Anthony Delaney

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.).

Percutaneous dilatational tracheostomy versus surgical tracheostomy in critically ill patients: a systematic review and meta-analysis

IntroductionTracheostomy is one of the more commonly performed procedures in critically ill patients yet the optimal method of performing tracheostomies in this population remains to be established. The aim of this study was to systematically review and quantitatively synthesize all randomized clinical trials (RCTs), comparing elective percutaneous dilatational tracheostomy (PDT) and surgical tracheostomy (ST) in adult critically ill patients with regards to major short and long term outcomes.MethodsMEDLINE, EMBASE, CINAHL and the Cochrane Controlled Clinical Trials Register databases were searched to identify relevant studies. Additionally, bibliographies and selected conference proceedings were reviewed, and experts in the field and manufacturers of two PDT kits were contacted. Randomized clinical trials comparing any method of elective PDT to ST that included critically ill adults and reported at least one clinically relevant outcome were included. Data extracted included trial characteristics, measures of study validity, and clinically relevant outcomes.ResultsSeventeen RCTs involving 1,212 patients were included. Most PDTs used a multiple dilator technique and were performed in the intensive care unit (ICU). The pooled odds ratio (OR) for wound infection was 0.28 (95% confidence interval (CI), 0.16 to 0.49, p < 0.0005), indicating a significant reduction with PDT compared to ST. Overall, PDT was equivalent to ST for bleeding, major peri-procedural and long-term complications; however, subgroup analysis suggested PDT resulted in a lower incidence of bleeding (OR = 0.29 (95% CI 0.12 to 0.75, p = 0.01)) and death (OR = 0.71 (95% CI 0.50 to 1.0, p = 0.05)) when the STs were performed in the operating theatre.ConclusionPDT reduces the overall incidence of wound infection and may further reduce clinical relevant bleeding and mortality when compared with ST performed in the operating theatre. PDT, performed in the ICU, should be considered the procedure of choice for performing elective tracheostomies in critically ill adult patients.

Very old patients admitted to intensive care in Australia and New Zealand: a multi-centre cohort analysis.

IntroductionOlder age is associated with higher prevalence of chronic illness and functional impairment, contributing to an increased rate of hospitalization and admission to intensive care. The primary objective was to evaluate the rate, characteristics and outcomes of very old (age ≥ 80 years) patients admitted to intensive care units (ICUs).MethodsRetrospective analysis of prospectively collected data from the Australian New Zealand Intensive Care Society Adult Patient Database. Data were obtained for 120,123 adult admissions for ≥ 24 hours across 57 ICUs from 1 January 2000 to 31 December 2005.ResultsA total of 15,640 very old patients (13.0%) were admitted during the study. These patients were more likely to be from a chronic care facility, had greater co-morbid illness, greater illness severity, and were less likely to receive mechanical ventilation. Crude ICU and hospital mortalities were higher (ICU: 12% vs. 8.2%, P < 0.001; hospital: 24.0% vs. 13%, P < 0.001). By multivariable analysis, age ≥ 80 years was associated with higher ICU and hospital death compared with younger age strata (ICU: odds ratio (OR) = 2.7, 95% confidence interval (CI) = 2.4 to 3.0; hospital: OR = 5.4, 95% CI = 4.9 to 5.9). Factors associated with lower survival included admission from a chronic care facility, co-morbid illness, nonsurgical admission, greater illness severity, mechanical ventilation, and longer stay in the ICU. Those aged ≥ 80 years were more likely to be discharged to rehabilitation/long-term care (12.3% vs. 4.9%, OR = 2.7, 95% CI = 2.6 to 2.9). The admission rates of very old patients increased by 5.6% per year. This potentially translates to a 72.4% increase in demand for ICU bed-days by 2015.ConclusionsThe proportion of patients aged ≥ 80 years admitted to intensive care in Australia and New Zealand is rapidly increasing. Although these patients have more co-morbid illness, are less likely to be discharged home, and have a greater mortality than younger patients, approximately 80% survive to hospital discharge. These data also imply a potential major increase in demand for ICU bed-days for very old patients within a decade.

Continuous versus intermittent renal replacement therapy for critically ill patients with acute kidney injury: a meta-analysis.

Objective: To appraise the literature on the effect of initial renal replacement therapy (RRT) modality on clinical outcomes. Design: Systematic review and meta-analysis. Setting: Academic medical center. Patients and Participants: Adult critically ill patients with acute kidney injury. Interventions: Continuous vs. intermittent RRT. Measurements and Results: MEDLINE, EMBASE, Cochrane Controlled Clinical Trials Register, and other sources were searched. We identified nine unique randomized trials (n = 1,403). No trial satisfied all quality indicators and several had limitations related to selection bias, randomization, imbalances in patient characteristics, and high treatment crossover. No trial standardized the timing, criteria, for initiation or dose of RRT. There was no statistical evidence that initial modality influenced mortality (odds ratio, 0.99; 95% confidence interval, 0.78–1.26, p = .93; I2 = 11%; nine trials, n = 1,403) or recovery to RRT independence (odds ratio, 0.76; 95% confidence interval, 0.28–2.07, p = .59; I2 = 0%; four trials, n = 306). There was suggestion that continuous RRT had fewer episodes of hemodynamic instability and better control of fluid balance. Conclusions: We identified numerous issues related to study design, conduct, and quality that dispute the validity and question any inferences that can be drawn from these trials. In the context of these limitations, the initial RRT modality did not seem to affect mortality or recovery to RRT independence. There is urgent need for additional high-quality and suitably powered trials to adequately address this issue.

The role of albumin as a resuscitation fluid for patients with sepsis: A systematic review and meta-analysis*

Objective:To assess whether resuscitation with albumin-containing solutions, compared with other fluids, is associated with lower mortality in patients with sepsis. Data Sources:MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases, the metaRegister of Controlled Trials, and the Medical Editors Trial Amnesty Register. Study Selection:Prospective randomized clinical trials of fluid resuscitation with albumin-containing solutions compared with other fluid resuscitation regimens, which included a population or subgroup of participants with sepsis, were included. Data Extraction:Assessment of the validity of included studies and data extraction were conducted independently by two authors. Data Synthesis:For the primary analysis, the effect of albumin-containing solutions on all-cause mortality was assessed by using a fixed-effect meta-analysis. Results:Seventeen studies that randomized 1977 participants were included in the meta-analysis. There were eight studies that included only patients with sepsis and nine where patients with sepsis were a subgroup of the study population. There was no evidence of heterogeneity, I2 = 0%. The use of albumin for resuscitation of patients with sepsis was associated with a reduction in mortality with the pooled estimate of the odds ratio of 0.82 (95% confidence limits 0.67–1.0, p = .047). Conclusions:In this meta-analysis, the use of albumin-containing solutions for the resuscitation of patients with sepsis was associated with lower mortality compared with other fluid resuscitation regimens. Until the results of ongoing randomized controlled trials are known, clinicians should consider the use of albumin-containing solutions for the resuscitation of patients with sepsis.

Polyclonal intravenous immunoglobulin for the treatment of severe sepsis and septic shock in critically ill adults: a systematic review and meta-analysis.

Objectives: To systematically review the literature to assess whether adjunctive therapy with polyclonal intravenous immunoglobulin (ivIg) reduces mortality among critically ill adults with severe sepsis and septic shock. Data Source: MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases; the meta‐register of controlled trials; and the Medical Editors Trial Amnesty register. Study Selection: Prospective randomized clinical trials (RCTs) evaluating ivIg treatment in critically ill adults with severe sepsis or septic shock were included. Two reviewers conducted assessment of suitability for inclusion. Data Extraction: Two authors independently determined the validity of included studies and extracted data. Data Synthesis: The effect of ivIg on all‐cause mortality was quantified using a fixed‐effect meta‐analysis. Results: Fourteen RCTs published between 1988 and 2006 were included. Most were small, used relatively low doses of ivIg, and included predominantly surgical patients with Gram‐negative infections. There was a significant reduction in mortality associated with use of ivIg treatment with a pooled odds ratio of 0.66 (95% confidence interval 0.53–0.83; p < .0005). In general, a greater treatment effect was seen among studies of lower methodological quality, studies using higher doses of ivIg, and studies that did not use albumin as a control. There was evidence of between‐study heterogeneity (chi‐square p = .009), and this was at least moderate as measured by the I2 value (I2 = 53.8%). When only high‐quality studies were pooled, the odds ratio for mortality was 0.96 (95% confidence interval 0.71–1.3; p = .78). Conclusions: This meta‐analysis demonstrates an overall reduction in mortality with the use of ivIg for the adjunctive treatment of severe sepsis and septic shock in adults, although significant heterogeneity exists among the included trials and this result was not confirmed when only high‐quality studies were analyzed. These data warrant a well‐designed, adequately powered, and transparently reported clinical trial.

A systematic evaluation of the quality of meta-analyses in the critical care literature.

IntroductionMeta-analyses have been suggested to be the highest form of evidence available to clinicians to guide clinical practice in critical care. The purpose of this study was to systematically evaluate the quality of meta-analyses that address topics pertinent to critical care.MethodsTo identify potentially eligible meta-analyses for inclusion, a systematic search of Medline, EMBASE and the Cochrane Database of Systematic Reviews was undertaken, using broad search terms relevant to intensive care, including: intensive care, critical care, shock, resuscitation, inotropes and mechanical ventilation. Predetermined inclusion criteria were applied to each identified meta-analysis independently by two authors. To assess report quality, the included meta-analyses were assessed using the component and overall scores from the Overview Quality Assessment Questionnaire (OQAQ). The quality of reports published before and after the publication of the QUOROM statement was compared.ResultsA total of 139 reports of meta-analyses were included (kappa = 0.93). The overall quality of reports of meta-analyses was found to be poor, with an estimated mean overall OQAQ score of 3.3 (95% CI; 3.0–3.6). Only 43 (30.9%) were scored as having minimal or minor flaws (>5). We noted problems with the reporting of key characteristics of meta-analyses, such as performing a thorough literature search, avoidance of bias in the inclusion of studies and appropriately referring to the validity of the included studies. After the release of the QUOROM statement, however, an improvement in the overall quality of published meta-analyses was noted.ConclusionThe overall quality of the reports of meta-analyses available to critical care physicians is poor. Physicians should critically evaluate these studies prior to considering applying the results of these studies in their clinical practice.

Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial

IMPORTANCE Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation. OBJECTIVE To determine the effectiveness of dexmedetomidine when added to standard care in patients with agitated delirium receiving mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium. The study was conducted at 15 intensive care units in Australia and New Zealand from May 2011 until December 2013. Patients with advanced dementia or traumatic brain injury were excluded. INTERVENTIONS Bedside nursing staff administered dexmedetomidine (or placebo) initially at a rate of 0.5 µg/kg/h and then titrated to rates between 0 and 1.5 µg/kg/h to achieve physician-prescribed sedation goals. The study drug or placebo was continued until no longer required or up to 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES Ventilator-free hours in the 7 days following randomization. There were 21 reported secondary outcomes that were defined a priori. RESULTS Of the 74 randomized patients (median age, 57 years; 18 [24%] women), 2 withdrew consent later and 1 was found to have been randomized incorrectly, leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively; median difference between groups, 17.0 hours [95% CI, 4.0 to 33.2 hours]; P = .01). Among the 21 a priori secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo; median difference between groups, 19.5 hours [95% CI, 5.3 to 31.1 hours]; P < .001) and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours; median difference between groups, 16.0 hours [95% CI, 3.0 to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics, allocation to dexmedetomidine was significantly associated with earlier extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007). CONCLUSIONS AND RELEVANCE Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit, the addition of dexmedetomidine to standard care compared with standard care alone (placebo) resulted in more ventilator-free hours at 7 days. The findings support the use of dexmedetomidine in patients such as these. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01151865.

The quality of reports of critical care meta-analyses in the Cochrane Database of Systematic Reviews : An independent appraisal

Objective:To independently appraise the methodological quality of a sample of reports of meta-analyses that address critical care topics in the Cochrane Database of Systematic Reviews compared with the quality of reports published in regular journals, using a validated assessment instrument, the Overview Quality Assessment Questionnaire (OQAQ). Data Source:Studies were selected from a search of MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from 1994 to 2003, using multiple search terms for critical care and sensitive filters to identify meta-analyses. Study Selection:Two authors independently selected meta-analyses that addressed topics pertinent to critical care medicine. Data Extraction:Two authors independently extracted the data. The proportion of reports that met each component of the OQAQ was determined, as was the overall quality score. Meta-analyses published in the Cochrane Database of Systematic Reviews were compared with those published in regular journals. Data Synthesis:There were 36 reports of meta-analyses in the Cochrane Database of Systematic Reviews and 103 reports of meta-analyses published in regular journals; 11 of these were reports of Cochrane reviews. The meta-analyses published in the Cochrane Database of Systematic Reviews were more likely to fulfill most components of the OQAQ. The median overall OQAQ scores indicated significant methodological problems in the reports regardless of the source of publication, although the reports in the Cochrane database scored higher than those in regular journals (five compared with two, p < .001). Major methodological flaws, notably failure to appropriately refer to the validity of included studies, were found in meta-analyses in both the Cochrane Database of Systematic Reviews and regular journals (44.4% and 79.3%, respectively). Conclusions:Although the quality of reports of meta-analyses published in the Cochrane Database of Systematic Reviews is superior to the quality of reports of meta-analyses published in regular journals, there is significant room for improvement. Clinicians should critically appraise all reports of meta-analyses before considering the results, regardless of the source of publication.

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.