Pediatric Acute Respiratory Distress Syndrome Treatment & Management
- Author: Prashant Purohit, MD; Chief Editor: Timothy E Corden, MD more...
The cornerstone of management is impeccable intensive care. Careful utilization of mechanical ventilation while minimizing the risk of ventilator-induced lung injury (VILI) and multiple organ dysfunction syndrome (MODS) is essential. Critical aspects are maintaining nutrition, meticulous management of fluid and hemodynamics, appropriate levels of sedation and judicious consideration of neuromuscular blocking agents. Early anticipatory management may avoid late complications including sepsis and poor outcome. Treat the primary cause (eg, sepsis, pneumonia), whenever possible.
Many of the therapies and strategies proposed for ARDS are founded on rational physiologic and pathologic principles, but they have not been shown to have unequivocal benefits. Reasons include an incomplete understanding of the pathophysiology of ARDS, the lack of a standardized diagnostic test, and the heterogeneity of the illness and the patient population. Research is evolving in this area.
Although they have shown promise in animal and small-scale human studies, many pharmaceutical agents have not demonstrated an unequivocal benefit in large trials. These agents include systemic pulmonary vasodilators, pentoxifylline, various antioxidants, ketoconazole, anticytokines, and antiproteases. Their use is not discussed further.
It is important that patients get appropriate level of care from the beginning while the ARDS is still under evolution, especially those who qualify for at risk of PARDS. When patients present in the ED with increased work of breathing secondary to worsening lung compliance, increasing mean airway pressure and instituting other alveoli-recruiting maneuvers may offer the most benefit in addition to administering supplemental oxygen. This can be achieved either invasively (ie, with tracheal intubation and mechanical ventilation) or noninvasively.
If the patient continues to have good respiratory effort and adequate oxygenation, noninvasive positive airway pressure support may be all that is required in the ED setting.
If intrahospital transfer from the ED to the pediatric intensive care unit (PICU) is indicated, the patient must be accompanied by providers who are competent to secure and manage the airway. This team often includes a physician, a nurse, and a respiratory therapist.
Interhospital transfer may be indicated. Transfer to a center skilled in pediatric intensive care should be mandatory for any patient at risk of developing ARDS or any patient with full-blown ARDS. Ideally, a dedicated team with expertise in the transport of critically ill children should perform the transfer via ground, rotor, or fixed wing transport. In critically ill children, transporting them to a facility that offers pediatric extracorporeal membrane oxygenation (ECMO) capabilities is preferable.
Ventilation is the cornerstone of treating the patient with ARDS. Striking a balance between the levels of ventilator support while minimizing VILI is essential.
Noninvasive ventilation has been used early in ALI and ARDS in adult population.[50, 51] Continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) therapies via nasal mask or face mask have been successful in maintaining adequate oxygenation and ventilation in some patients who present with impending acute respiratory failure and who otherwise would require tracheal intubation. Lack of improvement of P/F ratio in first few hours or on first day can be a good indicator for failure of NPPV.[52, 53] The benefits of NPPV include improvement of oxygenation and work of breathing without the expense of invasive mechanical ventilation, none or minimal sedation, and patients are able to regulate their own minute ventilation. Pediatric experience in use of NPPV for ARDS or acute hypoxemic respiratory failure is growing as well. Immunocompromised individuals would be at more advantage from the avoidance of invasive mechanical ventilation. Panel of experts had a week agreement on recommendations for use of NPPV in early PARDS cases (88% agreement) and for immunocompromised children with PARDS (80% agreement). [2, 54, 55, 56, 57, 58]
More recently use of high-flow nasal cannula system including Vapotherm (Vapotherm; Stevensville, MD) is becoming popular mode. The literature is minimal for its use in ARDS.
Conventional Mechanical Ventilation
In the event that a patient requires intubation for ARDS, it may be prudent to use a cuffed endotracheal tube regardless of the age of the patient. Historically, children younger than 8 years used to be intubated with uncuffed tubes. However, because of worsen lung compliance in ARDS; cuffed tubes are often required to effectively inflate the lungs. Otherwise, excessive air may leak around the endotracheal tube resulting in inadequate oxygenation and ventilation.
It is difficult to attain gas exchange in the collapsed and fluid-filled alveoli. A nearly linear increase in functional residual capacity (FRC) develops as positive end-expiratory pressure (PEEP) is increased over a range from 0-15 mm Hg with recruitment of terminal airways and alveoli and improved oxygenation. Meticulous use of alveolar recruitment maneuver with incremental and decremental PEEP to achieve adequate oxygenation has been recommended as well. PEEP more than 15 might be required in severe ARDS cases. Close monitoring of plateau pressure and hemodynamics are imperative while using high PEEP. Lower levels of oxygen saturations in the range of 88-92% are acceptable after PEEP is as high as 10. Mercat et al reported that a strategy of using PEEP to maximize alveolar recruitment in the adult population reduced the duration of organ failure and mechanical ventilation.
To minimize the barotrauma and volutrauma, it is recommended to limit the inspiratory plateau pressure to 28 cm H2O in most of the cases and in the range of 29-32 in patients with reduced chest wall compliance from obesity or other reasons.
Traditionally, a low tidal volume strategy has been emphasized. Ranieri et al provided additional information to suggest that low tidal volume may be beneficial, reporting reported lowered levels of cytokines in bronchoalveolar lavage (BAL) fluid and plasma in patients treated with low tidal volume. The authors postulated that decreased levels of cytokines reflect reduced inflammation in organs other than the lungs, leading to a possible survival benefit. The study by Amato et al showed improved 28 days survival and decreased incidence of barotrauma. The results were confirmed by a large multicenter study conducted by ARDS Network trial. In this NIH study, the control group was ventilated with a tidal volume of 12 mL/kg adjusted to maintain a plateau pressure of 45-50 cm water. In the study group, tidal volume was reduced to 6 mL/kg and then as low as 4 mL/kg to maintain a plateau pressure less than 30 cm water. The trial was prematurely terminated when an interim analysis showed a markedly reduced mortality rate in the group receiving low tidal volume (31% vs 39.8%, p=0.007). Since then low tidal volume has become a routine practice for ARDS patients and no further trials are required at this stage.
The twin goals of permissive hypercapnia and open lung maintenance are achieved by optimizing PEEP and minimizing delivered tidal volumes. PEEP is optimized by keeping it above the lower inflection point on a pressure-volume curve (ie, Pflex) and below the upper inflection point where overdistention occurs (see the image below). This general approach has been assessed in a number of studies.
Hickling et al gave one of the original descriptions of permissive hypercapnia, reporting a significant reduction in mortality rates, associated with ventilator strategy that will allow permissive hypercapnia. Amato et al reported that their strategy of ventilating at a low tidal volume with an elevated carbon dioxide level and preventing alveolar closure by optimizing PEEP was associated with lower mortality rate (38% versus 71%). Most recent recommendations were to maintain pH between 7.15 – 7.30 to maintain lung protective strategy with permissive hypercapnia. It will not be recommended in cases with intracranial hypertension, pulmonary hypertension, hemodynamic instability and significant ventricular dysfunction. Although there was a weak agreement (92%) for the recommendation regarding permissive hypercapnia. 
Numerous ventilator modes are available; however, there are few if any data to indicate that any of these modes is superior to any other.
Another technique that has been studied is high-frequency ventilation (HFV). Two modes of HFV are high-frequency oscillatory ventilation (HFOV) and high-frequency jet ventilation (HFJV). HFJV is rarely used in pediatric practice and therefore will not be discussed further.
High Frequency Oscillatory Ventilation (HFOV)
HFOV may be thought of as the ultimate in high-PEEP low-tidal-volume strategy. Because of the extremely small tidal volumes used, HFOV minimizes repetitive opening and closing and possibly reduces VILI, if the lung is sufficiently recruited. Because of the extremely high respiratory rates, carbon dioxide can be maintained at satisfactory levels. Recruiting (or opening) the atelectatic areas of the lung is critical to maintaining lung volume at the FRC. Optimal lung volume is gauged with clinical assessment, monitoring of arterial oxygen saturation, ABG measurements, and lung inflation on chest radiography.
Historically use of HFOV has been reported to have association with some form of adversity. The first ever HFOV trial was in animals by Lunkenheimer in Germany. It was designed to for the purpose of ventilation during thoracic surgery and bronchoscopy avoiding lung excursions. However, it was not pursued further because it was associated with decreased cardiac output from high mean airway pressures. Later on, HFOV became popular among neonatologists and a large multicenter trial was conducted in USA. The “HIFI study” showed that HFOV did not offer any advantages over CMV and was associated with increased incidences of air leak and grade 3 and 4 intraventricular hemorrhages. A recent large multicenter trial was conducted in five countries among the adult population by the OSCILLATE Trial Investigators showed that the early application of HFOV as compared with low tidal volume high PEEP strategy did not reduce, but might increase mortality. In fact, the study was stopped after 548 of planned 1200 patients based on the recommendations of data monitoring committee. Another multicenter trial by the OSCAR study group showed no difference in 30 days mortality. There was one pediatric multicenter, prospective, randomized control trial which showed improved oxygenation (A-a gradient and OI) but did not show any reduction in 30 days mortality or days on mechanical ventilation. Of note this study was cross over study and was not powered to evaluate mortality. In a recent study, application of both the HFOV and early HFOV had poor outcomes as compared to the CMV group.
However, it still remains a question if HFOV helps in “rescue” situations where patients are severely ill and have failed conventional ventilation treatment. Other therapeutic modalities for the rescue of ARDS patients, such as ECMO, have their own potential harms. Benefits of inhaled nitric oxide in ARDS is limited to improved oxygenation only and has not shown improvement in mortality. While the other modalities of mechanical ventilation like APRV (airway pressure release ventilation) or VDR (volumetric diffusive respiration) have not undergone enough trials to prove their benefits or harms, current options are limited.
After above mentioned rigorous discussion, it is apparent that the potential harms associated with HFOV may not be trivial. Choosing HFOV as a ventilator strategy should be individualized and carefully evaluated for every patient until further larger studies are available to provide definite evidence in favor or against the use of HFOV. Current recommendations are to consider it for moderate to severe ARDS cases with plateau pressure higher than 28. Although there was a weak agreement (92%). 
Airway pressure–release ventilation (APRV) is a relatively new mode of ventilation that allows spontaneous ventilation with mean airway pressures similar to that achieved with HFOV. Case studies report the successful use of APRV in ARDS; however, data are insufficient to compare it with conventional ventilation or HFOV.
As an adjunct to ventilator management, prone positioning has been advanced as a means of improving oxygenation in adults and children with severe ARDS. It is thought that turning patients prone helps optimize ventilation/perfusion (V/Q) matching by reducing atelectasis in dependent areas of the lung.
Many trials have shown improved oxygenation with prone positioning; however, a multicenter trial of 102 patients demonstrated no significant difference in clinical outcomes, including ventilator-free days. The study population had a mortality rate of only 8%, suggesting that prone positioning may still have a role in extremely ill patients with ARDS. Prone positioning is not recommended as routine therapy for ARDS until further pediatric studies in this context. Although there was weak agreement on this recommendation (92%). It can still be attempted in a patient with profound hypoxemia. But the decision should be determined by the treating physician based on patient’s condition and risk versus benefit ratio.
Use of neuromuscular blocking agents
Use of the neuromuscular blocking agent cisatracurium over the initial 48 hours of treatment for adults with severe ARDS—that is, arterial oxygen tension (PaO2)/FiO2 ratio < 150—appears to increase ventilator-free days, reduce barotrauma, and possibly improve survival without increasing the occurrence of muscle weakness in this patient population. Care should be used in extrapolating those results to the pediatric population, given the differences in ARDS mortality rates and the varying causes of ARDS mortality. Current recommendations are in favor of neuromuscular blockade (NMB), if sedation alone is inadequate to achieve effective mechanical ventilation. There was a strong agreement for this recommendation by the panel of experts.
Go to Barotrauma and Mechanical Ventilation for complete information on this topic.
One of the key events in the progression of ARDS is a reduction in both volume and function of surfactant. In addition, surfactant inhibitors may be present in the alveolus. Based on positive results of many clinical trials of infant respiratory distress syndrome (IRDS), numerous studies have been conducted to examine the role of exogenous surfactant in the treatment of ARDS.
Administration of exogenous surfactant has many theoretical benefits, as demonstrated in vitro. These include the prevention of alveolar collapse, maintenance of pulmonary compliance, optimization of oxygenation, enhancement of ciliary function, enhancement of bacterial killing, and downregulation of the inflammatory response.
Studies of various surfactants and different modes of delivery in adults have not yielded a consensus regarding the efficacy of surfactant in ARDS. In vitro data and extrapolated data from neonatal in vivo studies suggest that animal-derived surfactant may be superior to synthetic surfactant. In addition, inhalation may be inefficient as a means of delivery.
A growing body of literature supports the use of surfactant for severe pediatric ARDS. A retrospective chart review of 19 patients showed improvement in oxygenation index and hypoxemia score but no change in other outcome measures. Prospective studies from the late 1990s to early 2000 involving porcine or bovine surfactant showed variable outcomes, ranging from improvement in only oxygenation to shortened ventilation and PICU stay.[76, 77, 78, 79]
A randomized, controlled multicenter study by Willson et al using a natural exogenous surfactant (calfactant) demonstrated a significant reduction in mortality, with an absolute risk reduction of 17%. This reduction was most pronounced in patients younger than 12 months, who had a corresponding absolute risk reduction of 33%.
Significant improvement was also demonstrated in the oxygenation index, in ventilator-free days, and in rates of failure with conventional mechanical ventilation. One confounding factor was that the placebo group had more immunocompromised patients than the treatment group.
Data from a cost-effectiveness study suggested that the use of exogenous surfactant may be cost-effective in an American healthcare setting. The expense of the surfactant was offset by early PICU discharge. Mortality benefits and ventilator-free days were not factored into the model.
According to most recent recommendations from Pediatric Acute Lung Injury group, use of exogenous surfactant is not recommended in PARDS until further studies.
Nitric Oxide Therapy
Nitric oxide (NO) is a potent vasodilator, first described in 1989. Its use in neonatal persistent pulmonary hypertension was described over 2 decades ago. The action of vasodilatation is mediated via cyclic GMP pathway. Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator, as it rapidly binds to hemoglobin and is inactivated before reaching the systemic circulation. It may have numerous attractive properties in patients with ARDS. Mainly, it reduces hypoxic pulmonary vasoconstriction (HPV). Inhaled NO diffuses to only relatively well-aerated parts of the lung lessen any local HPV. This helps in improvement of ventilation-perfusion mismatch and so oxygenation. By reducing hypoxic pulmonary vasoconstriction (HPV), iNO may reduce right-sided pulmonary pressures. This, in turn, lessens the degree of leftward septal shift, which improves cardiac output. Other benefits may include decreased pulmonary edema while pulmonary pressures are reduced.
Initial studies showed improvement in OI and improvement in outcome with use of iNO in pediatric patient with acute hypoxemic respiratory failure (AHRF). This was a small study.
A systematic review and meta-analysis of 12 different trials showed that although NO temporarily improves oxygenation, it does not improve survival and actually it may cause harm in both children and adults. A recent study that looked to test the hypothesis that inhaled nitric oxide (iNO) would lead to improved oxygenation and a decrease in duration of mechanical ventilation in pediatric patients with acute respiratory distress syndrome reported that the use of iNO was associated with a significantly reduced duration of mechanical ventilation and significantly greater rate of extracorporeal membrane oxygenation-free survival.
A multicenter study of the use of iNO (10-ppm dose) in children with acute hypoxic respiratory failure was reported. Although oxygenation acutely improved at 4 hrs and 12 hrs in the group treated with iNO, there was no difference at 72 hrs and there was no survival benefit. Data from a post-hoc analysis suggested that patients with severe respiratory failure (oxygenation index >25) or immunocompromise may have benefited from the use of iNO.
Although many studies demonstrated improvement in surrogate measures (eg, oxygenation, degree of ventilator support), no differences are noted in primary outcome measures (eg, mortality, ventilator-free days, time to extubation). Reasons for this lack of clinical benefit are unclear. One possible explanation is that ARDS tends to be a heterogeneous lung disease, in contrast to persistent pulmonary hypertension of the newborn. Alternatively, the fact that most patients with ARDS die from sepsis, MODS, or their primary illness may imply that no survival benefit is observed with improved oxygenation and decreased ventilator support.
According to most recent recommendation from Pediatric Acute Lung Injury Consensus Conference Group, the routine use of inhaled nitric oxide is not recommended. It may be considered in patients with pulmonary hypertension or right ventricular dysfunction. It may also be considered in severe form and in cases for bridge to extra corporeal life support.
Perfluorocarbons (PFCs) have numerous attractive properties that facilitate their use in liquid ventilation. Because PFCs are chemically and biologically inert, with a high vapor pressure that ensures rapid evaporation when exposed to the atmosphere, both oxygen and carbon dioxide dissolve easily in PFC liquid.
Perceived advantages of PFCs in the treatment of ARDS include the ability to maintain an open lung and to minimize repetitive opening and closing of the alveoli. This ability has given rise to the terms “liquid PEEP” and “PEEP in a bottle.” In addition, a lavage effect may clear the alveoli and small airways of debris and inflammatory mediators, reducing ongoing inflammation. PFCs are also thought to have intrinsic anti-inflammatory actions.
By flowing preferentially to dependent areas of the lung where alveolar collapse is maximal, intra-alveolar pressure is increased; hence, perfusion to these areas is decreased, which may improve V/Q matching.
Two types of liquid ventilation have been described: partial liquid ventilation (PLV), in which a volume of liquid equal to the FRC is instilled, and total liquid ventilation (TLV). In contrast to PLV, TLV requires that the lung be filled completely with PFC and that the patient be ventilated with a specially designed liquid ventilator. For logistical reasons and because no data suggest that TLV is superior to PLV, PLV has been used more widely than TLV.
Little convincing data are available to assess the use of PFC liquid ventilation in ARDS. Investigators from 2 uncontrolled trials (1 in adults and 1 in pediatric patients) described its use in conjunction with extracorporeal life support (ECLS).[87, 88] However, according to review by Cochrane database, there were no benefits from PLV and there were increased risk of adversity from PLV. According to most recent recommendation from Pediatric Acute Lung Injury Consensus Conference Group, the routine use of liquid ventilation (partial or total) is not recommended.
Extracorporeal Life Support
ECLS has been used since the 1970s to improve oxygenation, ventilation, or both in critically ill patients with severe ARDS. A number of modalities have been reported, including ECMO, which may consist of an arterial and venous cannula (AV-ECMO) or 2 venous cannulae (VV-ECMO), and extracorporeal carbon dioxide removal (ECCO2 R), which has been used most commonly in Europe.
Extracorporeal membrane oxygenation
A large randomized study of the efficacy of ECMO in adults with severe ARDS was published in 1979. The study demonstrated improvement in gas exchange but no improvement in mortality.
A report from single university center had a total of 2000 patients from 1973 to 2010. This included neonate, children and adults with various indications for ECMO. In children with respiratory failure, they reported discharge in 76% of patients. They suggested that ECMO may be of benefit in children with severe acute respiratory failure unresponsive to maximal conventional therapy.
In a multicenter retrospective cohort trial of 331 children across 32 hospitals reported data that ECMO was associated with improved survival. This study had a number of limitations. It was not a controlled trial. Secondly, it was not sufficiently powered.
Numerous studies from the United Kingdom showed that the use of ECMO in neonates with respiratory failure was associated with improved outcomes.[93, 94, 95]
With pediatric ECMO, the survival rate is approximately 50%. This is markedly less than the reported survival rate of 80% in neonates treated with ECMO. The reasons for this disparity may include the heterogeneity of illness leading to respiratory failure in the pediatric population, the relatively limited experience with pediatric versus neonatal ECMO, or a reluctance to commence ECMO that leads to delays that further exacerbate lung damage.
At present, the question of who should receive ECMO has no certain answer. Candidates should have severe lung disease that progresses despite maximal conventional medical therapy. The disease process leading to respiratory failure should have a reasonable potential for reversibility and recovery. Objective indicators include alveolar-arterial (A-a) gradients of more than 450 mm Hg and ventilator peak pressures of more than 40 cm water.
Exclusion criteria include cerebral hemorrhage, preexisting chronic lung disease, congenital or acquired immunodeficiency, congenital anomalies, or other organ failure associated with poor outcomes. Ventilation for more than 10 days before ECMO may require a meticulous evaluation for patient's candidacy for ECMO. However, there are no strict criteria at this time for patient selection.
Why ECMO may confer a survival benefit is unclear. Possibilities include the ability to rest the lung by reducing excess stretch (ie, high pressures) and reducing repetitive opening and closing (ie, high ventilator rates). Oxygen toxicity may be minimized. Fluid balance can be optimized with aggressive diuresis or with renal replacement therapy.
According to PALICC, ECMO should be considered in children with severe PARDS where rest of the other strategies discuss above failed. It is difficult to determine who would benefit from ECMO and who will not.
Extracorporeal carbon dioxide removal
The rationale of ECCO2 R is similar to that for ECMO—namely, to allow the lung to rest while carbon dioxide is removed and excessive hypercarbia is prevented. Limited data are available concerning this modality in the pediatric population.
The use of steroids is reported as a therapy for ARDS. Numerous reported trials demonstrated no benefit with large doses of steroids administered as a short course in the early phases of ARDS. However, many investigators contend that ongoing or late-stage ARDS is partly an inflammatory condition. Hence, by virtue of their anti-inflammatory properties, steroids may be beneficial when used in the fibroproliferative phase.
In a randomized double-blind placebo-controlled trial in adults with ARDS who were not improving, Meduri et al suggested late use of steroids to attenuate ARDS and improve survival. Another study of randomly assigned 180 patients, who were in to at least seventh day of ARDS, showed no improvement in survival at 60 days. Additionally, the patients who received steroid on or after 14th day of illness demonstrated increased risk of death. Moreover, the incidence of neuromuscular weakness was higher in the steroid group. In a meta-analysis of five cohort studies and four randomized controlled trial, use of low dose steroid was associated with improved survival and morbidity. No adverse effects were seen with use of steroid. Children meeting criteria for ARDS (both Berlin 2012 and AECC 1994 acute lung injury) and pediatric ARDS (PARDS, as defined by PALICC 2015) were enrolled for an observational, single-center prospective trial. This study showed increased duration of ventilator with steroid use.
Studies conducted thus far have shown variable results. The use of steroid in pediatric ARDS is not recommended per PALICC.
To the authors’ knowledge, no study has been performed to examine the potential role of inhaled steroids in ARDS.
Diet and Activity
The thinking regarding the role of nutrition in patients with ARDS has undergone a paradigm shift. As attention was being given to the role of adequate nutrition in the critically ill patient, bacterial overgrowth in the gastrointestinal (GI) tract resulting from antibiotic use and the late introduction of feeding was postulated to contribute to bacterial translocation across the bowel wall. Hence, the standard practice of introducing early enteral feeding when possible has expanded.
In situations of feeding intolerance, efforts to optimize enteral nutrition include the placing of a transpyloric tube (duodenal or jejunal), administering continuous drip feeds, and administering promotility agents (metoclopramide or erythromycin).
In some patients with limited pulmonary reserve, high-energy loads may lead to respiratory failure because of marked carbon dioxide production.
Intravenous fat emulsions have been associated with worsening pulmonary mechanics in some patients with ARDS. At present, the published evidence is inconclusive, being limited to animal data and findings in small case series. Caution should be exercised if parenteral nutrition is required during the early stages of ARDS.
In general, the patient’s activity depends on the severity of the precipitating illness (eg, trauma, sepsis) and ARDS limits. If the patient recovers, no limitation on activity is usually necessary, except in the few patients with evidence of extensive pulmonary scarring or fibrosis.
Few cases of ARDS can be anticipated before presentation; however, all children with chronic lung disease should receive influenza and pneumococcal vaccines. Administer respiratory syncytial virus (RSV)–specific vaccines as indicated.
ARDS secondary to aspiration may be prevented by the use of appropriate intubation techniques (eg, rapid-sequence intubation). Although no evidence is definitive, early intervention with noninvasive ventilation in patients with respiratory failure may reduce the risk of progression of ARDS.
Consultations and Long-Term Monitoring
Consult a pediatric intensivist. Consider also consulting a critical care specialist, an infectious diseases specialist, an otolaryngologist, or a pulmonologist as necessary.
Periodic outpatient follow-up may be necessary for those with severe residual lung damage to assess the need for oxygen supplementation and to monitor for the development of restrictive lung disease. The most common complaint after intensive-care hospitalization for ARDS is muscular weakness, which may persist for weeks after discharge.
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