Effects of Vitamin C Administration on Extravascular Lung Water in Patients With Severe Features of Preeclampsia: a Randomized, Placebo-controlled Trial

Risk of fluid over-resuscitation is high in preeclampsia due to endothelial dysfunction and resulting increased vascular permeability. The Confidential Enquiry into Maternal Deaths in the UK reported six maternal deaths between 1994 and 1996 due to adult respiratory distress syndrome (ARDS) that appeared to be related to poor fluid management in women with preeclampsia. On the basis of these reported deaths, recommendations on limiting intravenous fluids to not more than to 80 ml/hour (or 1 ml/kg/h) have been made. Nevertheless, preeclampsia remains the leading cause of pulmonary edema in the peripartum period. Moreover, in some preeclamptic patients higher rates of intravenous fluid administration may be necessary to adequately correct tissue hypoperfusion.

Zieleskiewicz et al. were the first to demonstrate that lung ultrasound (LUS) can be used to objectively evaluate increased extravascular lung water (EVLW) in patients with preeclampsia. Ambrozic et al. recently confirmed these results and showed that the amount of EVLW assessed by LUS is increased in preeclamptic patients compared to healthy controls and that it decreases rapidly in the first four days following delivery.

It has been reported that administration of high-dose ascorbic acid (vitamin C) reduces vascular permeability in animals. In 2000, Tanaka et al. reported an RCT involving 37 patients with major burns (>30% body surface area) randomized regarding whether or not to receive an infusion of IV vitamin C, 66 mg/kg/h for the first 24 hours of hospitalization. Patients in the vitamin C group required less fluid resuscitation, had higher urine output, and developed less wound edema. This translated into improved oxygenation and less time on mechanical ventilation among the vitamin C group (average of 12 vs. 21 days of ventilation, p=0.03). In 2002, Nathens et al. randomized patients shortly after admission to a surgical ICU to no therapy vs. a combination of enteral vitamin E plus IV vitamin C 1000 mg/8h until ICU discharge. The primary endpoint was a composite of pneumonia or ARDS. Although there were trends towards fewer pulmonary complications among patients treated with antioxidants, these did not reach statistical significance (the study was underpowered due to low rates of respiratory complications). However, patients treated with vitamins E and C fared better on a variety of secondary endpoints including less time on the ventilator and less multiorgan failure.

In women with established preeclampsia, there is evidence of oxidative stress and decreased concentrations of vitamin C. An initial RCT on prophylactic supplementation with oral antioxidants, including 1g vitamin C daily, showed a significant reduction in preeclampsia (8 percent vs. 17 percent) in high-risk pregnancies. Subsequent large RCTs have, however, reported no significant reduction in the risks of preeclampsia, intrauterine growth restriction, or the risk of death or other serious outcomes in infants associated with oral vitamin C supplementation.There are no studies to date on use of higher dose IV vitamin C administration for reduction of capillary leak and consequently EVLW in patients with severe forms of preeclampsia. Given the safety (see below) and low costs of vitamin C this could be a promising approach to increase fluid tolerance in these patients. If vitamin C reduces vascular permeability in preeclampsia patients to the same degree that it seems to reduce vascular permeability in other conditions, such as burns, it could reduce the risk of pulmonary complications associated with this disease. At the same time, vitamin C therapy could allow safe additional fluid administration in patients with preeclampsia who are fluid responsive and in whom further increases in preload would be beneficial for preventing end-organ damage such as pre-renal acute kidney injury.

Safety of vitamin C