Effects of Vitamin C Administration on Extravascular Lung Water in Patients With Severe Features of Preeclampsia
Condition: Preeclampsia Severe; Preeclampsia Postpartum
MeSH terms: Pre-Eclampsia
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Vitamin C; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 1,5g of IV vitamin C in 100 ml 0.9% NaCl within 30 min of delivery and then every 6 hours for the first 72 hours post-partum.; 100 ml of IV 0.9% NaCl within 30 min of delivery and then every 6 hours for the first 72 hours post-partum.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: preeclampsia; vitamin C; lung ultrasound