The rate of protein digestion and amino acid absorption determines the postprandial rise in circulating amino acids and modulates postprandial muscle protein synthesis rates.
We sought to compare ...protein digestion, amino acid absorption kinetics, and the postprandial muscle protein synthetic response following ingestion of intact milk protein or an equivalent amount of free amino acids.
Twenty-four healthy, young participants (mean ± SD age: 22 ± 3 y and BMI 23 ± 2 kg/m2; sex: 12 male and 12 female participants) received a primed continuous infusion of l-ring-2H5-phenylalanine and l-ring-3,5–2H2-tyrosine, after which they ingested either 30 g intrinsically l-1–13C-phenylalanine–labeled milk protein or an equivalent amount of free amino acids labeled with l-1–13C-phenylalanine. Blood samples and muscle biopsies were obtained to assess protein digestion and amino acid absorption kinetics (secondary outcome), whole-body protein net balance (secondary outcome), and mixed muscle protein synthesis rates (primary outcome) throughout the 6-h postprandial period.
Postprandial plasma amino acid concentrations increased after ingestion of intact milk protein and free amino acids (both P < 0.001), with a greater increase following ingestion of the free amino acids than following ingestion of intact milk protein (P-time × treatment < 0.001). Exogenous phenylalanine release into plasma, assessed over the 6-h postprandial period, was greater with free amino acid ingestion (76 ± 9%) than with milk protein treatment (59 ± 10%; P < 0.001). Ingestion of free amino acids and intact milk protein increased mixed muscle protein synthesis rates (P-time < 0.001), with no differences between treatments (from 0.037 ± 0.015%/h to 0.053 ± 0.014%/h and 0.039 ± 0.016%/h to 0.051 ± 0.010%/h, respectively; P-time × treatment = 0.629).
Ingestion of a bolus of free amino acids leads to more rapid amino acid absorption and greater postprandial plasma amino acid availability than ingestion of an equivalent amount of intact milk protein. Ingestion of free amino acids may be preferred over ingestion of intact protein in conditions where protein digestion and amino acid absorption are compromised.
BACKGROUND: The liver plays a central role in amino acid metabolism. However, because of limited accessibility of the portal vein, human data on this subject are scarce. OBJECTIVE: We studied hepatic ...amino acid metabolism in noncirrhotic fasting patients undergoing liver surgery. DESIGN: Twenty patients undergoing hepatectomy for colorectal metastases in a normal liver were studied. Before resection, blood was sampled from a radial artery, portal vein, hepatic vein, and renal vein. Organ blood flow was measured by duplex ultrasound scan. RESULTS: The intestine consumed glutamine and released citrulline. Citrulline was taken up by the kidney. This was accompanied by renal arginine release, which supports the view that glutamine is a precursor for arginine synthesis through an intestinal-renal pathway. The liver was found to extract citrulline from this pathway at a rate that was dependent on intestinal citrulline release (P < 0.0001) and hepatic citrulline influx (P = 0.03). Fractional hepatic extractions of citrulline (8.4%) and arginine (11.5%) were not significantly different. Eighty-eight percent of arginine reaching the liver passed it unchanged. Splanchnic citrulline release could account for one-third of renal citrulline uptake. CONCLUSIONS: This is the first study of hepatic and interorgan amino acid metabolism in humans with a normal liver. The data indicate that glutamine is a precursor of ornithine, which can be converted to citrulline by the intestine; citrulline is transformed in the kidneys to arginine. Hepatic citrulline uptake limits the amount of gut-derived citrulline reaching the kidney. These findings may have implications for interventions aimed at increasing systemic arginine concentrations.
A recent large multicentre trial found no difference in clinical outcomes but identified a possibility of increased mortality rates in patients with acute kidney injury (AKI) receiving higher ...protein. These alarming findings highlighted the urgent need to conduct an updated systematic review and meta-analysis to inform clinical practice.
From personal files, citation searching, and three databases searched up to 29-5-2023, we included randomized controlled trials (RCTs) of adult critically ill patients that compared higher vs lower protein delivery with similar energy delivery between groups and reported clinical and/or patient-centred outcomes. We conducted random-effect meta-analyses and subsequently trial sequential analyses (TSA) to control for type-1 and type-2 errors. The main subgroup analysis investigated studies with and without combined early physical rehabilitation intervention. A subgroup analysis of AKI vs no/not known AKI was also conducted.
Twenty-three RCTs (n = 3303) with protein delivery of 1.49 ± 0.48 vs 0.92 ± 0.30 g/kg/d were included. Higher protein delivery was not associated with overall mortality (risk ratio RR: 0.99, 95% confidence interval CI 0.88-1.11; I
= 0%; 21 studies; low certainty) and other clinical outcomes. In 2 small studies, higher protein combined with early physical rehabilitation showed a trend towards improved self-reported quality-of-life physical function measurements at day-90 (standardized mean difference 0.40, 95% CI - 0.04 to 0.84; I
= 30%). In the AKI subgroup, higher protein delivery significantly increased mortality (RR 1.42, 95% CI 1.11-1.82; I
= 0%; 3 studies; confirmed by TSA with high certainty, and the number needed to harm is 7). Higher protein delivery also significantly increased serum urea (mean difference 2.31 mmol/L, 95% CI 1.64-2.97; I
= 0%; 7 studies).
Higher, compared with lower protein delivery, does not appear to affect clinical outcomes in general critically ill patients but may increase mortality rates in patients with AKI. Further investigation of the combined early physical rehabilitation intervention in non-AKI patients is warranted.
CRD42023441059.
A metabolic relation exists between glutamine and arginine, 2 amino acids with properties that enhance the recovery of seriously ill patients. It is possible that glutamine exerts part of its ...beneficial effects by enhancing the availability of arginine.
We aimed to quantify under postabsorptive conditions the metabolic pathway of plasma glutamine into arginine via the intermediate citrulline and to establish the contribution of the kidneys to the synthesis of arginine.
The study was conducted in patients during surgery. The metabolism of glutamine, citrulline, and arginine was studied by using intravenous administration of stable isotope tracers of the amino acids. Results were interpreted by using established equations. Parametric tests were used to test and correlate results. P < 0.05 was regarded as significant.
Mean (+/-SE) whole-body plasma turnover rates of glutamine, citrulline, and arginine were 240 +/- 14, 6.2 +/- 0.6, and 42 +/- 2.9 micromol x kg(-1) x h(-1), respectively (P < 0.01). Plasma turnover of citrulline derived from glutamine was shown to be 5.1 +/- 0.7 micromol x kg(-1) x h(-1), and arginine derived from citrulline was shown to be 4.9 +/- 0.9 micromol x kg(-1) x h(-1) (P < 0.01). The contribution of plasma glutamine to plasma arginine derived from plasma citrulline was calculated to be 64%. The kidneys were observed to take up >50% of circulating plasma citrulline and to release equimolar amounts of arginine into plasma.
This study shows that glutamine is an important precursor for the synthesis of arginine in humans. It also provides a firm basis for future studies exploring the effect of a treatment dose and the route of administration (enteral or parenteral) of glutamine.
Critically ill patients are subject to severe skeletal muscle wasting during intensive care unit (ICU) stay, resulting in impaired short- and long-term functional outcomes and health-related quality ...of life. Increased protein provision may improve functional outcomes in ICU patients by attenuating skeletal muscle breakdown. Supporting evidence is limited however and results in great variety in recommended protein targets.
The PRECISe trial is an investigator-initiated, bi-national, multi-center, quadruple-blinded randomized controlled trial with a parallel group design. In 935 patients, we will compare provision of isocaloric enteral nutrition with either a standard or high protein content, providing 1.3 or 2.0 g of protein/kg/day, respectively, when fed on target. All unplanned ICU admissions with initiation of invasive mechanical ventilation within 24 h of admission and an expected stay on ventilator support of at least 3 days are eligible. The study is designed to assess the effect of the intervention on functional recovery at 1, 3, and 6 months following ICU admission, including health-related quality of life, measures of muscle strength, physical function, and mental health. The primary endpoint of the trial is health-related quality of life as measured by the Euro-QoL-5D-5-level questionnaire Health Utility Score. Overall between-group differences will be assessed over the three time points using linear mixed-effects models.
The PRECISe trial will evaluate the effect of protein on functional recovery including both patient-centered and muscle-related outcomes.
ClinicalTrials.gov Identifier: NCT04633421 . Registered on November 18, 2020. First patient in (FPI) on November 19, 2020. Expected last patient last visit (LPLV) in October 2023.
Abstract
Patients with SARS-CoV-2 infection present with different lung compliance and progression of disease differs. Measures of lung mechanics in SARS-CoV-2 patients may unravel different ...pathophysiologic mechanisms during mechanical ventilation. The objective of this prospective observational study is to describe whether Electrical Impedance Tomography (EIT) guided positive end-expiratory pressure (PEEP) levels unravel changes in EIT-derived parameters over time and whether the changes differ between survivors and non-survivors. Serial EIT-measurements of alveolar overdistension, collapse, and compliance change in ventilated SARS-CoV-2 patients were analysed. In 80 out of 94 patients, we took 283 EIT measurements (93 from day 1–3 after intubation, 66 from day 4–6, and 124 from day 7 and beyond). Fifty-one patients (64%) survived the ICU. At admission mean PaO
2
/FiO
2
-ratio was 184.3 (SD 61.4) vs. 151.3 (SD 54.4) mmHg, (
p
= 0.017) and PEEP was 11.8 (SD 2.8) cmH
2
O vs. 11.3 (SD 3.4) cmH
2
O, (
p
= 0.475), for ICU survivors and non-survivors. At day 1–3, compliance was ~ 55 mL/cmH
2
O vs. ~ 45 mL/cmH
2
O in survivors vs. non-survivors. The intersection of overdistension and collapse curves appeared similar at a PEEP of ~ 12–13 cmH
2
O. At day 4–6 compliance changed to ~ 50 mL/cmH
2
O vs. ~ 38 mL/cmH
2
O. At day 7 and beyond, compliance was ~ 38 mL/cmH
2
O with the intersection at a PEEP of ~ 9 cmH
2
O vs. ~ 25 mL/cmH
2
O with overdistension intersecting at collapse curves at a PEEP of ~ 7 cmH
2
O. Surviving SARS-CoV-2 patients show more favourable EIT-derived parameters and a higher compliance compared to non-survivors over time. This knowledge is valuable for discovering the different groups.
Abstract Background The outcomes of several randomized trials on extracorporeal cardiopulmonary resuscitation (ECPR) in patients with refractory out-of-hospital cardiac arrest were examined using ...frequentist methods, resulting in a dichotomous interpretation of results based on p-values rather than in the probability of clinically relevant treatment effects. To determine such a probability of a clinically relevant ECPR-based treatment effect on neurological outcomes, the authors of these trials performed a Bayesian meta-analysis of the totality of randomized ECPR evidence. Methods A systematic search was applied to three electronic databases. Randomized trials that compared ECPR-based treatment with conventional CPR for refractory out-of-hospital cardiac arrest were included. The study was preregistered in INPLASY (INPLASY2023120060). The primary Bayesian hierarchical meta-analysis estimated the difference in 6-month neurologically favorable survival in patients with all rhythms, and a secondary analysis assessed this difference in patients with shockable rhythms (Bayesian hierarchical random-effects model). Primary Bayesian analyses were performed under vague priors. Outcomes were formulated as estimated median relative risks, mean absolute risk differences, and numbers needed to treat with corresponding 95% credible intervals (CrIs). The posterior probabilities of various clinically relevant absolute risk difference thresholds were estimated. Results Three randomized trials were included in the analysis (ECPR, n = 209 patients; conventional CPR, n = 211 patients). The estimated median relative risk of ECPR for 6-month neurologically favorable survival was 1.47 (95%CrI 0.73–3.32) with a mean absolute risk difference of 8.7% (− 5.0; 42.7%) in patients with all rhythms, and the median relative risk was 1.54 (95%CrI 0.79–3.71) with a mean absolute risk difference of 10.8% (95%CrI − 4.2; 73.9%) in patients with shockable rhythms. The posterior probabilities of an absolute risk difference > 0% and > 5% were 91.0% and 71.1% in patients with all rhythms and 92.4% and 75.8% in patients with shockable rhythms, respectively. Conclusion The current Bayesian meta-analysis found a 71.1% and 75.8% posterior probability of a clinically relevant ECPR-based treatment effect on 6-month neurologically favorable survival in patients with all rhythms and shockable rhythms. These results must be interpreted within the context of the reported credible intervals and varying designs of the randomized trials. Registration INPLASY (INPLASY2023120060, December 14th, 2023, https://doi.org/10.37766/inplasy2023.12.0060 ).
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