Functional outcomes at 12 months for patients with traumatic brain injury, intracerebral haemorrhage and subarachnoid haemorrhage treated in an Australian neurocritical care unit: A prospective cohort study.

BACKGROUND: Acute severe brain injury is associated with significant morbidity and mortality. Patients and their families need accurate information regarding expected outcomes. Few studies have reported the long-term functional outcome of patients with acute severe brain injury treated in an Australian neurocritical care unit. OBJECTIVE: The objective of this study was to describe 12-month functional outcomes (using the extended Glasgow Outcome Scale) of patients with acute severe brain injury treated in an Australian neurocritical care unit. METHODS: This was a single-centre prospective cohort study. Patients with a diagnosis of traumatic brain injury, subarachnoid haemorrhage or intracranial haemorrhage admitted between 2015 and 2019 were enrolled. RESULTS: In total, 915 participants were enrolled during the 51-month study period. Of the cohort, 403 (44%) were admitted after traumatic brain injury, 274 (30%) after subarachnoid haemorrhage and 238 (26%) after intracranial haemorrhage. The median duration of intensive care admission was 5 days (interquartile range: 2-13), 458 (50%) received invasive ventilation, 417 (46%) received vasopressor support and 286 (31%) received an external ventricular drain. At discharge from intensive care, 150 of 915 (16.4%) had died, and the in-hospital mortality was seen in 191 of 915 patients (20.9%). Favourable functional outcome, as defined by an extended Glasgow Outcome Scale score of 5-8, was reported in 358 of available 795 patients (45.0%) at six months and in 311 of 672 available patients (46.3%) at 12 months. Those with intracranial haemorrhage reported the highest rates of unfavourable outcomes with 112 of 166 patients (67.4%) at 12 months. CONCLUSIONS: In this selected population, admission to a neurocritical care unit was associated with significant resource use. At 12 months after admission, almost half of those admitted to an Australian neurocritical unit with traumatic brain injury, subarachnoid haemorrhage and intracerebral haemorrhage report a good functional outcome.

Early Magnesium Treatment After Aneurysmal Subarachnoid Hemorrhage: Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Trials of magnesium treatment starting <4 days after symptom onset found no effect on poor outcome or DCI in SAH. Earlier installment of treatment might be more effective, but individual trials had not enough power for such a subanalysis. We performed an individual patient data meta-analysis to study whether magnesium is effective when given within different time frames within 24 hours after the SAH. METHODS: Patients were divided into categories according to the delay between symptom onset and start of the study medication: <6, 6 to 12, 12 to 24, and >24 hours. We calculated adjusted risk ratios with corresponding 95% confidence intervals for magnesium versus placebo treatment for poor outcome and DCI. RESULTS: We included 5 trials totaling 1981 patients; 83 patients started treatment<6 hours. For poor outcome, the adjusted risk ratios of magnesium treatment for start <6 hours were 1.44 (95% confidence interval, 0.83-2.51); for 6 to 12 hours 1.03 (0.65-1.63), for 12 to 24 hours 0.84 (0.65-1.09), and for >24 hours 1.06 (0.87-1.31), and for DCI, <6 hours 1.76 (0.68-4.58), for 6 to 12 hours 2.09 (0.99-4.39), for 12 to 24 hours 0.80 (0.56-1.16), and for >24 hours 1.08 (0.88-1.32). CONCLUSIONS: This meta-analysis suggests no beneficial effect of magnesium treatment on poor outcome or DCI when started early after SAH onset. Although the number of patients was small and a beneficial effect cannot be definitively excluded, we found no justification for a new trial with early magnesium treatment after SAH.

A Randomized Controlled Trial of Regional Citrate Versus Regional Heparin Anticoagulation for Continuous Renal Replacement Therapy in Critically Ill Adults.

OBJECTIVE: To determine whether regional anticoagulation of continuous renal replacement therapy circuits using citrate and calcium prolongs circuit life and/or affects circulating cytokine levels compared with regional anticoagulation using heparin and protamine. DESIGN: Multicenter, parallel group randomized controlled trial. SETTING: Seven ICUs in Australia and New Zealand. PATIENTS: Critically ill adults requiring continuous renal replacement therapy. INTERVENTIONS: Patients were randomized to receive one of two methods of regional circuit anticoagulation: citrate and calcium or heparin and protamine. MEASUREMENTS AND MAIN RESULTS: The primary outcome was functional circuit life measured in hours, assessed using repeated events survival analysis. In addition, we measured changes in interleukin-6, interleukin-8, and interleukin-10 blood levels. We randomized 212 subjects who were treated with 857 continuous renal replacement therapy circuits (median 2 circuits per patient [interquartile range, 1-6], 390 in citrate group vs 467 in heparin group). The groups were well matched for baseline characteristics. Patients receiving regional continuous renal replacement therapy anticoagulation with heparin and protamine were more likely to experience circuit clotting than those receiving citrate and calcium (hazard ratio, 2.03 [1.36-3.03]; p < 0.0005; 857 circuits). The median lifespan of the first study circuit in each patient was 39.2 hours (95% CI, 32.1-48.0 hr) in the citrate and calcium group versus 22.8 hours (95% CI, 13.3-34.0 hr) in the heparin and protamine group (log rank p = 0.0037, 204 circuits). Circuit anticoagulation with citrate and calcium had similar effects on cytokine levels compared with heparin and protamine anticoagulation. There were more adverse events in the group assigned to heparin and protamine anticoagulation (11 vs 2; p = 0.011). CONCLUSIONS: Regional citrate and calcium anticoagulation prolongs continuous renal replacement therapy circuit life compared with regional heparin and protamine anticoagulation, does not affect cytokine levels, and is associated with fewer adverse events.

Short term outcomes following clipping and coiling of ruptured intracranial aneurysms: does some of the benefit of coiling stem from less procedural impact on deranged physiology at presentation?

BACKGROUND: Endovascular coiling (EVC) has been shown to yield superior clinical outcomes to surgical clipping (SC) in the treatment of ruptured cerebral aneurysms. The reasons for these differences remain obscure. We aimed to assess outcomes of EVC and SC relative to baseline physiological derangement. METHODS: This was an exploratory analysis of prospectively collected trial data. Physiological derangement was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system. Other contributory variables such as age, World Federation of Neurosurgical Societies (WFNS) grade, and development of complications, including hydrocephalus and vasospasm, were included in the analysis. Clinical outcome was independently assessed at 90 days using the modified Rankin Scale (mRS). Hospital stay, ventilated days, and total norepinephrine dose were also used as secondary outcomes. Multivariate analysis was performed using binary logistic regression. RESULTS: EVC was performed in 69 patients and SC in 66 patients. More profound physiological derangement (APACHE II score >15) was the strongest predictor of poor outcome in the overall cohort (OR 17.80, 95% CI 4.78 to 66.21, p<0.0001). For those with more deranged physiology (APACHE II score>15; 59 patients), WFNS grade ≥4 (OR 6.74, 1.43 to 31.75) and SC (OR 6.33, 1.27 to 31.38) were significant predictors of poor outcome (p<0.05). Favorable outcome (mRS 0-2) was seen in 11% of SC patients compared with 38% of EVC patients in this subgroup. SC patients had significantly increased total norepinephrine dose, ventilated days, and hospital stay (p<0.05). CONCLUSIONS: More profound physiological derangement at baseline is a strong predictor of eventual poor outcome, and outcomes for patients with more profound baseline physiological derangement may be improved if undergoing a coiling procedure.

The detrimental clinical impact of severe angiographic vasospasm may be diminished by maximal medical therapy and intensive endovascular treatment.

OBJECTIVE: Severe angiographic vasospasm (aVSP) is a risk factor for poor functional outcome following subarachnoid hemorrhage. We investigated the impact of angiographic surveillance and intensive endovascular treatment using transluminal balloon angioplasty (TBA) and/or verapamil infusion for severe aVSP through comparison of clinical outcomes in patients of similar presenting grade but with no/mild vasospasm. METHODS: This was an analysis of prospectively acquired clinical trial data. World Federation of Neurosurgical Societies (WFNS) grade 1-2 patients presenting within 72 h were included. Angiographic screening for vasospasm was undertaken at days 5-7 or in response to clinical deterioration. Severe aVSP was defined as >50% luminal narrowing on digital subtraction angiography. Treatment was instituted on the basis of radiographic findings and/or clinical deterioration. Discharge destination and favorable clinical outcomes (discharge Glasgow Outcome Score (GOS) 4-5, 90 day modified Rankin Scale (mRS) score 0-2, and GOS 4-5) for patients with severe aVSP were compared with those without significant vasospasm. Statistical analysis was undertaken using Fisher's exact test. RESULTS: 63 WFNS grade 1-2 patients with minimal vasospasm were compared with 17 WFNS grade 1-2 patients with severe aVSP treated with induced hypertension and endovascular therapy. Results were available in 62 and 16 patients, respectively. Rates of favorable outcome did not differ significantly between the two groups. For patients with treated severe vasospasm, 90 day mRS 0-2 was seen in 15/17 (88.2%) and GOS 4-5 was achieved in 16/17 (94.1%). CONCLUSIONS: An intensive endovascular approach of TBA and/or intra-arterial verapamil in combination with induced hypertension for severe aVSP may result in comparable clinical outcomes to those without vasospasm.

A randomised controlled trial of induced hypermagnesaemia following aneurysmal subarachnoid haemorrhage.

BACKGROUND: The effect of serum magnesium concentration on the incidence of cerebral arterial vasospasm following aneurysmal subarachnoid haemorrhage (SAH) is unclear. OBJECTIVE: To test whether induced hypermagnesaemia reduces the incidence of cerebral arterial vasospasm following aneurysmal SAH. METHODS: The study was conducted at two tertiary hospitals in Australia and patients were recruited between 1 April 2005 and 31 December 2009. Within 72 hours of aneurysmal SAH, patients were randomly assigned to a high or normal target for serum magnesium concentration (1.60-2.50 mmol/L or 0.65-1.05 mmol/L, respectively). The primary end point was cerebral arterial vasospasm diagnosed by blinded assessment of digital subtraction angiography. Secondary outcomes included severity of vasospasm and functional recovery at 90 days. Analysis was by intention to treat. RESULTS: Of 162 patients, 81 were assigned to the normal range group and 81 were assigned to the high-range group; the primary outcome was available for 78 and 79 patients, respectively. The groups had similar baseline characteristics. Vasospasm occurred in 40 patients (50.6%) and 50 patients (64.1%) assigned to high-range and normal-range groups, respectively (adjusted OR, 0.51; 95% CI, 0.26-1.02; P = 0.06). At 90 days, neurological recovery between the groups was not significantly different (adjusted OR for worse outcome, 0.71; 95% CI, 0.39-1.32; P = 0.28). Patients in the high-range group were treated with more noradrenaline to support arterial blood pressure (79 [16- 218] mg) v 59 [14-129] mg; P = 0.03) and had lower mean (SD) serum calcium concentration (1.9 [0.2] mmol/L v 2.1 [0.2] mmol/L, P < 0.001). CONCLUSION: Patients assigned a higher serum magnesium concentration had a reduced incidence of vasospasm as seen by angiography, but the difference was not statistically significant. Clinically significant outcomes were not different between groups. A firm recommendation for induced hypermagnesaemia cannot be made from this study. TRIAL REGISTRATION NUMBER: ACTRN12605000058673.

Levosimendan for the treatment of acute severe heart failure: a meta-analysis of randomised controlled trials.

BACKGROUND: The objective of this study was to critically review the literature to evaluate whether levosimendan compared to standard therapy, in patients with acute severe heart failure, is associated with improved clinical outcomes. METHODS: Medline, EMBASE, and the Cochrane central register of clinical trials were searched. We also searched clinical trials registries, bibliographies of included studies and review articles and contacted the manufacturers of levosimendan to identify unpublished studies. Randomised clinical trials comparing levosimendan to standard therapy or placebo, in adult patients with acute severe heart failure, reporting at least one outcome of interest were included. Data were extracted regarding the characteristics, methodological quality and clinical outcomes, and combined using a fixed-effect meta-analysis. RESULTS: We identified 19 RCTs enrolling 3650 patients, only two studies fulfilled all of the validity criteria. There was a non-significant reduction in mortality with levosimendan compared with placebo (OR 0.83, 95%CI, 0.62-1.10, p=0.20). Levosimendan was associated with reduced mortality compared to dobutamine (OR 0.75, 95%CI, 0.61-0.92, p=0.005). Levosimendan was associated with improvements in haemodynamic parameters when compared to either placebo or dobutamine. CONCLUSIONS: Levosimendan improved haemodynamic parameters when compared with placebo, without showing evidence of survival benefit. Levosimendan improved both haemodynamics and survival when compared with dobutamine.

Is there a place for levosimendan in the intensive care unit?

INTRODUCTION: Levosimendan is a novel calcium-sensitising agent that has been proposed as a potentially valuable inotrope for the treatment of acute or decompensated severe heart failure. Early clinical trials described some improvements in surrogate haemodynamic parameters, and suggested a possible survival benefit. However, before concluding that there is a place for routine use of levosimendan in the intensive care unit, a careful appraisal of all available evidence is needed. THE EVIDENCE: Two phase II clinical trials, RUSSLAN and LIDO, have shown reduced mortality when levosimendan was compared with placebo and dobutamine, respectively. The CASINO study, yet to be fully reported, also purports to show a beneficial effect of levosimendan. In contrast, the two largest studies, REVIVE and SURVIVE -- also yet to be fully reported -- show no effect of levosimendan. CONCLUSIONS: The best available evidence comes from the two large clinical trials, REVIVE and SURVIVE. These studies suggest that levosimendan does not improve survival for patients with acute severe heart failure. Until their results can be fully scrutinised, and placed in the context of all available evidence, we should conclude that there is no place for levosimendan in the ICU.