Mechanical ventilation can be indispensable for assuring adequate gas exchange for patients with acute respiratory failure. However, it may exacerbate, or even initiate, lung injury and inflammation and has, therefore, been identified as a risk factor for poor patient outcome. The development of ventilator-induced lung injury (VILI) has led to the concept of lung-protective ventilation strategies. Such an approach is based on two primary principles. The first is to avoid overdistension (i.e., volutrauma) and the other is to avoid or minimize the cyclic opening and closing of alveoli (i.e., atelectrauma) (1).
Ventilatory strategies that limit tidal stretch of the alveoli (e.g., low tidal volume ventilation and high-frequency ventilation), permissive gas exchange strategies (e.g., permissive hypercapnia and permissive hypoxemia), positive end-expiratory pressure (PEEP) titration with or without recruitment maneuvers, and ventilatory modes that partially or proportionally assist spontaneous breathing have been advocated. Unfortunately, specific pediatric outcome data on lung-protective ventilation are sparse, especially with regard to the ventilator strategy and/or mode(s) used to manage patients with pediatric acute respiratory distress syndrome (PARDS). There is generally a low level of evidence for most of the recommendations described in this article, and thus, specific recommendations are largely based on the experience in the adult population for patients with acute respiratory distress syndrome (ARDS), with consensus-based modifications for pediatrics.
MODES OF CONVENTIONAL VENTILATION
3.1.1 There are no outcome data on the influence of mode (control or assisted) during conventional mechanical ventilation. Therefore, no recommendation can be made on the ventilator mode to be used in patients with PARDS. Future clinical studies should be designed to assess the control and assisted modes of ventilation on outcome. Strong agreement
Controlled Versus Assisted Modes.
Ventilator-delivered breaths can be either imposed on the patient independent of his/her own respiratory activity (i.e., nonsynchronized intermittent mechanical ventilation [IMV]) or used to partially (i.e., synchronized IMV [SIMV]) or fully (i.e., assist control, pressure control, or pressure support ventilation [PSV]) assist a patient’s own respiratory effort. Each ventilator-assisted breath is defined by its cycle (i.e., transition from inspiration to expiration), trigger (i.e., initiation of inspiration), limit (i.e., size of the breath—pressure or volume), and inspiratory flow pattern (i.e., variable, decelerating or square-wave, constant).
Breath cycling (transition from inspiration to exhalation) can be determined by a clinician-set inspiratory time or by the patient based on the rate of inspiratory flow decay (i.e., flow termination criteria). Time-cycled breaths are typified by mechanical breaths, such as pressure-controlled or volume-controlled breaths. Flow-cycled breaths are typified by pressure support and volume support modes.
Traditionally, a ventilator breath is triggered by volume, flow, or pressure. In patients without adequate spontaneous effort, inspiration has to be triggered by time, that is, the respiratory rate setting. In spontaneously breathing patients, a ventilator-assisted breath is generally triggered by changes in flow in the ventilator circuit. Alternatively, variations in the pressure signal can be used and are especially favored for noninvasive ventilation or invasive ventilation with a significant air leak around the endotracheal tube (ETT).
Although trigger and cycling systems have technically been brought to high performance, especially for mechanical ventilators designed for the neonatal and/or pediatric patient population (2), there is no solid published experience in the pediatric population documenting that breath synchronization improves outcome (i.e., time on mechanical ventilation, duration of weaning, time spent in the PICU, or mortality) in patients with respiratory failure (3, 4). Similarly, in the neonatal setting, patient-ventilator synchronization has not shown improvement in outcome or long-term efficacy when compared with nonsynchronized ventilation (5).
Novel modes of ventilation have been developed with alternative triggers. The most common of these approaches is neurally adjusted ventilatory assist (NAVA) that uses the electrical activity signal of the diaphragm to trigger inspiration. This mode has been shown to improve patient-ventilator synchrony when compared with PSV in invasively (6–9) and noninvasively (10) ventilated patients. Furthermore, NAVA has shown in comparison with PSV in adult patients recovering from ARDS to not only improve patient-ventilator synchrony but also limit the risk of ventilator overassistance (11). Although NAVA has been shown in a nested study to reduce the duration of respiratory support for infants recovering from ARDS (12), it has not been demonstrated to improve overall outcome in any population studied.
Bilevel Ventilation With Spontaneous Breathing Throughout the Respiratory Cycle.
Airway pressure release ventilation (APRV) is a mode of ventilation that allows for spontaneous breathing throughout all phases of the machine-imposed respiratory cycle. APRV is a pressure-limited, time-triggered, and time-cycled mode that maintains an elevated baseline pressure (Phi) with deflations or “releases” of gas to a lower pressure setting (Plow). With this mode of ventilation, adult experience has shown the possibility of using lower inspiratory plateau pressures for a given tidal volume when compared with volume ventilation as well as decreased sedation requirements (13).
Two randomized controlled trials (RCTs) have explored the use of APRV on outcomes in adult patients with ARDS. The first trial showed a significantly shorter duration of ventilation and ICU stay; however, it must be recognized that the control group of patients received neuromuscular blockade for unclear reasons for the first 3 days of ventilation. These results in favor of APRV, therefore, have to be questioned (14). The second RCT assigned 58 patients to either APRV or SIMV plus 10 cm H2O of pressure support. This study demonstrated no differences in gas exchange, sedation requirements, or outcome (ventilator-free days or mortality) (15). Pediatric experience is limited to the results of one clinical trial. This prospective randomized crossover clinical trial compared APRV with volume-controlled synchronized IMV in children with mild-to-moderate lung injury (16). This study showed that APRV resulted in comparable levels of ventilation and oxygenation at significantly lower peak pressures.
Ventilator Mode and Outcome.
Unfortunately, none of the various modes of ventilation has been demonstrated to improve the outcome in the pediatric population, including the patients with PARDS. From the adult experience, observational data have suggested that a high incidence of patient-ventilator asynchrony is related to increased morbidity (e.g., length on mechanical ventilation) in patients with ARDS, whereas a low incidence was associated with lower morbidity (17).
VENTILATORY STRATEGIES DURING CONVENTIONAL VENTILATION
Tidal Volume Delivery
3.2.1 In any mechanically ventilated pediatric patient, we recommend in controlled ventilation to use tidal volumes in or below the range of physiologic tidal volumes for age/body weight (i.e., 5 to 8 mL/kg predicted body weight [PBW) according to lung pathology and respiratory system compliance. Weak agreement (88% agreement)
3.2.2 We recommend to use patient-specific tidal volumes according to disease severity. Tidal volumes should be 3–6 mL/kg PBW for patients with poor respiratory system compliance and closer to the physiologic range (5–8 mL/kg ideal body weight) for patients with better preserved respiratory system compliance. Weak agreement (84% agreement)
In adult patients with ARDS, a large RCT comparing 6 versus 12 mL/kg of tidal volume showed a significantly lower mortality for the 6 mL/kg tidal volume group with a relative risk reduction of 24% and an absolute risk reduction of 9% (18). From subsequent meta-analyses, including four other studies comparing either small versus large tidal volume ventilation or pressure limitation at higher versus lower airway pressures, it was concluded that a Vt less than or equal to 10 mL/kg PBW (19, 20) is associated with improved survival. It is important to note that no pediatric or neonatal RCT has adequately studied the effects of small tidal volume ventilation or pressure limitation as a lung-protective ventilation strategy on outcome. However, it must be noted that two observational studies (one prospective and another retrospective in design) have shown an inverse relationship between applied tidal volumes and mortality in children (21, 22). Furthermore, a large retrospective multicenter analysis of patients with acute hypoxic respiratory failure (n = 439), of whom 345 (78.6%) developed ARDS according to the American-European Consensus definitions, did not show an association between tidal volume (even when tidal volumes < 6 mL/kg or > 10 mL/kg PBW were used) and mortality or ventilator-free days (23).
When considering small tidal volume ventilation as a lung-protective concept, it must be noted that physiologic tidal volumes in a normal person are in the range of 6–8 mL/kg PBW (24–29). When considering these clinical data in composite, tidal volumes above the physiologic range do not seem reasonable for any mechanically ventilated pediatric patients regardless of lung condition.
Patients with more severe lung injury, as expressed by poorer oxygenation, lower compliance (i.e., reflecting a small residual inflatable lung volume available for alveolar ventilation and gas exchange—“baby lung” concept) (30, 31), and a higher lung injury score by Murray et al (32) should receive tidal volumes below physiologic values. A subgroup analysis from the Acute Respiratory Distress Syndrome (ARDS) Network trial (18) in adult patients with ARDS (6 vs 12 mL/kg) compared patients with low versus high respiratory system compliance (using a compliance of 0.6 mL/cm H2O/kg as a cutoff point) showed that only patients with poor respiratory system compliance at study entry had a survival benefit when randomized to the 6-mL/kg study arm (33). Similarly, there are appealing data from pediatric experience showing an inverse relationship to outcome with tidal volumes but a direct relationship with maximal airway pressures (21). This observation suggests strongly that clinicians tend to use lower Vt resulting in relatively higher inspiratory airway pressures in the sicker patients (i.e., patients with lower respiratory system compliance) at the onset of mechanical ventilation for ARDS. This latter observation is in alignment with data from the other pediatric observational study (22), showing that patients with higher initial lung injury scores were ventilated with smaller tidal volumes and showed worse outcome. These findings are consistent with the recent concept of keeping lung tissue strain (i.e., ratio between inflated volume and functional residual capacity) low to protect the lung (34).
Thus, the clinical observations from adult and pediatric ventilation studies would strongly suggest that targeting a Vt of 6 mL/kg PBW for every patient with ARDS, as would strongly be suggested by the results of the ARDS Network trial (18), may not be appropriate when reasoning on individual patient- and disease-specific pathophysiologic conditions. Interpretation of the available data suggests that each patient has a maximal allowable tidal volume that could avoid unacceptable high lung tissue strain. This thought process leads to the conclusion that Vt should be adapted not only per patient body weight (mL/kg) but also on the amount of inflatable lung volume above functional residual capacity (i.e., Vt/baby lung/kg, or Vt/specific compliance/kg).
Various methods, most of them based on gender and height measures, have been proposed for estimating the body weight of infants and children in emergency settings when determining appropriate drug dosing (35–38), whereas for lung function measurements, it has been suggested that PBW should be calculated by using gender and height prediction from ulna length (39). This later method was developed to accurately predict the degree of restrictive lung pathologies in patients presenting with scoliosis and other syndromes associated with skeletal anomalies. For the purpose of estimating PBW in the ventilated child in the PICU setting, classical growth charts may allow reasonably accurate estimations for ventilation purposes by using gender, length/height, and head circumference.
3.2.3 In the absence of transpulmonary pressure measurements, we recommend an inspiratory plateau pressure limit of 28 cm H2O, allowing for slightly higher plateau pressures (29–32 cm H2O) for patients with increased chest wall elastance (i.e., reduced chest wall compliance). Weak agreement (72% agreement)
Inspiratory pressure is a result of applied PEEP and the added volume of gas delivered above this pressure value. In a pressure-limited mode, peak inspiratory pressure (PIP) is defined by the change in pressure above the PEEP setting (Δ-P). In volume-limited ventilation, the PIP is defined by the Vt chosen and the pressure required above PEEP. Volutrauma (i.e., excessive volume delivery) by overdistension of lung units has been recognized to be a more injurious mechanism than barotrauma (i.e., excessive airway pressure) (1). However, limiting maximal inspiratory pressure is commonly proposed. It should be noted that the recommended pressure limitations often do not consider differences in chest wall elastance between patients of different body habitus or variations of elastance in the evolution of the disease process. To take these latter variables in account, one would need to measure transpulmonary pressures in every ventilated patient (40).
Because airway pressures are related to delivered Vt and respiratory system compliance, pressure limitation will result in a smaller Vt in conditions of lower compliance and in a larger Vt in more compliant lung conditions. As such, pressure limitation allows to some degree the “automatic” adaptation of the delivered tidal volume and, therefore, adjusts lung tissue strain to the actual pulmonary condition. As pressure-limited ventilation adjusts tidal volume based on the actual lung compliance and amount of residual inflatable lung volume in a sick lung, it can be recommended as a lung-protective strategy. However, in patients with severe reduced chest wall compliance (e.g., chest wall edema or obesity) or severely increased abdominal pressures, pressure limitation to pressure ranges of 25–28 cm H2O may result in overly low transpulmonary pressures and, therefore, not allow sufficient inflation of the lungs to assure adequate alveolar ventilation and oxygenation.
Of importance, high inspiratory airway pressures have been associated in two observational pediatric studies with increased mortality (21, 22). One of these clinical reports demonstrates a clear and almost linear increase in adverse outcome with PIP greater than 25 cm H2O (21).
Positive End-Expiratory Pressure
3.3.1 We recommend moderately elevated levels of PEEP (10–15 cm H2O) titrated to the observed oxygenation and hemodynamic response in patients with severe PARDS. Weak agreement (88% agreement)
3.3.2 We recommend that PEEP levels greater than 15 cm H2O may be needed for severe PARDS although attention should be paid to limiting the plateau pressure as previously described. Strong agreement
3.3.3 We recommend that markers of oxygen delivery, respiratory system compliance, and hemodynamics should be closely monitored as PEEP is increased. Strong agreement
3.3.4 We recommend that clinical trials should be designed to assess the effects of elevated PEEP on outcome in the pediatric population. Strong agreement
Levels of PEEP should be set to prevent lung unit collapse at end-expiration and avoid tidal recruitment at each breath cycle (collapse—opening—recollapse injury or so called atelectatic injury). This concept has been addressed in several experimental studies (41, 42) but not adequately in the clinical setting. Three randomized trials (43–45) in adult ARDS addressed higher versus lower levels of PEEP according various PEEP/FIO2 tables but did not analyze PEEP in relation to collapse during end-expiration. None of these clinical investigations could demonstrate a difference in any outcome parameter. However, two systematic meta-analyses suggest that higher levels of PEEP as part of a lung-protective strategy may be associated with lower hospital mortality in adult patients with ARDS as defined by a ratio of partial pressure of oxygen to fraction of inspired oxygen concentration (PaO2/FIO2) of 200 mm Hg or less (46, 47). However, this positive effect of PEEP was not seen in patients with milder forms of acute lung injury.
Lung Recruitment Maneuvers
3.3.5 We recommend careful recruitment maneuvers in the attempt to improve severe oxygenation failure by slow incremental and decremental PEEP steps. Sustained inflation maneuvers cannot be recommended due to lack of available data. Weak agreement (88% agreement)
3.3.6 We recommend that clinical trials should be designed to assess optimal recruitment strategies in infants and children with PARDS. Strong agreement
With the advent of small tidal volume ventilation, lung recruitment has gained new interest in patients with acute hypoxic respiratory failure with elevated requirements for inspired oxygen concentrations. However, it has been recognized that recruitability of a diseased lung depends on various factors. Among others, it is dependent on the type of lung disease (e.g., diffuse alveolar disease vs pneumonia-like alveolar consolidations), time course (e.g., early vs late PARDS), and mechanics of the respiratory system (e.g., pulmonary compliance). In general, patients with predominantly increased lung elastance (i.e., decreased lung compliance) show less positive response to recruitment maneuvers than patients with increased chest wall elastance (i.e., decreased chest wall compliance) (48). However, lung pathology characterized predominantly by alveolar collapse (e.g., infant respiratory distress syndrome) or by inflammatory edema demonstrates a high potential for lung recruitment, despite being characterized mechanically by a low lung compliance. Similarly, application of a recruitment maneuver can improve oxygenation in adult patients with early ARDS (predominant inflammatory edema) who do not have impairment of chest wall mechanics (49).
Significant controversy exists on how to best apply recruitment maneuvers in clinical practice. Sigh maneuvers by increasing airway pressures to a level of 30–40 cm H2O (or even higher) over a short period of time (generally 30–40 s) have shown variable results because their efficiency depends on the type of lung disease and respiratory system mechanics. Adult patients presenting with ARDS with high lung elastance (i.e., low lung compliance) and a primary ARDS etiology did not respond with improvement in oxygenation with such maneuvers to the degree that patients with low lung elastance due to a secondary ARDS did (49). In summary, patients with predominant lung unit collapse or inflammatory edema formation (e.g., early PARDS, infant respiratory distress syndrome, or similar pathologies) usually respond well to such recruitment maneuvers, especially if due to a secondary PARDS etiology.
Because it is often impossible to predict how an individual patient will respond to a lung recruitment attempt, careful individual PEEP titration seems to be a reasonable approach and has been shown to be efficient in terms of improvement of oxygenation and safe in adults and children with PARDS (50, 51).
A decremental PEEP titration trial has repeatedly been shown to be an efficient and safe method to determine a patient’s optimal PEEP setting; however, recruitment and oxygenation have not yet been demonstrated to be determinants of clinically relevant outcomes (52, 53). No data exist on the effect of recruitment maneuvers on mortality, morbidity, length of stay, or duration of mechanical ventilation (54).
VENTILATORY STRATEGIES DURING “NONCONVENTIONAL” MECHANICAL VENTILATION
The term “nonconventional” mechanical ventilation is commonly used for ventilator modes that do not rely on convective gas exchange, the latter requiring tidal volumes above anatomical and apparatus dead space volumes. The respective modes are various types of high-frequency ventilation (e.g., high-frequency oscillatory ventilation [HFOV], high-frequency jet ventilation [HFJV], and high-frequency percussive ventilation [HFPV]) and tracheal gas insufflation. High-frequency ventilation is defined by a high-frequency rate (> 120 bpm for adults and > 150 bpm for infants and children) and a delivered tidal volume that is less than anatomic dead space.
High-Frequency Oscillatory Ventilation
3.4.1 We recommend that HFOV should be considered as an alternative ventilatory mode in hypoxic respiratory failure in patients in whom plateau airway pressures exceed 28 cm H2O in the absence of clinical evidence of reduced chest wall compliance. Such an approach should be considered for those patients with moderate-to-severe PARDS. Weak agreement (92% agreement)
3.4.2 In HFOV, we recommend that the optimal lung volume be achieved by exploration of the potential for lung recruitment by a stepwise increase and decrease of the mean airway pressure (continuous distending pressure) under continuous monitoring of the oxygenation and CO2 response as well as hemodynamic parameters. Strong agreement
Despite extensive experience with HFOV and multiple RCTs for neonatal respiratory failure, the use of HFOV as an elective or rescue ventilator mode for PARDS has not been studied extensively in children in the low tidal volume ventilation era.
The initial prospective study by Arnold et al (55) demonstrated that HFOV, using a high mean lung volume strategy, was safe in pediatric patients with respiratory failure and a high predicted mortality rate. In a post hoc analysis of retrospectively and prospectively collected data of 12 children (4 mo to 15 yr old) with acute severe respiratory failure refractory to conventional ventilation strategies, high-frequency ventilation was noted to improve gas exchange supporting the concept of HFOV as a rescue ventilatory mode (56).
The first RCT comparing HFOV to conventional mechanical ventilation studied 70 children with diffuse alveolar disease and/or airleak syndrome showed that HFOV resulted in a significant improvement in oxygenation and a decreased requirement for supplemental oxygen at 30 days by using an aggressive volume recruitment strategy. However, 30-day mortality was not changed. It should be noted that the control group in this study used a high delivered tidal volume in comparison with today’s general management approach (57). A second RCT enrolling 61 patients (children > 35 kg and adults) with ARDS compared HFOV (n = 37) with conventional mechanical ventilation (CMV) (n = 24) showed no statistically significant differences in survival without chronic respiratory support, mortality, therapy failure, or crossover days (58).
Combined pediatric and adult experience with HFOV in ARDS was until recently promising for ARDS treatment showing a risk reduction (risk ratio, 0.77; 95% CI, 0.61–0.98) for the outcome parameter “hospital or 30-day mortality” as documented in a meta-analysis of six RCTs involving a total of 365 patients, most of them adults (59). This view has changed with the results of two recent large randomized studies, OSCillation in ARDS (60) and OSCILLATE (61), in which the adult patients with a PaO2/FIO2 less than 200 (i.e., moderate-to-severe ARDS) were randomized to HFOV or CMV. The OSCAR trial showed no difference in outcome (30-day mortality), whereas the OSCILLATE trial was prematurely stopped (after the 500 patient analyses) by the steering committee because of a significantly higher in-hospital (47% vs 35%) and 60-day mortality (47% vs 38%) in the HFOV group. The results of the OSCAR and OSCILLATE studies can be partially explained by the observation that lung-protective ventilation strategies were applied in the CMV arm. Furthermore, concern has been raised about the OSCILLATE study given the number of patients in the HFOV group who required high vasopressor support because of hemodynamic compromise, suggesting the use of excessively high mean airway pressures and/or patients who were intravascularly deplete (e.g., shock) (62).
Similar to the OSCILLATE study, in a retrospective observational study by using the Virtual PICU System database, Gupta et al (63) concluded that HFOV had worse outcome when compared with conventional ventilation in children with acute respiratory failure. However, it must be noted that in addition to the limitations of a retrospective database analysis, the propensity scoring approach used in this study did not include clinically significant variables, such as airway pressures, fraction of inspired oxygen, and parameters of gas exchange (64).
Similarly, meta-analysis of neonatal RCTs comparing HFOV with CMV demonstrated that when both ventilatory modes were applied with a similar open lung-protective strategy, no difference existed in measured outcomes (65). However, from neonatal experience, it is strongly advocated to explore the volume-pressure (i.e., oxygenation-pressure) relationship during HFOV to maintain the oscillatory cycle on the deflation limb at an optimal open lung volume (i.e., open the lung at the lowest pressure required) (66). This approach has proven to be safe, but there are no outcome data with this technique. However, a recent relatively small RCT in neonates less than 28-week gestational age presenting with infant respiratory distress syndrome showed a reduction in time on the ventilator with HFOV at optimal lung volumes when compared with conventional mechanical ventilation at optimal lung volumes (i.e., after an lung recruitment attempt and determining the lowest airway pressure needed to maintain the lung open (67). This appears to be the first clinical trial comparing HFOV versus CMV that vigorously controlled for the applied ventilator strategy in both study arms.
In summary, data from pediatric and adult patients with diffuse alveolar disease and ARDS have demonstrated the safety of HFOV as well as improvements in short-term physiologic endpoints. However, it should be noted that the use of HFOV in the pediatric and adult populations has not yet been associated with significant improvements in clinically meaningful outcome measures. HFOV, although seemingly simple and straightforward in its application, requires multidisciplinary expertise to use, as is true of any mode of mechanical ventilation, and expertise with HFOV use was missing in many of the randomized controlled studies to date. Until more definitive data are obtained, it would seem reasonable to continue to include HFOV in the ventilatory armamentarium for the management of pediatric ARDS.
High-Frequency Jet Ventilation
3.4.3 We cannot recommend the routine use of HFJV in children with PARDS. Strong agreement
3.4.4 We recommend that, in addition to the use of HFOV, HFJV might be considered in patients with severe air leak syndrome. Weak agreement (64% agreement)
Evidence from a small RCT in adult patients demonstrates that ventilation and oxygenation can be achieved at lower peak airway pressures and tidal volumes with HFJV when compared with conventional ventilation (68). HFJV has certainly found its place as a ventilatory mode during laryngotracheal surgery. HFJV in PARDS has been reported only in a small series (29 children with severe ARDS complicated by pulmonary barotraumas) showing a survival rate of 69%. The authors speculated that the application of HFJV early in the course of severe hypoxemic respiratory failure complicated by airleak does allow for reduced airway pressures, thereby minimizing pulmonary barotrauma, and allowing the lung to recover from the underlying insult (69).
High-Frequency Percussive Ventilation
3.4.5 HFPV is not recommended for routine ventilatory management of PARDS. Strong agreement
3.4.6 We recommend that HFPV can be considered in patients with PARDS and secretion-induced lung collapse, which cannot be resolved with routine clinical care (e.g., inhalational injuries). Weak agreement (72% agreement)
HFPV is a lung-protective modality with the distinct advantage of improved secretion clearance, especially in those patients with burn injuries (70). Extrapolating the experience in these patients, HFPV has been extended to other populations of critically ill patients, including those with acute hypoxic respiratory failure (71, 72).
3.5.1 The clinical use of liquid ventilation cannot be recommended. Strong agreement
Although partial liquid ventilation (PLV) has been deemed a promising novel strategy for patients with acute hypoxemic respiratory failure, no study has demonstrated its efficacy. A recent Cochrane Review concluded that no evidence supports the use of PLV in ARDS, and some evidence suggests an increased risk of adverse events associated with its use (73).
3.6.1 Cuffed ETTs are recommended when conventionally ventilating a patient with PARDS. Strong agreement
3.6.2 We recommend allowing for an ETT air leak during HFOV to augment ventilation, if needed, assuming mean airway pressure can be maintained. Strong agreement
Although there are no large-scale clinical trials that address cuffed versus uncuffed ETTs, there is a growing body of suggestive literature that cuffed tubes are safe and may limit the need for repeat airway manipulations (74, 75). The use of cuffed ETTs may have the most benefit in those conditions with poor pulmonary compliance (i.e., those patients whose airleak may become excessive as pulmonary compliance worsens).
During HFOV, maintaining an ETT air leak may help to improve CO2 washout, according to the principle of tracheal insufflations methods, and, therefore, such an approach can be recommended. However, leaks around the tube may reduce the effective distending pressure and lung-delivered oscillation volumes (76), for which the operator may need to compensate by increasing the mean airway pressure and amplitude settings.
3.7.1 We recommend that oxygenation and ventilation goals be titrated based on the “perceived” risks of the toxicity of the ventilatory support required. Strong agreement
3.7.2 We recommend that, for mild PARDS with PEEP less than 10 cm H2O, SpO2 should generally be maintained at 92–97%. Weak agreement (92% agreement)
3.7.3 We recommend that, after optimizing PEEP, lower SpO2 levels (in the range of 88–92%) should be considered for those with PARDS with PEEP greater than or equal to 10 cm H2O. Strong agreement
3.7.4 Insufficient data exist to recommend a lower SpO2 limit. Strong agreement
3.7.5 When SpO2 is less than 92%, monitoring of central venous saturation and markers of oxygen delivery is recommended. Strong agreement
In patients with ARDS, improved oxygenation has not been correlated with improved clinical outcomes (18, 77, 78). In the landmark ARDS Network low tidal volume study, the findings of improved mortality in the low tidal volume group of 6 mL/kg was not associated with improved oxygenation (18). Indeed, this study demonstrated that maximizing oxygenation may require increased ventilatory support, which resulted in worse outcome.
The concept of accepting lower arterial oxygenation saturation is termed “permissive hypoxemia” (79, 80). Although the acceptable arterial oxygen saturation target remains controversial, ventilatory strategies should aim to provide adequate tissue and organ oxygenation, while minimizing oxygen toxicity and VILI. Because the long-term neurologic and other end-organ (e.g., renal) effects of permissive hypoxemia have not been studied, clinicians must weigh the potential benefits and risks of this approach for each individual clinical situation.
3.7.6 We recommend that permissive hypercapnia should be considered for moderate-to-severe PARDS to minimize VILI. Strong agreement
3.7.7 We recommend maintaining pH 7.15–7.30 within lung-protective strategy guidelines as previously described. There are insufficient data to recommend a lower limit for pH. Exceptions to permissive hypercapnia should include intracranial hypertension, severe pulmonary hypertension, select congenital heart disease lesions, hemodynamic instability, and significant ventricular dysfunction. Weak agreement (92% agreement)
3.7.8 Bicarbonate supplementation is not routinely recommended. Strong agreement
By reducing minute ventilation, low tidal volume ventilation physiologically leads to hypercapnia. Although the exact degree of respiratory acidosis that can be tolerated is controversial, most undesirable effects are reversible and minor when the pH is greater than approximately 7.20, although the lower limit of acceptable pH is similarly debated (81). The medical literature suggests that low tidal volume pressure-limited ventilation with permissive hypercapnia may improve outcome in patients with ARDS (82, 83) Laboratory data from an ischemia-reperfusion acute lung injury model indicate that hypercapnic acidosis is protective and that buffering of the hypercapnic acidosis attenuates its protective effects (84). Permissive hypercapnia, however, is not applicable to all patient groups. Generally, this strategy should be avoided in patients with intracranial hypertension, severe pulmonary hypertension, select congenital heart disease lesions, hemodynamic instability, and significant ventricular dysfunction.
Unfortunately, it must be recognized that clinical evidence for the various modes and ventilator strategies discussed for supporting pediatric patients with ARDS remains sparse. The lack of data is the primary reason that only weak agreement in expert opinion could be achieved for several of the recommendations included in this section. Future research will be essential to identify the optimal mode, ventilator parameters, and overall management strategy to optimally support and protect the lungs of patients with PARDS at the various points of disease evolution. Furthermore, clinically relevant outcome markers (beyond the classically used outcome measures of mortality and ventilator-free days) must be defined. These could potentially include functional short- and long-term outcome criteria, exercise capacity, and quality of life measures. Despite the multitude of pediatric patients who have been ventilated for acute lung injury, the questions related to optimal ventilator management continue to outnumber the available definitive answers.
1. Dreyfuss D, Saumon G. Ventilator-induced lung injury
: Lessons from experimental studies. Am J Respir Crit Care Med. 1998;157:294–323
2. Vignaux L, Piquilloud L, Tourneux P, et al. Neonatal and adult ICU ventilators to provide ventilation in neonates, infants, and children: A bench model study. Respir Care. 2014;59:1463–1475
3. Moraes MA, Bonatto RC, Carpi MF, et al. Comparison between intermittent mandatory ventilation and synchronized intermittent mandatory ventilation with pressure support in children. J Pediatr (Rio J). 2009;85:15–20
4. Ortiz G, Frutos-Vivar F, Ferguson ND, et al.Ventila Group. Outcomes of patients ventilated with synchronized intermittent mandatory ventilation with pressure support: A comparative propensity score study. Chest. 2010;137:1265–1277
5. Greenough A, Dimitriou G, Prendergast M, et al. Synchronized mechanical ventilation
for respiratory support in newborn infants. Cochrane Database Syst Rev. 2008;1:CD000456
6. Bordessoule A, Emeriaud G, Morneau S, et al. Neurally adjusted ventilatory assist improves patient–ventilator interaction in infants as compared with conventional ventilation. Pediatr Res. 2012;72:194–202
7. Breatnach C, Conlon NP, Stack M, et al. A prospective crossover comparison of neurally adjusted ventilatory assist and pressure-support ventilation in a pediatric and neonatal intensive care unit population. Pediatr Crit Care Med. 2010;11:7–11
8. de la Oliva P, Schuffelmann C, Gomez-Zamora A, et al. Asynchrony, neural drive, ventilatory variability and COMFORT: NAVA versus pressure support in pediatric patients. A non-randomized cross-over trial. Intensive Care Med. 2012;38:838–846
9. Vignaux L, Grazioli S, Piquilloud L, et al. Optimizing patient-ventilator synchrony during invasive ventilator assist in children and infants remains a difficult task*. Pediatr Crit Care Med. 2013;14:e316–e325
10. Vignaux L, Grazioli S, Piquilloud L, et al. Patient-ventilator asynchrony during noninvasive pressure support ventilation and neurally adjusted ventilatory assist in infants and children. Pediatr Crit Care Med. 2013;14:e357–e364
11. Terzi N, Pelieu I, Guittet L, et al. Neurally adjusted ventilatory assist in patients recovering spontaneous breathing after acute respiratory distress syndrome: Physiological evaluation. Crit Care Med. 2010;38:1830–1837
12. Piastra M, De Luca D, Costa R, et al. Neurally adjusted ventilatory assist vs pressure support ventilation in infants recovering from severe acute respiratory distress syndrome: Nested study. J Crit Care. 2014;29:312.e1–312.e5
13. Frawley PM, Habashi NM. Airway pressure release ventilation: Theory and practice. AACN Clin Issues. 2001;12:234–46; quiz 328
14. Putensen C, Zech S, Wrigge H, et al. Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury
. Am J Respir Crit Care Med. 2001;164:43–49
15. Varpula T, Jousela I, Niemi R, et al. Combined effects of prone positioning and airway pressure release ventilation on gas exchange in patients with acute lung injury
. Acta Anaesthesiol Scand. 2003;47:516–524
16. Schultz TR, Costarino AJA, Durning SM, et al. Airway pressure release ventilation in pediatrics. Pediatr Crit Care Med. 2001;2:243–246
17. Thille AW, Rodriguez P, Cabello B, et al. Patient-ventilator asynchrony during assisted mechanical ventilation
. Intensive Care Med. 2006;32:1515–1522
18. . Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury
and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301–1308
19. Brower RG, Rubenfeld GD. Lung-protective ventilation strategies in acute lung injury
. Crit Care Med. 2003;31:S312–S316
20. Burns KE, Adhikari NK, Slutsky AS, et al. Pressure and volume limited ventilation for the ventilatory management of patients with acute lung injury
: A systematic review and meta-analysis. PLoS One. 2011;6:e14623
21. Erickson S, Schibler A, Numa A, et al.Paediatric Study Group; Australian and New Zealand Intensive Care Society. Acute lung injury
in pediatric intensive care in Australia and New Zealand: A prospective, multicenter, observational study. Pediatr Crit Care Med. 2007;8:317–323
22. Khemani RG, Conti D, Alonzo TA, et al. Effect of tidal volume in children with acute hypoxemic respiratory failure. Intensive Care Med. 2009;35:1428–1437
23. Zhu YF, Xu F, Lu XL, et al.Chinese Collaborative Study Group for Pediatric Hypoxemic Respiratory Failure. Mortality and morbidity of acute hypoxemic respiratory failure and acute respiratory distress syndrome in infants and young children. Chin Med J (Engl). 2012;125:2265–2271
24. Adams JA, Zabaleta IA, Stroh D, et al. Tidal volume measurements in newborns using respiratory inductive plethysmography. Am Rev Respir Dis. 1993;148:585–588
25. Crapo RO, Morris AH, Clayton PD, et al. Lung volumes in healthy nonsmoking adults. Bull Eur Physiopathol Respir. 1982;18:419–425
26. Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981;123:659–664
27. Hjalmarson O, Sandberg K. Abnormal lung function in healthy preterm infants. Am J Respir Crit Care Med. 2002;165:83–87
28. Olden C, Symes E, Seddon P. Measuring tidal breathing parameters using a volumetric vest in neonates with and without lung disease. Pediatr Pulmonol. 2010;45:1070–1075
29. Tenney SM, Remmers JE. Comparative quantitative morphology of the mammalian lung: diffusing area. Nature. 1963;197:54–56
30. Gattinoni L, Pesenti A.. ARDS: The non-homogeneous lung; facts and hypothesis. Intensive Crit Care Digest. 1987;6:1–4
31. Gattinoni L, Pesenti A, Baglioni S, et al. Inflammatory pulmonary edema and positive end-expiratory pressure: Correlations between imaging and physiologic studies. J Thorac Imaging. 1988;3:59–64
32. Murray JF, Matthay MA, Luce JM, et al. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720–723
33. Deans KJ, Minneci PC, Suffredini AF, et al. Randomization in clinical trials of titrated therapies: Unintended consequences of using fixed treatment protocols. Crit Care Med. 2007;35:1509–1516
34. Liu Q, Li W, Zeng QS, et al. Lung stress and strain during mechanical ventilation
in animals with and without pulmonary acute respiratory distress syndrome. J Surg Res. 2013;181:300–307
35. Black K, Barnett P, Wolfe R, et al. Are methods used to estimate weight in children accurate? Emerg Med (Fremantle). 2002;14:160–165
36. Flannigan C, Bourke TW, Sproule A, et al. Are APLS formulae for estimating weight appropriate for use in children admitted to PICU? Resuscitation. 2014;85:927–931
37. Geduld H, Hodkinson PW, Wallis LA. Validation of weight estimation by age and length based methods in the Western Cape, South Africa population. Emerg Med J. 2011;28:856–860
38. Graves L, Chayen G, Peat J, et al. A comparison of actual to estimated weights in Australian children attending a tertiary children’s’ hospital, using the original and updated APLS, Luscombe and Owens, Best Guess formulae and the Broselow tape. Resuscitation. 2014;85:392–396
39. Gauld LM, Kappers J, Carlin JB, et al. Height prediction from ulna length. Dev Med Child Neurol. 2004;46:475–480
40. Soroksky A, Esquinas A. Goal-directed mechanical ventilation
: Are we aiming at the right goals? A proposal for an alternative approach aiming at optimal lung compliance, guided by esophageal pressure in acute respiratory failure. Crit Care Res Pract. 2012;2012:597932
41. Muscedere JG, Mullen JB, Gan K, et al. Tidal ventilation at low airway pressures can augment lung injury
. Am J Respir Crit Care Med. 1994;149:1327–1334
42. Neumann P, Berglund JE, Mondéjar EF, et al. Effect of different pressure levels on the dynamics of lung collapse and recruitment in oleic-acid-induced lung injury
. Am J Respir Crit Care Med. 1998;158:1636–1643
43. Brower RG, Lanken PN, MacIntyre N, et al.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;351:327–336
44. Meade MO, Cook DJ, Guyatt GH, et al.Lung Open Ventilation Study Investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury
and acute respiratory distress syndrome: A randomized controlled trial. JAMA. 2008;299:637–645
45. Mercat A, Richard JC, Vielle B, et al.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;299:646–655
46. Briel M, Meade M, Mercat A, 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;303:865–873
47. Phoenix SI, Paravastu S, Columb M, et al. Does a higher positive end expiratory pressure decrease mortality in acute respiratory distress syndrome? A systematic review and meta-analysis. Anesthesiology. 2009;110:1098–1105
48. Pelosi P, D’Onofrio D, Chiumello D, et al. Pulmonary and extrapulmonary acute respiratory distress syndrome are different. Eur Respir J Suppl. 2003;42:48s–56s
49. Grasso S, Mascia L, Del Turco M, et al. Effects of recruiting maneuvers in patients with acute respiratory distress syndrome ventilated with protective ventilatory strategy. Anesthesiology. 2002;96:795–802
50. Cruces P, Donoso A, Valenzuela J, et al. Respiratory and hemodynamic effects of a stepwise lung recruitment maneuver in pediatric ARDS: A feasibility study. Pediatr Pulmonol. 2013;48:1135–1143
51. Póvoa P, Almeida E, Fernandes A, et al. Evaluation of a recruitment maneuver with positive inspiratory pressure and high PEEP in patients with severe ARDS. Acta Anaesthesiol Scand. 2004;48:287–293
52. Badet M, Bayle F, Richard JC, et al. Comparison of optimal positive end-expiratory pressure and recruitment maneuvers during lung-protective mechanical ventilation
in patients with acute lung injury
/acute respiratory distress syndrome. Respir Care. 2009;54:847–854
53. Stahl CA, Möller K, Schumann S, et al. Dynamic versus static respiratory mechanics in acute lung injury
and acute respiratory distress syndrome. Crit Care Med. 2006;34:2090–2098
54. Halbertsma FJ, van der Hoeven JG. Lung recruitment during mechanical positive pressure ventilation in the PICU: What can be learned from the literature? Anaesthesia. 2005;60:779–790
55. Arnold JH, Truog RD, Thompson JE, et al. High-frequency oscillatory ventilation in pediatric respiratory failure. Crit Care Med. 1993;21:272–278
56. Rosenberg RB, Broner CW, Peters KJ, et al. High-frequency ventilation for acute pediatric respiratory failure. Chest. 1993;104:1216–1221
57. Arnold JH, Hanson JH, Toro-Figuero LO, et al. Prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation
in pediatric respiratory failure. Crit Care Med. 1994;22:1530–1539
58. Bollen CW, van Well GT, Sherry T, et al. High frequency oscillatory ventilation compared with conventional mechanical ventilation
in adult respiratory distress syndrome: A randomized controlled trial [ISRCTN24242669]. Crit Care. 2005;9:R430–R439
59. Sud S, Sud M, Friedrich JO, et al. High frequency oscillation in patients with acute lung injury
and acute respiratory distress syndrome (ARDS): Systematic review and meta-analysis. BMJ. 2010;340:c2327
60. Young D, Lamb SE, Shah S, et al.OSCAR Study Group. High-frequency oscillation for acute respiratory distress syndrome. N Engl J Med. 2013;368:806–813
61. Ferguson ND, Cook DJ, Guyatt GH, et al.OSCILLATE Trial Investigators; Canadian Critical Care Trials Group. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013;368:795–805
62. Malhotra A, Drazen JM. High-frequency oscillatory ventilation on shaky ground. N Engl J Med. 2013;368:863–865
63. Gupta P, Green JW, Tang X, et al. Comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation
in pediatric respiratory failure. JAMA Pediatr. 2014;168:243–249
64. Rimensberger PC, Bachman TE. It is too early to declare early or late rescue high-frequency oscillatory ventilation dead. JAMA Pediatr. 2014;168:862–863
65. Cools F, Henderson-Smart DJ, Offringa M, et al. Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants. Cochrane Database Syst Rev. 2009;3:CD000104
66. De Jaegere A, van Veenendaal MB, Michiels A, et al. Lung recruitment using oxygenation during open lung high-frequency ventilation in preterm infants. Am J Respir Crit Care Med. 2006;174:639–645
67. Salvo V, Zimmermann LJ, Gavilanes AW, et al. First intention high-frequency oscillatory and conventional mechanical ventilation
in premature infants without antenatal glucocorticoid prophylaxis. Pediatr Crit Care Med. 2012;13:72–79
68. Carlon GC, Howland WS, Ray C, et al. High-frequency jet ventilation. A prospective randomized evaluation. Chest. 1983;84:551–559
69. Smith DW, Frankel LR, Derish MT, et al. High-frequency jet ventilation in children with the adult respiratory distress syndrome complicated by pulmonary barotrauma. Pediatr Pulmonol. 1993;15:279–286
70. Chung KK, Wolf SE, Renz EM, et al. High-frequency percussive ventilation and low tidal volume ventilation in burns: A randomized controlled trial. Crit Care Med. 2010;38:1970–1977
71. Eastman A, Holland D, Higgins J, et al. High-frequency percussive ventilation improves oxygenation in trauma patients with acute respiratory distress syndrome: A retrospective review. Am J Surg. 2006;192:191–195
72. Lucangelo U, Zin WA, Fontanesi L, et al. Early short-term application of high-frequency percussive ventilation improves gas exchange in hypoxemic patients. Respiration. 2012;84:369–376
73. Galvin IM, Steel A, Pinto R, et al. Partial liquid ventilation for preventing death and morbidity in adults with acute lung injury
and acute respiratory distress syndrome. Cochrane Database Syst Rev. 2013;7:CD003707
74. Newth CJ, Rachman B, Patel N, et al. The use of cuffed versus uncuffed endotracheal tubes in pediatric intensive care. J Pediatr. 2004;144:333–337
75. Weiss M, Dullenkopf A, Fischer JE, et al.European Paediatric Endotracheal Intubation Study Group. Prospective randomized controlled multi-centre trial of cuffed or uncuffed endotracheal tubes in small children. Br J Anaesth. 2009;103:867–873
76. Singh R, Courtney SE, Weisner MD, et al. Respiratory mechanics during high-frequency oscillatory ventilation: A physical model and preterm infant study. J Appl Physiol (1985). 2012;112:1105–1113
77. Dobyns EL, Anas NG, Fortenberry JD, et al. Interactive effects of high-frequency oscillatory ventilation and inhaled nitric oxide in acute hypoxemic respiratory failure in pediatrics. Crit Care Med. 2002;30:2425–2429
78. Curley MA, Hibberd PL, Fineman LD, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury
: A randomized controlled trial. JAMA. 2005;294:229–237
79. Abdelsalam M, Cheifetz IM. Goal-directed therapy for severely hypoxic patients with acute respiratory distress syndrome: Permissive hypoxemia. Respir Care. 2010;55:1483–1490
80. Randolph AG. Management of acute lung injury
and acute respiratory distress syndrome in children. Crit Care Med. 2009;37:2448–2454
81. Feihl F, Perret C. Permissive hypercapnia. How permissive should we be? Am J Respir Crit Care Med. 1994;150:1722–1737
82. Hickling KG, Walsh J, Henderson S, et al. Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: A prospective study. Crit Care Med. 1994;22:1568–1578
83. Milberg JA, Davis DR, Steinberg KP, et al. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA. 1995;273:306–309
84. Laffey JG, Engelberts D, Kavanagh BP. Buffering hypercapnic acidosis worsens acute lung injury
. Am J Respir Crit Care Med. 2000;161:141–146
APPENDIX 1. Pediatric Acute Lung Injury Consensus Conference Group
Organizing Committee: Philippe Jouvet, University of Montreal, Canada; Neal J. Thomas, Pennsylvania State University; and Douglas F. Willson, Medical College of Virginia.
Section 1, Definition, incidence, and epidemiology: Simon Erickson, Princess Margaret Hospital for Children, Australia; Robinder Khemani, University of Southern California; Lincoln Smith, University of Washington; and Jerry Zimmerman, University of Washington.
Section 2, Pathophysiology, comorbidities, and severity: Mary Dahmer, University of Michigan; Heidi Flori, Children’s Hospital & Research Center Oakland; Michael Quasney, University of Michigan; and Anil Sapru, University of California San Francisco.
Section 3, Ventilatory support: Ira M. Cheifetz, Duke University; and Peter C. Rimensberger, University Hospital of Geneva, Switzerland.
Section 4, Pulmonary-specific ancillary treatment: Martin Kneyber, University Medical Center Groningen, The Netherlands; and Robert F. Tamburro, Pennsylvania State University.
Section 5, Nonpulmonary treatment: Martha A. Q. Curley, University of Pennsylvania; Vinay Nadkarni, University of Pennsylvania; and Stacey Valentine, Harvard University.
Section 6, Monitoring: Guillaume Emeriaud, University of Montreal, Canada; and Christopher Newth, University of Southern California.
Section 7, Noninvasive support and ventilation: Christopher L. Carroll, University of Connecticut; and Sandrine Essouri, Université Pierre et Marie Curie, France.
Section 8, Extracorporeal support: Heidi Dalton, University of Arizona; and Duncan Macrae, Royal Brompton Hospital, United Kingdom.
Section 9, Morbidity and long-term outcomes: Yolanda Lopez, Cruces University Hospital, Spain; Michael Quasney, University of Michigan; Miriam Santschi, Université de Sherbrooke, Canada; and R. Scott Watson, University of Pittsburgh.
Literature Search Methodology: Melania Bembea, Johns Hopkins University.