Sandra L. Peake

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.

Goal-directed resuscitation for patients with early septic shock.

BACKGROUND Early goal-directed therapy (EGDT) has been endorsed in the guidelines of the Surviving Sepsis Campaign as a key strategy to decrease mortality among patients presenting to the emergency department with septic shock. However, its effectiveness is uncertain. METHODS In this trial conducted at 51 centers (mostly in Australia or New Zealand), we randomly assigned patients presenting to the emergency department with early septic shock to receive either EGDT or usual care. The primary outcome was all-cause mortality within 90 days after randomization. RESULTS Of the 1600 enrolled patients, 796 were assigned to the EGDT group and 804 to the usual-care group. Primary outcome data were available for more than 99% of the patients. Patients in the EGDT group received a larger mean (±SD) volume of intravenous fluids in the first 6 hours after randomization than did those in the usual-care group (1964±1415 ml vs. 1713±1401 ml) and were more likely to receive vasopressor infusions (66.6% vs. 57.8%), red-cell transfusions (13.6% vs. 7.0%), and dobutamine (15.4% vs. 2.6%) (P<0.001 for all comparisons). At 90 days after randomization, 147 deaths had occurred in the EGDT group and 150 had occurred in the usual-care group, for rates of death of 18.6% and 18.8%, respectively (absolute risk difference with EGDT vs. usual care, -0.3 percentage points; 95% confidence interval, -4.1 to 3.6; P=0.90). There was no significant difference in survival time, in-hospital mortality, duration of organ support, or length of hospital stay. CONCLUSIONS In critically ill patients presenting to the emergency department with early septic shock, EGDT did not reduce all-cause mortality at 90 days. (Funded by the National Health and Medical Research Council of Australia and the Alfred Foundation; ARISE ClinicalTrials.gov number, NCT00975793.).

Tympanic temperature measurements: Are they reliable in the critically ill? A clinical study of measures of agreement*

Objective: Accurate measurement of temperature is vital in the intensive care setting. A prospective trial was performed to compare the accuracy of tympanic, urinary, and axillary temperatures with that of pulmonary artery (PA) core temperature measurements. Design: A total of 110 patients were enrolled in a prospective observational cohort study. Setting: Multidisciplinary intensive care unit of a university teaching hospital. Patients: The cohort was (mean ± sd) 65 ± 16 yrs of age, Acute Physiology and Chronic Health Evaluation (APACHE) II score was 25 ± 9, 58% of the patients were men, and 76% were mechanically ventilated. The accuracy of tympanic (averaged over both ears), axillary (averaged over both sides), and urinary temperatures was referenced (as mean difference, &Dgr; degrees centigrade) to PA temperatures as standard in 6,703 recordings. Lin concordance correlation (pc) and Bland–Altman 95% limits of agreement (degrees centigrade) described the relationship between paired measurements. Regression analysis (linear mixed model) assessed covariate confounding with respect to temperature modes and reliability formulated as an intraclass correlation coefficient. Measurements and Main Results: Concordance of PA temperatures with tympanic, urinary, and axillary was 0.77, 0.92, and 0.83, respectively. Compared with PA temperatures, &Dgr; (limits of agreement) were 0.36°C (−0.56°C, 1.28°C), −0.05°C (−0.69°C, 0.59°C), and 0.30°C (−0.42°C, 1.01°C) for tympanic, urinary, and axillary temperatures, respectively. Temperature measurement mode effect, estimated via regression analysis, was consistent with concordance and &Dgr; (PA vs. urinary, p = .98). Patient age (p = .03), sedation score (p = .0001), and dialysis (p = .0001) had modest negative relations with temperature; quadratic relationships were identified with adrenaline and dobutamine. No interactions with particular temperature modes were identified (p ≥ .12 for all comparisons) and no relationship was identified with either mean arterial pressure or APACHE II score (p ≥ .64). The average temperature mode intraclass correlation coefficient for test–retest reliability was 0.72. Conclusion: Agreement of tympanic with pulmonary temperature was inferior to that of urinary temperature, which, on overall assessment, seemed more likely to reflect PA core temperature.

The effect of obesity on 12-month survival following admission to intensive care: A prospective study*

Objective:Evaluate the effect of intensive care (ICU) admission body mass index (BMI) on 30-day and 12-month survival in critically ill patients and determine the impact of obesity on outcome. Design:Prospective, observational cohort study. Setting:Fourteen-bed medical and surgical ICU of a university-affiliated hospital. Patients:Four hundred and ninety-three adult patients. Interventions:None. Measurements and Main Results:BMI (kg/m2) was calculated from height (m) and measured weight (kg) within 4 hrs of ICU admission, using the PROMED weighing device, or premorbid weight (documented in the previous month) (BMImeasured). Follow-up was for ≥12 months post-ICU admission. Time to mortality outcome, censored at 30 and 365 days (12-months), was analyzed using a log-normal accelerated failure time regression model. Predictor variables were parameterized as time ratios (TR), where TR <1 is associated with decreased survival time and TR >1 is associated with prolonged survival time. Mean (sd) age and Acute Physiology and Chronic Health Evaluation II score were 62.3 (17.5) years and 20.7(8.4), respectively; 56.0% (285 of 493) of patients were male and 60.6% (299 of 493) medical. ICU admission weight and BMImeasured (available in 433 patients) were 79.1 (22.1) kg and 27.8 (7.0) kg/m2, respectively. In 16.9% (73 of 433) of patients, weight was ≥100 kg, and in 29.8% (129 of 433), BMImeasured was ≥30 kg/m2. Raw intensive care, 30-day, and 12-month mortality rates were 15.2% (66 of 433), 22.3% (95 of 433), and 37.3% (159 of 433), respectively. BMImeasured was a significant determinant of mortality at 30 days (TR 1.853, 95% confidence interval 1.053–3.260, p = .032) and 12 months (TR 1.034, 95% confidence interval 1.005–1.063, p = .019). The effect of BMI on 12-month mortality was linear, such that increasing BMI was associated with decreasing mortality. Conclusions:ICU admission BMI was a determinant of short- to medium-term survival. Obesity was not associated with adverse outcomes and may be protective.

N-acetyl-L-cysteine depresses cardiac performance in patients with septic shock

OBJECTIVE To investigate the effects of adjunctive therapy with parenteral N-acetyl-L-cysteine in patients with newly diagnosed septic shock. DESIGN Prospective, randomized, double-blind, placebo-controlled study. SETTING Multidisciplinary intensive care unit at a university teaching hospital. PATIENTS Twenty patients (N-acetyl-L-cysteine group [n = 10], placebo group [n = 10]), 15 male and five female, of mean age 64 +/- 15 (SD) yrs and Acute Physiology and Chronic health Evaluation (APACHE) II score 33 +/- 6, with septic shock within 24 hrs of diagnosis. INTERVENTIONS After a 2-hr stabilization period (time-zero minus 2 hrs to time-zero), patients received either N-acetyl-L-cysteine in 5% dextrose (150 mg/kg in 100 mL over 15 mins, followed by 50 mg/kg in 250 mL over 4 hrs, and then 100 mg/kg/24 hrs in 500 mL for 44 hrs; N-acetyl-L-cysteine group) or the equivalent volume of 5% dextrose (placebo group). MEASUREMENTS AND MAIN RESULTS Hemodynamic and oxygen transport indices were measured at time-zero minus 2 hrs and time-zero, and at multiple time points thereafter until completion of the trial infusion (time-zero plus 48 hrs). A daily Organ Failure Score was recorded for 14 days. Treatment group demographics and hemodynamic variables did not differ significantly between the two groups at time-zero. Mean (SD), pooled mean arterial pressure (MAP), and cardiac index were 75 +/- 15 mm Hg and 3.9 +/- 1.2 L/min/m2, respectively. Over the next 48 hrs, in the N-acetyl-L-cysteine group, there was a progressive decrease, relative to both time-zero and the placebo group, in MAP, cardiac index, and left ventricular stroke work index (p < .01, repeated-measures analysis of variance). Percentage reductions in these values relative to the placebo group at 48 hrs were 23%, 18%, and 43%, respectively Oxygen transport indices, arterial blood gas analyses, Pao2/Fio2 ratio, and shunt did not differ over time between the groups. There was no difference in either daily Organ Failure Score over time (p > .01, repeated-measures analysis of variance) or hospital mortality rate (90% N-acetyl-L-cysteine group, 50% placebo group) (p > .1, logistic regression) between the two groups. CONCLUSION Adjunctive therapy with N-acetyl-L-cysteine in newly diagnosed septic shock was associated with a depression in cardiovascular performance, as indicated by progressive reductions in cardiac index, left ventricular stroke work index, and MAP.

Does Beta-lactam Pharmacokinetic Variability in Critically Ill Patients Justify Therapeutic Drug Monitoring? A Systematic Review

The pharmacokinetics of beta-lactam antibiotics in intensive care patients may be profoundly altered due to the dynamic, unpredictable pathophysiological changes that occur in critical illness. For many drugs, significant increases in the volume of distribution and/or variability in drug clearance are common. When “standard” beta-lactam doses are used, such pharmacokinetic changes can result in subtherapeutic plasma concentrations, treatment failure, and the development of antibiotic resistance. Emerging data support the use of beta-lactam therapeutic drug monitoring (TDM) and individualized dosing to ensure the achievement of pharmacodynamic targets associated with rapid bacterial killing and optimal clinical outcomes. The purpose of this work was to describe the pharmacokinetic variability of beta-lactams in the critically ill and to discuss the potential utility of TDM to optimize antibiotic therapy through a structured literature review of all relevant publications between 1946 and October 2011. Only a few studies have reported the utility of TDM as a tool to improve beta-lactam dosing in critically ill patients. Moreover, there is little agreement between studies on the pharmacodynamic targets required to optimize antibiotic therapy. The impact of TDM on important clinical outcomes also remains to be established. Whereas TDM may be theoretically rational, clinical studies to assess utility in the clinical setting are urgently required.

Parenteral magnesium sulfate versus amiodarone in the therapy of atrial tachyarrhythmias: a prospective, randomized study.

OBJECTIVE To compare the efficacy of parenteral magnesium sulfate vs. amiodarone in the therapy of atrial tachyarrhythmias in critically ill patients. DESIGN Prospective, randomized study. SETTING Multidisciplinary intensive care unit (ICU) at a university teaching hospital. PATIENTS Forty-two patients, 21 medical and 21 surgical, of mean (SD) age 67 +/- 15 yrs and mean Acute Physiology and Chronic Health Evaluation II score of 22 +/- 6, with atrial tachyarrhythmias (ventricular response rate of > or = 120 beats/min) sustained for > or = 1 hr. INTERVENTIONS After correction of the plasma potassium concentration to > or = 4.0 mmol/L, patients were randomly allocated to treatment with either a) magnesium sulfate 0.037 g/kg (37 mg/kg) bolus followed by 0.025 g/kg/hr (25 mg/kg/hr); or b) amiodarone 5 mg/kg bolus and 10 mg/kg/24-hr infusion. Therapeutic plasma magnesium concentration in the magnesium sulfate group was 1.4 to 2.0 mmol/L. Therapeutic end point was conversion to sinus rhythm over 24 hrs. MEASUREMENTS AND MAIN RESULTS At study entry (time 0), initial mean ventricular response rate and systolic blood pressure were 151 +/- 16 (SD) beats/min and 127 +/- 30 mm Hg in the magnesium sulfate group vs. 153 +/- 23 beats/min and 123 +/- 23 mm Hg in the amiodarone group, respectively (p = .8 and .65). Plasma magnesium (time 0) was 0.84 +/- 0.20 vs. 1.02 +/- 0.22 mmol/L in the magnesium and amiodarone group, respectively (p = .1). Eight patients had chronic dysrhythmias (magnesium 3, amiodarone 5). Excluding the two patient deaths (amiodarone group, time 0 + 12 to 24 hrs), no significant change in systolic blood pressure subsequently occurred in either group. In the magnesium group, mean plasma magnesium concentrations were 1.48 +/- 0.36, 1.82 +/- 0.41, 2.16 +/- 0.45, and 1.92 +/- 0.49 mmol/L at time 0 + 1, 4, 12 and 24 hrs, respectively. By logistic regression, the probability of conversion to sinus rhythm was significantly better for magnesium than for amiodarone at time 0 + 4 (0.6 vs. 0.44), 12 (0.72 vs. 0.5), and 24 (0.78 vs. 0.5) hrs. In patients not converting to sinus rhythm, a significant decrease in ventricular response rate occurred at time 0 + to 0.5 hrs (mean decrease 19 beats/min, p = .0001), but there was no specific treatment effect between the magnesium and the amiodarone groups; thereafter, there was no significant reduction in ventricular response rate over time in either group. CONCLUSIONS Intravenous magnesium sulfate is superior to amiodarone in the conversion of acute atrial tachyarrhythmias, while initial slowing of ventricular response rate in nonconverters appears equally efficacious with both agents.

Australasian resuscitation of sepsis evaluation(ARISE): A multi-centre, prospective, inception cohort study

AIM Determine current resuscitation practices and outcomes in patients presenting to the emergency department (ED) with sepsis and hypoperfusion or septic shock in Australia and New Zealand (ANZ). METHODS Three-month prospective, multi-centre, observational study of all adult patients with sepsis and hypoperfusion or septic shock in the ED of 32 ANZ tertiary-referral, metropolitan and rural hospitals. RESULTS 324 patients were enrolled (mean [SD] age 63.4 [19.2] years, APACHE II score 19.0 [8.2], 52.5% male). Pneumonia (n=138/324, 42.6%) and urinary tract infection (n=98/324, 30.2%) were the commonest sources of sepsis. Between ED presentation and 6hours post-enrolment (T6hrs), 44.4% (n=144/324) of patients received an intra-arterial catheter, 37% (n=120/324) a central venous catheter and 0% (n=0/324) a continuous central venous oxygen saturation (ScvO(2)) catheter. Between enrolment and T6hrs, 32.1% (n=104/324) received a vasopressor infusion, 7.4% (n=24/324) a red blood cell transfusion, 2.5% (n=8/324) a dobutamine infusion and 18.5% (n=60/324) invasive mechanical ventilation. Twenty patients (6.2%) were transferred from ED directly to the operating theatre, 36.4% (n=118/324) were admitted directly to ICU, 1.2% (n=4/324) died in the ED and 56.2% (n=182/324) were transferred to the hospital floor. Overall ICU admission rate was 52.4% (n=170/324). ICU and overall in-hospital mortality were 18.8% (n=32/170) and 23.1% (n=75/324) respectively. In-hospital mortality was not different between patients admitted to ICU (24.7%, n=42/170) and the hospital floor (21.4%, n=33/154). CONCLUSIONS Management of ANZ patients presenting to ED with sepsis does not routinely include protocolised, ScvO(2)-directed resuscitation. In-hospital mortality compares favourably with reported mortality in international sepsis trials and nationwide surveys of resuscitation practices.

Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis.

BACKGROUND After a single‐center trial and observational studies suggesting that early, goal‐directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta‐analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS We harmonized entry criteria, intervention protocols, outcomes, resource‐use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol‐based standard‐therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90‐day mortality. Secondary outcomes included 1‐year survival, organ support, and hospitalization costs. We tested for treatment‐by‐subgroup interactions for 16 patient characteristics and 6 care‐delivery characteristics. RESULTS We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS In this meta‐analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158.)

Procalcitonin Algorithm in Critically Ill Adults with Undifferentiated Infection or Suspected Sepsis A Randomized Controlled Trial

RATIONALE The role of procalcitonin (PCT), a widely used sepsis biomarker, in critically ill patients with sepsis is undetermined. OBJECTIVES To investigate the effect of a low PCT cut-off on antibiotic prescription and to describe the relationships between PCT plasma concentration and sepsis severity and mortality. METHODS This was a multicenter (11 Australian intensive care units [ICUs]), prospective, single-blind, randomized controlled trial involving 400 patients with suspected bacterial infection/sepsis and expected to receive antibiotics and stay in ICU longer than 24 hours. The primary outcome was the cumulative number of antibiotics treatment days at Day 28. MEASUREMENTS AND MAIN RESULTS PCT was measured daily while in the ICU. A PCT algorithm, including 0.1 ng/ml cut-off, determined antibiotic cessation. Published guidelines and antimicrobial stewardship were used in all patients. Primary analysis included 196 (PCT) versus 198 standard care patients. Ninety-three patients in each group had septic shock. The overall median (interquartile range) number of antibiotic treatment days were 9 (6-21) versus 11 (6-22), P = 0.58; in patients with positive pulmonary culture, 11 (7-27) versus 15 (8-27), P = 0.33; and in patients with septic shock, 9 (6-22) versus 11 (6-24), P = 0.64; with an overall 90-day all-cause mortality of 35 (18%) versus 31 (16%), P = 0.54 in the PCT versus standard care, respectively. Using logistic regression, adjusted for age, ventilation status, and positive culture, the decline rate in log(PCT) over the first 72 hours independently predicted hospital and 90-day mortality (odds ratio [95% confidence interval], 2.76 [1.10-6.96], P = 0.03; 3.20 [1.30-7.89], P = 0.01, respectively). CONCLUSIONS In critically ill adults with undifferentiated infections, a PCT algorithm including 0.1 ng/ml cut-off did not achieve 25% reduction in duration of antibiotic treatment. Clinical trial registered with http://www.anzctr.org.au (ACTRN12610000809033).