Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial.

IMPORTANCE: Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE: To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS: Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES: The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS: A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE: Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ISRCTN 20769191.

Pulmonary dead space fraction and pulmonary artery systolic pressure as early predictors of clinical outcome in acute lung injury.

STUDY OBJECTIVE: The primary objective of this study was to test whether an elevated systolic pulmonary artery (PA) pressure or an elevated pulmonary dead space fraction (Vd/Vt) in early acute lung injury (ALI) is associated with poor clinical outcomes in the era of lung-protective ventilation. DESIGN: Prospective observational cohort study. SETTING: ICUs of a university hospital. PATIENTS: Forty-two patients with ALI receiving mechanical ventilation. MEASUREMENTS: PA pressure was measured noninvasively using transthoracic echocardiography. Vd/Vt was measured by volumetric capnography (NICO Cardiopulmonary Management System; Novametrix; Wallingford, CT). MAIN RESULTS: There was no difference in the mean systolic PA pressure in patients who died compared to those who survived (43 +/- 9 mm Hg vs 41 +/- 9 mm Hg, p = 0.54) [mean +/- SD]. In contrast to the PA systolic pressure, Vd/Vt was significantly higher in patients who died compared to those who survived (0.61 +/- 0.09 vs 0.53 +/- 0.10, p = 0.02). Similarly, Vd/Vt was higher in patients with < 7 ventilator-free days during the first 28 days after enrollment compared to those with > 7 ventilator-free days (0.61 +/- 0.08 vs 0.52 +/- 0.11, p = 0.008). CONCLUSION: In the era of lung-protective ventilation, systolic PA pressure early in the course of ALI is elevated but not predictive of outcome. However, elevated Vd/Vt in early ALI is associated with increased mortality and with fewer ventilator-free days.

Biological markers of lung injury before and after the institution of positive pressure ventilation in patients with acute lung injury.

BACKGROUND: Several biological markers of lung injury are predictors of morbidity and mortality in patients with acute lung injury (ALI). The low tidal volume lung-protective ventilation strategy is associated with a significant decrease in plasma biomarker levels compared to the high tidal volume ventilation strategy. The primary objective of this study was to test whether the institution of lung-protective positive pressure ventilation in spontaneously ventilating patients with ALI exacerbates pre-existing lung injury by using measurements of biomarkers of lung injury before and after intubation. MATERIALS AND METHODS: A prospective observational cohort study was conducted in the intensive care unit of a tertiary care university hospital. Twenty-five intubated, mechanically ventilated patients with ALI were enrolled. Physiologic data and serum samples were collected within 6 hours before intubation and at two different time points within the first 24 hours after intubation to measure the concentration of interleukin (IL)-6, IL-8, intercellular adhesion molecule 1 (ICAM-1), and von Willebrand factor (vWF). The differences in biomarker levels before and after intubation were analysed using repeated measures analysis of variance and a paired t test with correction for multiple comparisons. RESULTS: Before endotracheal intubation, all of the biological markers (IL-8, IL-6, ICAM-1, and vWF) were elevated in the spontaneously breathing patients with ALI. After intubation and the institution of positive pressure ventilation (tidal volume 7 to 8 ml/kg per ideal body weight), none of the biological markers was significantly increased at either an early (3 +/- 2 hours) or later (21 +/- 5 hours) time point. However, the levels of IL-8 were significantly decreased at the later time point (21 +/- 5 hours) after intubation. During the 24-hour period after intubation, the PaO2/FiO2 (partial pressure of arterial oxygen/fraction of the inspired oxygen) ratio significantly increased and the plateau airway pressure significantly decreased. CONCLUSION: Levels of IL-8, IL-6, vWF, and ICAM-1 are elevated in spontaneously ventilating patients with ALI prior to endotracheal intubation. The institution of a lung-protective ventilation strategy with positive pressure ventilation does not further increase the levels of biological markers of lung injury. The results suggest that the institution of a lung-protective positive pressure ventilation strategy does not worsen the pre-existing lung injury in most patients with ALI.

Clinical significance of elevated B-type natriuretic peptide in patients with acute lung injury with or without right ventricular dilatation: an observational cohort study.

BACKGROUND: The primary objective of this study was to examine levels of B-type natriuretic peptide (BNP) in mechanically ventilated patients with acute lung injury and to test whether the level of BNP would be higher in patients with right ventricular dilatation and would predict mortality. METHODS: This was a prospective, observational cohort study of 42 patients conducted in the intensive care unit of a tertiary care university hospital. BNP was measured and transthoracic echocardiography was performed within 48 hours of the onset of acute lung injury. The left ventricular systolic and diastolic function, right ventricular systolic function, and cardiac output were assessed. BNP was compared in patients with and without right ventricular dilatation, as well as in survivors versus nonsurvivors. RESULTS: BNP was elevated in mechanically ventilated patients with acute lung injury (median 420 pg/ml; 25-75% interquartile range 156-728 pg/ml). There was no difference between patients with and without right ventricular dilatation (420 pg/ml, 119-858 pg/ml vs. 387 pg/ml, 156-725 pg/ml; p = 0.96). There was no difference in BNP levels between the patients who died and those who survived at 30 days (420 pg/ml, 120-728 pg/ml vs. 385 pg/ml, 159-1070 pg/ml; p = 0.71). CONCLUSIONS: In patients with acute lung injury the level of BNP is increased, but there is no difference in the BNP level between patients with and without right ventricular dilatation. Furthermore, BNP level is not predictive of mortality in this population.

Pharmacotherapy of acute lung injury and the acute respiratory distress syndrome.

Acute lung injury and the acute respiratory distress syndrome are common syndromes with a high mortality rate that affect both medical and surgical patients. Better understanding of the pathophysiology of acute lung injury and the acute respiratory distress syndrome and advances in supportive care and mechanical ventilation have led to improved clinical outcomes since the syndrome was first described in 1967. Although several promising pharmacological therapies, including surfactant, nitric oxide, glucocorticoids and lysofylline, have been studied in patients with acute lung injury and the acute respiratory distress syndrome, none of these pharmacological treatments reduced mortality. This article provides an overview of pharmacological therapies of acute lung injury and the acute respiratory distress syndrome tested in clinical trials and current recommendations for their use as well as a discussion of potential future pharmacological therapies including beta(2)-adrenergic agonist therapy, keratinocyte growth factor, and activated protein C.