Coronary Angiography after Cardiac Arrest without ST-Segment Elevation.

BACKGROUND: Ischemic heart disease is a major cause of out-of-hospital cardiac arrest. The role of immediate coronary angiography and percutaneous coronary intervention (PCI) in the treatment of patients who have been successfully resuscitated after cardiac arrest in the absence of ST-segment elevation myocardial infarction (STEMI) remains uncertain. METHODS: In this multicenter trial, we randomly assigned 552 patients who had cardiac arrest without signs of STEMI to undergo immediate coronary angiography or coronary angiography that was delayed until after neurologic recovery. All patients underwent PCI if indicated. The primary end point was survival at 90 days. Secondary end points included survival at 90 days with good cerebral performance or mild or moderate disability, myocardial injury, duration of catecholamine support, markers of shock, recurrence of ventricular tachycardia, duration of mechanical ventilation, major bleeding, occurrence of acute kidney injury, need for renal-replacement therapy, time to target temperature, and neurologic status at discharge from the intensive care unit. RESULTS: At 90 days, 176 of 273 patients (64.5%) in the immediate angiography group and 178 of 265 patients (67.2%) in the delayed angiography group were alive (odds ratio, 0.89; 95% confidence interval [CI], 0.62 to 1.27; P = 0.51). The median time to target temperature was 5.4 hours in the immediate angiography group and 4.7 hours in the delayed angiography group (ratio of geometric means, 1.19; 95% CI, 1.04 to 1.36). No significant differences between the groups were found in the remaining secondary end points. CONCLUSIONS: Among patients who had been successfully resuscitated after out-of-hospital cardiac arrest and had no signs of STEMI, a strategy of immediate angiography was not found to be better than a strategy of delayed angiography with respect to overall survival at 90 days. (Funded by the Netherlands Heart Institute and others; COACT Netherlands Trial Register number, NTR4973.).

Citrate dose for continuous hemofiltration: effect on calcium and magnesium balance, parathormone and vitamin D status, a randomized controlled trial.

BACKGROUND: Regional citrate anticoagulation may cause a negative calcium balance, systemic hypocalcemia and parathormone (PTH) activation but randomzed studies are not available. Aim was to determine the effect of citrate dose on calcium (Ca) and magnesium (Mg) balance, PTH and Vitamin D. METHODS: Single center prospective randomized study. Patients, requiring continuous venovenous hemofiltration (CVVH) with citrate, randomized to low dose citrate (2.5 mmol/L) vs. high dose (4.5 mmol/L) for 24 h, targeting post-filter ionized calcium (pfiCa) of 0.325-0.4 mmol/L vs. 0.2-0.275 mmol/L, using the Prismaflex® algorithm with 100% postfilter calcium replacement. Extra physician-ordered Ca and Mg supplementation was performed aiming at systemic iCa > 1.0 mmol/L. Arterial blood, effluent and post-filter aliquots were taken for balance calculations (area under the curve), intact (i), oxidized (ox) and non-oxidized (nox) PTH, 25-hydroxy-Vitamin D (25D) and 1,25-dihydroxy-Vitamin D (1,25D). RESULTS: 35 patients were analyzed, 17 to high, 18 to low citrate. Mean 24-h Ca balance was - 9.72 mmol/d (standard error 1.70) in the high vs - 1.18 mmol/d (se 1.70)) (p = 0.002) in the low citrate group and 24-h Mg-balance was - 25.99 (se 2.10) mmol/d vs. -17.63 (se 2.10) mmol/d (p = 0.008) respectively. Physician-ordered Ca supplementation, higher in the high citrate group, resulted in a positive Ca-balance in both groups. iPTH, oxPTH or noxPTH were not different between groups. Over 24 h, median PTH decreased from 222 (25th-75th percentile 140-384) to 162 (111-265) pg/ml (p = 0.002); oxPTH from 192 (124-353) to 154 pg/ml (87-231), p = 0.002. NoxPTH did not change significantly. Mean 25 D (standard deviation), decreased from 36.5 (11.8) to 33.3 (11.2) nmol/l (p = 0.003), 1,25D rose from 40.9 pg/ml (30.7) to 43.2 (30.7) pg/ml (p = 0.046), without differences between groups. CONCLUSIONS: A higher citrate dose caused a more negative CVVH Ca balance than a lower dose, due to a higher effluent Calcium loss. Physician-ordered Ca supplementation, targeting a systemic iCa > 1.0 mmol/L, higher in the high citrate group, resulted in a positive Ca-balance in both groups. iPTH and oxPTH declined, suggesting decreased oxidative stress, while noxPTH did not change. 25D decreased while 1,25-D rose. Mg balance was negative in both groups, more so in the high citrate group. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02194569. Registered 18 July 2014.

Effect of Low-Normal vs High-Normal Oxygenation Targets on Organ Dysfunction in Critically Ill Patients: A Randomized Clinical Trial.

Importance: Hyperoxemia may increase organ dysfunction in critically ill patients, but optimal oxygenation targets are unknown. Objective: To determine whether a low-normal Pao2 target compared with a high-normal target reduces organ dysfunction in critically ill patients with systemic inflammatory response syndrome (SIRS). Design, Setting, and Participants: Multicenter randomized clinical trial in 4 intensive care units in the Netherlands. Enrollment was from February 2015 to October 2018, with end of follow-up to January 2019, and included adult patients admitted with 2 or more SIRS criteria and expected stay of longer than 48 hours. A total of 9925 patients were screened for eligibility, of whom 574 fulfilled the enrollment criteria and were randomized. Interventions: Target Pao2 ranges were 8 to 12 kPa (low-normal, n = 205) and 14 to 18 kPa (high-normal, n = 195). An inspired oxygen fraction greater than 0.60 was applied only when clinically indicated. Main Outcomes and Measures: Primary end point was SOFARANK, a ranked outcome of nonrespiratory organ failure quantified by the nonrespiratory components of the Sequential Organ Failure Assessment (SOFA) score, summed over the first 14 study days. Participants were ranked from fastest organ failure improvement (lowest scores) to worsening organ failure or death (highest scores). Secondary end points were duration of mechanical ventilation, in-hospital mortality, and hypoxemic measurements. Results: Among the 574 patients who were randomized, 400 (70%) were enrolled within 24 hours (median age, 68 years; 140 women [35%]), all of whom completed the trial. The median Pao2 difference between the groups was -1.93 kPa (95% CI, -2.12 to -1.74; P < .001). The median SOFARANK score was -35 points in the low-normal Pao2 group vs -40 in the high-normal Pao2 group (median difference, 10 [95% CI, 0 to 21]; P = .06). There was no significant difference in median duration of mechanical ventilation (3.4 vs 3.1 days; median difference, -0.15 [95% CI, -0.88 to 0.47]; P = .59) and in-hospital mortality (32% vs 31%; odds ratio, 1.04 [95% CI, 0.67 to 1.63]; P = .91). Mild hypoxemic measurements occurred more often in the low-normal group (1.9% vs 1.2%; median difference, 0.73 [95% CI, 0.30 to 1.20]; P < .001). Acute kidney failure developed in 20 patients (10%) in the low-normal Pao2 group and 21 patients (11%) in the high-normal Pao2 group, and acute myocardial infarction in 6 patients (2.9%) in the low-normal Pao2 group and 7 patients (3.6%) in the high-normal Pao2 group. Conclusions and Relevance: Among critically ill patients with 2 or more SIRS criteria, treatment with a low-normal Pao2 target compared with a high-normal Pao2 target did not result in a statistically significant reduction in organ dysfunction. However, the study may have had limited power to detect a smaller treatment effect than was hypothesized. Trial Registration: ClinicalTrials.gov Identifier: NCT02321072.

Observational Research for Therapies Titrated to Effect and Associated With Severity of Illness: Misleading Results From Commonly Used Statistical Methods.

OBJECTIVES: In critically ill patients, treatment dose or intensity is often related to severity of illness and mortality risk, whereas overtreatment or undertreatment (relative to the individual need) may further increase the odds of death. We aimed to investigate how these relationships affect the results of common statistical methods used in observational studies. DESIGN: Using Monte Carlo simulation, we generated data for 5,000 patients with a treatment dose related to the pretreatment mortality risk but with randomly distributed overtreatment or undertreatment. Significant overtreatment or undertreatment (relative to the optimal dose) further increased the mortality risk. A prognostic score that reflects the mortality risk and an outcome of death or survival was then generated. The study was analyzed: 1) using logistic regression to estimate the effect of treatment dose on outcome while controlling for prognostic score and 2) using propensity score matching and inverse probability weighting of the effect of high treatment dose on outcome. The data generation and analyses were repeated 1,500 times over sample sizes between 200 and 30,000 patients, with an increasing accuracy of the prognostic score and with different underlying assumptions. SETTING: Computer-simulated studies. MEASUREMENTS AND MAIN RESULTS: In the simulated 5,000-patient observational study, higher treatment dose was found to be associated with increased odds of death (p = 0.00001) while controlling for the prognostic score with logistic regression. Propensity-matched analysis led to similar results. Larger sample sizes led to equally biased estimates with narrower CIs. A perfect risk predictor negated the bias only under artificially perfect assumptions. CONCLUSIONS: When a treatment dose is associated with severity of illness and should be dosed "enough," logistic regression, propensity score matching, and inverse probability weighting to adjust for confounding by severity of illness lead to biased results. Larger sample sizes lead to more precisely wrong estimates.

Gastrointestinal dysfunction in the critically ill: a systematic scoping review and research agenda proposed by the Section of Metabolism, Endocrinology and Nutrition of the European Society of Intensive Care Medicine.

BACKGROUND: Gastrointestinal (GI) dysfunction is frequent in the critically ill but can be overlooked as a result of the lack of standardization of the diagnostic and therapeutic approaches. We aimed to develop a research agenda for GI dysfunction for future research. We systematically reviewed the current knowledge on a broad range of subtopics from a specific viewpoint of GI dysfunction, highlighting the remaining areas of uncertainty and suggesting future studies. METHODS: This systematic scoping review and research agenda was conducted following successive steps: (1) identify clinically important subtopics within the field of GI function which warrant further research; (2) systematically review the literature for each subtopic using PubMed, CENTRAL and Cochrane Database of Systematic Reviews; (3) summarize evidence for each subtopic; (4) identify areas of uncertainty; (5) formulate and refine study proposals that address these subtopics; and (6) prioritize study proposals via sequential voting rounds. RESULTS: Five major themes were identified: (1) monitoring, (2) associations between GI function and outcome, (3) GI function and nutrition, (4) management of GI dysfunction and (5) pathophysiological mechanisms. Searches on 17 subtopics were performed and evidence summarized. Several areas of uncertainty were identified, six of them needing consensus process. Study proposals ranked among the first ten included: prevention and management of diarrhoea; management of upper and lower feeding intolerance, including indications for post-pyloric feeding and opioid antagonists; acute gastrointestinal injury grading as a bedside tool; the role of intra-abdominal hypertension in the development and monitoring of GI dysfunction and in the development of non-occlusive mesenteric ischaemia; and the effect of proton pump inhibitors on the microbiome in critical illness. CONCLUSIONS: Current evidence on GI dysfunction is scarce, partially due to the lack of precise definitions. The use of core sets of monitoring and outcomes are required to improve the consistency of future studies. We propose several areas for consensus process and outline future study projects.

Metabolic support in the critically ill: a consensus of 19.

Metabolic alterations in the critically ill have been studied for more than a century, but the heterogeneity of the critically ill patient population, the varying duration and severity of the acute phase of illness, and the many confounding factors have hindered progress in the field. These factors may explain why management of metabolic alterations and related conditions in critically ill patients has for many years been guided by recommendations based essentially on expert opinion. Over the last decade, a number of randomized controlled trials have been conducted, providing us with important population-level evidence that refutes several longstanding paradigms. However, between-patient variation means there is still substantial uncertainty when translating population-level evidence to individuals. A cornerstone of metabolic care is nutrition, for which there is a multifold of published guidelines that agree on many issues but disagree on others. Using a series of nine questions, we provide a review of the latest data in this field and a background to promote efforts to address the need for international consistency in recommendations related to the metabolic care of the critically ill patient. Our purpose is not to replace existing guidelines, but to comment on differences and add perspective.

Amino Acid Loss during Continuous Venovenous Hemofiltration in Critically Ill Patients.

BACKGROUND/OBJECTIVES: During continuous venovenous hemofiltration (CVVH), there is unwanted loss of amino acids (AA) in the ultrafiltrate (UF). Solutes may also be removed by adsorption to the filter membrane. The aim was to quantify the total loss of AA via the CVVH circuit using a high-flux polysulfone membrane and to differentiate between the loss by ultrafiltration and adsorption. METHODS: Prospective observational study in ten critically ill patients, receiving predilution CVVH with a new filter, blood flow 180 mL/min, and predilution flow 2,400 mL/h. Arterial blood, postfilter blood, and UF samples were taken at baseline, and 1, 8, and 24-h after CVVH initiation, to determine AA concentrations and hematocrit. Mass transfer calculations were used to determine AA loss in the filter and by UF, and the difference between these 2. RESULTS: The median AA loss in the filter was 10.4 g/day, the median AA loss by UF was 13.4 g/day, and the median difference was -2.9 g/day (IQR -5.9 to -1.4 g/day). For the individual AA, the difference ranged from -1 g/day to +0.4 g/day, suggesting that some AA were consumed or adsorbed and others were generated. AA losses did not significantly change over the 24-h study period. CONCLUSION: During CVVH with a modern polysulfone membrane, the estimated AA loss was 13.4 g/day, which corresponds to a loss of about 11.2 g of protein per day. Adsorption did not play a major role. However, individual AA behaved differently, suggesting complex interactions and processes at the filter membrane or peripheral AA production.

Predictors of 90-Day Restart of Renal Replacement Therapy after Discontinuation of Continuous Renal Replacement Therapy, a Prospective Multicenter Study.

BACKGROUND: Restart of renal replacement therapy (RRT) after initial discontinuation of continuous RRT (CRRT) is frequently needed. The aim of the present study was to evaluate whether renal markers after discontinuation of CRRT can predict restart of RRT within 90 days. METHODS: Prospective multicenter observational study in 90 patients, alive, still on the intensive care unit at day 2 after discontinuation of CRRT for expected recovery with urinary neutrophil gelatinase-associated lipocalin (NGAL) available. The endpoint was restart of RRT within 90 days. Baseline and renal characteristics were compared between outcome groups no restart or restart of RRT. Logistic regression and receiver operator characteristic curve analysis were performed to determine the best predictive and discriminative variables. RESULTS: Restart of RRT was needed in 32/90 (36%) patients. Compared to patients not restarting, patients restarting RRT demonstrated a higher day 2 urinary NGAL, lower day 2 urine output, and higher incremental creatinine ratio (day 2/0). In multivariate analysis, only incremental creatinine ratio (day 2/0) remained independently associated with restart of RRT (OR 5.28, 95% CI 1.45-19.31, p = 0.012). The area under curve for incremental creatinine ratio to discriminate for restart of RRT was 0.76 (95% CI 0.64-0.88). The optimal cutoff was 1.49 (95% CI 1.44-1.62). CONCLUSION: In this prospective multicenter study, incremental creatinine ratio (day 2/0) was the best predictor for restart of RRT. Patients with an incremental creatinine ratio at day 2 of 1.5 times creatinine at discontinuation are likely to need RRT within 90 days. These patients might benefit from nephrological follow-up.

Predictors of short-term successful discontinuation of continuous renal replacement therapy: results from a prospective multicentre study.

BACKGROUND: Prediction of successful discontinuation of continuous renal replacement therapy (CRRT) might reduce complications of over- and under-treatment. The aim of this study was to identify renal and non-renal predictors of short-term successful discontinuation of CRRT in patients in whom CRRT was stopped because renal recovery was expected and who were still in the Intensive Care Unit (ICU) at day 2 after stop CRRT. METHODS: Prospective multicentre observational study in 92 patients alive after discontinuation of CRRT for acute kidney injury (AKI), still in the ICU and free from renal replacement therapy (RRT) at day 2 after discontinuation. Successful discontinuation was defined as alive and free from RRT at day 7 after stop CRRT. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and clinical variables were collected. Logistic regression and Receiver Operator Characteristic (ROC) curve analysis were performed to determine the best predictive and discriminative variables. RESULTS: Discontinuation of CRRT was successful in 61/92 patients (66%). Patients with successful discontinuation of CRRT had higher day 2 urine output, better renal function indicated by higher creatinine clearance (6-h) or lower creatinine ratio (day 2/day 0), less often vasopressors, lower urinary NGAL, shorter duration of CRRT and lower cumulative fluid balance (day 0-2). In multivariate analysis renal function determined by creatinine clearance (Odds Ratio (OR) 1.066, 95% confidence interval (CI) 1.022-1.111, p = 0.003) or by creatinine ratio (day 2/day 0) (OR 0.149, 95% CI 0.037-0.583, p = 0.006) and non-renal sequential organ failure assessment (SOFA) score (OR 0.822, 95% CI 0.678-0.996, p = 0.045) were independently associated with successful discontinuation of CRRT. The area under the curve of creatinine clearance to predict successful discontinuation was 0.791, optimal cut-off of 11 ml/min (95% CI 6-16 ml/min) and of creatinine ratio 0.819 (95% CI 0.732-0.907) optimal cut-off of 1.41 (95% CI 1.27-1.59). CONCLUSION: In this prospective multicentre study we found higher creatinine clearance or lower creatinine ratio as best predictors of short-term successful discontinuation of CRRT, with a creatinine ratio of 1.41 (95% CI 1.27-1.59) as optimal cut-off. This study provides a practical bedside tool for clinical decision making.

Hyperoxia does not affect oxygen delivery in healthy volunteers while causing a decrease in sublingual perfusion.

OBJECTIVE: To determine the human dose-response relationship between a stepwise increase in arterial oxygen tension and its associated changes in DO2 and sublingual microcirculatory perfusion. METHODS: Fifteen healthy volunteers breathed increasing oxygen fractions for 10 minutes to reach arterial oxygen tensions of baseline (breathing air), 20, 40, 60 kPa, and max kPa (breathing oxygen). Systemic hemodynamics were measured continuously by the volume-clamp method. At the end of each period, the sublingual microcirculation was assessed by SDF. RESULTS: Systemic DO2 was unchanged throughout the study (Pslope  = .8). PVD decreased in a sigmoidal fashion (max -15% while breathing oxygen, SD18, Pslope  = .001). CI decreased linearly (max -10%, SD10, Pslope  < .001) due to a reduction in HR (max -10%, SD7, Pslope  = .009). There were no changes in stroke volume or MAP. Most changes became apparent above an arterial oxygen tension of 20 kPa. CONCLUSIONS: In healthy volunteers, supraphysiological arterial oxygen tensions have no effect on systemic DO2 . Sublingual microcirculatory PVD decreased in a dose-dependent fashion. All hemodynamic changes appear negligible up to an arterial oxygen tension of 20 kPa.

Vitamin C: should we supplement?

PURPOSE OF REVIEW: Hypovitaminosis C and vitamin C deficiency are very common in critically ill patients due to increased needs and decreased intake. Because vitamin C has pleiotropic functions, deficiency can aggravate the severity of illness and hamper recovery. RECENT FINDINGS: Vitamin C is a key circulating antioxidant with anti-inflammatory and immune-supporting effects, and a cofactor for important mono and dioxygenase enzymes. An increasing number of preclinical studies in trauma, ischemia/reperfusion, and sepsis models show that vitamin C administered at pharmacological doses attenuates oxidative stress and inflammation, and restores endothelial and organ function. Older studies showed less organ dysfunction when vitamin C was administered in repletion dose (2-3 g intravenous vitamin C/day). Recent small controlled studies using pharmacological doses (6-16 g/day) suggest that vitamin C reduces vasopressor support and organ dysfunction, and may even decrease mortality. SUMMARY: A short course of intravenous vitamin C in pharmacological dose seems a promising, well tolerated, and cheap adjuvant therapy to modulate the overwhelming oxidative stress in severe sepsis, trauma, and reperfusion after ischemia. Large randomized controlled trials are necessary to provide more evidence before wide-scale implementation can be recommended.

Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

Hemodynamic effects of acute hyperoxia: systematic review and meta-analysis.

BACKGROUND: In clinical practice, oxygen is generally administered to patients with the intention of increasing oxygen delivery. Supplemental oxygen may, however, cause arterial hyperoxia, which is associated with hemodynamic alterations. We performed a systematic review and meta-analysis of the literature to determine the effect of hyperoxia on central hemodynamics and oxygen delivery in healthy volunteers and cardiovascular-compromised patients. METHODS: PubMed and EMBASE were searched up to March 2017. Studies with adult humans investigating changes in central hemodynamics or oxygen delivery induced by acute normobaric hyperoxia were included. Studies focusing on lung, retinal, or brain parameters were not included. We extracted subject and oxygen exposure characteristics, indexed and unindexed values for heart rate, stroke volume, cardiac output, mean arterial pressure (MAP), systemic vascular resistance, and oxygen delivery during normoxia and hyperoxia. For quantitative synthesis of the data, a random-effects ratio of means (RoM) model was used. RESULTS: We identified 33 studies with 42 datasets. Study categories included healthy volunteers (n = 22 datasets), patients with coronary artery disease (CAD; n = 6), heart failure (HF; n = 6), coronary artery bypass graft (CABG; n = 3) and sepsis (n = 5). Hyperoxia (arterial oxygen tension of 234-617 mmHg) reduced cardiac output (CO) by 10-15% in both healthy volunteers (-10.2%, 95% confidence interval (CI) -12.9% to -7.3%) and CAD (-9.6%, 95% CI -12.3% to -6.9%) or HF patients (-15.2%, 95% CI -21.7% to -8.2%). No significant changes in cardiac output were seen in CABG or septic patients (-3%). Systemic vascular resistance increased remarkably in patients with heart failure (24.6%, 95% CI 19.3% to 30.1%). In healthy volunteers, and those with CAD and CABG, the effect was smaller (11-16%) and was virtually absent in patients with sepsis (4.3%, 95% CI -3.2% to 12.3%). No notable effect on MAP was found in any group (2-3%). Oxygen delivery was not altered by hyperoxia. Considerable heterogeneity existed between study results, likely due to methodological differences. CONCLUSIONS: Hyperoxia may considerably decrease cardiac output and increase systemic vascular resistance, but effects differ between patient categories. Heart failure patients were the most sensitive while no hemodynamic effects were seen in septic patients. There is currently no evidence supporting the notion that oxygen supplementation increases oxygen delivery.

Effects of hyperoxia on vascular tone in animal models: systematic review and meta-analysis.

BACKGROUND: Arterial hyperoxia may induce vasoconstriction and reduce cardiac output, which is particularly undesirable in patients who already have compromised perfusion of vital organs. Due to the inaccessibility of vital organs in humans, vasoconstrictive effects of hyperoxia have primarily been studied in animal models. However, the results of these studies vary substantially. Here, we investigate the variation in magnitude of the hyperoxia effect among studies and explore possible sources of heterogeneity, such as vascular region and animal species. METHOD: Pubmed and Embase were searched for eligible studies up to November 2017. In vivo and ex vivo animal studies reporting on vascular tone changes induced by local or systemic normobaric hyperoxia were included. Experiments with co-interventions (e.g. disease or endothelium removal) or studies focusing on lung, brain or fetal vasculature or the ductus arteriosus were not included. We extracted data pertaining to species, vascular region, blood vessel characteristics and method of hyperoxia induction. Overall effect sizes were estimated with a standardized mean difference (SMD) random effects model. RESULTS: We identified a total of 60 studies, which reported data on 67 in vivo and 18 ex vivo experiments. In the in vivo studies, hyperoxia caused vasoconstriction with an SMD of - 1.42 (95% CI - 1.65 to - 1.19). Ex vivo, the overall effect size was SMD - 0.56 (95% CI - 1.09 to - 0.03). Between-study heterogeneity (I2) was high for in vivo (72%, 95% CI 62 to 85%) and ex vivo studies (86%, 95% CI 78 to 98%). In vivo, in comparison to the overall effect size, hyperoxic vasoconstriction was less pronounced in the intestines and skin (P = 0.03) but enhanced in the cremaster muscle region (P < 0.001). Increased constriction was seen in vessels 15-25 µm in diameter. Hyperoxic constriction appeared to be directly proportional to oxygen concentration. For ex vivo studies, heterogeneity could not be explained with subgroup analysis. CONCLUSION: The effect of hyperoxia on vascular tone is substantially higher in vivo than ex vivo. The magnitude of the constriction is most pronounced in vessels ~ 15-25 µm in diameter and is proportional to the level of hyperoxia. Relatively increased constriction was seen in muscle vasculature, while reduced constriction was seen in the skin and intestines.

Correction to: Letter to the Editor: Functional Compromise Cohort Study (FCCS): Sarcopenia is a Strong Predictor of Mortality in the Intensive Care Unit.

The article title for this Letter to the Editor is correct as reflected here. The original article has been corrected.

SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis.

BACKGROUND: The sequential organ failure assessment score (SOFA) is increasingly used as an endpoint in intensive care randomized controlled trials (RCTs). Although serially measured SOFA is independently associated with mortality in observational cohorts, the association between treatment effects on SOFA vs. effects on mortality has not yet been quantified in RCTs. The aim of this study was to quantify the relationship between SOFA and mortality in RCTs and to identify which SOFA derivative best reflects between-group mortality differences. METHODS: The review protocol was prospectively registered (Prospero CRD42016034014). We performed a literature search (up to May 1, 2016) for RCTs reporting both SOFA and mortality, and analyzed between-group differences in these outcomes. Treatment effects on SOFA and mortality were calculated as the between-group SOFA standardized difference and log odds ratio (OR), respectively. We used random-effects meta-regression to (1) quantify the linear relationship between RCT treatment effects on mortality (logOR) and SOFA (i.e. responsiveness) and (2) quantify residual heterogeneity (i.e. consistency, expressed as I 2). RESULTS: Of 110 eligible RCTs, 87 qualified for analysis. Using all RCTs, SOFA was significantly associated with mortality (slope = 0.49 (95% CI 0.17; 0.82), p = 0.006, I 2 = 5%); the overall mortality effect explained by SOFA score (R 2) was 9%. Fifty-eight RCTs used Fixed-day SOFA as an endpoint (i.e. the score on a fixed day after randomization), 25 studies used Delta SOFA as an endpoint (i.e. the trajectory from baseline score) and 15 studies used other SOFA derivatives as an endpoint. Fixed-day SOFA was not significantly associated with mortality (slope = 0.35 (95% CI -0.04; 0.75), p = 0.08, I 2 = 12%) and explained 3% of the overall mortality effect (R 2). Delta SOFA was significantly associated with mortality (slope = 0.70 (95% CI 0.26; 1.14), p = 0.004, I 2 = 0%) and explained 32% of the overall mortality effect (R 2). CONCLUSIONS: Treatment effects on Delta SOFA appear to be reliably and consistently associated with mortality in RCTs. Fixed-day SOFA was the most frequently reported outcome among the reviewed RCTs, but was not significantly associated with mortality. Based on this study, we recommend using Delta SOFA rather than Fixed-day SOFA as an endpoint in future RCTs.

Skeletal muscle quality as assessed by CT-derived skeletal muscle density is associated with 6-month mortality in mechanically ventilated critically ill patients.

BACKGROUND: Muscle quantity at intensive care unit (ICU) admission has been independently associated with mortality. In addition to quantity, muscle quality may be important for survival. Muscle quality is influenced by fatty infiltration or myosteatosis, which can be assessed on computed tomography (CT) scans by analysing skeletal muscle density (SMD) and the amount of intermuscular adipose tissue (IMAT). We investigated whether CT-derived low skeletal muscle quality at ICU admission is independently associated with 6-month mortality and other clinical outcomes. METHODS: This retrospective study included 491 mechanically ventilated critically ill adult patients with a CT scan of the abdomen made 1 day before to 4 days after ICU admission. Cox regression analysis was used to determine the association between SMD or IMAT and 6-month mortality, with adjustments for Acute Physiological, Age, and Chronic Health Evaluation (APACHE) II score, body mass index (BMI), and skeletal muscle area. Logistic and linear regression analyses were used for other clinical outcomes. RESULTS: Mean APACHE II score was 24 ± 8 and 6-month mortality was 35.6%. Non-survivors had a lower SMD (25.1 vs. 31.4 Hounsfield Units (HU); p < 0.001), and more IMAT (17.1 vs. 13.3 cm2; p = 0.004). Higher SMD was associated with a lower 6-month mortality (hazard ratio (HR) per 10 HU, 0.640; 95% confidence interval (CI), 0.552-0.742; p < 0.001), and also after correction for APACHE II score, BMI, and skeletal muscle area (HR, 0.774; 95% CI, 0.643-0.931; p = 0.006). Higher IMAT was not significantly associated with higher 6-month mortality after adjustment for confounders. A 10 HU increase in SMD was associated with a 14% shorter hospital length of stay. CONCLUSIONS: Low skeletal muscle quality at ICU admission, as assessed by CT-derived skeletal muscle density, is independently associated with higher 6-month mortality in mechanically ventilated patients. Thus, muscle quality as well as muscle quantity are prognostic factors in the ICU. TRIAL REGISTRATION: Retrospectively registered (initial release on 06/23/2016) at ClinicalTrials.gov: NCT02817646 .

Moderate hyperoxic versus near-physiological oxygen targets during and after coronary artery bypass surgery: a randomised controlled trial.

BACKGROUND: The safety of perioperative hyperoxia is currently unclear. Previous studies in patients undergoing coronary artery bypass surgery suggest reduced myocardial damage when avoiding extreme perioperative hyperoxia (>400 mmHg). In this study we investigated whether an oxygenation strategy from moderate hyperoxia to a near-physiological oxygen tension reduces myocardial damage and improves haemodynamics, organ dysfunction and oxidative stress. METHODS: This was a single-blind, single-centre, open-label, randomised controlled trial in patients undergoing elective coronary artery bypass surgery. Fifty patients were randomised to a partial pressure of oxygen in arterial blood (PaO2) target of 200-220 mmHg during cardiopulmonary bypass and 130-150 mmHg during intensive care unit (ICU) admission (control group) versus lower targets of 130-150 mmHg during cardiopulmonary bypass and 80-100 mmHg at the ICU (conservative group). Primary outcome was myocardial injury (CK-MB and Troponin-T) at ICU admission and 2, 6 and 12 hours thereafter. RESULTS: Weighted PaO2 during cardiopulmonary bypass was 220 mmHg (interquartile range (IQR) 211-233) vs. 157 (151-162) in the control and conservative group, respectively (P < 0.0001). During ICU admission, weighted PaO2 was 107 mmHg (86-141) vs. 90 (84-98) (P = 0.03), respectively. Area under the curve of CK-MB was median 23.5 µg/L/h (IQR 18.4-28.1) vs. 21.5 (15.8-26.6) (P = 0.35) and 0.30 µg/L/h (0.25-0.44) vs. 0.39 (0.24-0.43) (P = 0.81) for Troponin-T. Cardiac index, systemic vascular resistance index, creatinine, lactate and F2-isoprostane levels were not different between groups. CONCLUSIONS: Compared to moderate hyperoxia, a near-physiological oxygen strategy does not reduce myocardial damage in patients undergoing coronary artery bypass surgery. Conservative oxygen administration was not associated with increased lactate levels or hypoxic events. TRIAL REGISTRATION: Netherlands Trial Registry NTR4375, registered on 30 January 2014.

Hemostasis and thrombosis in continuous renal replacement treatment.

During continuous renal replacement therapy, the delicate equilibrium of hemostasis is disturbed. Owing to a complex interaction of critical illness, uremia, use of an extracorporeal circuit and anticoagulation, patients exhibit both hypercoagulability and an increased risk of bleeding. Contact of blood with foreign material initiates coagulation by triggering the contact activation coagulation pathway, the tissue factor-factor VIIa pathway and activation of platelets and monocytes, which adhere to the membrane. The interaction with critical illness induced alterations further enhances coagulation and inflammation. Classical markers of coagulation, prothrombin and activated thromboplastin time, and platelet count do not detect the procoagulant state. Critically ill patients also have in increased risk of bleeding and anticoagulation used for circuit clotting enhances this risk. Heparin is most commonly used. Heparin increases the risk of bleeding. Its efficacy and safety are further compromised by antithrombin deficiency, heparin binding to acute phase proteins and apoptotic and necrotic cells, and by its unpredictable effects on inflammation. Its interference with anticoagulation is therefore unreliable during critical illness. Citrate provides regional anticoagulation and increases biocompatibility. It is better tolerated than heparin and confers less bleeding, less transfusion, and longer circuit life.

Vitamin C supplementation in the critically ill patient.

PURPOSE OF REVIEW: Vitamin C is not only an essential nutrient involved in many anabolic pathways, but also an important player of the endogenous antioxidant defense. Low plasma levels are very common in critical care patients and may reflect severe deficiency states. RECENT FINDINGS: Vitamin C scavenges reactive oxygen species such as superoxide and peroxynitrite in plasma and cells (preventing damage to proteins, lipids and DNA), prevents occludin dephosphorylation and loosening of the tight junctions. Ascorbate improves microcirculatory flow impairment by inhibiting tumor-necrosis-factor-induced intracellular adhesion molecule expression, which triggers leukocyte stickiness and slugging. Clinical trials in sepsis, trauma and major burns testing high-dose vitamin C show clinical benefit. Restoration of normal plasma levels in inflammatory patients requires the administration of 3 g/day for several days, which is 30 times the daily recommended dose. SUMMARY: The recent research on the modulation of oxidative stress and endothelial protection offer interesting therapeutic perspectives, based on the biochemical evidence, with limited or even absent side-effects.