Andrew Walden

Target temperature management after out-of-hospital cardiac arrest-a randomized, parallel-group, assessor-blinded clinical trial-rationale and design

BACKGROUND Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32°C to 34°C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known. METHODS The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33°C or 36°C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm. DISCUSSION The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.

Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33°C vs 36°C After Out-of-Hospital Cardiac Arrest A Randomized Clinical Trial

IMPORTANCE Brain injury affects neurologic function and quality of life in survivors after cardiac arrest. OBJECTIVE To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939. INTERVENTIONS Targeted temperature management at 33°C vs 36°C. MAIN OUTCOMES AND MEASURES Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2. RESULTS In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33°C group (interquartile range [IQR], 0-28) vs 17 in the 36°C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33°C and 36°C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33°C group median, 28; IQR, 26-30; vs 36°C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33°C group median, 79.5; IQR, 78.0-85.9; vs 36°C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33°C group vs 61.8% in the 36°C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm. CONCLUSIONS AND RELEVANCE Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33°C or 36°C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales. TRIAL REGISTRATION ClinicalTrials.gov NCT01020916.

Plasma and urine neutrophil gelatinase-associated lipocalin in the diagnosis of new onset acute kidney injury in critically ill patients

IntroductionNeutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a useful early diagnostic biomarker of acute kidney injury (AKI) where the timing of the insult is certain. However, NGAL is not well validated in adult critical care practice because of indeterminate timing of injury. Therefore, we sought to establish the predictive ability of both urine and plasma NGAL to detect AKI in ICU patients.MethodThis prospective observational study was performed in a busy large district general hospital mixed surgical-medical ICU in Reading, UK. Consecutive adult admissions to the ICU, with absence of chronic kidney disease, renal transplant or AKI as defined by RIFLE criteria were included. Blood and urine specimens were collected at admission and every 24 hours until 72 hours and tested for NGAL. The purpose of the study was to assess whether urinary NGAL (uNGAL) or plasma NGAL (pNGAL) can predict the occurrence of AKI at an earlier point of time than the conventional markers, that is creatinine and urine output as is used in RIFLE criteria.ResultsOver a 12-month period, 194 patients were enrolled. In total, 59 (30.4%) patients developed AKI. The admission pNGAL and uNGAL were significantly higher in the patients who developed AKI compared to the non-AKI patients (436 ng/mL (240, 797) versus 168 ng/mL (121.3, 274.3) P <0.001 and 342 ng/mL (61.5, 1,280) versus 34.5 ng/mL (11.5, 107.75) P <0.001 respectively). Hospital mortality was higher in the AKI group (17% versus 4%). Plasma NGAL performed fairly on admission (AUROC 0.77) and thereafter performance improved at 24 and 48 hours (AUROC 0.88 and 0.87) following ICU admission. Urine NGAL had a fair predictive value on admission (AUROC 0.79) and at 24 hours (AUROC 0.78) and was good at 48 hours (AUROC 0.82).ConclusionsIn critically ill patients without pre-existing kidney disease, both pNGAL and uNGAL measured at admission can predict AKI (defined by RIFLE criteria) occurrence up to 72 hours post-ICU admission and their performance (AUROC) was fair. The accuracy of NGAL appeared to improve slightly as patients progressed through their ICU stay. Serial measurements of NGAL (both pNGAL and uNGAL) may be of added value in an ICU setting to predict the occurrence of AKI.

Clinical review: The role of ultrasound in estimating extra-vascular lung water

The estimation of extra-vascular lung water (EVLW) is an essential component in the assessment of critically ill patients. EVLW is independently associated with mortality and its manipulation has been shown to improve outcome. Accurate assessment of lung water is possible with CT and MR imaging but these are impractical for real-time measurement in sick patients and have been superseded by single thermal dilution techniques. While useful, single thermo-dilution requires repeated calibration and is prone to error, suggesting a need for other monitoring methods. Traditionally the lung was not thought amenable to ultrasound examination owing to the high acoustic impedance of air; however, the identification of artefacts in diseased lung has led to increased use of ultrasound as a point of care investigation for both diagnosis and to monitor response to interventions. Following the initial description of B-lines in association with increased lung water, accumulating evidence has shown that they are a useful and responsive measure of the presence and dynamic changes in EVLW. Animal models have confirmed a correlation with lung gravimetry and the utility of B-lines has been demonstrated in many clinical situations and correlated against other established measures of EVLW. With increasing availability and expertise the role of ultrasound in estimating EVLW should be embedded in clinical practice and incorporated into clinical algorithms to aid decision making. This review looks at the evidence for ultrasound as a valid, easy to use, non-invasive point of care investigation to assess EVLW.

Bench to bedside: A role for erythropoietin in sepsis

Sepsis is the systemic inflammatory response to infection and can result in multiple organ dysfunction syndrome with associated high mortality, morbidity and health costs. Erythropoietin is a well-established treatment for the anaemia of renal failure due to its anti-apoptotic effects on red blood cells and their precursors. The extra-haemopoietic actions of erythropoietin include vasopressor, anti-apoptotic, cytoprotective and immunomodulating actions, all of which could prove beneficial in sepsis. Attenuation of organ dysfunction has been shown in several animal models and its vasopressor effects have been well characterised in laboratory and clinical settings. Clinical trials of erythropoietin in single organ disorders have suggested promising cytoprotective effects, and while no randomised trials have been performed in patients with sepsis, good quality data exist from studies on anaemia in critically ill patients, giving useful information of its pharmacokinetics and potential for harm. An observational cohort study examining the microvascular effects of erythropoietin is underway and the evidence would support further phase II and III clinical trials examining this molecule as an adjunctive treatment in sepsis.

Does the evidence support the use of mild hypothermia after cardiac arrest? Yes

Several guidelines recommend hypothermia for comatose patients who have had a cardiac arrest outside hospital. Jerry Nolan and Jasmeet Soar believe the data support this advice, but Andrew Walden, Niklas Nielsen, and Matt Wise (doi:10.1136/bmj.d5889) question the quality of the evidence

Sustained effects of thoracocentesis on oxygenation in mechanically ventilated patients

Background and objective:  No consensus exists as to the benefit of pleural drainage in mechanically ventilated patients with conflicting data concerning the effects on gas exchange. We determined the effects on gas exchange over a 48‐hour period of draining, by thoracocentesis, large volume pleural effusions.

Protocol-driven neurological prognostication and withdrawal of life-sustaining therapy after cardiac arrest and targeted temperature management.

BACKGROUND Brain injury is reportedly the main cause of death for patients resuscitated after out-of-hospital cardiac arrest (OHCA). However, the majority may actually die following withdrawal of life-sustaining therapy (WLST) with a presumption of poor neurological recovery. We investigated how the protocol for neurological prognostication was used and how related treatment recommendations might have affected WLST decision-making and outcome after OHCA in the targeted temperature management (TTM) trial. METHODS Analyses of prospectively recorded data: details of neurological prognostication; recommended level-of-care; WLST decisions; presumed cause of death; and cerebral performance category (CPC) 6 months following randomization. RESULTS Of 939 patients, 452 (48%) woke and 139 (15%) died, mostly for non-neurological reasons, before a scheduled time point for neurological prognostication (72h after the end of TTM). Three hundred and thirteen (33%) unconscious patients underwent prognostication at a median 117 (IQR 93-137) hours after arrest. Thirty-three (3%) unconscious patients were not neurologically prognosticated and for 2 patients (1%) data were missing. Related care recommendations were: continue in 117 (37%); not escalate in 55 (18%); and withdraw in 141 (45%). WLST eventually occurred in 196 (63%) at median day 6 (IQR 5-8). At 6 months, only 2 patients with WLST were alive and 248 (79%) of prognosticated patients had died. There were significant differences in time to WLST and death after the different recommendations (log rank <0.001). CONCLUSION Delayed prognostication was relevant for a minority of patients and related to subsequent decisions on level-of-care with effects on ICU length-of-stay, survival time and outcome.

Pleural effusions on the intensive care unit; Hidden morbidity with therapeutic potential

Despite 50–60% of intensive care patients demonstrating evidence of pleural effusions, there has been little emphasis placed on the role of effusions in the aetiology of weaning failure. Critical illness and mechanical ventilation lead to multiple perturbations of the normal physiological processes regulating pleural fluid homeostasis, and consequently, failure of normal pleural function occurs. Effusions can lead to deleterious effects on respiratory mechanics and gas exchange, and when extensive, may lead to haemodynamic compromise. The widespread availability of bedside ultrasound has not only facilitated earlier detection of pleural effusions but also safer fluid sampling and drainage. In the majority of patients, pleural drainage leads to improvements in lung function, with data from spontaneously breathing individuals demonstrating a consistent symptomatic improvement, while a meta‐analysis in critically ill patients shows an improvement in oxygenation. The effects on respiratory mechanics are less clear, possibly reflecting heterogeneity of underlying pathology. Limited data on clinical outcome from pleural fluid drainage exist; however, it appears to be a safe procedure with a low risk of major complications. The current level of evidence would support a clinical trial to determine whether the systematic detection and drainage of pleural effusions improve clinical outcomes.

Distributive shock due to systemic capillary leak syndrome treated with high-dose immunosuppression

A female patient in her 60s presented with a history of malaise, chills, headache and vomiting. She was in shock on presentation with a high haematocrit and a low albumin with evidence of rhabdomyolysis. Severe limb and truncal oedema developed with worsening hypotension leading to intensive care unit admission for multiple organ support. Extensive radiological, microbiological and immunological work up was negative with the exception of a monoclonal gammopathy. A review of patient investigations led to a diagnosis of Clarksons disease. Treatment with high-dose methylprednisolone and intravenous immunoglobulins led to a rapid decline in the creatine kinase (CK) level and vasopressor requirements. The patient was discharged home on long-term terbutaline and has made a good recovery.