Beta-hydroxy-beta-methylbutyrate supplementation and functional outcomes in multitrauma patients: A pilot randomized controlled trial.

BACKGROUND: Beta-hydroxy-beta-methylbutyrate (HMB) is a nutrition supplement that may attenuate muscle wasting from critical illness. This trial aimed to determine feasibility of administering a blinded nutrition supplement in the intensive care unit (ICU) and continuing it after ICU discharge. METHODS: Single-center, parallel-group, blinded, placebo-controlled, randomized feasibility trial. After traumatic injury necessitating admission to ICU, participants were randomized to receive an enteral study supplement of 3 g of HMB (intervention) or placebo daily for 28 days or until hospital discharge. Primary outcome was feasibility of administering the study supplement, quantified as protocol adherence. Secondary outcomes included change in quadriceps muscle thickness, measured weekly until day 28 or hospital discharge by using ultrasound and analyzed by using a linear mixed model. RESULTS: Fifty randomized participants (intervention, n = 26; placebo, n = 24) showed comparable baseline characteristics. Participants received 862 (84.3%) of the 1022 prescribed supplements during hospitalization with 543 (62.8%) delivered via an enteral feeding tube. The median (IQR) number of study supplements successfully administered per participant was 19.5 (13.0-24.0) in the intervention group and 16.5 (8.5-23.5) in the placebo group. Marked loss of quadriceps muscle thickness occurred in both groups, with the point estimate favoring attenuated muscle loss with the intervention, albeit with wide CIs (mean intervention difference after 28 days, 0.26 cm [95% CI, -0.13 to 0.64]). CONCLUSION: A blinded, placebo-controlled, randomized clinical trial of daily enteral HMB supplementation for up to 28 days in hospital is feasible. Any effect of HMB supplementation to attenuate muscle wasting after traumatic injury remains uncertain.

Relationship of blood thiamine pyrophosphate to plasma phosphate and the response to enteral nutrition plus co-administration of intravenous thiamine during critical illness.

BACKGROUND: Hypovitamin B1 occurs frequently during critical illness but is challenging to predict or rapidly diagnose. The aim of this study was to evaluate whether plasma phosphate concentrations predict hypovitamin B1, enteral nutrition prevents hypovitamin B1 and intravenous thiamine supplementation achieves supraphysiological concentrations in critically ill patients. METHODS: Thirty-two enterally fed critically ill patients, with a plasma phosphate concentration ≤0.65 mmol/L, formed a nested cohort within a larger randomised clinical trial. Patients were assigned to receive intravenous thiamine (200 mg) twice daily, and controls were not administered intravenous thiamine. Thiamine pyrophosphate concentrations were measured at four time points (pre- and post-infusion and 4- and 6-h post-infusion) on days 1 and 3 in those allocated to thiamine and once in the control group. RESULTS: Baseline thiamine pyrophosphate concentrations were similar (intervention 88 [67, 93] vs. control 89 [62, 110] nmol/L, p = 0.49). Eight (25%) patients had hypovitamin B1 (intervention 3 vs. control 5), with two patients in the control group remaining insufficient at day 3. There was no association between baseline phosphate and thiamine pyrophosphate concentrations. Intravenous thiamine achieved supraphysiological concentrations 6 h post first infusion, with concentrations increasing to day 3. In the control group, thiamine pyrophosphate concentrations were not statistically different between baseline and day 3 (mean change: 8.6 [-6.0, 23.1] nmol/L, p = 0.25). CONCLUSIONS: Phosphate concentrations did not predict hypovitamin B1, which was observed in 25% of the participants. Enteral nutrition alone prevented the development of new hypovitamin B1. Administration of a single 200-mg dose of intravenous thiamine achieved supraphysiological concentrations of thiamine pyrophosphate, with repeated dosing sustaining this effect.

Methodological Rigor and Transparency in Clinical Practice Guidelines for Nutrition Care in Critically Ill Adults: A Systematic Review Using the AGREE II and AGREE-REX Tools.

Background: To evaluate the methodological quality of (1) clinical practice guidelines (CPGs) that inform nutrition care in critically ill adults using the AGREE II tool and (2) CPG recommendations for determining energy expenditure using the AGREE-REX tool. Methods: CPGs by a professional society or academic group, intended to guide nutrition care in critically ill adults, that used a systematic literature search and rated the evidence were included. Four databases and grey literature were searched from January 2011 to 19 January 2022. Five investigators assessed the methodological quality of CPGs and recommendations specific to energy expenditure determination. Scaled domain scores were calculated for AGREE II and a scaled total score for AGREE-REX. Data are presented as medians (interquartile range). Results: Eleven CPGs were included. Highest scoring domains for AGREE II were clarity of presentation (82% [76-87%]) and scope and purpose (78% [66-83%]). Lowest scoring domains were applicability (37% [32-42%]) and stakeholder involvement (46% [33-51%]). Eight (73%) CPGs provided recommendations relating to energy expenditure determination; scores were low overall (37% [36-40%]) and across individual domains. Conclusions: Nutrition CPGs for critically ill patients are developed using systematic methods but lack engagement with key stakeholders and guidance to support application. The quality of energy expenditure determination recommendations is low.

Protocol summary and statistical analysis plan for Intensive Nutrition Therapy comparEd to usual care iN criTically ill adults (INTENT): a phase II randomised controlled trial.

INTRODUCTION: It is plausible that a longer duration of nutrition intervention may have a greater impact on clinical and patient-centred outcomes. The Intensive Nutrition care Therapy comparEd to usual care iN criTically ill adults (INTENT) trial will determine if a whole hospital nutrition intervention is feasible and will deliver more total energy compared with usual care in critically ill patients with at least one organ system failure. METHODS AND ANALYSIS: This study is a prospective, multicentre, unblinded, parallel-group, phase II randomised controlled trial (RCT) conducted in 23 hospitals in Australia and New Zealand. Mechanically ventilated critically ill adult patients with at least one organ failure who have been in intensive care unit (ICU) for 72-120 hours and meet all of the inclusion and none of the exclusion criteria will be randomised to receive either intensive or usual nutrition care. INTENT started recruitment in October 2018 and a sample size of 240 participants is anticipated to be recruited in 2022. The study period is from randomisation to hospital discharge or study day 28, whichever occurs first, and the primary outcome is daily energy delivery from nutrition therapy. Secondary outcomes include daily energy and protein delivery during ICU and in the post-ICU period, duration of ventilation, ventilator-free days, total bloodstream infection rate and length of hospital stay. All other outcomes are considered tertiary and results will be analysed on an intention-to-treat basis. ETHICS AND DISSEMINATION: Ethics approval has been received in Australia (Alfred Hospital Ethics Committee (HREC/18/Alfred/101) and Human Research Ethics Committee of the Northern Territory Department of Health (2019-3372)) and New Zealand (Northern A Health and Disability Ethics Committee (18/NTA/222). Results will be disseminated in an international peer-reviewed journal(s), at scientific meetings and via social media. TRIAL REGISTRATION NUMBER: NCT03292237.

Quantifying Response to Nutrition Therapy During Critical Illness: Implications for Clinical Practice and Research? A Narrative Review.

Critical illness causes substantial muscle loss that adversely impacts recovery and health-related quality of life. Treatments are therefore needed that reduce mortality and/or improve the quality of survivorship. The purpose of this Review is to describe both patient-centered and surrogate outcomes that quantify responses to nutrition therapy in critically ill patients. The use of these outcomes in randomized clinical trials will be described and the strengths and limitations of these outcomes detailed. Outcomes used to quantify the response of nutrition therapy must have a plausible mechanistic relationship to nutrition therapy and either be an accepted measure for the quality of survivorship or highly likely to lead to improvements in survivorship. This Review identified that previous trials have utilized diverse outcomes. The variety of outcomes observed is probably due to a lack of consensus as to the most appropriate surrogate outcomes to quantify response to nutrition therapy during research or clinical practice. Recent studies have used, with some success, measures of muscle mass to evaluate and monitor nutrition interventions administered to critically ill patients.

Metabolic support in sepsis: corticosteroids and vitamins: the why, the when, the how.

PURPOSE OF REVIEW: Sepsis is a global health issue, and there is a need for effective, low-cost adjunct metabolic treatments. Corticosteroids have been investigated in many trials for decades, and recently the administration of vitamin C, thiamine (vitamin B1), and vitamin D have been proposed as novel therapies in patients with sepsis. RECENT FINDINGS: APROCCHSS (N = 1241) and ADRENAL (N = 3800) trial reported inconsistent results in mortality outcome; however, both demonstrated a decreased duration of shock with low-dose corticosteroids. The CITRIS-ALI trial (N = 170) examined the effects of intravenous vitamin C 200 mg/kg/day and reported no effect on organ dysfunction or biomarkers. The VITAMINS trial (N = 216) compared combination therapy of vitamin C 6 g/day, thiamine 200 mg/day, and hydrocortisone 200 mg/day with hydrocortisone alone to find that the combination did not increase vasopressor free time. A single trial (N = 88) evaluating the effect of thiamine in patients with sepsis reported a neutral result. Two randomized trials (N = 475 and N = 1360) on the supplementation of vitamin D in the critically ill patients did not identify statistically significant reduction in mortality. SUMMARY: Evidence from high-quality research is still insufficient to support the use of vitamin C, thiamine, and vitamin D as metabolic support in sepsis treatment.

Update on nutritional assessment and therapy in critical care.

PURPOSE OF REVIEW: To summarize recent data regarding nutritional assessment and interventions in the ICU. RECENT FINDINGS: Current methods to assess nutritional risk do not allow identification of ICU patients who may benefit from specific nutritional intervention. Early full energy delivery does not appear to improve outcomes at the population level. Specific nutrient composition of formula has been shown to improve glycemic outcomes in patients with hyperglycemia but patient-centered outcomes are unaffected. SUMMARY: Based on recent studies, full energy feeding early during critical illness has no measurable beneficial effect, and may even be harmful, when applied to entire populations. The mechanisms underlying this are unknown and remain proposed theories. Tools to assess nutritional risk in the ICU that identify patients who will benefit from a specific nutritional intervention are lacking. The optimal composition of feeds, and indications for specific interventions for enteral feeding intolerance remain uncertain.

Pharmacokinetic data support 6-hourly dosing of intravenous vitamin C to critically ill patients with septic shock.

OBJECTIVES: To study vitamin C pharmacokinetics in septic shock. DESIGN: Prospective pharmacokinetic study. SETTING: Two intensive care units. PARTICIPANTS: Twenty-one patients with septic shock enrolled in a randomised trial of high dose vitamin C therapy in septic shock. INTERVENTION: Patients received 1.5 g intravenous vitamin C every 6 hours. Plasma samples were obtained before and at 1, 4 and 6 hours after drug administration, and vitamin C concentrations were measured by high performance liquid chromatography. MAIN OUTCOME MEASURES: Clearance, volume of distribution, and half-life were calculated using noncompartmental analysis. Data are presented as median (interquartile range [IQR]). RESULTS: Of the 11 participants who had plasma collected before any intravenous vitamin C administration, two (18%) were deficient (concentrations < 11 µmol/L) and three (27%) had hypovitaminosis C (concentrations between 11 and 23 µmol/L), with a median concentration 28 µmol/L (IQR, 11-44 µmol/L). Volume of distribution was 23.3 L (IQR, 21.9-27.8 L), clearance 5.2 L/h (IQR, 3.3-5.4 L/h), and half-life 4.3 h (IQR, 2.6-7.5 h). For the participants who had received at least one dose of intravenous vitamin C before sampling, T0 concentration was 258 µmol/L (IQR, 162- 301 µmol/L). Pharmacokinetic parameters for subsequent doses were a median volume of distribution 39.9 L (IQR, 31.4-44.4 L), clearance 3.6 L/h (IQR, 2.6-6.5 L/h), and half-life 6.9 h (IQR, 5.7-8.5 h). CONCLUSION: Intravenous vitamin C (1.5 g every 6 hours) corrects vitamin C deficiency and hypovitaminosis C and provides an appropriate dosing schedule to achieve and maintain normal or elevated vitamin C levels in septic shock.

The hospital-based evaluation of laxative prophylaxis in ICU (HELP-ICU): A pilot cluster-crossover randomized clinical trial.

PURPOSE: Prophylactic laxative regimens may prevent constipation but may increase diarrhea and subsequent rectal tube insertion. Our aim was to compare three prophylactic laxative regimens on the rate of rectal tube insertion (primary outcome) and major constipation- or diarrhea-associated complications. MATERIAL AND METHODS: We conducted a cluster-crossover trial. Three pods in a single ICU were each randomized to one of three regimens for four months with rolling cross-over. All mechanically-ventilated and enterally-fed adult patients received either regimen: A) one coloxyl with senna BD from day one; B) two coloxyl with senna +20 ml lactulose BD commencing on day 3; or C) two coloxyl with senna tablets +20 ml lactulose BD commencing on day 6. RESULTS: We enrolled 570 patients (A = 170, B = 205, C = 195) with similar baseline features. Overall, 53 (9.3%) patients received a rectal tube, and insertion rate was not statistically different between the three regimens (A = 12.9%, B = 7.8%, C = 7.7%; p = 0.15). The proportions of patients with other major constipation- or diarrhea-associated complications were similar, as were major patient-centred outcomes. CONCLUSION: Earlier commencement of a prophylactic coloxyl-based laxative regimen (day 1 or 3) did not affect the rates of complications associated with constipation or diarrhea when compared to delayed introduction (day 6).

What Happens to Nutrition Intake in the Post-Intensive Care Unit Hospitalization Period? An Observational Cohort Study in Critically Ill Adults.

BACKGROUND: Little is currently known about nutrition intake and energy requirements in the post-intensive care unit (ICU) hospitalization period in critically ill patients. We aimed to describe energy and protein intake, and determine the feasibility of measuring energy expenditure during the post-ICU hospitalization period in critically ill adults. METHODS: This is a nested cohort study within a randomized controlled trial in critically ill patients. After discharge from ICU, energy and protein intake was quantified periodically and indirect calorimetry attempted. Data are presented as n (%), mean (SD), and median (interquartile range [IQR]). RESULTS: Thirty-two patients were studied in the post-ICU hospitalization period, and 12 had indirect calorimetry. Mean age and BMI was 56 (18) years and 30 (8) kg/m2 , respectively, 75% were male, and the median estimated energy and protein requirement were 2000 [1650-2550] kcal and 112 [84-129] g, respectively. Oral nutrition either alone (n = 124 days, 55%) or in combination with enteral nutrition (n = 96 days, 42%) was the predominant mode. Over 227 total days in the post-ICU hospitalization period, a median [IQR] of 1238 [869-1813] kcal and 60 [35-89.5] g of protein was received from nutrition therapy. In the 12 patients who had indirect calorimetry, the median measured daily energy requirement was 1982 [1843-2345] kcal and daily energy deficit was -95 [-1050 to 347] kcal compared with the measured energy requirement. CONCLUSIONS: Energy and protein intake in the post-ICU hospitalization period was less than estimated and measured energy requirements. Oral nutrition provided alone was the most common mode of nutrition therapy.

Nutrition Adequacy Therapeutic Enhancement in the Critically Ill: A Randomized Double-Blind, Placebo-Controlled Trial of the Motilin Receptor Agonist Camicinal (GSK962040): The NUTRIATE Study.

BACKGROUND: Camicinal is a novel, nonmacrolide, motilin receptor agonist that accelerates gastric emptying in critically ill patients with established feed intolerance. The primary question was whether the preemptive administration of camicinal increased the provision of enteral nutrition (EN) to critically ill patients with risk factors that predisposed to feed intolerance. METHODS: This was an international, multicenter, parallel-group, blinded, randomized controlled trial. Patients at risk for feed intolerance, defined as receiving moderate to high doses of vasopressors or opiates, or admitted because of multiple traumatic injuries or with brain injury, received either enteral camicinal 50 mg or placebo daily for a maximum of 7 days, along with EN administered according to a standardized feeding protocol. The primary outcome was the daily adequacy of enteral feed delivered, as assessed by percentage of goal volume (delivered/prescribed × 100) before development of intolerance. RESULTS: Eighty-four patients participated. The administration of camicinal did not result in a statistically significant clinical difference in the daily average percentage goal volume delivered (camicinal vs placebo: 77% [95% confidence interval: 71, 83] vs 68% (58, 78); mean difference 9% [-5, 23]; P = 0.21). Similarly, there were no differences in the percentage goal calories (76% [65, 88] vs 68% [60, 77]) and protein (76% [66, 86] vs 70% [61, 80]) administered, or the incidence of feed intolerance (15% vs 14%). CONCLUSION: The incidence of feed intolerance was low in both groups. In this cohort the preemptive administration of enteral camicinal did not significantly augment the provision of goal EN.

Nutrition Therapy in Australia and New Zealand Intensive Care Units: An International Comparison Study.

BACKGROUND: The Augmented Versus Routine Approach to Giving Energy Trial (TARGET) is the largest blinded enteral nutrition (EN) intervention trial evaluating energy delivery to be conducted in the critically ill. To determine the external validity of TARGET results, nutrition practices in intensive care units (ICUs) in Australia and New Zealand (ANZ) are described and compared with international practices. METHODS: This was a retrospective analysis of prospectively collected data for the International Nutrition Surveys, 2007-2013. Data are presented as mean (SD). RESULTS: A total of 17,154 patients (ANZ: n = 2776 vs international n = 14,378) from 923 ICUs (146 and 777, respectively) were included. EN was the most common route of feeding (ANZ: 85%, n = 2365 patients vs international: 84%, n = 12,034; P = .258), and EN concentration was also similar (<1.25 kcal/mL ANZ: 70%, n = 12,396 vs international: 65%, n = 56,891 administrations; P < .001). Protein delivery was substantially below the estimated prescriptions but similar between the regions (0.6 [0.4] g/kg/day vs 0.6 [0.4] g/kg/day; P = .849). Patients in ANZ received slightly more energy (1133 [572] vs 948[536] kcal/day; P < .001), possibly because more energy was prescribed (1947 [348] vs 1747 [376] kcal/day; P < .001), nutrition protocols were more commonly used (98% vs 75%; P < .001) and included recommendations for therapies such as prokinetic agents (87% vs 51%, n = 399; P < .001) and small bowel feeding (62% vs 40%; P < .001) when compared with international ICUs. CONCLUSIONS: Key elements of nutrition practice are similar in ANZ and international ICUs. These data can be used to determine the external validity and relevance of TARGET results.

Event-rate and delta inflation when evaluating mortality as a primary outcome from randomized controlled trials of nutritional interventions during critical illness: a systematic review.

BACKGROUND: There is a lack of high-quality evidence that proves that nutritional interventions during critical illness reduce mortality. OBJECTIVES: We evaluated whether power calculations for randomized controlled trials (RCTs) of nutritional interventions that used mortality as the primary outcome were realistic, and whether overestimation was systematic in the studies identified to determine whether this was due to overestimates of event rate or delta. DESIGN: A systematic review of the literature between 2005 and 2015 was performed to identify RCTs of nutritional interventions administered to critically ill adults that had mortality as the primary outcome. Predicted event rate (predicted mortality during the control), predicted mortality during intervention, predicted delta (predicted difference between mortality during the control and intervention), actual event rate (observed mortality during control), observed mortality during intervention, and actual delta (difference between observed mortality during the control and intervention) were recorded. The event-rate gap (predicted event rate minus observed event rate), the delta gap (predicted delta minus observed delta), and the predicted number needed to treat were calculated. Data are shown as median (range). RESULTS: Fourteen articles were extracted, with power calculations provided for 10 studies. The predicted event rate was 29.9% (20.0­52.4%), and the predicted delta was 7.9% (3.0­20.0%). If the study hypothesis was proven correct then, on the basis of the power calculations, the number needed to treat would have been 12.7 (5.0­33.3) patients. The actual event rate was 25.3% (6.1­50.0%), the observed mortality during the intervention was 24.4% (6.3­39.7%), and the actual delta was 0.5% (−10.2­10.3%), such that the event-rate gap was 2.6% (−3.9­23.7%) and delta gap was 7.5% (3.2­25.2%). CONCLUSIONS: Overestimates of delta occur frequently in RCTs of nutritional interventions in the critically ill that are powered to determine a mortality benefit. Delta inflation may explain the number of "negative" studies in this field of research.

Energy and protein deficits throughout hospitalization in patients admitted with a traumatic brain injury.

BACKGROUND AND AIMS: Patients with traumatic brain injury (TBI) experience considerable energy and protein deficits in the intensive care unit (ICU) and these are associated with adverse outcomes. However, nutrition delivery after ICU discharge during ward-based care, particularly from oral diet, has not been measured. This study aimed to quantify energy and protein delivery and deficits over the entire hospitalization for critically ill TBI patients. METHODS: Consecutively admitted adult patients with a moderate-severe TBI (Glasgow Coma Scale 3-12) over 12 months were eligible. Observational data on energy and protein delivered from all routes were collected until hospital discharge or day 90 and compared to dietician prescriptions. Oral intake was quantified using weighed food records on three pre-specified days each week. Data are mean (SD) unless indicated. Cumulative deficit is the mean absolute difference between intake and estimated requirements. RESULTS: Thirty-seven patients [45.3 (15.8) years; 87% male; median APACHE II 18 (IQR: 14-22)] were studied for 1512 days. Median duration of ICU and ward-based stay was 13.4 (IQR: 6.4-17.9) and 19.9 (9.6-32.0) days, respectively. Over the entire hospitalization patients had a cumulative deficit of 18,242 (16,642) kcal and 1315 (1028) g protein. Energy and protein intakes were less in ICU than the ward (1798 (800) vs 1980 (915) kcal/day, p = 0.015; 79 (47) vs 89 (41) g/day protein, p = 0.001). Energy deficits were almost two-fold greater in patients exclusively receiving nutrition orally than tube-fed (806 (616) vs 445 (567) kcal/day, p = 0.016) while protein deficits were similar (40 (5) vs 37 (6) g/day, p = 0.616). Primary reasons for interruptions to enteral and oral nutrition were fasting for surgery/procedures and patient-related reasons, respectively. CONCLUSIONS: Patients admitted to ICU with a TBI have energy and protein deficits that persist after ICU discharge, leading to considerable shortfalls over the entire hospitalization. Patients ingesting nutrition orally are at particular risk of energy deficit.

International observational study of nutritional support in mechanically ventilated patients following burn injury.

INTRODUCTION: It has been proposed that nutritional therapy in critically ill patients after major burn reduces mortality. However, the actual practice of nutrient delivery, and the effect on outcome, has not been described. STUDY OBJECTIVES: To evaluate international practices related to nutritional support and outcomes in mechanically ventilated patients with burn injury. METHODS: Data from the International Nutrition Surveys (2007-2011) for patients with a primary diagnosis of burn were extracted and analysed. RESULTS: Eighty-eight of 90 patients (aged 16-84 years) received enteral nutrition. The median time for initiation of enteral feeding was 17 h [range 0-65]. Fifty patients (57%) had interruptions to nutrient delivery, most often these interruptions were fasting for operative procedures. There were substantive energy and protein deficits [943 (654) kcal/day and 49 (41) g/day, respectively; mean (SD)]. Nineteen (21%) patients died within 60 days of admission, and the energy and protein deficits were greater in those that died compared with survivors [died vs. survived, energy: 1251 (742) vs. 861 (607) kcal/d; p=0.02; and protein 67(42) vs. 44(39) g/d; p=0.03]. Energy and protein deficits were associated with increased mortality with the greater the deficit, the stronger the association with death (odds ratio for death: energy deficit/100 kcal 1.10 (1.01, 1.19); p=0.028 and protein/10 g 1.16 (1.01, 1.33); p=0.037). Results were similar and remained significant after adjusting for severity of illness. CONCLUSIONS: Mechanically ventilated patients following burn develop substantial energy and protein deficits, with lesser deficits observed in survivors.

Randomized double-blind crossover study to determine the effects of erythromycin on small intestinal nutrient absorption and transit in the critically ill.

BACKGROUND: The gastrokinetic drug erythromycin is commonly administered to critically ill patients during intragastric feeding to augment small intestinal nutrient delivery. However, erythromycin has been reported to increase the prevalence of diarrhea, which may reflect reduced absorption and/or accelerated small intestinal transit. OBJECTIVE: The objective was to evaluate the effects of intravenous erythromycin on small intestinal nutrient absorption and transit in the critically ill. DESIGN: On consecutive days, erythromycin (200 mg in 20 mL 0.9% saline) or placebo (20 mL 0.9% saline) were infused intravenously between -20 and 0 min in a randomized, blinded, crossover fashion. Between 0 and 30 min, a liquid nutrient containing 3-O-methylglucose (3-OMG), [13C]triolein, and [(99m)Tc]sulfur colloid was administered directly into the small intestine at 2 kcal/min. Serum 3-OMG concentrations and exhaled (13)CO2 (indices of glucose and lipid absorption, respectively) were measured. Cecal arrival of the infused nutrient was determined by scintigraphy. Data are medians (ranges) and were analyzed by using Wilcoxon's signed-rank test. RESULTS: Thirty-two mechanically ventilated patients were studied. Erythromycin increased small intestinal glucose absorption [3-OMG AUC360: 105.2 (28.9-157.0) for erythromycin compared with 91.8 (51.4-147.9) mmol/L · min for placebo; P = 0.029] but tended to reduce lipid absorption [cumulative percentage dose (13)CO2 recovered: 10.4 (0-90.6) compared with 22.6 (0-100) %; P = 0.06]. A trend to slower transit was observed after erythromycin [300 (39-360) compared with 228 (33-360) min; P = 0.07]. CONCLUSIONS: Acute administration of erythromycin increases small intestinal glucose absorption in the critically ill, but there was a tendency for the drug to reduce small intestinal lipid absorption and slow transit. These observations have implications for the use of erythromycin as a gastrokinetic drug in the critically ill. This trial was registered in the Australian New Zealand Clinical Trials Registry as ACTRN 12610000615088.

Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) attenuates the glycaemic response to small intestinal nutrient infusion in stress-induced hyperglycaemia and reduces fasting glucose concentrations in critically ill patients with type-2 diabetes. The objective of this study was to evaluate the effects of acute administration of GLP-1 on the glycaemic response to small intestinal nutrient infusion in critically ill patients with pre-existing type-2 diabetes. METHODS: Eleven critically ill mechanically-ventilated patients with known type-2 diabetes received intravenous infusions of GLP-1 (1.2 pmol/kg/minute) and placebo from t = 0 to 270 minutes on separate days in randomised double-blind fashion. Between t = 30 to 270 minutes a liquid nutrient was infused intraduodenally at a rate of 1 kcal/min via a naso-enteric catheter. Blood glucose, serum insulin and C-peptide, and plasma glucagon were measured. Data are mean ± SEM. RESULTS: GLP-1 attenuated the overall glycaemic response to nutrient (blood glucose AUC30-270 min: GLP-1 2,244 ± 184 vs. placebo 2,679 ± 233 mmol/l/minute; P = 0.02). Blood glucose was maintained at < 10 mmol/l in 6/11 patients when receiving GLP-1 and 4/11 with placebo. GLP-1 increased serum insulin at 270 minutes (GLP-1: 23.4 ± 6.7 vs. placebo: 16.4 ± 5.5 mU/l; P < 0.05), but had no effect on the change in plasma glucagon. CONCLUSIONS: Exogenous GLP-1 in a dose of 1.2 pmol/kg/minute attenuates the glycaemic response to small intestinal nutrient in critically ill patients with type-2 diabetes. Given the modest magnitude of the reduction in glycaemia the effects of GLP-1 at higher doses and/or when administered in combination with insulin, warrant evaluation in this group. TRIAL REGISTRATION: ANZCTR:ACTRN12610000185066.

The effect of exogenous glucagon-like peptide-1 on the glycaemic response to small intestinal nutrient in the critically ill: a randomised double-blind placebo-controlled cross over study.

INTRODUCTION: Hyperglycaemia occurs frequently in the critically ill, affects outcome adversely, and is exacerbated by enteral feeding. Furthermore, treatment with insulin in this group is frequently complicated by hypoglycaemia. In healthy patients and those with type 2 diabetes, exogenous glucagon-like peptide-1 (GLP-1) decreases blood glucose by suppressing glucagon, stimulating insulin and slowing gastric emptying. Because the former effects are glucose-dependent, the use of GLP-1 is not associated with hypoglycaemia. The objective of this study was to establish if exogenous GLP-1 attenuates the glycaemic response to enteral nutrition in patients with critical illness induced hyperglycaemia. METHODS: Seven mechanically ventilated critically ill patients, not previously known to have diabetes, received two intravenous infusions of GLP-1 (1.2 pmol/kg/min) and placebo (4% albumin) over 270 minutes. Infusions were administered on consecutive days in a randomised, double-blind fashion. On both days a mixed nutrient liquid was infused, via a post-pyloric feeding catheter, at a rate of 1.5 kcal/min between 30 and 270 minutes. Blood glucose and plasma GLP-1, insulin and glucagon concentrations were measured. RESULTS: In all patients, exogenous GLP-1 infusion reduced the overall glycaemic response during enteral nutrient stimulation (AUC30-270 min GLP-1 (2077 +/- 144 mmol/l min) vs placebo (2568 +/- 208 mmol/l min); P = 0.02) and the peak blood glucose (GLP-1 (10.1 +/- 0.7 mmol/l) vs placebo (12.7 +/- 1.0 mmol/l); P < 0.01). The insulin/glucose ratio at 270 minutes was increased with GLP-1 infusion (GLP-1 (9.1 +/- 2.7) vs. placebo (5.8 +/- 1.8); P = 0.02) but there was no difference in absolute insulin concentrations. There was a transient, non-sustained, reduction in plasma glucagon concentrations during GLP-1 infusion (t = 30 minutes GLP-1 (90 +/- 12 pmol/ml) vs. placebo (104 +/- 10 pmol/ml); P < 0.01). CONCLUSIONS: Acute, exogenous GLP-1 infusion markedly attenuates the glycaemic response to enteral nutrition in the critically ill. These observations suggest that GLP-1 and/or its analogues have the potential to manage hyperglycaemia in the critically ill. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry number: ACTRN12609000093280.