Effects of Vitamin C Administration on Extravascular Lung Water in Patients With Severe Features of Preeclampsia
Effects of Vitamin C Administration on Extravascular Lung Water in Patients With Severe Features of Preeclampsia
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.
Inclusion Criteria:

 Singleton pregnancy with severe featutes of preeclampsia (any of the following):

 -  Systolic blood pressure of 160 mm Hg or higher, or diastolic blood pressure of 110 mm
 Hg or higher on two occasions at least 4 hours apart while the patient is on bed rest
 (unless antihypertensive therapy is initiated before this time)

 -  Thrombocytopenia (platelet count less than 100x109/L)

 -  Impaired liver function as indicated by abnormally elevated blood concentrations of
 liver enzymes (to twice normal concentration), severe persistent right upper quadrant
 or epigastric pain unresponsive to medication and not accounted for by alternative
 diagnoses, or both

 -  Progressive renal insufficiency (serum creatinine concentration greater 97 µmol/L or a
 doubling of the serum creatinine concentration in the absence of other renal disease)

 -  Pulmonary edema

 -  New-onset cerebral or visual disturbances