Vitamin c to Improve Tissue healing by Administration of Multiple INtravenous dosages

Vascular Surgical patients are eligible for revascularization surgery to
improve blood flow in the corresponding tissue. Case reports from the Meander
Medical Centre show that the healing process of surgical wounds from such
procedures is sometimes far from optimal. This gives the patient a prolonged
situation with risk of infections, frequent hospital visits and possibly
re-surgery. Ascorbic acid supplementation in the case reports gave remarkably
fast and good results in the healing process. Literature can theoretically
confirm this.

Ascorbic acid is involved in several processes in the body, including tissue
repair. Following tissue damage it has a function in the migration of
neutrophils during the inflammatory phase and a function in the formation of
cross-links between collagen during the proliferative phase. In trauma patients
it is also found that ascorbic acid levels at admission were significantly
lower than in a healthy population. This suggests possible depletion as a
result of tissue damage.

A RCT from 1974 with 20 surgical patients already demonstrated that ascorbic
acid in a oral dose of 500mg twice daily versus placebo after one month,
resulted in a significant reduction of the wound surface of ulcers in
paraplegic patients. Such an effect was attempted to reproduce in a study among
nursing home patients where twice daily 500mg ascorbic acid was administered
orally and compared to 10mg orally twice daily with as endpoint the reduction
of wound surface area per week for 12 weeks. There was no difference. A pilot
study in the Meander Medical Centre in vascular surgery patients showed that
36% the ascorbicacid levels were below the desired level (target 25 mmol/L). In
another study, ascorbic acid levels were compared in patients with an ulcer on
the leg versus patients without an ulcer. This showed that the prevalence of
low to very low levels was significantly higher in the ulcer group. It is
unclear whether this effect is causal.

Several animal studies have investigated the effects of ascorbic acid. Three
groups of rats which were treated with placebo versus ascorbic acid
100mg/kg/day intramuscular versus ascorbic acid 200mg/kg/day intramuscular were
compared with eachother on the basis of healing of a gastrointestinal
anastomosis after bowel resection. This showed a positive correlation between
the anastomotic strength and dosage of ascorbic acid. A significant difference
in wound healing was also found in a different rat study. The effect of
ascorbic acid (100mg/kg orally) versus control on the healing of end-to-end
anastomoses was examined after a gastrointestinal resection. The effect was
significant in favor of the ascorbic acid group. A similar effect was found
when comparing rats, divided into four groups. Here, a control group was
compared with an intramuscular vitamin A group, an ascorbic acid 100 mg/kg/day
orally, and a group of ascorbic acid orally, vitamin A intramuscular group.
This study showed reduced adhesion, inflamation and fibrosis in favor of the
vitamin A + ascorbic acid group.

A surgical procedure creates oxidative stress. The effect of this on the
ascorbicacid level was examined and showed a decrease during surgery. In
addition, the population of vascular surgery patients contains a large number
of smokers. Smoking also works oxidative. They are therefore required
approximately 30% higher doses of ascorbic acid to achieve the same level as
non-smokers. All these effects may explain reduced wound healing in vascular
surgery patients.

This double-blind placebo-controlled randomized study examines the effect of
once daily intravenous supplementation with ascorbic acid for four days
starting one hour before surgery. As primary endpoint the percentage of wound
healing four weeks after surgery has been chosesn. Secondary the percentage of
wound healing of any ulcers on the lower extremities 4 weeks after surgery, the
number of wound infections within 30 days from the day of surgery, the number
and type of complications within 30 days from the day of surgery, the duration
of hospital stay from the day of surgery, the number of readmissions within 30
days from the day of surgery and the number of deaths within 30 days from the
day of surgery is being investigated.

When studying wound healing the time to complete wound healing is often used as
a primary endpoint. The time till complete wound healing is probably
unrealistic and not feasible within the available time of this study. From
literature, the degree of wound healing is after 4 weeks, however, seems to be
a clear prognostic factor for the probability of complete wound healing.

During this study deficient as well as non-deficient patiënts are included.
Being deficient or not depends on the target bloodlevel of ascorbic acid. The
current target is based on the occurence of Scorbutus (scurvy) and lies around
the 2-35 µmol/L (Meander MC 25 µmol/L). It is questionable whether this target
value is also the lower limit for all of the other processes in which ascorbic
acid plays a role. There currently is no target value for the improvement of
woundhealing. Also, as mentioned before, there is oxidative stress during
surgical intervention. This can lead to a decrease in ascorbic acid level
during the surgical procedure in patients who where not defined as deficient.
It is of importance to know whether this phenomenon also occurs in our
population, and it also provides information whether the proposed suppletion
scheme is sufficient to prevent such a fall in ascorbic acid level.
Due to the extra information delivered by the non-deficient group, combined
with the minimal risks of ascorbic acid administration, the choice has been
made to include patients indepent of their baseline ascorbic acid level.

The investigation of the effect of ascorbic acid in this category of patients
is of interest. If there actually exists an effect, then this can lead to an
inexpensive, simple and safe intervention in a vulnerable group of patients.

Primary
Improved woundhealing in 30 days in patients with an open revascularisation of
the lower extremities after treatment with 4 dosages of 2 grams ascorbic acid
on 4 consecutive days. (First dosage 1 hour preoperative)

Secondary
With preoperative existent ulcers of the lower extremities: Improved
woundhealing of the ulcers of the lower extremities in 30 days.

Reduction of the postoperative complications within 30 days postoperative
(woundinfections, readmissions, all cause complications, death).

Reduction of postoperative hospital duration.

Doubleblind placebo controlled randomised monocentre study.

Interventiongroup receives 4 administrations of 2000mg ascorbic acid (20ml)
intravenously in 4 consecutive days.
Controlgroup receives 4 administrations of NaCl 0.9% (20ml) intravenously in 4
consecutive days.
First dosage in both situaties is given 1 hour preoperative.

Patients are not affected by the administration of the study drug because they
already have a venflon because of the surgery. In addition, they experience
minimal discomfort of the six blood samples throughout the study which all
coincide with the regular blood tests. There is no additional work in the form
of questionnaires, nor are there additional policlinical visits. All of the
measurements take place during the regular policlinical visits.

The likelihood that patients will experience side effects of the administered
amounts of ascorbic acid is small. The dosage used is registered and may result
in some cases nausea and diarrhea. With prolonged use, the risk of side effects
is greater. Within the framework of this study, however, with only 4 dosages,
the expected risk of side effects is minimal. Moreover, the literature suggests
that the therapeutic index of intravenous ascorbic acid is very large and the
incidence of adverse events is limited to mild symptoms that also occur
sporadically.

The risk of unknown side effects is almost non existent because the used drug
has been registered for a long period of time.