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The Effect of Valproic Acid on Blood Loss in Patients with Cerebral Palsy

Article  in  Journal of Pediatric Orthopaedics · November 1999

DOI: 10.1097/01241398-199911000-00018 · Source: PubMed

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Journal of Pediatric Orthopaedics

Issue: Volume 19(6), November/December 1999, p 792
Copyright: © 1999 Lippincott Williams & Wilkins, Inc.
Publication Type: [Cerebral Palsy]
ISSN: 0271-6798
Accession: 01241398-199911000-00018
Keywords: Blood loss, Cerebral palsy, Valproic acid

[Cerebral Palsy]

The Effect of Valproic Acid on Blood Loss in Patients with Cerebral Palsy
Chambers, Henry G. M.D.; Weinstein, Craig H. M.D.; Mubarak, Scott J. M.D.; Wenger, Dennis R. M.D.; Silva,
Patricia D. M.S.

Author Information
Study conducted at Children's Hospital, San Diego, California, U.S.A.
From Children's Hospital and Health Center, and University of California Medical School, San Diego, California,
U.S.A.
Address correspondence and reprint requests to Dr. H. G. Chambers, Pediatric Orthopaedic & Scoliosis Center,
3030 Children's Way, MOB 410, San Diego, CA 92123, U.S.A.
Abstract

Summary: Valproic acid (VPA) is used in the treatment of seizure disorders often
present in patients with cerebral palsy. The charts of 114 patients with cerebral palsy
were reviewed to evaluate the effect of VPA on blood loss during spine surgery.
Forty-one patients had seizure disorders. Of these, 18 were taking VPA as monotherapy
(group III) and the remaining 23 patients were taking other antiseizure medications,
including two taking VPA (group II). There was a significant increase in the number of
patients with abnormal bleeding times and a significant difference (p< 0.001) in blood
loss (ml/kg) in patients taking VPA as monotherapy (38.6 ml/kg vs. 30.0 ml/kg). There
was also increased blood-product administration postoperatively in the VPA
monotherapy patients. Physicians should be aware of this potential association between
VPA use and increased blood loss. The routine laboratory tests of complete blood count,
prothrombin time, and partial thromboplastin time will not adequately screen for the
platelet-mediated effects of VPA.

Sodium valproate (VPA) is an anticonvulsant used with increasing frequency in the

treatment of seizure disorders often present in patients with cerebral palsy (5,16). It is
particularly valuable in children who have minor motor seizures (petit mal) and
mixed-type seizures. As with any effective therapeutic agent, there are occasional side
effects. Minor side effects include drowsiness (14,15), weight gain in 20%,
gastrointestinal complaints in 4%, hair thinning in 7%, and wavy hair in 2%(17,27). More
severe adverse effects include hepatotoxicity (11,13,30), pancreatitis (11,35), red cell

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aplasia (9,19), neonatal afibrinogenemia transmitted transplacentally (20), bone

marrow suppression (12,27,29,33), and thrombocytopenia (4,8,10,17,18,21–24,31,32).

Many spine surgeons have noted increased blood loss during surgery on patients who
have a neurologic disorder; however, there are few published data regarding this
observation. Winter et al. in 1996 (34) found that there was increased blood-product
transfusion requirements in neuromuscular pediatric patients taking VPA, but that other
confounding factors such as ambulatory status, diagnosis of cerebral palsy, and surgeon
were present. Recent studies have suggested that thrombocytopenia appears to be
related to high VPA doses and plasma concentrations but that the risk of bleeding is
affected by an unknown mechanism that produces qualitative platelet dysfunction
(1,6,7). In an attempt to determine the effect of VPA therapy on surgical blood loss, a
retrospective evaluation of patients with cerebral palsy who had spinal surgery for
scoliosis was undertaken.

MATERIALS AND METHODS

A review of the charts of patients with total-body-involvement cerebral palsy who

had a spinal fusion for progressive scoliosis from 1984 to 1993 at a tertiary-care
children's hospital was done. The specific surgical procedure performed, presence of a
seizure disorder, medication, body weight, blood loss, units transfused, complete blood
count with platelet count, prothrombin time (PT), partial thromboplastin time (PTT),
and bleeding times were noted.

Patients were grouped based of the presence of seizures and the type of medication
they were taking at the time of the procedure. Three groups were determined: Group I
had no seizure disorder; Group II had a seizure disorder and was taking multiple
antiseizure medications including two taking VPA; and Group III had a seizure disorder
and was taking VPA as monotherapy.

The three groups were then compared with respect to blood loss, blood loss per
kilogram, transfusion requirements, preoperative prothrombin time, partial
thromboplastin time, and bleeding times.

Statistical analysis

To test the primary null hypothesis of equal group means for blood loss/kilogram,
one-way analysis of variance (ANOVA) was used. The ANOVA assumptions of normally
distributed data and equal variances among groups were tested and found to hold. An
[alpha] level of 0.05 was chosen. Significant results were further analyzed by using the
Bonferroni method for each pair of means. The [alpha] level was adjusted for the

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number of comparisons, which was three. Nonsignificant results were considered

inconclusive. After the data were collected, it was decided to examine the effect of
group and laboratory results on excessive bleeding. Excessive bleeding was defined as
>30 ml/kg. Laboratory results were classified as abnormal (PT, >13 s; PTT, >36 s;
bleeding time, >7 min; or platelet count, <200,000) or normal. To assess whether there
was an association between groups (Groups I, II, and III) and excessive bleeding (<30
ml/kg, 30 ml/kg) or between laboratory results (abnormal, normal) and excessive
bleeding, Pearson [chi]2 tests were done. An [alpha] level of 0.05 was chosen. Relative
risks and 95% confidence intervals (CIs) for excessive bleeding were calculated based on
group and laboratory results (3).

RESULTS

In this 10-year retrospective review, 111 patients with cerebral palsy and three
patients who were near-drowning survivors (114 total patients) were identified as having
had a spinal fusion for progressive paralytic scoliosis. All but five of the operations used
Luque segmental spinal instrumentation for fixation of the posterior spinal fusions.
Seventy-one (62%) patients had fusion to the pelvis (Galveston technique) because of
pelvic obliquity (2). Those patients who did not have the Galveston technique had the
use of autogenous iliac crest graft. Those with the Galveston technique had allograft for
the fusion. Ten (9%) patients had anterior spinal fusion before the posterior spinal
fusion. The overall female-to-male ratio was 1.6:1 (70:44;Table 1).

TABLE 1.Characteristics of the study groupAll values are means or means ± standard
deviation.

Seventy-three patients did not have a seizure disorder (Group I). The remaining 41
(36%) patients had a seizure disorder requiring medication. Of these 41 patients, 18
were taking VPA as monotherapy (Group III). The remaining 23 patients were receiving
polytherapy (phenobarbital, phenytoin, and/or carbamazepine) including two who were
also taking VPA (Group II).

All patients had general endotracheal anesthesia with the hypotonic anesthetic
technique. The cell saver was used in all patients except those who were Jehovah's
Witnesses (there was one Jehovah's Witness in each group, and their data are excluded
from the “units transfused” parameter). The units of blood transfused from the cell
saver were similar in each group (p= 0.46). There was no difference among the weight
of the three groups. There was no difference in the complication rates, although many

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patients required a higher level of care (Intensive Care Unit) for monitoring after noting
a decrease in the hemoglobin on the postoperative floor. One of the patients, who was a
Jehovah's Witness, died of pulmonary failure and adult respiratory distress syndrome
(ARDS). The preoperative hemoglobin concentration was similar in all groups (Table 2).
The postoperative hemoglobin tended to be lower in Group III; however, this difference
was not statistically significant with the sample sizes present. There were no significant
differences among the groups with respect to PT or PTT. Although the bleeding time
was not routinely measured in all patients, the mean bleeding times of all three groups
were normal. Forty-four percent of the patients in Group III, however, had abnormal
bleeding times (Table 2). The serum VPA level was measured only preoperatively in
seven patients and was found to be therapeutic in this group.

TABLE 2.Laboratory resultsAll values are means.

When the three groups were compared with respect to blood loss normalized to
body weight, the loss from Group III was significantly greater than that from Group II,
which was significantly greater than that from Group I (Table 3, Fig. 1). Group III
required more RBC transfusions than Group II, which required more than Group I. There
was no difference in cell saver use (Fig. 2). The use of other blood products, such as
fresh-frozen plasma and platelets, was increased in Group III. No other products were
used in any of the patients in Groups I or II.

TABLE 3.Blood loss and replacementaJehovah's Witnesses (one in each group).All values
are means or means ± standard deviation.

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FIG. 1. Blood loss, mean ± SD.

FIG. 2. Units of blood transfused. Solid bar, cell saver. Open bar, blood bank.

When the blood loss per kilogram, group, and abnormal laboratory values are
combined, a relative risk for excessive bleeding (>30 ml/kg) can be determined (Fig. 3).
The relative risk of having excessive blood loss in patients taking VPA is 23 times greater
than in those not taking VPA. Any patient with a laboratory value outside the normal
range for our hospital was considered to have an abnormal test. The relative risk of
excessive bleeding when VPA use and an abnormal laboratory test are present is 2.2
(95% confidence limits, 1.1, 4.3) compared with a child with normal laboratory results.
The risk may actually be higher as the bleeding time test was not performed in all
patients, and these were, therefore, assumed to be normal (Fig. 3).

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FIG. 3. Relative risk of bleeding (>30 ml/kg). Circle, normal laboratory results. Triangle,
abnormal.

DISCUSSION

These data suggest that VPA and other anticonvulsants may contribute to increased
blood loss in patients with cerebral palsy undergoing spinal fusion for scoliosis. Blood
loss has multiple etiologies and a retrospective, or even a prospective study, cannot
completely control for all the factors responsible. Degree of neurologic involvement,
nutritional status, room and body temperature, surgical technique, operative time, use
of the cell saver, and anesthetic technique all contribute to blood loss and cannot be
exactly controlled. The indication for transfusion has also changed with the acceptance
of lower hemoglobin levels as a trigger for transfusion in the past decade. Our patient
population is a fairly homogeneous one with two surgeons (D.R.W. and S.J.M.) doing
>95% of the operations with similar technique.

VPA is a well-absorbed medication that is 80–95% bound to plasma proteins. The

half-life is 6–15 h, and there is a therapeutic range of 50–100 µ/ml. There is a major
drug–drug interaction between VPA and phenobarbital, and this must be remembered
when changing the dosage of either drug (16). Dosages of >40 mg/kg/day should be
avoided (18).

Although VPA has proven to be an effective and relatively safe medication in the
treatment of seizure disorders, there is a large body of literature addressing the side
effects as these can be significant (16). The effect of VPA on coagulation is not
understood. Some authors pointed to a direct hepatotoxic effect, which would alter
production of the clotting factors, whereas others pointed to an immune
thrombocytopenia with antiplatelet autoantibodies (14,30). Barr et al. (4) suggested
that structural similarities found between VPA and the fatty acids in the thrombocyte

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membrane may induce antibodies to form altering the function of the platelets as well
as depleting their number. Both Barr and his group and Terui (4,31) thought it was
immunoglobulin (IgG) mediated. Smith and Boots (29) and Sandler et al. (26) suggested
that it was an IgM-mediated effect. It is disputed whether this effect on the platelets is
dose dependent or idiosyncratic (17,18). VPA may act at several levels with
hepatotoxicity, marrow suppression, and immune thrombocytopenia or dysfunction
(25,26). Recent evidence points to a dose-dependent relation between VPA and
thrombocytopenia; however, these studies fail clearly to demonstrate an increased risk
of surgical bleeding or to define the mechanism of action of this adverse affect (1,6,7).

The surgeon is faced with a dilemma if the patient is taking VPA, either alone or in
combination with other anticonvulsants. Based on the results of this study, there may be
a significant risk of increased blood loss if a major procedure is contemplated. There
was a threefold increased risk of losing >30 ml/kg if the patient was taking VPA and had
a single abnormal clotting test. If bruising, hematoma formation, or epistaxis occur, a
platelet count, bleeding time, and, if possible, thromboelastography should be
performed (28). The bleeding time is a somewhat unreliable test in that it is nonspecific
and very tester dependent. It is, however, a possible screening test and, in this study,
predicted increased blood loss in the 44% of patients in whom it was obtained
preoperatively. Prothrombin time, partial thromboplastin time, and bleeding time
should also be studied in all patients undergoing surgery. If possible, VPA therapy should
be replaced by another antiepileptic drug 1 month before anticipated elective surgery
(16,17,27). The VPA level should also be assayed before surgery.

SUMMARY

This retrospective review of spinal surgery in patients with cerebral palsy suggests
that VPA, and other anticoagulants, may be associated with increased blood loss.
Physicians should be aware of this potential before major surgery. The routine screening
laboratory tests of complete blood count, platelet count, PT, and PTT may not
adequately screen for the platelet-mediated effects of VPA. Bleeding time and
thromboelastography, if available, should be performed in all patients taking VPA
before major orthopaedic surgery. Preoperative planning should include strategies for
decreasing blood loss (careful hemostasis, use of the cell saver, hypotonic anesthesia,
and maintenance of adequate body temperature) and for preparation for safe
replacement (autologous blood donation, fresh-frozen plasma, and platelets).
Anticoagulants including aspirin should be avoided. The patient's neurologist should be
consulted before surgery to determine whether therapeutic levels of VPA are present
and, if possible, to change to another medication in the perioperative period.

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Key Words: Blood loss; Cerebral palsy; Valproic acid

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