et al
    ; on behalf of the Collaborative Pediatric Critical Care Research Network (CPCCRN). Pediatr Crit Care Med 2006;7(4):301–307.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Yung M,
    2. Slater A,
    3. Festa M,
    4. Williams G,
    5. Erickson S,
    6. Pettila V,
    7. et al
    ; on behalf of the Australia and New Zealand Intensive Care Influenza Investigators and the Paediatric Study Group and the Clinical Trials Group of the Australia New Zealand Intensive Care Society. Pandemic H1N1 in children requiring intensive care in Australia and New Zealand during winter 2009. Pediatrics 2011;127(1):e156–e163.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    The ANZIC Influenza Investigators. Critical care services and 2009 H1N1 influenza in Australia and New Zealand. N Engl J Med 2009;361(20):1925–1934.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Khemani RG,
    2. Markovitz BP,
    3. Curley MAQ
    . Characteristics of children Intubated and mechanically ventilated in 16 PICUs. Chest 2009;136(3):765–771.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Randolph AG
    . Management of acute lung injury and acute respiratory distress syndrome in children. Crit Care Med 2009;37(8):2448–2454.
    OpenUrlPubMed
  27. 27.↵
    1. Khemani RG,
    2. Newth CJ
    . The design of future pediatric mechanical ventilation trials for acute lung injury. Am J Respir Crit Care Med 2010;182(12):1465–1474.
    OpenUrlCrossRefPubMed
  28. 28.↵
    The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342(18):1301–1308.
    OpenUrlCrossRefPubMed
  29. 29.
    1. Amato MB,
    2. Barbas CS,
    3. Medeiros DM,
    4. et al
    . Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998;338(6):347–354.
    OpenUrlCrossRefPubMed
  30. 30.
    1. Brochard L,
    2. Roudot-Thoraval F,
    3. Roupie E,
    4. Delclaux C,
    5. Chastre J,
    6. Fernandez-Mondejar E,
    7. et al
    . Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 1998;158(6):1831–1838.
    OpenUrlPubMed
  31. 31.↵
    1. Brower RG,
    2. Shanholtz CB,
    3. Fessler HE,
    4. Shade DM,
    5. White P Jr.,
    6. Wiener CM,
    7. et al
    . Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 1999;27(8):1492–1498.
    OpenUrlCrossRefPubMed
  32. 32.
    1. Eichacker PQ,
    2. Gerstenberger EP,
    3. Banks SM,
    4. Cui X,
    5. Natanson C
    . Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med 2002;166(11):1510–1514.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Stewart TE,
    2. Meade MO,
    3. Cook DJ,
    4. Granton JT,
    5. Hodder RV,
    6. Lapinsky SE,
    7. et al
    . Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group N Engl J Med 1998;338(6):355–361.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Brower RG,
    2. Lanken PN,
    3. MacIntyre N,
    4. Matthay MA,
    5. Morris A,
    6. Ancukiewicz M,
    7. et al
    ; on behalf of the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351(4):327–336.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Meade MO,
    2. Cook DJ,
    3. Guyatt GH,
    4. Slutsky AS,
    5. Arabi YM,
    6. Cooper DJ,
    7. et al
    . Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome. JAMA 2008;299(6):637–645.
    OpenUrlCrossRefPubMed
  36. 36.↵
    1. Mercat A Richard JC,
    2. Vielle B,
    3. Jaber S,
    4. Osman D,
    5. Diehl JL,
    6. et al
    ; on behalf of the Expiratory Pressure (Express) Study Group. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299(6):646–655.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Briel M,
    2. Meade M,
    3. Mercat A,
    4. Brower RG,
    5. Talmor D,
    6. Walter SD,
    7. et al
    . Higher vs. lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010;303(9):865–873.
    OpenUrlCrossRefPubMed
  38. 38.↵
    1. Albuali WH,
    2. Singh RN,
    3. Fraser DD,
    4. Seabrook JA,
    5. Kavanagh BP,
    6. Parshuram CS,
    7. Kornecki A
    . Have changes in ventilation practice improved outcome in children with acute lung injury? Pediatr Crit Care Med 2007;8(4):324–330.
    OpenUrlCrossRefPubMed
  39. 39.↵
    1. Cannon ML,
    2. Cornell J,
    3. Tripp DS,
    4. Gentile MA,
    5. Hubble CL,
    6. Meliones JN,
    7. Cheifetz IM
    . Tidal volumes for ventilated infants should be determined with a pneumotachometer placed at the endotracheal tube. Am J Respir Crit Care Med 2000;162(6):2109–2112.
    OpenUrlPubMed
  40. 40.↵
    1. Castle RA,
    2. Dunne CJ,
    3. Mok Q,
    4. Wade AM,
    5. Stocks J
    . Accuracy of displayed tidal volume in the pediatric intensive care unit. Crit Care Med 2002;39(11):2566–2574.
    OpenUrl
  41. 41.↵
    1. Chow LC,
    2. Vanderhal A,
    3. Raber J,
    4. Sola A
    . Are tidal volume measurements in neonatal pressure-controlled ventilation accurate? Pediatr Pulmonol 2002;34(3):196–202.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Heulitt MJ,
    2. Thurman TL,
    3. Holt SJ,
    4. Jo CH,
    5. Simpson P
    . Reliability of displayed tidal volume in infants and children during dual-controlled ventilation. Pediatr Crit Care Med 2009;10(6):661–667.
    OpenUrlCrossRefPubMed
  43. 43.↵
    1. Hess DR
    . Approaches to conventional mechanical ventilation of the patient with acute respiratory distress syndrome. Respir Care 2011:56(10):1555–1572.
    OpenUrlAbstract/FREE Full Text
  44. 44.↵
    1. Arnold JH,
    2. Hanson JH,
    3. Toro-Figuero LO,
    4. Gutiérrez J,
    5. Berens RJ,
    6. Anglin DL
    . Prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure. Crit Care Med 1994;22(10):1530–1539.
    OpenUrlPubMed
  45. 45.↵
    1. Sud S,
    2. Sud M,
    3. Friedrich JO,
    4. Meade MO,
    5. Ferguson ND,
    6. Wunsch H,
    7. Adhikari NK
    . High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): systematic review and meta-analysis. BMJ 2010;340:c2327. DOI: 10.1136/bmj.c2327.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Ten IS,
    2. Anderson MR
    . Is high-frequency ventilation more beneficial than low-tidal volume conventional ventilation? Respir Care Clin N Am 2006;12(3):437–451.
    OpenUrlPubMed
  47. 47.
    1. Ventre KM,
    2. Arnold JH
    . High frequency oscillatory ventilation in acute respiratory failure. Paediatr Respir Rev 2004;5(4):323–332.
    OpenUrlPubMed
  48. 48.↵
    1. Arnold JH,
    2. Anas NG,
    3. Luckett P,
    4. Cheifetz IM,
    5. Reyes G,
    6. Newth CJ,
    7. et al
    . High-frequency oscillatory ventilation in pediatric respiratory failure: a multicenter experience. Crit Care Med 2000;28(12):3913–3919.
    OpenUrlCrossRefPubMed
  49. 49.↵
    1. Jobe AH
    . Pulmonary surfactant therapy. N Engl J Med 1993;328(12):861–868.
    OpenUrlCrossRefPubMed
  50. 50.
    1. Soll RF
    . Surfactant therapy in the USA: trials and current routines. Biol Neonate 1997;71(Suppl 1):1–7.
    OpenUrlPubMed
  51. 51.
    1. Findlay RD,
    2. Taeusch HW,
    3. Walther FJ
    . Surfactant replacement therapy for meconium aspiration syndrome. Pediatrics 1996;97(1):48–52.
    OpenUrlAbstract/FREE Full Text
  52. 52.
    1. Lotze A,
    2. Knight GR,
    3. Martin GR,
    4. Bulas DI,
    5. Hull WM,
    6. O'Donnell RM,
    7. et al
    . Improved pulmonary outcome after exogenous surfactant therapy for respiratory failure in term infants requiring extracorporeal membrane oxygenation. J Pediatr 1993;122(2):261–268.
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. Lotze A,
    2. Mitchell BR,
    3. Bulas DI,
    4. Zola EM,
    5. Shalwitz RA,
    6. Gunkel JH
    . Multicenter study of surfactant (beractant) use in the treatment of term infants with severe respiratory failure. J Pediatr 1998;132(1):40–47.
    OpenUrlCrossRefPubMed
  54. 54.↵
    1. Willson DF,
    2. Chess PR,
    3. Notter RH
    . Surfactant for pediatric acute lung injury. Pediatr Clin North Am 2008;55(3):545–575.
    OpenUrlCrossRefPubMed
  55. 55.
    1. Willson DF,
    2. Zaritsky A,
    3. Bauman LA,
    4. Dockery K,
    5. James RL,
    6. Conrad D,
    7. et al
    . Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure. Members of the Mid-Atlantic Pediatric Critical Care Network. Crit Care Med 1999;27(1):188–195.
    OpenUrlCrossRefPubMed
  56. 56.↵
    1. Willson DF,
    2. Jiao JH,
    3. Bauman LA,
    4. Zaritsky A,
    5. Craft H,
    6. Dockery K,
    7. et al
    . Calf's lung surfactant extract in acute hypoxemic respiratory failure in children. Crit Care Med 1996;24(8):1316–1322.
    OpenUrlCrossRefPubMed
  57. 57.↵
    1. Czaja AS
    . A critical appraisal of a randomized controlled trial: Willson et al: Effect of exogenous surfactant (calfactant) in pediatric acute lung injury (JAMA 2005, 293: 470-476). Pediatr Crit Care Med 2007;8(1):50–53.
    OpenUrlCrossRefPubMed
  58. 58.↵
    1. Kesecioglu J,
    2. Beale R,
    3. Stewart TE,
    4. Findlay GP,
    5. Rouby JJ,
    6. Holzapfel L,
    7. et al
    . Exogenous natural surfactant for treatment of acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 2009;180(10):989–994.
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Willson DF,
    2. Notter RH
    . The future of exogenous surfactant therapy. Respir Care 2011;56(9):1369–1386; discussion 1386-1388.
    OpenUrlAbstract/FREE Full Text
  60. 60.↵
    1. Gerlach H,
    2. Keh D,
    3. Semmerow A,
    4. Busch T,
    5. Lewandowski K,
    6. Pappert DM,
    7. et al
    . Dose response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Am J Respir Crit Care Med 2003;167(7):1008–1015.
    OpenUrlCrossRefPubMed
  61. 61.
    1. Dellinger RP,
    2. Zimmerman JL,
    3. Taylor RW,
    4. Straube RC,
    5. Hauser DL,
    6. Criner GJ,
    7. et al
    . on behalf of the Inhaled Nitric Oxide in ARDS Study Group. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Crit Care Med 1998;26(1):15–23.
    OpenUrlCrossRefPubMed
  62. 62.↵
    1. Taylor RW,
    2. Zimmerman JL,
    3. Dellinger RP,
    4. Straube RC,
    5. Criner GJ,
    6. Davis K Jr.,
    7. et al
    . on behalf of the Inhaled Nitric Oxide in ARDS Study Group. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004;291(13):1603–1609.
    OpenUrlCrossRefPubMed
  63. 63.↵
    1. Adhikari NK,
    2. Burns KE,
    3. Friedrich JO,
    4. Granton JT,
    5. Cook DJ,
    6. Meade MO
    . Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ 2007;334(7597):779.
    OpenUrlAbstract/FREE Full Text
  64. 64.↵
    1. Afshari A,
    2. Brok J,
    3. Møller AM,
    4. Wetterslev J
    . Inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and children: a systematic review with Meta-analysis and trial sequential analysis. Anesth Analg 2011;11(6):1411–1421.
    OpenUrl
  65. 65.↵
    1. Afshari A,
    2. Brok J,
    3. Moller AM,
    4. Wetterslev J
    . Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev 2010;(7):CD002787.
  66. 66.↵
    1. Dahlem P,
    2. van Aalderen WMC,
    3. de Neef M,
    4. Dijkgraaf MGW,
    5. Bos AP
    . Randomized controlled trial of aerosolized prostacyclin therapy in children with acute lung injury. Crit Care Med 2004;32(4):1055–1060.
    OpenUrlCrossRefPubMed
  67. 67.↵
    1. Wiedemann HP,
    2. Wheeler AP,
    3. Bernard GR,
    4. Thompson BT,
    5. Hayden D,
    6. de Boisblanc B,
    7. et al
    ; on behalf of the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid management strategies in acute lung injury N Engl J Med 2006;354(24):2564–2575.
    OpenUrlCrossRefPubMed
  68. 68.↵
    1. Ognibene KL,
    2. Vawdrey DK,
    3. Biagas KV
    . The association of age, illness severity, and glycemic status in a pediatric intensive care unit. Pediatr Crit Care Med 2011 [Epub ahead of print].
  69. 69.
    1. Meyfroidt G,
    2. Ingels C,
    3. Van den Berghe G
    . Glycemic control in the ICU. N Engl J Med 2011;364(13):1280–1281.
    OpenUrlCrossRefPubMed
  70. 70.
    1. Vlasselaers D,
    2. Milants I,
    3. Desmet L,
    4. Wouters PJ,
    5. Vanhorebeek I,
    6. van den Heuvel I,
    7. et al
    . Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet 2009;373(9663):547–556.
    OpenUrlCrossRefPubMed
  71. 71.
    1. Van den Berghe G
    . First do no harm. hypoglycemia or hyperglycemia? Crit Care Med 2006;34(11):2843–2844.
    OpenUrlCrossRefPubMed
  72. 72.↵
    1. Kavanagh BP,
    2. McCowen KC
    . Clinical practice. Glycemic control in the ICU. N Engl J Med 2010;363(26):2540–2546.
    OpenUrlCrossRefPubMed
  73. 73.↵
    1. Lacroix J,
    2. Hébert PC,
    3. Hutchison JS,
    4. Hume HA,
    5. Tucci M,
    6. Ducruet T,
    7. et al
    ; on behalf of the TRIPICU Investigators, the Canadian Critical Care Trials Group, and the Pediatric Acute Lung Injury and Sepsis Investigators Network. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007;356(16):1609–1619.
    OpenUrlCrossRefPubMed
  74. 74.↵
    1. Abdelsalam M,
    2. Cheifetz IM
    . Goal-directed therapy for severely hypoxemic patients with acute respiratory distress syndrome: permissive hypoxemia. Respir Care 2010;55(11):1483–1490.
    OpenUrlPubMed
  75. 75.↵
    Extracorporeal Life Support Organization (ELSO) Database. January, 2011.
  76. 76.↵
    The Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators. Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome. JAMA 2009;302(17):1888–1895.
    OpenUrlCrossRefPubMed
  77. 77.
    1. Turner DA,
    2. Rehder KJ,
    3. Peterson-Carmichael SL,
    4. Ozment CP,
    5. Al-Hegelan MS,
    6. Williford WL,
    7. et al
    . Extracorporeal membrane oxygenation for severe refractory respiratory failure secondary to 2009 H1N1 influenza A. Respir Care 2011;56(7):941–946.
    OpenUrlAbstract/FREE Full Text
  78. 78.↵
    1. Turner DA,
    2. Peters MA,
    3. Williford WL,
    4. Thalman JJ,
    5. Shearer IR,
    6. Walczak RJ,
    7. et al
    . Development of a collaborative program to provide extracorporeal membrane oxygenation for adult refractory hypoxemia within the framework of a pandemic. Pediatr Crit Care Med 2011;12(4):426–430.
    OpenUrlCrossRefPubMed
  79. 79.↵
    1. Dalton HJ
    . Extracorporeal life support: moving at the speed of light. Respir Care 2011;56(9):1445–1453; discussion 1454-1456.
    OpenUrlAbstract/FREE Full Text
  80. 80.↵
    1. Turner DA,
    2. Cheifetz IM,
    3. Rehder KJ,
    4. Williford WL,
    5. Banuelos SJ,
    6. Lin SS,
    7. David RD,
    8. Zaas D
    . Active rehabilitation and physical therapy during extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach. Crit Care Med 2011; in press.
  81. 81.↵
    1. Zabrocki LA,
    2. Brogan TV,
    3. Statler KD,
    4. Poss WB,
    5. Rollins MD,
    6. Bratton SL
    . Extracorporeal membrane oxygenation for pediatric respiratory failure: survival and predictors of mortality. Crit Care Med 2011;39(2):364–370.
    OpenUrlCrossRefPubMed
  82. 82.↵
    1. Ijland MM,
    2. Heunks LM,
    3. van der Hoeven JG
    . Bench-to-bedside review: hypercapnic acidosis in lung injury: from permissive to therapeutic. Crit Care 2010;14(6):237.
    OpenUrlPubMed
  83. 83.
    1. Peltekova V,
    2. Engelberts D,
    3. Otulakowski G,
    4. Uematsu S,
    5. Post M,
    6. Kavanagh BP
    . Hypercapnic acidosis in ventilator-induced lung injury. Intensive Care Med 2010;36(5):869–878.
    OpenUrlCrossRefPubMed
  84. 84.
    1. Masood A,
    2. Yi M,
    3. Lau M,
    4. Belcastro R,
    5. Shek S,
    6. Pan J,
    7. et al
    . Therapeutic effects of hypercapnia on chronic lung injury and vascular remodeling in neonatal rats. Am J Physiol Lung Cell Mol Physiol 2009;297(5):L920–L930.
    OpenUrlAbstract/FREE Full Text
  85. 85.
    1. Hassett P,
    2. Laffey JG
    . Permissive hypercapnia: balancing risks and benefits in the peripheral microcirculation. Crit Care Med 2007;35(9):2229–2231.
    OpenUrlPubMed
  86. 86.↵
    1. Cheifetz IM,
    2. Hamel DS
    . Is permissive hypoxemia a beneficial strategy for pediatric acute lung injury? Respir Care Clin N Am 2006;12(3):359–369.
    OpenUrlPubMed
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