Droperidol- diphenhydramine for hyperemesis gravidarum

Gerald G. Briggs, BAChem, BPharm
CareLine Pharmacist, Women's Hospital/Clinical Coordinator, Oncology Pain Control/Clinical Coordinator, Post-Operative Pain Control/ Clinical Coordinator, Hyperemesis Gravidarum Therapy, Women's Hospital/Clinical Coordinator, Insulin Therapy, Women's Hospital, Long Beach Memorial Medical Center, California, U.S.A.

Approximately ten years ago we developed a protocol for treating severe nausea and vomiting of pregnancy with droperidol and diphenhydramine. The rationale for selecting droperidol is because it is one of the most effective antiemetic drugs available. It compares favourably with other antiemetic agents in terms of maternal and foetal safety, potency, efficacy and drug cost. Adverse effects in the mother are mild and easily controlled with diphenhydramine, an agent that also possesses antiemetic activity via a mechanism different from droperidol. The addition of intravenous vitamins, especially pyridoxine, has been beneficial in some patients with prolonged courses of hyperemesis gravidarum prior to entering our program. Two step-down oral agents, metoclopramide and hydroxyzine, were selected because they prevent nausea and vomiting by mechanisms similar to the intravenous drugs and were considered to be as safe for the pregnant woman as other available oral agents. Our patient population to date is somewhere over 400. We now treat about 50 to 60 patients per year with severe hyperemesis in pregnancy.

Although intravenous hydration and drug therapy quickly control the pernicious nausea and vomiting that characterize hyperemesis gravidarum, additional therapeutic interventions are required for the satisfactory resolution of this disease. These interventions include diet control, both in the hospital and at home, a nursing staff experienced in the care of these patients, and a social service worker that can act, if required, as a patient advocate. Moreover, continued close monitoring of the patient following discharge appears to decrease the already small number of hospital readmissions.

The following have been reported regarding the animal and human teratogenicity and toxicity of drugs used as antiemetics:1

  • chlorpromazine
- embryo/foetal death, central nervous system damage (rats)
  • diphenhydramine
- none (rats, rabbits)
- withdrawal syndrome in newborn when used throughout pregnancy; retrolental fibroplasia when used near term in premature infants (humans)
  • hydroxyzine
- oral clefts, orofacial defects, micromelia (rats)
- abortion (monkeys)
  • promethazine
- no animal data
  • droperidol
- none (rats)
  • prochlorperazine
- oral clefts, anencephaly (mice, rats)
- foetal death, postnatal weight loss (rats)
  • dexamethasone
- neural tube defects (rabbit)
- defects of cranium/scalp (mice)
  • hydrocortisone
- oral clefts, neural tube defects, omphalocele (mice, rats, rabbits)
- intrauterine growth retardation (rabbits, sheep)
- oral clefts (humans)
  • methylprednisolone
- oral clefts (mice)
  • prednisolone
- oral clefts, omphalocele, intrauterine growth retardation (mice, rats, rabbits)
- oral clefts (humans)
  • ondansetron
- none (rats, rabbits)
  • metoclopramide
- none (mice, rats, rabbits)

Looking at maternal toxicity, we have the following findings:

  • diphenhydramine
- dizziness, sedation
  • promethazine
- sedation
  • droperidol
- extrapyramidal symptoms (akathisia), sedation
  • chlorpromazine
- extrapyramidal symptoms (dystonia), sedation, hypotension
  • prochlorperazine
- extrapyramidal symptoms (dystonia), sedation, hypotension
  • corticosteroids
- dizziness, headache, muscle weakness (side effects in this population are not very common)
  • metoclopramide
- extrapyramidal symptoms (dystonia, akathisia), gastric dysfunction
  • ondansetron
- headache, pruritus, paresthesiae (relatively rare)

We conducted a study including 80 patients matched with 73 historical controls with severe hyperemesis gravidarum.2 Control patients had received various antiemetic therapies, but not droperidol. Intervention patients were treated with intravenous hydration and droperidol 1.0-2.5 mg as an intravenous loading dose over 15 minutes, dependent upon severity of the patient's symptoms, followed by a continuous infusion of 1.0 mg/hour. If nausea or vomiting had not ceased within four hours, the dose was increased to 1.25 mg/hour. Subsequent changes were made in increments of 0.25 mg at four-hour intervals, according to the patient's symptoms. Diphenhydramine was started simultaneously with the droperidol, 50 mg intravenously over 30 minutes and repeated every six hours until the droperidol was discontinued. Diphenhydramine has two therapeutic effects here: to block the droperidol side effect of akathisia, and to act as another antiemetic. Patients received nothing orally for a minimum of 12 hours and were then started on clear fluids at room temperature; progress was then to a low fat, bland, dry diet. Once the diet was tolerated, droperidol and diphenhydramine were stopped and one hour later oral metoclopramide 10 mg and hydroxyzine 50 mg were given. Thereafter, these medications were given four times daily, one-half hour before meals and at bedtime. Treatment was continued at home for one week after discharge.

Data on 162 patients treated over three years according to the study protocol are of interest:

  • average length of hospital stay
- 2.2 days
  • days/pregnancy
- 2.7
  • no. of readmissions

- 19.8% (now 13%, since patients are seen twice weekly in outpatient clinic)

  • no. requiring parenteral nutrition
- 0
  • no. of pregnancy terminations
- 0
  • gestational age at birth
- 38.7 ± 2.7 weeks
  • birth weight
- 3,286 ± 659 g
  • delivery at < 37 weeks
- 11 (6.8%)
  • SGA
- 6 (3.7%)
  • major malformations
- 3 (1.9%)

These numbers are comparable to our normal population.

We inform our current patients that the goal of therapy after they are discharged from hospital is weight gain, not to be free of nausea and vomiting. They are told that they may experience some symptoms such as morning sickness. Oral therapy (metoclopramide 5-10 mg four times daily, hydroxyzine 25-50 mg four times daily) is then continued for one to two weeks at home.

References:

  1. Briggs GG, Freeman RK, Yaffe SJ. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 5th Ed. Baltimore: Williams & Wilkins, 1998.
  2. Nageotte MP, Briggs GG, Towers CV, Asrat T. Droperidol and diphenhydramine in the management of hyperemesis gravidarum. Am J Obstet Gynecol 1996;174:1801-6.

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