Abstract
Background: Complex regional pain syndrome type I is treated
symptomatically. A protective effect of vitamin C (ascorbic acid) has been
reported previously. A dose-response study was designed to evaluate its effect
in patients with wrist fractures.
Methods: In a double-blind, prospective, multicenter trial, 416
patients with 427 wrist fractures were randomly allocated to treatment with
placebo or treatment with 200, 500, or 1500 mg of vitamin C daily for fifty
days. The effect of gender, age, fracture type, and cast-related complaints on
the occurrence of complex regional pain syndrome was analyzed.
Results: Three hundred and seventeen patients with 328 fractures
were randomized to receive vitamin C, and ninety-nine patients with
ninety-nine fractures were randomized to receive a placebo. The prevalence of
complex regional pain syndrome was 2.4% (eight of 328) in the vitamin C group
and 10.1% (ten of ninety-nine) in the placebo group (p = 0.002); all of the
affected patients were elderly women. Analysis of the different doses of
vitamin C showed that the prevalence of complex regional pain syndrome was
4.2% (four of ninety-six) in the 200-mg group (relative risk, 0.41; 95%
confidence interval, 0.13 to 1.27), 1.8% (two of 114) in the 500-mg group
(relative risk, 0.17; 95% confidence interval, 0.04 to 0.77), and 1.7% (two of
118) in the 1500-mg group (relative risk, 0.17; 95% confidence interval, 0.04
to 0.75). Early cast-related complaints predicted the development of complex
regional pain syndrome (relative risk, 5.35; 95% confidence interval, 2.13 to
13.42).
Conclusions: Vitamin C reduces the prevalence of complex regional
pain syndrome after wrist fractures. A daily dose of 500 mg for fifty days is
recommended.
Level of Evidence: Therapeutic Level I. See Instructions
to Authors for a complete description of levels of evidence.
Complex regional pain syndrome type I (formerly known as reflex sympathetic
dystrophy) is treated symptomatically, and the clinical focus is on
prevention. In patients who have sustained major trauma, the capacity of
homeostasis can be overwhelmed, which can lead to systemic inflammatory
response syndrome and multiple-organ distress
syndrome1. Systemic
inflammatory response syndrome is an excessive inflammatory reaction to an
event such as a trauma, burn, or massive infection (as in the case of
pancreatitis). These processes appear to be mediated by the same host-derived
inflammatory
mediators2. In an
earlier report, we suggested a parallel between burn wounds and the
development of complex regional pain syndrome because of the inflammatory
reaction and the involved
microangiopathy3.
Complex regional pain syndrome and burn wounds may involve a cascade of
deterioration and exaggeration of a similar process. Tanaka et al. reported
that, in the clinical setting, ascorbic acid given in high doses during the
first twenty-four hours of burn resuscitation significantly reduces
resuscitation fluid volume requirements and wound
edema4. The severity
of respiratory dysfunction was also reduced in these patients. The increased
vascular permeability in patients with burns is a result of damage to the
microvascular endothelial cells caused by oxygen free radicals. Vitamin C
reduces lipid peroxidation, scavenges hydroxyl radicals, protects the
capillary endothelium, and inhibits vascular
permeability2,3.
In a previous randomized trial, we reported that treatment with 500 mg of
vitamin C, as compared with placebo, reduced the risk of reflex sympathetic
dystrophy in patients with nonoperatively treated wrist
fractures3.
Therefore, we performed a dose-response study to replicate and further
evaluate our earlier findings. A steady state in human plasma at doses of
>200 mg of ascorbic acid (vitamin C) per day has been
reported5. We
performed a multicenter dose-response study of patients with all types of
wrist fractures that were treated operatively and nonoperatively; the analysis
was performed on the basis of the intention-to-treat principle.
Study Design
The trial was designed as a multicenter, randomized, controlled study.
Three hospitals in The Netherlands participated in the study. The appropriate
medical ethics committees of these three hospitals approved the study. An
independent physician was appointed (as required under Dutch legislation) for
the patients' guidance in case they requested extra information about clinical
trials in general or this trial in particular.
Adult patients (defined as those who were eighteen years of age or older)
with a wrist fracture who were seen in the emergency department of each
hospital were asked by the emergency department physician to participate in
the study. Patients with a fracture of both wrists were also included. All
wrist fractures were included, independent of treatment choice. Nonoperative
treatment consisted of the use of a plaster cast, with the fracture being
reduced under local anesthesia if necessary. Operative treatment varied and
was applied at the surgeon's discretion.
After informed consent had been obtained, the protocol was initiated in the
emergency department. Patients were asked to start the trial medication from
that moment, on the day of the fracture. This medication was delivered in a
box containing 100 capsules, with two capsules to be taken once daily for
fifty days. Patients were allocated randomly to receive either placebo or a
dosage of 200, 500, or 1500 mg of vitamin C daily.
The pharmacist in one of the participating hospitals, who also made up the
medication for the other hospitals, executed the randomization in block form,
with blocks of ten according to a table of random numbers. All capsules had
the same appearance and taste. The trial was double-blind, with the pharmacist
being the only individual with access to the code until the conclusion of the
trial.
The end point of the study was defined as the presence of complex regional
pain syndrome at any time within one year after the fracture. All participants
and physicians were unaware of the treatment allocation. Complex regional pain
syndrome was diagnosed by a physician in the treating department and not by
anyone involved in the conduct of the trial.
At the time of enrollment, specific study parameters were recorded,
including gender, age, the side of the fracture, dominance, fracture type
according to the AO/ASIF classification
system6,
dislocation, reduction, the number of the box containing the allocated
treatment, drug intake, and the history with respect to previous wrist
fractures or earlier episodes of complex regional pain syndrome.
Patients were evaluated after one week, four or five weeks (or when the
cast was removed), six or seven weeks, twelve weeks, and twenty-six weeks.
After one year, patients were interviewed by telephone or were sent an inquiry
letter with a postage-paid envelope for their reply. Fracture treatment was
not compromised by the protocol. If necessary, patients were seen more often
and/or at other times. Attention was paid to early complaints related to the
cast, such as pain, swelling, and numbness.
Complex regional pain syndrome type I was diagnosed if four of the
following five symptoms were present at the wrist, including the area distal
to the wrist (the hand and fingers), and if they occurred (or increased) after
activity: (1) unexplained diffuse pain that was not normal in relation to the
stage of fracture treatment, (2) a difference in skin color relative to the
other hand and wrist, (3) diffuse edema, (4) a difference in skin temperature
relative to the other hand and wrist, and (5) limited active range of motion
of the wrist and fingers that was unrelated to the stage of fracture
treatment7.
If complex regional pain syndrome was diagnosed, the end point of the study
was reached and the protocol was terminated to allow for the treatment of
complex regional pain syndrome.
Statistical Analysis
Statistical analysis was performed with SPSS version 11.0 (SPSS, Chicago,
Illinois) and MedCalc version 9.2 (MedCalc Software, Mariakerke, Belgium)
software on a personal computer. Sample and group sizes were estimated a
priori with use of results of our previous study, a planned power of 90%, and
a significance level (a) of
0.053.
The chi-square test, analysis of variance, and the Student t test were used
as applicable for univariate analysis. Measures of association, along with
their confidence intervals, were calculated with the Pearson chi-square test
or the Fisher exact test. The significant independent variables from the
univariate analysis were entered in a multivariate logistic regression with
the occurrence of complex regional pain syndrome as a dependent variable. The
likelihood ratio backward test was conducted to find the best-fit model by
selecting the variables one by one. The probability for entry was set at 0.05,
and the probability for removal was set at 0.10.
Kaplan-Meier curves with 95% confidence intervals were generated to show
the time between the fracture and the diagnosis of complex regional pain
syndrome. The curves for the placebo and vitamin C groups were compared with
use of a log-rank test.
Between January 2001 and December 2004, we enrolled 416 patients with 427
fractures from a total population of 2137 patients with wrist fractures who
presented to the three emergency departments at the three hospitals. The
follow-up period ended in December 2005.
Ten patients had a bilateral fracture, and one had an ipsilateral
refracture. All fractures were assessed individually. None of the randomized
patients were excluded from the study. No adverse events occurred.
Randomization involved 416 patients from the three centers: 317 patients
with 328 fractures received vitamin C, and ninety-nine patients with
ninety-nine fractures received a placebo. The trial profile is shown in
Figure 1. The 1721 patients who
were excluded comprised 463 patients who refused to take part for various
reasons, 297 patients who wanted to be sure that they received vitamin C, and
961 patients who had not been invited to take part in the study.
The patients who were given vitamin C and those who were given a placebo
did not differ significantly in terms of demographic characteristics
(Table I). Analysis of the
groups receiving the three different doses of vitamin C and the placebo showed
no significant differences with regard to gender, age, the side of the
fracture, dominance, fracture type, dislocation, reduction, or treatment
modality (Table I).
After one year, all patients were interviewed by telephone, with the
exception of eighteen patients who received an inquiry letter and one patient
who was visited at home. It was not necessary to see any of the patients in
the outpatient clinic again as there was no suspicion of a missed diagnosis of
complex regional pain syndrome. None of the patients were lost to
follow-up.
Twenty-five patients had been taking vitamin supplements prior to the
fracture. Of these, nine had been taking vitamin B, two had been taking
vitamin D, and thirteen had been taking a multivitamin preparation. None of
those twenty-four patients had been consuming vitamin C in high doses (>50
mg daily, which is the recommended daily intake), and therefore none of them
were excluded. The remaining patient had been taking 1000 mg of vitamin C
daily. She was asked to stop taking this supplement during the trial. In
retrospect, she was randomized to 1500 mg of vitamin C daily.
The prevalence of complex regional pain syndrome was 2.4% (eight of 328) in
the vitamin C group and 10.1% (ten of ninety-nine) in the placebo group (p =
0.002) (Table I). All of the
affected patients were elderly women. For the entire cohort, the prevalence of
complex regional pain syndrome was 4.2% (eighteen of 427).
Analysis of the different doses of vitamin C showed that the prevalence of
complex regional pain syndrome in the 200-mg group (4.2%; four of ninety-six)
was lower than that among those in the placebo group (10.1%; ten of
ninety-nine) (Table I), but
this difference was not significant (relative risk, 0.41; 95% confidence
interval, 0.13 to 1.27) (Table
II). Significant differences were seen in the 500 (p = 0.007) and
1500-mg (p = 0.005) groups, in which the relative risks of complex regional
pain syndrome were 0.17 (95% confidence interval, 0.04 to 0.77) and 0.17 (95%
confidence interval, 0.04 to 0.75), respectively. Overall, there was a
significant difference between the vitamin C group and the placebo group
(relative risk, 0.24; 95% confidence interval, 0.10 to 0.60) (p = 0.002)
(Table II).
In the present study, all patients with complex regional pain syndrome were
female; for male patients, the relative risk that complex regional pain
syndrome would not develop was 0.95 (95% confidence interval, 0.93 to 0.97).
Complex regional pain syndrome occurred significantly more frequently in older
patients (Table II).
One patient had a refracture and was randomized twice over an interval of
four months, the first time to 500 mg and the second time to 1500 mg of
vitamin C. Fracture treatment was nonoperative on both occasions, and complex
regional pain syndrome did not develop.
One seventy-four-year-old patient in the 1500-mg vitamin C group who had a
fracture of both wrists had development of complex regional pain syndrome on
the right side, where she had a simple AO 23-A2-type fracture that had been
inadequately reduced. On the left side, where the patient had an adequately
reduced AO 23-A3-type fracture, there were no signs of complex regional pain
syndrome.
Complex regional pain syndrome was not associated with the side of the
fracture, dominance, the type of fracture, the need to undergo reduction, or
the type of treatment (operative or nonoperative)
(Table II).
Early complaints related to the plaster cast were predictive of the
occurrence of complex regional pain syndrome (relative risk, 5.35; 95%
confidence interval, 2.13 to 13.42). Overall, complex regional pain syndrome
was diagnosed at an average of seventy-six days (range, thirty to 166 days)
after the fracture (Fig. 2).
The diagnosis of complex regional pain syndrome was made earlier for the
patients in the vitamin C group than for those in the placebo group
(sixty-eight compared with eighty-three days), but this difference was not
significant.
The logistic regression analysis of the predictive factors yielded
significant odds ratios for cast-related complaints and vitamin C doses of 500
and 1500 mg daily (Table
III).
The present study confirms that vitamin C can have an inhibiting effect on
the occurrence of complex regional pain syndrome after wrist fractures. Some
limitations of the study should be mentioned.
The number of patients enrolled in the study was low in relation to the
number of eligible patients who presented with wrist fractures, but after
randomization no patient was lost to follow-up. It is difficult in an
emergency department setting to motivate staff and patients to participate in
any study. The possible lack of interest explains the high number of uninvited
patients (961). Furthermore, during the informed-consent process, patients
were informed about our previous
study3, which showed
a positive effect of vitamin C. Therefore, 297 patients wanted to be sure that
they received vitamin C and decided not to participate in the study.
The confidence intervals for all reported values were wide. Our power
analysis was based on our previous
study3, but the
prevalence of complex regional pain syndrome in the present study was lower
than expected.
In The Netherlands, the intake of vitamin supplements is slowly increasing
but is still low. Only twenty-five patients had already been taking vitamin
supplements before the occurrence of the wrist fracture. None of them had been
taking high-dose vitamin C (>50 mg daily) (except for the patient mentioned
earlier, who had been asked to stop doing so), and therefore none of those
patients were excluded. Because of the low numbers of patients who were known
to have been taking supplements before the fracture and the high doses that
were used in the study, this source of bias was limited. It is known that
vitamin C rapidly reaches a steady state in human plasma at doses of >200
mg per day5. With a
normal dietary intake of 50 to 60 mg of vitamin C per day added to our trial
doses, we did not believe that there was a need to measure plasma levels of
vitamin C. Compliance with taking the vitamins as recommended was not
confirmed; however, all patients stated that they had consumed all fifty
doses.
The overall prevalence of complex regional pain syndrome in the present
study was 4.2%, and the prevalence for the placebo group was 10.1%. This rate
in the placebo group is lower than those in our previous
study3 (22%) and in
the studies reported by Atkins et
al.8,9
(25% and 37%, respectively). A possible explanation for the lower prevalence
in the present study might be found in the more precise criteria (as described
by Veldman et al.7)
that we used for the diagnosis of complex regional pain syndrome. In the
present study the diagnosis was made if four of five symptoms were present,
whereas in our previous study the diagnosis was made if four of six symptoms
were present. Clinicians in The Netherlands are more acquainted with the
criteria of Veldman et
al.7 than they are
with other criteria such as those from the International Association for the
Study of Pain (the so-called IASP criteria) or the modified research criteria
proposed by Bruehl and
others10,11.
Another reason for the lower prevalence might be the fact that surgically
treated wrist fractures were included in the present study. The number needed
to treat (NNT) was 12 for the 500-mg dose of vitamin C in this study.
We found that complaints related to the use of the plaster cast were
strongly predictive of the development of complex regional pain syndrome. This
finding has been described in previous
studies3,12
and should alert physicians who treat fractures with a plaster cast. In the
present study, all patients with complex regional pain syndrome were female,
and this was significant in univariate analysis. From this observation that
complex regional pain syndrome occurs more often in elderly women, the
suggestion has been made that estrogen status could be a confounding
factor3.
The mean time-interval between the wrist fracture and the diagnosis of
complex regional pain syndrome was seventy-six days for all cases. The mean
interval was sixty-eight days for patients in the vitamin C group and
eighty-three days for patients in the placebo group. The length of this
time-interval is consistent with the results reported by Geertzen et al., who
reported a mean interval of 2.3 months for the development of upper limb
complex regional pain syndrome resulting from various
causes13.
The pharmacodynamic behavior of vitamin C in the treatment of fracture or
the prevention of complex regional pain syndrome is not fully understood.
Nevertheless, previous studies have shown a positive effect of vitamin C in
different healing processes. Yilmaz et al., in a study of experimental
fractures in rats, suggested that vitamin C enhanced fracture-healing in
comparison with that in a control
group14, and
Sarisozen et al. confirmed that vitamin C accelerated fracture-healing in
rats15. We did not
study the time needed for fracture-healing.
Ischemia-reperfusion injury is caused by endothelial and subendothelial
damage by neutrophil-derived
oxidants5. Kearns et
al. noted that pretreatment with oral vitamin C protected against this injury
in rats, possibly by diminishing neutrophil respiratory burst
activity5. In a
later study, they provided experimental evidence of a potential role for
antioxidants, such as vitamin C, in the reduction of injury to skeletal muscle
caused by compartment
syndrome16. With
the knowledge that the production of oxidants in neutrophils is reduced by the
administration of vitamin C and that vitamin C can protect the endothelium
from direct injury by oxidants, one can postulate that it can prevent
microvascular dysfunction and the microangiopathy of an inflammatory reaction
as is seen in complex regional pain
syndrome2,17-20.
The strength of our conclusion is limited by two issues. First, our two
vitamin C studies yielded relative risks with wide confidence intervals, which
must be interpreted as a lack of precision, limiting the validity of our
conclusion. Second, with vitamin C, we prevented a group of symptoms defined
by us as complex regional pain syndrome. Due to the lack of precision with
this diagnosis, we cannot be sure that we actually prevented complex regional
pain syndrome.
In conclusion, we recommend the administration of 500 mg of vitamin C daily
for fifty days after a wrist fracture because we believe that such treatment
may prevent complex regional pain syndrome. Whether vitamin C can also be used
as a treatment for complex regional pain syndrome should be the subject of
further study. ?
Note: The authors thank all of the patients who participated in
the study. Special thanks go to Jan Prins (pharmacist, Red Cross Hospital),
Pieter Bakx, orthopaedic surgeon, and B.R.H. Jansen, orthopaedic surgeon, as a
member of the Data and Safety Monitoring Board. We are indebted to all of the
residents and trainees who participated in this study in the three hospitals,
and we especially thank Michiel van de Rest, Guus Haeseker, Agnita Stadhouder,
Jacco van Doorn, and Niels Schep for clinical management. We thank Huub van
der Meulen, surgeon, and Napoleon Coene, orthopaedic surgeon, at the Haga
Hospital, and Maarten van der Elst, surgeon, and Rolf Bloem, orthopaedic
surgeon, at the Reinier de Graaf Group. In addition, we express our
appreciation to Irene van der Sloot and Tineke Visser for collecting data.
Lastly, the authors thank the orthopaedic cast technicians Rob Schram, Ronald
Deij, John Wissenburg, Peter van den Berg, and Han Goudappel. This work was
kindly supported by a grant from Stichting Achmea Slachtoffer en Samenleving
(SASS), a Dutch foundation for encouraging research objectives in relation to
aid to victims. The separate medical ethics committees of the three hospitals
approved the study.
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