D. James Cooper

Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock

BACKGROUND Vasopressin is commonly used as an adjunct to catecholamines to support blood pressure in refractory septic shock, but its effect on mortality is unknown. We hypothesized that low-dose vasopressin as compared with norepinephrine would decrease mortality among patients with septic shock who were being treated with conventional (catecholamine) vasopressors. METHODS In this multicenter, randomized, double-blind trial, we assigned patients who had septic shock and were receiving a minimum of 5 microg of norepinephrine per minute to receive either low-dose vasopressin (0.01 to 0.03 U per minute) or norepinephrine (5 to 15 microg per minute) in addition to open-label vasopressors. All vasopressor infusions were titrated and tapered according to protocols to maintain a target blood pressure. The primary end point was the mortality rate 28 days after the start of infusions. RESULTS A total of 778 patients underwent randomization, were infused with the study drug (396 patients received vasopressin, and 382 norepinephrine), and were included in the analysis. There was no significant difference between the vasopressin and norepinephrine groups in the 28-day mortality rate (35.4% and 39.3%, respectively; P=0.26) or in 90-day mortality (43.9% and 49.6%, respectively; P=0.11). There were no significant differences in the overall rates of serious adverse events (10.3% and 10.5%, respectively; P=1.00). In the prospectively defined stratum of less severe septic shock, the mortality rate was lower in the vasopressin group than in the norepinephrine group at 28 days (26.5% vs. 35.7%, P=0.05); in the stratum of more severe septic shock, there was no significant difference in 28-day mortality (44.0% and 42.5%, respectively; P=0.76). A test for heterogeneity between these two study strata was not significant (P=0.10). CONCLUSIONS Low-dose vasopressin did not reduce mortality rates as compared with norepinephrine among patients with septic shock who were treated with catecholamine vasopressors. (Current Controlled Trials number, ISRCTN94845869 [controlled-trials.com].).

Decompressive Craniectomy in Diffuse Traumatic Brain Injury

BACKGROUND It is unclear whether decompressive craniectomy improves the functional outcome in patients with severe traumatic brain injury and refractory raised intracranial pressure. METHODS From December 2002 through April 2010, we randomly assigned 155 adults with severe diffuse traumatic brain injury and intracranial hypertension that was refractory to first-tier therapies to undergo either bifrontotemporoparietal decompressive craniectomy or standard care. The original primary outcome was an unfavorable outcome (a composite of death, vegetative state, or severe disability), as evaluated on the Extended Glasgow Outcome Scale 6 months after the injury. The final primary outcome was the score on the Extended Glasgow Outcome Scale at 6 months. RESULTS Patients in the craniectomy group, as compared with those in the standard-care group, had less time with intracranial pressures above the treatment threshold (P<0.001), fewer interventions for increased intracranial pressure (P<0.02 for all comparisons), and fewer days in the intensive care unit (ICU) (P<0.001). However, patients undergoing craniectomy had worse scores on the Extended Glasgow Outcome Scale than those receiving standard care (odds ratio for a worse score in the craniectomy group, 1.84; 95% confidence interval [CI], 1.05 to 3.24; P=0.03) and a greater risk of an unfavorable outcome (odds ratio, 2.21; 95% CI, 1.14 to 4.26; P=0.02). Rates of death at 6 months were similar in the craniectomy group (19%) and the standard-care group (18%). CONCLUSIONS In adults with severe diffuse traumatic brain injury and refractory intracranial hypertension, early bifrontotemporoparietal decompressive craniectomy decreased intracranial pressure and the length of stay in the ICU but was associated with more unfavorable outcomes. (Funded by the National Health and Medical Research Council of Australia and others; DECRA Australian Clinical Trials Registry number, ACTRN012605000009617.).

Bicarbonate Does Not Improve Hemodynamics in Critically III Patients Who Have Lactic Acidosis: A Prospective, Controlled Clinical Study

Abstract Study Objective:To determine whether correction of acidemia using bicarbonate improves hemodynamics in patients who have lactic acidosis. Design:Prospective, randomized, blinded, crossover...STUDY OBJECTIVE To determine whether correction of acidemia using bicarbonate improves hemodynamics in patients who have lactic acidosis. DESIGN Prospective, randomized, blinded, crossover study. Each patient sequentially received sodium bicarbonate and equimolar sodium chloride. The order of the infusions was randomized. SETTING Intensive care unit of a tertiary care hospital. PATIENTS Fourteen patients who had metabolic acidosis (bicarbonate less than 17 mmol/L and base excess less than -10) and increased arterial lactate (mean, 7.8 mmol/L). All had pulmonary artery catheters and 13 were receiving catecholamines. MEASUREMENTS AND MAIN RESULTS Sodium bicarbonate (2 mmol/kg body weight over 15 minutes) increased arterial pH (7.22 to 7.36, P less than 0.001), serum bicarbonate (12 to 18 mmol/L, P less than 0.001), and partial pressure of CO2 in arterial blood (PaCO2) (35 to 40 mm Hg, P less than 0.001) and decreased plasma ionized calcium (0.95 to 0.87 mmol/L, P less than 0.001). Sodium bicarbonate and sodium chloride both transiently increased pulmonary capillary wedge pressure (15 to 17 mm Hg, and 14 to 17 mm Hg, P less than 0.001) and cardiac output (18% and 16%, P less than 0.01). The mean arterial pressure was unchanged. Hemodynamic responses to sodium bicarbonate and sodium chloride were the same. These data have more than 90% power of detecting a 0.5 L/min (7%) change in mean cardiac output after administration of sodium bicarbonate compared with that after sodium chloride. Even the 7 most acidemic patients (mean pH, 7.13; range, 6.90 to 7.20) had no significant hemodynamic changes after either infusion. CONCLUSIONS Correction of acidemia using sodium bicarbonate does not improve hemodynamics in critically ill patients who have metabolic acidosis and increased blood lactate or the cardiovascular response to infused catecholamines in these patients. Sodium bicarbonate decreases plasma ionized calcium and increases PaCO2.

Epidemiology and 12-month outcomes from traumatic brain injury in Australia and New Zealand

BACKGROUND An epidemiologic profile of traumatic brain injury (TBI) in Australia and New Zealand was obtained following the publication of international evidence-based guidelines. METHODS Adult patients with TBI admitted to the intensive care units (ICU) of major trauma centers were studied in a 6-month prospective inception cohort study. Data including mechanisms of injury, prehospital interventions, secondary insults, operative and intensive care management, and outcome assessments 12-months postinjury were collected. RESULTS There were 635 patients recruited from 16 centers. The mean (+/-SD) age was 41.6 years +/- 19.6 years; 74.2% were men; 61.4% were due to vehicular trauma, 24.9% were falls in elderly patients, and 57.2% had severe TBI (Glasgow Coma Scale score </=8). Secondary brain insults were recorded in 28.5% and 34.8% underwent neurosurgical procedures before ICU admission. There was concordance with TBI and ICU practice guidelines, although intracranial pressure monitoring was used in 44.5% patients with severe TBI. Twelve-month mortality was 26.9% in all patients and 35.1% in patients with severe TBI. Favorable outcomes at 12 months were recorded in 58.8% of all patients and in 48.5% of patients with severe TBI. CONCLUSIONS In Australia and New Zealand, mortality and favorable neurologic outcomes after TBI were similar to published data before the advent of evidence-based guidelines. A high incidence of prehospital secondary brain insults and an ageing population may have contributed to these outcomes. Strategies to improve outcomes from TBI should be directed at preventive public health strategies and interventions to minimize secondary brain injuries in the prehospital period.

Interaction of vasopressin infusion, corticosteroid treatment, and mortality of septic shock

Objective:Vasopressin and corticosteroids are often added to support cardiovascular dysfunction in patients who have septic shock that is nonresponsive to fluid resuscitation and norepinephrine infusion. However, it is unknown whether vasopressin treatment interacts with corticosteroid treatment. Design:Post hoc substudy of a multicenter randomized blinded controlled trial of vasopressin vs. norepinephrine in septic shock. Setting:Twenty-seven Intensive Care Units in Canada, Australia, and the United States. Patients:Seven hundred and seventy-nine patients who had septic shock and were ongoing hypotension requiring at least 5 &mgr;g/min of norepinephrine infusion for 6 hours. Interventions:Patients were randomized to blinded vasopressin (0.01–0.03 units/min) or norepinephrine (5–15 &mgr;g/min) infusion added to open-label vasopressors. Corticosteroids were given according to clinical judgment at any time in the 28-day postrandomization period. Measurements:The primary end point was 28-day mortality. We tested for interaction between vasopressin treatment and corticosteroid treatment using logistic regression. Secondary end points were organ dysfunction, use of open-label vasopressors and vasopressin levels. Main Results:There was a statistically significant interaction between vasopressin infusion and corticosteroid treatment (p = 0.008). In patients who had septic shock and were also treated with corticosteroids, vasopressin, compared to norepinephrine, was associated with significantly decreased mortality (35.9% vs. 44.7%, respectively, p = 0.03). In contrast, in patients who did not receive corticosteroids, vasopressin was associated with increased mortality compared with norepinephrine (33.7% vs. 21.3%, respectively, p = 0.06). In patients who received vasopressin infusion, use of corticosteroids significantly increased plasma vasopressin levels by 33% at 6 hours (p = 0.006) to 67% at 24 hours (p = 0.025) compared with patients who did not receive corticosteroids. Conclusions:There is a statistically significant interaction between vasopressin and corticosteroids. The combination of low-dose vasopressin and corticosteroids was associated with decreased mortality and organ dysfunction compared with norepinephrine and corticosteroids.

Percutaneous tracheostomy in critically ill patients: a prospective, randomized comparison of two techniques.

ObjectiveTo prospectively compare two commonly used methods for percutaneous dilational tracheostomy (PDT) in critically ill patients. DesignProspective, randomized, clinical trial. SettingTrauma and general intensive care units of a university tertiary teaching hospital, which is also a level 1 trauma center. PatientsOne hundred critically ill patients with an indication for PDT. InterventionsPDT with the Ciaglia technique using the Ciaglia PDT introducer set and the Griggs technique using a Griggs PDT kit and guidewire dilating forceps. Measurements and Main ResultsSurgical time, difficulties, and surgical and anesthesia complications were measured at 0–2 hrs, 24 hrs, and 7 days postprocedure. Groups were well matched, and there were no differences between the two methods in surgical time or in anesthesia complications. Major bleeding complications were 4.4 times more frequent with the Griggs PDT kit. With the Ciaglia PDT kit, both intraoperative and at 2 and 24 hrs, surgical complications were less common (p = .023) and the procedure was more often completed without expert assistance (p = .013). Tracheostomy bleeding was not associated with either anticoagulant therapy or an abnormal clotting profile. Multivariate analysis identified the predictors of PDT complications as the Griggs PDT kit (p = .027) and the Acute Physiology and Chronic Health Evaluation (APACHE) II score (p = .041). The significant predictors of time required to complete PDT were the APACHE II score (p = .041), a less experienced operator (p = .0001), and a female patient (p = .013). ConclusionsPatients experiencing PDT with the Ciaglia PDT kit had a lower surgical complication rate (2% vs. 25%), less operative and postoperative bleeding, and less overall technical difficulties than did patients undergoing PDT with the Griggs PDT kit. Ciaglia PDT is, therefore, the preferred technique for percutaneous tracheostomy in critically ill patients.

Stopping vs. Continuing Aspirin before Coronary Artery Surgery

BACKGROUND Most patients with coronary artery disease receive aspirin for primary or secondary prevention of myocardial infarction, stroke, and death. Aspirin poses a risk of bleeding in patients undergoing surgery, but it is unclear whether aspirin should be stopped before coronary artery surgery. METHODS We used a 2-by-2 factorial trial design to randomly assign patients who were scheduled to undergo coronary artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the aspirin trial are reported here. Patients were randomly assigned to receive 100 mg of aspirin or matched placebo preoperatively. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. RESULTS Among 5784 eligible patients, 2100 were enrolled; 1047 were randomly assigned to receive aspirin and 1053 to receive placebo. A primary outcome event occurred in 202 patients in the aspirin group (19.3%) and in 215 patients in the placebo group (20.4%) (relative risk, 0.94; 95% confidence interval, 0.80 to 1.12; P=0.55). Major hemorrhage leading to reoperation occurred in 1.8% of patients in the aspirin group and in 2.1% of patients in the placebo group (P=0.75), and cardiac tamponade occurred at rates of 1.1% and 0.4%, respectively (P=0.08). CONCLUSIONS Among patients undergoing coronary artery surgery, the administration of preoperative aspirin resulted in neither a lower risk of death or thrombotic complications nor a higher risk of bleeding than that with placebo. (Funded by the Australian National Health and Medical Research Council and others; Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639.).

Early decompressive craniectomy for patients with severe traumatic brain injury and refractory intracranial hypertension—A pilot randomized trial

PURPOSE The aims of this study were to test the feasibility and to assess potential recruitment rates in a pilot study preliminary to a phase III randomized trial of decompressive craniectomy surgery in patients with diffuse traumatic brain injury (TBI) and refractory intracranial hypertension. MATERIALS AND METHODS A study protocol was developed, inclusion and exclusion criteria were defined, and a standardized surgical technique was established. Neurologic outcomes were assessed 6 months after injury with a validated structured questionnaire and a single trained assessor blind to treatment group. RESULTS During the 8-month pilot study at a level 1 trauma center in Melbourne, Australia, 69 intensive care patients with severe TBI were assessed for inclusion. Six patients were eligible, and 5 (8%) were randomized. Six months after injury, 100% of patients received outcome assessments. Key improvements to the multicenter Decompressive Craniectomy study protocol were enabled by the pilot study. CONCLUSIONS In patients with severe TBI and refractory intracranial hypertension, the frequency of favorable neurologic outcomes (independent living) was low and similar to predicted values (40% favorable). A future multicenter phase III trial involving 18 neurotrauma centers with most sites conservatively recruiting at just 25% of the pilot study rate would require at least 5 years to achieve an estimated 210-patient sample size. Collaboration with neurotrauma centers in countries other than Australia and New Zealand would be required for such a phase III trial to be successful.

Albumin Resuscitation for Traumatic Brain Injury: Is Intracranial Hypertension the Cause of Increased Mortality?

Mortality is higher in patients with traumatic brain injury (TBI) resuscitated with albumin compared with saline, but the mechanism for increased mortality is unknown. In patients from the Saline vs. Albumin Fluid Evaluation (SAFE) study with TBI who underwent intracranial pressure (ICP) monitoring, interventional data were collected from randomization to day 14 to determine changes in ICP (primary outcome) and in therapies used to treat increased ICP. Pattern mixture modelling, designed to address informative dropouts, was used to compare temporal changes between the albumin and saline groups, and 321 patients were identified, of whom 164 (51.1%) received albumin and 157 (48.9%) received saline. There was a significant linear increase in mean ICP and significantly more deaths in the albumin group compared with saline when ICP monitoring was discontinued during the first week (1.30±0.33 vs. -0.37±0.36, p=0.0006; and 34.4% vs. 17.4%; p=0.006 respectively), but not when monitoring ceased during the second week (-0.08±0.44 vs. -0.23±0.38, p=0.79; and 18.6% vs. 12.1%; p=0.36 respectively). There were statistically significant differences in the mean total daily doses of morphine (-0.42±0.07 vs. -0.66±0.0, p=0.0009), propofol (-0.45±0.11 vs. -0.76±0.11; p=0.034) and norepinephrine (-0.50±0.07 vs. -0.74±0.07) and in temperature (0.03±0.03 vs. 0.16±0.03; p=0.0014) between the albumin and saline groups when ICP monitoring ceased during the first week. The use of albumin for resuscitation in patients with severe TBI is associated with increased ICP during the first week. This is the most likely mechanism of increased mortality in these patients.

Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery

Background Tranexamic acid reduces the risk of bleeding among patients undergoing cardiac surgery, but it is unclear whether this leads to improved outcomes. Furthermore, there are concerns that tranexamic acid may have prothrombotic and proconvulsant effects. Methods In a trial with a 2‐by‐2 factorial design, we randomly assigned patients who were scheduled to undergo coronary‐artery surgery and were at risk for perioperative complications to receive aspirin or placebo and tranexamic acid or placebo. The results of the tranexamic acid comparison are reported here. The primary outcome was a composite of death and thrombotic complications (nonfatal myocardial infarction, stroke, pulmonary embolism, renal failure, or bowel infarction) within 30 days after surgery. Results Of the 4662 patients who were enrolled and provided consent, 4631 underwent surgery and had available outcomes data; 2311 were assigned to the tranexamic acid group and 2320 to the placebo group. A primary outcome event occurred in 386 patients (16.7%) in the tranexamic acid group and in 420 patients (18.1%) in the placebo group (relative risk, 0.92; 95% confidence interval, 0.81 to 1.05; P=0.22). The total number of units of blood products that were transfused during hospitalization was 4331 in the tranexamic acid group and 7994 in the placebo group (P<0.001). Major hemorrhage or cardiac tamponade leading to reoperation occurred in 1.4% of the patients in the tranexamic acid group and in 2.8% of the patients in the placebo group (P=0.001), and seizures occurred in 0.7% and 0.1%, respectively (P=0.002 by Fishers exact test). Conclusions Among patients undergoing coronary‐artery surgery, tranexamic acid was associated with a lower risk of bleeding than was placebo, without a higher risk of death or thrombotic complications within 30 days after surgery. Tranexamic acid was associated with a higher risk of postoperative seizures. (Funded by the Australian National Health and Medical Research Council and others; ATACAS Australia New Zealand Clinical Trials Registry number, ACTRN12605000557639.)