Early neuromuscular blockade in the acute respiratory distress syndrome. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Et al. N Engl J Med. 2019 May 23; 380(21): 1997-2008.
Acute Respiratory Distress Syndrome (ARDS) is a familiar problem for the surgical intensivist, but ideal treatment is controversial. One adjunct of care in the management of moderate to severe ARDS is the use of continuous neuromuscular blockade (NMB). Although the previous prospective ACURASYS multicenter trial identified a significant improvement in mortality in patients managed with early NMB when compared to those with standard therapy, early NMB remains poorly adopted with weak recommendations. With this in mind, the Prevention and Early Treatment of Acute Lung Injury (PETAL) Clinical Trials Network of the NHLBI performed the multicenter Re-evaluation of Systemic Early Neuromuscular Blockade (ROSE) trial to determine the efficacy and safety of early NMB in patients with moderate to severe ARDS.
ROSE was a 48-site multicenter, prospective, randomized, unblinded study of patients with moderate to severe ARDS (defined as PaO2:FiO2 <150 mmHg, PEEP≥8, and with bilateral pulmonary opacities) from January 2016 to April 2018. Patients were randomized in 1:1 fashion to receive early (within 48 hours of onset) continuous NMB with deep sedation or to undergo standard care with light sedation targets. All patients were managed with low tidal volume ventilation and high PEEP. Prone positioning was utilized per clinician discretion. The primary end point was all cause in-hospital death at 90 days. Secondary endpoints included organ failure scores, inpatient hospital death at 28 days, ICU free days, mechanical ventilator free days, and hospital free days. Analyses were performed on an intention to treat basis with pre-specified analyses based on ARDS severity (PaO2:FiO2 < 120 mmHg or ≥ 120 mmHg) and by duration of ARDS (either lesser than or greater than median time from meeting study criteria to study inclusion). Adverse events were analyzed by weighted Poisson regression while mortality was compared using a z-test. Survival, disability, health-related quality of life (HRQL), and patient reported outcomes were assessed at 3, 6, and 12 months.
The study was prematurely halted at the second interim analysis for futility by an independent review board. Prior to cessation, 4,848 patients were screened and 1,006 included for analysis, with 501 patients randomized to intervention and 505 controls. Pneumonia was the most common cause of ARDS among participants. Demographics, inciting lung injury, and initial ventilatory requirements were similar between groups. In-hospital death was equivalent (42.5 vs. 42.8%; p=0.93) between cases and controls at 90 days. Days free from the hospital, ICU, and mechanical ventilator were similar between groups. Patients treated with NMB demonstrated increased early cardiovascular SOFA scores and suffered significantly more serious cardiovascular adverse events (14 vs 4, p = 0.02). No differences were present based on ARDS severity or duration. Patient reported outcomes were not significantly different at 3, 6, or 12 months. Estimated mean mortality at one year was similar between the intervention and control groups (51.1±2.2% vs. 51.1±2.2%).
The ROSE study is a large, prospective, randomized, multicenter study that should influence current practice. Routine use of continuous NMB among patients with ARDS does not appear to offer any benefit in survival compared to standard care. Use of NMB should be determined on an individual basis and restricted to those patients with ventilator dyssynchrony.
Predictors of post-injury ARDS: Lung injury persists in the era of hemostatic resuscitation. Kornblith LZ, Robles AJ, Conroy AS, et al. J Trauma Acute Care Surg. 2019 Aug;87(2):371-378.
Resuscitation following injury is a commonly cited risk factor for the development of ARDS. However, resuscitation practices have drastically shifted over the last 20 years. It is unclear what effect this change has had on rates of ARDS in the trauma population. The authors therefore sought to identify the true incidence and risk factors for development of ARDS in the modern era of resuscitative practice through a prospective, single center, observational study. Patients who received highest trauma level activation, required intubation, and survived at least six hours from 2005-2016 were included. ARDS was diagnosed by the Berlin Definition, during the initial eight days of hospitalization. During this time period, all chest x-rays of patients with a PaO2:FiO2 ≤ 300 were reviewed by experts for the presence of bilateral infiltrates in order to establish the diagnosis of ARDS. Initial bivariate analyses were followed by multivariable logistic regression to identify risk factors associated with development of late ARDS (>24 hours following admission).
During the study period, 914 patients were identified as meeting criteria for inclusion. Of those patients, 63% (572/914) met PaO2:FiO2 criteria and 36% (204/572), or 22% overall, were diagnosed with ARDS following adjudication of chest x-ray. Early ARDS (≤24 hours) was identified in 43% of patients compared to 57% with late ARDS. Patients with early ARDS received significantly more crystalloid and blood product administration within 6 and 24 hours and had significantly lower platelets on admission (median platelet count 129 vs. 188 x109, p=0.0043). Multivariate analysis identified head injury (head AIS; OR 1.38, 95% CI 1.21-1.57), chest injury (chest AIS; OR 1.35, 95% CI 1.17-1.55), early crystalloid administration (500 mL 0-6 hours; OR 1.10, 95% CI 1.04-1.15), and early (1 unit 0-6 hours; OR 2.34, 95% CI 1.04-5.25, p=0.04) and late platelet transfusion (1 unit 7-24 hours; OR 5.40, 95% CI 2.58-11.31) as significantly associated with the development of late ARDS.
ARDS remains a persistent problem despite changes to resuscitation practice, complicating the care of over 1 in 5 intubated patients. The authors further clarify the heterogeneous presentation of ARDS following injury, with nearly half of patients developing ARDS at both early and late phases. Platelet transfusion appears to play a significant role in the development of ARDS.
Association between age and acute respiratory distress syndrome development and mortality following trauma. Killien EY, Mills B, Vavilala MS, Watson RS, et al. J Trauma Acute Care Surg. 2019 May; 86(5): 844-852.
The epidemiology of ARDS across different age groups is poorly understood. Killien et al. sought to compare the incidence and all-cause mortality of ARDS following trauma between different age groups and to compare differences in these rates over time. A retrospective review of the NTDB from 2007-2016 was performed and included all trauma patients with one or more ICU days at a Level I or II trauma center. Diagnosis of ARDS was determined in the NTDB by the American-European Consensus Conference through 2011 then with the Berlin criteria from 2012-2016. Patients were divided into eight, a priori determined age groups (≤4 years, 5-12 years, 13-17 years, 18-34 years, 35-49 years, 50-64 years, 65-79 years, and ≥80 years old). Incidence and in-hospital mortality were compared between groups.
Mortality was compared overall and with risk adjustment for age, ISS, admission heart rate, admission hypotension, total GCS at admission, need for ventilator use, and mechanism of injury. Linear Poisson regression models were used to estimate the association between comorbidities with ARDS development and the incidence of ARDS across age groups. A bivariate and multivariable linear Poisson regression was used to compare the incidence of mortality for patients with and without ARDS across age groups.
During the study period, the authors identified 1,297,190 patients eligible for inclusion. Pediatric patients comprised 11.5% (148,749) of the total number of eligible patients. Overall, the incidence of ARDS was 3.1%. Patients in the ≤4 years and 5-12 years old cohorts shared the lowest rates of ARDS at 1.4% while those in the 35-49 years and 50-64 years old cohorts shared the highest rates of ARDS at 3.5%. Mortality overall was 22.8% in patients with ARDS compared to 8.0% for patients without ARDS. Those patients with ARDS in the ≤4 years old cohort demonstrated a 25.3% mortality, which fell below 20% for all subsequent age groups until increasing to 21.5% in the 50-64 years old cohort. Rates of mortality then continued to increase with each subsequent group, reaching a maximum of 43.9% in the ≥80 year olds. Comparing rates of mortality in patients with ARDS over time, there was an increase overall from 20.5% to 27.4%. During that time, mortality increased in all age groups between 18-79 years old. ARDS was significantly associated with mortality following traumatic injury (RR 1.51, 95% CI 1.42-1.62).
This study highlights the different impact seen in patients with ARDS based on age. Patients at the extremes of age are the most likely to suffer mortality with development of ARDS. Further, it is important to note that rates of mortality in trauma patients with ARDS have actually increased over the last decade.