Creatine supplementation for optimization of physical function in the patient at risk of functional disability: A systematic review and meta-analysis.

BACKGROUND: The efficacy of creatine replacement through supplementation for the optimization of physical function in the population at risk of functional disability is unclear. METHODS: We conducted a systematic literature search of MEDLINE, EMBASE, the Cochrane Library, and CINAHL from inception to November 2022. Studies included were randomized controlled trials (RCTs) comparing creatine supplementation with placebos in older adults and adults with chronic disease. The primary outcome was physical function measured by the sit-to-stand test after pooling data using random-effects modeling. We also performed a Bayesian meta-analysis to describe the treatment effect in probability terms. Secondary outcomes included other measures of physical function, muscle function, and body composition. The risk of bias was assessed using the Cochrane risk-of-bias tool. RESULTS: We identified 33 RCTs, comprising 1076 participants. From six trials reporting the primary outcome, the pooled standardized mean difference (SMD) was 0.51 (95% confidence interval [CI]: 0.01-1.00; I2 = 62%; P = 0.04); using weakly informative priors, the posterior probability that creatine supplementation improves physical function was 66.7%. Upper-body muscle strength (SMD: 0.25; 95% CI: 0.06-0.44; I2 = 0%; P = 0.01), handgrip strength (SMD 0.23; 95% CI: 0.01-0.45; I2 = 0%; P = 0.04), and lean tissue mass (MD 1.08 kg; 95% CI: 0.77-1.38; I2 = 26%; P < 0.01) improved with creatine supplementation. The quality of evidence for all outcomes was low or very low because of a high risk of bias. CONCLUSION: Creatine supplementation improves sit-to-stand performance, muscle function, and lean tissue mass. It is crucial to conduct high-quality prospective RCTs to confirm these hypotheses (PROSPERO number, CRD42023354929).

Is there a role for ketones as alternative fuel in critical illness?

PURPOSE OF REVIEW: The evidence base advocating ketones as an alternative substrate for critically ill patients is expanding. We discuss the rationale for investigating alternatives to the traditional metabolic substrates (glucose, fatty acids and amino acids), consider evidence relating to ketone-based nutrition in a variety of contexts, and suggest the necessary future steps. RECENT FINDINGS: Hypoxia and inflammation inhibit pyruvate dehydrogenase, diverting glucose to lactate production. Skeletal muscle beta-oxidation activity falls, decreasing acetyl-CoA generation from fatty acids and subsequent ATP generation reduction.The benefits of induced ketosis are well established in epilepsy, whilst the evidence base for ketogenic diet therapy in other neurological pathology, such as traumatic brain injury and neurodegenerative diseases, is expanding. Evidence of upregulation of ketone metabolism in the hypertrophied and failing heart suggests that ketones may be utilized as an alternative fuel source to sustain myocardial function. Ketogenic diets stabilize immune cell homeostasis, promote cell survival following bacterial infection and inhibit the NLRP3 inflammasome, preventing the release of pro-inflammatory cytokines - interleukin (IL)-1ß and IL-18. SUMMARY: Whilst ketones provide an attractive nutritional option, further research is required to determine whether the proposed benefits are translatable to critically unwell patients.

Novel nutritional strategies to prevent muscle wasting.

PURPOSE OF REVIEW: Muscle wasting in critical illness has proven to be refractory to physical rehabilitation, and to conventional nutritional strategies. This presents one of the central challenges to critical care medicine in the 21st century. Novel strategies are needed that facilitate nutritional interventions, identify patients that will benefit and have measurable, relevant benefits. RECENT FINDINGS: Drug repurposing was demonstrated to be a powerful technique in the coronavirus disease 2019 pandemic, and may have similar applications to address the metabolic derangements of critical illness. Newer biological signatures may aid the application of these techniques and the association between changes in urea:creatinine ratio and the development of skeletal muscle wasting is increasing. A core outcome set for nutrition interventions in critical illness, supported by multiple international societies, was published earlier this year should be adopted by future nutrition trials aiming to attenuate muscle wasting. SUMMARY: The evidence base for the lack of efficacy for conventional nutritional strategies in preventing muscle wasting in critically ill patients continues to grow. Novel strategies such as metabolic modulators, patient level biological signatures of nutritional response and standardized outcome for measurements of efficacy will be central to future research and clinical care of the critically ill patient.

Can pioglitazone be used for optimization of nutrition in critical illness? A systematic review.

BACKGROUND: Skeletal muscle wasting is a determinant of physical disability in survivors of critical illness. Intramuscular bioenergetic failure, altered substrate metabolim, and inflammation are likely underpinning mechanisms. We examined the effect of pioglitazone, a peroxisome proliferator-activated receptor γ agonist, on muscle-related outcomes in adults. METHODS: We included randomized controlled trials in which pioglitazone was administered (no dose/dosage restrictions) and muscle-related outcomes were reported. We searched MEDLINE, CENTRAL, EMBASE, CINAHL, and trial registries. Risk of bias was assessed using RoB 2. Primary outcomes were physical function and symptoms, muscle mass and function, or body composition and muscular compositional change. Secondary outcomes included muscle insulin sensitivity, mitochondrial effects, and intramuscular inflammation. RESULTS: Fourteen studies over 19 publications (n = 474 patients) were included. Lean body mass was unaffected in three studies (n = 126) and increased by 1.8-1.92 kg in two studies (P = 0.02 and 0.003, respectively; n = 48). Pioglitazone was associated with increased peripheral insulin sensitivity (+23%-72%, standardized mean difference of 0.97 from trial start point to end point [95% CI, 0.36-1.58; n = 213]). Treatment reduced intramuscular tumor necrosis factor-α (TNF-α) levels (-30%; P = 0.02; n = 29), with mixed effects on serum TNF-α and intramyocellular lipid concentrations. Treatment increased intramuscular markers of adenosine triphosphate (ATP) biosynthesis (ATP5A [+33%, P ≤ 0.05], ETFA [+60%, P ≤ 0.05], and CX6B1 [+ 33%, P = 0.01] [n = 24]), PGC1α and PGC1ß messenger RNA expression (P < 0.05; n = 26), and AMPK phosphorylation (+38%, P < 0.05; n = 26). These data have low-quality evidence profiles owing to risk of bias. CONCLUSIONS: Pioglitazone therapy increases skeletal muscle insulin sensitivity and can decrease intramuscular inflammation.

A large chronic pericardial effusion in an ultramarathon runner with anti-CCP positive rheumatoid arthritis.

Pericardial effusions arise as an extra-articular manifestation of rheumatoid arthritis (RA). Pericardial effusions are often asymptomatic, particularly in the early phase, but patients are at risk of cardiac tamponade as the effusion progresses. We discuss the case of a 40-year-old male ultramarathon runner with RA who presented with mild pleuritic chest pain and exertional dyspnoea after a recent long-haul flight. Despite a relative tachycardia, his observations were otherwise unremarkable. His blood tests revealed a C-reactive protein (CRP) of 86 mg/L and an anti-cyclic citrullinated peptide (anti-CCP) titre of 360 units/mL. He was initially diagnosed with a pulmonary embolism; however, a large pericardial effusion was found incidentally on CT pulmonary angiogram with over 1500 mL subsequently drained. The patient's symptoms resolved and CRP normalised 2 weeks later. This unique case illustrates that physically fit patients may physiologically compensate for large pericardial effusions and that arthritic symptoms do not correlate with the severity of extra-articular features in RA.