Colin McArthur

Intensive versus conventional glucose control in critically ill patients

BACKGROUND The optimal target range for blood glucose in critically ill patients remains unclear. METHODS Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). We defined the primary end point as death from any cause within 90 days after randomization. RESULTS Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39). CONCLUSIONS In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987.)

Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care

BACKGROUND The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy. RESULTS A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001). CONCLUSIONS In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).

Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients

BACKGROUND The optimal intensity of continuous renal-replacement therapy remains unclear. We conducted a multicenter, randomized trial to compare the effect of this therapy, delivered at two different levels of intensity, on 90-day mortality among critically ill patients with acute kidney injury. METHODS We randomly assigned critically ill adults with acute kidney injury to continuous renal-replacement therapy in the form of postdilution continuous venovenous hemodiafiltration with an effluent flow of either 40 ml per kilogram of body weight per hour (higher intensity) or 25 ml per kilogram per hour (lower intensity). The primary outcome measure was death within 90 days after randomization. RESULTS Of the 1508 enrolled patients, 747 were randomly assigned to higher-intensity therapy, and 761 to lower-intensity therapy with continuous venovenous hemodiafiltration. Data on primary outcomes were available for 1464 patients (97.1%): 721 in the higher-intensity group and 743 in the lower-intensity group. The two study groups had similar baseline characteristics and received the study treatment for an average of 6.3 and 5.9 days, respectively (P=0.35). At 90 days after randomization, 322 deaths had occurred in the higher-intensity group and 332 deaths in the lower-intensity group, for a mortality of 44.7% in each group (odds ratio, 1.00; 95% confidence interval [CI], 0.81 to 1.23; P=0.99). At 90 days, 6.8% of survivors in the higher-intensity group (27 of 399), as compared with 4.4% of survivors in the lower-intensity group (18 of 411), were still receiving renal-replacement therapy (odds ratio, 1.59; 95% CI, 0.86 to 2.92; P=0.14). Hypophosphatemia was more common in the higher-intensity group than in the lower-intensity group (65% vs. 54%, P<0.001). CONCLUSIONS In critically ill patients with acute kidney injury, treatment with higher-intensity continuous renal-replacement therapy did not reduce mortality at 90 days. (ClinicalTrials.gov number, NCT00221013.)

Critical care services and 2009 H1N1 influenza in Australia and New Zealand

BACKGROUND Planning for the treatment of infection with the 2009 pandemic influenza A (H1N1) virus through health care systems in developed countries during winter in the Northern Hemisphere is hampered by a lack of information from similar health care systems. METHODS We conducted an inception-cohort study in all Australian and New Zealand intensive care units (ICUs) during the winter of 2009 in the Southern Hemisphere. We calculated, per million inhabitants, the numbers of ICU admissions, bed-days, and days of mechanical ventilation due to infection with the 2009 H1N1 virus. We collected data on demographic and clinical characteristics of the patients and on treatments and outcomes. RESULTS From June 1 through August 31, 2009, a total of 722 patients with confirmed infection with the 2009 H1N1 virus (28.7 cases per million inhabitants; 95% confidence interval [CI], 26.5 to 30.8) were admitted to an ICU in Australia or New Zealand. Of the 722 patients, 669 (92.7%) were under 65 years of age and 66 (9.1%) were pregnant women; of the 601 adults for whom data were available, 172 (28.6%) had a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 35. Patients infected with the 2009 H1N1 virus were in the ICU for a total of 8815 bed-days (350 per million inhabitants). The median duration of treatment in the ICU was 7.0 days (interquartile range, 2.7 to 13.4); 456 of 706 patients (64.6%) with available data underwent mechanical ventilation for a median of 8 days (interquartile range, 4 to 16). The maximum daily occupancy of the ICU was 7.4 beds (95% CI, 6.3 to 8.5) per million inhabitants. As of September 7, 2009, a total of 103 of the 722 patients (14.3%; 95% CI, 11.7 to 16.9) had died, and 114 (15.8%) remained in the hospital. CONCLUSIONS The 2009 H1N1 virus had a substantial effect on ICUs during the winter in Australia and New Zealand. Our data can assist planning for the treatment of patients during the winter in the Northern Hemisphere.

Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial

IMPORTANCE Saline (0.9% sodium chloride) is the most commonly administered intravenous fluid; however, its use may be associated with acute kidney injury (AKI) and increased mortality. OBJECTIVE To determine the effect of a buffered crystalloid compared with saline on renal complications in patients admitted to the intensive care unit (ICU). DESIGN AND SETTING Double-blind, cluster randomized, double-crossover trial conducted in 4 ICUs in New Zealand from April 2014 through October 2014. Three ICUs were general medical and surgical ICUs; 1 ICU had a predominance of cardiothoracic and vascular surgical patients. PARTICIPANTS All patients admitted to the ICU requiring crystalloid fluid therapy were eligible for inclusion. Patients with established AKI requiring renal replacement therapy (RRT) were excluded. All 2278 eligible patients were enrolled; 1152 of 1162 patients (99.1%) receiving buffered crystalloid and 1110 of 1116 patients (99.5%) receiving saline were analyzed. INTERVENTIONS Participating ICUs were assigned a masked study fluid, either saline or a buffered crystalloid, for alternating 7-week treatment blocks. Two ICUs commenced using 1 fluid and the other 2 commenced using the alternative fluid. Two crossovers occurred so that each ICU used each fluid twice over the 28 weeks of the study. The treating clinician determined the rate and frequency of fluid administration. MAIN OUTCOMES AND MEASURES The primary outcome was proportion of patients with AKI (defined as a rise in serum creatinine level of at least 2-fold or a serum creatinine level of ≥3.96 mg/dL with an increase of ≥0.5 mg/dL); main secondary outcomes were incidence of RRT use and in-hospital mortality. RESULTS In the buffered crystalloid group, 102 of 1067 patients (9.6%) developed AKI within 90 days after enrollment compared with 94 of 1025 patients (9.2%) in the saline group (absolute difference, 0.4% [95% CI, -2.1% to 2.9%]; relative risk [RR], 1.04 [95% CI, 0.80 to 1.36]; P = .77). In the buffered crystalloid group, RRT was used in 38 of 1152 patients (3.3%) compared with 38 of 1110 patients (3.4%) in the saline group (absolute difference, -0.1% [95% CI, -1.6% to 1.4%]; RR, 0.96 [95% CI, 0.62 to 1.50]; P = .91). Overall, 87 of 1152 patients (7.6%) in the buffered crystalloid group and 95 of 1110 patients (8.6%) in the saline group died in the hospital (absolute difference, -1.0% [95% CI, -3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40). CONCLUSIONS AND RELEVANCE Among patients receiving crystalloid fluid therapy in the ICU, use of a buffered crystalloid compared with saline did not reduce the risk of AKI. Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality. TRIAL REGISTRATION clinicaltrials.gov Identifier: ACTRN12613001370796.

Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units

IntroductionRecent evidence suggests that choice of fluid used for resuscitation may influence mortality in critically ill patients.MethodsWe conducted a cross-sectional study in 391 intensive care units across 25 countries to describe the types of fluids administered during resuscitation episodes. We used generalized estimating equations to examine the association between patient, prescriber and geographic factors and the type of fluid administered (classified as crystalloid, colloid or blood products).ResultsDuring the 24-hour study period, 1,955 of 5,274 (37.1%) patients received resuscitation fluid during 4,488 resuscitation episodes. The main indications for administering crystalloid or colloid were impaired perfusion (1,526/3,419 (44.6%) of episodes), or to correct abnormal vital signs (1,189/3,419 (34.8%)). Overall, colloid was administered to more patients (1,234 (23.4%) versus 782 (14.8%)) and during more episodes (2,173 (48.4%) versus 1,468 (32.7%)) than crystalloid. After adjusting for patient and prescriber characteristics, practice varied significantly between countries with country being a strong independent determinant of the type of fluid prescribed. Compared to Canada where crystalloid, colloid and blood products were administered in 35.5%, 40.6% and 28.3% of resuscitation episodes respectively, odds ratios for the prescription of crystalloid in China, Great Britain and New Zealand were 0.46 (95% confidence interval (CI) 0.30 to 0.69), 0.18 (0.10 to 0.32) and 3.43 (1.71 to 6.84) respectively; odds ratios for the prescription of colloid in China, Great Britain and New Zealand were 1.72 (1.20 to 2.47), 4.72 (2.99 to 7.44) and 0.39 (0.21 to 0.74) respectively. In contrast, choice of fluid was not influenced by measures of illness severity (for example, Acute Physiology and Chronic Health Evaluation (APACHE) II score).ConclusionsAdministration of resuscitation fluid is a common intervention in intensive care units and choice of fluid varies markedly between countries. Although colloid solutions are more expensive and may possibly be harmful in some patients, they were administered to more patients and during more resuscitation episodes than crystalloids were.

Critical Illness Due to 2009 A/H1N1 Influenza in Pregnant and Postpartum Women: Population Based Cohort Study

Objective To describe the epidemiology of 2009 A/H1N1 influenza in critically ill pregnant women. Design Population based cohort study. Setting All intensive care units in Australia and New Zealand. Participants All women with 2009 H1N1 influenza who were pregnant or recently post partum and admitted to an intensive care unit in Australia or New Zealand between 1 June and 31 August 2009. Main outcome measures Maternal and neonatal mortality and morbidity. Results 64 pregnant or postpartum women admitted to an intensive care unit had confirmed 2009 H1N1 influenza. Compared with non-pregnant women of childbearing age, pregnant or postpartum women with 2009 H1N1 influenza were at increased risk of admission to an intensive care unit (relative risk 7.4, 95% confidence interval 5.5 to 10.0). This risk was 13-fold greater (13.2, 9.6 to 18.3) for women at 20 or more weeks’ gestation. At the time of admission to an intensive care unit, 22 women (34%) were post partum and two had miscarried. 14 women (22%) gave birth during their stay in intensive care and 26 (41%) were discharged from an intensive care unit with ongoing pregnancy. All subsequently delivered. 44 women (69%) were mechanically ventilated. Of these, nine (14%) were treated with extracorporeal membrane oxygenation. Seven women (11%) died. Of 60 births after 20 weeks’ gestation, four were stillbirths and three were infant deaths. 22 (39%) of the liveborn babies were preterm and 32 (57%) were admitted to a neonatal intensive care unit. Of 20 babies tested, two were positive for the 2009 H1N1 virus. Conclusions Pregnancy is a risk factor for critical illness related to 2009 H1N1 influenza, which causes maternal and neonatal morbidity and mortality.

An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy trial

Objective:To examine associations between mean daily fluid balance during intensive care unit study enrollment and clinical outcomes in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level (RENAL) replacement therapy study. Design:Statistical analysis of data from multicenter, randomized, controlled trials. Setting:Thirty-five intensive care units in Australia and New Zealand. Patients:Cohort of 1453 patients enrolled in the RENAL study. Interventions:We analyzed the association between daily fluid balance on clinical outcomes using multivariable logistic regression, Cox proportional hazards, time-dependent analysis, and repeated measure analysis models. Measurements and Main Results:During intensive care unit stay, mean daily fluid balance among survivors was –234 mL/day compared with +560 mL/day among nonsurvivors (p < .0001). Mean cumulative fluid balance over the same period was –1941 vs. +1755 mL (p = .0003). A negative mean daily fluid balance during study treatment was independently associated with a decreased risk of death at 90 days (odds ratio 0.318; 95% confidence interval 0.24–0.43; p < .000.1) and with increased survival time (p < .0001). In addition, a negative mean daily fluid balance was associated with significantly increased renal replacement-free days (p = .0017), intensive care unit-free days (p < .0001), and hospital-free days (p = .01). These findings were unaltered after the application of different statistical models. Conclusions:In the RENAL study, a negative mean daily fluid balance was consistently associated with improved clinical outcomes. Fluid balance may be a target for specific manipulation in future interventional trials of critically ill patients receiving renal replacement therapy.

Acetaminophen for Fever in Critically Ill Patients with Suspected Infection.

BACKGROUND Acetaminophen is a common therapy for fever in patients in the intensive care unit (ICU) who have probable infection, but its effects are unknown. METHODS We randomly assigned 700 ICU patients with fever (body temperature, ≥38°C) and known or suspected infection to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. The primary outcome was ICU-free days (days alive and free from the need for intensive care) from randomization to day 28. RESULTS The number of ICU-free days to day 28 did not differ significantly between the acetaminophen group and the placebo group: 23 days (interquartile range, 13 to 25) among patients assigned to acetaminophen and 22 days (interquartile range, 12 to 25) among patients assigned to placebo (Hodges-Lehmann estimate of absolute difference, 0 days; 96.2% confidence interval [CI], 0 to 1; P=0.07). A total of 55 of 345 patients in the acetaminophen group (15.9%) and 57 of 344 patients in the placebo group (16.6%) had died by day 90 (relative risk, 0.96; 95% CI, 0.66 to 1.39; P=0.84). CONCLUSIONS Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days. (Funded by the Health Research Council of New Zealand and others; HEAT Australian New Zealand Clinical Trials Registry number, ACTRN12612000513819.).

Early goal-directed sedation versus standard sedation in mechanically ventilated critically ill patients: a pilot study*.

Objective:To assess the feasibility and safety of delivering early goal-directed sedation compared with standard sedation. Design:Pilot prospective, multicenter, randomized, controlled trial. Setting:Six ICUs. Patients:Critically ill adults mechanically ventilated for greater than 24 hours. Interventions:Patients randomized to early goal-directed sedation received a dexmedetomidine-based algorithm targeted to light sedation (Richmond Agitation Sedation Score of –2 to 1). Patients randomized to standard sedation received propofol and/or midazolam-based sedation as clinically appropriate. Measurements and Main Results:The main feasibility outcomes were time to randomization and proportion of Richmond Agitation Sedation Score assessments in the first 48 hours in the light and deep sedation range. Safety outcomes were delirium-free days, vasopressor and physical restraints use, and device removal. Randomization occurred within a median (interquartile range) of 1.1 hours (0.46–1.9) after intubation or ICU admission for out of ICU intubation. Patients in the early goal-directed sedation (n = 21) mean (SD) Acute Physiology and Chronic Health Evaluation II score was 20.2 (6.2) versus 18.6 (8.8; p = 0.53) in the standard sedation (n = 16). A significantly higher proportion of patients was lightly sedated on days 1, 2, and 3 (12/19 [63.2%], 19/21 [90.5%], and 18/20 [90%] vs 2/14 [14.3%], 8/15 [53.3%], and 9/15 [60%]; p = 0.005, 0.011, 0.036) and more Richmond Agitation Sedation Scale assessments between (–2 and 1), in the first 48 hours (203/307 [66%] versus (74/197 [38%]; p = 0.01) in the early goal-directed sedation versus standard sedation, respectively. Early goal-directed sedation patients received midazolam on 6 of 173 (3.5%) versus 4 of 114 (3.5%) standard sedation patient-days when dexmedetomidine was given. Propofol was given to 16 of 21 (76%) of early goal-directed sedation versus 16 of 16 (100%) of standard sedation patients (p = 0.04). Early goal-directed sedation patients had 101 of 175 (58%) versus 54 of 114 (47%; p = 0.27) delirium-free days and required significantly less physical restraints 1 (5%) versus 5 (31%; p = 0.03) than standard sedation patients. There were no differences in vasopressor use and self-extubation. Conclusions:Delivery of early goal-directed sedation was feasible, appeared safe, achieved early light sedation, minimized benzodiazepines and propofol, and decreased the need for physical restraints. The findings of this pilot study justify further investigation of early goal-directed sedation.