Alisa Higgins

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.).

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.

Expert consensus and recommendations on safety criteria for active mobilization of mechanically ventilated critically ill adults.

IntroductionThe aim of this study was to develop consensus recommendations on safety parameters for mobilizing adult, mechanically ventilated, intensive care unit (ICU) patients.MethodsA systematic literature review was followed by a meeting of 23 multidisciplinary ICU experts to seek consensus regarding the safe mobilization of mechanically ventilated patients.ResultsSafety considerations were summarized in four categories: respiratory, cardiovascular, neurological and other. Consensus was achieved on all criteria for safe mobilization, with the exception being levels of vasoactive agents. Intubation via an endotracheal tube was not a contraindication to early mobilization and a fraction of inspired oxygen less than 0.6 with a percutaneous oxygen saturation more than 90% and a respiratory rate less than 30 breaths/minute were considered safe criteria for in- and out-of-bed mobilization if there were no other contraindications. At an international meeting, 94 multidisciplinary ICU clinicians concurred with the proposed recommendations.ConclusionConsensus recommendations regarding safety criteria for mobilization of adult, mechanically ventilated patients in the ICU have the potential to guide ICU rehabilitation whilst minimizing the risk of adverse events.

A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis

RATIONALE Observational studies link statin therapy with improved outcomes in patients with severe sepsis. OBJECTIVES To test whether atorvastatin therapy affects biologic and clinical outcomes in critically ill patients with severe sepsis. METHODS Phase II, multicenter, prospective, randomized, double-blind, placebo-controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo. MEASUREMENTS AND MAIN RESULTS There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (P = 0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (P = 0.26). Baseline plasma IL-6 was lower among previous statin users (129 [87-191] vs. 244 [187-317] pg/ml; P = 0.01). There was no difference in length of stay, change in Sequential Organ Failure Assessment scores or mortality at intensive care unit discharge, hospital discharge, 28- or 90-day (15% vs. 19%), or adverse effects between the two groups. Cholesterol was lower in patients treated with atorvastatin (2.4 [0.07] vs. 2.6 [0.06] mmol/L; P = 0.006). In the predefined group of 77 prior statin users, those randomized to placebo had a greater 28-day mortality (28% vs. 5%; P = 0.01) compared with those who received atorvastatin. The difference was not statistically significant at 90 days (28% vs. 11%; P = 0.06). CONCLUSIONS Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12607000028404).

Early mobilization and recovery in mechanically ventilated patients in the ICU: a bi-national, multi-centre, prospective cohort study.

The aim of this study was to investigate current mobilization practice, strength at ICU discharge and functional recovery at 6 months among mechanically ventilated ICU patients. This was a prospective, multi-centre, cohort study conducted in twelve ICUs in Australia and New Zealand. Patients were previously functionally independent and expected to be ventilated for >48 hours. We measured mobilization during invasive ventilation, sedation depth using the Richmond Agitation and Sedation Scale (RASS), co-interventions, duration of mechanical ventilation, ICU-acquired weakness (ICUAW) at ICU discharge, mortality at day 90, and 6-month functional recovery including return to work. We studied 192 patients (mean age 58.1 ± 15.8 years; mean Acute Physiology and Chronic Health Evaluation (APACHE) (IQR) II score, 18.0 (14 to 24)). Mortality at day 90 was 26.6% (51/192). Over 1,351 study days, we collected information during 1,288 planned early mobilization episodes in patients on mechanical ventilation for the first 14 days or until extubation (whichever occurred first). We recorded the highest level of early mobilization. Despite the presence of dedicated physical therapy staff, no mobilization occurred in 1,079 (84%) of these episodes. Where mobilization occurred, the maximum levels of mobilization were exercises in bed (N = 94, 7%), standing at the bed side (N = 11, 0.9%) or walking (N = 26, 2%). On day three, all patients who were mobilized were mechanically ventilated via an endotracheal tube (N = 10), whereas by day five 50% of the patients mobilized were mechanically ventilated via a tracheostomy tube (N = 18). In 94 of the 156 ICU survivors, strength was assessed at ICU discharge and 48 (52%) had ICU-acquired weakness (Medical Research Council Manual Muscle Test Sum Score (MRC-SS) score <48/60). The MRC-SS score was higher in those patients who mobilized while mechanically ventilated (50.0 ± 11.2 versus 42.0 ± 10.8, P = 0.003). Patients who survived to ICU discharge but who had died by day 90 had a mean MRC score of 28.9 ± 13.2 compared with 44.9 ± 11.4 for day-90 survivors (P <0.0001). Early mobilization of patients receiving mechanical ventilation was uncommon. More than 50% of patients discharged from the ICU had developed ICU-acquired weakness, which was associated with death between ICU discharge and day-90. ClinicalTrials.gov NCT01674608. Registered 14 August 2012.

Measuring functional and quality of life outcomes following major head injury: Common scales and checklists

Traumatic brain injury (TBI) is a major public health issue, which results in significant mortality and long term disability. The profound impact of TBI is not only felt by the individuals who suffer the injury but also their care-givers and society as a whole. Clinicians and researchers require reliable and valid measures of long term outcome not only to truly quantify the burden of TBI and the scale of functional impairment in survivors, but also to allow early appropriate allocation of rehabilitation supports. In addition, clinical trials which aim to improve outcomes in this devastating condition require high quality measures to accurately assess the impact of the interventions being studied. In this article, we review the properties of an ideal measure of outcome in the TBI population. Then, we describe the key components and performance of the measurement tools most commonly used to quantify outcome in clinical studies in TBI. These measurement tools include: the Glasgow Outcome Scale (GOS) and extended Glasgow Outcome Scale (GOSe); Disability Rating Scale (DRS); Functional Independence Measure (FIM); Functional Assessment Measure (FAM); Functional Status Examination (FSE) and the TBI-specific and generic quality of life measures used in TBI patients (SF-36 and SF-12, WHOQOL-BREF, SIP, EQ-5D, EBIQ, and QOLIBRI).

A randomised controlled trial of an open lung strategy with staircase recruitment, titrated PEEP and targeted low airway pressures in patients with acute respiratory distress syndrome

IntroductionTidal volume and plateau pressure minimisation are the standard components of a protective lung ventilation strategy for patients with acute respiratory distress syndrome (ARDS). Open lung strategies, including higher positive end-expiratory pressure (PEEP) and recruitment manoeuvres to date have not proven efficacious. This study examines the effectiveness and safety of a novel open lung strategy, which includes permissive hypercapnia, staircase recruitment manoeuvres (SRM) and low airway pressure with PEEP titration.MethodTwenty ARDS patients were randomised to treatment or ARDSnet control ventilation strategies. The treatment group received SRM with decremental PEEP titration and targeted plateau pressure < 30 cm H2O. Gas exchange and lung compliance were measured daily for 7 days and plasma cytokines in the first 24 hours and on days 1, 3, 5 and 7 (mean ± SE). Duration of ventilation, ICU stay and hospital stay (median and interquartile range) and hospital survival were determined.ResultsThere were significant overall differences between groups when considering plasma IL-8 and TNF-α. For plasma IL-8, the control group was 41% higher than the treatment group over the seven-day period (ratio 1.41 (1.11 to 1.79), P = 0.01), while for TNF-α the control group was 20% higher over the seven-day period (ratio 1.20 (1.01 to 1.42) P = 0.05). PaO2/FIO2 (204 ± 9 versus 165 ± 9 mmHg, P = 0.005) and static lung compliance (49.1 ± 2.9 versus 33.7 ± 2.7 mls/cm H2O, P < 0.001) were higher in the treatment group than the control group over seven days. There was no difference in duration of ventilation (180 (87 to 298) versus 341 (131 to 351) hrs, P = 0.13), duration of ICU stay (9.9 (5.6 to 14.8) versus 16.0 (8.1 to 19.3) days, P = 0.19) and duration of hospital stay (17.9 (13.7 to 34.5) versus 24.7 (20.5 to 39.8) days, P = 0.16) between the treatment and control groups.ConclusionsThis open lung strategy was associated with greater amelioration in some systemic cytokines, improved oxygenation and lung compliance over seven days. A larger trial powered to examine clinically-meaningful outcomes is warranted.Trial registrationACTRN12607000465459

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.)

Randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor in patients with septic shock.

Objective: To investigate the effect of early administration of granulocyte colony-stimulating factor (G-CSF) on hospital mortality in nonneutropenic patients with septic shock, excluding patients with melioidosis. Design: A randomized, placebo-controlled, double-blinded clinical trial. Setting and Patients: Adult patients with septic shock admitted to the Royal Darwin Hospital Intensive Care Unit. Interventions: Patients were randomized to receive G-CSF or placebo intravenously daily for 10 days, in addition to routine management of septic shock. Measurements: Primary outcome was hospital mortality. Secondary outcomes included intensive care unit mortality, intensive care unit and hospital length of stay, ventilator hours, and time to resolution of shock. Patient comorbidities, baseline and daily physiology, and organ function were collected. Results: Of 166 patients enrolled, 83 were allocated to receive G-CSF (81 included in analysis) and 83 were allocated to receive placebo. At baseline, 30% of patients had diabetes, 18% were known to have renal impairment or failure, and 38% had a history of hazardous alcohol use. The two groups had similar comorbidities at baseline and a similar severity of illness. The in-hospital mortality was 27% in the G-CSF group and 25% in the placebo group. Secondary end points were not different between groups. There was a higher rate of new organ failure in G-CSF–treated patients than placebo-treated patients (50% vs. 33%, p = .03), most of which was accounted for by new liver dysfunction (11% vs. 1%, p = .007). There was no significant difference in the proportion of patients with troponin I of >0.08 mg/L (78% vs. 66%, p = .09), and the prevalence of acute myocardial infarction (6% vs. 4%, p = .55) was not different during the study. The median peak troponin I level was higher in the G-CSF group (0.5 vs. 0.14 mg/L, p = .007), but baseline levels were not available. Conclusion: G-CSF does not improve outcomes in patients with septic shock, excluding melioidosis. Increased hepatic dysfunction and higher peak troponin levels in patients receiving G-CSF have not been reported in previous clinical trials and warrant further investigation.