American Journal of Emergency Medicine 32 (2014) 1520–1525

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

Review

The critical care literature 2013 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 Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA Departments of Emergency Medicine and Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

1. Introduction Over the past decade, the annual number of hours of that critical care has been provided in emergency departments (EDs) has increased dramatically [1]. In addition to increases in the number of ED patients admitted to an intensive care unit (ICU), it is clear that critically ill patients are staying longer in the ED. In fact, more than 33% of critically ill patients now remain in the ED for more than 6 hours [1]. Delays in ICU admission can have disastrous outcomes. In a single-center cohort of critically ill patients, Cardoso et al demonstrated an increase in mortality of 1.5% per hour that ICU admission was delayed [2]. Emergency physicians are often the first clinicians to resuscitate and manage critically ill patients, so it is imperative for them to be knowledgeable regarding recent advances in critical care. The article presents reviews of important articles published in 2013, pertaining to the care of critically ill patients in the ED. The following topics are covered: cardiac arrest, post-cardiac arrest, sepsis, intracerebral hemorrhage, blood transfusion, pulmonary embolism, and fluid resuscitation.

2. Cardiac arrest Westfall M, Krantz S, Mullin C, Kaufman C. Mechanical versus manual chest compressions in out-of-hospital cardiac arrest: a meta-analysis. Crit Care Med 2013; 41:1824-6. The resuscitation of cardiopulmonary arrest has undergone fundamental change in the past 5 to 10 years, particularly with a renewed emphasis on high quality chest compressions and early defibrillation. In fact, the recognition of the importance of high quality, uninterrupted chest compressions has altered the priorities of management during cardiac arrest, particularly in the first 4 to 8 minutes of resuscitation. This renewed emphasis on chest compressions has rekindled interest in mechanical cardiopulmonary resuscitation (CPR) devices. Theoretically, these devices produce high quality, continuous chest compressions. The two basic device configurations are the piston and load-distributing band models. Manual chest compressions delivered by healthcare providers are not always performed in a fashion consistent with current guidelines. It is well known that healthcare providers experience fatigue, frequently early in the resuscitation event. Fatigue can reduce the rate and depth of compressions, thereby reducing the effectiveness of CPR. Furthermore, healthcare providers are often distracted by other therapies and interventions, which can also adversely ⁎ Corresponding author. E-mail address: [email protected] (M.E. Winters). http://dx.doi.org/10.1016/j.ajem.2014.09.052 0735-6757/© 2014 Elsevier Inc. All rights reserved.

impact the effectiveness of CPR. Fatigue and distraction is not encountered with mechanical CPR devices. Westfall et al [3] performed a meta-analysis of mechanical CPR devices in the resuscitation of patients with out-of-hospital cardiac arrest (OHCA). The authors pooled data from 12 studies (6538 patients) with an overall successful resuscitation rate of 28%. Eight studies involved band devices, whereas the remaining 4 studies investigated piston models. Compared to manual CPR, the adjusted odds ratio for survival using mechanical devices was 1.53 (95% confidence intervals [CI] 1.32-1.78; P b .001). When the two mechanical device types were analyzed separately, the load-distributing band device demonstrated better outcomes, with an adjusted odds ratio for survival of 1.62 (95% CI 1.36-1.92, P b 0.001). The piston device produced less optimal outcomes, with an adjusted odds ratio for survival of 1.25 (95% CI 0.921.68, P = .51). The authors conclude that mechanical CPR devices produce a modest improvement in survival of OHCA patients, a result that appeared to be primarily from load-distributing band devices. It is important to note that other literature examining the utility of mechanical CPR devices for patients in cardiac arrest have reported less favorable results [4,5]. It is also important to recognize the potential for publication bias, as device manufacturers have funded many of the current studies on mechanical CPR devices, including the current study by Westfall et al. Notwithstanding, it may be reasonable to consider the use of the mechanical CPR devices, especially in environments where the quality of CPR may be adversely affected by resource limitations. Additional research is needed to guide the clinician in selecting the most appropriate application of mechanical CPR devices in the resuscitation of patients with OHCA. Hasegawa K, Hiraide A, Chang Y, Brown DF. Association of prehospital advanced airway management with neurologic outcome and survival in patients with out-of-hospital cardiac arrest. JAMA 2013; 309:257-66. Previous resuscitation recommendations emphasized the placement of an advanced airway early in the care of patients with OHCA. Recent literature, however, has suggested that the early placement of an advanced airway may not be associated with improved survival compared to basic life support (BLS) management strategies. Reasons for this surprising finding are unclear, but are believed to be due to fewer interruptions of high-quality CPR and early defibrillation. Hasegawa and colleagues performed a review of Japan's nationwide, population-based registry of OCHA to determine the association of advanced airway placement with neurologic outcome and survival in patients with OHCA. The authors included adult patients over the age of 18 years who had OHCA and resuscitation attempted by prehospital personnel. CPR was performed according to Japan's guidelines and the choice of an advanced airway (endotracheal intubation or supraglottic

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device) was left to the prehospital provider. While there are differences in these advanced airway devices, the ability to oxygenate and ventilate are not dissimilar. The primary outcome of the study was favorable neurologic outcome at 1-month, defined by the Glasgow-Pittsburgh Cerebral Performance Category (CPC). Secondary outcomes included return of spontaneous circulation (ROSC) before hospital arrival and survival at 1 month. Overall, 649,359 patients were included in the current study. Approximately 57% of patients received BLS therapy with bag-valvemask (BVM) ventilation, whereas 43% of patients received an advanced airway. Of the 43% who received an advanced airway, 37% received a supraglottic device and 6% received an endotracheal tube. Neurologically favorable survival at 1-month was 2.9% for those who received BVM ventilation, 1.1% for those who received a supraglottic airway, and 1.0% for patients who were intubated with an endotracheal tube. In this large study of OHCA patients, the placement of an advanced airway was not associated with improved neurologically favorable survival. In fact, the adjusted odds ratio for both 1-month neurologically favorable outcome and 1-month survival were less than 1.0, suggesting that an advanced airway did not improve survival compared to the BLS therapy with BVM ventilation. This paper challenges the dogma regarding the priority of advanced airway management early in the resuscitation of patients with OHCA. Primary limitations of the study include an observational design and the lack of any information regarding the intubation procedure for the 6% of patients receiving an endotracheal tube. In addition, it is important to note that the authors considered both endotracheal intubation and supraglottic airway devices as advanced airway management. While both allow for oxygenation and ventilation, the placement techniques for each device are different, namely increased skill and time for endotracheal intubation. Despite these limitations, the current study questions whether advanced airway techniques should be performed in the prehospital management of patients with OHCA. A randomized, controlled trial is desperately needed to determine which, if any, patients benefit from advanced airway placement in the prehospital management of cardiac arrest. Mentzelopoulos SD, Malachias S, Chamos C et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. J Am Med Assoc 2013; 310:270-9. The outcome from vasopressor-resistant cardiac arrest is dismal in both prehospital and hospital settings, with survival-to-discharge rates ranging from 1% to 5%. Though multiple strategies have been studied in this patient population, none have led to any significant improvement in outcome. Mentzelopoulos et al performed a prospective, randomized, controlled trial, investigating a combination of vasopressin, methylprednisolone, and epinephrine (VSE) on ROSC rates and survival to hospital discharge for in-hospital adult patients sustaining cardiac arrest. Patients in the VSE group received 20 IU of vasopressin plus 1 mg of epinephrine during the first 5 CPR cycles, with 40 mg of methylprednisolone given only during the first CPR cycle. VSE patients who remained in circulatory shock 4 hours after return of spontaneous circulation were given hydrocortisone for 7 days. Patients in the control group received 1 mg of epinephrine plus normal saline during the first 5 CPR cycles. Control group patients were not given corticosteroids. Primary outcomes included ROSC for at least 20 minutes and survival-todischarge (STD) with favorable neurologic recovery, defined as Glasgow-Pittsburgh CPC of 1 or 2. A total of 268 patients were included in the current study, with 130 patients randomized to the VSE group and 138 patients randomized to the Control group. ROSC for more than 20 minutes occurred more often in the VSE group (84%) compared to the Control group (66%). In addition, STD with favorable neurologic outcome occurred in 14% of VSE patients compared to 5% of Control patients. STD for patients who developed post-ROSC shock was 21% in the VSE group compared to 8% in the Control group.

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This study continues earlier work by the same investigators, in which they demonstrated improved outcome in a smaller cohort of cardiac arrest patients who received the VSE combination [6]. Similar to the prior study, the results of the current study demonstrate an impressive improvement in STD with favorable neurologic recovery in patients receiving the VSE combination. Reasons for the marked difference in survival are not clear. The authors suggest that the addition of steroid therapy may reduce the inflammatory response typically seen in the early post-resuscitation phase of cardiac arrest. They also suggest that the addition of steroid therapy may augment the effects of vasopressor agents. Regardless of the mechanism, it is important to note several study limitations. First, the study enrolled only hospitalized patients who sustained cardiac arrest. It is uncertain if this can be generalized to ED patients who present with OHCA. In addition, baseline differences were present between the two groups, with metabolic causes of arrest and asystole occurring more frequently in patients randomized to the Control group. Perhaps most importantly, this study examined multiple interventions, thereby making it difficult to tease out which component of therapy resulted in improved outcome. Finally, the overall number of patients enrolled in the study remains small. This may lessen the validity of the VSE combination, given that the overall survival for cardiac arrest patients is low. While additional data is needed to determine which component of therapy is beneficial, the combination of VSE can be considered in the management of patients sustaining cardiac arrest. 3. Post-cardiac arrest management Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med 2013; 369:2197-206. Current international resuscitation guidelines recommend therapeutic hypothermia (TH) for comatose survivors of out-of-hospital cardiac arrest (OHCA) caused by ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) [7]. This recommendation is based on two landmark trials that demonstrated improved neurologic function and survival to hospital discharge for comatose survivors of OHCA caused by VF or pulseless VT, who were cooled to 32°C to 34°C for 12 to 24 hours following return of spontaneous circulation (ROSC) [8,9]. Since the publication of these two trials, experts have debated the optimal target temperature and duration of TH. Some have also argued whether the beneficial effects of TH are actually related to cooler temperatures or simply the prevention of fever in OHCA patients [10,11]. Neilsen and colleagues sought to evaluate the effects of two hypothermia temperature targets in survivors of OHCA. This prospective, randomized trial was conducted in 36 ICUs across Europe and Australia. Study participants (1) were N 18 years of age, (2) had an OHCA, presumed to be of cardiac origin, (3) had a Glasgow Coma Scale score b8, and (4) had more than 20 consecutive minutes of spontaneous circulation. Exclusion criteria were the following: (1) an un-witnessed arrest with asystole as an initial rhythm, (2) initial body temperature b30°C, (3) suspected or confirmed ischemic stroke or intracerebral hemorrhage, and (4) time between ROSC and study screening N4 hours. Enrolled patients were randomly assigned to a target temperature of 33°C or 36°C. Both groups were maintained at their target temperature for 28 hours, after which they were rewarmed by 0.5°C per hour until they reached 37°C. At 36 hours, sedative medications were tapered or discontinued. At 72 hours, a physician unaware of the target temperature assignment performed neurologic prognostication. The primary outcome of this study was all-cause mortality. A secondary outcome was a composite of neurologic function or death, as measured by the CPC or Modified Rankin Scale. A total of 950 patients were enrolled in this study: 476 were assigned to the 33°C group and 474 to the 36°C group. There were no significant differences in baseline characteristics between the two groups. Importantly, there was no statistical difference in all-cause mortality between the groups (48% for the 36°C group vs 50% for the 33°C

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group). No significant difference was found between the groups for the composite outcome of poor neurologic function or death. Finally, there was no statistically significant difference in the rate of adverse events between the groups (90% in the 36°C group vs 93% in the 33°C group). Of note, hypokalemia occurred more often in patients in the 33°C group. This prospective, multicenter trial did not demonstrate a difference in cooling patients to either 33°C or 36°C. The trial was exceptionally well done and included significantly more patients than the original landmark articles combined. In addition, approximately 20% of patients in the current trial had non-shockable rhythms, a cohort traditionally excluded from many studies on TH. Although this study has numerous strengths, certain important aspects must be noted. First, the trial was not designed to compare TH with normal body temperatures; rather, the trial evaluated two hypothermia temperature targets for OHCA patients. Second, temperature management was only a component of a more comprehensive post-arrest management strategy, a strategy that might not be available in many centers that care for OHCA patients. In addition, it is important to examine the method of cooling used in this trial. Most patients were actively cooled using intravascular catheters, another resource not available in many EDs. At the time of this writing, international guidelines for the management of OHCA patients have not been updated to include this latest trial. Until such time, it seems reasonable to use a target 33°C or 36°C, and avoid fever, for comatose patients with ROSC from OHCA presumed to have a cardiac cause. 4. Sepsis Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 2013; 310:1683-91. Patients with septic shock often have elevated plasma catecholamine levels, resulting in a high sympathetic state [12]. This state is believed to be an adaptive response, designed to improve cardiac output through increases in heart rate and contractility. Excessive sympathetic output, however, has been associated with numerous adverse effects, such as myocardial depression, immunosuppression, and insulin resistance [13–15]. Exogenous catecholamine administration (i.e., norepinephrine) can further compound elevations in intrinsic levels, leading to worse outcomes. Interestingly, animal studies, and limited human data, suggest that the administration of beta-blockers may offset the effects of excessive catecholamines and improve hemodynamics by decreasing heart rate, increasing diastolic filling time, and improving stroke volume [16–18]. The authors of the current trial sought to determine whether the beta-blocker esmolol could reduce the heart rate in patients with septic shock. This is a randomized, single-center, open-label, phase 2 trial. Patients included in the study (1) were more than 18 years of age, (2) had septic shock, (3) required norepinephrine to maintain a mean arterial blood pressure above 65 mm Hg, and (4) had a heart rate greater than 95 beats per minute. Patients who were younger than 18 years of age, had significant cardiac dysfunction or valvular heart disease, were pregnant, or received beta-blocker therapy prior to randomization were excluded. Once enrolled, patients were randomized to receive either a continuous infusion of esmolol to maintain heart rate between 80 and 94 beats per minute or no infusion (control). Esmolol was continued until patients were discharged from the ICU or died. The primary outcome of the study was to determine if esmolol could maintain a heart rate between 80 and 94 beats per minute throughout the patient's ICU course. Secondary outcomes included 28-day mortality, cumulative doses of norepinephrine, cardiopulmonary and oxygenation indices, and markers of organ injury. A total of 154 patients were included in this study, with 77 assigned to the esmolol group and 77 assigned to the control group. All patients were intubated, sedated, and ventilated with lung-protective strategies and received 300 mg of hydrocortisone as part of their care. The target

heart rate was reached and maintained in all patients assigned to esmolol. Furthermore, patients randomized to the esmolol group required significantly less norepinephrine and less intravenous fluid therapy and had lower lactate concentrations, higher arterial pH values, and significantly higher stroke volume and systemic vascular resistance values. Perhaps most impressive is the marked reduction in mortality rate for those receiving esmolol compared with the control group (49.4% versus 80.5%, respectively). The results of this study demonstrate an impressive reduction in mortality for patients in septic shock who receive esmolol. Importantly, this was a single-center study, raising the question of generalizability to other clinical settings. The mortality rate in the control group is much higher than that reported from most studies on patients with septic shock, suggesting selection bias. In addition, the authors chose an arbitrary heart rate range of 80 to 94 beats per minute. It is unclear if this range leads to optimal diastolic filling time and augmentation of stroke volume. Finally, it is uncertain if the benefit seen was due to simply to reductions in heart rate or another physiologic mechanism of betablockade. Despite these limitations, this novel study is thought provoking and awaits confirmation from randomized controlled trials. At present, beta-blockade in patients with septic shock should not be considered standard care. 5. Intracerebral hemorrhage Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 2013; 368:2355-65. Patients with an acute intracerebral hemorrhage (ICH) often present to the ED with markedly elevated blood pressure [19]. Controversy remains as to whether elevations in blood pressure are an adaptive response to maintain cerebral perfusion or are deleterious, resulting in further bleeding, hematoma expansion, and worse outcomes. In addition, it is unclear if reductions in blood pressure for patients with an acute ICH are beneficial. Current guidelines for the management of patients with an acute ICH recommend reducing systolic blood pressure (SBP) below 180 mm Hg or keeping the mean arterial blood pressure below 110 mm Hg [20]. However, the evidence base for this recommendation is not strong. Furthermore, the optimal blood pressure target is unknown. The authors of the current study (INTERACT 2) sought to compare the effect of rapidly lowering blood pressure to the current treatment guideline in patients with an acute ICH. INTERACT 2 is a multicenter, prospective, open-label, randomized trial performed in more than 140 hospitals in 21 countries. Patients were included in the study if they presented within 6 hours after the onset of a spontaneous ICH, had a SBP between 150 and 220 mm Hg, and had no contraindications to blood-pressure-lowering therapy. Patients were excluded from this study if they had a Glasgow Coma Scale score between 3 and 5, had a massive hematoma with poor prognosis, were scheduled for early surgical hematoma evacuation, or were believed to have a structural cause of their ICH. Enrolled patients were randomized to either an intensive treatment group, with a targeted reduction in SBP to b 140 mm Hg within 1 hour, or a standard treatment group, with a targeted a reduction in SBP to b180 mm Hg. The primary outcome of the study was a composite of death or major disability (defined by a Modified Rankin Scale score between 3 and 6) at 90 days. Secondary outcomes included all-cause mortality and cause-specific mortality. A total of 2839 patients were included in the analysis, with 1436 randomized to the standard treatment group and 1403 randomized to the intensive treatment group. The two groups were similar in terms of baseline characteristics. Though there was a positive trend in the direction of intensive treatment, there was no statistically significant difference in death or major disability (52% in the intensive treatment group versus 56% in the standard treatment group [P = .06]). Ordinal analysis demonstrated improved functional outcomes for patients in

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the intensive treatment group. The mortality rate, however, remained unchanged and was approximately 12% for both groups. Furthermore, there were no differences in hematoma size, neurologic deterioration, or the number of serious adverse events between the two groups. Many clinicians have already changed their management of blood pressure in patients with ICH based on the results of this study, citing the positive ordinal analysis and absence of harm in the intensive treatment group. Importantly, this study has numerous limitations that must be noted before rapid blood pressure reduction can be routinely recommended. First, approximately 70% of patients were from China, thereby limiting generalizability of the results to other clinical settings. Second, more than seven medications were used to lower blood pressure. The medication most commonly used to lower SBP, urapadil, is not available in the United States. Furthermore, only one-third of patients in the intensive treatment group achieved the SBP target of b 140 mm Hg in the first hour of therapy. Third, the majority of patients enrolled in the study had small ICHs (median of 11 ml), which are unlikely to cause clinical deterioration. Finally, and perhaps most importantly, is the use of ordinal analysis to demonstrate favorable results, despite a lack of benefit to intensive treatment in the primary outcome of death. While rapid blood pressure lowering may be beneficial, the current trial does not provide overwhelming evidence that it should be considered standard care for patients with ICH. Ongoing trials, such as the Antihypertensive Treatment of Acute Cerebral Hemorrhage II trial, will further clarify the role of intensive blood pressure reduction in patients with acute ICH. 6. Transfusions Villaneuva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med 2013; 368:11-21. Critically ill patients frequently receive packed red blood cell (PRBC) transfusions. In fact, up to 50% of critically ill patients receive at least 1 unit of PRBCs during their hospital course [21]. Recent literature has demonstrated the benefits of a restrictive transfusion strategy, using a hemoglobin threshold of 7 g/dL for PRBC transfusion, compared with a liberal transfusion strategy that uses a hemoglobin threshold of 9 g/dL [22,23]. As a result, current guidelines recommend a hemoglobin threshold of 7 g/dL as a trigger for PRBC transfusion in hemodynamically stable critically ill patients [21,24]. Importantly, patients with acute gastrointestinal hemorrhage have often been excluded from many of the trials evaluating restrictive transfusion strategies. The authors of the current study sought to evaluate whether a restrictive transfusion strategy was safe and effective in patients with acute upper gastrointestinal hemorrhage. The current study is a randomized, controlled trial performed in a single center in Spain. Patients included in the study were more than 18 years of age and had hematemesis, melena, or both at the time of initial evaluation. Importantly, patients with evidence of massive exsanguinating hemorrhage, acute coronary syndrome, acute cerebrovascular accident, lower gastrointestinal bleeding, or recent surgery or trauma and those with a clinical Rockall score of 0 and hemoglobin N12 g/dL were excluded. Enrolled patients were randomized to a restrictive threshold group (7 g/dL) or a liberal threshold group (9 g/dL). All patients underwent esophagogastroduodenoscopy within 6 hours after presentation and were stratified according to the presence or absence of cirrhosis. The primary outcome of the study was all-cause 45-day mortality, with secondary outcomes of additional bleeding and in-hospital complications. A total of 921 patients were included in this study: 444 were randomized to the restrictive threshold group and 445 to the liberal threshold group. The mortality rate was significantly lower in the restrictive threshold group compared with the liberal threshold group (5% versus 9%, respectively). Notably, the mortality benefit was seen primarily in patients with Child-Pugh class A and B cirrhosis, whereas there was no difference in the mortality rate for patients with Child-Pugh class C cirrhosis. Patients in the restrictive threshold group also had less

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bleeding (10% versus 16%, respectively), shorter hospital lengths of stay, and fewer complications (40% versus 48%, respectively) compared with the liberal threshold group. As expected, patients in the restrictive threshold group received significantly fewer PRBC transfusions. This study adds to the growing body of literature supporting a hemoglobin threshold of 7 g/dL for PRBC transfusion for many critically ill patients. Importantly, the trial was not blinded, raising the possibility of selection bias. Furthermore, the trial was performed at a single center, limiting its generalizability to all patients with acute upper gastrointestinal hemorrhage. The trial also excluded patients with massive exsanguinating hemorrhage, a subgroup of patients with acute upper gastrointestinal bleeding that might benefit from aggressive PRBC transfusion and higher hemoglobin targets. Despite these limitations, this study supports the use of 7 g/dL as a hemoglobin threshold for PRBC transfusion in patients with acute upper gastrointestinal bleeding. 7. Pulmonary embolism Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the MOPETT trial). Am J Cardiol 2013; 111:273-7. Thrombolytic therapy is recommended for the treatment of hemodynamically unstable patients with massive pulmonary embolism (PE) [25]. Controversy remains, however, regarding the benefit of thrombolytic therapy in patients with submassive PE. To date, there is no evidence to support the routine use of thrombolytic therapy in this patient population. Furthermore, the risk of intracranial hemorrhage for patients with a PE following thrombolytic therapy is approximately 2% [26,27]. Physiologically, the lungs are the only organs to receive 100% of the cardiac output. As such, they might be uniquely sensitive to the effects of thrombolytic medications. The authors of this study sought to assess the effects of a lower dose of tissue plasminogen activator (tPA) in patients with moderate PE. This article describes an open-label, prospective, randomized, controlled, trial performed in a single center in the United States. Study participants were adults diagnosed with “moderate” PE, which was defined as the presence of signs or symptoms (chest pain, dyspnea, cough, tachycardia, tachypnea, pulse oximetry reading b 95%, elevated jugular venous pressure [N12 cm H2O]) and either computer tomographic pulmonary angiography evidence of N70% thrombus in two or more pulmonary lobes or left or right main pulmonary artery involvement or a high-probability ventilation perfusion scan in two or more lobes. Enrolled patients were then randomized to receive tPA (0.5 mg/kg for patients weighing b50 kg; 50 mg for those weighing N 50 kg) plus anticoagulation or anticoagulation alone (control group). All patients received either unfractionated heparin or enoxaparin. Echocardiography was performed prior to tPA administration and then repeated at 24 to 48 hours after medication administration. The primary endpoint of the study was the development of pulmonary hypertension, as measured by echocardiography. Secondary endpoints included mortality, hospital length of stay, recurrent PE, and bleeding. A total of 121 patients were included in the final analysis of this study, with 61 patients randomized to receive tPA and 60 patients randomized to the control group. There were no significant differences in baseline characteristics between the groups. The primary endpoint of pulmonary hypertension developed in 16% of patients treated with tPA and in 57% of patients in the control group. Though not statistically significant, there was a trend toward lower mortality (1.6% versus 5%) and fewer recurrent PEs (0 versus 3) in the tPA group compared with the control group. None of the patients in this trial experienced any major or minor bleeding events. The results of this trial suggest that a lower dose of tPA might be beneficial for patients with moderate PE and reduce the long-term complication of pulmonary hypertension. Importantly, this study was performed at a single center, thereby limiting its generalizability to other patient populations. In addition, the authors chose the development of pulmonary hypertension as their primary outcome, rather

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than death or a patient-centered outcome, such as exercise tolerance or dyspnea. Furthermore, the authors did not include right ventricular dysfunction on echocardiography or elevations in troponin or B-natriuretic peptide in their definition of “moderate” PE—markers that are traditionally used to define patients with submassive PE. Finally, the trial was relatively small, including just over 120 patients. Given the high-risk nature of PE, caution is warranted before changing practice based on a small, single-center study. While a larger, multicenter trial is clearly needed to confirm the results, the current trial is encouraging and indicates that select patients might benefit from smaller doses of tPA.

randomization also appears to be poor, as there were differences in patient characteristics between the groups. Furthermore, because of protocol violations, almost 20% of patients in the colloid group received crystalloid fluids. Though the current trial did not demonstrate an increase in renal replacement therapy for patients treated with colloids, several recent studies found an association with increased renal injury and mortality in patients treated with hydroxyethyl starches [28,29]. Even though proponents of colloid fluids will cite the absence of harm, the current study should not change practice. Given the lack of benefit, potential harm, and cost of colloids, crystalloids will likely remain the fluid of choice for resuscitation for many clinicians.

8. Fluid resuscitation Annane D, Siami S, Jaber S, et al. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA 2013; 310:1809-17. Fluid resuscitation is one of the most common therapies administered to critically ill patients. Despite decades of research, the optimal resuscitation fluid remains unknown. Historically, the debate regarding the selection of an appropriate intravenous fluid has focused on the broad categories of crystalloids and colloids. Often, the choice of fluid for resuscitation depends on the region and training of the individual clinician. For example, crystalloids remain the fluid of choice for clinicians practicing in the United States. The authors of the current study sought to assess whether colloids decreased the mortality rate compared with crystalloids for the resuscitation of critically ill patients. The randomized, parallel-group CRISTAL trial was performed in 57 ICUs across France, Belgium, Canada, Algeria, and Tunisia. Patients included in the study were those who required intravenous fluid resuscitation for acute hypovolemia, as defined by a SBP b 90 mm Hg or a mean arterial pressure b 60 mm Hg, orthostatic hypotension, signs of tissue hypoperfusion or hypoxia, or evidence of low filling pressures and low cardiac index. Importantly, patients could not have received intravenous fluids for resuscitation prior to enrollment. Once enrolled, patients were randomized to a crystalloid group (control) or colloid group (experimental). Patients in the control group could receive isotonic saline, hypertonic saline, or any buffered solution. Patients in the colloid group could receive either hypooncotic (4% or 5% albumin) or hyperoncotic (hydroxyethyl starches, 20%-25% albumin) solutions. Patients were also stratified by center and admission diagnosis (eg, sepsis, trauma). Following randomization, patients where managed with the category of fluids to which they were randomized. The primary outcome of the study was 28-day mortality. Secondary outcomes included 90-day mortality; number of days without organ failure; and number of days alive and not receiving renal replacement therapy, vasopressor medications, or mechanical ventilation. A total of 2857 patients were included in the analysis of this trial: 1443 were randomized to the crystalloid group and 1414 to the colloid group. Approximately 86% of patients in the crystalloid group received isotonic saline, whereas approximately 70% of patients in the colloid group received hydroxyethyl starches. Severe sepsis accounted for the main diagnosis requiring fluid resuscitation in both groups. Ultimately, there was no significant difference in 28-day mortality between the two groups (25.4% in the colloid group vs 27% in the crystalloid group). Similarly, there was no statistical difference in the need for renal replacement therapy (11% in the colloid group vs. 12.5% in the crystalloid group). There was, however, a statistically significant difference in 90-day mortality (30% in the colloid group vs. 34% in the crystalloid group) and the number of days alive without mechanical ventilation at 28 days (13.5 days for the colloid group vs 14.6 for the crystalloid group). The results of the CRISTAL trial suggest equivalent outcomes in critically ill patients resuscitated with either crystalloid or colloid fluids. However, the results should be interpreted with significant caution. The trial was a non-blinded, open-label study that needed approximately 9 years to recruit patients. This raises concern for selection bias. The

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