Diazoxide in treatment of severe pre-eclampsia and hypertensive encephalopathy

Diazoxide in treatment of severe pm-eclsmpsia and hypertensive encephabpathy To the Editors: In recent publications, the potential use of diazoxide* has been promoted as the drug of choice for severe hypertensive manifestations of toxemia of pregnancy. This drug has been found enormously effective in the treatment of maiignant hypertension and, in fact, is currently considered the drug of choice for crises of this nature. In a recent article, Finnerty’ proposes, in essence, that the drug be considered the medication of choice for the treatment of severe preeclampsia and hypertensive encephalopathy. The fusion of these two entities into one indication is highly regrettable. Although encephalopathy may indeed supervene in neglected “toxemia,” it is rare that such a development may not be adequately treated by safer measures, particularly for the fetus. Objections to the use of diazoxide include, by the authors’s own statement, that the medication reduces renal blood flow, a circumstance commonly presumed to be associated with coincident reduction of uterine blood flow; such a condition is to be abhorred in an already precarious state. Despite the encouraging claims of its use in human subjects,” 3 it has been demonstrated with intensive use in laboratory animals to cause extensive pancreatic and, in some cases, peripheral muscle destruction.” The author notes also the well-recognized tendency for the drug to produce hyperglycemia, limiting its use, at least in patients with unstable diabetes mellitus. The author proposes the use of furosemide to counteract the obligatory reduction in renal blood flow and to maintain adequate urinary output. Furosemide is specifically considered by the manufacturer to be contraindicated in pregnancy except under extreme circumstances.” This is not to say that the circumstances surrounding hypertensive crisis in pregnancy may not be extreme, but the potential fetal toxicity of some medications when used at times when other measures would be adequate seems highly ill-advised. Poisoning the renal tubular mechanisms for the sake of maintaining adequate urinary output should be restricted to incipient renal failure, a development to which the “toxemic” patient may be predisposed, but also a condition to which she should not be predisposed by therapy. The author also proposes the use of tolbutamide as a “Hyperstat, Jersey 07083.

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possible remedy for the hyperglycemia noted in the mother (and in laboratory fetuses). Tolbutamide is considered by most perinatologists as relatively contraindicated in pregnancy due to its well-known potential to produce unstable glucose-insulin homeostasis in the fetus. Until such time as investigators can satisfy perinatal specialists that the long term follow-up of infants exposed to diazoxide as fetuses does not ultimately result in late-developing evidence of pancreatic islet cell insufficiency or other more immediate complications, the drug should not, in the opinion of this author, be used except in conscientiously conducted research. Is it not possible that the absence of neonatal hypoglycemia, even in growth-retarded infants in whom such events are common, may be the result of partial islet cell destruction and renal suppression. limiting the ability to mobilize and distribute glucose stores at a normal rate? It is the responsibility of responsible perinatal specialists to prevent this disaster in the future. Others, as yet unquantitated, risks of diazoxide therapy also need to be investigated.6 The drug has been associated with a high incidence of arrest of uterine contractions. Some even propose its use for this purpose.’ Severe but reversible hypotension can occur; potassium, chloride, bicarbonate, and uric acid excretion is reduced. The combination of diazoxide and furosemide can result in a marked decrease in extracellular fluid volume, and patients are generally advised to avoid the upright posture for eight to 10 hours following its administration. This potential effect is unthinkable in the severely volume-depleted, typical patient with severe pre-eclampsia. Diazoxide decreases cortisol excretion to minimal levels after 200 to 400 mg. daily. Diazoxide in children has been reported to decrease immunoglobulin G production and the mitotic response to phytohemagglutinin at markedly elevated doses in vitro. Diazoxide is reversibly bound to albumin and might be a Factor in displacement 01 bilirubin from albumin-binding sites in the fetus. Transient cerebral or myocardial ischemia with hypotension has been reported. Neutropenia, thrombocytopenia, and eosinophilia (related to transient adrenal insufficiency?) have been reported with diazoxide, although these effects are reversible. Finally, the use of tolbutamide in dogs has been shown to reverse the hypoglycemic effect of diazoxide but also to reverse the hypotensive and antidiuretic effects as well. This seems potentially to mitigate against the effective use of tolbutamide to antagonize the unwanted side

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effects, removing one of the proponents’ proposed safeguards against hyperglycemia. Hyperosmolar nonketotic coma has been associated with diazoxide therapy for hypoglycemia in one child.8 All things considered, it would seem that the enthusiastic use of diazoxide in severe “toxemia” cannot be supported except as a research tool, with informed consent on the part of the patient and prolonged and conscientious follow-up of the newborn infant. With modern premature intensive care capabilities, it would seem that using a drug with all of the above-cited potential risks is not yetjustified except in the most dire of circumstances. Richard P. Perkins, M.D. Department of Obstetrics and Gynecology IJniver.~ity qf Colorado Medical Center 4.200 E&t 9th Avrnw Box R 198 Denver, Colorado 80220 REFEREWCES

Finnerty, F. A.: Management of hypertension in toxemia of pregnancy, Hosp. Med. 11: 52, 1975. Michael, C. A.: The control of hypertension in labour, Aust. N. Z. J. Obstet. Gynaecol. 14: 48, 1972. Pohl, J. E. F., Thurston, H., Davis, D., and Morgan, M. Y.: Successful use of oral diazoxide in the treatment of severe toxemia of pregnancy, Br. Med. J. 2: 568, 1972. Boulos, B. M., Davis, L. E., Almond, C. H., and Jackson, R. L..: Placental transfer of diazoxide and its hazardous effect on the newborn, J. Clin. Pharmacol. 11: 206, 1971. Product information brochure, Lasix (furosemide), Hoechst Pharmaceuticals, Inc. 6. Symposium on diazoxide, Drugs 2: 73, 1971. 7. Landesman, R., DeSousa, F. J. A., Coutinho, E. M., Wilson, K. H., and DeSousa, F. M. B.: Inhibitory effect of diazoxide in normal term labor, AM. J. OBSTET. GYNECOL. 103:430, 1969. 8. Balsam, M. F., Baker, L., and Kaye, R.: Hyperosmolar nonketotic coma associated with diazoxide therapy for hypoglycemia, J. Pediatr. 78: 523, 1971.

Sudden fetal death during monitored labor To the Editors: I read with great interest the “Communication in brief,” “ Unforeseen sudden intrapartum fetal death in a monitored labor,” by Drs. Hayashi and Fox (AM. J. OBSTET.GYNECOL. 122: 786.1975. The authors claim that there was no ominous fetal heart rate (FHR) pattern and that retrospective analysis of the tracings revealed a short-term, beat-tobeat variation but a conspicuous absence of long-term periodic variation. In addition, they failed to find a narrowed oscillation (sinusoidal FHR) pattern which may be associated with fetal compromise. I submit that the monitor tracings did indeed indicate a compromised fetal status and were not normal or reassuring and that the failure to fully recognize the true nature of the FHR pattern was mainly due to the limitations of the particular fetal monitor utilized and the slow (1 cm. per minute) paper speed recording.

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Unfortunately, there is a total lack of standardization in fetal monitoring system (FMS) strip-chart displays produced by various manufacturers. Paul’ has shown that by altering the vertical scaling and changing the horizontal paper speed the FHR-uterine contraction patterns can be dramatically altered. For example, type I dips (Caldeyro-Barcia) may refer to both early and variable decelerations (Hon), but Won was able to make this distinction because of a display technique which utilized a 3 cm. per minute paper speed and vertical scaling of FHR = 30 beats per centimeter, as opposed to a I cm. per minute paper speed and vertical scaling of FHR = 20 beats per centimeter (Caldevro-Barcia). In the case report, a Hewlett-Packard FMS with a paper speed of 1 cm. per minute and vertical scaling of FHR = 20 beats per centimeter was used. and this led to difficulty in fully intepreting the data present. At our institution, in the past year, we have had two similar experiences at a 1 cm. per miuute paper speed, resulting in babies with low Apgar scores, one of whom died neonatally. In each case close re+w of the records indicated late deceleration that would have been more clearly interpretable if the machine had been speeded to 3 cm. per minute. As a result, we now run our monitors at 3 cm. per minute on all patients in active labor. The authors describe short-term, beat-to-beat variation but do not indicate whether they thought this was diminished, average. or increased beat-to-beat variability. It is apparent ;o me that the base-line FHR is rather fixed (at about 150) and therta are subtle changes suggestive of late deceleration in the tracings in Figs. 2A to 2C. I submit that an instrumentation display at 3 cm. per minute paper speed and vertical scaling of FHR = 30 beats per centimeter (as in the Corometrics* or Berkeley? FMS) would have clearly indicated markedly reduced beat-to-beat variability and mild late deceleration (