Intravenous vitamin C therapy in adult patients with sepsis: A rapid practice guideline.

BACKGROUND: This Rapid Practice Guideline provides an evidence-based recommendation to address the question: in adults with sepsis or septic shock, should we recommend using or not using intravenous vitamin C therapy? METHODS: The panel included 21 experts from 16 countries and used a strict policy for potential financial and intellectual conflicts of interest. Methodological support was provided by the Guidelines in Intensive Care, Development, and Evaluation (GUIDE) group. Based on an updated systematic review, and the grading of recommendations, assessment, development, and evaluation approach, we evaluated the certainty of evidence and developed recommendations using the evidence-to-decision framework. We conducted an electronic vote, requiring >80% agreement among the panel for a recommendation to be adopted. RESULTS: At longest follow-up, 90 days, intravenous vitamin C probably does not substantially impact (relative risk 1.05, 95% confidence interval [CI] 0.94 to 1.17; absolute risk difference 1.8%, 95% CI -2.2 to 6.2; 6 trials, n = 2148, moderate certainty). Effects of vitamin C on mortality at earlier timepoints was of low or very low certainty due to risk of bias of the included studies and significant heterogeneity between study results. Few adverse events were reported with the use of vitamin C. The panel did not identify any major differences in other outcomes, including duration of mechanical ventilation, ventilator free days, hospital or intensive care unit length of stay, acute kidney injury, need for renal replacement therapy. Vitamin C may result in a slight reduction in duration of vasopressor support (MD -18.9 h, 95% CI -26.5 to -11.4; 21 trials, n = 2661, low certainty); but may not reduce sequential organ failure assessment scores (MD -0.69, 95% CI -1.55 to 0.71; 24 trials, n = 4002, low certainty). The panel judged the undesirable consequences of using IV vitamin C to probably outweigh the desirable consequences, and therefore issued a conditional recommendation against using IV vitamin C therapy in sepsis. CONCLUSIONS: The panel suggests against use of intravenous vitamin C in adult patients with sepsis, beyond that of standard nutritional supplementation. Small and single center trials on this topic should be discouraged.

Adjuvant Analgesic Use in the Critically Ill: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis addresses the efficacy and safety of nonopioid adjunctive analgesics for patients in the ICU. DATA SOURCES: We searched PubMed, Embase, the Cochrane Library, CINAHL Plus, and Web of Science. STUDY SELECTION: Two independent reviewers screened citations. Eligible studies included randomized controlled trials comparing efficacy and safety of an adjuvant-plus-opioid regimen to opioids alone in adult ICU patients. DATA EXTRACTION: We conducted duplicate screening of citations and data abstraction. DATA SYNTHESIS: Of 10,949 initial citations, we identified 34 eligible trials. These trials examined acetaminophen, carbamazepine, clonidine, dexmedetomidine, gabapentin, ketamine, magnesium sulfate, nefopam, nonsteroidal anti-inflammatory drugs (including diclofenac, indomethacin, and ketoprofen), pregabalin, and tramadol as adjunctive analgesics. Use of any adjuvant in addition to an opioid as compared to an opioid alone led to reductions in patient-reported pain scores at 24 hours (standard mean difference, -0.88; 95% CI, -1.29 to -0.47; low certainty) and decreased opioid consumption (in oral morphine equivalents over 24 hr; mean difference, 25.89 mg less; 95% CI, 19.97-31.81 mg less; low certainty). In terms of individual medications, reductions in opioid use were demonstrated with acetaminophen (mean difference, 36.17 mg less; 95% CI, 7.86-64.47 mg less; low certainty), carbamazepine (mean difference, 54.69 mg less; 95% CI, 40.39-to 68.99 mg less; moderate certainty), dexmedetomidine (mean difference, 10.21 mg less; 95% CI, 1.06-19.37 mg less; low certainty), ketamine (mean difference, 36.81 mg less; 95% CI, 27.32-46.30 mg less; low certainty), nefopam (mean difference, 70.89 mg less; 95% CI, 64.46-77.32 mg less; low certainty), nonsteroidal anti-inflammatory drugs (mean difference, 11.07 mg less; 95% CI, 2.7-19.44 mg less; low certainty), and tramadol (mean difference, 22.14 mg less; 95% CI, 6.67-37.61 mg less; moderate certainty). CONCLUSIONS: Clinicians should consider using adjunct agents to limit opioid exposure and improve pain scores in critically ill patients.

Dual LABA/LAMA Therapy versus LABA or LAMA Monotherapy for Chronic Obstructive Pulmonary Disease. A Systematic Review and Meta-analysis in Support of the American Thoracic Society Clinical Practice Guideline.

Rationale: There is uncertainty on the optimal first-line therapy for symptomatic chronic obstructive pulmonary disease (COPD). Long-acting ß2-receptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) have long been mainstays of treatment, though it is still not clear if dual therapy with LABA/LAMA is superior to monotherapy for symptomatic COPD.Objectives: To clarify the evidence landscape, we conducted a systematic review to answer the following question: in patients with COPD who complain of dyspnea and/or exercise intolerance, is LABA/LAMA combination therapy more effective and equally safe compared with LABA or LAMA monotherapy?Methods: A search of Medline, EMBASE, and the Cochrane Library databases was conducted by a medical librarian for randomized controlled trials enrolling patients with COPD who complain of dyspnea and/or exercise intolerance that compare LABA/LAMA combination therapy to LABA or LAMA monotherapy. A systematic approach was used to screen, abstract, and critically appraise the emerging study evidence. The Grading of Recommendations Assessment, Development, and Evaluation method was applied to rate the certainty and quality of the evidence.Results: A total of 24 studies were eligible for inclusion (n = 45,441). Pairwise random-effects meta-analysis revealed reductions in hospital admissions (11% reduction; P < 0.01) and acute exacerbations of COPD (20% reduction; P < 0.002), all in favor of LABA/LAMA dual therapy. Although there is reduced dyspnea (0.10 standardized mean difference; P < 0.001) and improved health-related quality of life (-0.13 standardized mean difference; P < 0.001), both values did not meet a clinical meaningful difference threshold. LABA/LAMA combination therapy showed no difference in treatment-emergent adverse effects (risk ratio, 0.99; P = 0.34) when compared with either LAMA or LABA monotherapy.Conclusions: Based on the reviewed evidence, in patients with symptomatic COPD who complain of dyspnea and/or exercise intolerance, dual LABA/LAMA therapy is superior to either LABA or LAMA monotherapy based on the reduced risk of exacerbations and hospitalizations.

ESPEN guideline on clinical nutrition in the intensive care unit.

Following the new ESPEN Standard Operating Procedures, the previous guidelines to provide best medical nutritional therapy to critically ill patients have been updated. These guidelines define who are the patients at risk, how to assess nutritional status of an ICU patient, how to define the amount of energy to provide, the route to choose and how to adapt according to various clinical conditions. When to start and how to progress in the administration of adequate provision of nutrients is also described. The best determination of amount and nature of carbohydrates, fat and protein are suggested. Special attention is given to glutamine and omega-3 fatty acids. Particular conditions frequently observed in intensive care such as patients with dysphagia, frail patients, multiple trauma patients, abdominal surgery, sepsis, and obesity are discussed to guide the practitioner toward the best evidence based therapy. Monitoring of this nutritional therapy is discussed in a separate document.

Omega-3 supplementation in patients with sepsis: a systematic review and meta-analysis of randomized trials.

BACKGROUND: Nutritional supplementation of omega-3 fatty acids has been proposed to modulate the balance of pro- and anti-inflammatory mediators in sepsis. If proved to improve clinical outcomes in critically ill patients with sepsis, this intervention would be easy to implement. However, the cumulative evidence from several randomized clinical trials (RCTs) remains unclear. METHODS: We searched the Cochrane Library, MEDLINE, and EMBASE through December 2016 for RCTs on parenteral or enteral omega-3 supplementation in adult critically ill patients diagnosed with sepsis or septic shock. We analysed the included studies for mortality, intensive care unit (ICU) length of stay, and duration of mechanical ventilation, and used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the quality of the evidence for each outcome. RESULTS: A total of 17 RCTs enrolling 1239 patients met our inclusion criteria. Omega-3 supplementation compared to no supplementation or placebo had no significant effect on mortality [relative risk (RR) 0.85; 95% confidence interval (CI) 0.71, 1.03; P = 0.10; I 2 = 0%; moderate quality], but significantly reduced ICU length of stay [mean difference (MD) -3.79 days; 95% CI -5.49, -2.09; P < 0.0001, I 2 = 82%; very low quality] and duration of mechanical ventilation (MD -2.27 days; 95% CI -4.27, -0.27; P = 0.03, I 2 = 60%; very low quality). However, sensitivity analyses challenged the robustness of these results. CONCLUSION: Omega-3 nutritional supplementation may reduce ICU length of stay and duration of mechanical ventilation without significantly affecting mortality, but the very low quality of overall evidence is insufficient to justify the routine use of omega-3 fatty acids in the management of sepsis.

Fluid resuscitation in sepsis: a systematic review and network meta-analysis.

BACKGROUND: Fluid resuscitation is the cornerstone of sepsis treatment. However, whether balanced or unbalanced crystalloids or natural or synthetic colloids confer a survival advantage is unclear. PURPOSE: To examine the effect of different resuscitative fluids on mortality in patients with sepsis. DATA SOURCES: MEDLINE, EMBASE, ACP Journal Club, CINAHL, HealthSTAR, the Allied and Complementary Medicine Database, and the Cochrane Central Register of Controlled Trials through March 2014. STUDY SELECTION: Randomized trials that evaluated different resuscitative fluids in adult patients with sepsis or septic shock and death. No language restrictions were applied. DATA EXTRACTION: Two reviewers extracted data on study characteristics, methods, and outcomes. Risk of bias for individual studies and quality of evidence were assessed. DATA SYNTHESIS: 14 studies (18916 patients) were included with 15 direct comparisons. Network meta-analysis at the 4-node level showed higher mortality with starches than with crystalloids (high confidence) and lower mortality with albumin than with crystalloids (moderate confidence) or starches (moderate confidence). Network meta-analysis at the 6-node level showed lower mortality with albumin than with saline (moderate confidence) and low-molecular-weight starch (low confidence) and with balanced crystalloids than with saline (low confidence) and low- and high-molecular-weight starches (moderate confidence). LIMITATIONS: These trials were heterogeneous in case mix, fluids evaluated, duration of fluid exposure, and risk of bias. Imprecise estimates for several comparisons in this network meta-analysis contribute to low confidence in most estimates of effect. CONCLUSION: Among patients with sepsis, resuscitation with balanced crystalloids or albumin compared with other fluids seems to be associated with reduced mortality. PRIMARY FUNDING SOURCE: The Hamilton Chapter of the Canadian Intensive Care Foundation and the Critical Care Medicine Residency Program and Critical Care Division Alternate Funding Plan at McMaster University.

The effect of selenium therapy on mortality in patients with sepsis syndrome: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Patients with sepsis syndrome commonly have low serum selenium levels. Several randomized controlled trials have examined the efficacy of selenium supplementation on mortality in patients with sepsis. OBJECTIVE: To determine the efficacy and safety of high-dose selenium supplementation compared to placebo for the reduction of mortality in patients with sepsis. SOURCES OF DATA: We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, SciFinder, and Clinicaltrials.gov. SELECTION CRITERIA: Randomized controlled parallel group trials comparing selenium supplementation in doses greater than daily requirement to placebo on the outcome of mortality in patients with sepsis syndrome. DATA COLLECTION AND ANALYSIS: Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcome was mortality; secondary outcomes were ICU length of stay, nosocomial pneumonia, and adverse events. Trial authors were contacted for additional or clarifying information. RESULTS: Nine trials enrolling a total of 792 patients were included. Selenium supplementation in comparison to placebo was associated with lower mortality (odds ratio, 0.73; 95% CI, 0.54, 0.98; p = 0.03; I = 0%). Among patients receiving and not receiving selenium, there was no difference in ICU length of stay (mean difference, 2.03; 95% CI, -0.51, 4.56; p = 0.12; I = 0%) or nosocomial pneumonia (odds ratio, 0.83; 95% CI, 0.28, 2.49; p = 0.74; I = 56%). Significant heterogeneity among trials in adverse event reporting precluded pooling of results. CONCLUSIONS: In patients with sepsis, selenium supplementation at doses higher than daily requirement may reduce mortality. We observed no impact of selenium on ICU length of stay or risk of nosocomial pneumonia.