ARDS (Acute Respiratory Distress Syndrome)
Classically defined as (1994 American European Consensus Conference):
bilateral opacities on CXR
PaO2/FiO2 ("PF ratio") <300 for ALI and <200 for ARDS,
pulmonary capillary wedge pressure of <18 mmHg (or no suspicion of cardiac disease)
Definition revised in 2012, ARDS definition Task force or the "Berlin Definition" (JAMA 2012)
PaO2/FiO2 ratio: <100= severe, 100-200= moderate, 200-300= mild. Requires minimum PEEP of 5 and bilateral infiltrates. Correlate with increased mortality.
Ancillary variables such as radiographic severity, respiratory system compliance, PEEP, and expired volume/minute did not contribute to predictive validity
The Pediatric Acute Lung Injury Consensus Conference released pediatric specific definitions that center on oxygenation index [(FiO2 * Mean Airway pressure/PaO2) *100 (with FiO2 expressed as 0.21 to 1)] as the defining variable with:
Mild: OI of 4 to <8
Moderate 8 to to <16
Severe: OI of >16.
Etiology is wide-ranging and can be due to direct lung injury (ie aspiration, pneumonia, acute chest syndrome etc.) or due to a systemic disease (ie septic shock, pancreatitis, severe trauma, near drowning, transfusions, etc)
Various phases of ALI/ARDS:
Pulmonary edema: Increased permeability of alveolar/capillary membrane leads to protein rich edema fluid entering the alveoli
Diffuse alveolar damage and epithelial injury impairs fluid transport, hence alveolar fluid clearance is reduced
Surfactant deficiency: Alveolar type II cell injury reduces production
Inflammatory exudate as cytokines (IL-1, IL-6, TNF-a) are released and activate neutrophils
Figure 1: Pathophysiology of ARDS (Ware et al, NEJM 2000)
Ventilator induced lung injury also contributes to ongoing lung injury
High FIO2 (generally thought of as >50-60%) contribute to reactive oxygen species and free radical production which can contribute to lung injury
Cellular Biotrauma describes the upregulation of the inflammatory response as a result to the mechanical forces imposed by mechanical ventilation
Barotrauma as a result of excessive distending pressures. In general, plateau pressure (what the alveoli sees vs. peak pressures which are determined both by lung compliance and airway resistance) goals are <30 cm H20.
Volutrauma: One of the landmark ARDSnet trials compared 6 cc/kg tidal volume with 12 cc/kg tidal volume and demonstrated improved mortality with lower tidal volume (31 vs 40%, respectively). Similarly, animal models in which a cuirass is used to bind the thoracic cavity and limit lung volumes demonstrated that pressure alone did not lead to significant lung injury, but rather large volume changes led to lung injury. Similarly, when negative pressure was used instead to achieve these high volumes, lung injury occurred, suggesting it is primarily volume, and not pressure that contribute to lung injury
Active transport of fluid from alveoli to interstitium (ie apical ENaC channels, regulated by beta-adrenergic agents)
Removal of proteins
Restoration of normal alveolar epithelial membrane
Occurs approximately 5-10 days after initial lung injury
Marked by fibroblasts which deposit collagen into the alveolar space
Results in a fibrosing alveolitis
Lung disease is heterogeneous, meaning some regions are atelectatic while others may be overdistended. This leads to regional areas of relative dead space ventilation as well as areas of relative intrapulmonary shunt, leading to hypercarbia and hypoxemia, respectively.
Minimize oxygen toxicity as able. Generally, try to wean FiO2 to 50-60%, maintaining oxygen saturations >88-90%. Nonetheless, it does appear that injured lungs are actually more tolerant of high levels of oxygen than normal, uninjured lungs
Permissive Hypercapnea: Aim for tidal volumes of approximately 6 cc/kg, and accept hypercapnea. While we know 6 cc/kg is better than 12 cc/kg (ARDSNET, NEJM 2000) it is not certain whether tidal volumes in between make a significant difference. As long as pH is above 7.15 and tolerated hemodynamically, it is tolerated clinically in order to avoid volutrauma and barotrauma
PEEP: can aid in oxygenation but excess PEEP also leads to overdistension of some lung regions and likely volutrauma. Hence, optimal PEEP is sought. Various strategies employed to achieve optimal PEEP (using the lower inflection point of the pressure-volume loop as a rough guide), utilizing esophageal pressures to estimate pleural pressures, etc. Nonetheless, the ARDSnet trial comparing high (12) to low (8) PEEP showed no significant differences between the two. However, some data suggests that children with pARDS managed with lower PEEP than the ARDSNet protocol (the protocol is represented by "Lower PEEP/Higher FiO2" in the table below) had higher mortality (Khemani et al, AJRCCM 2018)
Measurement of esophageal pressure with a balloon in the distal 1/3 of the esophagus can approximate pleural pressure (PPl) and allow one to titrate PEEP physiologically (Video of esophageal pressure monitoring and PEEP titration from ATS)
Itime: Generally set for a I:E ratio of 1:2 given a physiologic respiratory rate. However, in the setting of continued hypoxemia, can be increased to I:E ratios of 1:1 or even inverse ratios to improve mean airway pressure and thereby oxygenation
Delta P: While not traditionally thought of as a significant risk factor for lung injury as long as Plateau pressures are kept below 30 cm H2O, Amato et al found that Delta P was an independent, and the most significant risk factor for mortality even after taking into account the baseline severity of lung injury (Amato et al, NEJM 2015). Driving Pressure Explained (ATS Video)
ETCO2: Dead space fraction, (ie PacO2-EtCO2/PaCO2) is independently associated with mortality (ie higher dead space fraction= higher mortality).
Figure 2: Adult ARDSNet Protocol For Reference (not primarily used in the PICU)
Initially thought to improve oxygenation but not improve clinical outcomes (Gattinoni, NEJM 2001), the most recent trial, PROSEVA, demonstrated improved mortality with prone positioning (>16 hours/day in patients with more severe ARDS (PF<150)).
Nonetheless, Curley et al showed NO improvement in clinical outcomes in a RCT of prone positioning with pediatric ALI (PROSEVA was done in the adult population)
Ongoing PROSPECT trial investigating effect of prone positioning and HFOV in pediatric ARDS
FACCT trial compared liberal to conservative fluid management with the conservative fluid management arm (CVP <4) showing decreased duration of mechanical ventilation and ICU stay without increasing organ failure (ie renal failure)
Acurasys Trial showed early use of 48 hours of neuromuscular blockade (cisatracurium) in adult patients with severe ARDS improved outcome (31 vs 40% mortality, NNT of 11 to prevent one death at 90 days, NNT of 7 for those with PF ratio <120)
ROSE trial, completed by the PETAL network, in contrast to ACURASYS, found no differences in outcomes comparing early NMB (cisatracurium) to standard sedation in adult patients with moderate/severe ARDS (PF<150)
Early work in pediatrics demonstrated improved outcomes with HFOV in ARDS vs. conventional ventilation. Further trials, including MOAT, OSCILLATE, and OSCAR, all in adult patients, have failed to show any significant difference in outcomes between HFOV and conventional ventilation. In fact, OSCILLATE showed increased mortality (47 vs 35%, p=0.005) in the HFOV group vs. the control group.
Gupta et al, in a retrospective (propensity matched) analysis, showed worse outcomes for pediatric patients who received HFOV vs. CMV. Similarly, Bateman et al reported in AJRCCM increased duration of ventilation with HFOV compared to CMV using propensity analysis.
Utilized for refractory hypoxemia with ARDS. No clear guidelines on when to initiate ECMO, however, clinicians often follow the oxygenation index, utilizing an oxygenation index ~40 as a guide for ECMO (traditionally used in the neonatal population).
The CESAR Trial from the UK/NHS demonstrated improved outcomes (63 vs 47% survival to 6 months without disability) in this randomized trial of referral to an ECMO center vs conventional management (only 75% of patients in the ECMO referral group actually received ECMO).
Propensity and case matched analysis by Barbaro et al using the RESTORE database also shows no significant difference in outcomes (mortality and secondary outcomes) between those supported by ECMO vs. those not supported by ECMO (pediatric ARDS patients).
EOLIA Trial: Combes et al, in a randomized multicenter RCT of 249 adult patients with severe ARDS (P/F <50 for 3 hours, P/F <80 for 6 hours, or pH <7.25 and pCO2 >60 for 6 hours) demonstrated no significant difference in mortality utilizing VV ECMO vs. conventional mechanical ventilation with crossover (to ECMO) (RR 0.76, 0.55-1.04, p=0.09) (Combes et al, NEJM 2018)
iNO: inhaled nitric oxide transiently improves oxygenation in the first 24 hours (Dobyns et al, J Peds 1999) and is often used as salvage therapy. In theory, it produces local pulmonary vasodilation at the alveoli that are ventilated, thus improving VQ matching and reducing dead space and intrapulmonary shunt. However, it has not been shown to improve clinical outcomes and in adults, may be associated with increased renal injury. Nonetheless, one study (Ehrenkranz et al., NEJM 1997) did demonstrate a reduction in the use of ECMO, although not mortality, in near-term/term neonates with oxygenation index >25 treated with iNO. More recent data by Bronicki et al (J Peds 2015) did demonstrate significantly reduced duration of mechanical ventilation and significantly greater rate of extracorporeal membrane oxygenation–free survival in a RCT of 55 pediatric patients with ARDS.
Steroids: Steroids are controversial in ARDS. Meduri et al. demonstrated in a small trial of 91 patients, improved outcomes (decreased length of ventilation and ICU stay)with early use of corticosteroids (within 72 hours) and a slow taper. Subsequent studies (Steinberg, NEJM 2006) showed comparable mortality and potential harm in those treated with steroids late (>14 days). Hence, if steroids are utilized with ARDS, they should probably be given earlier rather than later
Surfactant: Despite biological plausability, there is no evidence to support the use of surfactant in ARDS. Despite initial evidence from a pediatric trial that seemed to suggest benefit (Willson et al, JAMA 2005), a subsequent trial (Willson et al, PCCM 2013) was stopped early due to presumed futility. EXOSURF, an adult trial also failed to show any benefit.
APRV: open lung strategy of ventilation that can be utilized in spontaneously breathing patients, no clear evidence to support its use at this time
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