Randomized Phase 3 Trial of Ruxolitinib for COVID-19-Associated Acute Respiratory Distress Syndrome.

OBJECTIVES: Evaluate the safety and efficacy of the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib in COVID-19-associated acute respiratory distress syndrome requiring mechanical ventilation. DESIGN: Phase 3 randomized, double-blind, placebo-controlled trial Ruxolitinib in Participants With COVID-19-Associated Acute Respiratory Distress Syndrome Who Require Mechanical Ventilation (RUXCOVID-DEVENT; NCT04377620). SETTING: Hospitals and community-based private or group practices in the United States (29 sites) and Russia (4 sites). PATIENTS: Eligible patients were greater than or equal to 12 years old, hospitalized with severe acute respiratory syndrome coronavirus 2 infection, and mechanically ventilated with a Pa o2 /F io2 of less than or equal to 300 mm Hg within 6 hours of randomization. INTERVENTIONS: Patients were randomized 2:2:1 to receive twice-daily ruxolitinib 15 mg, ruxolitinib 5 mg, or placebo, each plus standard therapy. MEASUREMENTS AND MAIN RESULTS: The primary endpoint, 28-day mortality, was tested for each ruxolitinib group versus placebo using a mixed-effects logistic regression model and one-tailed significance test (significance threshold: p < 0.025); no type 1 error was allocated to secondary endpoints. Between May 24, 2020 and December 15, 2020, 211 patients (age range, 24-87 yr) were randomized (ruxolitinib 15/5 mg, n = 77/87; placebo, n = 47). Acute respiratory distress syndrome was categorized as severe in 27% of patients (58/211) at randomization; 90% (190/211) received concomitant steroids. Day-28 mortality was 51% (39/77; 95% CI, 39-62%) for ruxolitinib 15 mg, 53% (45/85; 95% CI, 42-64%) for ruxolitinib 5 mg, and 70% (33/47; 95% CI, 55-83%) for placebo. Neither ruxolitinib 15 mg (odds ratio, 0.46 [95% CI, 0.201-1.028]; one-sided p = 0.029) nor 5 mg (odds ratio, 0.42 [95% CI, 0.171-1.023]; one-sided p = 0.028) significantly reduced 28-day mortality versus placebo. Numerical improvements with ruxolitinib 15 mg versus placebo were observed in secondary outcomes including ventilator-, ICU-, and vasopressor-free days. Rates of overall and serious treatment-emergent adverse events were similar across treatments. CONCLUSIONS: The observed reduction in 28-day mortality rate between ruxolitinib and placebo in mechanically ventilated patients with COVID-19-associated acute respiratory distress syndrome was not statistically significant; however, the trial was underpowered owing to early termination.

Efficacy of 4-Factor Prothrombin Complex Concentrates in Factor Xa Inhibitor-Associated Intracranial Bleeding.

BACKGROUND/OBJECTIVE: Intracranial bleeding (ICB) is a feared complication of systemic anticoagulation. Factor Xa inhibitors (FXaI) are used frequently due to their improved safety profile and predictable kinetics. Andexanet alfa was recently approved for emergent reversal of FXaI agents but was not compared formally to 4-Factor Prothrombin Complex Concentrates (4FPCC) which are the current standard of care in many centers. The objective of this study is to formally evaluate the hemostatic efficacy of 4FPCC in patients with FXaI-associated ICB. METHODS: We performed a retrospective cohort study of patients receiving 4FPCC for the reversal of a FXaI in the setting of acute ICB. Hemostatic efficacy was adjudicated via evaluation of post-4FPCC CT scan using the criteria closely mirroring those outlined in Annexa-4 (excellent < 20% expansion, good > 20% but ≤ 35% expansion, poor > 35% expansion). Each image was reviewed by two neurointensivist attendings for grading. Mortality was assessed until date of discharge. Charts were screened for thrombotic events out to 30 days post-4FPCC administration. RESULTS: A total of 59 patients were included in the final analysis. The mean age in years was 78.5 ± 10.9 and 56% were male. Apixaban was the most common FXaI prescribed at the time of presentation (67.8%). Most patients were on FXaI therapy for stroke prevention in the setting of atrial fibrillation (81.3%). Median Glasgow Coma Scale at presentation was 15(IQR 12-15), with the most frequently presenting ICB type being intracerebral hemorrhage (52.5%). The mean dose of 4FPCC prescribed was 46.6 (± 8.2) units/kg. Of those receiving 4FPCC for FXaI ICB, 88% were graded as having an excellent or good hemostatic outcome with excellent interrater reliability. Survival was high at 89.8%, and thrombotic events were seen in seven patients (11.9%). CONCLUSION: 4FPCC appears to be an effective and safe option for FXaI-associated ICB with outcomes comparable to andexanet alfa. A formal prospective evaluation of this strategy versus andexanet alpha including cost analysis is warranted.

Ascorbic Acid, Thiamine, and Steroids in Septic Shock: Propensity Matched Analysis.

INTRODUCTION: We aimed to study the use of ascorbic acid, thiamine, and steroids (ATS) in patients with septic shock (SS). METHODS: Data on 62 patients with SS were collected from Acute Physiologic and Chronic Health Evaluation (APACHE) Outcome database and medical records. The ATS group received full doses of intravenous (IV) ATS (ascorbic acid [1.5 g every 6 hours for 4 days], hydrocortisone [50 mg every 6 hours for 7 days], and thiamine [200 mg every 12 hours for 4 days]). Data included age, gender, APACHE III, acute physiologic score (APS), mechanical ventilation (MV), lactic acid (LA), serum creatinine (Cr), duration of vasopressors (VP, days, median: interquartile ranges [IQR]: [Q1, Q3]), MV-free days (median: IQR [Q1-Q3]), percentage of patients requiring renal replacement therapy (RRT) for acute kidney injury (AKI), and mortality. Propensity analysis was used to match patients on age, gender, MV, APACHE III, APS, LA, and Cr. RESULTS: The ATS group had longer duration of VP (4.5: 4.0-6.0 vs 2.0: 1.0-2.0, P = .001), similar RRT for AKI (26% vs 29%, P = .8), similar MV-free days (10.2: 5.0-15.0 vs 10.2: 1.6-18.0, P > .9), lower intensive care unit mortality (9.6% vs 42%, P = .004), and a trend toward lower hospital mortality (29% vs 45%, P = .2) compared to the NO ATS group. CONCLUSIONS: The use of IV ascorbic acid, thiamine, and hydrocortisone might be beneficial in patients with SS.

Angiotensin II in septic shock.

Septic shock is a life threatening condition and a medical emergency. It is associated with organ dysfunction and hypotension despite optimal volume resuscitation. Refractory septic shock carries a very high rate of mortality and is associated with ischemic and arrhythmogenic complications from high dose vasopressors. Angiotensin II (AT-II) is a product of the renin-angiotensin-aldosterone system. It is a vasopressor agent that has been recently approved by FDA to be used in conjunction with other vasopressors (catecholamines) in refractory shock and to reduce catecholamine requirements. We have reviewed the physiology and current literature on AT-II in refractory septic/vasodilatory shock. Larger trials with longer duration of follow-up are warranted to address the questions which are unanswered by the ATHOS-3 trial, especially pertaining to its effects on lungs, brain, microcirculation, inflammation, and venous thromboembolism risk.

Is it possible to recover from traumatic brain injury and a Glasgow coma scale score of 3 at emergency department presentation?

INTRODUCTION: A Glasgow Coma Scale (GCS) score of 3 on presentation in patients with traumatic brain injury (TBI) portends a poor prognosis. Consequently, there is often a tendency to treat these patients less aggressively because of low expectations for a good outcome. METHODS AND RESULTS: We performed a retrospective review of patients with TBI and a GCS score of 3. Patients were divided into 2 groups based on Glasgow Outcome Scale (GOS): Group 1 (GOS=1-3) and Group 2 (GOS=4-5). A total of 62 patients were included. The overall mortality rate was 80.6%. At 6-month, 9 patients (14.5%) achieved a GOS 4-5. Compared to Group 2 (n=9), Group 1 (n=53) had higher average APACHE IV score (104±19 vs 89±27, p=0.04), more patients with bilateral fixed pupils (59% vs 22%, p=0.04), and higher ICP burden (50±34 vs 0±0, p=0.0001). Using the CRASH calculator, the estimated mortality at 14days was 66% compared to actual mortality of 81%; difference of 15%, (p=0.05), and the estimated GOS 1-3 was 85.5% compared to actual of 85.5%, (p=1.0). CONCLUSIONS: 14.5% of patients with TBI and a GCS of 3 at presentation achieved a good outcome at 6months, and 6.9% of patients with GCS of 3 and bilateral fixed pupils on presentation to the ED achieved a good outcome at 6months.

Mildly elevated lactate levels are associated with microcirculatory flow abnormalities and increased mortality: a microSOAP post hoc analysis.

BACKGROUND: Mildly elevated lactate levels (i.e., 1-2 mmol/L) are increasingly recognized as a prognostic finding in critically ill patients. One of several possible underlying mechanisms, microcirculatory dysfunction, can be assessed at the bedside using sublingual direct in vivo microscopy. We aimed to evaluate the association between relative hyperlactatemia, microcirculatory flow, and outcome. METHODS: This study was a predefined subanalysis of a multicenter international point prevalence study on microcirculatory flow abnormalities, the Microcirculatory Shock Occurrence in Acutely ill Patients (microSOAP). Microcirculatory flow abnormalities were assessed with sidestream dark-field imaging. Abnormal microcirculatory flow was defined as a microvascular flow index (MFI) < 2.6. MFI is a semiquantitative score ranging from 0 (no flow) to 3 (continuous flow). Associations between microcirculatory flow abnormalities, single-spot lactate measurements, and outcome were analyzed. RESULTS: In 338 of 501 patients, lactate levels were available. For this substudy, all 257 patients with lactate levels ≤ 2 mmol/L (median [IQR] 1.04 [0.80-1.40] mmol/L) were included. Crude ICU mortality increased with each lactate quartile. In a multivariable analysis, a lactate level > 1.5 mmol/L was independently associated with a MFI < 2.6 (OR 2.5, 95% CI 1.1-5.7, P = 0.027). CONCLUSIONS: In a heterogeneous ICU population, a single-spot mildly elevated lactate level (even within the reference range) was independently associated with increased mortality and microvascular flow abnormalities. In vivo microscopy of the microcirculation may be helpful in discriminating between flow- and non-flow-related causes of mildly elevated lactate levels. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01179243 . Registered on August 3, 2010.

A Model for Identifying Patients Who May Not Need Neurologic Intensive Care Unit Admission: Resource Utilization Study.

PURPOSE: Limited resources, neurointensivists, and neurologic intensive care unit (neuro-ICU) beds warrant investigating models for predicting who will benefit from admission to neuro-ICU. This study presents a possible model for identifying patients who might be too well to benefit from admission to a neuro-ICU. METHODS: We retrospectively identified all patients admitted to our 16-bed neuro-ICU between November 2009 and February 2013. We used the Acute Physiology and Chronic Health Evaluation (APACHE) outcomes database to identify patients who on day 1 of neuro-ICU admission received 1 or more of 30 subsequent active life-supporting treatments. We compared 2 groups of patients: low-risk monitor (LRM; patients who did not receive active treatment [AT] on the first day and whose risk of ever receiving AT was ≤ 10%) and AT (patients who received at least 1 of the 30 ICU treatments on any day of their ICU admission). RESULTS: There were 873 (46%) admissions in the LRM group and 1006 (54%) admissions in the AT group. The ICU length of stay in days was 1.7 (± 1.9) for the LRM group versus 4.5 (± 5.5) for the AT group. The ICU mortality was 0.8% for the LRM group compared to 14% for the AT group (odds ratio [OR] = 17.6; 95% confidence interval [CI], 8.2-37.8, P < .0001). Hospital mortality was 1.9% for the LRM group compared to 19% for the AT group (OR = 9.7; 95% CI, 5.8-16.1, P < .0001). CONCLUSION: The outcome for LRM patients in our neuro-ICU suggests they may not require admission to neurologic intensive care. This may provide a measure of neuro-ICU resource use. Improved resource use and reduced costs might be achieved by strategies to provide care for these patients on floors or intermediate care units. This model will need to be validated in other neuro-ICUs and prospectively studied before it can be adopted for triaging admissions to neuro-ICUs.

Comparison of the Full Outline of UnResponsiveness score and the Glasgow Coma Scale in predicting mortality in critically ill patients*.

OBJECTIVE: Impaired consciousness has been incorporated in prediction models that are used in the ICU. The Glasgow Coma Scale has value but is incomplete and cannot be assessed in intubated patients accurately. The Full Outline of UnResponsiveness score may be a better predictor of mortality in critically ill patients. SETTING: Thirteen ICUs at five U.S. hospitals. SUBJECTS: One thousand six hundred ninety-five consecutive unselected ICU admissions during a six-month period in 2012. DESIGN: Glasgow Coma Scale and Full Outline of UnResponsiveness score were recorded within 1 hour of admission. Baseline characteristics and physiologic components of the Acute Physiology and Chronic Health Evaluation system, as well as mortality were linked to Glasgow Coma Scale/Full Outline of UnResponsiveness score information. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We recruited 1,695 critically ill patients, of which 1,645 with complete data could be linked to data in the Acute Physiology and Chronic Health Evaluation system. The area under the receiver operating characteristic curve of predicting ICU mortality using the Glasgow Coma Scale was 0.715 (95% CI, 0.663-0.768) and using the Full Outline of UnResponsiveness score was 0.742 (95% CI, 0.694-0.790), statistically different (p = 0.001). A similar but nonsignificant difference was found for predicting hospital mortality (p = 0.078). The respiratory and brainstem reflex components of the Full Outline of UnResponsiveness score showed a much wider range of mortality than the verbal component of Glasgow Coma Scale. In multivariable models, the Full Outline of UnResponsiveness score was more useful than the Glasgow Coma Scale for predicting mortality. CONCLUSIONS: The Full Outline of UnResponsiveness score might be a better prognostic tool of ICU mortality than the Glasgow Coma Scale in critically ill patients, most likely a result of incorporating brainstem reflexes and respiration into the Full Outline of UnResponsiveness score.

International study on microcirculatory shock occurrence in acutely ill patients.

OBJECTIVES: Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. The prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables. DESIGN: Multicenter observational point prevalence study. SETTING: The Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide. PATIENTS: A heterogeneous ICU population consisting of 501 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10-21), a Sequential Organ Failure Assessment score of 5 (2-8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67-4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963-0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11-3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28-3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. In reference to microvascular flow index, a significant interaction was observed with tachycardia. In patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30-8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients. CONCLUSIONS: In a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.

Continuous Electroencephalogram in Comatose Postcardiac Arrest Syndrome Patients Treated With Therapeutic Hypothermia: Outcome Prediction Study.

PURPOSE: Therapeutic Hypothermia (TH) is the only therapeutic intervention proven to significantly improve survival and neurologic outcome in comatose postcardiac arrest patients and is now considered standard of care. When we discuss prognostication with regard to comatose survivors postcardiac arrest, we should look for tools that are both reliable and accurate and that achieve a false-positive rate (FPR) equal to or very closely approaching zero. METHODS: We retrospectively reviewed data that were prospectively collected on all cardiac arrest patients admitted to our ICU. Continuous electroencephalogram (cEEG) monitoring was performed as part of our protocol for therapeutic hypothermia in comatose postcardiac arrest patients. The primary outcome measure was the best score on hospital discharge on the 5-point Glasgow-Pittsburgh cerebral performance category (CPC) scores. RESULTS: A total of 58 patients were included in this study. Twenty five (43%) patients had a good neurologic outcome (CPC score of 1-2). Three (5.2%) patients had nonconvulsive status epilepticus, all of whom had poor outcome (CPC = 5). Seventeen (29%) patients had burst suppression (BS); all had poor outcome. Both nonconvuslsive seizures (NCS) and BS had a specificity of 100% (95% confidence interval [CI], 84%-100%), positive predictive values of 100% (95% CI, 31%-100%), and 100% (95% CI, 77%-100%), respectively. Both NCS and BS had FPRs of zero (95% CI, 0.0-0.69, and 0.0-0.23, respectively). CONCLUSIONS: In comatose postcardiac arrest patients treated with hypothermia, EEG during the maintenance and rewarming phase of hypothermia can contribute to prediction of neurologic outcome. Pending large multicenter prospective studies evaluating the role of cEEG in prognostication, our study adds to the existing evidence that cEEG can play a potential role in prediction of outcome in postcardiac arrest patients treated with hypothermia.

Fluid resuscitation in septic shock: the effect of increasing fluid balance on mortality.

PURPOSE: To determine whether progressively increasing fluid balance after initial fluid resuscitation for septic shock is associated with increased mortality. METHODS: A retrospective review of the use of intravenous fluids in patients with septic shock in a large university affiliated hospital with 56 medical-surgical intensive care unit beds. We analyzed the data of 350 patients with septic shock who were managed according to the Surviving Sepsis Campaign guidelines. Based on net fluid balance at 24 hours, we examined the results of increase in positive fluid balance on the risk of in-hospital mortality. Patients were divided into 4 groups based on the amount of fluid balance by 24 hours, based on 6-L aliquots. RESULTS: At 24 hours, the average fluid balance was +6.5 L. After correcting for age and sequential organ failure assessment score, a more positive fluid balance at 24 hours significantly increased the risk of in-hospital mortality. Using Cox proportional hazard analysis, excess 12-, 18-, and 24-L positive fluid balance had higher risk of mortality than those patients with a neutral to positive 6-L fluid balance (reference group). Adjusted hazard ratios, 1.519 (95% confidence interval [CI], 1.353-1.685), 1.740 (95% CI, 1.467-2.013), and 1.620 (95% CI, 1.197-2.043), respectively, P < .05. CONCLUSION: In patients with septic shock resuscitated according to current guidelines, a more positive fluid balance at 24 hours is associated with an increase in the risk of mortality. Optimal survival occurred at neutral fluid balance and up to 6-L positive fluid balance at 24 hours after the development of septic shock.

Red cell distribution width and outcome in patients with septic shock.

INTRODUCTION: Red cell distribution width (RDW) is reflective of systemic inflammation. The objective of this study was to investigate the association between RDW (on day 1 of development of septic shock) and mortality. METHODS: A total of 279 patients with septic shock were included. We categorized the patients into quintiles based on RDW as follows: <13.5%, 13.5% to 15.5%, 15.6% to 17.5%, 17.5% to 19.4%, and >19.4%. RESULTS: Red cell distribution width was a strong predictor of hospital mortality with a significant risk gradient across RDW quintiles after multivariable adjustment: RDW 13.5% to 15.5% (odds ratio [OR], 4.6; 95% confidence interval [CI], 1.0-23.4; P = .06); RDW 15.6% to 17.5% (OR, 8.0; 95% CI, 1.5-41.6; P = .01); RDW 17.6% to 19.4% (OR, 25.3; 95% CI, 4.3-149.2; P < .001); and RDW >19.4% (OR, 12.3; 95% CI, 2.1-73.3; P = .006), all relative to patients with RDW <13.5%. Similar significant robust associations were present for intensive care unit mortality. Estimating the receiver-operating characteristic area under the curve (AUC) showed that RDW has very good discriminative power for hospital mortality (AUC = 0.74). The AUC was 0.69 for Acute Physiologic and Chronic Health Evaluation II (APACHE II) and 0.69 for sequential organ failure assessment (SOFA). When adding RDW to APACHE II, the AUC increased from 0.69 to 0.77. CONCLUSIONS: Red cell distribution width on day 1 of septic shock is a robust predictor of mortality. The RDW is inexpensive and commonly measured. The RDW fared better than either APACHE II or SOFA, and the sum of RDW and APACHE II was a stronger predictor of mortality than either one alone.

Placement of intracranial pressure monitors by neurointensivists: case series and a systematic review.

PRIMARY OBJECTIVE: Placement of an intracranial pressure (ICP) monitor to guide the management of patients with severe traumatic brain injury (TBI) has been historically performed by neurosurgeons. It is hypothesized that ICP monitors can be placed by non-surgeon neurointensivists, with placement success and complication rates comparable to neurosurgeons. RESEARCH DESIGN: Retrospective review and systematic review of the literature. METHODS AND PROCEDURES: This study reviewed the medical records of patients with TBI who required insertion of parenchymal ICP monitors performed by four neurointensivists in a large level I trauma centre. Patient data recorded were age, gender, CT findings, ICP monitor placement, location and length of placement, complications related to the ICP monitor and patient outcomes. MAIN OUTCOMES AND RESULTS: Thirty-eight (38) monitors (Camino) were placed. Patients' average age was 43.0 years (SD = 21.6); 76% were males. The location of monitor was right frontal in 89% and left frontal in 11%. Mean ICP was 24 (SD = 15), duration of ICP monitor was 4.9 days (SD = 3.6). All monitors were placed successfully. There were no major technical complications, no episodes of major catheter-induced intracranial haemorrhage and no infectious complications. These findings were comparable to published outcomes from neurosurgeon placements. CONCLUSIONS: It is believed that insertion of ICP monitors by neurointensivists is safe and may aid in providing prompt monitoring of patients with severe TBI.

Therapeutic hypothermia for a comatose survivor of near-hanging.

Therapeutic hypothermia is recommended for comatose survivors of cardiac arrest. Therapeutic hypothermia ameliorates multiple pathophysiologic mechanisms involved in ischemia-reperfusion injury, which may occur after cardiac arrest and near-hanging. Therapeutic hypothermia has not been prospectively studied in near-hanging. Victims of near-hanging suffer from strangulation with cerebral ischemia and resultant reperfusion injury rather than a fatal cervical spine injury. We report a case where therapeutic hypothermia was applied to a comatose survivor of near-hanging. A 41-year-old man presented with coma following attempted suicide by hanging. The patient underwent 24 hours of mild therapeutic hypothermia. The patient was discharged without neurologic sequelae and a Modified Rankin Scale of 0 (back to his baseline status). We present a case where therapeutic hypothermia was used safely and successfully in a patient without cardiac arrest but still in coma after attempted suicide by hanging. No randomized controlled trials on therapeutic hypothermia for comatose survivors of near-hanging victims have been published. However, in the absence of better evidence, it seems reasonable to consider hypothermia treatment in comatose near-hanging victims until more evidence can be obtained.

Therapeutic hypothermia for the management of intracranial hypertension in severe traumatic brain injury: a systematic review.

BACKGROUND: Traumatic brain injury (TBI) is a major source of death and severe disability worldwide. Raised Intracranial pressure (ICP) is an important predictor of mortality in patients with severe TBI and aggressive treatment of elevated ICP has been shown to reduce mortality and improve outcome. The acute post-injury period in TBI is characterized by several pathophysiologic processes that start in the minutes to hours following injury. All of these processes are temperature-dependent; they are all aggravated by fever and inhibited by hypothermia. METHODS: This study reviewed the current clinical evidence in support of the use of therapeutic hypothermia (TH) for the treatment of intracranial hypertension (ICH) in patients with severe TBI. RESULTS: This study identified a total of 18 studies involving hypothermia for control of ICP; 13 were randomized controlled trials (RCT) and five were observational studies. TH (32-34°C) was effective in controlling ICH in all studies. In the 13 RCT, ICP in the TH group was always significantly lower than ICP in the normothermia group. In the five observational studies, ICP during TH was always significantly lower than prior to inducing TH. CONCLUSIONS: Pending results from large multi-centre studies evaluating the effect of TH on ICH and outcome, TH should be included as a therapeutic option to control ICP in patients with severe TBI.

The FOUR score predicts outcome in patients after traumatic brain injury.

BACKGROUND: The most widely used and most studied coma score to date is the Glasgow Coma Scale (GCS), which is used worldwide to assess level of consciousness and predict outcome after traumatic brain injury (TBI). Our aim was to determine whether the Full Outline of UnResponsiveness (FOUR) score is an accurate predictor of outcome in TBI patients and to compare its performance to GCS. METHODS: We prospectively identified TBI patients admitted to our Neuro-ICU between July 2010 and February 2011. We enrolled 51 patients. The FOUR score and GCS were determined by one of the investigators. Outcomes were in-hospital mortality, and poor neurologic outcome (Glasgow Outcome Scale (GOS) 1-3 and Modified Rankin Scale (mRS) score 3-6) at 3-6 months. RESULTS: There was a high degree of internal consistency for both the FOUR score (Cronbach's alpha = 0.89) and GCS (Cronbach's alpha = 0.85). In terms of predictive power for in-hospital mortality, the area under the receiver operating characteristic (ROC) curve was 0.93 for FOUR score and 0.89 for GCS. In terms of predictive power of poor neurologic outcome at 3-6 months, the area under the ROC curve was 0.85 for FOUR score and 0.83 for GCS as evidenced by GOS 1-3, and 0.80 for FOUR score and 0.78 for GCS as evidenced by mRS 3-6. The odds ratio (OR) for in-hospital mortality was 0.64 (0.46-0.88) from FOUR score and 0.63 (0.45-0.89) from GCS, for poor neurologic outcome was 0.67 (0.53-0.85) from FOUR score and 0.65 (0.51-0.83) from GCS for GOS, and was 0.71 (0.57-0.87) from FOUR score and 0.71 (0.57-0.87) from GCS for mRS. CONCLUSION: The FOUR score is an accurate predictor of outcome in TBI patients. It has some advantages over GCS, such as all components of FOUR score but not GCS can be rated in intubated patients.

Activated protein C in septic shock: a propensity-matched analysis.

INTRODUCTION: The use of human recombinant activated protein C (rhAPC) for the treatment of severe sepsis remains controversial despite multiple reported trials. The efficacy of rhAPC remains a matter of dispute. We hypothesized that patients with septic shock who were treated with rhAPC had an improved in-hospital mortality compared to patients with septic shock with similar acuity who did not receive rhAPC. METHODS: This retrospective cohort study was completed at a large university-affiliated hospital. All patients with septic shock admitted to a 50-bed ICU between July 2003 and February 2009 were included. Patients were treated according to sepsis management guidelines. RESULTS: A total of 563 septic shock patients were included (110 received rhAPC and 453 did not). Treated and untreated groups were matched in patient characteristics, comorbidities, and physiologic variables in a 1:1 propensity-matched analysis (108 received rhAPC, 108 did not). Mean Acute Physiology And Chronic Health Evaluation II (APACHE II) scores were 24.5 for the matched treated and 23.9 for the matched untreated group (P = 0.54). Receipt of rhAPC was associated with reduced in-hospital mortality (35.2% vs. 53.8%, P = 0.005), similar mean days on vasopressors (2 vs. 2, P = 0.90), similar mean days on mechanical ventilation (9 vs. 8.7, P = 0.80), similar mean length of ICU stay in days (11.0 vs. 11.3, P = 0.90), and similar mean length of hospital stay in days (19.5 vs 27, P = 0.11). No patients in either group had intracranial bleeding; differences in gastrointestinal bleeding and transfusion requirements were not statistically significant. CONCLUSIONS: Patients in our institution with septic shock who were treated with rhAPC had a reduced in-hospital mortality compared with patients with septic shock with similar acuity who were not treated with rhAPC. In addition, time on mechanical ventilation, time on vasopressors, lengths of stay and bleeding complications did not differ between the groups.

Theophylline for bradycardia secondary to cervical spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a devastating disease process that can occur as a consequence of motor vehicle collisions, falls, or other traumatic injuries. Persistent bradycardia was found to be universally present in all high cervical SCI patients. Limited data exists to suggest the most effective therapy for the bradycardia associated with high cervical SCI. Treatment includes atropine, epinephrine, dopamine, and even implantable cardiac pacemakers, all of which have their risks and side effects. There are no prospective studies to evaluate methylxanthines for the treatment of bradycardia secondary to cervical SCI. METHODS: We report on four patients in whom Theophylline was successfully used enterally as a second line agent to treat bradycardia secondary to cervical SCI. We also reported on two patients in whom Theophylline was successfully used as a first line agent. Bradycardia resolved in all patients RESULTS: Theophylline levels were below toxic levels in all of the patients and no side effects from theophylline were observed. CONCLUSIONS: Theophylline's use via enteral route can successfully and safely treat SCI-related bradycardia, and may help avoid the long term use of inotropic and chronotropic infusions and pacemakers and their associated risks and complications. We strongly recommend further studies to establish the role of this agent as a first line therapy in this specific patient population. Optimal dosing and duration of therapy will also need to be established.

Thrombocytopenia: A possible side effect of apixaban.

Apixaban is becoming more frequently prescribed for stroke prevention in patients with atrial fibrillation, and even rare side effects such as thrombocytopenia should be considered and monitored closely.

Correction to: Variability in functional outcome and treatment practices by treatment center after out-of-hospital cardiac arrest: analysis of International Cardiac Arrest Registry.

The original version of this article unfortunately contained a mistake.