A Patient-Level Meta-Analysis of Intensive Glucose Control in Critically Ill Adults.

BACKGROUND: Whether intensive glucose control reduces mortality in critically ill patients remains uncertain. Patient-level meta-analyses can provide more precise estimates of treatment effects than are currently available. METHODS: We pooled individual patient data from randomized trials investigating intensive glucose control in critically ill adults. The primary outcome was in-hospital mortality. Secondary outcomes included survival to 90 days and time to live cessation of treatment with vasopressors or inotropes, mechanical ventilation, and newly commenced renal replacement. Severe hypoglycemia was a safety outcome. RESULTS: Of 38 eligible trials (n=29,537 participants), 20 (n=14,171 participants) provided individual patient data including in-hospital mortality status for 7059 and 7049 participants allocated to intensive and conventional glucose control, respectively. Of these 1930 (27.3%) and 1891 (26.8%) individuals assigned to intensive and conventional control, respectively, died (risk ratio, 1.02; 95% confidence interval [CI], 0.96 to 1.07; P=0.52; moderate certainty). There was no apparent heterogeneity of treatment effect on in-hospital mortality in any examined subgroups. Intensive glucose control increased the risk of severe hypoglycemia (risk ratio, 3.38; 95% CI, 2.99 to 3.83; P<0.0001). CONCLUSIONS: Intensive glucose control was not associated with reduced mortality risk but increased the risk of severe hypoglycemia. We did not identify a subgroup of patients in whom intensive glucose control was beneficial. (Funded by the Australian National Health and Medical Research Council and others; PROSPERO number CRD42021278869.).

Intensive glucose control in critically ill adults: a protocol for a systematic review and individual patient data meta-analysis.

OBJECTIVE: The optimal target for blood glucose concentration in critically ill patients is unclear. We will perform a systematic review and meta-analysis with aggregated and individual patient data from randomized controlled trials, comparing intensive glucose control with liberal glucose control in critically ill adults. DATA SOURCES: MEDLINE®, Embase, the Cochrane Central Register of Clinical Trials, and clinical trials registries (World Health Organization, clinical trials.gov). The authors of eligible trials will be invited to provide individual patient data. Published trial-level data from eligible trials that are not at high risk of bias will be included in an aggregated data meta-analysis if individual patient data are not available. METHODS: Inclusion criteria: randomized controlled trials that recruited adult patients, targeting a blood glucose of ≤ 120mg/dL (≤ 6.6mmol/L) compared to a higher blood glucose concentration target using intravenous insulin in both groups. Excluded studies: those with an upper limit blood glucose target in the intervention group of > 120mg/dL (> 6.6mmol/L), or where intensive glucose control was only performed in the intraoperative period, and those where loss to follow-up exceeded 10% by hospital discharge. PRIMARY ENDPOINT: In-hospital mortality during index hospital admission. Secondary endpoints: mortality and survival at other timepoints, duration of invasive mechanical ventilation, vasoactive agents, and renal replacement therapy. A random effect Bayesian meta-analysis and hierarchical Bayesian models for individual patient data will be used. DISCUSSION: This systematic review with aggregate and individual patient data will address the clinical question, 'what is the best blood glucose target for critically ill patients overall?'Protocol version 0.4 - 06/26/2023PROSPERO registration:CRD42021278869.

Predictive power of serum NSE and OHCA score regarding 6-month neurologic outcome after out-of-hospital ventricular fibrillation and therapeutic hypothermia.

AIM OF THE STUDY: To determine the predictive power of the out-of-hospital cardiac arrest (OHCA) score and serum neuron-specific enolase (NSE) in patients resuscitated from ventricular fibrillation treated with therapeutic hypothermia (TH) and glucose control. METHODS: An analysis of prospectively collected data of 90 TH patients. Serum NSE was measured at 24 and 48 h. Outcome was measured by neurologic exam 6 months after cardiac arrest with good outcome defined as a Cerebral Performance Category (CPC) of 1 or 2. RESULTS: In multiple logistic regression analysis, age (odds ratio [OR], 95% confidence interval 1.1 [1.03-1.18]/year), NSE at 48 h (OR 1.1 [1.02-1.26]/microg/l), and increase in NSE levels (OR 7.2 [1.7-31.3]) were predictors of poor outcome, but the OHCA score was not. Cut-off points with 100% specificity in predicting poor outcome were 33microg/l for NSE at 48h (sensitivity 43% [28-60%]) and 6.4microg/l for delta NSE 24-48 h (sensitivity 44% [28-60%]). CONCLUSION: Increase in NSE between 24 and 48h and NSE at 48h is specific but only moderately sensitive markers of 6-month outcome. Outcome prediction at ICU admission using the OHCA score was not possible in this selected patient population.

Lower heart rate is associated with good one-year outcome in post-resuscitation patients.

BACKGROUND: Optimal hemodynamic goals in post-resuscitation patients are not clear. Previous studies have reported an association between lower heart rate and good outcome in patients receiving targeted temperature management (TTM) after out-of-hospital cardiac arrest. METHODS: We analyzed heart rate (HR) and outcome data of 504 post-resuscitation patients from the prospectively collected database of the FINNRESUSCI study. One-year neurologic outcome was dichotomized by the Cerebral Performance Category (CPC) to good (1-2) or poor (3-5). RESULTS: Of 504 patients, 40.1% (202/504) had good and 59.9% (302/ 504) had poor one-year neurologic outcome. Patients with good outcome had lower time-weighted mean HR during the first 48 h in the ICU (69.2 bpm [59.2-75.1] vs. 76.6 bpm [65.72-89.6], p < 0.001) and the first 72 h in the ICU (71.2 bpm [65.0-79.0] vs. 77.1 bpm [69.1-90.1, p < 0.001]). The percentage of HR registrations below HR threshold values (60, 80 and 100 bpm) were higher for patients with good neurologic outcome, p < 0.001 for all. Lower time-weighted HR for 0-48 h and 0-72 h, and a higher percentage of HR recordings below threshold values were independently associated with good neurological one-year outcome (p < 0.05 for all). When TTM and non-TTM patients were analyzed separately, HR parameters were independently associated with one-year neurologic outcome only in non-TTM patients. CONCLUSION: Lower heart rate was independently associated with good neurologic outcome. Whether HR in post-resuscitation patients is a prognostic indicator or an important variable to be targeted by treatment, needs to be assessed in future prospective controlled clinical trials.

Intensive glucose control in critically ill adults: a protocol for a systematic review and individual patient data meta-analysis / Controle intensivo da glicose em adultos em estado grave: um protocolo de revisão sistemática e metanálise de dados individuais de pacientes

ABSTRACT Objective: The optimal target for blood glucose concentration in critically ill patients is unclear. We will perform a systematic review and meta-analysis with aggregated and individual patient data from randomized controlled trials, comparing intensive glucose control with liberal glucose control in critically ill adults. Data sources: MEDLINE®, Embase, the Cochrane Central Register of Clinical Trials, and clinical trials registries (World Health Organization, clinical trials.gov). The authors of eligible trials will be invited to provide individual patient data. Published trial-level data from eligible trials that are not at high risk of bias will be included in an aggregated data meta-analysis if individual patient data are not available. Methods: Inclusion criteria: randomized controlled trials that recruited adult patients, targeting a blood glucose of ≤ 120mg/dL (≤ 6.6mmol/L) compared to a higher blood glucose concentration target using intravenous insulin in both groups. Excluded studies: those with an upper limit blood glucose target in the intervention group of > 120mg/dL (> 6.6mmol/L), or where intensive glucose control was only performed in the intraoperative period, and those where loss to follow-up exceeded 10% by hospital discharge. Primary endpoint: In-hospital mortality during index hospital admission. Secondary endpoints: mortality and survival at other timepoints, duration of invasive mechanical ventilation, vasoactive agents, and renal replacement therapy. A random effect Bayesian meta-analysis and hierarchical Bayesian models for individual patient data will be used. Discussion: This systematic review with aggregate and individual patient data will address the clinical question, 'what is the best blood glucose target for critically ill patients overall?' Protocol version 0.4 - 06/26/2023 PROSPERO registration: CRD42021278869

RESUMO Objetivo: Não está claro qual é a meta ideal de concentração de glicose no sangue em pacientes em estado grave. Realizaremos uma revisão sistemática e uma metanálise com dados agregados e de pacientes individuais de estudos controlados e randomizados, comparando o controle intensivo da glicose com o controle liberal da glicose em adultos em estado grave. Fontes de dados: MEDLINE®, Embase, Cochrane Central Register of Clinical Trials e registros de ensaios clínicos (Organização Mundial da Saúde, clinical trials.gov). Os autores dos estudos qualificados serão convidados a fornecer dados individuais de pacientes. Os dados publicados em nível de ensaio qualificado que não apresentem alto risco de viés serão incluídos em uma metanálise de dados agregados se os dados individuais de pacientes não estiverem disponíveis. Métodos: Critérios de inclusão: ensaios clínicos controlados e randomizados que recrutaram pacientes adultos, com meta de glicemia ≤ 120mg/dL (≤ 6,6mmol/L) comparada a uma meta de concentração de glicemia mais alta com insulina intravenosa em ambos os grupos. Estudos excluídos: aqueles com meta de glicemia no limite superior no grupo de intervenção > 120mg/dL (> 6,6mmol/L), ou em que o controle intensivo de glicose foi realizado apenas no período intraoperatório, e aqueles em que a perda de seguimento excedeu 10% até a alta hospitalar. Desfecho primário: Mortalidade intra-hospitalar durante a admissão hospitalar. Desfechos secundários: Mortalidade e sobrevida em outros momentos, duração da ventilação mecânica invasiva, agentes vasoativos e terapia de substituição renal. Utilizaremos metanálise bayesiana de efeito randômico e modelos bayesianos hierárquicos para dados individuais de pacientes. Discussão: Essa revisão sistemática com dados agregados e de pacientes individuais abordará a questão clínica: Qual é a melhor meta de glicose no sangue de pacientes graves em geral? Protocolo versão 0.4 - 26/06/2023 Registro PROSPERO: CRD42021278869

Strict versus moderate glucose control after resuscitation from ventricular fibrillation.

OBJECTIVE: Elevated blood glucose is associated with poor outcome in patients resuscitated from out-of-hospital cardiac arrest (OHCA). Our aim was to determine whether strict glucose control with intensive insulin treatment improves outcome of OHCA patients. DESIGN: A randomized, controlled trial. SETTING: Two university hospital intensive care units. PATIENTS: Ninety patients resuscitated from OHCA with ventricular fibrillation detected as the initial rhythm were treated with therapeutic hypothermia. INTERVENTIONS: Patients were randomized into two treatment groups: a strict glucose control group (SGC group), with a blood glucose target of 4-6 mmol/l, or a moderate glucose control group (MGC group), with a blood glucose target of 6-8 mmol/l. Both groups were treated with insulin infusion for 48 h, because a control group with no treatment was considered unethical. MEASUREMENTS AND RESULTS: Baseline data were similar in both groups. In the SGC group 71% of the glucose measurements were within the target range compared with 41% in the MGC group. Median glucose was 5.0 mmol/l in the SGC group and 6.4 mmol/l in the MGC group. The occurrence of moderate hypoglycemic episodes was 18% in the SGC group and 2% in the MGC group (p = 0.008). No episodes of severe hypoglycemia occurred. Mortality by day 30 was 33% in the SGC group and 35% in the MGC group (p = 0.846); the difference was 2% (95% CI -18% to +22%). CONCLUSIONS: We found no additional survival benefit from strict glucose control compared with moderate glucose control with a target between 6 and 8 mmol/l in OHCA patients.

Targeting low- or high-normal Carbon dioxide, Oxygen, and Mean arterial pressure After Cardiac Arrest and REsuscitation: study protocol for a randomized pilot trial.

BACKGROUND: Arterial carbon dioxide tension (PaCO2), oxygen tension (PaO2), and mean arterial pressure (MAP) are modifiable factors that affect cerebral blood flow (CBF), cerebral oxygen delivery, and potentially the course of brain injury after cardiac arrest. No evidence regarding optimal treatment targets exists. METHODS: The Carbon dioxide, Oxygen, and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial is a pilot multi-center randomized controlled trial (RCT) assessing the feasibility of targeting low- or high-normal PaCO2, PaO2, and MAP in comatose, mechanically ventilated patients after out-of-hospital cardiac arrest (OHCA), as well as its effect on brain injury markers. Using a 23 factorial design, participants are randomized upon admission to an intensive care unit into one of eight groups with various combinations of PaCO2, PaO2, and MAP target levels for 36 h after admission. The primary outcome is neuron-specific enolase (NSE) serum concentration at 48 h after cardiac arrest. The main feasibility outcome is the between-group differences in PaCO2, PaO2, and MAP during the 36 h after ICU admission. Secondary outcomes include serum concentrations of NSE, S100 protein, and cardiac troponin at 24, 48, and 72 h after cardiac arrest; cerebral oxygenation, measured with near-infrared spectroscopy (NIRS); potential differences in epileptic activity, monitored via continuous electroencephalogram (EEG); and neurological outcomes at six months after cardiac arrest. DISCUSSION: The trial began in March 2016 and participant recruitment has begun in all seven study sites as of March 2017. Currently, 115 of the total of 120 patients have been included. When completed, the results of this trial will provide preliminary clinical evidence regarding the feasibility of targeting low- or high-normal PaCO2, PaO2, and MAP values and its effect on developing brain injury, brain oxygenation, and epileptic seizures after cardiac arrest. The results of this trial will be used to evaluate whether a larger RCT on this subject is justified. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02698917 . Registered on 26 January 2016.

Functional outcome, cognition and quality of life after out-of-hospital cardiac arrest and therapeutic hypothermia: data from a randomized controlled trial.

BACKGROUND: To study functional neurologic and cognitive outcome and health-related quality of life (HRQoL) in a cohort of patients included in a randomised controlled trial on glucose control following out-of-hospital cardiac arrest (OHCA) from ventricular fibrillation (VF) treated with therapeutic hypothermia. METHODS: Patients alive at 6 months after being discharged from the hospital underwent clinical neurological and extensive neuropsychological examinations. Functional outcome was evaluated with the Cerebral Performance Category scale, the modified Rankin scale and the Barthel Index. Cognitive outcome was evaluated by neuropsychological test battery including two measures of each cognitive function: cognitive speed, execution, memory, verbal skills and visuospatial performance. We also assessed quality of life with a HRQoL 15D questionnaire. RESULTS: Of 90 OHCA-VF patients included in the original trial, 57 were alive at 6 months. Of these, 52 (91%) were functionally independent and 54 (95%) lived at their previous home. Focal neurological deficits were scarce. Intact cognitive performance was observed in 20 (49%), mild to moderate deficits in 14 (34%) and severe cognitive deficits in 7 (17%) of 41 patients assessed by a neuropsychologist. Cognitive impairments were most frequently detected in executive and memory functions. HRQoL of the CA survivors was comparable to that of age- and gender matched population. CONCLUSIONS: Functional outcome six months after OHCA and therapeutic hypothermia was good in the great majority of the survivors, and half of them were cognitively intact. Of note, the HRQoL of CA survivors did not differ from that of age- and gender matched population.

Postresuscitation hemodynamics during therapeutic hypothermia after out-of-hospital cardiac arrest with ventricular fibrillation: a retrospective study.

AIMS OF THE STUDY: To evaluate the incidence of postresuscitation myocardial depression (PRMD) and hemodynamical parameters associated with PRMD in patients treated with therapeutic hypothermia (TH) after out-of-hospital cardiac arrest with ventricular fibrillation (OHCA-VF). METHODS: Analysis of hemodynamical data from computerized clinical databases of two academic ICUs during two year period. We analyzed hemodynamical data from a subgroup of patients with pulmonary artery catheter (PAC). We defined PRMD as a cardiac index (CI) less than 1.5l/(minm(2)) any time during the first 12h and compared clinical variables and hemodynamical parameters in patients with or without PRMD. RESULTS: Of 120 included patients PAC monitoring was used in 47 (39%). Of 47, 31 (66%, 95% CI 52% to 80%) developed PRMD. There was no difference in urinary output, lactate, mean arterial or central venous pressures or mixed venous saturation between patients with or without PRMD. Low CI was reversed with dobutamine infusion. Presence or absence PRMD was not associated with 6-month neurological outcome. CONCLUSION: Two-thirds of the OHCA-VF patients develops transient postresuscitation myocardial depression not easily detected without monitoring of CI during therapeutic hypothermia. Further controlled studies are warranted to evaluate the value of different hemodynamic targets and monitoring after cardiac arrest in terms of outcome.

Therapeutic hypothermia after out-of-hospital cardiac arrest in Finnish intensive care units: the FINNRESUSCI study.

PURPOSE: We aimed to evaluate post-resuscitation care, implementation of therapeutic hypothermia (TH) and outcomes of intensive care unit (ICU)-treated out-of-hospital cardiac arrest (OHCA) patients in Finland. METHODS: We included all adult OHCA patients admitted to 21 ICUs in Finland from March 1, 2010 to February 28, 2011 in this prospective observational study. Patients were followed (mortality and neurological outcome evaluated by Cerebral Performance Categories, CPC) within 1 year after cardiac arrest. RESULTS: This study included 548 patients treated after OHCA. Of those, 311 patients (56.8%) had a shockable initial rhythm (incidence of 7.4/100,000/year) and 237 patients (43.2%) had a non-shockable rhythm (incidence of 5.6/100,000/year). At ICU admission, 504 (92%) patients were unconscious. TH was given to 241/281 (85.8%) unconscious patients resuscitated from shockable rhythms, with unfavourable 1-year neurological outcome (CPC 3-4-5) in 42.0% with TH versus 77.5% without TH (p < 0.001). TH was given to 70/223 (31.4%) unconscious patients resuscitated from non-shockable rhythms, with 1-year CPC of 3-4-5 in 80.6% (54/70) with TH versus 84.0% (126/153) without TH (p = 0.56). This lack of difference remained after adjustment for propensity to receive TH in patients with non-shockable rhythms. CONCLUSIONS: One-year unfavourable neurological outcome of patients with shockable rhythms after TH was lower than in previous randomized controlled trials. However, our results do not support use of TH in patients with non-shockable rhythms.