Critical care literature 2010″>American Journal of Emergency Medicine (2012) 30, 1268-1273

Review

The critical care literature 2010

Michael E. Winters MD^a,b,?, Tsuyoshi Mitarai MD^c, William J. Brady MD^d

^aDepartment of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA

^bDepartment of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA

^cDivision of Emergency Medicine, Department of Surgery, Stanford University, Stanford, CA 94305, USA

^dDepartment of Emergency Medicine and Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA, 22908

Received 28 June 2011; accepted 25 August 2011

1. Sepsis

Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs Central venous oxygen saturation as goals of early sepsis therapy. JAMA 2010;303(8):739-746.

Protocol-driven resuscitation of the patient with severe sepsis or septic shock is common since the 2001 study by Rivers et al [1] detailing “early goal- directed therapy” (EGDT). The quantitative protocol of EGDT includes resuscitation goals for cardiac preload, mean arterial pressure, and Tissue oxygenation. In the EGDT study, tissue oxygenation was assessed using a commercially available device capable of continuously monitoring central venous oxygen saturation . Citing this study, the international Surviving Sepsis Campaign recommends the quantitative EGDT protocol, including the measurement of ScvO2, for the management of patients with severe sepsis or septic shock [2]. For various reasons, many have not implemented a quantitative resuscitation protocol for patients with sepsis, citing the time, expertise, and specialized equipment for the protocol, namely, the continuous measurement of ScvO2 [3,4]. In contrast to ScvO2, lactate can be measured without central venous access or specialized monitoring equipment and has been known for decades to correlate with severity of illness and outcome.

The authors of the current multicenter, prospective, randomized, nonblinded trial sought to determine whether lactate clearance was noninferior to ScvO2 for assessing tissue oxygenation in septic emergency department (ED) patients. The current study was conducted from January 2007 to January 2009 and enrolled adult patients with confirmed or presumed infection, 2 or more criteria for the systemic inflammatory response syndrome, and evidence of hypoperfusion by either a systolic blood pressure (SBP) less than 90 mm Hg after a 20-mL/kg bolus of intravenous fluids (IVFs) or a blood lactate concentration greatercv than 4 mmol/L. Patients were randomly assigned to an ScvO2 group and a lactate clearance group. Both groups received protocol-driven resuscitation with

* Corresponding author. Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MA, USA.

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

similar goals for central venous pressure and mean arterial pressure. Importantly, antibiotics were administered to patients in both groups as soon as possible. Patients randomized to the ScvO2 group received pack red cell transfusions and/or dobutamine if the ScvO2 was less than 70% despite adequate central venous pressure and mean arterial pressure. Patients randomized to the lactate clearance group had venous lactate levels measured after a minimum of 2 hours from the initiation of resuscitation. Lactate clearance values less than 10% were used as triggers for packed red blood cell transfusion or initiation of dobutamine infusion. The primary end point of the study was absolute in-hospital mortality. Secondary end points included intensive care unit (ICU) and hospital length of stay , ventilator free days, and new-onset multiple organ failure.

Three hundred patients were included in the study, with 147 randomized to the ScvO2 group and 147 to the lactate clearance group. There were no significant differences between the groups in terms of demographics, comorbidities, or site of infection. Similarly, there were no differences between the groups in administerED treatments including IVFs, vasopres- sors, and mechanical ventilation. Importantly, only 10% of patients required either packed red cell transfusions or dobutamine. In-hospital mortality for patients randomized to the ScvO2 group was 23%, whereas mortality for patients in the lactate group was 17%. As the authors note, the lower limit of the mortality confidence interval (CI) met the predefined noninferiority threshold between lactate clearance and ScvO2.

The current study is the first to demonstrate that a protocol-driven resuscitation program for ED sepsis patients using lactate clearance as a measure of tissue oxygenation results in similar Short-term outcomes to quantitative protocols incorporating ScvO2. Primary limitations to the current study include its unblinded design and the fact that it is underpowered to detect mortality differences. In addition, the 3 participating institutions had robust resuscitation programs that included additional resources to help manage study patients, resources that are not present in many community and even academic settings. It is also important to note that only 10% of patients received treatments (dobutamine, transfusion) that were directed by assessing tissue oxygen- ation. This, combined with the overall lower mortality of the study groups, would suggest the inclusion of selection bias. Nevertheless, the results are promising for many emergency physicians unable to implement protocol- based sepsis resuscitation because of the challenges of continuously measuring ScvO2.

0735-6757/$ - see front matter (C) 2012 doi:10.1016/j.ajem.2011.08.014

Tekwani KL, Watts HF, Sweis RT, Rzechula KH, Kulstad EB. A comparison of the effects of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a prospective, randomized study. Ann Emerg Med 2010;56:481-489.

Etomidate is the preferred Induction agent of many emergency physicians. A well-known effect of etomidate is adrenal suppression. In fact, decreased cortisol levels can occur as soon as 30 minutes after a single dose and may persist for up to 24 hours [5-13]. Studies to date have demonstrated an association of etomidate with increased hospital and ICU LOSs, increased duration of mechanical ventilation, and increased mortality [6,8,11,14-17]. However, there is no randomized, controlled trial that demonstrates increased mortality from etomidate in patients with sepsis [18]. The authors of the current study compare the effect of a single dose of etomidate to midazolam on hospital LOS for patients with suspected sepsis undergoing rapid sequence intubation.

The current study is a prospective, randomized, double-blind study performed in a large, tertiary care center with an annual ED census exceeding 90 000 visits. Patients included in the study were at least 18 years old who were intubated in the ED and had infection as the suspected cause of illness. Patients who were younger than 18 years, were pregnant, had cardiopulmonary resuscitation (CPR) before ED arrival, or had a preexisting do-not-resuscitate order were excluded. Study patients were randomly assigned to received etomidate (0.3 mg/kg) or midazolam (0.1 mg/kg) before rapid sequence intubation. The primary outcome of the study was hospital LOS, with secondary outcomes of in-hospital mortality, ICU LOS, and duration of mechanical ventilation.

Of 303 eligible patients, 122 were enrolled in the study. Of these,

63 patients received etomidate, whereas the remaining 59 received midazolam. Of the 122 patients, 96 were found to have sepsis, of which 45 received etomidate and 51 received midazolam. Investigators found no difference in the primary outcome of hospital LOS for etomidate compared with midazolam (7.3 vs 9.5 days). Similarly, there was no difference between etomidate and midazolam for the secondary outcomes of ICU LOS (3.1 vs 4.2 days), ventilator free days (2.1 vs 2.8), and in-hospital mortality

(43% vs 36%).

The current study adds to the growing body of literature on etomidate. Importantly, the current study is underpowered to detect true differences in mortality between etomidate and midazolam. In addition, the possibility of selection bias exists, as less than half of patients eligible were included in the study. The authors cite the lack of a study coordinator or investigator as the primary reason for not enrolling all that were eligible. Finally, the use of sepsis therapies such as EGDT and Low tidal volume ventilation was not included in the analysis. Despite these limitations, the current study provides additional evidence that a single dose of etomidate does not significantly alter mortality in patients with sepsis.

Gaieski DF, Mikkelsen ME, Band RA, Pines JM, Massone R, Furia FF, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010;38:1045-1053.

For patients with severe sepsis or septic shock, current guidelines recommend the administration of antimicrobial therapy within 1 hour of diagnosis [2]. Recent literature has demonstrated that mortality rises sharply for each hour delay in antibiotic administration for patients in septic shock [19]. Despite these retrospective data, the exact timing of antimicrobial therapy that impacts outcome remains unclear. The authors of the current study evaluated the impact of timing of antimicrobial therapy on mortality in ED patients receiving EGDT.

The current study is a retrospective cohort of ED patients from a single, urban, tertiary care center. Patients included in the study were adult ED patients with severe sepsis or septic shock in which EGDT was initiated during the ED course. Study investigators evaluated in-hospital mortality

rates for patients receiving antimicrobial therapy at 4 different time cutoffs: time from triage to antibiotic administration, time from qualification for EGDT, time from triage to appropriate antimicrobial therapy, and time from qualification for EGDT to appropriate antimicrobial therapy.

A total of 261 patients were included in the study. All study patients received antibiotics in the ED with a medial length from time to triage of

119 minutes, time from qualification for EGDT to antibiotics of 42 minutes, time from triage to appropriate antibiotics of 127 minutes, and time from qualification for EGDT to appropriate antibiotics of 47 minutes. The overall mortality of the cohort was 31%. Overall, there was no relationship between time from triage and time from qualification for EGDT to antimicrobial therapy and mortality. However, mortality was significantly reduced for patients given appropriate antimicrobial therapy within 1 hour of triage (19.5% vs 33.2%) or 1 hour of qualification for EGDT (25% vs 38.5%).

The results of this study lend further evidence to the importance of providing early and appropriate antimicrobial therapy to patients with severe sepsis or septic shock. Important considerations and limitations to this study include its retrospective design and sample size. In addition, the study was performed at a single center with a robust resuscitation protocol for patients with sepsis, thereby limiting its applicability to all centers. Nonetheless, emergency physicians should continue to provide appropriate antimicrobial therapy as soon as possible for patients diagnosed with severe sepsis or septic shock.

1. Vasopressors

DeBacker D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, et al. Comparison of dopamine and norepinephrine in the treatment of shock. NEJM 2010;362:779-789.

Shock is defined as the inadequate delivery of oxygen to meet tissue metabolic demands. For patients in shock, initial therapy is typically the administration of IVFs to restore circulating volume. In addition to IVFs, many patients in shock require Vasopressor medications to maintain an adequate perfusion pressure. The 2 most common vasopressor medications used in clinical practice today are norepinephrine and dopamine [20]. Despite the frequent use of vasopressor medications, there is no con- vincing evidence that any agent is superior. The authors of this multi- center, prospective, randomized trial sought to evaluate whether the choice of norepinephrine over dopamine would reduce mortality in patients with shock.

The current study was performed at 8 centers in Belgium, Austria, and Spain from December 2003 to October 2006. Patients enrolled in the study were older than 18 years and required vasopressor medications for treatment of shock. Importantly, the authors defined shock as those who had a mean arterial blood pressure less than 70 mm Hg or SBP less than 100 mm Hg despite at least 1 L of crystalloids and signs of hypoperfusion (altered mental status, mottled skin, urine output b0.5 mL/kg per hour, lactate N2 mmol/L). Once the maximum study dose was reached for either dopamine (20 ug/kg per minute) or norepinephrine (0.19 ug/kg per minute), open-label norepinephrine could be added. Epinephrine, vasopressin, or inotropic agents could be used; however, open-label dopamine was not permitted. The primary end point of the study was 28-day mortality. Predefined subgroup analysis of mortality was planned according to the type of shock (septic, cardiogenic, hypovolemic). Secondary end points included ICU mortality, hospital mortality, ICU LOS, the number of days without need for organ support, and the time to achieve hemodynamic stability. Adverse events were categorized as arrhythmias, Myocardial necrosis, Skin necrosis, Limb ischemia, and secondary infections.

A total of 1679 patients were included in the study: 858 in the dopamine group and 821 in the norepinephrine group. Septic shock occurred in 1044 patients (62.2%), whereas cardiogenic shock was seen in 280 patients (16.7%), and hypovolemic shock, in 263 patients (15.7%). Baseline characteristics of patients in each group were similar. Overall, there was no difference in 28-day mortality between the groups. In addition, there was

no difference in ICU or hospital mortality at 6 or 12 months. Not surprisingly, arrhythmias were a common adverse effect (18.4% of patients) and occurred more frequently in the dopamine group. When stratified according to type of shock, the overall treatment effect did not significantly differ with the exception of a higher 28-day mortality in patients with cardiogenic shock who received dopamine.

The current study is one of the largest randomized trials to evaluate dopamine and norepinephrine in the treatment of circulatory shock. Notable limitations of the study include the definition of fluid refractory shock (no response to 1 L of crystalloid or 500 mL of colloid), the choice of “equipotent” doses of dopamine (20 ug/kg per minute) and norepinephrine (0.19 ug/kg per minute), and the identification of shock resolution (not formally defined). Perhaps most importantly, the study did not include a control group that simply received IVFs alone. Although it is important to note the higher mortality in patients with cardiogenic shock who received dopamine, the study serves to emphasize that there remains no ideal vasopressor agent for the treatment of circulatory shock.

1. Cardiac arrest

Rea TD, Fahrenbruch C, Culley L, Donohoe RT, Hambly C, Innes J, Bloomingdale M, Subido C, Romines S, Eisenberg MS. CPR with chest compression alone or with rescue breathing. NEJM 2010;363:423-433.

It is well established that early CPR can improve neurologic outcome for survivors of out-of-hospital cardiac arrest (OOHCA) [21,22]. Traditional CPR teaching for the layperson has focused on the combination of chest compressions and Rescue breathing. Recent animal studies, however, have demonstrated improved survival with just chest compressions for primary cardiac causes of OOHCA [23,24]. Human studies examining compression- only CPR are limited. As a result, the authors of the current study sought to compare outcomes of 911 dispatcher-assisted CPR for compressions alone with compressions plus rescue breathing.

The current study is a randomized trial of dispatcher-assisted CPR performed in King County (WA), Thurston County (WA), and London (England). Patients enrolled in the study were older than 18 years, unconscious, with abnormal respirations and no initiation of bystander CPR at the time of the 911 call. Patients excluded from the study were those younger than 18 years; already receiving CPR at the time of the 911 call; had existing do-not-resuscitate documents; and those with a Cardiac arrest secondary to trauma, drowning, or asphyxiation. Those found not to be in cardiac arrest by emergency medical services (EMS) or those with irreversible signs of death were also excluded. Dispatchers randomly assigned patients to either chest compressions alone (50 consecutive compressions) or chest compressions plus rescue breathing (ratio of 15 compressions to 2 breaths). The primary outcome was survival to hospital discharge. Secondary outcomes included return of spontaneous circulation (ROSC) at the end of EMS care and neurologic status at hospital discharge, as measured by the Cerebral Performance Category.

A total of 1941 patients were enrolled in the study, with 981 randomized to compression-only CPR and 960 randomized to compres- sions plus rescue breathing. Less than 50% of the patients had a witnessed cardiac arrest, and approximately one third had an Initial shockable rhythm. Approxmately 73% of arrests were due to a cardiac cause. Overall, there was no significant difference in survival to hospital discharge for patients receiving chest compression only compared with those receiving compressions plus rescue breathing (12.5% vs 11%). In addition, there was no significant difference in the proportion of patients discharged with a favorable neurologic status in the compression-only group compared with the compression-plus-breathing group (14.4% vs 11.5%). Subgroup analysis revealed that, for patients with a cardiac etiology of arrest and who received compression-only CPR, there was a trend toward increased survival (15.5% vs 12.3%) and favorable discharge neurologic status (18.9% vs 13.5%).

Although the current study did not demonstrate increased survival to hospital discharge for patients with OOHCA receiving chest compressions

alone, mortality rates were similar to those who received compressions plus rescue breathing. Important limitations to the study include the use of a now outdated ratio of 15 compressions to 2 rescue breaths, the inability to assess the quality of bystander compressions, and the fact that neurologic status was only determined at 2 of the 3 participating sites. Furthermore, the average EMS response time from dispatch to scene arrival was 6.5 minutes, a time that may not be attainable for many prehospital provider systems. Despite these limitations, the current study is important. With concern over transmissible diseases, many laypersons may be hesitant to initiate CPR because of recommendations for rescue breathing. Cardiopulmonary resuscitation that focuses only on chest compressions may be viewed more favorably by laypersons and may result in earlier initiation of CPR for patients with OOHCA. The current study demonstrates that survival rates with chest compressions only for patients with OOHCA are no worse than for patients receiving compressions plus rescue breathing.

Svensson L, Bohm K, Castren M, Pettersson H, Engerstrom L, Herlitz J, Rosenqvist M. Compression-only CPR or standard CPR in out-of-hospital cardiac arrest. NEJM 2010;363:434-442.

The early initiation of CPR by bystanders for patients with OOHCA is vitally important. Unfortunately, it is difficult for many bystanders to accurately coordinate rescue breathing with chest compressions. In addition, many laypersons are hesitant to initiate CPR because of ventilation recommendations and concern over transmissible diseases. Recent studies have demonstrated similar survival rates for compression-only CPR compared with standard CPR, composed of both chest compressions and ventilation [25-27]. The authors of the current study sought to compare EMS dispatcher-assisted compression-only CPR to standard CPR for bystanders of patients with witnessed OOHCA.

The current study is a prospective, randomized trial performed in Sweden. Emergency medical services dispatchers enrolled patients older than 8 years who had a witnessed collapse and were unconscious with either absent or abnormal respirations. Importantly, bystander CPR had not been initiated at the time of the call, and the caller was not previously trained in CPR. Patients younger than 8 years and those with a cause of collapse due to trauma, airway obstruction, drowning, or intoxication were excluded. Patients were also excluded from enrollment if the dispatcher had trouble communicating with the caller. Once inclusion criteria were met, dispatchers provided callers with either compression-only or standard CPR instructions. Standard CPR instructions consisted of 15 chest compressions alternating with 2 respirations. Dispatchers assigned patients to either CPR technique based on the next available data sheet but were permitted to diverge if necessary. The primary end point of the study was 30-day mortality, with secondary end points of 1-day mortality and survival to hospital discharge.

A total of 1276 patients were included in the final analysis of this study, with 620 randomized to compression-only CPR and 656 randomized to standard CPR. Patients were predominantly male between 50 and 75 years old who collapsed at home. The initial cardiac rhythm in more than 50% of patients was asystole. Overall, there was no significant difference in 30-day mortality for patients receiving compression-only CPR compared with those receiving standard CPR (8.7% vs 7.0%). In addition, there was no significant difference in 1-day mortality (24.9% vs 20.9%) or survival to hospital discharge (19.1% vs 14.8%) between the 2 groups. Subgroup analysis based on age, interval between the call and EMS arrival, and initial cardiac rhythm also did not yield any difference in 30-day mortality between study groups.

The results of this study are similar to the trial by Rea et al [28] that demonstrated that outcomes for compression-only CPR were no worse than that for CPR that included both compressions and ventilations. Limitations of the current study are several. Perhaps most importantly, more than 3800 patients were enrolled in the study, but only 1276 were included in the final analysis. Many patients were subsequently excluded, thereby raising

post-cardiac arrest care“>the possibility of selection bias. In addition, study investigators calculated that more than 2200 patients were required to detect a difference in 30-day mortality. Thus, the study is underpowered. In addition, dispatchers deviated from the randomization assignment for a small quantity of patients. Reasons for this deviation are unclear. Finally, investigators used a compression-to-ventilation ratio of 15:2. National guidelines for CPR were updated during the course of the study, but the investigators chose to continue with the 15:2 ratio. Nonetheless, the current study adds to the growing body of evidence that compression-only CPR by bystanders of patients with OOHCA leads to similar outcomes when compared with standard CPR.

1. Post-cardiac arrest care

Kilgannon JH, Jones AE, Shapiro NI, Angelos MG, Milcarek B, Hunter K, et al. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA 2010;303(21):2165-2171.

There is, perhaps, nothing more exhilarating to the emergency physician than achieving ROSC in a patient with sudden cardiac arrest. In recent years, significant emphasis has been placed on caring for the post-cardiac arrest patient. Although providing oxygen is routinely recommended, the amount of supplemental oxygen administered to the post-cardiac arrest patient has been questioned. In Experimental models of cardiac arrest, too much oxygen worsens reperfusion oxidative stress and can lead to worse neurologic outcomes [29-33]. Authors of the current study sought to determine whether exposure to hyperoxia (defined by the authors as a PaO2 N300 mm Hg) after ROSC was associated with poor outcome.

The current study is a Multicenter cohort study using the Project IMPACT database, a database containing information from more than 400 000 patients from more than 130 ICUs across the United States. Patients included in the study were older than 17 years, had CPR within 24 hours of ICU arrival from a nonTraumatic cause of cardiac arrest, and had an arterial blood gas analysis within 24 hours of ICU admission. A priori, patients were divided into 3 exposure groups: hyperoxia (PaO2 N300 mm Hg), hypoxia (PaO2 b60 mm Hg), and normoxia (60 mm Hg b PaO2 b 300 mm Hg). The primary end point of the study was in-hospital mortality.

A total of 6326 patients from 120 hospitals were included in the study. Patients were predominantly white (75%) and admitted to community, nonacademic hospitals (79%). Forty-three percent of patients were admitted to an ICU from the ED. Eighteen percent of patients were in the hyperoxia group, whereas 63% were in the hypoxia group, and the remaining 19% were in the normoxia group. Just more than half (56%) of patients met the primary outcome of in-hospital mortality. Mortality was found to be highest in the hyperoxia group (63%). Mortality was lower in the hypoxia group (57%) and the normoxia group (45%). Hyperoxia was found to be a significant predictor of in-hospital mortality (odds ratio, 1.8; CI, 1.5-2.2). Among those who survived to discharge, patients with hyperoxia were less likely to be functionally independent when compared with patients with normoxia (29% vs 38%).

Limitations of the current study are several. The study is a purely observational study and can, therefore, only identify an association of hyperoxia with increased mortality. Furthermore, the Project IMPACT database is an ICU database. It does not contain data about resuscitation treatments before ICU admission. In addition, the database does not capture whether therapeutic hypothermia was used, nor does it contain information about the cause of death or neurologic outcome. Finally, the study used arterial blood gas data within the first 24 hours of ICU admission. As a result, it is difficult to ascertain whether early hyperoxia, during a time when the patient is in the ED, is more deleterious than delayed hyperoxia. Despite these limitations, the current study demon- strates that hyperoxia is common in the postresuscitation period and is associated with lower survival rates. Although further prospective data are required to confirm the results of the current study, it would seem prudent to avoid leaving post-cardiac arrest patients on 100% supplemental oxygen indefinitely.

1. Trauma

Seamon MJ, Feather C, Smith BP, Kulp H, Gaughan JP, Goldberg AJ. Just one drop: the significance of a single hypotensive blood pressure reading during trauma resuscitations. J Trauma 2010;68:1289-1295.

Managing the critically ill trauma patient can be challenging. Once persistent hypotension develops, the patient has reached an advanced state of shock, and death may be inevitable [34,35]. Recent studies have confirmed that a transient episode of hypotension in the prehospital setting can be predictive of injury severity and outcome [34,36-41]. Transient drops in blood pressure during the initial trauma evaluation and resuscitation, however, are less well studied. The authors of the current study sought to determine if a single drop in blood pressure during trauma resuscitations indicated the presence of injuries that required immediate surgical or endovascular treatment [34].

The current study is a prospective, observational study on all trauma patients admitted between June 2008 and January 2009 to a single, urban, academic medical center. Patients included in the study were between the ages of 18 and 88 years and had a single SBP less than 110 mm Hg during the initial trauma resuscitation. Patients who had Prehospital hypotension only, were initially evaluated at an outside facility and transferred to the study hospital, sustained trauma more than 2 hours before ED presentation, and had at least 2 episodes of SBP less than 90 mm Hg during the resuscitation were excluded. Patients were subsequently divided into those with a single SBP less than 105 mm Hg and those with an SBP between 105 and 110 mm Hg. Initial blood pressure was recorded manually within 10 minutes of arrival with all subsequent values obtained via automated cuff measurement. The primary outcome of the study was the need for immediate operative intervention. immediate intervention was defined as any operating room procedure performed immediately after the trauma resuscitation.

One hundred forty-five patients were included in the current study. Almost 34% of patients underwent immediate operative repair or endovascular treatment. The authors determined that the cutoff SBP that was most predictive of immediate operative intervention was an SBP less than 105 mm Hg. Patients with an SBP less than 105 mm Hg more often had penetrating injury, had a greater Injury Severity Score, had higher lactate values, and received more IVFs and blood transfusions when compared with patients with a single hypotensive episode between 105 and 110 mm Hg. Patients with a single episode of SBP less than 105 mm Hg were more likely to need immediate operative or endovascular intervention (odds ratio, 12.4; CI, 2.58-59.23).

The current study has several limitations. Importantly, the authors only evaluated patients with an SBP less than 110 mm Hg and did not have a comparison group composed of normotensive trauma patients. In addition, SBP measurements, with the exception of the initial manual recording, were done at 15-minute intervals via automated cuff measurements. It is well established that automated blood pressure recordings are progressively less reliable with increasing severity of hypotension. The authors also included patients with spinal cord injury, a group of patients that are commonly hypotensive and bradycardic. Finally, 97% of study patients survived despite the need for immediate operative intervention. This high survival rate raises the suspicion for selection bias. Nevertheless, the current study challenges the traditional SBP threshold value of 90 mm Hg to identify patients with significant injury and the potential for worse outcomes.

CRASH-2 Collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of Tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomized, placebo-controlled trial. Lancet 2010;376:23-32.

Trauma is a leading cause of death worldwide, with hemorrhage accounting for approximately one third of in-hospital trauma-related deaths

[42-44]. With trauma and Vascular injury, the coagulation system is activated, including fibrinolysis. Occasionally, fibrinolysis can be excessive and may lead to increased bleeding. In surgical studies, antifibrinolytic medications have been shown to reduce blood loss in those with excessive fibrinolytic activity [45]. Tranexamic acid is an antifibrinolytic medication that has been shown to reduce the need for blood transfusion in patients undergoing elective surgery [45]. Studies on tranexamic acid in trauma are lacking [46]. The authors of the current study sought to evaluate the effects of early administration of tranexamic acid in trauma patients who are at risk for significant bleeding.

The current study is a randomized, placebo-controlled trial performed in more than 270 hospitals in 40 countries. Patients included in the study were adult trauma patients believed to either have significant hemorrhage (defined as an SBP b90 mm Hg or heart rate N110 beats per minute) or be at risk for significant bleeding. Furthermore, patients had to present within 8 hours of injury and were enrolled only when the treating physician was uncertain about administering tranexamic acid. Patients randomized to tranexamic acid received a 1-g loading dose, followed by an infusion of 1 g given over 8 hours, whereas those randomized to placebo received isotonic sodium chloride solution. The primary outcome was 4-week in-hospital mortality. Causes of death were categorized into hemorrhage, vascular occlusion, multiorgan failure, head injury, and “other.” Secondary outcomes included the need for blood transfusion, surgical intervention, and vascular occlusive events.

A total of 20 211 patients were included in the study, with 10 060 analyzed in the tranexamic group and 10 067 analyzed in the placebo group. Most patients were male between the ages of 25 and 44 years. In addition, most patients sustained blunt trauma, had a mean time to presentation from injury of 2.8 hours, had an initial SBP greater than 90 mm Hg, and had a Glasgow Coma Score between 13 and 15. Overall, all-cause mortality was reduced in the tranexamic acid group compared with placebo (14.5% vs 16%). In addition, mortality due to bleeding was also reduced in the tranexamic group compared with controls (4.9% vs 5.7%). There was no difference, however, in the quantity of patients receiving a blood transfusion (50.4% in the tranexamic acid group vs 51.3% in controls). Importantly, there was no difference in the number of vascular occlusive events for those receiving tranexamic acid compared with placebo (1.7% vs 2%).

The results of the current study suggest that the use of tranexamic acid in trauma patients either with or at risk for significant bleeding reduces hemorrhagic mortality without increasing the risk of vasocclusive events. An important consideration and limitation of the trial is the inclusion of predominantly young patients who were not critically ill. Young patients tend to have less preexisting cardiovascular conditions, which may have lead to an underrepresentation of the true thrombotic risk of tranexamic acid. Furthermore, the trial did not take into account quality of prehospital care, nor did it address resuscitation strategies such as transfusion protocols. Finally, although the 1.5% absolute reduction in mortality reached statistical significance, is it clinically significant? Although the results of the study are important and encouraging, additional data are required before tranexamic acid should be widely administered to trauma patients with significant hemorrhage.

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