Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

A Canadian survey of perceptions and practices related to ordering of blood tests in the intensive care unit.

PURPOSE: The ordering of routine blood test panels in advance is common in intensive care units (ICUs), with limited consideration of the pretest probability of finding abnormalities. This practice contributes to anemia, false positive results, and health care costs. We sought to understand practices and attitudes of Canadian adult intensivists regarding ordering of blood tests in critically ill patients. METHODS: We conducted a nationwide Canadian cross-sectional survey consisting of 15 questions assessing three domains (global perceptions, test ordering, daily practice), plus 11 demographic questions. The target sample was one intensivist per adult ICU in Canada. We summarized responses using descriptive statistics and present data as mean with standard deviation (SD) or count with percentage as appropriate. RESULTS: Over seven months, 80/131 (61%) physicians responded from 77 ICUs, 50% of which were from Ontario. Respondents had a mean (SD) clinical experience of 12 (9) years, and 61% worked in academic centres. When asked about their perceptions of how frequently unnecessary blood tests are ordered, 61% responded "sometimes" and 23% responded "almost always." Fifty-seven percent favoured ordering complete blood counts one day in advance. Only 24% of respondents believed that advanced blood test ordering frequently led to changes in management. The most common factors perceived to influence blood test ordering in the ICU were physician preferences, institutional patterns, and order sets. CONCLUSION: Most respondents to this survey perceived that unnecessary blood testing occurs in the ICU. The survey identified possible strategies to decrease the number of blood tests.

RéSUMé: OBJECTIF: La prescription à l'avance de tests sanguins de routine est courante dans les unités de soins intensifs (USI), avec une prise en compte limitée de la probabilité de découverte d'anomalies avant le test. Cette pratique contribue à l'anémie, aux résultats faussement positifs et aux coûts des soins de santé. Nous avons cherché à comprendre les pratiques et les attitudes des intensivistes pour adultes au Canada en ce qui concerne la prescription d'analyses sanguines chez la patientèle gravement malade. MéTHODE: Nous avons mené un sondage transversal à l'échelle nationale au Canada en posant 15 questions évaluant trois domaines (perceptions globales, commande de tests, pratique quotidienne), ainsi que 11 questions démographiques. L'échantillon cible était composé d'un·e intensiviste par unité de soins intensifs pour adultes au Canada. Nous avons résumé les réponses à l'aide de statistiques descriptives et présenté les données sous forme de moyennes avec écarts type (ET) ou de dénombrements avec pourcentages, selon le cas. RéSULTATS: Sur une période de sept mois, 80 médecins sur 131 (61%) ont répondu dans 77 unités de soins intensifs, dont 50% en Ontario. Les répondant·es avaient une expérience clinique moyenne (ET) de 12 (9) ans, et 61% travaillaient dans des centres universitaires. Lorsqu'on leur a demandé ce qu'ils ou elles pensaient de la fréquence à laquelle des tests sanguins inutiles étaient prescrits, 61% ont répondu « parfois ¼ et 23% ont répondu « presque toujours ¼. Cinquante-sept pour cent étaient en faveur de la réalisation d'une formule sanguine complète un jour à l'avance. Seulement 24% des personnes interrogées estimaient que la prescription de tests sanguins à l'avance entraînait fréquemment des changements dans la prise en charge. Les facteurs les plus souvent perçus comme influençant la prescription d'analyses sanguines à l'unité de soins intensifs étaient les préférences des médecins, les habitudes institutionnelles et les ensembles d'ordonnances. CONCLUSION: La plupart des répondant·es à ce sondage ont l'impression que des tests sanguins inutiles sont prescrits aux soins intensifs. L'enquête a permis d'identifier des stratégies possibles pour réduire le nombre de tests sanguins.

I SURVIVE: inter-rater reliability of three physical functional outcome measures in intensive care unit survivors.

PURPOSE: We prospectively assessed inter-rater reliability of three physical function measures in Canadian intensive care unit (ICU) survivors in the inpatient setting. METHODS: We enrolled patients who had an ICU length of stay of ≥ three days, were mechanically ventilated for ≥ 24 hr, and were ambulating independently before hospital admission. Weekly from ICU discharge to hospital discharge, two trained frontline clinicians, blinded to each other's findings, independently performed the Physical Function ICU Test-scored (PFIT-s; score out of 10), 30-sec sit-to-stand (30STS; # of stands), and two-minute walk test (2MWT; distance in m), all within 24 hr. We calculated the intraclass correlation coefficient (ICC), standard error of measurement (SEM), and minimal detectable change (MDC90). RESULTS: We enrolled 42 patients. PFIT-s: in 36 patients with 66 paired scores, the ICC was 0.78 (95% confidence interval [CI], 0.66 to 0.86), the SEM was 1.04, and the MDC90 was 2.42. 30STS: in 35 patients with 67 paired scores, the ICC was 0.85 (95% CI, 0.76 to 0.90), the SEM was 1.91, and the MDC90 was 4.45. 2MWT: in 35 patients with 58 paired scores, the ICC was 0.78 (95% CI, 0.66 to 0.87), the SEM was 20.87, and the MDC90 was 48.69. CONCLUSION: These three measures show good inter-rater reliability when used by trained frontline clinicians to assess physical function in ICU survivors in the inpatient setting.

RéSUMé: OBJECTIF: Nous avons évalué de manière prospective la fidélité interobservateurs de trois mesures de la capacité physique fonctionnelle auprès de survivants des unités de soins intensifs (USI) canadiennes dans un cadre hospitalier. MéTHODE: Nous avons recruté des patients qui avaient séjourné à l'USI ≥ trois jours, avaient été sous ventilation mécanique ≥ 24 h et se déplaçaient de façon autonome avant leur admission à l'hôpital. Entre le congé de l'USI et le congé de l'hôpital, deux cliniciens de première ligne formés ont réalisé chaque semaine et de manière indépendante trois tests : le PFIT (Test de la capacité physique fonctionnelle à l'USI - Physical Function ICU Test-scored; score sur 10), le test de 30 sec pour se lever d'une position assise (30STS; # de fois debout), et le test de marche pendant deux minutes (2MWT; distance en m). Les cliniciens n'avaient pas accès aux résultats de leur collègue. Nous avons calculé le coefficient de corrélation intraclasse (CCI), l'erreur type sur la mesure (ETM), et le changement minimal détectable (CMD90). RéSULTATS: Nous avons recruté 42 patients, et observé les résultats suivants : pour le PFIT : chez 36 patients avec 66 scores appariés, le CCI était de 0,78 (intervalle de confiance [IC] 95 %, 0,66 à 0,86), l'ETM de 1,04, et le CMD90 de 2,42; pour le test 30STS : chez 35 patients avec 67 scores appariés, le CCI était de 0,85 (IC 95 %, 0,76 à 0,90), l'ETM de 1,91, et le CMD90 de 4,45; pour le 2MWT : chez 35 patients avec 58 scores appariés, le CCI était de 0,78 (IC 95 %, 0,66 à 0,87, l'ETM de 20,87, et le CMD90 de 48,69. CONCLUSION: Ces trois mesures affichent une bonne fidélité interobservateurs lorsqu'elles sont utilisées par des cliniciens de première ligne formés afin d'évaluer la capacité physique fonctionnelle des survivants de l'USI dans un cadre hospitalier.

Chloride and Other Electrolyte Concentrations in Commonly Available 5% Albumin Products.

OBJECTIVE: Use of hyperchloremic IV fluids for resuscitation in sepsis may be associated with increased mortality and use of renal replacement therapy. After crystalloids, 5% human albumin represents the second most common resuscitation fluid in the ICU. Its chloride concentration is rarely considered in the clinical setting. This study quantifies previously undocumented chloride concentrations of three 5% albumin solutions using biochemical analysis. DESIGN: We performed blinded analysis of the electrolyte concentration of albumin samples obtained directly from the national blood supplier (Canadian Blood Services). Two-tailed independent t tests were performed for all possible comparative analyses. Analysis of variance testing was performed for relevant three-way comparisons. Significance threshold was set at p less than 0.05. SETTING: All samples were analyzed in the core laboratory at an academic hospital associated with McMaster University in Hamilton, Ontario, Canada. SUBJECTS: We analyzed 65 albumin samples from three available brands obtained through Canadian Blood Services. They include Plasbumin (n = 21), Alburex (n = 24), Octalbin (n = 20). INTERVENTION: Laboratory technologists blinded to product identification measured the concentration of electrolytes, extended electrolytes, lactate, and albumin of each sample using the Abbott ARCHITECT c8000 chemistry analyzer. MEASUREMENTS AND MAIN RESULTS: The mean chloride concentration of Plasbumin, Alburex, and Octalbin, respectively, were 109.4 mmol/L (SD, 1.3), 123.6 mmol/L (SD, 1.3), and 136.8 mmol/L (SD, 0.4). The mean sodium concentration of Plasbumin, Alburex, and Octalbin, respectively, were 139.6 mmol/L (SD, 1.6), 137.3 mmol/L (SD, 2.2), and 149.4 mmol/L (SD, 0.5). The chloride and sodium concentration differed significantly for all two-way comparisons (p < 0.0001) and multiple comparison testing (p < 0.0001). CONCLUSION: This study is the first to identify and document a statistically significant variability in the chloride concentration of available 5% albumin products. This study has also informed a pilot randomized controlled trial examining the effect of administering high chloride versus low chloride fluids in critically ill patients with sepsis.

Monitoring and auditing protocol adherence, data integrity and ethical conduct of a randomized clinical trial: A case study.

PURPOSE: To categorize, quantify and interpret findings documented in feedback letters of monitoring or auditing visits for an investigator-initiated, peer-review funded multicenter randomized trial testing probiotics for critically ill patients. MATERIALS & METHODS: In 37 Canadian centers, monitoring and auditing visits were performed by 3 trained individuals; findings were reported in feedback letters. At trial termination, we performed duplicate content analysis on letters, categorizing observations first into unique findings, followed by 10 pre-determined trial quality management domains. We further classified each observation into a) missing operational records, b) errors in process, and potential threats to c) data integrity, d) patient privacy or e) safety. RESULTS: Across 37 monitoring or auditing visits, 75 unique findings were categorized into 10 domains. Most frequently, observations were in domains of training documentation (180/566 [32%]) and the informed consent process (133/566 [23%]). Most observations were missing operational records (438/566 [77%]) rather than errors in process (128/566 [23%]). Of 75 findings, 13 (62/566 observations [11%]) posed a potential threat to data integrity, 1 (1/566 observation [0.18%]) to patient privacy, and 9 (49/566 observations [8.7%]) to patient safety. CONCLUSIONS: Monitoring and auditing findings predominantly concerned missing documentation with minimal threats to data integrity, patient privacy or safety. TRIAL REGISTRATION: PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590.

Lessening Organ dysfunction with VITamin C (LOVIT): protocol for a randomized controlled trial.

BACKGROUND: Sepsis is a health problem of global importance; treatments focus on controlling infection and supporting failing organs. Recent clinical research suggests that intravenous vitamin C may decrease mortality in sepsis. We have designed a randomized controlled trial (RCT) to ascertain the effect of vitamin C on the composite endpoint of death or persistent organ dysfunction at 28 days in patients with sepsis. METHODS: LOVIT (Lessening Organ dysfunction with VITamin C) is a multicenter, parallel-group, blinded (participants, clinicians, study personnel, Steering Committee members, data analysts), superiority RCT (minimum n = 800). Eligible patients have sepsis as the diagnosis for admission to the intensive care unit (ICU) and are receiving vasopressors. Those admitted to the ICU for more than 24 h are excluded. Eligible patients are randomized to high-dose intravenous vitamin C (50 mg/kg every 6 h for 96 h) or placebo. The primary outcome is a composite of death or persistent organ dysfunction (need for vasopressors, invasive mechanical ventilation, or new and persisting renal replacement therapy) at day 28. Secondary outcomes include persistent organ dysfunction-free days to day 28, mortality and health-related quality of life at 6 months, biomarkers of dysoxia, inflammation, infection, endothelial function, and adverse effects (hemolysis, acute kidney injury, and hypoglycemia). Six subgroup analyses are planned. DISCUSSION: This RCT will provide evidence of the effect of high-dose intravenous vitamin C on patient-important outcomes in patients with sepsis. TRIAL REGISTRATION: clinicaltrials.gov, NCT03680274, first posted 21 September 2018.

Assessing frailty in the intensive care unit: A reliability and validity study.

PURPOSE: To describe pre-ICU frailty in critically ill patients using the Clinical Frailty Scale (CFS). METHODS: We included patients ≥18years admitted to 2 ICUs in Hamilton, Canada. The ICU Research Coordinator (RC) generated 3 CFS scores using: 1) chart review, 2) family interview, 3) patient interview. Subsequently, an overall impression was captured in a final score. Mean differences were calculated to assess the RC intra-rater reliability and inter-rater reliability of chart reviews by the RC, Occupational Therapist (OT), and Geriatrics Resident (GR). Scores were also compared between younger and older patients. We also analyzed the relationship between CFS scores and mortality. RESULTS: We prospectively enrolled 150 patients (mean age 63.8 [SD 15.3] years, APACHE II score 21 [SD 7.3]). CFS were similar between RC, OT, and GR chart reviews (p>0.05 for all comparisons). There was no difference between RC chart review and RC final score, or between RC patient interview and RC final score. Scores following the RC family interview and the RC final score were significantly different (-0.24, 95% CI -0.38, -0.09, p<0.01). Each 1-point increase in the final CFS scored by the RC was weakly associated with ICU mortality (odds ratio 1.18, 95% CI 0.84-1.66, p=0.33), and hospital mortality (OR 1.19, 95% CI 0.89, -1.59, p=0.24). CONCLUSIONS: CFS scores can be generated using medical chart review and can be reliably completed by ICU clinicians and research staff.

Fluids in Sepsis and Septic Shock (FISSH): protocol for a pilot randomised controlled trial.

INTRODUCTION: Observational evidence suggests physiological benefits and lower mortality with lower chloride solutions; however, 0.9% saline remains the most widely used fluid worldwide. Given uncertainty regarding the association of lower chloride on mortality, it is unlikely that practice will change without direct randomised clinical trial (RCT) evidence. This pilot RCT will investigate the feasibility of a large-scale trial directly comparing low chloride with high chloride fluids in patients with septic shock. METHODS AND ANALYSIS: This is a randomised, concealed, blinded parallel-group multicentre pilot trial. We will include adult critically ill patients with septic shock, defined as ongoing hypotension despite 1 L of fluid, or a serum lactate >4 mmol/L, who are within 6 hours of hospital presentation or rapid response team activation. We will exclude patients if they have an aetiology of shock other than sepsis, if they have acute burn injury, elevated intracranial pressure, intent to withdraw life support or previous enrolment in this or a competing trial. Following informed consent, patients will be randomised to a low chloride fluid strategy or a high chloride fluid strategy for the duration of their ICU stay or until 30 days postrandomisation. Clinicians, patients, families and research staff will be blinded. The primary outcome for this trial will be feasibility, assessed by consent rate, recruitment success and protocol adherence. Patient-important clinical outcomes include mortality, receipt of renal replacement therapy, intensive care unit and hospital lengths of stay and surrogate outcomes of incidence of acidosis, hyperkalaemia and acute kidney injury. ETHICS AND DISSEMINATION: This pilot trial will test the feasibility of conducting the main trial, which will examine the effect of high versus low chloride fluids in patients with septic shock on patient-important outcomes. TRIAL REGISTRATION NUMBER: NCT02748382, registered 8 April 2016. PROTOCOL DATE: 1 July 2016.