Acute Respiratory Distress Syndrome (ARDS) continues to contribute significantly to the disease burden in today’s arena of pediatric critical care medicine. It is an acute, diffuse, inflammatory lung injury caused by diverse pulmonary and non-pulmonary etiologies. Pathophysiology is characterized by increased vascular permeability, increased lung weight and loss of aerated tissue within the 7 days of insult. Hypoxemia, bilateral opacities on the chest x-ray, decreased lung compliance and increased physiological dead space are telltale clinical signs. Diffuse alveolar damage characterized by edema, inflammation, hyaline membrane formation or pulmonary hemorrhage are the pathological hallmark.[1]
Here are the most recent practice essentials from critical care stand point. The Berlin definition eliminated the taxonomy of Acute Lung Injury (ALI) and classified ARDS in to mild, moderate and severe categories based on severity of oxygenation compromise. Minimum PEEP requirement was included for the assessment of oxygen requirement. It also eliminated necessity of pulmonary artery wedge pressure criteria for pulmonary edema. They instead suggested utilization of clinical criteria, in case of presence of risk factors of ARDS. They recommended echocardiogram and the other objective assessment, if the risk factors for ARDS are not present.[1]
A panel of 27 pediatric experts, the Pediatric Acute Lung Injury Consensus Conference (PALICC) Group, subsequently developed nomenclature pertinent for pediatric patients. They included oxygenation index (OI), oxygen saturation index (OSI) and the pulse oximetric saturation to fraction of inspired oxygen ratio - S/F (SPO2/FiO2). The committee recommended utilization of low tidal volume (5-8 mL/kg of predicted body weight), positive end expiratory pressure (PEEP) in the range of 0-15 cm H2O, limiting plateau pressure to 28-32 cm H2O, permissive hypercapnia strategy and acceptance of low SPO2 in the range of 88-92% if PEEP is as high as 10 cm H2O. Routine use of steroids, prone positioning, surfactant and liquid ventilation is not recommended. Utilization of High Frequency Oscillatory Ventilation (HFOV) can be considered in cases with plateau airway pressure higher than 28. Although PALICC had a weak agreement on this recommendation. Meticulous consideration of inhaled nitric oxide therapy in severe ARDS cases and in cases bridging to extra corporeal life support (ECLS).[2]
The discussion of ARDS is incomplete without appreciating historic work by Ashbaugh and colleagues, who were first to describe the concept of ARDS in 1967. They presented eleven adults and one pediatric patient who suffered from acute onset of tachypnea and hypoxemia refractory to supplemental oxygen. The authors also discussed the benefits of positive end expiratory pressure (PEEP) for the management of atelectasis and a plausible role of corticosteroids in certain cases. The loss of lung compliance was noted clinically and pulmonary inflammation, edema and hyaline membrane formation were seen on autopsy.These observations were significant and remain indispensable even after 48 years.[3]
ARDS was referred as Adult Respiratory Distress Syndrome in some of the studies.[4] But now it is consistently known as acute respiratory distress syndrome (ARDS), because it is a well-known entity in pediatric population since the first description in 1967.[3] In the last 5 decades, our knowledge and experience has grown substantially and the definition continues to evolve. The American-European Consensus Conference (AECC) definition of ARDS was published in 1994[5, 6] and had certain limitations which were addressed seventeen years later by Berlin definition in 2012.[1] The Pediatric Acute Lung Injury Consensus Conference Group made recommendations relevant to the pediatric population afterwards.[2]
See the image below.
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Chest radiograph in 3-year-old girl who developed acute respiratory distress syndrome due to overwhelming gram-negative sepsis. Salient features inclu....
See Acute Respiratory Distress Syndrome: A Complex Clinical Condition, a Critical Images slideshow, for more information on this life-threatening condition characterized by acute respiratory failure, hypoxemia, and pulmonary edema.
Definition
Berlin definition requires all of the following criteria to diagnose ARDS.[1]
Onset: within one week of known insult or new/worsening respiratory symptoms
Chest imaging (a radiograph or a computed tomogram) showing bilateral opacities consistent with pulmonary edema. This must not be fully explainable by effusion, collapse or nodules.
Origin of edema: patient can be diagnosed with ARDS provided respiratory failure cannot be fully explained by cardiac failure or fluid overload as determined by treating physician based on available clinical information. If the risk factors for ARDS are not present, objective evidence (e.g. echocardiography) would be required to exclude cardiac failure or fluid overload.
Oxygenation impairment: presence of hypoxemia is essential to the diagnosis of ARDS. The subgroup stratification of ARDS is determined by the degree of hypoxemia as below.
Mild: PaO2/FiO2 ratio > 200 to < 300 mm Hg with PEEP or CPAP > 5 cm H2O (could be derived from noninvasive ventilation in mild ARDS)
Moderate: PaO2/FiO2 ratio > 100 to < 200 mm Hg, PEEP > 5 cm H2O
Severe: PaO2/FiO2 ratio < 100 mm Hg, PEEP > 5 cm H2O
This PaO2/FiO2 ratio is applicable at the altitude < 1000 m. For altitudes > 1000 m, following correction factor should be applied: PaO2/FiO2 X (barometric pressure/760)
The Berlin definition eliminated the taxonomy of Acute Lung Injury (ALI) and created three 3 exclusive subgroups of ARDS as described above. A minimum PEEP level was also added across the subgroups along with the requirement of FiO2. They also removed the requirement of Pulmonary Artery Wedge Pressure (PAWP) to exclude cardiac origin of pulmonary edema. Instead, they suggest utilization of noninvasive tests like echocardiography to exclude hydrostatic edema, if the risk factors for ARDS are not present.
Pediatric ARDS is distinct from adult ARDS in various aspects. Hence a panel of 27 experts met over the period of 2 years from March, 2012 to March 2014 to identify distinguishing features of pediatric ARDS, to define nomenclature and provide recommendation pertinent to the pediatric population with ARDS. The committee made 132 recommendations with strong agreement and 19 recommendations with weak agreement.48 The relevant recommendations are discussed throughout this article. Below are the two definitions (pediatric ARDS and at risk of pediatric ARDS) recommended by The Pediatric Acute Lung Injury Consensus Conference Group. (PALICC) [2]
Pediatric ARDS (PARDS) definition has incorporated Berlin definition criteria for onset of disease, chest imaging and origin of edema. The panel also included specific criteria for age, utilization of oxygen saturations (SPO2), OI (oxygenation index) and OSI (oxygen saturation index) as mentioned below. The purpose of utilizing SPO2 and OSI was to avoid invasive monitoring needed for obtaining PaO2.
Age: The panel recommended excluding patients with peri-natal lung diseases, otherwise no age specific criteria.
Oxygenation: Presence of hypoxemia is essential to the diagnosis of ARDS. Utilization of OI or SF ratio instead of P/F ratio was recommended.
Non-invasive mechanical ventilation, no stratification of severity
Full face mask bi-level ventilation or CPAP > 5 cm of H2O, PF ratio < 300 or SF ratio < 264
Invasive mechanical ventilation, with stratification of severity
Mild: OI 4-<8, OSI 5-<7.5; Moderate: OI 8-<16, OSI 7.5-<12.3, Severe: OI>16, OSI > 12.3
Special population (chronic lung disease, left ventricular dysfunction, cyanotic heart disease): Presence of standard criteria for age, onset, origin of edema, new infiltrates on chest imaging, and acute onset hypoxemia from baseline which meet the criteria of oxygenation as discussed above. All of these cannot be explained by underlying disease.
The panel also developed definition of “At risk of PARDS”. The definition had same criteria as PARDS for age, onset, chest imaging and origin of edema. The criteria for oxygenation were different as mentioned below.
Oxygenation:
Non-invasive mechanical ventilation
Nasal mask CPAP or BiPAP, FiO2 > 40 to maintain oxygen saturations (SPO2) 88-97%
Oxygen via mask, nasal canula or high flow: SPO2 88-97 with age specific flow; 2L/min for age < 1 year, 4L/min for age 1-5 years, 6L/min for age 5-10 years and 8L/min for age > 10 years.
Invasive mechanical ventilation
Oxygen supplementation to maintain SPO2 from > 88%, OI < 4 or OSI < 5
The equations can be derived as below.
Oxygenation Index (OI) = (FiO2 X mean airway pressure X 100)/PaO2
Oxygen Saturation Index (OSI) = FiO2 X mean airway pressure X 100 / SPO2
The PaO2/FiO2 (P/F) ratio can be calculated using PaO2 in mm of Hg and FiO2 in decimal from 0.21 to 1.0.
For example, a patient receiving mechanical ventilation with a mean airway pressure of 20 cm H2O, FiO2 of 0.6 has SPO2 of 98% and PaO2 of 85 mm Hg.
OI = (0.6 X 20 x 100)/85 = 14.11
OSI = (0.6 X 20 x 100)/98 = 12.24
P/F ratio = 85/0.6 = 141.66
This patient has moderate ARDS.
Go to Acute Respiratory Distress Syndrome and Barotrauma and Mechanical Ventilation for complete information on these topics.
ARDS follows cascade of events after direct pulmonary or systemic insult resulting into the disruption of alveolar-capillary unit. The pathophysiology of ARDS is complex and multifaceted involving 3 distinct components: (1) nature of the stimulus (2) host response to the stimulus, and (3) the role of iatrogenic factors. To understand this complex process, it is important to understand the physiology and functional anatomy.
Physiology and functional anatomy
Human lung development begins with 50 million alveoli in the neonatal lung and completes with 500 million alveoli and approximately 50 m2 of surface area in an adult lung. Substantial part of the alveolarization occurs during first 2 years of life. The normal alveolar epithelium is comprised of two distinct types of cells. Type I alveolar cells are flat, account for 90% of the alveolar surface area and are covered with a thin layer of alveolar lining fluid. They participate in the gas exchange and are exposed to very high oxygen concentration. So they are vulnerable to oxidative injury, but recent literature suggests that type I cells may have an active system against the oxidative stress. They are end cells because they are incapable of proliferation and differentiation. They actually arise from type II cells. Type II alveolar cells are cuboidal or rounded cells that account for the remaining 10% of alveolar surface area and are resistant to injury. They do not participate in the gas exchange but are involved in surfactant production, ion transport and other pulmonary defense mechanisms. [7, 8, 9, 10, 11, 12]
Alveolar epithelium and pulmonary microvascular endothelium create a two-layered alveolar-capillary barrier. This barrier serves the function of gas exchange, maintains the integrity of pulmonary morphology and protection from external injury. Disruption of this barrier results in increased permeability, influx of protein rich edema fluid into the alveolar sacs, dysfunction of surfactant production, and defective ion transport leading to impaired fluid clearance from alveolar cells. These changes are the hallmark of ARDS pathophysiology and are accompanied by dysregulated inflammation from dysfunctional leukocytes and influx of pro-inflammatory cytokines like interleukins and tumor-necrosis factor. The role of neutrophils in this mechanism is controversial. Animal models have favored both neutrophil dependent and neutrophil independent lung injury. It is also unclear if neutrophilic inflammation is the cause or the result of lung injury. Dysfunction of platelets and coagulation cascade results in microvascular thrombosis and capillary occlusion.[7, 8, 9, 10, 11, 12]
This course of ARDS pathophysiology was previously described into 3 histopathologic stages including exudative, proliferative and fibrotic phase. The timing of these stages is variable and in fact, recent evidence is suggestive of beginning of resolution and fibrotic phase early in the course of ARDS.[10]
At clinical level, respiratory distress occurs secondary to surfactant depletion, alveolar edema, cellular debris within the alveoli, and increased airway resistance. Surfactant loss leads to alveolar collapse because of increased surface tension, which is analogous to the situation observed in premature infants with infant RDS (IRDS). As alveoli collapse, closing lung volume capacity rises above the patient’s functional residual capacity (FRC), further increasing atelectasis and the work of breathing. This is reflected as reduced lung. In addition, the remaining viable lung may be conceptualized as being smaller rather than stiff. Although the total lung compliance is reduced, a small portion of the lung may be participating in the gas exchange. Those remaining intact lung regions have better compliance and are thus subject to overdistention and potential air leak complications (eg, pneumothorax) when exposed to excessive inflating pressures.
The net effect is impairment in oxygenation. A widened interstitial space between the alveolus and the vascular endothelium decreases oxygen-diffusing capacity. Hypoxia arises as a result of the change described above. Collapsed alveoli result in either low ventilation-perfusion (V/Q) units or a right-to-left pulmonary shunt. The end result is marked venous admixture, the process whereby deoxygenated blood passing through the lungs does not absorb sufficient oxygen and causes a relative desaturation of arterial blood when it mixes with blood that is already oxygenated.
Pulmonary hypertension may also ensue from ARDS. Hypoxemia, hypercarbia, and small-vessel thrombosis together can elevate pulmonary arterial pressures. Persistent pulmonary hypertension can result in increased right ventricular work, right ventricular dilatation, and, ultimately, left ventricular outflow tract obstruction secondary to intraventricular septum shifting toward the left ventricle. These changes, in turn, may decrease cardiac output and further reduce oxygen delivery to vital organs.
Iatrogenic factors may further complicate the clinical picture. Oxygen toxicity, volutrauma, barotraumas, fluid overload can further aggravate the lung injury and worsening lung compliance and oxygenation.
Resolution of ARDS is again very complex and active process. Alveolar edema resolves by active transport mechanism, where water follows sodium and chloride ions. Termination of inflammation involves anti-inflammatory mediators like IL-10, tissue growth factor (TGF) β and pre resolution mediators like polyunsaturated fatty acids including lipoxins, resolvins, and protectins. Animal models have shown the role of platelets in repair of vascular endothelium, whereas epithelial repair is carried out by alveolar progenitor cells including type II alveolar cells, Clara cells and integrin α6β4 alveolar epithelial cells.[11] If the injury is severe, disorganized and insufficient, epithelial repair may result into fibrosis and loss of lung function.
The description of ARDS pathophysiology comes from adults and mature animal studies. Future research has been encouraged in pediatric population and juvenile animals.[11]
ARDS occurs as consequences of diverse pulmonary and non-pulmonary etiologies. Most common conditions associated with ARDS are sepsis and infectious pneumonia (bacterial and viral).[8] [13, 14, 15, 16, 17] Sepsis related ARDS cases may carry poor prognosis, if they are associated with shock and thrombocytopenia. [15] Other more common etiologies include bronchiolitis, aspiration pneumonia, aspiration of gastric contents, major trauma, pulmonary contusion, burns, inhalational injury, massive transfusions or transfusion-related acute lung injury (TRALI).[8, 13, 14, 15, 16, 17] Transfusion of all type of blood products including packed red blood cells, fresh frozen plasma and platelets has been associated with development of ARDS.[18, 19] Other causes include acute pancreatitis, fat embolism, envenomation, drowning or submersion injuries, drug reaction, malignancy and lung transplantation.[8, 13, 14, 15, 16, 17] Ventilator induced lung injury (VILI) has also been documented as one of the etiologies for development of ARDS.[20] Noninfectious lung injury can occur after stem cell transplantation. However, a separate entity of idiopathic pulmonary syndrome has been described as well in this context.[21, 22, 23]
The incidence of ARDS is certainly lower in pediatric population as compared to the adults. The adult studies have reported very wide range of incidence; from 17.9-86.2 per 100,000 person-years.[24, 25, 26, 27] For the population 15 years and older, age adjusted incidence was 86.2 per 100,000 person-years, 38.5% hospital mortality; accounting for estimated 190,600 cases of acute lung injury, 74,500 deaths and 3.6 million hospital days each year in the United States.[27]
The incidence in the pediatric population is reported between 2.2 to 12.8 per 100,000 person-years. From the critical care perspective, ALI/ARDS accounts for 2.2% to 2.6% of PICU admissions, [13, 28] 8.3% of those receiving mechanical ventilation for more than 24 hours[29] and the PICU and the hospital mortality ranging between 18% to 32.8%.[13, 30, 29, 31, 28]
The age related statistics of ARDS can be obtained by comparing the results of two different studies from King County, Washington, USA that were conducted around the same time between 1999 and 2000.[27, 31]
Table.
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See Table
Incidence and severity of ARDS is somewhat similar at different geographical location. The study from Australia and New Zealand reported incidence of 2.95 per 100,000 person-years, 2.2% of PICU admissions and 30% of PICU mortality.[13] A Dutch study reported incidence of 2.2 per 100,000 person-years and 20.4% mortality.[30] Investigators in Spain found the incidence of 3.9 per 100,000 patients-years and the PICU mortality of 26%.[29] German study showed incidence of 3.2 per 100,000 person-years.[32] The incidence in the US based study was a little higher of 12.8 per 100,000 person-years, however the mortality was slightly lower 18%.[31] Chinese literature revealed 2.6% of PICU admission for ARDS with a mortality of 32.8%.[28]
Of note, the above reported epidemiological data is from the studies prior to the Berlin definition, a study which eliminated the category of ALI and classified ARDS in to mild, moderate and severe. So the epidemiology of both ALI and ARDS has been included here.
Environmental and Genetic Influence
ARDS develops after the insult from diverse etiologies discussed above. However the heterogeneity of susceptibility and the outcome is intriguing. This could partially be explained by environmental and genetic influences. However, the research is still growing in this area.
From the environmental stand point, literature from adult population has shown increased risk of ARDS with alcohol abuse[33, 34] and smoking (active and passive) after blunt trauma.[35] The association of passive smoking could be implied to the pediatric population.
From genetic stand point, a total of 34 genes have been reported to impact the ARDS susceptibility.[36] Majority of them are linked to the currently described pathophysiological pathways of ARDS. These include inflammation, epithelial cell function, endothelial cell function, coagulation, oxidative injuries, apoptosis and platelet cellular process.[36, 37, 38] [39, 40] The other reported genetic mutations associated with ARDS were linked to surfactant dysfunction[36] and to the epidermal growth factor gene polymorphism in males.[41]
There is not enough literature suggesting ethnic differences for ARDS incidence and outcomes. Vast majority of initial genetic studies were in European population. The literature is scant for the other ethnic backgrounds. Thus far approximately nine genes in African population and three genes in Asian population have been reported to be linked with ARDS.[36] Studies have reported poor outcomes in African American with ARDS as compared to the patients of the other ethnicity.[42, 43, 44] Although in one study higher mortality was associated with higher severity of illness on presentation in patients with black race. Higher mortality in Hispanic patients was not explainable by severity of illness on presentation in the same study.[43]
Some of the epidemiological studies have reported slightly higher incidence of ARDS among male children (54% to 63%)[13, 29, 31] , however the mortality (31% in male children) was not significantly different.[13] Although one adult study reported higher mortality among males.[44]
There is also not enough literature in the area of genetics pertinent to the pediatric ARDS in the context of growing lung and developing immunity.[2]
The onset of ARDS can be as rapid as few hours, but it can have a gradual onset with evolution of clinical features over 1 to 5 days. The evolution of clinical signs depends on the type, acuity, and severity of the initial insult. As lungs undergo changes during the first exudative stage of the disease, tachypnea is typically noted as the initial physical finding. Respiratory distress, agitation and hypoxemia could be other initial clinical features at this stage. Crackles may be audible throughout the lung fields, signifying pulmonary edema coinciding with infiltrates on chest radiographs. Concomitant fever may reflect the underlying process causing ARDS (eg, pneumonia, sepsis) or may reflect massive cytokine release. Although these are non-specific features and can be seen with any other respiratory or even systemic illness. Hypoxemia might be evident by high oxygen requirement, higher CPAP or PEEP and elevated alveolar-arterial (A-a) oxygen gradient. A-a gradient can be calculated from the equation as mentioned below for the sea level assuming 100% humidification at the alveolar level. Link the equation.
This is for the patient that was discussed earlier for other calculations, who was on mechanical ventilation with FiO2 0.6, PaO2 of 85, SPO2 of 98% and PCO2 of 40 mm Hg.
Reduction in lung compliance and functional residual capacity is noticed with the development of pulmonary edema. Hypoxemia results from intrapulmonary shunting and ventilation-perfusion mismatch. At this stage, utilization of high PEEP will help in oxygenation by alveolar recruitment. Certain areas of lung still would have maintained normal lung compliance and remain at risk of air leak syndromes from high PEEP. After the initiation of fibro proliferation, lung compliance is further reduced. Benefit of PEEP on oxygenation is less remarkable at this stage. In fact, difficulty in achieving adequate ventilation might be experienced at this stage with resultant hypercarbia and respiratory acidosis. The requirement of mechanical ventilation might be as long as few weeks with overall clinical recovery in months. Pediatric patients have exhibited reduced lung function, broncho reactivity, muscle wasting and weakness for a prolonged period of time after survival from ARDS.[45]
Several complications are associated with ARDS, though many of these are due to the precipitating conditions that lead to ARDS. Acute complications include air-leak syndromes, ventilator-induced lung infection (VILI), and multiple organ dysfunction syndrome (MODS), although definitive evidence linking this syndrome to ARDS or ventilator use remains controversial.
Numerous pulmonary complications may result from ARDS. The most common are the air-leak syndromes, particularly pneumothorax but also pneumomediastinum, pneumopericardium, pneumoperitoneum, and subcutaneous emphysema. Features of a pneumothorax include decreased air entry on the side of the air leak, an increased percussion note on the same side, and tracheal deviation away from the affected side in a tension pneumothorax. Heart sounds may be muffled, and signs of decreased cardiac output may be observed with a tension pneumothorax. Clinicians must also maintain a high index of suspicion for tension pneumothoraces as a cause for acute onset of decreased cardiac output.
VILI is an entity receiving attention with the publication of landmark trials suggesting that a “kinder, gentler” form of mechanical ventilation improves outcomes in ARDS. VILI most likely has several causes, including excessive lung stretching due to high tidal volumes, repetitive opening and closing of alveoli leading to shear stress, oxygen toxicity, and cytokine release.
ARDS patients may also be compromised from a cardiovascular standpoint. Patients with sepsis, trauma, or other multisystem insults may lose their ability to tolerate higher airway pressures often required to maintain adequate oxygenation. Higher airway pressures lead to a higher net intrathoracic pressure, which results in decreased preload and cardiac output. Moreover, hypoxia, hypercarbia, and acidosis may elevate pulmonary artery pressures, increasing right ventricular afterload and leading to increased right ventricular work. Right ventricular dilatation can develop and then result in leftward movement of the intraventricular septum and cause left ventricular outflow tract obstruction.
Gastrointestinal complications commonly observed in the critically ill population include stress ulcers, liver failure, pancreatitis, and pancreatic insufficiency, leading to glucose intolerance.
Renal failure may result from the primary illness or may occur secondarily as a result of poor cardiac output, acute tubular necrosis, and MODS.
Secondary or nosocomial pneumonia is not uncommon in critically ill children. In addition to Staphylococcus aureus, other organisms more typically isolated include Pseudomonas species, Acinetobacter baumannii, Stenotrophomonas maltophilia, Escherichia coli, and Candida species. Bacteremia from indwelling vascular catheters and skin ulcerations may also occur. Risk of urinary tract infection increases with prolonged indwelling Foley catheters.
Critical illness polyneuropathy and myopathy (CIPNM) is seen in a subset of patients of unclear etiology. Many factors have been identified to have an increased association with CIPNM, such as sepsis, systemic inflammatory response syndrome, MODS, and prolonged mechanical ventilation. Use of muscle relaxants, especially in conjunction with steroids, appears to have a particularly high association with CIPNM. Initial reports describe CIPNM with concomitant use of nondepolarizing muscle relaxants and corticosteroids. However, case reports of weakness with cisatracurium and corticosteroids have also been described. Clinically, patients develop profound or flaccid weakness that is often prolonged. This may complicate the mechanical ventilator weaning process and may also require inpatient rehabilitation care upon discharge from the hospital.[46, 47]
The diagnosis of ARDS is established based on the definitions described above, Berlin definition for adults and The Pediatric Acute Lung Injury Consensus Conference Group definition of PARDS for children. Chest imaging including a radiograph and/or a computed tomogram are part of both the definitions. Rest of the work up is usually geared towards identification of underlying disease, assessment of ARDS progress, prevention and treatment of co-morbidities and the other aspects of ongoing management as discussed below.
Chest radiography may be useful beyond its use as part of the diagnostic criteria, as discussed below in radiography section. Computed tomography (CT) of the chest, although not routinely performed, may be helpful in differentiating between atelectasis and consolidation. Ultrasonography is an easy method of further assessing pleural effusions and differentiating between transudative and exudative fluid. Echocardiography may help exclude cardiogenic edema and would provide information regarding cardiac contractility, intraventricular volume, pulmonary hypertension, and other potential anatomic abnormalities. There appears at present to be no particular indication for magnetic resonance imaging (MRI). Other laboratory work up including hematology and blood chemistry would help identify involvement of the other organ system and further management accordingly. Persistent regional areas of atelectasis may suggest the use of bronchoscopy including bronchoalveolar lavage (BAL) for diagnostic and therapeutic consideration. Routine use of BAL is not recommended in ARDS. Indications, risks and yield of the procedure should be determined by the treating physician. Similarly, there are no specific guidelines for other laboratory work up. Utility of the other tests should be determined by treating physician.
Go to Acute Respiratory Distress Syndrome and Barotrauma and Mechanical Ventilation for complete information on these topics.
The only role for chest ultrasonography in patients with ARDS is to define the presence of pleural effusions and to determine whether loculation of the pleural fluid is present if drainage of the effusion is being considered.
To the authors’ knowledge, no data are available concerning the role of MRI in patients with ARDS.
The primary role of echocardiography in ARDS is to detect congenital or acquired heart disease as a cause of respiratory distress and pulmonary edema. Echocardiography may provide evidence of pulmonary hypertension; however, the practical implications of this finding are unclear, because little evidence supports the clinical benefit of pulmonary vasodilators in ARDS.
Many authorities debate the use of determining pulmonary mechanics as a means of defining optimal ventilatory strategies. As of yet, no clear consensus on their use has been established.
Three classic histopathologic phases of ARDS are described. These correspond to the time course of the disease.
Typical histologic appearances of the exudative phase include diffuse hemorrhage, edema, leukocyte infiltration, and cellular necrosis or apoptosis. Evidence of the initiating illness may also be apparent, such as pneumonia or aspiration.
The main features of the proliferative phase include fibroblast proliferation, hyperplasia of type II pneumocytes, and ongoing evidence of inflammation.
The fibrotic phase is characterized by the presence of fibrosis, honeycombing, and bronchiectasis.
Suggested laboratory tests include arterial blood gas (ABG) measurements, a complete blood count (CBC) with differential, and an electrolyte panel with blood urea nitrogen (BUN) and creatinine.
Arterial blood gas measurements
Measurement of P/F ratio is an essential part of Berlin definition. However, the Pediatric Acute Lung Injury Consensus Conference group has recommended utilization of oxygen saturation and OSI. This would eliminate the burden of invasive tests in pediatric population. In case of presence of arterial catheter, the group also recommended utilizing OI ratio. All these parameters (P/F ratio, OI and OSI) will also help identify the severity of ARDS.
The onset of capillary congestion and changes in the alveolar epithelium during the initial exudative stage leads to significant ventilation/perfusion (V/Q) mismatching and intrapulmonary shunting. During this stage of ARDS, oxygen diffusion is impeded to a much greater extent than carbon dioxide diffusion. Respiratory alkalosis reflecting a relative hyperventilation and hypocarbia is an early sign of ALI/ARDS. This difference is attributable to the much greater solubility of carbon dioxide. Hypercarbia develops with worsening disease, reflecting an increasing shunt fraction and an increased dead space.
Complete blood count
The CBC may indicate an infectious etiology. Leukocytosis may be evident, reflecting either the initiating stimulus or a nonspecific inflammatory response. The CBC may also uncover significant anemia, which will further compromise oxygen-carrying capacity. Anemia may secondary to acute illness, underlying chronic disease, acute blood loss, or hemodilution from massive fluid resuscitation. Thrombocytopenia may be present.
Electrolyte panel
An electrolyte panel may also screen intravascular volume status, anion gap acidosis, and other potential comorbidities. Additional laboratory tests would be indicated pending specific concerns toward individual patients.
Chest radiography is essential for diagnosing ARDS or ALI. The radiologic findings in ARDS are nonspecific (see the images below). Radiographic findings immediately after the inciting event may be entirely normal or may show only the primary disease process. Early changes reflect increased pulmonary alveolar and endothelial permeability. Studies of pediatric and adult patients reveal low levels of interobserver agreement for radiographs obtained early in the course.
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Eight-year-old girl with diagnosis of pneumonia. Chest radiograph on day of admission.
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Eight-year-old girl with pneumonia and impending respiratory failure. Chest radiograph on day 2.
Subsequently, progressive bilateral interstitial and alveolar infiltrates develop without cardiomegaly.
As the disease progresses, the lung fields become diffusely and homogeneously opaque. However, this homogeneous appearance is misleading, as chest CT scanning demonstrates. Although the radiographic appearance may initially be indistinguishable from that observed in cardiac failure, numerous characteristic differences are present.
ARDS-related edema and edema secondary to heart failure may be difficult to distinguish on radiographs. Cardiomegaly is not a feature of ARDS; it is usually present with marked cardiac failure. Kerley B lines, which indicate interstitial edema or lymphatic swelling, are rarely observed in ARDS.
Other radiologic differential diagnoses of the infiltrates observed in ARDS include aspiration, hemorrhage, pneumonia, and atelectasis. Distinguishing these entities on the basis of chest radiographic appearances is often difficult. As opacification of the lung fields increases, air bronchograms may become apparent.
Air-leak syndromes are commonly observed on plain chest radiographs of patients with ARDS. These include pneumothorax (see the image below), pneumomediastinum, pneumopericardium, subcutaneous emphysema (see the image below), pneumoperitoneum, and pneumoretroperitoneum (free air in the retroperitoneal space).
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Subcutaneous emphysema and pneumothorax.
In intubated patients, free air rises to the high caudal areas overlying the diaphragm because of their supine position. Early and subtle signs suggestive of free air include the deep sulcus sign, which is increased radiolucency in the costophrenic angle of the affected side and increased acuteness of the costophrenic angle on the same side.
The double-diaphragm sign is also reported in association with air leaks; subpulmonic air produces the impression of a second diaphragm formed by the basal border of the lower lobe. Air below the diaphragm, which does not cross the midline, suggests pneumoretroperitoneum.
Characteristic radiologic changes of late ARDS corresponding to histopathologic changes are well described. After a variable period (ie, usually days to weeks), patchy areas of increased lucency appear. Associated with clinical resolution of illness, radiologic improvement follows slowly.
Although radiologic changes completely resolve in most children, chronic changes are apparent in a small subset. Whether the persisting changes (often ascribed to fibrosis) are the result of the primary illness or ventilator-induced lung injury (VILI) is often unclear. Iatrogenic features visible on a chest radiograph in a patient with ARDS may include an endotracheal tube (see the first image below), central venous lines, and chest tubes (see the second image below).
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Chest radiograph in 3-year-old girl who developed acute respiratory distress syndrome due to overwhelming gram-negative sepsis. Salient features inclu....
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Chest radiograph demonstrates complication of acute respiratory distress syndrome. Patient presented with respiratory failure after near-drowning epis....
Since CT scanning of the chest was first reported, its usefulness for understanding the pathophysiologic mechanisms underlying ARDS and the response of the ARDS lung to ventilator maneuvers has been described many times.
Gattinoni et al have been at the forefront of this research.[48] Before the introduction of CT imaging, clinicians assumed that ARDS was a homogeneous lung process. The use of chest CT scanning demonstrated that although pulmonary involvement in ARDS was diffuse, it also was heterogeneous. In 1994, Gattinoni et al reported that, in adults with ARDS, areas of normal lung were interspersed with poorly aerated lung parenchyma.[48]
Researchers have shown a marked spatial distribution of parenchymal collapse in the lungs of ARDS patients. In patients ventilated in a supine position, collapse was most pronounced in the more dorsal regions. A combination of edematous lung, the weight of the chest wall and mediastinal structures (specifically, the heart), and supine positioning are postulated to play a part in the development of dorsal atelectasis (see the image below). These findings provide an intellectual basis for the role of prone positioning in severe ARDS (see Treatment).
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Chest CT in 6-month-old male infant with newly diagnosed cystic fibrosis. Patient was intubated for respiratory failure and subsequently developed acu....
CT findings support the "baby lung" hypothesis. Simply stated, the lungs of patients with ARDS are functionally smaller than normal lungs. Indeed, some authors suggest that the volume reduction may be approximately 75% of total lung volume. Hence, ventilation with normal physiologic tidal volume may lead to iatrogenic lung damage. The data showing improved outcomes in patients with ARDS ventilated with small tidal volumes lend credence to this theory.
Gattinoni proposed 2 types of ARDS: ARDS due to primary pulmonary disease (eg, aspiration, pneumonia) and ARDS arising secondary to extrapulmonary disease (eg, sepsis, trauma).[48]
In support of this hypothesis, Goodman et al described CT findings in adults with ARDS due to pulmonary and extrapulmonary disease and noted marked differences between populations.[49] The group with pulmonary-related ARDS had ground-glass opacification or consolidation, which tended to be asymmetric. The group with extrapulmonary ARDS generally had symmetric ground-glass opacification.
In both groups, pleural effusions and air bronchograms were common, whereas Kerley B lines and pneumatoceles were rare. Mortality tended to increase in the group with extensive consolidation versus those with extensive ground-glass opacification; this difference was not statistically significant.
In the present clinical setting, the main use of chest CT scanning is for determining the presence of coexisting illness—specifically, thoracic abscess formation, barotrauma undefined on plain radiography, or other unsuspected pathology. CT is not routinely required for diagnosis or management of ARDS.
BAL is not required for diagnosis of ARDS. It may be useful in determining the underlying etiology in patients with primary pulmonary ARDS in whom pneumonia or an infective pneumonitis is thought to be the cause. This is especially true for immunocompromised patients. It is also used in cases of persistent regional areas of atelectasis for diagnostic and therapeutic consideration. Routine use of BAL is not recommended in ARDS. Indications, risks and yield of the procedure should be determined by the treating physician. Many investigators are interested in the use of BAL as a research tool.
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.
Go to Acute Respiratory Distress Syndrome and Barotrauma and Mechanical Ventilation for complete information on these topics.
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
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.[59] 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.[2]
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.[2] 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.[60]
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.[2]
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.[61] The study by Amato et al[62] showed improved 28 days survival and decreased incidence of barotrauma. The results were confirmed by a large multicenter study conducted by ARDS Network trial.[63] 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.[64]
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.
View Image
Typical pressure-volume curve may provide information regarding lung compliance, lung hysteresis, and critical opening and closing pressures. Evidence....
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.[65] 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%).[62] 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. [2]
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.[66] 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.[67] 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.[68] Another multicenter trial by the OSCAR study group showed no difference in 30 days mortality.[69] 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.[70] In a recent study, application of both the HFOV and early HFOV had poor outcomes as compared to the CMV group.[71]
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.[72] 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%). [2]
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.
Prone positioning
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.[73] 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%).[2] 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.[74] 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.[2]
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.[75] 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%.[80] 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.[81]
According to most recent recommendations from Pediatric Acute Lung Injury group, use of exogenous surfactant is not recommended in PARDS until further studies.[2]
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.[82] 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.[83]
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.[72] 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.[84]
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.[85] 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.[86]
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.[2]
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.[89] 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.[2]
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.[90]
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.[91]
In a multicenter retrospective cohort trial of 331 children across 32 hospitals reported data that ECMO was associated with improved survival.[92] 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.[2]
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.[2]
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.[96] 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.[97] Another study of randomly assigned 180 patients, who were into at least the 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.[98] 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.[99] 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.[100]
Studies conducted thus far have shown variable results. The use of steroid in pediatric ARDS is not recommended per PALICC.[2]
To the authors’ knowledge, no study has been performed to examine the potential role of inhaled steroids in ARDS.
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.
Activity restriction
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.
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.
No specific drug therapy for acute respiratory distress syndrome (ARDS) exists, and many drugs relating to ARDS therapy will not be indicated during the early emergency department (ED) intervention period beyond supportive care. However, as a sequela to intubation and mechanical ventilation, high mean airway pressures for poor oxygenation may compromise cardiac output and may require fluid resuscitation and the initiation of vasoactive agents.
Routine use of corticosteroids is not recommended at this time by PALICC. It might be beneficial to use in patients with ARDS associated with Pneumocystis jiroveci (previously carinii) pneumonia.
Inhaled nitric oxide (iNO) has produced short-term physiologic improvements in ventilation-perfusion matching and intrapulmonary shunting; however, no randomized clinical studies have documented improved patient outcome. Based on current evidence, it can be used in patients with severe PARDS, and in cases to bridge to ECLS/ECMO.
Evidence is insufficient at this stage to recommend use of exogenous surfactant.
Discussion provided below is brief. Detailed discussion of these medication is beyond the scope for the topic of Pediatric ARDS.
Clinical Context:
Dobutamine is a sympathomimetic agent with predominant beta one agonist followed by beta 2 and than alpha agonist. It provides inotropy, chronotropy and systemic vasodilation. Adverse effects include tachycardia, increased myocardial oxygen requirement and so can exacerbate myocardial ischemia.
Clinical Context:
In low doses (2-5 µg/kg/min), dopamine acts on dopaminergic receptors in renal and splanchnic vascular beds, potentially causing vasodilatation in these beds. In the doses 5-15 µg/kg/min, it acts on beta-adrenergic receptors creating inotropy and chronotropy. At high doses (15-20 µg/kg/min), it acts on alpha-adrenergic receptors to increase systemic vascular resistance. Higher doses have been associated with risks of arrhythmia and local tissue necrosis.
Clinical Context:
Epinephrine stimulated beta 1 and produces inotropy and chronotropy. At lower doses, it causes peripheral vascular dilatation from beta-2 effects. Beta2-agonist effects also include bronchodilatation. At higher doses, it predominantly activate alpha receptors and causes peripheral vasoconstriction.
Adrenergic agonist agents are used to increase cardiac output and improve hemodynamics induced by various mechanism including elevated mean airway pressures from mechanical ventilation, sedation, multi organ failure etc. These agents should be administered via central line.
These agents increase cellular levels of cAMP, which results in a positive inotropic effect, peripheral vasodilatation and increased cardiac output. Milrinone is commonly used phosphodiesterase inhibitor.
Corticosteroids have anti-inflammatory and immunosuppressive properties. They cause profound and varied metabolic effects, and they modify the body’s immune response to diverse stimuli. As discussed previously, current evidence is insufficient for use of corticosteroids in PARDS patients.
Exogenous surfactant can be helpful in treating airspace disease (eg, respiratory distress syndrome [RDS] in neonates). Surfactant dysfunction is well known pathophysiology in pediatric ARDS patients. However, current evidence is insufficient to use exogenous surfactant in pediatric ARDS patients.
Prashant Purohit, MD, Pediatric Intensivist, Kapi’olani Medical Center for Women and Children
Disclosure: Nothing to disclose.
Coauthor(s)
Dale W Steele, MD, MS, Professor of Emergency Medicine, Pediatrics, and Health Services, Policy, and Practice, Warren Alpert Medical School of Brown University; Attending Physician, Department of Pediatric Emergency Medicine, Rhode Island Hospital
Disclosure: Nothing to disclose.
G Patricia Cantwell, MD, FCCM, Professor of Clinical Pediatrics, Chief, Division of Pediatric Critical Care Medicine, University of Miami Leonard M Miller School of Medicine/ Holtz Children's Hospital, Jackson Memorial Medical Center; Medical Director, Palliative Care Team, Holtz Children's Hospital; Medical Manager, FEMA, South Florida Urban Search and Rescue, Task Force 2
Disclosure: Nothing to disclose.
Lennox H Huang, MD, FAAP, Chief Medical Officer, The Hospital for Sick Children; Associate Professor of Pediatrics, University of Toronto Faculty of Medicine; Associate Clinical Professor of Pediatrics, McMaster University School of Medicine, Canada
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Grace M Young, MD, Associate Professor, Department of Pediatrics, University of Maryland Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Disclosure: Nothing to disclose.
Additional Contributors
Andrew K Feng, MD, Attending Physician, Division of Pediatric Critical Care, Kapiolani Medical Center for Women and Children
Disclosure: Nothing to disclose.
Garry Wilkes, MBBS, FACEM, Director of Clinical Training (Simulation), Fiona Stanley Hospital; Clinical Associate Professor, University of Western Australia; Adjunct Associate Professor, Edith Cowan University, Western Australia
Chest radiograph in 3-year-old girl who developed acute respiratory distress syndrome due to overwhelming gram-negative sepsis. Salient features include endotracheal tube; diffuse, bilateral infiltrates; air bronchograms on left side; and central venous catheter. Ratio of arterial oxygen tension to fraction of inspired oxygen at time of chest radiography was 100.
Eight-year-old girl with diagnosis of pneumonia. Chest radiograph on day of admission.
Eight-year-old girl with pneumonia and impending respiratory failure. Chest radiograph on day 2.
Subcutaneous emphysema and pneumothorax.
Chest radiograph in 3-year-old girl who developed acute respiratory distress syndrome due to overwhelming gram-negative sepsis. Salient features include endotracheal tube; diffuse, bilateral infiltrates; air bronchograms on left side; and central venous catheter. Ratio of arterial oxygen tension to fraction of inspired oxygen at time of chest radiography was 100.
Chest radiograph demonstrates complication of acute respiratory distress syndrome. Patient presented with respiratory failure after near-drowning episode. Peak inspiratory pressures were 40 cm water. Patient had sudden desaturation and decreased bilateral air entry, as well as cool peripheries and decreased blood pressure. Needle evacuation of both pleural spaces confirmed pleural air. Chest tubes were placed, with immediate improvement in clinical status. Pulmonary status continued to deteriorate; high-frequency oscillatory ventilation was given. Patient subsequently required second chest tube on left side.
Chest CT in 6-month-old male infant with newly diagnosed cystic fibrosis. Patient was intubated for respiratory failure and subsequently developed acute respiratory distress syndrome. Image demonstrates numerous cystic and bronchiectatic areas. Note dorsal distribution of atelectasis, particularly on right side.
Typical pressure-volume curve may provide information regarding lung compliance, lung hysteresis, and critical opening and closing pressures. Evidence of pulmonary overdistention may also be observed.
Eight-year-old girl with diagnosis of pneumonia. Chest radiograph on day of admission.
Fourteen-month-old boy with diagnosis of exacerbation of bronchopulmonary dysplasia. Chest radiograph on day of admission.
Eight-year-old girl with pneumonia and impending respiratory failure. Chest radiograph on day 2.
Fourteen-month-old boy with exacerbation of bronchopulmonary dysplasia and impending respiratory failure. Chest radiograph on morning of day 2.
Fourteen-month-old boy with exacerbation of bronchopulmonary dysplasia and respiratory failure. Chest radiograph on afternoon of day 2.
Fourteen-month-old boy with exacerbation of bronchopulmonary dysplasia, respiratory failure, and severe hypoxemia. Chest radiograph on evening of day 2.
Chest radiograph in 3-year-old girl who developed acute respiratory distress syndrome due to overwhelming gram-negative sepsis. Salient features include endotracheal tube; diffuse, bilateral infiltrates; air bronchograms on left side; and central venous catheter. Ratio of arterial oxygen tension to fraction of inspired oxygen at time of chest radiography was 100.
Chest radiograph demonstrates complication of acute respiratory distress syndrome. Patient presented with respiratory failure after near-drowning episode. Peak inspiratory pressures were 40 cm water. Patient had sudden desaturation and decreased bilateral air entry, as well as cool peripheries and decreased blood pressure. Needle evacuation of both pleural spaces confirmed pleural air. Chest tubes were placed, with immediate improvement in clinical status. Pulmonary status continued to deteriorate; high-frequency oscillatory ventilation was given. Patient subsequently required second chest tube on left side.
Chest CT in 6-month-old male infant with newly diagnosed cystic fibrosis. Patient was intubated for respiratory failure and subsequently developed acute respiratory distress syndrome. Image demonstrates numerous cystic and bronchiectatic areas. Note dorsal distribution of atelectasis, particularly on right side.
Typical pressure-volume curve may provide information regarding lung compliance, lung hysteresis, and critical opening and closing pressures. Evidence of pulmonary overdistention may also be observed.
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