The systematic review included a total of four moderate-quality randomized controlled trials. The results demonstrated that l-carnitine supplementation was not associated with 28-day mortality in patients with sepsis. In light of the disparate doses and time windows employed in each study, we also investigated the impact of a 12 g/12 h dosing regimen on mortality and the influence of l-carnitine on long-term outcomes (12-month mortality) in patients with sepsis. In comparison to previous meta-analyses, this study employed a larger sample size [16] and addressed the potential for bias due to the inclusion of a duplicate population [17]. Accordingly, the results are deemed to be reliable.

The results of our study indicate that there is no statistically significant association between l-carnitine and reduced mortality in patients with sepsis. However, there is considerable heterogeneity in the comparison of mortality rates across the studies included in our analysis. Therefore, it is essential to conduct a thorough examination of the characteristics of the studied populations in different studies to gain a better understanding of the potential associations between l-carnitine and mortality in patients with sepsis. Puskarich [9] included a greater number of patients with mechanical ventilation and renal insufficiency in the experimental group, and the SOFA score of the patients was high, indicating that the severity of the enrolled patients was relatively high. In the study conducted by Jones [10], a greater prevalence of organ dysfunction was observed, and notable variations in drug dosage were evident across the study population. Among these, the high-dose group demonstrated a tendency to reduce the risk of mortality to a certain extent, which may be associated with the occurrence of negative results. In comparison to other included studies, Keshani [12] exhibited a lower SOFA score and a positive result, which may indicate that the early detection of sepsis and the timely administration of l-carnitine may be advantageous.

Although our study failed to detect an improvement in mortality, l-carnitine still exhibits certain positive effects on energy metabolism. l-Carnitine maintains the equilibrium between fatty acylcarnitine and fatty acyl-coA through the activity of acetylcarnitine transferase, thereby ensuring the optimal functionality of mitochondria [18, 19]. l-Carnitine can stabilize the mitochondrial membrane by maintaining the activities of enzymes related to mitochondrial energy metabolism and key enzymes of oxidative phosphorylation [20], enhance the ultrastructure of damaged mitochondria, maintain the length of mitochondria, and reduce the quantity of mitochondrial damage, thereby preventing cell apoptosis [21]. Therefore, in sepsis patients, l-carnitine can optimize the aerobic metabolism of the heart and other organs by reducing mitochondrial damage caused by oxidative stress, which might have a certain influence on some sepsis patients [12]. However, it must be clarified that the core treatment strategy for sepsis patients remains active anti-infection, reversing excessive inflammation and multiple organ function impairments secondary to immune response, and additional supplementation of l-carnitine alone might be difficult to achieve this goal. Furthermore, it is important to recognize that sepsis is a highly heterogenous disease, which may have contributed to the inconsistencies observed in the reported outcomes. Further studies could be conducted through phenotypic analysis using pharmacometabonomics, including an assessment of l-carnitine deficiency in patients with sepsis [22, 23].

Future studies might consider the application of sepsis at various times, even in combination with other drugs, to further scrutinize the effect on mortality. Some limitations of this study deserve to be noted here. Firstly, diverse doses and administration timings, different degrees of sepsis severity, and various comorbidities among patients could augment the uncertainty of the study conclusions. Additionally, the current number of randomized controlled trials is relatively scarce, and some trials have relatively small sample sizes. Hence, it is suggested that studies with larger sample sizes be incorporated in future research.