Preeclampsia Severe Clinical Trial
Official title:
Effects of Vitamin C Administration on Extravascular Lung Water in Patients With Severe Features of Preeclampsia: a Randomized, Placebo-controlled Trial
The objective of the study is to determine whether administration of vitamin C (1.5g/6 hours) in the first three days post-partum reduces the amount of extravascular lung water assessed by lung ultrasound in patients with severe preeclampsia.
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
Safety of vitamin C has been well established even at high doses. For example, none of the
above studies reported any adverse event, despite the use of very high doses by Tanaka et al.
(1.6 grams/kg over 24 hours). One potential concern regarding vitamin C is that it may be
metabolized into oxalic acid, leading to calcium oxalate nephropathy. This doesn't seem to be
a significant problem for several reasons:
- Oxalate formation is a dose-dependent toxicity. This has rarely been reported from short
courses of IV vitamin C, but only at much higher doses (>40 grams/day).
- In 2014, Fowler et al. published a phase I safety trial of vitamin C in patients with
severe sepsis. Their prospective RCT involved patients with severe sepsis in a medical
ICU. 24 patients were randomized to receive placebo, low-dose vitamin C (12.5 mg/kg
IV/6hr), or high-dose vitamin C (50 mg/kg IV/6hr). The primary endpoint was safety and
tolerability, with no adverse events noted.
- Recently Marik et al. published a before-after study investigating the impact of
treating sepsis with a combination of thiamine 200 mg IV/12hr, Vitamin C 1.5 g/6hr, and
hydrocortisone 50 mg IV/6hr. Mortality was substantially reduced in patients receiving
vitamin C (p<0.001). Moreover, vitamin C use correlated with improved renal outcomes
(the rate of dialysis was reduced from 33% to 10%, p=0.02).
Another concern which has been raised is that vitamin C at extremely high doses may have a
pro-oxidant effect. This was shown not to occur even at a dose of 7.5 grams IV daily.
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