Use of days alive without life support and similar count outcomes in randomised clinical trials - an overview and comparison of methodological choices and analysis methods.

BACKGROUND: Days alive without life support (DAWOLS) and similar outcomes that seek to summarise mortality and non-mortality experiences are increasingly used in critical care research. The use of these outcomes is challenged by different definitions and non-normal outcome distributions that complicate statistical analysis decisions. METHODS: We scrutinized the central methodological considerations when using DAWOLS and similar outcomes and provide a description and overview of the pros and cons of various statistical methods for analysis supplemented with a comparison of these methods using data from the COVID STEROID 2 randomised clinical trial. We focused on readily available regression models of increasing complexity (linear, hurdle-negative binomial, zero-one-inflated beta, and cumulative logistic regression models) that allow comparison of multiple treatment arms, adjustment for covariates and interaction terms to assess treatment effect heterogeneity. RESULTS: In general, the simpler models adequately estimated group means despite not fitting the data well enough to mimic the input data. The more complex models better fitted and thus better replicated the input data, although this came with increased complexity and uncertainty of estimates. While the more complex models can model separate components of the outcome distributions (i.e., the probability of having zero DAWOLS), this complexity means that the specification of interpretable priors in a Bayesian setting is difficult. Finally, we present multiple examples of how these outcomes may be visualised to aid assessment and interpretation. CONCLUSIONS: This summary of central methodological considerations when using, defining, and analysing DAWOLS and similar outcomes may help researchers choose the definition and analysis method that best fits their planned studies. TRIAL REGISTRATION: COVID STEROID 2 trial, ClinicalTrials.gov: NCT04509973, ctri.nic.in: CTRI/2020/10/028731.

Abnormal serum levels of magnesium, phosphate, and zinc in ICU patients-Characteristics, management, and outcomes: The WhyTrace cohort study.

BACKGROUND: Abnormal serum levels of magnesium, phosphate, and zinc appear common in intensive care unit (ICU) patients, but the epidemiology, management, and associations with outcomes are less well described. We described these factors and estimated associations with outcomes in a large dataset of Danish ICU patients. METHODS: We included adults who were acutely admitted to 10 general ICUs in Denmark between October 2011 and January 2018. From the dataset, we obtained characteristics of patients who had serum levels measured of magnesium, phosphate, or zinc, including data on supplementation. We used joint models with death as a competing outcome to estimate the associations between abnormal serum levels and time to successful extubation and, for magnesium, also incident tachyarrhythmia. RESULTS: We included 16,517 of 36,514 patients in the dataset. The cumulative probability of hypomagnesemia within 28 days was 64% (95% confidence interval [CI] 62-66); of hypophosphatemia 74% (95% CI 72-75); and of hypozincemia 98% (95% CI 98-98). Supplementation of magnesium was used in 3554 out of 13,506 (26%) patients, phosphate in 2115 out of 14,148 (15%) patients, and zinc in 4465 out of 9869 (45%) patients. During ICU stay, 38% experienced hypermagnesemia, 58% hyperphosphatemia, and 1% hyperzincemia. Low serum levels of magnesium, phosphate, and zinc were associated with shorter time to successful extubation, and high serum magnesium and phosphate and low serum zinc with the competing risk of increased mortality, but too few serum measurements made the results inconclusive. CONCLUSION: In this multicenter cohort study of acutely admitted ICU patients, most experienced low serum levels of magnesium, phosphate, or zinc during ICU stay, many received supplementation, and experiencing both low and high serum levels during ICU stay was not uncommon. Associations between serum levels and clinical outcomes appeared inconclusive because the data proved unfit for these analyses.

Effects of magnesium, phosphate, or zinc supplementation in intensive care unit patients-A systematic review and meta-analysis.

BACKGROUND: Low-serum levels of magnesium, phosphate, and zinc are observed in many intensive care unit (ICU) patients, but clinical equipoise exists regarding supplementation strategies. We aimed to assess the desirable and undesirable effects of supplementation with magnesium, phosphate, or zinc in adult ICU patients. METHODS: We conducted a systematic review with meta-analysis of randomised clinical trials assessing the effects of supplementation with magnesium, phosphate, or zinc in adult ICU patients. Primary outcomes were mortality and duration of mechanical ventilation. We registered the protocol, followed the Preferred Reporting Items for Systematic Review and Meta-Analysis statement, used the Cochrane risk of bias 2 tool, and the grading of recommendations, assessment, development and evaluation (GRADE) approach for assessing the certainty of the evidence. RESULTS: We identified no low risk of bias trials. For magnesium supplementation, we included three trials (n = 235); the relative risk (RR) for mortality was 0.54, 95% confidence interval (CI) 0.30-0.96 compared to no supplementation (very low certainty of evidence). For zinc supplementation, two trials were included (n = 168); the RR for mortality was 0.73, 95% CI 0.41-1.28 compared to control. No trials assessed the effects of phosphate supplementation on mortality. For outcomes other than mortality, only zero or one trial was available. CONCLUSIONS: In adult ICU patients, the certainty of evidence for the effects of supplementation with magnesium, phosphate, or zinc was very low. High-quality trials are needed to assess the value of supplementation strategies in these patients.

Preferences for the measurement and supplementation of magnesium, phosphate and zinc in ICUs: The international WhyTrace survey.

BACKGROUND: Patients admitted to the Intensive Care Unit (ICU) often have low magnesium, phosphate and zinc levels. Monitoring of serum concentrations and supplementation may be important, but there is no consensus on optimal practice. The objective of the WhyTrace survey was to describe current practice regarding the measurement and supplementation of magnesium, phosphate and zinc in ICUs. METHODS: A 54-item electronic questionnaire was developed in accordance with SURGE, SUrvey Reporting GuidelinE, to address international clinical practice in the ICU. National investigators recruited ICUs in ten countries with one physician responding per ICU using a unique e-mail distributed survey-link. RESULTS: The questionnaire was sent to clinicians in 336 ICUs of whom 283 (84%) responded. In 62% of the ICUs, a standard procedure was in place regarding the measurement of serum magnesium levels, in 58% for phosphate and in 9% for zinc. Zinc was never or rarely measured in 64% of ICUs. The frequency of requesting serum levels varied from twice daily to once weekly. Regarding supplementation, 66% of ICUs had a standard procedure for magnesium, 63% for phosphate and 15% for zinc. Most procedures recommended supplementation when serum levels were below the lower reference level, but some used the upper reference levels as the threshold for supplementation and others decided on a case-by-case basis. CONCLUSION: The practice of measuring and supplementing magnesium, phosphate and zinc differed substantially between ICUs. Our findings indicate that there is a need for high-quality prospective data on frequencies of measurements, treatment goals and effects of supplementation on patient-important outcomes.

Effects of magnesium, phosphate and zinc supplementation in ICU patients-Protocol for a systematic review.

BACKGROUND: Depletion of the trace elements magnesium, phosphate and zinc is common in patients admitted to the intensive care unit (ICU). Observational studies have suggested worse outcome in patients with hypomagnesaemia, hypophosphataemia or hypozincaemia, but also inverse associations with worse outcome with too high serum levels. However, it is unclear whether data from randomised clinical trials (RCTs) confirm this. Accordingly, we plan to assess the balance between benefits and harms of supplementation as compared with placebo or no supplementation in adult ICU patients. METHODS: We will conduct a systematic review of RCTs with meta-analysis and trial sequential analysis in accordance with the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement and the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach. We will assess the effects of any supplementation with magnesium, phosphate or zinc vs. placebo or no treatment in adult ICU patients. We will systematically search the Cochrane CENTRAL, Embase, PubMed, and for unpublished trials: ClinicalTrials.gov, the EU clinical Trials Register and the WHO International Clinical Trials Registry Platform. The primary outcomes will be days alive without mechanical ventilation and overall mortality. Secondary outcomes include use for mechanical ventilation, tachy-arrhythmias, use of vasopressors, length of hospital stay and use of renal replacement therapy. DISCUSSION: The benefits and harms of supplementation therapy with magnesium, phosphate and zinc in general ICU patients are unknown. This outlined systematic review will provide data on the evidence, on which future recommendations for supplementation may be founded.

The Effect of IV Amino Acid Supplementation on Mortality in ICU Patients May Be Dependent on Kidney Function: Post Hoc Subgroup Analyses of a Multicenter Randomized Trial.

OBJECTIVES: We investigated whether preexisting kidney function determines if ICU patients may benefit from increased (2.0 g/kg/d) protein intake. DESIGN: Post hoc, hypothesis-generating, subgroup analysis of a multicenter, phase 2, randomized clinical trial. All analyses were conducted by intention to treat and maintained group allocation. Ninety-day mortality was the primary outcome. SETTING: ICUs of 16 hospitals throughout Australia and New Zealand. PATIENTS: Adult critically ill patients expected to remain in the study ICU for longer than 2 days. INTERVENTIONS: Random allocation to receive a daily supplement of up to 100 g of IV amino acids to achieve a total protein intake of 2.0 g/kg/d or standard nutrition care. MEASUREMENTS AND MAIN RESULTS: A total of 474 patients were randomized: 235 to standard care and 239 to IV amino acid supplementation. There was a statistically significant interaction between baseline kidney function and supplementation with study amino acids (p value for interaction = 0.026). Within the subgroup of patients with normal kidney function at randomization, patients who were allocated to receive the study amino acid supplement were less likely to die before study day 90 (covariate-adjusted risk difference, -7.9%; 95% CI, -15.1 to -0.7; p = 0.034). Furthermore, amino acid supplementation significantly increased estimated glomerular filtration rate in these patients (repeated-measures treatment × time interaction p = 0.009). Within the subgroup of patients with baseline kidney dysfunction and/or risk of progression of acute kidney injury, a significant effect of the study intervention on mortality was not found (covariate-adjusted risk difference, -0.6%; 95% CI, -16.2 to 15.2; p = 0.95). CONCLUSIONS: In this post hoc, hypothesis-generating, subgroup analysis, we observed reduced mortality and improved estimated glomerular filtration rate in ICU patients with normal kidney function who were randomly allocated to receive increased protein intake (up to 2.0 g/kg/d). We strongly recommend confirmation of these results in trials with low risk of bias before this treatment is recommended for routine care.

Pharmacological interventions for delirium in intensive care patients: a protocol for an overview of reviews.

BACKGROUND: The prevalence of delirium in intensive care unit (ICU) patients is high. Delirium has been associated with morbidity and mortality including more ventilator days, longer ICU stay, increased long-term mortality and cognitive impairment. Thus, the burden of delirium for patients, relatives and societies is considerable. Today, reviews of randomised clinical trials are produced in large scales sometimes making it difficult to get an overview of the available evidence. A preliminary search identified several reviews investigating the effects of pharmacological interventions for the management and prevention of delirium in ICU patients. The conclusions of the reviews showed conflicting results. Despite this unclear evidence, antipsychotics, in particular, haloperidol is often the recommended pharmacological intervention for delirium in ICU patients. The objective of this overview of reviews is to critically assess the evidence of reviews of randomised clinical trials on the effect of pharmacological management and prevention of delirium in ICU patients. METHODS/DESIGN: We will search for reviews in the following databases: Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS, Cumulative Index to Nursing and Allied Health Literature, Latin American and Caribbean Health Sciences Literature, and Allied and Complementary Medicine Database. Two authors will independently select references for inclusion using Covidence, extract data and assess the methodological quality of the included systematic reviews using the ROBIS tool. Any disagreement will be resolved by consensus. We will present the data as a narrative synthesis and summarise the main results of the included reviews. In addition, we will present an overview of the bias risk assessment of the systematic reviews. DISCUSSION: Results of this overview may establish a way forward to find and update or to design a high quality systematic review assessing the effects of the most promising pharmacological intervention for delirium in ICU patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO - CRD42016046628 .

A Novel Noninvasive Method for Measuring Fatigability of the Quadriceps Muscle in Noncooperating Healthy Subjects.

BACKGROUND: Critical illness is associated with muscle weakness leading to long-term functional limitations. OBJECTIVES: To assess the reliability of a novel method for evaluating fatigability of the quadriceps muscle in noncooperating healthy subjects. METHODS: On two occasions, separated by seven days, nonvoluntary isometric contractions (twitch and tetanic) of the quadriceps femoris muscle evoked by transcutaneous electrical muscle stimulation were recorded in twelve healthy adults. For tetanic contractions, the Fatigue Index (ratio of peak torque values) and the slope of the regression line of peak torque values were primary outcome measures. For twitch contractions, maximum peak torque and rise time were calculated. Relative (intraclass correlation, ICC3.1) and absolute (standard error of measurement, SEM) reliability were assessed and minimum detectable change was calculated using a 95% confidence interval (MDC95%). RESULTS: The Fatigue Index (ICC3.1, 0.84; MDC95%, 0.12) and the slope of the regression line (ICC3.1, 0.99; MDC95%, 0.03) showed substantial relative and absolute reliability during the first 15 and 30 contractions, respectively. CONCLUSION: This method for assessing fatigability of the quadriceps muscle produces reliable results in healthy subjects and may provide valuable data on quantitative changes in muscle working capacity and treatment effects in patients who are incapable of producing voluntary muscle contractions.

Effect of transcutaneous electrical muscle stimulation on muscle volume in patients with septic shock.

OBJECTIVE: Intensive care unit admission is associated with muscle wasting and impaired physical function. We investigated the effect of early transcutaneous electrical muscle stimulation on quadriceps muscle volume in patients with septic shock. DESIGN: Randomized interventional study using a single-legged exercise design with the contralateral leg serving as a paired control. SETTING: A mixed 18-bed intensive care unit at a tertiary care university hospital. PATIENTS: Eight adult male intensive care unit patients with septic shock included within 72 hrs of diagnosis. INTERVENTIONS: After randomization of the quadriceps muscles, transcutaneous electrical muscle stimulation was applied on the intervention side for 7 consecutive days and for 60 mins per day. All patients underwent computed tomographic scans of both thighs immediately before and after the 7-day treatment period. The quadriceps muscle was manually delineated on the computed tomography slices, and muscle volumes were calculated after three-dimensional reconstruction. MEASUREMENTS AND MAIN RESULTS: Median age and Acute Physiology and Chronic Health Evaluation II score were 67 years (interquartile range, 64-72 years) and 25 (interquartile range, 20-29), respectively. During the 7-day study period, the volume of the quadriceps muscle on the control thigh decreased by 16% (4-21%, p=.03) corresponding to a rate of 2.3% per day. The volume of the stimulated muscle decreased by 20% (3-25%, p=.04) corresponding to a rate of 2.9% per day (p=.12 for the difference in decrease). There was no difference in muscle volume between the stimulated and nonstimulated thigh at baseline (p=.10) or at day 7 (p=.12). The charge delivered to the muscle tissue per training session (0.82 [0.66-1.18] coulomb) correlated with the maximum sequential organ failure assessment score. CONCLUSIONS: We observed a marked decrease in quadriceps volume within the first week of intensive care for septic shock. This loss of muscle mass was unaffected by transcutaneous electrical muscle stimulation applied for 60 mins per day for 7 days.

Tetrahydrobiopterin restores endothelial dysfunction induced by an oral glucose challenge in healthy subjects.

An oral glucose challenge causes transient impairment of endothelial function, probably because of increased oxidative stress. During oxidative stress, endothelial nitric oxide (NO) synthase (eNOS) becomes uncoupled because of decreased bioavailability of tetrahydrobiopterin (BH4), an essential cofactor of eNOS. Therefore, we examined whether an acute supplement of BH4 could restore endothelial dysfunction induced by an oral glucose challenge. Healthy subjects were examined in 53 experiments. Forearm blood flow was measured by venous occlusion plethysmography. Dose-response studies were obtained during intra-arterial infusion of serotonin to elicit endothelium-dependent, NO-specific vasodilation and during sodium nitroprusside (SNP) infusion to elicit endothelium-independent vasodilation. Subjects were examined before (fasting) and 1 and 2 h after an oral glucose challenge (75 g) with serotonin (n = 10) and SNP (n = 8). On different days (6R)-5,6,7,8-tetrahydro-l-biopterin dihydrochloride (6R-BH4; n = 10), the active cofactor of eNOS or its stereoisomer (6S)-5,6,7,8-tetrahydro-l-biopterin sulfate (6S-BH4; n = 10), which is inactive as a cofactor, was added 10 min (500 microg/min) before and during the 1-h postchallenge serotonin dose-response study. In vitro studies showed that 6R-BH4 and 6S-BH4 were equipotent antioxidants. Serotonin response was reduced by 24 +/- 7% (at the highest dose) at 1 h postchallenge compared with fasting (P = 0.001) and was restored 2 h postchallenge. The reduction was reversed by the administration of 6R-BH4 but not by 6S-BH4. SNP responses were slightly increased 1 and 2 h postchallenge (increased by 15 +/- 13% at third dose 2 h postchallenge, P = 0.0001). An oral glucose challenge causes transient, NO-specific, endothelial dysfunction, which may be reversed by BH4. Transient postprandial endothelial dysfunction may be partly explained by reduced bioavailability of BH4 and NO.