Coronavirus disease 2019 (COVID-19) still remains a pandemic accounting for at least 15% of intensive care unit (ICU) admissions. Recently, it has been observed that l-carnitine levels, which play an important role in fatty acid metabolism, have an inverse association with the severity of COVID-19 and its complications, hence a potential role for supplementing with this nutraceutical has been suggested. The current protocol describes a trial aiming to an evaluation of the effect of l-carnitine intervention on mortality and clinical outcomes in ICU-admitted patients with COVID-19.

This parallel-group, randomized, placebo-controlled, and double-blind clinical trial involves 50 participants and will be performed at the ICU of Artesh (AJA) Hospital, Mashhad, IRAN. Eligible participants will be randomized into two groups: 1) the intervention group will receive 1000 mg l-carnitine capsules 3 times a day, and 2) the placebo group will receive 1000 mg placebo capsules 3 times a day. Assessments will be performed at baseline, 7 and 28 days after study initiation. The primary outcome includes changes in serum levels of C-reactive protein (CRP). Secondary outcomes include the length of stay in the ICU, ICU mortality, hospital mortality, 28-day mortality, duration of mechanical ventilation (MV), and the neutrophil-lymphocyte ratio (NLR).

Based on previous evidence, l-carnitine may reduce inflammation and oxidation stress and improve respiratory function. However, the effects of l-carnitine on ventilator-dependent COVID-19 critically ill patients have not been assessed yet, justifying the necessity to conduct a clinical study in this field. c.

A stay in intensive care unit (ICU) exposes patients to a risk of carnitine deficiency. Moreover, acylated derivates of carnitine (acylcarnitines, AC) are biomarkers for metabolic mitochondrial dysfunction that have been linked to post-ICU disorders. This study aimed to describe the AC profile of survivors of a prolonged ICU stay (≥7 days). Survivors enrolled in our post-ICU clinic between September 2020 and July 2021 were included. Blood analysis was routinely performed during the days after ICU discharge, focusing on metabolic markers and including AC profile. Serum AC concentrations were determined by LC-MS/MS and were compared to the reference ranges (RR) established from serum samples of 50 non-hospitalized Belgian adults aged from 18 to 81 years. A total 162 patients (65.4% males, age 67 (58.7−73) years) survived an ICU stay of 9.7 (7.1−19.3) days and were evaluated 5 (3−8) days after discharge. Their AC profile was significantly different compared to RR, mostly in terms of short chain AC: the sum of C3, C4 and C5 derivates reached 1.36 (0.98−1.99) and 0.86 (0.66−0.99) µmol/L respectively (p < 0.001). Free carnitine (C0) concentration of survivors (46.06 (35.04−56.35) µmol/L) was similar to RR (43.64 (36.43−52.96) µmol/L) (p = 0.55). C0 below percentile 2.5 of RR was observed in 6/162 (3.7%) survivors. Their total AC/C0 ratio was 0.33 (0.22−0.42). A ratio above 0.4 was observed in 45/162 (27.8%) patients. In ICU survivors, carnitine deficiency was rare, but AC profile was altered and AC/C0 ratio was abnormal in more than 25%. The value of AC profile as a marker of post-ICU dysmetabolism needs further investigations.

Insulin resistance (IR) can negatively affect clinical outcomes in acute ischemic stroke (IS) patients. Safe and cost-saving interventions are still needed to improve glycemic indices in this population. The primary objective was to evaluate L-carnitine (LC) effects in acute IS patients' homeostatic model assessment of IR (HOMA-IR).

In this randomized, double-blind placebo-controlled clinical trial, critically ill IS patients were allocated to receive daily oral L-carnitine (1.5 g) or a placebo for six days. Fasting serum levels of glucose, insulin, C-reactive protein, LC, and HOMA-IR were measured on days 1 and 7. Mechanical ventilation duration, ICU/hospital duration, illness severity score, sepsis, and death events were assessed.

Forty-eight patients were allocated to the research groups, 24 patients in each group, and all were included in the final analysis. LC administration showed a decrease in mean difference of HOMA-IR and insulin levels at day 7 compared to placebo, -0.94 ± 1.92 vs 0.87 ± 2.24 (P = 0.01) and -2.26 ± 6.81 vs 0.88 ± 4.95 (P = 0.03), respectively. However, LC administration did not result in significant improvement in clinical outcomes compared to placebo. The short duration of intervention and low sample size limited our results.

Supplementation of L-carnitine improved HOMA-IR index in acute IS patients admitted to the critical care unit. Supplementation of LC would be a potential option to help to control IR in critically ill acute IS patients.

In this review, we discussed the biological targets of carnitine, its effects on immune function, and how L-carnitine supplementation may help critically ill patients. L-carnitine is a potent antioxidant. L-carnitine depletion has been observed in prolonged intensive care unit (ICU) stays, while L-carnitine supplementation has beneficial effects in health promotion and regulation of immunity. It is essential for the uptake of fatty acids into mitochondria. By inhibiting the ubiquitin-proteasome system, down-regulation of apelin receptor in cardiac tissue, and reducing β-oxidation of fatty acid, carnitine may decrease vasopressor requirement in septic shock and improve clinical outcomes of this group of patients. We also have an overview of animal and clinical studies that have been recruited for evaluating the beneficial effects of L-carnitine in the management of sepsis/ septic shock. Additional clinical data are required to evaluate the optimal daily dose and duration of L-carnitine supplementation.

Carnitine plays a key role in energy production in the myocardium and is efficiently removed by continuous kidney replacement therapy (CKRT). Effects of levocarnitine supplementation on myocardial function in children receiving CKRT have not been investigated.

This controlled pilot cohort study of 48 children investigated effects of levocarnitine supplementation on myocardial strain in children receiving CKRT for acute kidney injury (AKI). Children (n = 9) with AKI had total (TC) and free plasma carnitine (FC) measurements and echocardiogram for longitudinal and circumferential strain at baseline (prior to CKRT) and follow-up (on CKRT for > 1 week with intravenous levocarnitine supplementation, 20 mg/kg/day). Intervention group was compared with three controls: (1) CKRT controls (n = 10) received CKRT > 1 week (+AKI, no levocarnitine), (2) ICU controls (n = 9) were parenteral nutrition-dependent for > 1 week (no AKI, no levocarnitine), and (3) healthy controls (n = 20).

In the Intervention group, TC and FC increased from 36.0 and 18 μmol/L to 93.5 and 74.5 μmol/L after supplementation. TC and FC of unsupplemented CKRT controls declined from 27.2 and 18.6 μmol/L to 12.4 and 6.6 μmol/L, which was lower vs. ICU controls (TC 32.0, FC 26.0 μmol/L), p < 0.05. Longitudinal and circumferential strain of the Intervention group improved from - 18.5% and - 18.3% to - 21.1% and - 27.6% after levocarnitine supplementation; strain of CKRT controls (-14.4%, -20%) remained impaired and was lower vs. Intervention and Healthy Control groups at follow-up, p < 0.05.

Levocarnitine supplementation is associated with repletion of plasma carnitine and improvement in myocardial strain and may benefit pediatric patients undergoing prolonged CKRT.

Recent clinical trial studies have reported that L-carnitine supplementation can reduce the mortality rate in patients with sepsis, but there are no definitive results in this context. The current systematic review and meta-analysis aimed to evaluate the effect of L-carnitine supplementation on 28-day and one-year mortality in septic patients.

A systematic search conducted on Pubmed, Scopus and Cochrane Library databases up to June 2019 without any language restriction. The publications were reviewed based on the Cochrane handbook and preferred reporting items for systematic reviews and meta-analyses (PRISMA). To compare the effects of L-carnitine with placebo, Risk Ratio (RR) with 95% confidence intervals (CI) were pooled according to the random effects model.

Across five enrolled clinical trials, we found that L-carnitine supplementation reduce one-year mortality in septic patients with SOFA> 12 (RR: 0.68; 95% CI: 0.49 to 0.96; P= 0.03) but had no significant effect on reducing 28-day mortality ((RR: 0.93; 95% CI: 0.68 to 1.28; P= 0.65) compared to placebo. Finally, we observed that based on current trials, L-carnitine supplementation may not have clinically a significant effect on mortality rate.

L-carnitine patients with higher SOFA score can reduce the mortality rate. However, the number of trials, study duration and using a dosage of L-carnitine are limited in this context and further large prospective trials are required to clarify the effect of L-carnitine on mortality rate in septic patients.

One of the major concerns about taking amino acid supplements is their potential adverse effects on the kidney as a major organ involved in the metabolism and excretion of exogenous substances. The aim of this study is to review available data about renal safety of the most prominent amino acid supplements including L-arginine, glutamine and also L-carnitine as well as creatine (as amino acid derivatives) in athletes and bodybuilders. The literature was searched by keywords such as "L-carnitine", "L-arginine", "glutamine", and "kidney injury" in databases such as Scopus, Medline, Embase, and ISI Web of Knowledge. Articles published from 1950 to December 2017 were included. Among 3171, 5740, and 1608 records after primary search in the relevant databases, 8, 7, and 5 studies have been finally included, respectively, for L-carnitine, L-arginine, and glutamine in this review. Arginine appears to have both beneficial and detrimental effects on kidney function. However, adverse effects are unlikely to occur with the routine doses (from 3 to >100 g/day). The risks and benefits of L-carnitine on the athletes' and bodybuilders' kidney have not been evaluated yet. However, L-carnitine up to 6000 mg/day is generally considered to be a safe supplement at least in healthy adults. Both short-term (20-30 g within a few hours) and long-term (0.1 g/kg four times daily for 2 weeks) glutamine supplementation in healthy athletes were associated with no significant adverse effects, but it can cause glomerulosclerosis and serum creatinine level elevation in the setting of diabetic nephropathy. Creatine supplementation (ranged from 5 to 30 g/day) also appears to have no detrimental effects on kidney function of individuals without underlying renal diseases. More clinical data are warranted to determine the optimal daily dose and intake duration of common supplemental amino acids associated with the lowest renal adverse effects in sportsmen and sports women.

Persistent physical impairment is frequently encountered after critical illness. Recent data point towards mitochondrial dysfunction as an important determinant of this phenomenon. This narrative review provides a comprehensive overview of the present knowledge of mitochondrial function during and after critical illness and the role and potential therapeutic applications of specific micronutrients to restore mitochondrial function. Increased lactate levels and decreased mitochondrial ATP-production are common findings during critical illness and considered to be associated with decreased activity of muscle mitochondrial complexes in the electron transfer system. Adequate nutrient levels are essential for mitochondrial function as several specific micronutrients play crucial roles in energy metabolism and ATP-production. We have addressed the role of B vitamins, ascorbic acid, α-tocopherol, selenium, zinc, coenzyme Q10, caffeine, melatonin, carnitine, nitrate, lipoic acid and taurine in mitochondrial function. B vitamins and lipoic acid are essential in the tricarboxylic acid cycle, while selenium, α-tocopherol, Coenzyme Q10, caffeine, and melatonin are suggested to boost the electron transfer system function. Carnitine is essential for fatty acid beta-oxidation. Selenium is involved in mitochondrial biogenesis. Notwithstanding the documented importance of several nutritional components for optimal mitochondrial function, at present, there are no studies providing directions for optimal requirements during or after critical illness although deficiencies of these specific micronutrients involved in mitochondrial metabolism are common. Considering the interplay between these specific micronutrients, future research should pay more attention to their combined supply to provide guidance for use in clinical practise. REVISION NUMBER: YCLNU-D-17-01092R2.

Neonatal sepsis is associated with high mortality and morbidity, yet challenges with available diagnostic approaches can lead to delays in therapy. Our study assessed whether newborn screening analytes could be utilized to identify associations with neonatal sepsis. We linked a newborn screening registry with health databases to identify cases of sepsis among infants born in Ontario from 2010-2015. Correlations between sepsis and screening analytes were examined within three gestational age groups (early preterm: <34 weeks; late preterm: 34-36 weeks; term: ≥37 weeks), using multivariable logistic regression models. We started with a model containing only clinical factors, then added groups of screening analytes. Among 793,128 infants, 4,794 were diagnosed with sepsis during the neonatal period. Clinical variables alone or in combination with hemoglobin values were not strongly predictive of neonatal sepsis among infants born at term or late preterm. However, model fit improved considerably after adding markers of thyroid and adrenal function, acyl-carnitines, and amino acids. Among infants born at early preterm gestation, neither clinical variables alone nor models incorporating screening analytes adequately predicted neonatal sepsis. The combination of clinical variables and newborn screening analytes may have utility in identifying term or late preterm infants at risk for neonatal sepsis.

This study aims to demonstrate the patterns of free carnitine (FC) and acylcarnitine (AC) esters in familial Mediterranean fever (FMF) patients.

A total of 205 patients (106 males, 99 females; mean age 131.3±52.1 months; range 24 to 254 months) with FMF and 50 healthy controls (27 males, 23 females; mean age 125.7±49.6 months; range 32 to 217 months) were enrolled. Fasting dried blood samples were taken for showing FC and AC ester levels with tandem mass spectrometry from both patients and controls.

Screening of AC profile revealed increased FC, 3-hydroxypalmitoylcarnitine (C16-OH), and 3-Hydroxy octadecanoylcarnitine (C18:2-OH) carnitine levels, while decreased acetyl-carnitine (C2), propionyl-carnitine (C3), butyryl-carnitine (C4), tiglyl-carnitine (C5:1), hexanoyl-carnitine (C6), octanoyl-carnitine (C8), decenoylcarnitine (C10:1), decadienoylcarnitine (C10:2), malonylcarnitine (C3DC), methylmalonylcarnitine (C4DC), glutarylcarnitine (C5DC), hexadecenoylcarnitine (C16:1), 3-Hydroxy butyrylcarnitine (C4-OH), and 3-Hydroxy oleylcarnitine (C18:1-OH) carnitine levels in FMF patients compared to controls. Total AC levels (p<0.001) and AC to FC ratio (p<0.001) were also lower in FMF patients than the controls.

In this study, we were able to detect some of the AC profile variations in FMF patients; however, usage of carnitine in all patients with FMF is not recommended since we were not able to demonstrate secondary carnitine deficiency in FMF patients of this study.

Carnitine plays an essential role in fatty acid metabolism, exerts substantial antioxidant action and regulates immune functions. We hypothesized that a disturbed carnitine metabolism could be involved in progression of HIV infection.

Plasma levels of L-carnitine, its precursors, and short-, medium- and long-chain acylcarnitines were analysed with HPLC/mass spectrometry in HIV-infected patients with various disease severities including patients who acquired Mycobacterium avium complex (MAC) infection. In vitro, we examined the MAC-purified protein derivate (PPD)-induced release of TNF-α and IFN-γ in peripheral blood mononuclear cells (PBMCs) from patients with either high or low plasma levels of acylcarnitines.

Plasma levels of the short-chain (e.g. propionyl-carnitine) and medium-chain (e.g. octanoyl-carnitine) acylcarnitines were reduced in patients with advanced HIV infection. These acylcarnitines gradually decreased in rapid progressors, while minimal changes were observed in the nonprogressors. Plasma levels of propionyl-carnitine and octanoyl-carnitine significantly increased during antiretroviral therapy (ART). However, ART did not restore levels to those observed in healthy controls. Depletion of propionyl-carnitine and octanoyl-carnitine was observed prior to MAC infection, and the release of TNF-α and IFN-γ from PBMC was decreased after stimulation with MAC-PPD in samples from HIV-infected patients with low levels of propionyl-carnitine or octanoyl-carnitine.

Our findings suggest an association between disturbed acylcarnitine metabolism, immune dysregulation and disease progression in HIV-infected patients. Low levels of propionyl-carnitine and octanoyl-carnitine were associated with increased susceptibility to MAC infection in HIV patients with advanced disease.

Maple Syrup Urine Disease (MSUD) is a metabolic disorder caused by a severe deficiency of the branched-chain α-keto acid dehydrogenase complex activity which leads to the accumulation of branched-chain amino acids (BCAA) leucine (Leu), isoleucine and valine and their respective α-keto-acids in body fluids. The main symptomatology presented by MSUD patients includes ketoacidosis, failure to thrive, poor feeding, apnea, ataxia, seizures, coma, psychomotor delay and mental retardation, but, the neurological pathophysiologic mechanisms are poorly understood. The treatment consists of a low protein diet and a semi-synthetic formula restricted in BCAA and supplemented with essential amino acids. It was verified that MSUD patients present L-carnitine (L-car) deficiency and this compound has demonstrated an antioxidant and anti-inflammatory role in metabolic diseases. Since there are no studies in the literature reporting the inflammatory profile of MSUD patients and the L-car role on the inflammatory response in this disorder, the present study evaluates the effect of L-car supplementation on plasma inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), interferon-gamma (INF-ɣ), and a correlation with malondialdehyde (MDA), as a marker of oxidative damage, and with free L-car plasma levels in treated MSUD patients. Significant increases of IL-1β, IL-6, and INF-ɣ were observed before the treatment with L-car. Moreover, there is a negative correlation between all cytokines tested and L-car concentrations and a positive correlation among the MDA content and IL-1β and IL-6 values. Our data show that L-car supplementation can improve cellular defense against inflammation and oxidative stress in MSUD patients and may represent an additional therapeutic approach to the patients affected by this disease.

Resveratrol (RSV) has been shown to inhibit the inflammatory reaction and ameliorate the organ damage resulting from trauma-hemorrhage (TH). However, the effects of RSV on the metabolomic profiles under these conditions remain unclear. The aim of this study was to determine the metabolomic profiles of plasma in TH rats and to evaluate the therapeutic effects of RSV using high-performance liquid chromatography-mass spectrometry. Thirty male Sprague-Dawley rats were divided into sham operation (n = 10), sham-operation plus RSV treatment (n = 10), TH (n = 10), and TH plus RSV treatment (n = 10) groups. Plasma samples were obtained at 24 h after surgery. Electrospray ionization-tandem mass spectrometry was used to characterize the plasma metabolomes. The systemic analyses of plasma metabolomes and their targets were determined using a number of computational approaches, including principal component analysis, partial least squares discriminant analysis, and heat map analysis. Using these methods, the effects of RSV on the metabolomic profiles in animals that underwent trauma-hemorrhagic injury were determined. These approaches allowed a clear discrimination of the pathophysiological characteristics among the groups. The results demonstrate RSV treatment significantly reduced the metabolic derangements caused by TH. Compared with the sham-operated rats, the plasma levels of carnitine in the TH rats were relatively lower, but the levels of acetylcarnitine and butyrylcarnitine were higher, suggesting that RSV ameliorated the deranged carnitine metabolism in TH rats. There was a statistically significant increase in carnitine. In addition, RSV treatment reduced ketoacidosis and protein degradation, as evidenced by the attenuation of the elevated plasma branched-chain amino acid levels in the TH rats. Our study showed that the alterations of the metabolomic profiles in the rats subjected to trauma-hemorrhagic shock were attenuated by RSV treatment. In view of the metabolomic evidence, we conclude that RSV exerts beneficial effects in trauma-hemorrhagic shock injury and that these effects are partially mediated by improving energy metabolism and reducing protein degradation.

The pathogenesis and the progression of phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, have been associated with oxidative damage. Moreover, it has been increasingly postulated the antioxidant properties of L-Carnitine (LC). The aim of this study was to verify the effect of LC on Phe-induced DNA damage. The in vitro effect of different concentrations of LC (15, 30, 120 and 150 μM) on DNA damage-induced by high phenylalanine levels (1000 and 2500 μM) was examined in white blood cells from normal individuals using the comet assay. Urinary 8-hydroxydeoguanosine (8-OHdG) levels, a biomarker of oxidative DNA damage, and plasmatic sulfhydryl content were measured in eight patients with classical PKU, under therapy with protein restriction and supplemented with a special formula containing LC, and in controls individuals. Both in vitro tested Phe concentrations (1000 and 2500 μM) have resulted in DNA damage index significantly higher than control group. The in vitro co-treatment with Phe and LC reduced significantly DNA damage index when compared to Phe group. The urinary excretion of 8-OHdG and plasmatic sulfhydryl content presented similar levels in both groups analyzed (controls and treated PKU patients). In treated PKU patients, urinary 8-OHdG levels were positively correlated with blood Phe levels and negatively correlated with blood LC concentration and plasmatic sulfhydryl content. The present work yields experimental evidence that LC can reduce the in vitro DNA injury induced by high concentrations of phenylalanine, as well as, allow to hypothesize that LC protect against DNA damage in patients with PKU.

In the present study, the potential benefits of oral carnitine in preventing antituberculosis drug-induced hepatotoxicity (ATDH) were evaluated.

Fifty-four patients in the carnitine and 62 patients in the placebo group completed the study. The carnitine group received 1000 mg oral carnitine solution twice daily for 4 weeks. The placebo group received 10 mL of oral placebo solution twice daily for 4 weeks. ATDH was defined as an increase in the serum level of aspartate aminotransferase or alanine aminotransferase greater than three or five times of the upper limit of normal with or without clinical symptoms of hepatotoxicity, respectively.

During the study period, 29 (25%) patients experienced ATDH. Among these patients, nine (16.7%) and 20 (32.3%) were in the carnitine and placebo groups, respectively (P = 0.049). Based on multivariate logistic regression model, age over 35 years old (odds ratio [OR] = 7.01, P = 0.002), human immunodeficiency virus infection (OR = 40.4, P < 0.001), diabetes mellitus (OR = 37.6, P = 0.001), and placebo treatment (OR = 0.1, P = 0.01) were identified as predisposing factors for ATDH.

Results of our preliminary clinical trial suggested that cotreatment with 2000 mg oral L-carnitine solution daily for 4 weeks significantly decreased the rate of ATDH.

New insight in mitochondrial physiology has highlighted the importance of mitochondrial dysfunction in the metabolic and neuroendocrine changes observed in patients presenting with chronic critical illness. This review highlights specifically the importance of carnitine status in this particular patient population and its impact on beta-oxidation and mitochondrial function.

The main function of carnitine is long chain fatty acid esterification and transport through the mitochondrial membrane. Carnitine depletion should be suspected in critically ill patients with risk factors such as prolonged continuous renal replacement therapy or chronic parenteral nutrition, and evidence of beta-oxidation impairments such as inappropriate hypertriglyceridemia or hyperlactatemia. When fatty acid oxidation is impaired, acyl-CoAs accumulate and deplete the CoA intramitochondrial pool, hence causing a generalized mitochondrial dysfunction and multiorgan failure, with clinical consequences such as muscle weakness, rhabdomyolysis, cardiomyopathy, arrhythmia or sudden death. In such situations, carnitine plasma levels should be measured along with a complete assessment of plasma amino acid, plasma acylcarnitines and urinary organic acid analysis. Supplementation should be initiated if below normal levels (20 μmol/l) of carnitine are observed. In the absence of current guidelines, we recommend an initial supplementation of 0.5-1 g/day.

Metabolic modifications associated with chronic critical illness are just being explored. Carnitine deficiency in critically ill patients is one aspect of these profound and complex changes associated with prolonged stay in ICU. It is readily measurable in the plasma and can easily be substituted if needed, although guidelines are currently missing.

To assess carnitine serum levels and possible risk factors of its deficiency in patients with TB.

All newly diagnosed TB patients admitted to an infectious diseases ward were recruited. Demographic, clinical and paraclinical characteristics of the patients were collected. Total carnitine serum concentrations were measured. To investigate factors that can predict carnitine deficiency, logistic regression analysis with odds ratio and 95% CI was performed.

The mean ± standard deviation of carnitine serum levels of patients was 43.77 ± 32.92 µmol/l. Carnitine deficiency was detected in 47.7% of the study population. According to the final model of multivariate logistic regression analysis, increased serum triglyceride levels and hypoalbuminemia were identified as predictive factors of carnitine deficiency in TB patients aged over 35 years old.

Nearly half of Iranian patients with TB were carnitine-deficient. Increased serum triglyceride levels and hypoalbuminemia were identified as independent risk factors of carnitine deficiency in patients aged over 35 years. Considering malnutrition as a major risk factor of TB and the safety of carnitine supplementation, use of carnitine as an adjunctive modality instead of other standard interventions may show beneficial effects in patients with TB.