The critical care literature 2016

YAJEM-56822; No of Pages 8 American Journal of Emergency Medicine xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem

The critical care literature 2016 Michael E. Winters, MD a,⁎, Joseph P. Martinez, MD a, Haney Mallemat, MD b, William J. Brady, MD c a b c

Departments of Emergency Medicine and Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA Cooper Medical School of Rowan University, Camden, NJ, USA Departments of Emergency Medicine and Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

a r t i c l e

i n f o

Article history: Received 24 February 2017 Received in revised form 30 June 2017 Accepted 12 July 2017 Available online xxxx

a b s t r a c t An emergency physician (EP) is often the first health care provider to evaluate, resuscitate, and manage a critically ill patient. Between 2001 and 2009, the annual hours of critical care delivered in emergency departments (EDs) across the United States increased N200%! (Herring et al., 2013). This trend has persisted since then. In addition to seeing more critically ill patients, EPs are often tasked with providing critical care long beyond the initial resuscitation period. In fact, N33% of critically ill patients who are brought to an ED remain there for N6 h (Herring et al., 2013). During these crucial early hours of illness, detrimental pathophysiologic processes begin to take hold. During this time, lives can be saved or lost. Therefore, it is important for the EP to be knowledgeable about recent developments in critical care medicine. This review summarizes important articles published in 2016 pertaining to the care of select critically ill patients in the ED. The following topics are covered: intracerebral hemorrhage, traumatic brain injury, anti-arrhythmic therapy in cardiac arrest, therapeutic hypothermia, mechanical ventilation, sepsis, and septic shock. © 2017 Elsevier Inc. All rights reserved.

Contents 1. 2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Neurocritical care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.1. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med 2016;375(11):1033–43 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 2.2. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomized, open-label, phase 3 trial. Lancet 2016;387:2605–13 . . . . . . . 0 2.3. Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med 2016;375:1119–30 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Cardiac arrest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 3.1. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest. N Engl J Med 2016;374:1711–22 . 0 3.2. Bernard SA, Smith K, Finn J, et al. Induction of therapeutic hypothermia during out-of-hospital cardiac arrest using a rapid infusion of cold saline: The RINSE Trial (Rapid Infusion of Cold Normal Saline). Circulation 2016;134:797–805 . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Mechanical ventilation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4.1. Faust AC, Rajan P, Sheperd LA, et al. Impact of an analgesia-based sedation protocol on mechanically ventilated patients in the medical intensive care unit. Anesth Analg 2016;123:903–9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 4.2. Girardis M, Busani S, Damaini E, et al. Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit. The Oxygen-ICU Randomized Clinical Trial. JAMA 2016;316:1583–9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801–10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.2. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH randomized clinical trial. JAMA 2016;316:509–18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 5.3. Keh D, Trips E, Wirtz SP, et al. Effect of hydrocortisone on development of shock among patients with severe sepsis. The HYPRESS Randomized Clinical Trial. JAMA 2016;316:1775–85 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

⁎ Corresponding author. E-mail address: [email protected] (M.E. Winters).

http://dx.doi.org/10.1016/j.ajem.2017.07.036 0735-6757/© 2017 Elsevier Inc. All rights reserved.

Please cite this article as: Winters ME, et al, The critical care literature 2016, American Journal of Emergency Medicine (2017), http://dx.doi.org/ 10.1016/j.ajem.2017.07.036

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M.E. Winters et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx

6. Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction An emergency physician (EP) is often the first health care provider to evaluate, resuscitate, and manage a critically ill patient. Between 2001 and 2009, the annual hours of critical care delivered in emergency departments (EDs) across the United States increased N200%! [1]. This trend has persisted since then. In addition to seeing more critically ill patients, EPs are often tasked with providing critical care long beyond the initial resuscitation period. In fact, N 33% of critically ill patients who are brought to an ED remain there for N 6 h [1]. During these crucial early hours of illness, detrimental pathophysiologic processes begin to take hold. During this time, lives can be saved or lost. Therefore, it is important for the EP to be knowledgeable about recent developments in critical care medicine. This review summarizes important articles published in 2016 pertaining to the care of select critically ill patients in the ED. We selected these articles based on our opinion of the importance of study findings and the immediate application to clinical care. The following topics are covered: intracerebral hemorrhage, traumatic brain injury, anti-arrhythmic therapy in cardiac arrest, intra-arrest therapeutic hypothermia, mechanical ventilation, sepsis, and septic shock. 2. Neurocritical care 2.1. Qureshi AI, Palesch YY, Barsan WG, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med 2016;375(11):1033–43 The management of ED patients with acute intracerebral hemorrhage (ICH) is complex and challenging. Current guidelines for the management of spontaneous ICH emphasize the calculation of a baseline severity score (i.e., ICH score), rapid performance of neuroimaging, blood pressure management, reversal of coagulopathy, surgical therapy when appropriate, and admission to a dedicated intensive care unit (ICU) with expertise in neurocritical care [2]. Markedly elevated blood pressure is common in ED patients with acute ICH and has been associated with an increased risk of death [3-5]. Recently, the second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT-2) trial demonstrated a nonsignificant improvement in the outcomes (death or disability) of patients with acute ICH, who had an initial systolic blood pressure (SBP) between 150 and 220 mm Hg and received intensive blood pressure reduction to a target SBP b 140 mm Hg [6]. Important limitations of the INTERACT-2 trial included that fact that almost 70% of enrolled patients were from a single continent, 7 blood pressure medications were used, patients with SBP readings ≥ 220 mm Hg were not enrolled, and the majority of patients had small ICHs. As a result of the continued controversy regarding intensive blood pressure reduction in patients with ICH, Qureshi and colleagues sought to determine the efficacy of intensive antihypertensive treatment initiated within 4.5 h after symptom onset in patients with spontaneous supratentorial ICH. The Acute Cerebral Hemorrhage II (ATACH-2) trial was a randomized, two-group, open label trial conducted at 110 sites in the United States, Japan, China, Taiwan, South Korea, and Germany. Patients included in the study were 18 years of age or older, had a Glasgow Coma Scale (GCS) score of 5 or more upon ED arrival, had an ICH volume b60 cm3, and had at least one SBP reading of 180 mm Hg or more prior to initiation of antihypertensive treatment. Patients were randomized into two groups: a standard treatment group and an intensive treatment group. Patients in the standard treatment group received antihypertensive

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therapy to target a SBP between 140 and 170 mm Hg, whereas patients in the intensive treatment group received medications to target a SBP between 110 and 139 mm Hg. Importantly, antihypertensive treatment had to be initiated within 4.5 h after symptom onset. The primary antihypertensive medication used in this trial was nicardipine. Labetalol could be used if the SBP target was not reached with the maximum dose of nicardipine. Patients were assessed with repeat computed tomography (CT) scan of the head at 24 h after initiation of treatment. Follow-up was performed at 1 month with a telephone call and at 3 months with an in-person evaluation. The primary outcome of the study was the proportion of patients who died or had moderately severe to severe disability, as assessed by the modified Rankin Scale (mRS). One thousand patients were included in the ATACH-2 trial, with 500 randomized to each group. There was no difference in the primary outcome of death or moderately severe or severe disability between the groups (38.7% in the intensive treatment group, 37.7% in the standard group; relative risk 1.04, 95% confidence interval 0.85 to 1.27). Furthermore, there was no difference between the two groups in ordinal distribution of the mRS score at 3 months. Serious adverse events occurred in 1.6% of patients in the intensive treatment group compared with 1.2% in the standard treatment group. Limitations of the ATACH-2 trial should be noted. Importantly, the trial was stopped early for futility prior to enrolling the target of 1280 patients. Furthermore, the study was an open-label trial and was not blinded. Additional limitations include a lower than anticipated mortality rate in the standard treatment group and a higher proportion of treatment failure in the intensive treatment group compared with the standard treatment group (12% vs. 0.8%). Treatment failure was defined by the investigators as not reaching the target SBP of b 140 mm Hg in the intensive treatment group or b 180 mm Hg in the standard treatment group. Despite these limitations, the ATACH-2 trial provides valuable information for the EP who must manage blood pressure in a patient with acute ICH. Based on the results of this study, intensive reduction of SBP to b 140 mm Hg does not improve patient-centered outcomes. 2.2. Baharoglu MI, Cordonnier C, Al-Shahi Salman R, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomized, open-label, phase 3 trial. Lancet 2016;387:2605–13 Spontaneous ICH is a devastating illness that affects up to 2 million patients worldwide each year and has a 1-month mortality rate approaching 40% [7,8]. Limited data suggest that patients taking an antiplatelet medication might have a higher incidence of ICH than those not taking that type of medication [9]. In addition, patients with ICH who are taking an antiplatelet medication might have worse outcomes than those not taking an antiplatelet medication [10,11]. The benefit of an empiric platelet transfusion into patients with an ICH known to be taking an antiplatelet medication remains uncertain. Unfortunately, no randomized trials have evaluated the use of platelet transfusions in this setting to guide the bedside clinician. Therefore, the authors of the current trial sought to determine whether platelet transfusion would improve outcomes compared with standard care in patients with a spontaneous ICH who were taking an antiplatelet medication. The Platelet Transfusion Versus Standard Care after Acute Stroke Due to Spontaneous Cerebral Hemorrhage (PATCH) trial was a multicenter, randomized, open-label, parallel-group trial performed in 36 centers in the Netherlands, 13 centers in the United Kingdom, and 11 centers in France. Patients included in the study were 18 years of age or older

Please cite this article as: Winters ME, et al, The critical care literature 2016, American Journal of Emergency Medicine (2017), http://dx.doi.org/ 10.1016/j.ajem.2017.07.036

M.E. Winters et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx

with a nontraumatic supratentorial ICH, a GCS score of 8 to 15, and a pre-ICH mRS score of 0 or 1 and had taken antiplatelet medication for at least 7 days prior to the ICH. Antiplatelet medications included cyclooxygenase inhibitors (COX) (i.e., aspirin), adenosine diphosphate (ADP) receptor inhibitors (i.e., clopidogrel), and adenosine reuptake inhibitors (i.e., dipyridamole). Patients were randomized to two groups: standard care or standard care plus platelet transfusion. Patients in the standard care plus platelet transfusion group received leukocyte-depleted platelets within 6 h after symptom onset and within 90 min after neuroimaging. One platelet concentrate was transfused to patients taking a COXinhibitor, whereas two were transfused to patients taking an ADP receptor inhibitor. Patients in the standard care group received therapy according to current European and national guidelines. The primary outcome of the trial was the difference in functional outcome at 3 months, as assessed with the mRS. A total of 190 patients were enrolled in the PATCH trial, with 93 randomized to the standard care group and 97 to the standard care plus platelet transfusion group. No patients were lost to follow-up at 3 months. Surprisingly, patients who received a platelet transfusion had a higher rate of death or dependency at 3 months (OR 1.84, 95% confidence interval 1.1 to 3.08; P = 0.02). This finding remained consistent across the three countries. In addition, the rate of serious adverse events, though not statistically significant, was higher among patients who received a platelet transfusion than in the standard group (42% vs. 29%). Limitations of the PATCH trial include the small number of patients enrolled in the study, the non-blinded design, and the fact that almost 20% of enrolled patients met at least one exclusion criterion prior to enrollment. Nonetheless, the PATCH trial is an important contribution to the neurocritical care literature. Based on its results, the routine transfusion of platelets to patients with a spontaneous ICH who are taking an antiplatelet medication cannot be recommended. 2.3. Hutchinson PJ, Kolias AG, Timofeev IS, et al. Trial of decompressive craniectomy for traumatic intracranial hypertension. N Engl J Med 2016;375:1119–30 For patients with acute traumatic brain injury (TBI), it is imperative to maintain adequate cerebral perfusion and prevent secondary neurologic injury. Increased intracranial pressure (ICP) is found in many patients with severe TBI and is associated with increased morbidity and mortality [12,13]. Treatment for elevated ICP in these patients often includes sedation, analgesia, elevation of the head of the bed, hyperosmolar therapy, paralysis, and ventriculostomy. The role of surgical therapy for patients with increased ICP refractory to medical treatments remains controversial. In 2011, the Decompressive Craniectomy (DECRA) trial found no improvement in outcomes for TBI patients with increased ICP who were treated with bifrontal decompressive craniectomy [14]. The DECRA trial, however, was criticized for its generalizability and the use of a short time window (15 min) before defining refractory intracranial hypertension. Therefore, Hutchinson and colleagues performed the current study to determine whether decompressive craniectomy reduced the mortality rate and the incidence of neurologic morbidity when used as a last-tier intervention in TBI patients with refractory intracranial hypertension. The Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp) trial was an international, multicenter, randomized trial conducted over 10 years at 52 centers in 20 countries. Investigators enrolled TBI patients between the ages of 10 and 65 years who had an abnormal head CT scan and an ICP above 25 mm Hg for 1 to 12 h despite receiving “stage 1” and “stage 2” therapies. Stage 1 treatment included head elevation, sedation, analgesia, ventilation to target an arterial partial pressure of carbon dioxide (PaCO2) between 34 and 38 mm Hg, supplemental oxygen to target a pulse oximetry reading (SpO2) N97%, central venous pressure monitoring, arterial blood pressure monitoring, and intracranial pressure

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monitoring. Stage 2 treatments could include ventriculostomy, mannitol, hypertonic saline, hypothermia, loop diuretics, and inotropic medications. Importantly, barbiturate medications could not be administered. Patients with persistent elevations in ICP were then randomized to a surgical group or a medical group. Patients in the surgical group underwent decompressive craniectomy within 6 h following randomization. They underwent either unilateral frontotemporoparietal craniectomy or bifrontal craniectomy depending on surgeon preference. Patients randomized to the medical group continued to receive stage 1 and 2 treatments along with barbiturate medication. The primary outcome of the trial was the Extended Glasgow Outcome Scale (GOS-E) score at 6 months following randomization. The GOS-E is an outcome scale that has eight categories ranging from death to “upper good recovery.” The authors dichotomized GOS-E scores into unfavorable (death, vegetative state, lower severe disability) and favorable (severe upper disability, lower and upper moderate disability, and lower and upper good recovery) outcomes. A total of 408 patients were enrolled in the RESCUEicp trial: 206 were randomized to the surgical group and 202 to the medical group. The majority of patients were male, with a mean age between 32 and 35 years. The primary outcomes based on the GOS-E categories at 6 months are listed in Table 1. At 12 months, there was a significant improvement in favorable outcomes in the surgical group compared with the medical group (45.4% vs. 32.4%, P = 0.01). As anticipated, the surgical group had more complications and adverse events than the medical group (15.3% vs. 9.2%). Based on the results of this trial, the authors estimate that, for every 100 patients treated with decompressive craniectomy, 22 more people survive. Importantly, only 36% of these additional survivors would be expected to have favorable outcomes, as assessed by the GOS-E. Several limitations of this study should be noted. Perhaps most importantly, approximately 37% of patients in the medical group ultimately underwent decompressive craniectomy. In addition, recruitment was slow, requiring 10 years to reach the target number of patients. Finally, over 70% of the sites in this trial were in the United Kingdom, which could account for the fact that most patients in the surgical group received bifrontal craniectomy; in contrast, in the United States, patients more commonly received hemicraniectomy. The results of the RESCUEicp trial are not conclusive regarding the use of surgical therapy for patients with acute traumatic TBI. Nonetheless, the study demonstrates that select patients might benefit from this procedure.

3. Cardiac arrest 3.1. Kudenchuk PJ, Brown SP, Daya M, et al. Amiodarone, lidocaine, or placebo in out-of-hospital cardiac arrest. N Engl J Med 2016;374:1711–22 The tenets of ED resuscitation for patients with out-of-hospital cardiac arrest (OHCA) include effective team leadership, the delivery of high-quality chest compressions, and prompt defibrillation for those with a shockable rhythm (e.g., ventricular fibrillation, pulseless ventricular tachycardia). Unfortunately, defibrillation does not restore spontaneous circulation in a large percentage of these patients [15]. For patients with shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, antiarrhythmic medications (i.e., amiodarone, lidocaine) are often administered in an attempt to improve the chances of successful defibrillation and the return of spontaneous circulation (ROSC). Numerous trials have demonstrated that the use of amiodarone improves the chances of ROSC and survival to hospital admission for patients with OHCA [16,17]. Importantly, the data are less clear whether anti-arrhythmic medications improve survival to hospital discharge with meaningful neurologic survival. The authors of the current study sought to compare the effects of amiodarone, lidocaine, and placebo on survival to hospital discharge after OHCA in patients with shockrefractory ventricular fibrillation or pulseless ventricular tachycardia.

Please cite this article as: Winters ME, et al, The critical care literature 2016, American Journal of Emergency Medicine (2017), http://dx.doi.org/ 10.1016/j.ajem.2017.07.036

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M.E. Winters et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx

Table 1 Primary outcomes based on GOS-E at 6 months.

Death Vegetative state (unable to obey commands) Lower severe disability (dependent on others for care) Upper severe disability (independent at home) Lower moderate disability (independent at home with some physical or mental disability) Upper moderate disability (independent at home with some physical or mental disability with less disruption than lower moderate disability) Lower good recovery (able to resume normal activities with some injury-related problems) Upper good recovery (no problems)

This was a randomized, double-blind, placebo-controlled trial performed in 55 emergency medical services (EMS) agencies at 10 North American sites in the Resuscitation Outcomes Consortium. The investigators enrolled adult patients (18 years of age or older) who had nontraumatic OHCA and shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. The investigators defined shockrefractory as persistent or recurrent ventricular fibrillation or pulseless ventricular tachycardia after one or more shocks at any time during the resuscitation. These patients received a vasopressor medication and were randomized to receive amiodarone, lidocaine, or placebo. The initial bolus doses were 300 mg of amiodarone, 120 mg of lidocaine, or normal saline. If patients remained in ventricular fibrillation or pulseless ventricular tachycardia after the initial dose of study drug, they received standard resuscitation measures, another shock, and another dose of study medication. For patients with ROSC, post-arrest care was provided according to current guidelines, which could include open-label amiodarone or lidocaine. The primary outcome of the study was survival to hospital discharge. A secondary outcome of the study was survival to hospital discharge with favorable neurologic status, as assessed with the mRS. A total of 3026 patients were included in the per-protocol population of this study: 974 patients were randomized to amiodarone, 993 to lidocaine, and 1059 to placebo. Patient characteristics were well balanced between the three groups. The median number of EMS shocks delivered before the first dose of the study drug was 3 for the amiodarone, lidocaine, and placebo groups. Importantly, there was no statistical difference in the primary outcome of survival to hospital discharge for patients who received amiodarone (24.4%), lidocaine (23.7%), or placebo (21%). The absolute difference between amiodarone and placebo was 3.2 percentage points (95% CI −0.4 to 7.0; P = 0.08), whereas the absolute difference between lidocaine and placebo was 2.6 percentage points (95% CI −1.0 to 6.3; P = 0.16). Similarly, there was no statistical difference in survival to hospital discharge with favorable neurologic status among patients who received amiodarone (18.8%), lidocaine (17.5%), or placebo (16.6%). The absolute difference between amiodarone and placebo was 2.2 percentage points (95% CI −1.1 to 5.6; P = 0.19), whereas the absolute difference between lidocaine and placebo was 0.9 percentage points (95% CI −2.4 to 4.2; P = 0.59). In the subgroup of patients with bystander-witnessed cardiac arrest, the rate of survival was higher among those who received either amiodarone (27.7%) or lidocaine (27.8%) compared with those who received placebo (22.7%). The rate of adverse events did not differ between the three groups. This is the largest randomized trial to evaluate the benefit of amiodarone or lidocaine in patients with OHCA caused by ventricular fibrillation or pulseless ventricular tachycardia. Strengths of the study include the large number of enrolled patients, the randomized study design, appropriate blinding, and N99% patient follow up. Primary limitations of the study include the facts that it examined only one dosing strategy without allowing for crossover of medications and that it was underpowered to detect a smaller difference with amiodarone or lidocaine compared with placebo. An additional limitation of the study was the lack of standardization of post-arrest care across hospital sites. Specifically, early coronary catheterization and therapeutic

Surgical

Medical

P value

26.9% 8.5% 21.9% 15.4% 10.0% 13.4% 2.5% 1.5%

48.9% 2.1% 14.4% 8.0% 10.1% 9.6% 3.2% 3.7%

b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001

hypothermia have been shown to benefit select patients and may have confounded study results. Though the investigators did not control for hospital care, they did not find any significant differences in the frequency of cardiac catheterization, therapeutic hypothermia, or withdrawal of life-sustaining therapy. The results call into question the routine administration of amiodarone or lidocaine for patients with OHCA resulting from shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. In fact, no trial has demonstrated that anti-arrhythmic medications improve survival to hospital discharge with meaningful neurologic survival in patients with OHCA. 3.2. Bernard SA, Smith K, Finn J, et al. Induction of therapeutic hypothermia during out-of-hospital cardiac arrest using a rapid infusion of cold saline: The RINSE Trial (Rapid Infusion of Cold Normal Saline). Circulation 2016;134:797–805 Therapeutic hypothermia (also known as targeted temperature management [TTM]) has been shown to improve neurologic survival in patients who experience OHCA but remain comatose after ROSC [18-20]. Current international guidelines recommend the initiation of TTM for adults who remain unresponsive after OHCA regardless of the initial rhythm [21]. However, considerable controversy remains regarding its timing, method, and duration. Recent evidence suggests that TTM might be beneficial if it is initiated during cardiopulmonary resuscitation (CPR) rather than waiting until ROSC has been achieved [22]. The use of TTM during CPR has been termed intra-arrest cooling. The authors of the current study sought evaluate the prehospital induction of therapeutic hypothermia during CPR in patients with OHCA. The Rapid Infusion of Cold Normal Saline (RINSE) study was a multicenter, randomized, controlled trial conducted by EMS agencies in three Australian cities: Melbourne, Adelaide, and Perth. The investigators enrolled adults (18 years of age or older) who were in cardiac arrest upon EMS arrival and remained in arrest following establishment of intravenous access, administration of epinephrine, ventilation with 100% oxygen, and defibrillation. Pregnant patients, hospitalized patients, and those with cardiac arrest presumed to be caused by trauma or ICH were excluded from the study. Enrolled patients were then randomized to standard care, as recommended by the Australian Resuscitation Council for the treatment of OHCA, or standard care plus therapeutic hypothermia. Patients randomized to the hypothermia group received a rapid infusion of 30 mL/kg of cold saline to a maximum of 2 L. Temperature was monitored with a tympanic probe and the infusion was stopped if it reached 33C. Patients with ROSC were subsequently transported to a facility with both an ED and intensive care unit. Importantly, standard care at most of the hospitals who received patients in this study included initiation of TTM to a goal of 33C and cardiac catheterization or thrombolysis for patients with an ST-segment elevation myocardial infarction. The primary outcome of the study was survival to hospital discharge. The secondary outcome was the proportion of patients with shockable and nonshockable rhythms who achieved ROSC. A total of 1198 patients were included in the primary analysis of the RINSE trial—618 in the intra-arrest hypothermia group and 580 in the standard care group. More than 60% of patients received bystander CPR, approximately 96% were suspected to have a cardiac cause of the

Please cite this article as: Winters ME, et al, The critical care literature 2016, American Journal of Emergency Medicine (2017), http://dx.doi.org/ 10.1016/j.ajem.2017.07.036

M.E. Winters et al. / American Journal of Emergency Medicine xxx (2017) xxx–xxx

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arrest, 46% had ventricular fibrillation or pulseless ventricular tachycardia, and 33% had asystole as the initial rhythm. Overall, there was no difference in the rates of survival to hospital discharge among patients who received intra-arrest cooling and those who received standard care (10.2% vs. 11.4%; P = 0.51). For the subset of patients who had a shockable rhythm and received intra-arrest therapeutic hypothermia, there was also no difference in their rate of survival to hospital discharge and that among patients who received standard care (18.9% vs. 23.2%; P = 0.21). Importantly, the authors found a significant decrease in the number of patients with a shockable rhythm treated with hypothermia who subsequently achieved ROSC (41% vs. 51%; P = 0.031). The RINSE trial adds to the growing body of literature on TTM. In this study, the prehospital initiation of intra-arrest cooling for OHCA did not improve the rate of survival to hospital discharge. In fact, the rate of ROSC for patients who had an initial shockable rhythm was reduced. Limitations of the RINSE trial include the fact that it was not blinded, the investigators enrolled only about 10% of all cardiac arrests in these 3 cities during the study period, and the use of tympanic membrane temperatures. Perhaps most importantly, the trial was stopped early as a result of the publication of the TTM study by Nielsen and colleagues, after which numerous hospitals changed their hypothermia protocols. Based on the results and limitations of the current study, the prehospital initiation of intra-arrest cooling requires further exploration.

A total of 144 patients were included in this study: 65 in the preimplementation group and 79 in the postimplementation group. Overall, the postimplementation group had lighter levels of sedation (median Richmond Agitation-Sedation Scale − 2.57 vs. − 1.25; P = 0.001) and better pain management (median Critical Care Pain Observation Tool Score 2.0 vs. 1.5; P = 0.03) than the preimplementation group. In addition, the use of sedative infusions was reduced by N50% in the postimplementation group. Perhaps most importantly, the analgosedation protocol was associated with a shorter duration of mechanical ventilation when compared with the preimplementation protocol (92.9 h vs. 138.3 h; P = 0.01). The 2013 update from the American College of Critical Care Medicine resulted in a paradigm shift in the treatment of pain and agitation in critically ill patients. Faust's study demonstrates that the analgosedation approach to the management of pain and agitation results in improvements in the patient-centered outcomes of decreased duration of mechanical ventilation and improved pain control. Limitations of the study include its retrospective design, the potential for selection bias (it was performed in a medical ICU setting), and the fact that it was performed at a single center, thereby limiting generalizability. Nonetheless, it is important that clinicians treat pain and anxiety adequately, especially in intubated patients. Based on the results of this study and current guidelines, start with the analgesic.

4. Mechanical ventilation

4.2. Girardis M, Busani S, Damaini E, et al. Effect of conservative vs conventional oxygen therapy on mortality among patients in an intensive care unit. The Oxygen-ICU Randomized Clinical Trial. JAMA 2016;316:1583–9

4.1. Faust AC, Rajan P, Sheperd LA, et al. Impact of an analgesia-based sedation protocol on mechanically ventilated patients in the medical intensive care unit. Anesth Analg 2016;123:903–9 Critically ill patients experience pain and anxiety, which, if treated inadequately, can have both short- and long-term consequences [23, 24]. Unfortunately, health care providers consistently underrate and undertreat pain and anxiety, especially as in intubated patients, because they are often unable to communicate with the clinical staff. The traditional practice for treating pain, agitation, and anxiety in critically ill patients is to administer a sedative followed by intermittent doses of an analgesic, if deemed necessary. In 2013, the American College of Critical Care Medicine published clinical practice guidelines recommending an analgosedation approach to the management of pain and anxiety in ICU patients [25]. This approach focuses on initially treating pain with an analgesic medication (i.e., an opioid) followed by a sedative to address anxiety and agitation. To date, little has been published regarding the effect of a fentanylbased protocol for analgosedation on outcomes in ICU patients receiving mechanical ventilation. Faust and colleagues sought to evaluate the impact of an analgosedation protocol on the duration of mechanical ventilation, ICU length of stay, sedation levels, and medication costs. They designed a retrospective cohort study that was performed in the medical intensive care unit (MICU) of a single, large, teaching community hospital. Prior to 2012, patients were managed with a sedation/ analgesia protocol that began with a sedative (propofol) followed with an analgesic (morphine) as needed. In 2012, the protocol was changed to an analgosedation approach, whereby patients were initially treated with an analgesic (fentanyl), followed by a sedative infusion (propofol or dexmedetomidine). Investigators in the current study divided patients into preimplementation and postimplementation groups. The preimplementation group included adults who received mechanical ventilation during a 6-month period in 2011 and were managed with the sedation protocol in place prior to 2012. The postimplementation group included adults who received mechanical ventilation during a 6-month period in 2013 and who were treated with the analgosedation protocol. The primary outcome of the study was duration of mechanical ventilation. Secondary outcomes were MICU length of stay, sedative and analgesic medication use and cost, and mortality.

Because intubated patients tend to remain in the ED for a long time, it is imperative for the EP to be knowledgeable about critical aspects of mechanical ventilation. It is common practice to set the fraction of inspired oxygen (FiO2) at 100% immediately following intubation and initiation of mechanical ventilation. Unfortunately, it is often left at 100% for an extended time, thereby exposing patients to an excessive partial pressure of arterial oxygen (PaO2). This high level of PaO2, called hyperoxia, has been shown to induce peripheral vasoconstriction, increase the concentration of reactive oxygen species, and cause direct lung toxicity [26-29]. In addition, hyperoxia has been associated with poor outcome in a number of critical conditions, including cardiac arrest, traumatic brain injury, stroke, and myocardial infarction [30,31]. As a result of the potential detrimental effects of hyperoxia, many clinicians have recommended a more conservative approach to oxygen therapy in the critically ill patient. However, a conservative approach, in which patients are given a much lower FiO2, has not been validated as to its clinical efficacy or patient safety. Girardis and colleagues sought to determine if the use of a conservative protocol for oxygen therapy would decrease the mortality rate among ICU patients. Importantly, the study did not strictly target intubated patients. The Oxygen-ICU study was an open-label, parallel-group, randomized trial performed in a single-center in Italy. Patients included in the trial were 18 years of age or older and were admitted to the ICU with an expected length of stay of at least 72 h. They were randomized to receive conventional oxygen therapy or conservative oxygen therapy. Patients in the conventional therapy group received an FiO2 of at least 40% to target a pulse oximetry (SpO2) reading between 97% and 100% and a PaO2 up to 150 mm Hg. Patients in the conservative therapy group received the lowest possible FiO2 to target an SpO2 between 94% and 98% and a PaO2 of 70 to 100 mm Hg. The primary outcome of the study was death in the ICU. Secondary outcomes were new-onset respiratory, cardiovascular, hepatic, or renal failure occurring 48 h or more after ICU admission. A total of 480 patients were included in this trial: 244 were randomized to the conventional oxygen therapy group and 236 to the conservative oxygen therapy group. Ultimately, 434 patients were analyzed in a modified-intention-to-treat (MITT) population. The ICU mortality rate was significantly lower in the conservative therapy group than in the

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conventional therapy group (11.6% vs. 20.2%). In addition, patients in the conservative therapy group had a lower incidence of shock, hepatic failure, and incidence of new bloodstream infection. There was no difference between the groups in regard to the onset of new respiratory or renal failure. These MITT results are similar to those of an intentionto-treat analysis. The Oxygen-ICU trial adds to the growing body of literature demonstrating the harm of hyperoxia in critically ill patients. In fact, the mortality rate among patients who received conventional levels of FiO2 was almost double that of patients who received lower levels. These results demonstrate a number needed to treat with lower levels of FiO2 of just 12. Several limitations of this trial should be noted. It was not blinded and was performed in an ICU at a single center, which may limit generalizability of the findings to other patient populations. The trial was stopped early, before the planned enrollment of 660 patients, primarily because a natural disaster struck the hospital, which greatly impacted hospital resources. While it is important to confirm these findings in a multicenter trial, they highlight the importance of paying close attention to oxygen therapy in ventilated ED patients. When feasible, the FiO2 should be turned down to the lowest possible setting to avoid hyperoxia. 5. Sepsis 5.1. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801–10 Sepsis is one of the most common critical illnesses encountered by EPs. In fact, it is believed to be a leading cause of critical illness throughout the world [32,33]. The original definitions of sepsis, severe sepsis, and septic shock were written during a 1991 consensus conference of the American College of Chest Physicians and the Society of Critical Care Medicine (SCCM). They were based on the belief that sepsis is caused by the patient's inflammatory response to infection. In 2001, an International Sepsis Definitions Conference maintained the initial definitions from 1991 but expanded the list of diagnostic criteria for sepsis [34]. In the 15 years since that conference, additional research has significantly enhanced our understanding of numerous aspects of sepsis and septic shock. As a result, the European Society of Intensive Care Medicine (ESICM) and the SCCM convened a new task force to update the definitions of sepsis and septic shock, to identify clinical criteria for all elements of sepsis, and to differentiate patients with sepsis from those who simply have an infection. Members of the task force included specialists in critical care, infectious disease, surgery, and pulmonary medicine. Several recommendations from the current publication should be noted: the updated definitions for sepsis and septic shock, use of the Sequential (Sepsis-Related) Organ Failure Assessment (SOFA) score for ICU patients, introduction of the quick SOFA (qSOFA) score for nonICU patients, and elimination of the term severe sepsis. The task force redefined sepsis as “life-threatening organ dysfunction caused by a dysregulated host response to infection.” To clinically identify ICU patients with organ dysfunction, the task force endorsed the use of the SOFA score. A score of 2 or more or an increase in 2 points from the patient's baseline SOFA score is associated with an in-hospital mortality rate N 10%. For non-ICU patients, the task force recommended use of the qSOFA score to identify patients who could be at higher risk of death. The qSOFA score was retrospectively derived from a cohort of patients from 2010 to 2012 in the University of Pittsburgh Medical Center health care system. This cohort included all medical and surgical patients ≥ 18 years of age with suspected infection from the emergency departments, hospital wards, and ICUs of 12 community and academic centers. Multiple logistic regression was used to identify clinical variables that could easily be used by the bedside clinician. The clinical variables

from the derivation that comprise the qSOFA score are: respiratory rate ≥ 22 breaths/min, systolic blood pressure ≤ 100 mm Hg, and altered mental status (GCS score ≤ 13). Patients with a qSOFA score of 2 or more are likely to have an increased ICU length of stay and increased mortality rate. The task force defined septic shock as a “subset of sepsis in which profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality.” The clinical criteria for septic shock are the need for vasopressor medication to maintain a mean arterial blood pressure ≥ 65 mm Hg and a lactate concentration ≥ 2 mmol/L despite adequate volume resuscitation. Finally, the task force found the systemic inflammatory response syndrome (SIRS) criteria to be unhelpful in the identification of patients with organ dysfunction due to infection. The Sepsis-3 report is one of the most frequently cited and discussed publications of 2016. As discussed, the publication provides new definitions for sepsis and septic shock, standardizes the assessment of organ dysfunction among ICU patients, eliminates the term severe sepsis, and proposes a new screening tool for non-ICU patients. Nonetheless, several limitations and concerns should be noted. Perhaps most importantly for the EP, the qSOFA score was retrospectively derived from a large database of patients in a limited geographic region of the United States. This may limit generalizability to different patient populations and regions. At present, the qSOFA score has not been prospectively validated. In addition to the limitations of the qSOFA score, concerns have also been raised regarding the SOFA score. Specifically, the SOFA score is used to predict mortality among critically ill patients and is not specific for sepsis. These proposed clinical criteria for sepsis and septic shock require further exploration and evaluation to compare sensitivity and specificity with current screening tools for this complex disease. Despite these limitations and concerns, it is crucial that EPs be knowledgeable about this publication. 5.2. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. The VANISH randomized clinical trial. JAMA 2016;316:509–18 Vasopressor medications are recommended for patients in septic shock who fail to achieve a mean arterial blood pressure (MAP) of at least 65 mm Hg with intravenous fluids. Current international guidelines for the management of patients with severe sepsis and septic shock recommend norepinephrine (NE) as the initial vasopressor medication for patients in septic shock [35]. In recent years, vasopressin has become a popular adjunctive vasopressor medication to administer to patients who do not achieve a goal MAP with NE alone. Several studies have demonstrated that vasopressin may decrease the incidence of kidney dysfunction compared with NE [36-38]. In addition, the combination of vasopressin and corticosteroids has been associated with a reduced duration of shock and lower mortality rate [39,40]. Gordon and associates sought to determine whether the early use of vasopressin would improve renal outcomes compared with NE. The VANISH trial was a factorial (2 × 2), multicenter, double-blind, randomized clinical trial conducted in 18 ICUs in the United Kingdom. The investigators enrolled patients at least 16 years of age who had sepsis and required vasopressor medications to maintain blood pressure despite intravenous fluid (IVF) resuscitation. Patients were excluded if they had end-stage renal disease, systemic sclerosis, Raynaud's phenomenon, or mesenteric ischemic of had received vasopressor infusions earlier during their ICU course. Enrolled patients were then randomized in a 1:1:1:1 fashion to one of four treatment groups: vasopressin plus placebo, NE plus placebo, vasopressin plus hydrocortisone, and NE plus hydrocortisone. Patients were initially given study drug 1, which was either vasopressin (titrated to a maximum dose of 0.06 U/min) or NE (titrated to a dose of 12 mcg/min) to achieve a MAP between 65 and 75 mm Hg. Once the maximum infusion rate of study drug 1 was reached, patients were given study drug 2 (either hydrocortisone or placebo). Open-label vasopressor medications could be administered if

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patients remained hypotensive after the initial dose of study drug 2. The primary outcome of this trial was the number of days without kidney failure within 28 days following randomization, as defined by the Acute Kidney Injury Network. Secondary outcomes were rate and duration of renal replacement therapy (RRT), 28-day ICU and hospital mortality rates, number of organ-failure-free days within the first 28 days, and duration of kidney failure in survivors and nonsurvivors. A total of 421 patients were randomized in the VANISH trial, with 408 of them included in the intention-to-treat analysis. The treatment groups were well balanced. Overall, there was no significant difference in the number of 28-day survivors free of kidney failure: vasopressin plus placebo, 57.1%; NE plus placebo, 59.2%; vasopressin plus hydrocortisone, 56.8%; and NE plus hydrocortisone, 59.7%. For nonsurvivors, the median number of days alive and free of kidney failure were as follows: vasopressin plus placebo, 12 days; NE plus placebo, 14 days; vasopressin plus hydrocortisone, 5 days; and NE plus hydrocortisone, 13 days. There was no difference between the groups in terms of the secondary outcomes of 28-day mortality, ICU and hospital LOS, and rates of organ failure. Serious adverse events occurred in approximately 11% of patients who received vasopressin and 8% of patients who received NE. The VANISH trial adds to the growing body of literature on vasopressor medications for patients with septic shock. Importantly, the use of vasopressin alone, titrated to a dose of 0.06 U/min, did not reduce the incidence of kidney failure or lower the mortality rate among patients with septic shock. Furthermore, there was no beneficial effect when vasopressin was combined with corticosteroids. The few limitations of this study include the fact that long-term outcomes were not assessed and the initiation of RRT was not controlled among the sites. In addition, there was no standardization of hemodynamic monitoring across the clinical sites. Notwithstanding these limitations, vasopressin should not be used as the initial vasopressor medication for patients with fluid-refractory septic shock. Vasopressin can still be considered a second-line vasopressor agent that can be added to NE when NE alone fails to achieve the target MAP. 5.3. Keh D, Trips E, Wirtz SP, et al. Effect of hydrocortisone on development of shock among patients with severe sepsis. The HYPRESS Randomized Clinical Trial. JAMA 2016;316:1775–85 The role of corticosteroids in the treatment of patients with sepsis remains controversial. Current guidelines recommend the administration of hydrocortisone to patients with septic shock when IVF resuscitation and vasopressor therapy fail to achieve a MAP ≥ 65 mm Hg [35]. This recommendation is based on a few reports demonstrating that the administration of corticosteroids resulted in more rapid reversal of septic shock [41,42]. A lower mortality rate, however, has not been shown consistently in current studies. Regardless, patients with septic shock have a higher mortality rate than those with severe sepsis. Hydrocortisone has been associated with a reduction in the inflammatory response to sepsis and may prevent progression to septic shock in select patients [43]. Keh and associates sought to investigate the effects of hydrocortisone on progression to shock in patients with severe sepsis. The HYPRESS trial was a multicenter, placebo-controlled, doubleblind, randomized trial conducted at 34 sites in Germany. The study group consisted of adults (≥18 years of age) who had evidence of infection, a systemic response to infection, or organ dysfunction for no longer than 48 h prior to randomization and who were admitted to an intermediate care unit or ICU of the participating centers. The investigators excluded patients younger than 18 years of age; those with septic shock, a hypersensitivity to hydrocortisone or mannitol, or a history of glucocorticoid medication use with indication to continue therapy; and those who were pregnant. Patients in the study group were randomized to receive either hydrocortisone or placebo. The hydrocortisone group received a 50-mg bolus followed by a continuous infusion of 200 mg for 5 days, 100 mg on days 6 and 7, 50 mg on days 8 and 9, and 25 mg on days 10 and 11. Patients randomized to receive placebo were given

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mannitol for an equivalent duration. The primary outcome of the study was the occurrence of septic shock within 14 days after randomization. Secondary endpoints were time to development of shock, ICU and hospital mortality, ICU and hospital length of stay, duration of mechanical ventilation, and incidence of renal replacement therapy. The 380 patients who met the study's criteria were randomized evenly to the hydrocortisone and placebo groups. Ultimately, 353 patients were included in a modified intention-to-treat analysis. Baseline characteristics of the two groups were similar, with the exception that patients in the placebo group had a slightly higher incidence of pneumonia. Importantly, there was no difference between the groups for the primary endpoint of septic shock after 14 days (21.2% in the placebo group compared with 22.9% in the hydrocortisone group). Furthermore, there was no statistical difference in the secondary endpoints of 28-day, 90-day, 180-day, or all-cause ICU or hospital mortality. Similarly, there was no difference in ICU or hospital length of stay, need for mechanical ventilation, or need for RRT. Not unexpectedly, patients who received hydrocortisone had more episodes of hyperglycemia than those who received placebo (90.9% vs. 81.5%). However, there was no difference in the rate of secondary infections, muscle weakness, or hypernatremia. The HYPRESS trial demonstrated that hydrocortisone did not decrease the risk of progression to septic shock within 14 days for patients with severe sepsis. Several limitations of the trial should be noted. Most importantly, it was underpowered, due to a lower mortality rate in the placebo group than was anticipated. In addition, the authors performed a modified intention-to-treat analysis and therefore did not analyze all patients randomized within the study. It is possible that the study results would have been affected if all patients who were randomized to hydrocortisone or placebo had been included in the final analysis. Furthermore, patients could be included only after consent was obtained. As a result, investigators might have missed patients in the early stages of septic shock. Finally, investigators did not exclude patients who received etomidate for rapid sequence intubation. Although the number of patients who received etomidate was b 7% in both groups, it is known to suppress the hypothalamic-pituitary-adrenal axis and transiently decrease corticosteroid synthesis. The HYPRESS trial was underpowered, but it does add important information to the literature regarding the use of corticosteroids in sepsis. Quite simply, hydrocortisone should be considered primarily for the patient with established septic shock that is refractory to fluid resuscitation and vasopressor therapy. 6. Summary The 2016 medical literature provides numerous pearls for the EP in the care of select critically ill ED patients. For patients with a spontaneous nonaneurysmal ICH, aggressive SBP reduction to values b 140 mm Hg did not improve patient-centered outcomes. In patients with an ICH who are concomitantly taking an antiplatelet medication, empiric transfusion of platelets did not improve outcomes. In fact, platelet transfusion resulted in an increase in rates of death and dependency at 3 months. Decompressive craniectomy may be beneficial for select patients with TBI who have elevated ICP that is refractory to standard medical therapy. For patients with OHCA caused by refractory ventricular fibrillation or pulseless ventricular tachycardia, the use of amiodarone or lidocaine did not improve survival to hospital discharge. In addition, the use of intra-arrest cooling in the prehospital setting was found to decrease the rate of ROSC for OHCA patients with a shockable rhythm. In the intubated ED patient, an analgosedation protocol improves pain control and reduces the duration of mechanical ventilation. For the critically ill ED patient, the EP should reduce the FiO2 as soon as clinically possible to avoid hyperoxia. Sepsis-3 updated the definitions for sepsis and septic shock, recommended implementation of the qSOFA score for non-ICU patients, and eliminated the term severe sepsis. For the septic shock patient who requires vasopressor therapy, the use

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of vasopressin alone did not reduce the incidence of kidney failure or lower the mortality rate. Finally, the use of hydrocortisone did not impede progression to septic shock in patients with severe sepsis. Funding None. Conflict of interest The authors do not have any financial conflicts of interest. Acknowledgment The manuscript was copyedited by Linda J. Kesselring, MS, ELS, the technical editor/writer in the Department of Emergency Medicine at the University of Maryland School of Medicine. References [1] Herring AA, Ginde AA, Fahimi J, Alter HJ, Maselli JH, Espinola JA, et al. Increasing critical care admissions from U.S. emergency departments, 2001–2009. Crit Care Med 2013;41:1197–204. [2] Hemphill JC, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015;46:2032–60. [3] Dandapani BK, Suzuki S, Kelley RE, Reyes-Iglesias Y, Duncan RC. Relation between blood pressure and outcome in intracerebral hemorrhage. Stroke 1995;26:21–4. [4] Anderson CS, Huang Y, Arima H, Heeley E, Skulina C, Parsons MW, et al. Effects of early intensive blood pressure-lowering treatment on the growth of hematoma and perihematomal edema in acute intracerebral hemorrhage: the intensive blood pressure reduction in acute cerebral hemorrhage trial (INTERACT). Stroke 2010; 41:307–12. [5] Qureshi AI. The importance of acute hypertensive response in ICH. Stroke 2013; 44(Suppl. 1):S67–9. [6] Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, et al. Rapid bloodpressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013;368:2355–65. [7] Al-Shahi SR, Labovitz R, Stapf C. Spontaneous intracerebral hemorrhage. BMJ 2009; 339:b2586. [8] Baharoglu MI, Cordonnier C, Al-Shahi Salman R, de Gans K, Loppman MM, Brand A, et al. Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomized, open-label, phase 3 trial. Lancet 2016;387:2605–13. [9] Antithrombotic Trialists Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analyses of individual participant data from randomized trials. Lancet 2009;373:1849–60. [10] Naidech AM, Jovanovic B, Leibling S, et al. Reduced platelet activity is associated with early clot growth and worse 3-month outcome after intracerebral hemorrhage. Stroke 2009;40:2398–401. [11] Thompson BB, Bejot Y, Caso V, et al. Prior antiplatelet therapy and outcome following intracerebral hemorrhage: a systematic review. Neurology 2010;75:1333–42. [12] Balestreri M, Czosnyka M, Hutchinson P, et al. Impact of intracranial pressure and cerebral perfusion pressure on severe disability and mortality after head injury. Neurocrit Care 2006;4:8–13. [13] Badri S, Chen J, Barber J, et al. Mortality and long-term functional outcome associated with intracranial pressure after traumatic brain injury. Intensive Care Med 2012;38: 1800–9. [14] Cooper DJ, Rosenfield JV, Murray L, et al. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med 2011;364:1493–502. [15] Kudenchuk PJ, Cobb LA, Copass MK, Olsufka M, Maynard C, Nichol G. Transthoracic incremental monophasic versus biphasic defibrillation by emergency responders (TIMBER): a randomized comparison of monophasic with biphasic waveform ascending energy defibrillation for the resuscitation of out-of-hospital cardiac arrest due to ventricular fibrillation. Circulation 2006;114:2010–8. [16] Kudenchuk PJ, Cobb LA, Copass MK, et al. Amiodarone for resuscitation after out-ofhospital cardiac arrest due to ventricular fibrillation. N Engl J Med 1999;341:871–8.

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Please cite this article as: Winters ME, et al, The critical care literature 2016, American Journal of Emergency Medicine (2017), http://dx.doi.org/ 10.1016/j.ajem.2017.07.036