Medicine (RMH) - Research Publications
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ItemSystematic Review With Meta-Analysis of Patient-Centered Outcomes, Comparing International Guideline-Recommended Enteral Protein Delivery With Usual Care(WILEY, 2020-05)BACKGROUND: International guidelines recommend that protein be administered enterally to critically ill patients at doses between 1.2 and 2 g/kg per day Observational data indicate that patients frequently receive less protein. The aim of this systematic review was to evaluate patient-centered outcomes with guideline-recommended enteral protein compared with usual care. METHODS: A systematic review was performed of randomized controlled trials including critically ill adult patients provided predominately enteral nutrition with mean protein at ≥1.2 g/kg per day (intervention) and <1.2 g/kg per day (comparator). Random-effects models were applied for outcomes reported in ≥3 trials. RESULTS: Of 1375 abstracts, 69 full-text articles were reviewed, and 6 trials meet the inclusion criteria, including 511 patients. The intervention group received a mean (SD) of 1.3 (0.08) g/kg per day, and the comparator group received 0.75 (0.15) g/kg per day protein. Insufficient data were available for meta-analyses on the primary outcome (muscle mass or strength). According to our meta-analyses, mortality at 28 days (5 studies) (risk ratio 0.92 [95% Cl 0.63-1.35], P = .66) and the durations of intensive care unit (6 studies) and hospital admission (4 studies) were similar between the intervention and comparator, with some uncertainty due to sample sizes and heterogeneity. CONCLUSION: There are insufficient data to conclude whether protein provision within the current international guideline recommendations improves outcomes. In a limited dataset, enteral protein intakes near the lower level of current recommendations do not appear to reduce admission duration or mortality when compared with usual care in critically ill.
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ItemThe effects of ulimorelin, a ghrelin agonist, on liquid gastric emptying and colonic transit in humans(WILEY, 2020-03)BACKGROUND: Ulimorelin, a small molecule ghrelin agonist and prokinetic agent, was effective in animal models of gastroparesis and delayed transit. However, employing once daily administration, it failed in clinical trials of postoperative ileus (POI), a condition in which colonic motility recovers last. The aim of this study was to evaluate drug dosing and regional differences in drug activity between stomach and colon. METHODS: Gastric emptying was assessed by scintigraphy in healthy adults at single doses of 600-1200 µg kg-1 and multiple doses of 80-600 µg kg-1 Q8H for 7 days. Colonic motility was assessed by 7-region scintigraphic analysis at a dose of 600 µg kg-1 for 2 days. The primary endpoints were percent change in time to 50% (∆t50 ) liquid gastric emptying on Days 1, 4, and 6 and the geometric mean center of colonic transit at 24 hours (GC24 ). Plasma concentrations of free and total ulimorelin were measured for pharmacokinetic and exposure-response modeling. KEY RESULTS: Ulimorelin 150-600 µg kg-1 every 8 hours resulted in statistically significant improvements (∆t50 = 23% to 46% (P < .05)) in gastric emptying from baseline that were sustained through Day 6. However, no effects on GC24 were observed. Pharmacokinetic analyses suggested that the free concentrations of ulimorelin achieved in POI trials and dosing frequency may have been inadequate. CONCLUSIONS AND INFERENCES: Ulimorelin is a potent gastric prokinetic but lacks evidence of activity in the human colon, pointing to the stomach as the predominant site of action of ghrelin in humans; ClinicalTrials.gov NCT02993055.
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ItemOutcomes Six Months after Delivering 100% or 70% of Enteral Calorie Requirements during Critical Illness (TARGET) A Randomized Controlled Trial(AMER THORACIC SOC, 2020-04-01)Rationale: The long-term effects of delivering approximately 100% of recommended calorie intake via the enteral route during critical illness compared with a lesser amount of calories are unknown.Objectives: Our hypotheses were that achieving approximately 100% of recommended calorie intake during critical illness would increase quality-of-life scores, return to work, and key life activities and reduce death and disability 6 months later.Methods: We conducted a multicenter, blinded, parallel group, randomized clinical trial, with 3,957 mechanically ventilated critically ill adults allocated to energy-dense (1.5 kcal/ml) or routine (1.0 kcal/ml) enteral nutrition.Measurements and Main Results: Participants assigned energy-dense nutrition received more calories (percent recommended energy intake, mean [SD]; energy-dense: 103% [28] vs. usual: 69% [18]). Mortality at Day 180 was similar (560/1,895 [29.6%] vs. 539/1,920 [28.1%]; relative risk 1.05 [95% confidence interval, 0.95-1.16]). At a median (interquartile range) of 185 (182-193) days after randomization, 2,492 survivors were surveyed and reported similar quality of life (EuroQol five dimensions five-level quality-of-life questionnaire visual analog scale, median [interquartile range]: 75 [60-85]; group difference: 0 [95% confidence interval, 0-0]). Similar numbers of participants returned to work with no difference in hours worked or effectiveness at work (n = 818). There was no observed difference in disability (n = 1,208) or participation in key life activities (n = 705).Conclusions: The delivery of approximately 100% compared with 70% of recommended calorie intake during critical illness does not improve quality of life or functional outcomes or increase the number of survivors 6 months later.
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ItemOutcome Measures in Critical Care Nutrition Interventional Trials: A Systematic Review(WILEY, 2020-06)Historically, randomized controlled trials (RCTs) in critical care have used mortality as the primary outcome, yet most show no effect on this outcome. Therefore, there has been a shift in the literature to focus on alternative outcomes. This review aimed to describe primary outcomes selected in RCTs of nutrition interventions in critical illness. Systematic search of the literature identified RCTs of nutrition interventions in critically ill adults published between January 2007 and December 2018. Primary outcomes were documented and categorized as mortality, morbidity, health service/cost-effectiveness, or nutrition outcome. The direction of effect of the intervention on the primary outcome (positive, neutral, or negative) was extracted. Of 1163 citations identified and assessed for eligibility, 125 articles were included. However, 52 articles (42%) did not provide a sample-size calculation, leaving 73 articles (58%) for data extraction. The primary outcomes reported were morbidity (n = 24, 32.9%); health service/cost-effectiveness (n = 21, 28.8%); nutrition outcomes (n = 16, 21.9%); mortality (n = 11, 15.1%); and other (n = 1, 1.4%). No RCTs with mortality as the primary outcome reported a difference between intervention and control. Trials that included other primary outcomes frequently reported a difference (n = 27 of 62; 43.5%). Morbidity was the most frequently reported outcome category in RCTs that evaluated a nutrition intervention in critically ill adults, with mortality least frequent. Power calculations were only reported in 58% of included studies. Trials were more likely to show a significant result when an outcome other than mortality was the primary outcome.
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ItemLong term outcomes for Aboriginal and Torres Strait Islander Australians after hospital intensive care(WILEY, 2020-07)OBJECTIVES: To assess long term outcomes for Aboriginal and Torres Strait Islander (Indigenous) Australians admitted non-electively to intensive care units (ICUs). DESIGN: Data linkage cohort study; analysis of ICU patient data (Australian and New Zealand Intensive Care Society Adult Patient Database), prospectively collected during 2007-2016. SETTING: All four university-affiliated level 3 ICUs in South Australia. MAIN OUTCOMES: Mortality (in-hospital, and 12 months and 8 years after admission to ICU), by Indigenous status. RESULTS: 2035 of 39 784 non-elective index ICU admissions (5.1%) were of Indigenous Australians, including 1461 of 37 661 patients with South Australian residential postcodes. The median age of Indigenous patients (45 years; IQR, 34-57 years) was lower than for non-Indigenous ICU patients (64 years; IQR, 47-76 years). For patients with South Australian postcodes, unadjusted mortality at discharge and 12 months and 8 years after admission was lower for Indigenous patients; after adjusting for age, sex, diabetes, severity of illness, and diagnostic group, mortality was similar for both groups at discharge (adjusted odds ratio [aOR], 0.95; 95% CI, 0.81-1.10), but greater for Indigenous patients at 12 months (aOR, 1.14; 95% CI, 1.03-1.26) and 8 years (adjusted hazard ratio, 1.23; 95% CI, 1.13-1.35). The number of potential years of life lost was greater for Indigenous patients (median, 24.0; IQR, 15.8-31.8 v 12.5; IQR, 0-22.3), but, referenced to respective population life expectancies, relative survival at 8 years was similar (proportions: Indigenous, 0.78; 95% CI, 0.75-0.80; non-Indigenous, 0.77; 95% CI, 0.76-0.78). CONCLUSIONS: Adjusted long term mortality and median number of potential life years lost are higher for Indigenous than non-Indigenous patients after intensive care in hospital. These differences reflect underlying population survival patterns rather than the effects of ICU admission.
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ItemFaecal diversion system usage in an adult intensive care unit(AUSTRALASIAN MED PUBL CO LTD, 2020-06)OBJECTIVE: To determine the frequency, indications and complications associated with the use of faecal diversion systems (rectal tubes) in critically ill patients. DESIGN: A single centre observational study over 15 months. SETTING: Intensive care unit (ICU). PARTICIPANTS: Patients admitted during this period. MAIN OUTCOME MEASURES: Frequency of rectal tubes utilisation in ICU, as well as associated adverse events, with major events defined as lower gastrointestinal bleeding associated with defined blood transfusion of two or more units of red cells or endoscopy or surgical intervention. RESULTS: Of 3418 admission episodes, there were 111 episodes of rectal tubes inserted in 99 patients. Rectal tubes remained indwelling for a median of 5 days (range, 1-23) for a total of 641 patient-days. The most frequent indication for insertion was excessive bowel motions. A major adverse event was observed in three patients (3%; 0.5 events per 100 device days). Two patients underwent laparotomy and one patient sigmoidoscopy. These patients received between two and 23 units of packed red blood cells. Patients who had a rectal tube inserted had a substantially greater duration of ICU admission (mean, 14 days [SD, 14] v 2.8 days [SD, 3.7]) and hospital mortality (15% v 7.7%; risk ratio, 2.0; 95% CI, 1.2-3.4) as well as an overall higher Australian and New Zealand Risk of Death (ANZROD) score (mean, 27 [SD, 22] v 12.6 [SD, 20]). CONCLUSION: Rectal tubes appear to be frequently inserted and can lead to major adverse events in critically ill patients.
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ItemEffects of Routine Position Changes and Tracheal Suctioning on Intracranial Pressure in Traumatic Brain Injury Patients(Mary Ann Liebert, 2020-10-07)Patient position change and tracheal suctioning are routine interventions in mechanically ventilated traumatic brain injury (TBI) patients. We sought to better understand the impact of these interventions on intracranial pressure (ICP) and cerebral hemodynamics. We conducted a prospective study in TBI patients requiring ICP monitoring. The timing of position changes and suctioning episodes were recorded with concurrent blood pressure and ICP measurements. We collected data on 460 patient position changes and 204 suctioning episodes over 2404 h in 18 ventilated patients (mean age 34 [13] years, median Glasgow Coma Score 4 [3–7]). We recorded 24 (20–31) positioning and 11 (6–18) suctioning episodes per patient, with 54% and 39% of position changes associated with ICP ≥22 mm Hg and cerebral perfusion pressure (CPP) <60 mm Hg, respectively, and 22% and 27% of suctioning episodes associated with an ICP ≥22 mm Hg and CPP <60 mm Hg. The median change in ICP was 11 (6–16) mm Hg after position changes and 3 (1–9) mm Hg after suctioning. Reduction in CPP to <60 mm Hg lasted ≥10 min in 17% of positioning and 11% of suctioning episodes. The baseline ICP and its amplitude were both predictive of a rise in ICP ≥22 mm Hg after positioning and suctioning episodes, whereas cerebral autoregulation was not. Baseline CPP was predictive of a decrease in CPP <60 mm Hg after both interventions. Increases in ICP and reductions in CPP are common following patient positioning and tracheal suctioning episodes. Frequently, these changes are substantial and sustained.
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ItemEffect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock The VITAMINS Randomized Clinical Trial(AMER MEDICAL ASSOC, 2020-02-04)IMPORTANCE: It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock. OBJECTIVE: To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019. INTERVENTIONS: Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. MAIN OUTCOMES AND MEASURES: The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality. RESULTS: Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported. CONCLUSIONS AND RELEVANCE: In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03333278.
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ItemConservative Oxygen Therapy during Mechanical Ventilation in the ICU(MASSACHUSETTS MEDICAL SOC, 2020-03-12)BACKGROUND: Patients who are undergoing mechanical ventilation in the intensive care unit (ICU) often receive a high fraction of inspired oxygen (Fio2) and have a high arterial oxygen tension. The conservative use of oxygen may reduce oxygen exposure, diminish lung and systemic oxidative injury, and thereby increase the number of ventilator-free days (days alive and free from mechanical ventilation). METHODS: We randomly assigned 1000 adult patients who were anticipated to require mechanical ventilation beyond the day after recruitment in the ICU to receive conservative or usual oxygen therapy. In the two groups, the default lower limit for oxygen saturation as measured by pulse oximetry (Spo2) was 90%. In the conservative-oxygen group, the upper limit of the Spo2 alarm was set to sound when the level reached 97%, and the Fio2 was decreased to 0.21 if the Spo2 was above the acceptable lower limit. In the usual-oxygen group, there were no specific measures limiting the Fio2 or the Spo2. The primary outcome was the number of ventilator-free days from randomization until day 28. RESULTS: The number of ventilator-free days did not differ significantly between the conservative-oxygen group and the usual-oxygen group, with a median duration of 21.3 days (interquartile range, 0 to 26.3) and 22.1 days (interquartile range, 0 to 26.2), respectively, for an absolute difference of -0.3 days (95% confidence interval [CI], -2.1 to 1.6; P = 0.80). The conservative-oxygen group spent more time in the ICU with an Fio2 of 0.21 than the usual-oxygen group, with a median duration of 29 hours (interquartile range, 5 to 78) and 1 hour (interquartile range, 0 to 17), respectively (absolute difference, 28 hours; 95% CI, 22 to 34); the conservative-oxygen group spent less time with an Spo2 exceeding 96%, with a duration of 27 hours (interquartile range, 11 to 63.5) and 49 hours (interquartile range, 22 to 112), respectively (absolute difference, 22 hours; 95% CI, 14 to 30). At 180 days, mortality was 35.7% in the conservative-oxygen group and 34.5% in the usual-oxygen group, for an unadjusted odds ratio of 1.05 (95% CI, 0.81 to 1.37). CONCLUSIONS: In adults undergoing mechanical ventilation in the ICU, the use of conservative oxygen therapy, as compared with usual oxygen therapy, did not significantly affect the number of ventilator-free days. (Funded by the Health Research Council of New Zealand; ICU-ROX Australian and New Zealand Clinical Trials Registry number, ACTRN12615000957594.).
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ItemAutonomic function, postprandial hypotension and falls in older adults at one year after critical illness(College of Intensive Care Medicine of Australia and New Zealand, 2020-03)OBJECTIVE: Postprandial hypotension occurs frequently in older survivors of critical illness at 3 months after discharge. We aimed to determine whether postprandial hypotension and its predictors - gastric dysmotility and cardiovascular autonomic dysfunction - persist or resolve as older survivors of critical illness recover, and whether postprandial hypotension after intensive care unit (ICU) discharge is associated with adverse outcomes at 12 months. DESIGN: Prospective observational study. SETTING: Tertiary medical-surgical ICU. PARTICIPANTS: Older adults (aged ≥ 65 years) who had been studied 3 months after ICU discharge and who returned for a follow-up study at 12 months after discharge. MAIN OUTCOME MEASURES: On both occasions after fasting overnight, participants consumed a 300 mL drink containing 75 g glucose, radiolabelled with 20 MBq 99mTcphytate. Blood pressure, heart rate, blood glucose concentration and gastric emptying rate were measured concurrently before and after ingestion of the drink. Falls, quality of life, hospitalisation and mortality rates were also quantified. RESULTS: Out of 35 older adults studied at 3 months, 22 returned for the follow-up study at 12 months. Postprandial hypotension was evident in 29% of participants (95% CI, 14-44%) at 3 months and 10% of participants (95% CI, 1-30%) at 12 months. Postprandial hypotension at 3 months was associated with a more than threefold increase in the risk of falls in the year after ICU discharge (relative risk, 3.7 [95% CI, 1.6-8.8]; P = 0.003). At 12 months, gastric emptying was normal (mean time taken for 50% of gastric contents to empty, 101.6 [SD, 33.3] min) and cardiovascular autonomic dysfunction prevalence was low (9% [95% CI, 1-29%]). CONCLUSIONS: In older adults who were evaluated 3 and 12 months after ICU discharge, postprandial hypotension at 3 months was associated with an increased risk of subsequent falls, but the prevalence of postprandial hypotension decreased with time.