Paul Young

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.

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.

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.

Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest

BACKGROUND Arterial carbon dioxide tension (PaCO2) affects neuronal function and cerebral blood flow. However, its association with outcome in patients admitted to intensive care unit (ICU) after cardiac arrest (CA) has not been evaluated. METHODS AND RESULTS Observational cohort study using data from the Australian New Zealand (ANZ) Intensive Care Society Adult-Patient-Database (ANZICS-APD). Outcomes analyses were adjusted for illness severity, co-morbidities, hypothermia, treatment limitations, age, year of admission, glucose, source of admission, PaO2 and propensity score. We studied 16,542 consecutive patients admitted to 125 ANZ ICUs after CA between 2000 and 2011. Using the APD-PaCO2 (obtained within 24 h of ICU admission), 3010 (18.2%) were classified into the hypo- (PaCO2<35 mmHg), 6705 (40.5%) into the normo- (35-45 mmHg) and 6827 (41.3%) into the hypercapnia (>45 mmHg) group. The hypocapnia group, compared with the normocapnia group, had a trend toward higher in-hospital mortality (OR 1.12 [95% CI 1.00-1.24, p=0.04]), lower rate of discharge home (OR 0.81 [0.70-0.94, p<0.01]) and higher likelihood of fulfilling composite adverse outcome of death and no discharge home (OR 1.23 [1.10-1.37, p<0.001]). In contrast, the hypercapnia group had similar in-hospital mortality (OR 1.06 [0.97-1.15, p=0.19]) but higher rate of discharge home among survivors (OR 1.16 [1.03-1.32, p=0.01]) and similar likelihood of fulfilling the composite outcome (OR 0.97 [0.89-1.06, p=0.52]). Cox-proportional hazards modelling supported these findings. CONCLUSIONS Hypo- and hypercapnia are common after ICU admission post-CA. Compared with normocapnia, hypocapnia was independently associated with worse clinical outcomes and hypercapnia a greater likelihood of discharge home among survivors.

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 effect of hyperoxia following cardiac arrest – A systematic review and meta-analysis of animal trials

AIM There are conflicting findings from observational studies regarding the nature of the association between hyperoxia and risk of mortality in patients admitted to intensive care following cardiac arrest. This systematic review and meta-analysis evaluates animal data investigating the effect of administration of high concentrations of oxygen following cardiac arrest on neurological outcome and the clinical applicability of this data. METHODS A systematic search of Medline and Embase identified controlled animal studies modelling cardiac arrest with subsequent cardiopulmonary resuscitation that compared ventilation with 100% oxygen to lower concentrations following return of spontaneous circulation. Eligible studies were included in a meta-analysis in which the inverse variance weighted differences were calculated for the standardised mean difference of the primary outcome measure, the neurological deficit score. RESULTS Ten studies met the criteria for inclusion in the systematic review. In a meta-analysis of six studies, with 95 animals, treatment with 100% oxygen resulted in a significantly worse neurological deficit score than oxygen administered at lower concentrations, with a standardised mean difference of -0.64 (95% CI -1.06 to -0.22). In four of five studies, histological evidence of increased neuronal damage was present in animals that received 100% oxygen therapy. CONCLUSIONS The administration of 100% oxygen therapy is associated with worse neurological outcome than lower oxygen concentrations in animal models of cardiac arrest. However, due to limitations in study design and poor generalisability of the animal models to the situation of post cardiac arrest resuscitation in humans, the clinical applicability of this data is uncertain.

Conservative versus Liberal Oxygenation Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial.

RATIONALE There are no randomized controlled trials comparing different oxygenation targets for intensive care unit (ICU) patients. OBJECTIVES To determine whether a conservative oxygenation strategy is a feasible alternative to a liberal oxygenation strategy among ICU patients requiring invasive mechanical ventilation (IMV). METHODS At four multidisciplinary ICUs, 103 adult patients deemed likely to require IMV for greater than or equal to 24 hours were randomly allocated to either a conservative oxygenation strategy with target oxygen saturation as measured by pulse oximetry (SpO2) of 88-92% (n = 52) or a liberal oxygenation strategy with target SpO2 of greater than or equal to 96% (n = 51). MEASUREMENTS AND MAIN RESULTS The mean area under the curve and 95% confidence interval (CI) for SpO2 (93.4% [92.9-93.9%] vs. 97% [96.5-97.5%]), SaO2 (93.5% [93.1-94%] vs. 96.8% [96.3-97.3%]), PaO2 (70 [68-73] mm Hg vs. 92 [89-96] mm Hg), and FiO2 (0.26 [0.25-0.28] vs. 0.36 [0.34-0.39) in the conservative versus liberal oxygenation arm were significantly different (P < 0.0001 for all). There were no significant between-group differences in any measures of new organ dysfunction, or ICU or 90-day mortality. The percentage time spent with SpO2 less than 88% in conservative versus liberal arm was 1% versus 0.3% (P = 0.03), and percentage time spent with SpO2 greater than 98% in conservative versus liberal arm was 4% versus 22% (P < 0.001). The adjusted hazard ratio for 90-day mortality in the conservative arm was 0.77 (95% CI, 0.40-1.50; P = 0.44) overall and 0.49 (95% CI, 0.20-1.17; P = 0.10) in the prespecified subgroup of patients with a baseline PaO2/FiO2 less than 300. CONCLUSIONS Our study supports the feasibility of a conservative oxygenation strategy in patients receiving IMV. Larger randomized controlled trials of this intervention appear justified. Clinical trial registered with Australian New Zealand Clinical Trials Registry (ACTRN 12613000505707).

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.).

Angiotensin II for the Treatment of Vasodilatory Shock

Background Vasodilatory shock that does not respond to high‐dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. Methods We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. Results A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (‐1.75 vs. ‐1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). Conclusions Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS‐3 ClinicalTrials.gov number, NCT02338843.)

A systematic review and meta-analysis of the cardioprotective effects of remote ischaemic preconditioning in open cardiac surgery

Objective To investigate the cardioprotective efficacy of remote ischaemic preconditioning (RIPC) in cardiac surgery. Design We have performed a systematic search of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify randomized controlled trials involving RIPC. Setting Randomized controlled trials of RIPC in open cardiac surgery patients. Main outcome measures Meta-analysis was performed with the primary outcome the standardized mean difference between intervention and control groups in 12 hour postoperative troponin concentration. Heterogeneity was examined by fixed effects meta-regression. Results Ten studies with a total of 693 participants were included in the meta-analysis. RIPC reduced troponin levels 12 hours after surgery compared with control. The fixed and random effects differences were 0.35 (95% CI 0.19 to 0.51) and 0.53 (95% CI 0.18-0.88) respectively. However, important heterogeneity was present. Fixed effects meta-regression partially accounted for heterogeneity based on whether studies had full blinding, comprising blinding of patients, surgeons, anaesthetists and investigators. Studies with incomplete or no blinding demonstrated a larger estimate of effect, 0.74 (95% CI 0.47 to 1.00) compared to those with full blinding, 0.13 (95% CI - 0.07 to 0.33). Conclusions Although our analysis suggests RIPC may result in cardiac protection during cardiac surgery, the effect was most marked in studies without full blinding, with a smaller and statistically non-significant effect in fully blinded studies. We propose that further double blind randomized controlled trials investigating the cardioprotective effects of RIPC in cardiac surgery are required to resolve the current clinical uncertainty.