Venous thromboembolic events in critically ill traumatic brain injury patients

To estimate the prevalence, risk factors, prophylactic treatment and impact on mortality for venous thromboembolism (VTE) in patients with moderate to severe traumatic brain injury (TBI) treated in the intensive care unit. A post hoc analysis of the erythropoietin in traumatic brain injury (EPO-TBI) trial that included twice-weekly lower limb ultrasound screening. Venous thrombotic events were defined as ultrasound-proven proximal deep venous thrombosis (DVT) or clinically detected pulmonary embolism (PE). Results are reported as events, percentages or medians and interquartile range (IQR). Cox regression analysis was used to calculate adjusted hazard ratios (HR) with 95% confidence intervals (CI) for time to VTE and death. Of 603 patients, 119 (19.7%) developed VTE, mostly comprising DVT (102 patients, 16.9%) with a smaller number of PE events (24 patients, 4.0%). Median time to DVT diagnosis was 6 days (IQR 2-11) and to PE diagnosis 6.5 days (IQR 2-16.5). Mechanical prophylaxis (MP) was used in 91% of patients on day 1, 97% of patients on day 3 and 98% of patients on day 7. Pharmacological prophylaxis was given in 5% of patients on day 1, 30% of patients on day 3 and 57% of patients on day 7. Factors associated with time to VTE were age (HR per year 1.02, 95% CI 1.01-1.03), patient weight (HR per kg 1.01, 95% CI 1-1.02) and TBI severity according to the International Mission for Prognosis and Analysis of Clinical Trials risk of poor outcome (HR per 10% increase 1.12, 95% CI 1.01-1.25). The development of VTE was not associated with mortality (HR 0.92, 95% CI 0.51-1.65). Despite mechanical and pharmacological prophylaxis, VTE occurs in one out of every five patients with TBI treated in the ICU. Higher age, greater weight and greater severity of TBI increase the risk. The development of VTE was not associated with excess mortality.Peer reviewe

Особенности конфликтогенных зон у больных невротическими расстройствами женщин

Представлены данные о различии конфликтогенных зон у женщин и мужчин, страдающих невротическими расстройствами. Показано, что выявленные особенности необходимо учитывать в диагностике и психотерапии невротических расстройств.The authors report the data about the differences in conflectogenic zones among women and men with neurotic disorders. It was shown that the revealed peculiarities should be taken into consideration in diagnosis and psychotherapy of neurotic disorders

Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate-balanced solution

Introduction: As even small concentrations of acetate in the plasma result in pro-inflammatory and cardiotoxic effects, it has been removed from renal replacement fluids. However, Plasma-Lyte 148 (Plasma-Lyte), an electrolyte replacement solution containing acetate plus gluconate is a common circuit prime for cardio-pulmonary bypass (CPB). No published data exist on the peak plasma acetate and gluconate concentrations resulting from the use of Plasma-Lyte 148 during CPB

Targeted full energy and protein delivery in critically ill patients : A pilot randomized controlled trial (FEED Trial)

Background International guidelines recommend greater protein delivery to critically ill patients than they currently receive. This pilot randomized clinical trial aimed to determine whether a volume-target enteral protocol with supplemental protein delivered greater amounts of protein and energy to critically ill patients compared with standard care. Methods Sixty participants received either the intervention (volume-based protocol, with protein supplementation) or standard nutrition care (hourly-rate-based protocol, without protein supplementation) in the intensive care unit (ICU). Coprimary outcomes were average daily protein and energy delivery. Secondary outcomes included change in quadriceps muscle layer thickness (QMLT, ultrasound) and malnutrition (subjective global assessment) at ICU discharge. Results Mean (SD) protein and energy delivery per day from nutrition therapy for the intervention were 1.2 (0.30) g/kg and 21 (5.2) kcal/kg compared with 0.75 (0.11) g/kg and 18 (2.7) kcal/kg for standard care. The mean difference between groups in protein and energy delivery per day was 0.45 g/kg (95% CI, 0.33–0.56; P < .001) and 2.8 kcal/kg (95% CI, 0.67–4.9, P = .01). Muscle loss (QMLT) at discharge was attenuated by 0.22 cm (95% CI, 0.06–0.38, P = .01) in patients receiving the intervention compared with standard care. The number of malnourished patients was fewer in the intervention [2 (7%) vs 8 (28%); P = .04]. Mortality and duration of admission were similar between groups. Conclusions A high-protein volume-based protocol with protein supplementation delivered greater amounts of protein and energy. This intervention was associated with attenuation of QMLT loss and reduced prevalence of malnutrition at ICU discharge

Cause and Timing of Death and Subgroup Differential Effects of Erythropoietin in the EPO-TBI Study

The EPO-TBI study randomized 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal, or death during maximal care) and non-cerebral (death following withdrawal or during maximal care, which had a non-cerebral cause). The study included 305 patients treated with EPO and 297 treated with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (interquartile range [IQR] 5-16) compared with 29 days (IQR 7-56) (p = 0.01) for non-cerebral COD. When assessing subgroups by admission CT scan injury findings, we found no significant differential effects of EPO compared with placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to intensive care unit (ICU) admission (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.14-0.61, p = 0.001, p for interaction = 0.003) and in this subgroup, fewer patients died of cerebral causes in the EPO than in the placebo group (5% compared with 14%, p = 0.03). In conclusion, most TBI deaths were from cerebral causes that occurred during the first 2 weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomization.Peer reviewe

Vasopressin versus norepinephrine infusion in patients with septic shock

Background Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors

Early Osmotherapy in Severe Traumatic Brain Injury : An International Multicenter Study

The optimal osmotic agent to treat intracranial hypertension in patients with severe traumatic brain injury (TBI) remains uncertain. We aimed to test whether the choice of mannitol or hypertonic saline (HTS) as early (first 96 h) osmotherapy in these patients might be associated with a difference in mortality. We retrospectively analyzed data from 2015 from 14 tertiary intensive care units (ICUs) in Australia, UK, and Europe treating severe TBI patients with intracranial pressure (ICP) monitoring and compared mortality in those who received mannitol only versus HTS only. We performed multi-variable analysis adjusting for site and illness severity (Injury Severity Score, extended IMPACT score, and mean ICP over the first 96 h) using Cox proportional hazards regression. We collected data on 262 patients and compared patients who received early osmotherapy with mannitol alone (n = 46) with those who received HTS alone (n = 46). Mannitol patients were older (median age, 49.2 (19.2) vs. 40.5 (16.8) years; p = 0.02), with higher Injury Severity Scores (42 (15.9) vs. 32.1 [11.3]; p = 0.001), and IMPACT-TBI predicted 6-month mortality (34.5% [23-46] vs. 25% [13-38]; p = 0.02), but had similar APACHE-II scores, and mean and maximum ICPs over the first 96 h. The unadjusted hazard ratio for in-hospital mortality in patients receiving only mannitol was 3.35 (95% confidence interval [CI], 1.60-7.03; p = 0.001). After adjustment for key mortality predictors, the hazard ratio for in-hospital mortality in patients receiving only mannitol was 2.64 (95% CI, 0.96-7.30; p = 0.06). The choice of early osmotherapy in severe TBI patients may affect survival, or simply reflect clinician beliefs about their different roles, and warrants controlled investigation.Peer reviewe

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570