Abrupt termination of vitamin C from ICU patients may increase mortality: secondary analysis of the LOVIT trial

Abstract

Background The LOVIT trial examined the effect of vitamin C on sepsis patients, and concluded that in adults with sepsis receiving vasopressor therapy in the ICU, those who received 4-day intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. The aim of this study was to determine whether the abrupt termination of vitamin C administration could explain the increased mortality in the vitamin C group. Methods We used Cox regression with two time periods to model the distribution of deaths over the first 11 days in the LOVIT trial. Results Compared with a uniform difference between vitamin C and placebo groups over the 11-day follow-up period, addition of a separate vitamin C effect starting from day 5 improved the fit of the Cox model (p = 0.026). There was no difference in mortality between the groups during the 4-day vitamin C administration with RR = 0.97 (95% CI: 0.65–1.44). During the week after the sudden termination of vitamin C, there were 57 deaths in the vitamin C group, but only 32 deaths in the placebo group, with RR = 1.9 (95% CI: 1.2–2.9; p = 0.004). Conclusion The increased mortality in the vitamin C group in the LOVIT trial is not explained by ongoing vitamin C administration, but by the abrupt termination of vitamin C. The LOVIT trial findings should not be interpreted as evidence against vitamin C therapy for critically ill patients.

Vitamin C deficiency can lead to pulmonary hypertension: a systematic review of case reports

“…The LOVIT trial examined the effect of 4-day intravenous vitamin C administration on sepsis patients, and unexpectedly mortality was found to be elevated in the vitamin C group [ 155 ]. However, a secondary analysis showed that the increased mortality did not occur during vitamin C administration, but immediately after the abrupt termination of the vitamin [ 156 ]. A recent vitamin C for critically-ill COVID-19 patients trial observed similar harm from the abrupt termination of the 4-day vitamin C administration [ 157 , 158 ].…”

“…A recent vitamin C for critically-ill COVID-19 patients trial observed similar harm from the abrupt termination of the 4-day vitamin C administration [ 157 , 158 ]. Rapid termination of vitamin C can lead to very low plasma levels through the rebound effect [ 156 ]. It even seems possible that the extra deaths after the sudden termination of vitamin C in the LOVIT trial might have been due to RHF since vitamin C deficiency increases the risk of RHF [ 1 – 11 ], and RHF is common in sepsis patients [ 159 , 160 ].…”

Vitamin C in critical illness: end of the story or still a place?

“…Hemila ¨and Chalker conducted a secondary analysis of the LOVIT trial with the aim to determine whether the abrupt termination of high-dose vitamin C (''rebound effect'') could explain the increased mortality in the vitamin C arm [23]. Driven by a previous re-analysis of the CITRIS-ALI trial where the authors showed a time-dependent modification of the vitamin C effect by the termination of the vitamin treatment [24], Cox regression with two time periods to model the distribution of deaths over the first 11 days was used.…”

Apples and Oranges—All ‘Vitamin C’ May Not Be Created Equal

“…Second, it has been proposed that the signal for harm from administration of vitamin C as ascorbic acid in the LOVIT trial may not be due to the administration per se, but rather secondary to rebound effects on ascorbic acid cessation (7). In a post hoc Cox-risk regression analysis of LOVIT data, Hemilä et al (7) reported no difference in mortality between ascorbic acid and placebo during the 4-days of intervention (RR = 0.97 [95% CI, 0.65-1.44]) and significantly increased mortality in ascorbic acid group in the week postinfusion cessation RR = 1.9 (95% CI, 1.2-2.9; p = 0.004). They propose that the signal for harm may due to hypermetabolism of vitamin C on cessation leading to rebound reduction of plasma vitamin C to levels even lower than pretreatment levels (7).…”