Septic Shock Nonsurvivors Have Persistently Elevated Acylcarnitines Following Carnitine Supplementation

Abstract

Introduction: Sepsis-induced metabolic disturbances include hyperlactatemia, disruption of glycolysis, protein catabolism, and altered fatty acid metabolism. It may also lower serum L-carnitine that supports the use of L-carnitine supplementation as a treatment to ameliorate several of these metabolic consequences.

Methods: To further understand the association between L-carnitine-induced changes in serum acylcarnitines, fatty acid metabolism and survival, serum samples from (T0), 12 hfollowing completion (T24) of L-carnitine (n = 16) or placebo (n = 15) administration, and 48 h (T48) after enrollment from patients with septic shock enrolled in a randomized control trial were assayed for acylcarnitines, free fatty acids, and insulin. Data were analyzed comparing 1-year survivors and nonsurvivors within treatment groups.

Results: Mortality was 8 of 16 (50%) and 12 of 15 (80%) at 1 year for L-carnitine and placebo-treated patients, respectively. Free carnitine, C2, C3, and C8 acylcarnitines were higher among nonsurvivors at enrollment. L-Carnitine treatment increased levels of all measured acylcarnitines; an effect that was sustained for at least 36 h following completion of the infusion and was more prominent among nonsurvivors. Several fatty acids followed a similar, though less consistent pattern. Glucose, lactate, and insulin levels did not differ based on survival or treatment arm.

Conclusions: In human patients with septic shock, L-Carnitine supplementation increases a broad range of acylcarnitine concentrations that persist after cessation of infusion, demonstrating both immediate and sustained effects on the serum metabolome. Nonsurvivors demonstrate a distinct metabolic response to L-carnitine compared with survivors, which may indicate preexisting or more profound metabolic derangement that constrains any beneficial response to treatment.

Figure 1

Temporal changes in serum concentrations of carnitine and acylcarnitines highlight metabolic phenotypes of 1-y septic shock survival. Carnitine supplementation resulted in higher (A) carnitine, (B) acetylcarnitine, (C) C3, (D) C4, (E) C5, (F) C8, (G) C14 and a trend in higher (H) C16, between survivors and non-survivors. These patterns were distinct from placebo-treated patients for which survivors and non-survivors had similar trends in levels of carnitine and acylcarntines. Data are median and IQR.

Figure 2

Temporal changes in serum concentrations of 14:0–24:1 fatty acids in L-carnitine- and placebo-treated patients, stratified by survival (A–W). While L-carnitine treated, non-survivors demonstrated trends towards having higher levels of various long-chain (C14–C21) and very long-chain fatty acids than survivors [(C) 16:0, (G) 18:1(n-9), (K) 20:0 (Q) 22:0, (R) 22:1, and (V) 24:0], prior to and following [(J) 18:3(n-6), (P) 20:5, (Q) 22:0, and (W) 24:1] carnitine administration, no clear and consistent trend or single biochemical pathway appeared to be implicated as specifically impaired or altered. In placebo-treated patients, the findings were less remarkable in that there were no differences or trends in FA profiles between survivors and non-survivors.

Figure 2

Temporal changes in serum concentrations of 14:0–24:1 fatty acids in L-carnitine- and placebo-treated patients, stratified by survival (A–W). While L-carnitine treated, non-survivors demonstrated trends towards having higher levels of various long-chain (C14–C21) and very long-chain fatty acids than survivors [(C) 16:0, (G) 18:1(n-9), (K) 20:0 (Q) 22:0, (R) 22:1, and (V) 24:0], prior to and following [(J) 18:3(n-6), (P) 20:5, (Q) 22:0, and (W) 24:1] carnitine administration, no clear and consistent trend or single biochemical pathway appeared to be implicated as specifically impaired or altered. In placebo-treated patients, the findings were less remarkable in that there were no differences or trends in FA profiles between survivors and non-survivors.