B. Taylor Thompson

Drotrecogin Alfa (Activated) in Adults with Septic Shock

BACKGROUND There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 μg per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).

Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries

IMPORTANCE Limited information exists about the epidemiology, recognition, management, and outcomes of patients with the acute respiratory distress syndrome (ARDS). OBJECTIVES To evaluate intensive care unit (ICU) incidence and outcome of ARDS and to assess clinician recognition, ventilation management, and use of adjuncts-for example prone positioning-in routine clinical practice for patients fulfilling the ARDS Berlin Definition. DESIGN, SETTING, AND PARTICIPANTS The Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE) was an international, multicenter, prospective cohort study of patients undergoing invasive or noninvasive ventilation, conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. EXPOSURES Acute respiratory distress syndrome. MAIN OUTCOMES AND MEASURES The primary outcome was ICU incidence of ARDS. Secondary outcomes included assessment of clinician recognition of ARDS, the application of ventilatory management, the use of adjunctive interventions in routine clinical practice, and clinical outcomes from ARDS. RESULTS Of 29,144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation. The period prevalence of mild ARDS was 30.0% (95% CI, 28.2%-31.9%); of moderate ARDS, 46.6% (95% CI, 44.5%-48.6%); and of severe ARDS, 23.4% (95% CI, 21.7%-25.2%). ARDS represented 0.42 cases per ICU bed over 4 weeks and represented 10.4% (95% CI, 10.0%-10.7%) of ICU admissions and 23.4% of patients requiring mechanical ventilation. Clinical recognition of ARDS ranged from 51.3% (95% CI, 47.5%-55.0%) in mild to 78.5% (95% CI, 74.8%-81.8%) in severe ARDS. Less than two-thirds of patients with ARDS received a tidal volume 8 of mL/kg or less of predicted body weight. Plateau pressure was measured in 40.1% (95% CI, 38.2-42.1), whereas 82.6% (95% CI, 81.0%-84.1%) received a positive end-expository pressure (PEEP) of less than 12 cm H2O. Prone positioning was used in 16.3% (95% CI, 13.7%-19.2%) of patients with severe ARDS. Clinician recognition of ARDS was associated with higher PEEP, greater use of neuromuscular blockade, and prone positioning. Hospital mortality was 34.9% (95% CI, 31.4%-38.5%) for those with mild, 40.3% (95% CI, 37.4%-43.3%) for those with moderate, and 46.1% (95% CI, 41.9%-50.4%) for those with severe ARDS. CONCLUSIONS AND RELEVANCE Among ICUs in 50 countries, the period prevalence of ARDS was 10.4% of ICU admissions. This syndrome appeared to be underrecognized and undertreated and associated with a high mortality rate. These findings indicate the potential for improvement in the management of patients with ARDS. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02010073.

Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion.

Objective:Clinical predictors for acute respiratory distress syndrome (ARDS) have been studied in few prospective studies. Although transfusions are common in the intensive care unit, the role of submassive transfusion in non-trauma-related ARDS has not been studied. We describe here the clinical predictors of ARDS risk and mortality including the role of red cell transfusion. Design:Observational prospective cohort. Setting:Intensive care unit of Massachusetts General Hospital. Patients:We studied 688 patients with sepsis, trauma, aspiration, and hypertransfusion. Interventions:None. Measurements and Main Results:Two hundred twenty-one (32%) subjects developed ARDS with a 60-day mortality rate of 46%. Significant predictors for ARDS on multivariate analyses included trauma (adjusted odds ratio [ORadj] 0.22, 95% confidence interval [CI] 0.09–0.53), diabetes (ORadj 0.58, 95% CI 0.36–0.92), direct pulmonary injury (ORadj 3.78, 95% CI 2.45–5.81), hematologic failure (ORadj 1.84, 95% CI 1.05–3.21), transfer from another hospital (ORadj 2.08, 95% CI 1.33–3.25), respiratory rate >33 breaths/min (ORadj 2.39, 95% CI 1.51–3.78), hematocrit >37.5% (ORadj 1.77, 95% CI 1.14–2.77), arterial pH <7.33 (ORadj 2.00, 95% CI 1.31–3.05), and albumin ≤2.3 g/dL (ORadj 1.80, 95% CI 1.18–2.73). Packed red blood cell transfusion was associated with ARDS (ORadj 1.52, 95% CI 1.00–2.31, p = .05). Significant predictors for mortality in ARDS included age (ORadj 1.96, 95% CI 1.50–2.53), Acute Physiology and Chronic Health Evaluation III score (ORadj 1.78, 95% CI 1.16–2.73), trauma (ORadj 0.075, 95% CI 0.006–0.96), corticosteroids before ARDS (ORadj 4.65, 95% CI 1.47–14.7), and arterial pH <7.22 (ORadj 2.32, 95% CI 1.02–5.25). Packed red blood cell transfusions were associated with increased mortality in ARDS (ORadj 1.10 per unit transfused; 95% CI 1.04–1.17) with a significant dose-dependent response (p = .02). Conclusions:Important predictors for the development of and mortality in ARDS were identified. Packed red blood cell transfusion was associated with an increased development of and increased mortality in ARDS.

Vitamin D Therapy and Cardiac Structure and Function in Patients With Chronic Kidney Disease: The PRIMO Randomized Controlled Trial

CONTEXT Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking. OBJECTIVE To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2). DESIGN, SETTING, AND PARTICIPANTS Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010. INTERVENTION Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112). MAIN OUTCOME MEASURES Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function. RESULTS Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. CONCLUSION Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00497146.

Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury

CONTEXT The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with γ-linolenic acid and antioxidants, may modulate systemic inflammatory response and improve oxygenation and outcomes in patients with acute lung injury. OBJECTIVE To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28. DESIGN, SETTING, AND PARTICIPANTS The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up. INTERVENTIONS Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement. MAIN OUTCOME MEASURE Ventilator-free days to study day 28. RESULTS The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vs 17.2; P = .02) (difference, -3.2 [95% CI, -5.8 to -0.7]) and intensive care unit-free days (14.0 vs 16.7; P = .04). Patients in the n-3 group also had fewer nonpulmonary organ failure-free days (12.3 vs 15.5; P = .02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P = .054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P = .11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P = .001). CONCLUSIONS Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00609180.

Barriers to providing lung-protective ventilation to patients with acute lung injury.

Objective:No studies have explored the barriers to implementing lung-protective ventilation in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Our objective was to identify barriers to using lung-protective ventilation in patients with ALI/ARDS. Design:Survey with content analysis of open-ended responses. Setting:Medical center. Participants:Experienced intensive care unit nurses and respiratory therapists network identified through purposive sampling at hospitals from the ARDS Network, a National Institutes of Health-sponsored research consortium. Interventions:Survey. Results:Fifty-five surveys representing all ten ARDS Network sites were received. Twenty-seven (49%) of the respondents were intensive care unit nurses, 24 (44%) were respiratory therapists, and four did not indicate their profession. Clinicians had used lung-protective ventilation in a median of 20 (interquartile range, 10–50) patients with ALI/ARDS. Respondents identified physician willingness to relinquish control of ventilator, physician recognition of ALI/ARDS, and physician perceptions of patient contraindications to low tidal volumes as important barriers to initiating lung-protective ventilation. Important barriers to continuing patients on lung-protective ventilation were concerns over patient discomfort and tachypnea and concerns over hypercapnia, acidosis, and hypoxemia. Techniques for overcoming barriers were identified including specific ventilator setup recommendations, clinician education, and tools to assess patient discomfort. Conclusions:Experienced bedside clinicians perceive important barriers to implementing lung-protective ventilation. Successful strategies to increase use of lung-protective ventilation should target these barriers.

Neutrophil elastase inhibition in acute lung injury: Results of the STRIVE study

Objective:Neutrophil elastase is believed to be an important mediator of acute lung injury. Sivelestat (ONO-5046, Elaspol) is a small molecular weight inhibitor of neutrophil elastase. The primary objectives of this study were to determine whether sivelestat would reduce 28-day all-cause mortality or increase the number of ventilator-free days (days alive and free from mechanical ventilation from day 1 to day 28) compared with placebo in mechanically ventilated patients with acute lung injury. Design:Multiple-center, double-blind, placebo-controlled trial administering a continuous infusion of sivelestat at a dose of 0.16 mg·kg−1·hr−1. Setting:One hundred and five institutions in the United States, Canada, Belgium, Spain, Australia, and New Zealand. Patients:A total of 492 mechanically ventilated patients with acute lung injury. Interventions:Patients were randomized in a 1:1 fashion to sivelestat or placebo. Study drug was administered as a continuous infusion for the duration of mechanical ventilation plus 24 hrs for a maximum of 14 days. All patients were managed using low tidal volume mechanical ventilation. Measurements and Main Results:The study was stopped prematurely at the recommendation of an external Data and Safety Monitoring Board, which noted a negative trend in long-term mortality rate. Final analysis revealed no effect of sivelestat on the primary end points of ventilator-free days (day 1–day 28) or 28-day all-cause mortality. There were 64 deaths in each treatment group within the 28-day study period, and the mean number of ventilator-free days was 11.4 and 11.9 in the sivelestat and placebo treatment groups, respectively (p = .536). There was no evidence of effect on measures of pulmonary function, including Pao2/Fio2, static lung compliance, and time to meeting weaning criteria. There was no difference in adverse events or serious adverse events between treatment groups. A comparison of the Kaplan-Meier 180-day survival curves showed no difference between treatment groups (p = .102), but there was an increase in 180-day all-cause mortality in the sivelestat treatment group compared with the placebo group (p = .006). Conclusions:Intravenous sivelestat had no effect on 28-day all-cause mortality or ventilator-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation.

Hemodynamic effects of inhaled nitric oxide in heart failure.

OBJECTIVES This study was performed to assess the utility of inhaled nitric oxide as a selective pulmonary vasodilator in patients with severe chronic heart failure and to compare its hemodynamic effects with those of nitroprusside, a nonselective vasodilator. BACKGROUND Preoperative pulmonary vascular resistance is a predictor of right heart failure after heart transplantation. Non-selective vasodilators administered preoperatively to assess the reversibility of pulmonary vasoconstriction cause systemic hypotension, limiting their utility. METHODS Systemic and pulmonary hemodynamic measurement were made at baseline, during oxygen inhalation and with the addition of graded doses of inhaled nitric oxide or intravenous nitroprusside in 16 patients with New York Heart Association class III or IV heart failure referred for heart transplantation. RESULTS Pulmonary vascular resistance decreased to a greater extent with 80 ppm nitric oxide (mean +/- SEM 256 +/- 41 to 139 +/- 14 dynes.s.cm-5) than with the maximally tolerated dose of nitroprusside (264 +/- 49 to 169 +/- 30 dynes.s.cm-5, p < 0.05, nitric oxide vs. nitroprusside). Pulmonary capillary wedge pressure increased with 80 ppm nitric oxide (26 +/- 2 to 32 +/- 2 mm Hg, p < 0.05). Mean arterial pressure did not change with nitric oxide but decreased with nitroprusside. Seven of the 16 patients, including 1 patient who did not have an adequate decrease in pulmonary vascular resistance with nitroprusside but did with nitric oxide, have undergone successful heart transplantation. CONCLUSIONS Inhaled nitric oxide is a selective pulmonary vasodilator in patients with pulmonary hypertension due to left heart failure and may identify patients with reversible pulmonary vasoconstriction in whom agents such as nitroprusside cause systemic hypotension. Inhaled nitric oxide causes an increase in left ventricular filling pressure by an unknown mechanism.

The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: Long-Term Neuropsychological Function in Survivors of Acute Lung Injury

RATIONALE Cognitive and psychiatric morbidity is common and potentially modifiable after acute lung injury (ALI). However, practical measures of neuropsychological function for use in multicenter trials are lacking. OBJECTIVES To determine whether a validated telephone-based neuropsychological test battery is feasible in a multicenter trial. To determine the frequency and risk factors for long-term neuropsychological impairment. METHODS As an adjunct study to the Acute Respiratory Distress Syndrome Clinical Trials Network Fluid and Catheter Treatment Trial, we assessed neuropsychological function at 2 and 12 months post-hospital discharge. MEASUREMENTS AND MAIN RESULTS Of 406 eligible survivors, we approached 261 to participate and 213 consented. We tested 122 subjects at least once, including 102 subjects at 12 months. Memory, verbal fluency, and executive function were impaired in 13% (12 of 92), 16% (15 of 96), and 49% (37 of 76) of long-term survivors. Long-term cognitive impairment was present in 41 of the 75 (55%) survivors who completed cognitive testing. Depression, post-traumatic stress disorder, or anxiety was present in 36% (37 of 102), 39% (40 of 102), and 62% (63 of 102) of long-term survivors. Enrollment in a conservative fluid-management strategy (P = 0.005) was associated with cognitive impairment and lower partial pressure of arterial oxygen during the trial was associated with cognitive (P = 0.02) and psychiatric impairment (P = 0.02). CONCLUSIONS Neuropsychological function can be assessed by telephone in a multicenter trial. Long-term neuropsychological impairment is common in survivors of ALI. Hypoxemia is a risk factor for long-term neuropsychological impairment. Fluid management strategy is a potential risk factor for long-term cognitive impairment; however, given the select population studied and an unclear mechanism, this finding requires confirmation.

Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome.

What is the problem and what is known about it so far? Elderly people are much more likely to develop respiratory failure and require the use of a respirator than younger people. On the other hand, the results of respirator use in the elderly do not appear to be as good as in younger people, but the exact relationship between age and outcome is uncertain. The National Heart, Lung, and Blood Institute (NHLBI) sponsored a large study on acute lung injury that leads to respiratory failure. The data were made available to other researchers for further analysis. Why did the researchers do this particular study? To find out how advancing age affects survival from acute lung injury and whether recovery takes longer in older patients. Who was studied? 902 patients at 24 U.S. hospitals who participated in the NHLBI study between 1996 and 1999. Patients were included in the study if they had acute lung injury requiring use of a respirator, had low oxygen levels, and had a chest x-ray indicating that the respiratory problem was not due to heart failure. Of the participants, 729 were younger than 70 years of age and 173 were 70 years of age or older. How was the study done? Patients were evaluated each day to see if a respirator was still needed. Depending on the results of these evaluations, patients were allowed to breathe on their own for 5 minutes; if they did well, additional time off the respirator was prescribed and respiratory assistance was eventually discontinued. The time required to reach each landmark of recovery was recorded, as were the length of stay in the intensive care unit and the survival rate. What did the researchers find? Seventy percent of the younger patients and 40% of the older patients were discharged from the hospital alive within the first 180 days. At the time of entry into the study, the severity of lung injury was similar in both age groups. Older patients needed the respirator longer, were more likely to require reinstitution of respirator therapy after initial improvement, and stayed in the intensive care unit longer than younger patients. At 28 days after initiation of respirator use, the survival rate was lower with each decade of advancing age. What were the limitations of the study? Several nonrespiratory health problems (such as brain abnormalities) were not carefully monitored but could have affected the results. In addition, older patients may have been more likely than younger patients to have had life support withdrawn because of poor general condition. Furthermore, preexisting illness was difficult to take into account in interpreting the results. What are the implications of the study? Although elderly patients seem to recover initially from acute lung injury at a rate similar to younger patients, they are more likely to return to mechanical ventilation and are more likely to die of their acute lung illness. Age alone should not be used as a criterion to deny respirator care. Rather, more effort should be made to improve outcomes in elderly people who develop acute lung failure.