Observed differences in nutrition management at two time points spanning a decade in critically ill trauma patients with and without head injury.

BACKGROUND: Nutritional needs of trauma patients admitted to the intensive care unit may differ from general critically ill patients, but most current evidence is based on large clinical trials recruiting mixed populations. OBJECTIVE: The aim of the study was to investigate nutrition practices at two time points that span a decade in trauma patients with and without head injury. METHODS: This observational study recruited adult trauma patients receiving mechanical ventilation and artificial nutrition from a single-centre intensive care unit between February 2005 to December 2006 (cohort 1), and December 2018 to September 2020 (cohort 2). Patients were categorised into head injury and non-head injury subgroups. Data regarding energy and protein prescription and delivery were collected. Data are presented as median [interquartile range]. Wilcoxon rank-sum test assessed the differences between cohorts and subgroups, with a P value ≤ 0.05. The protocol was registered with the Australian and New Zealand Clinical Trials Registry (Trial ID: ACTRN12618001816246). RESULTS: Cohort 1 included 109 patients, and 112 patients were included in cohort 2 (age: 46 ± 19 vs 50 ± 19 y; 80 vs 79% M). Overall, nutrition practice did not differ between head-injured and non-head-injured subgroups (all P > 0.05). Energy prescription and delivery decreased from time point one to time point two, regardless of subgroup (Prescription: 9824 [8820-10 581] vs 8318 [7694-9071] kJ; Delivery: 6138 [5130-7188] vs 4715 [3059-5996] kJ; all P < 0.05). Protein prescription did not change from time point one to time point two. Although protein delivery remained constant from time point one to time point two in the head injury group, protein delivery reduced in the non-head injury subgroup (70 [56-82] vs 45 [26-64] g/d, P < 0.05). CONCLUSION: In this single-centre study, energy prescription and delivery in critically ill trauma patients reduced from time point one to time point two. Protein prescription did not change, but protein delivery reduced from time point one to time point two in non-head injury patients. Reasons for these differing trajectories require exploration. STUDY REGISTRATION: Trial registered at www.anzctr.org.au. TRIAL ID: ACTRN12618001816246.

Muscle Protein Synthesis after Protein Administration in Critical Illness.

Rationale: Dietary protein may attenuate the muscle atrophy experienced by patients in the ICU, yet protein handling is poorly understood. Objectives: To quantify protein digestion and amino acid absorption and fasting and postprandial myofibrillar protein synthesis during critical illness. Methods: Fifteen mechanically ventilated adults (12 male; aged 50 ± 17 yr; body mass index, 27 ± 5 kg⋅m-2) and 10 healthy control subjects (6 male; 54 ± 23 yr; body mass index, 27 ± 4 kg⋅m-2) received a primed intravenous L-[ring-2H5]-phenylalanine, L-[3,5-2H2]-tyrosine, and L-[1-13C]-leucine infusion over 9.5 hours and a duodenal bolus of intrinsically labeled (L-[1-13C]-phenylalanine and L-[1-13C]-leucine) intact milk protein (20 g protein) over 60 minutes. Arterial blood and muscle samples were taken at baseline (fasting) and for 6 hours following duodenal protein administration. Data are mean ± SD, analyzed with two-way repeated measures ANOVA and independent samples t test. Measurements and Main Results: Fasting myofibrillar protein synthesis rates did not differ between ICU patients and healthy control subjects (0.023 ± 0.013% h-1 vs. 0.034 ± 0.016% h-1; P = 0.077). After protein administration, plasma amino acid availability did not differ between groups (ICU patients, 54.2 ± 9.1%, vs. healthy control subjects, 61.8 ± 13.1%; P = 0.12), and myofibrillar protein synthesis rates increased in both groups (0.028 ± 0.010% h-1 vs. 0.043 ± 0.018% h-1; main time effect P = 0.046; P-interaction = 0.584) with lower rates in ICU patients than in healthy control subjects (main group effect P = 0.001). Incorporation of protein-derived phenylalanine into myofibrillar protein was ∼60% lower in ICU patients (0.007 ± 0.007 mol percent excess vs. 0.017 ± 0.009 mol percent excess; P = 0.007). Conclusions: The capacity for critically ill patients to use ingested protein for muscle protein synthesis is markedly blunted despite relatively normal protein digestion and amino acid absorption.

Nocturnal Hypoglycemia in Patients With Diabetes Discharged From ICUs: A Prospective Two-Center Cohort Study.

OBJECTIVES: There is very limited information about glycemic control after discharge from the ICU. The aims of this study were to evaluate the prevalence of hypoglycemia in ICU survivors with type-2 diabetes and determine whether hypoglycemia is associated with cardiac arrhythmias. DESIGN: Prospective, observational, two-center study. Participants underwent up to 5 days of simultaneous blinded continuous interstitial glucose monitoring and ambulatory 12-lead electrocardiogram monitoring immediately after ICU discharge during ward-based care. Frequency of arrhythmias, heart rate variability, and cardiac repolarization markers were compared between hypoglycemia (interstitial glucose ≤ 3.5 mmol/L) and euglycemia (5-10 mmol/L) matched for time of day. SETTING: Mixed medical-surgical ICUs in two geographically distinct university-affiliated hospitals. PATIENTS: Patients with type-2 diabetes who were discharged from ICU after greater than or equal to 24 hours with greater than or equal to one organ failure and were prescribed subcutaneous insulin were eligible. MEASUREMENTS AND MAIN RESULTS: Thirty-one participants (mean ± sd, age 65 ± 13 yr, glycated hemoglobin 64 ± 22 mmol/mol) were monitored for 101 ± 32 hours post-ICU (total 3,117 hr). Hypoglycemia occurred in 12 participants (39%; 95% CI, 22-56%) and was predominantly nocturnal (40/51 hr) and asymptomatic (25/29 episodes). Participants experiencing hypoglycemia had 2.4 ± 0.7 discrete episodes lasting 45 minutes (interquartile range, 25-140 min). Glucose nadir was less than or equal to 2.2 mmol/L in 34% of episodes. The longest episode of nocturnal hypoglycemia was 585 minutes with glucose nadir less than 2.2 mmol/L. Simultaneous electrocardiogram and continuous interstitial glucose monitoring recordings were obtained during 44 hours of hypoglycemia and 991 hours of euglycemia. Hypoglycemia was associated with greater risk of bradycardia but did not affect atrial or ventricular ectopics, heart rate variability, or cardiac repolarization. CONCLUSIONS: In ICU survivors with insulin-treated type-2 diabetes, hypoglycemia occurs frequently and is predominantly nocturnal, asymptomatic, and prolonged.

Incident Diabetes in Survivors of Critical Illness and Mechanisms Underlying Persistent Glucose Intolerance: A Prospective Cohort Study.

OBJECTIVES: Stress hyperglycemia occurs in critically ill patients and may be a risk factor for subsequent diabetes. The aims of this study were to determine incident diabetes and prevalent prediabetes in survivors of critical illness experiencing stress hyperglycemia and to explore underlying mechanisms. DESIGN: This was a prospective, single center, cohort study. At admission to ICU, hemoglobin A1c was measured in eligible patients. Participants returned at 3 and 12 months after ICU admission and underwent hemoglobin A1c testing and an oral glucose tolerance test. Blood was also collected for hormone concentrations, whereas gastric emptying was measured via an isotope breath test. ß-cell function was modeled using standard techniques. SETTING: Tertiary-referral, mixed medical-surgical ICU. PATIENTS: Consecutively admitted patients who developed stress hyperglycemia and survived to hospital discharge were eligible. MEASUREMENTS AND MAIN RESULTS: Consent was obtained from 40 patients (mean age, 58 yr [SD, 10], hemoglobin A1c 36.8 mmol/mol [4.9 mmol/mol]) with 35 attending the 3-month and 26 the 12-month visits. At 3 months, 13 (37%) had diabetes and 15 (43%) had prediabetes. At 12 months, seven (27%) participants had diabetes, whereas 11 (42%) had prediabetes. Mean hemoglobin A1c increased from baseline during the study: +0.7 mmol/mol (-1.2 to 2.5 mmol/mol) at 3 months and +3.3 mmol/mol (0.98-5.59 mmol/mol) at 12 months (p = 0.02). Gastric emptying was not significantly different across groups at either 3 or 12 months. CONCLUSIONS: Diabetes and prediabetes occur frequently in survivors of ICU experiencing stress hyperglycemia. Based on the occurrence rate observed in this cohort, structured screening and intervention programs appear warranted.

Are point-of-care measurements of glycated haemoglobin accurate in the critically ill?

INTRODUCTION: Critically ill patients with type 2 diabetes mellitus (T2DM) and chronic hyperglycaemia may benefit from a more liberal approach to glucose control than patients with previously normal glucose tolerance. It may therefore be useful to rapidly determine HbA1c concentrations. Point-of-care (POC) analysers offer rapid results but may be less accurate than laboratory analysis. AIM(S): The aim of this study was to determine agreement between POC and laboratory HbA1c testing in critically ill patients with T2DM. METHODS: Critically ill patients with T2DM had concurrent laboratory, capillary-, and arterial-POC HbA1c measurements performed. Data are presented as mean (standard deviation) or median [interquartile range]. Measurement agreement was assessed by Lin's concordance correlation coefficient, Bland-Altman 95% limits of agreement, and classification by Cohen's kappa statistic. RESULTS: HbA1c analysis was performed for 26 patients. The time to obtain a result from POC analysis took a median of 9 [7, 10] minutes. Laboratory analysis took a median of 328 [257, 522] minutes from the time of test request to the time of report. Lin's correlation coefficient showed almost perfect agreement (0.99%) for arterial- vs capillary-POC and both POC methods vs arterial laboratory analysis. Bland-Altman plots showed a mean difference of 2.0 (3.7) with 95% limits of agreement of -5.4 to 9.3 for capillary vs laboratory, 1.6 (3.4) and -5.1 to 8.4 for arterial vs laboratory, and -0.137 (2.6) and -5.2 to 4.9 for capillary vs arterial. Patient classification as having inadequately controlled diabetes (>53 mmol/mol) showed 100% agreement across all tests. CONCLUSIONS: HbA1c values can be accurately and rapidly obtained using POC testing in the critically ill.

Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies.

Recently our group and others have identified DDX41 mutations both as germ line and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML), suggesting that DDX41 acts as a tumor suppressor. To determine whether novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our group screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine (3%) with DDX41 mutations. As previously observed, MDS and AML were the most common malignancies, often of the erythroblastic subtype, and 1 family displayed early-onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germ line DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.

Assessment of physiological barriers to nutrition following critical illness.

BACKGROUND & AIMS: Nutrition may be important for recovery from critical illness. Gastrointestinal dysfunction is a key barrier to nutrition delivery in the Intensive Care Unit (ICU) and metabolic rate is elevated exacerbating nutritional deficits. Whether these factors persist following ICU discharge is unknown. We assessed whether delayed gastric emptying (GE) and impaired glucose absorption persist post-ICU discharge. METHODS: A prospective observational study was conducted in mechanically ventilated adults at 3 time-points: in ICU (V1); on the post-ICU ward (V2); and 3-months after ICU discharge (V3); and compared to age-matched healthy volunteers. On each visit, all participants received a test-meal containing 100 ml of 1 kcal/ml liquid nutrient, labelled with 0.1 g 13C-octanoic acid and 3 g 3-O-Methyl-glucose (3-OMG), and breath and blood samples were collected over 240min to quantify GE (gastric emptying coefficient (GEC)), and glucose absorption (3-OMG concentration; area under the curve (AUC)). Data are mean ± standard error of the mean (SEM) and differences shown with 95% confidence intervals (95%CI). RESULTS: Twenty-six critically ill patients completed V1 (M:F 20:6; 62.0 ± 2.9 y; BMI 29.8 ± 1.2 kg/m2; APACHE II 19.7 ± 1.9), 15 completed V2 and eight completed V3; and were compared to 10 healthy volunteers (M:F 6:4; 60.5 ± 7.5 y; BMI 26.0 ± 1.0 kg/m2). GE was significantly slower on V1 compared to health (GEC difference: -0.96 (95%CI -1.61, -0.31); and compared to V2 (-0.73 (-1.16, -0.31) and V3 (-1.03 (-1.47, -0.59). GE at V2 and V3 were not different to that in health (V2: -0.23 (-0.61, 0.14); V3: 0.10 (-0.27, 0.46)). GEC: V1: 2.64 ± 0.19; V2: 3.37 ± 0.12; V3: 3.67 ± 0.10; health: 3.60 ± 0.13. Glucose absorption (3-OMG AUC0-240) was impaired on V1 compared to V2 (-37.9 (-64.2, -11.6)), and faster on V3 than in health (21.8 (0.14, 43.4) but absorption at V2 and V3 did not differ from health. Intestinal glucose absorption: V1: 63.8 ± 10.4; V2: 101.7 ± 7.0; V3: 111.9 ± 9.7; health: 90.7 ± 3.8. CONCLUSION: This study suggests that delayed GE and impaired intestinal glucose absorption recovers rapidly post-ICU. This requires further confirmation in a larger population. The REINSTATE trial was prospectively registered at www.anzctr.org.au. TRIAL ID: ACTRN12618000370202.

Muscle size, strength, and physical function in response to augmented calorie delivery: A TARGET sub-study.

PURPOSE: Augmented calories may attenuate muscle loss experienced in critical illness. This exploratory sub-study assessed the effect of augmented calorie delivery on muscle mass, strength, and function. MATERIALS AND METHODS: Patients in The Augmented versus Routine approach to Giving Energy Trial (TARGET) randomised to 1.5 kcal/ml or 1.0 kcal/ml enteral formulae at a single-centre were included. Ultrasound-derived muscle layer thickness (MLT) at quadriceps, forearm and mid-upper arm, and handgrip strength, were measured weekly from baseline to hospital discharge, and 3- and 6-months. Physical function was assessed at 3- and 6-months using the 'get up and go' and 6-min walk tests. Data are mean ± SD. RESULTS: Eighty patients were recruited (1.5 kcal: n = 38, 58 ± 14y, 60%M, APACHE II 20 ± 7; 1.0 kcal: n = 42, 54 ± 18y, 66%M, APACHE II 22 ± 10). The 1.5 kcal/ml group received more calories with no difference in quadriceps MLT at any timepoint including ICU discharge (primary outcome) (2.90 ± 1.27 vs 2.39 ± 1.06 cm; P = 0.141). Relationships were similar for all MLT measures, handgrip strength, and 6-min walk test. Patients in the 1.5 kcal/ml group had improved 'get up and go' test at 3-months (6.66 ± 1.33 vs. 9.11 ± 2.94 s; P = 0.014). CONCLUSION: Augmented calorie delivery may not attenuate muscle loss or recovery of strength or function 6-months post-ICU, but this requires exploration in a larger trial.

Effects of Standard vs Energy-Dense Formulae on Gastric Retention, Energy Delivery, and Glycemia in Critically Ill Patients.

BACKGROUND: Energy-dense formulae are often provided to critically ill patients with enteral feed intolerance with the aim of increasing energy delivery, yet the effect on gastric emptying is unknown. The rate of gastric emptying of a standard compared with an energy-dense formula was quantified in critically ill patients. METHODS: Mechanically ventilated adults were randomized to receive radiolabeled intragastric infusions of 200 mL standard (1 kcal/mL) or 100 mL energy-dense (2 kcal/mL) enteral formulae on consecutive days in this noninferiority, blinded, crossover trial. The primary outcome was scintigraphic measurement of gastric retention (percentage at 120 minutes). Other measures included area under the curve (AUC) for gastric retention and intestinal energy delivery (calculated from gastric retention of formulae over time), blood glucose (peak and AUC), and intestinal glucose absorption (using 3-O-methyl-D-gluco-pyranose [3-OMG] concentrations). Comparisons were undertaken using paired mixed-effects models. Data presented are mean ± SE. RESULTS: Eighteen patients were studied (male/female, 14:4; age, 55.2 ± 5.3 years). Gastric retention at 120 minutes was greater with the energy-dense formula (standard, 17.0 ± 5.9 vs energy-dense, 32.5 ± 7.1; difference, 12.7% [90% confidence interval, 0.8%-30.1%]). Energy delivery (AUC120 , 13,038 ± 1119 vs 9763 ± 1346 kcal/120 minutes; P = 0.057), glucose control (peak glucose, 10.1 ± 0.3 vs 9.7 ± 0.3 mmol/L, P = 0.362; and glucose AUC120 8.7 ± 0.3 vs 8.5 ± 0.3 mmol/L.120 minutes, P = 0.661), and absorption (3-OMG AUC120 , 38.5 ± 4.0 vs 35.7 ± 4.0 mmol/L.120 minutes; P = .508) were not improved with the energy-dense formula. CONCLUSION: In critical illness, administration of an energy-dense formula does not reduce gastric retention, increase energy delivery to the small intestine, or improve glucose absorption or glucose control; instead, there is a signal for delayed gastric emptying.

Outcome Measures in Critical Care Nutrition Interventional Trials: A Systematic Review.

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.

Autonomic function, postprandial hypotension and falls in older adults at one year after critical illness.

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.

Observed appetite and nutrient intake three months after ICU discharge.

BACKGROUND & AIMS: Oral intake is diminished immediately after ICU discharge, yet factors affecting nutritional intake after hospital discharge have not been evaluated. The aim of this study was to evaluate dietary intake and factors which may influence intake - appetite and gastric emptying - 3-months after ICU discharge. METHODS: Inception cohort study with ICU survivors compared to healthy subjects. Following an overnight fast, all participants consumed a standardized carbohydrate drink, containing 13C-octanoic acid, to measure gastric emptying. Dietary intake was assessed by recall of the preceding day and a standard weighed buffet meal 4-h post-drink. Appetite was assessed pre-drink (fasting) and pre- and post-buffet using visual analogue scales. RESULTS: Fifty-one ICU survivors (82% male; 70 ± 9 y; BMI 28 ± 6 kg/m2) and 25 healthy subjects (60% male; 67 ± 12 y; BMI 27 ± 4 kg/m2) were evaluated. From the 24-h recall ICU survivors consumed less calories (ICU 1876 (708) vs. healthy subjects 2291 (834) kcal; p = 0.025) with no difference in macronutrient intake, however reported a lower preference for fat (p < 0.001). Calorie and macronutrient intake from the weighed buffet was similar between groups: calories (ICU: 658 (301) vs. healthy subjects: 736 (325) kcal; p = 0.149); protein (ICU: 37 (19) vs. healthy subjects: 40 (17) g; p = 0.275); fat (ICU: 23 (12) vs healthy subjects: 26 (13) g; p = 0.261); and carbohydrates (ICU: 69 (35) vs. healthy subjects: 79 (42) g; p = 0.141). ICU survivors reported feeling less full regardless of time-point (p = 0.041). There was no difference in the rate of gastric emptying between the two groups (p = 0.216). CONCLUSIONS: ICU survivors reported less preference for fat and less calorie consumption than healthy subjects. However, intake of calories and macronutrients at a weighed meal was similar in the two groups, as was the rate of gastric emptying. ICU survivors reported being less full after the test meal, suggesting factors other than appetite may influence intake.

Postprandial hypotension in older survivors of critical illness.

PURPOSE: In older people postprandial hypotension occurs frequently; and is an independent risk factor for falls, cardiovascular events, stroke and death. The primary aim of this pilot study was to estimate the frequency of postprandial hypotension and evaluate the mechanisms underlying this condition in older survivors of an Intensive Care Unit (ICU). MATERIALS AND METHODS: Thirty-five older (>65 years) survivors were studied 3 months after discharge. After an overnight fast, participants consumed a 300 mL drink containing 75 g glucose, labelled with 20 MBq 99mTc-calcium phytate. Patients had concurrent measurements of blood pressure, heart rate, blood glucose and gastric emptying following drink ingestion. Proportion of participants is presented as percent (95% CI) and continuous variables as mean (SD). RESULTS: Postprandial hypotension was evident in 10 (29%; 95% CI 14-44), orthostatic hypotension in 2 (6%; 95% CI 0-13) and cardiovascular autonomic dysfunction in 2 (6%; 95% CI 0-13) participants. The maximal postprandial nadir for systolic blood pressure and diastolic blood pressures were -29 (14) mmHg and -18 (7) mmHg. CONCLUSIONS: In this cohort of older survivors of ICU postprandial hypotension occurred frequently . This suggests that postprandial hypotension is an unrecognised issue in older ICU survivors.