PHENYTOIN INFUSION IN SEVERE PRE-ECLAMPSIA

1417

Therapeutics PHENYTOIN INFUSION IN SEVERE PRE-ECLAMPSIA ROGER M. SLATER FRANK L. WILCOX WILLIAM D. SMITH PAUL DONNAI TOM RICHARDSON JANET PATRICK STEPHEN W. D’SOUZA GEORGE E. MAWER JOHN M. ANDERTON

Department of Anaesthetics, Manchester Royal Infirmary; University Department of Obstetrics and Gynaecology, St Mary’s Hospital, Manchester; and Department of Pharmacology, Manchester Medical School

phenytoin sodium was given high-dose infusion (10·8-18 mg/kg) for anticonvulsive prophylaxis to 2 eclamptic patients and to 24 patients with moderate to severe pre-eclampsia. There were no major maternal or neonatal side-effects. Plasma were within the levels therapeutic range (7-20 phenytoin mg/l) at 30 min and 6 h after the infusion in all patients, and remained at a therapeutic level in 21 patients after 12 h. After a second dose of phenytoin in 19 patients, drug levels were within the therapeutic range at 24 h. Summary

Intravenous

of absorption follow oral and intramuscular administration, and after a small intravenous bolus of phenytoin, brain and plasma concentrations rapidly fall as the drug is redistributed.3 Cranford et al4 reported that in non-pregnant

patients a single loading-dose of phenytoin (18 mg/kg) can be given safely and leads to serum concentrations in the therapeutic range for 24 h in most cases. This dose of phenytoin was effective in controlling recurrent seizures in over 80% of epileptic patients. Others have confirmed the efficacy of high-dose phenytoin in the treatment of status epilepticus and repetitive seizures.5-7 Seizure prophylaxis in eclampsia with intravenous phenytoin has not been reported, although Rubin has suggested its use.8 We have studied mothers with moderate to severe pre-eclampsia who were given a high-dose, intravenous phenytoin regimen to determine whether therapeutic blood-levels of phenytoin could be achieved without harm to mother or baby.

as a

INTRODUCTION

IN the Confidential Enquiry into Maternal Deaths (1979-81)1 there were 20 deaths associated with eclamptic convulsions; 12 of these deaths occurred in patients who had been admitted before the first seizure, and 11 occurred in mothers who had had only one or two seizures. Deaths related to exclampsia also resulted from excessive sedation that was given after delivery and caused respiratory arrest. These findings support the need for better anticonvulsive control in severe pre-eclampsia and, whenever possible, the prevention of eclamptic convulsions. An anticonvulsant that does not depress mother or baby would be useful. Continuous neurological assessment of the eclamptic patient is important in monitoring the intracranial effects of eclampsia and in distinguishing other conditions that may present with seizures in pregnancy. The prolonged use of sedatives such as diazepam or chlormethiazole may interfere with neurological assessment and may cause excessive sedation with the risks of impaired respiration, airway obstruction, and aspiration of gastric contents. Phenytoin is an effective anticonvulsant that does not depress consciousness in therapeutic doses.2 However, reduced rates

2. Maxwell

D, Czepulkowski B, Lilford R, Heaton D, Coleman D. Transabdominal chorionic villus sampling. Lancet 1986; i: 123-26. 3. Lilford RJ. Chorion villus biopsy. Clin Obstet Gynaecol 1986; 13: 611-32. 4. Smidt-Jensen S, Hahnemann N. Transabdominal fine needle biopsy from chorionic villi in the first trimester. Prenatal Diagn 1984; 4: 163-69. 5. Maxwell D, Czepulkowski BH, Heaton DE, Coleman DV, Lilford R. A practical assessment of ultrasound-guided transcervical aspiration of chorionic villi and subsequent chromosomal analysis. Br J Obstet Gynaecol 1985; 92: 660-65. 6. Heaton DE, Czepulkowski BH, Horwell DH, Coleman DV. Chromosome analysis of first trimester chorionic villus biopsies prepared by a maceration technique. Prenatal Diagn 1984; 4: 279-87. 7. Simoni G, Brambati B, Danesino C, et al. Efficient direct chromosome analyses and enzyme determinations from chorionic villi samples in the first trimester of pregnancy. Hum Genet 1983; 63: 349-57. 8. Kleijer WJ, van Diggelen OP, Janse HC, Galjaard H, Dumez Y, Boue J. First trimester diagnosis of Hunter syndrome on chorionic villi. Lancet 1984; ii: 472. 9. Williamson R, Eskdale J, Coleman DV, Niazi M, Loeffler FE, Modell BM. Direct gene analysis of chorionic villi: a possible technique for first trimester antenatal diagnosis of haemoglobinopathies. Lancet 1986; ii: 1125-27.

PATIENTS AND METHODS

Patients 26 patients (gestation range 25-41 weeks and weight range 57-116 kg) who comprised all acute admissions for pre-eclampsia over a 16-month period at St Mary’s Hospital, Manchester, were studied. Ethical approval for the study was obtained. 24 of the patients were classified as having moderate to severe pre-eclampsia9 and 2 were eclamptic. No patient had a history of phenytoin allergy or significant heart disease, for which they would have been excluded from the study. On admission, 24 patients had blood pressure over 140/90 mm Hg on repeated readings; of these patients, 7 had blood pressure over 160/110 mm Hg. All 26 patients were oedematous with proteinuria (ranging from 2 + to 4 + on ’Uristix’ reagent strips). 19 patients were hyperreflexic, 13 presented with headache and visual disturbances, and 3 had epigastric pain. 12 patients were hyperuricaemic (over 0-36 mmol/1) and a further 5 had relative hyperuricaemia (over 0-31 mmol/1 at less than 34 weeks’ gestation).10 8 patients had creatinine clearance of less than 100 ml/min (range 51-91 ml/min) for the 24 h after admission.

Phenytoin Administration Phenytoin (ready-mixed phenytoin sodium injection BP, 250 mg ml) was diluted in 250 ml normal saline and administered intravenously with an infusion pump (’IVAC 531’) at up to 25 mg/min. Patients weighing 40-50 kg received 750 mg phenytoin, those weighing 51-70 kg received 1000 mg, and those over 70 kg in 5

received 1250 mg. The rate of infusion was 250 mg over 15, 12, and 10 min in these three groups, respectively, and the rest was given at a slower rate. A 40-um filter was placed in-line to prevent any risk of microprecipitates reaching the vein. Those patients who needed continued anticonvulsive prophylaxis 12 h after the end of the infusion (depending on the

10. Maxwell D, Lilford R, Morsman J, Rodeck C, Old J, Thein S. Direct DNA analysis for diagnosing fetal sickle status in first trimester chorion tissue J Obstet Gynaecol

1985; 5: 133-35 11.

Foy HM, Kenny GE, Wentworth BB, Johnson WL, Grayston JT. Isolation of mycoplasma hominis, T-strains and cytomegalovirus from the cervix of pregnant women. Am J Obstet Gynecol 1970; 106: 635-43 12. Barela AI, Kleinman GE, Golditch IM, Menke DJ, Hogge WA, Golbus MS. Septic shock with renal failure after chononic villus sampling. Am JObstet Gynecol 1986; 154: 1100-02

13. Wilson RD, Kendnck V, Wittmann BK, McGillivrary B Spontaneous abortion and pregnancy outcome after normal first-trimester ultrasound examination. Obstet Gynecol 1986; 67: 352-55. 14. Schuize B, Miller K. Chromosomal mosaicism and maternal cell contamination in chorionic villi cultures. Clin Genet 1986; 30: 239-40

Holgreve W, Reisch A, Miny P, Beller FK. Sample size needed to assess risk of abortion after chononic villus sampling Lancet 1985; i: 223. 16. Irving HC Interventional ultrasound. In Leski R, ed. Practical ultrasound. Oxford. IRL Press (in press). 15.

1418 pressure fell from 130/80 mm Hg immediately before the start of the infusion to 95/50 mm Hg 30 min later. In this case the blood pressure rose to 120/55 mm Hg over the next 30 min without any adjustment in the infusion rate. There were no spontaneous complaints of side-effects during the infusion, and on questioning two days later, there were no new complaints of nausea, dizziness, or blurred vision that might have been attributable to phenytoin. -

Phenytoin Levels

Plasma phenytoin levels after first infusion (n = 26), and after second dose (n 19). =

Second dose oral (0)

or

intravenous

(A).).

of resolution of pre-eclampsia) received a further 500 mg phenytoin either as a single oral dose or as a second intravenous infusion. Maintenance oral phenytoin was continued as necessary. rate

Clinical Assessments

During the infusion the electrocardiogram (ECG) was continuously monitored, and the blood pressure and pulse rate automatically recorded at 10-min intervals (Critikon ’Dynamap’). Conscious level (best motor and verbal responses, and eye opening) assessed at the beginning and end of the infusion. All fetuses monitored either by continuous cardiotocography (CTG) or by intermittent auscultation. The mothers were interviewed 2 days after the infusion about side-effects. Hypertension (defmed as > 160 mm Hg systolic or > 110 mm Hg diastolic blood pressure) was controlled with increments of hydralazine (10 mg intrawas

were

venously). The baby’s condition at 1 and 5 min after birth was assessed with Apgar score based on respiration, heart rate, and colour, with a maximum possible score of 6.11 Where possible, phenytoin levels were assayed in cord blood at delivery. a modified

Phenytoin Assay Plasma phenytoin levels were assayed at 30 min, and 6 and 12 h after the end of the first infusion, and 12 h after the second dose. Plasma phenytoin was measured by high-performance liquid chromatography (adapted from the method described by L. Larson in application sheet 89, Varian Associates). Within-batch precision had a coefficient of variation (CV) of 2% at 10 mg/1, and between-batch precision had a CV of 3-3% at the same mean concentration. RESULTS

Mothers 23 of the 26 patients started intravenous phenytoin before delivery, and the others started in the immediate postpartum period. 2 patients were admitted to hospital having had a single convulsion at home. No patient had a convulsion at any time during or after treatment with phenytoin. 19 babies (73%) were delivered by caesarean section under general anaesthesia. In 2 cases, delivery occurred before completion of the infusion, which was maintained during the general anaesthetic. Except for these 2, all the mothers remained fully conscious throughout the infusion.

No ECG abnormalities were seen and there was no significant change in mean heart rate 30 min from the start of the infusion. Generally in those patients who did not receive concurrent hypotensive therapy, mean blood pressure decreased 30 min after the start of the infusion by less than 10% of pre-infusion blood pressure. In 1 patient the blood

The mean duration of infusion was 175 min (range 60-220 and the mean phenytoin dose was 15-3 mg/kg (range 10-8-18). At 30 min and 6 h after the infusion all patients had plasma phenytoin levels within or just above the therapeutic range of 7-20 mg/1 (figure). At 12 h all but 5 patients had plasma levels within the therapeutic range; the levels in the 5 ranged from 6 to 6-6 mg/l. 19 patients received a second dose of 500 mg phenytoin, 7 intravenously and 12 orally. All these patients had therapeutic plasma phenytoin levels at 12 h after the second dose. There was no significant difference in the mean plasma phenytoin level between the oral and intravenous groups (t test). Fetal Condition In 19 cases the fetal heart rate remained within normal limits (baseline between 120 and 160 beats/min with good variability) during the phenytoin infusion. Of the other cases 1 had early decelerations to between 60 and 90 beats/min in association with rapidly advancing labour (case H, table); another had early decelerations and meconium (case P); another, at 28 weeks’ gestation, had an increase in baseline fetal heart rate to 170 beats/min which returned to 140 beats/min after the infusion (case S); and a fourth had normal CTG before the infusion but, because delivery occurred by caesarian section soon afterwards for maternal reasons, no record was available during the infusion. In 5 cases early decelerations or uncomplicated tachycardia occurred in labour after the end of the infusion (cases J, K, N, U, and V). In 1 eclamptic patient in labour, late decelerations occurred both before and after the phenytoin infusion.

Neonatal Outcome In the antenatally treated group there were 23 live births (weight range 670-3690 g, gestational age 25-41weeks). All babies received parenteral vitamin K at delivery. 1 infant died on day 101 of problems related to delivery at 25 weeks’ gestation. Of the 15 cases admitted to the special-care baby unit, all were less than 35 weeks’ gestation and 14 weighed under 2000 g. 11 babies had modified Apgar scores of 5 or 6 at 1 min (table). 12 babies had poor scores (4) at 1 min. Half of these had scores of 6 at 5 min. The other 6 cases were less than 32 weeks’ gestation and were all delivered by caesarian section under general anaesthesia. In 12 cases, serum phenytoin levels were measured in the umbilical cord at delivery and ranged from 5-0 to 20.7

mg/1 (table). In the first 24 h, 10 infants (43%) were born preterm and nursed on the special-care baby unit. 8 required resuscitation at birth-4 had intubation and intermittent positive-pressure ventilation for 1-8 min (cases A, B, I, and S) and in 4, ventilation was continued when the baby was transferred to the unit 20-40 min after birth (cases D, G, 0, and W). The other 2 preterm infants required only routine were

1419 NEONATAL OUTCOME

The remaining 13 infants (57 %) were born at or near term and were nursed on the postnatal wards. At birth, except for case U who received oxygen by bag and mask for 1 min, these babies required only routine care. On admission to the ward the rectal temperatures were 35-4 to 37’5°C, heart rates were 100 to 156 beats/min, and respiratory rates were 36 to 50/min. 3 infants were breast-fed and the rest were bottle-fed. However, 2 were reluctant to suck initially, so milk was given via a nasogastric tube (cases F and Q). Case H had grunting respiration and a cephalohaematoma but, after the grunting settled in 12 to 24 h, respiration was normal. DISCUSSION

-

I

I

I

section except for

*All

caesarean

case

V = forceps delivery.

I

cases

i

F, H, J, K, N,

I

and

U =normal, and

tThese cases received 500 mg phenytoin intravenously 12 h after first infusion. tGiven phototherapy. Bronchopulmonary dysplasia and focal pulmonary haemorrhage at necropsy.

IRDS=idiopathic respiratory distress syndrome; IVH=intraventricular haemorrhage ; and SEH subependymat haemorrhage. =

(cases M and T). On admission

to the unit the rectal in these 10 infants were 34.0-36.8°C temperatures preterm and the heart rates were 70-160 beats/min. In 6 infants who were not ventilated on arrival the respiratory rates were 40-70/min. Subsequently, 8 infants with idiopathic respiratory distress syndrome were ventilated, and of the remained infants, case S was nursed in 40-60% oxygen with a head-box, and case T was nursed in air. The only other clinical conditions were jaundice, and conjunctivitis which occurred in case T. All 10 infants received intravenous infusions of 5-10% dextrose, but no milk feeds. care

Inadequate anticonvulsive therapy may fail to prevent eclamptic fits.1 However, excessive sedation may worsen an already precarious situation in the fulminating preeclamptic patient who is at risk from both cerebrap2 and laryngeal oedema,13 and may be recovering from general anaesthesia for operative delivery. The ideal anticonvulsant for severe pre-eclampsia/eclampsia would be rapidly effective, have a reliable and predictable duration of action, have a wide safety margin, and be non-depressive and non-toxic to both mother and baby. None of the drugs in use-diazepam and chlormethiazole in the UK and magnesium sulphate in the USA-fills all these criteria. Whilst diazepam is effective in controlling convulsions, it has unwanted effects on the fetus and baby.14 Loss of beat-to-beat variation in the fetal heart rate is seen during intravenous administration of diazepam.15 Given in high dose (30 mg or more) in labour, diazepam causes in the infant delayed onset of respiration, apnoea, hypotonia, lowered temperature, and poor sucking.16-18 Diazepam is excreted in breast-milk, and this may sedate the baby and lead to feeding difficulties.19 Intravenous chlormethiazole has been widely used as a sedative and anticonvulsant in pre-eclampsia since the first report by Duffus et apo The drug is given as a 0-8% solution, and large volumes of crystalloid fluid may be administered over a prolonged period, which may be undesirable especially in the presence of renal impairment. Careful supervision and control of dose are essential to prevent deep sedation and respiratory distress.21 Both respiratory depression and obstruction are complications of intravenous chlormethiazole and have been implicated in most deaths reported after its use in the non-pregnant patient. 2223 Chlormethiazole crosses the placenta and, although rapidly excreted from the fetus, some short-lived respiratory depression is likely. Wood and Renoull stated that chlormethiazole therapy in pre-eclampsia may be associated with sleepy and hypotonic infants for 1-5 days after delivery. Respiratory depression in the infant has been reported after maternal diazoxide and chlormethiazole therapy.2However, Tunstall et ap6 advised that breastfeeding need not be delayed just because of maternal chlormethiazole administration, since only insignificant amounts of the drug are absorbed from breast-milk. Magnesium sulphate, given by the intravenous or intramuscular route, is used extensively in the USA in the management of eclampsia. Pritchard et aI,27 in their review of 245 cases of eclampsia, found magnesium sulphate to be effective in controlling seizures in most cases. However, the one

maternal

death

in

this

series

was

caused

by

cardiorespiratory arrest in a patient given an intravenous overdose of magnesium sulphate; 3 others had magnesiuminduced respiratory depression or arrest. In a review of 67 cases, Sibai et ap8 stated that magnesium sulphate remained

1420

their

therapeutic choice to prevent convulsions in preeclampsia, although they noted that its use intravenously did convulsions in every case. A later paper from the found that magnesium therapy did not alter abnormal electroencephalogram findings in pre-eclamptic

not prevent

same centre

or

eclamptic patients despite therapeutic magnesium

levels.29 The mode of action of magnesium as an anticonvulsant remains uncertain, with some believing its effect to be mainly peripheral at the neuromuscular junction,21.3Q while others believe it to have a specific cortical effect.31 Respiratory arrest is the most dangerous consequence of magnesium intoxication and is likely at blood levels of 6-5 mmol/1 or more,27.32 with anticonvulsive levels being 3-4 mmol/1. Magnesium has no maternal sedative effects and although it readily crosses the placenta, Stone and Pritchard33 found no evidence of magnesium toxicity in fetuses or newborn infants after therapy. However, Lipsitz34 concluded that after 24 h of intravenous magnesium sulphate, signs of neonatal hypermagnesaemia could be anticipated. The present study showed that high-dose phenytoin can be administered intravenously to women at risk of or having eclamptic seizures with no alteration in consciousness or other major complications, and that therapeutic plasma levels can be achieved over a 24-h period. Hypotension is the commonest reported complication of phenytoin infusions. However, its occurrence is dependent on the rate of infusion rather than the total dose.4 In our study the rate did not exceed 25 mg/min, which is below the maximum recommended rate of 50 mg/min.4°5 In all but 1 case there was no significant fall in blood pressure during the infusion. No ECG abnormalities were seen although phenytoin does have membrane-stabilising properties and is used in the treatment of arrhythmias. The previously reported cardiotoxicity of intravenous phenytoin, as shown by conduction disturbances, is related to pre-existing heart disease rather than to the amount of drug administered.4 To maintain therapeutic blood levels we gave a second dose of phenytoin 12 h after the infusion, as suggested by Wilder et al.5 A single intravenous or oral dose of 500 mg was sufficient in all cases. Because phenytoin is heavily proteinbound35 and all our patients had plasma albumin levels below 37 g/1 (consistent with pre-eclampsia), it may have been better to assay free phenytoin levels. This can be done by measuring salivary concentrations of phenytoin; however, practical problems here include the collection of specimens and the fact that lower concentrations of the drug are present for assay.35 Brain penetration of phenytoin after intravenous infusion occurs promptly and exceeds plasma levels within 20 min after infusion.5 This distribution is maintained during chronic therapy.36 Phenytoin loading should therefore achieve high brain levels for a prolonged period. It has been estimated that the first convulsion occurs after delivery in about 25% of eclamptic patients. 37 Anticonvulsive prophylaxis for at least 24 h in high risk cases is indicated. Because acidic phenytoin may be precipitated when parenteral phenytoin sodium is combined with certain drugs and solutions, we avoided concurrent therapy via the same intravenous route. Although Cloyd et al7,8 have demonstrated that parenteral phenytoin is compatible with normal saline and that the dilute solution can be given safely, we incorporated a filter into the infusion line to reduce any risk of microprecipitates reaching the vein. Newborn infants exposed to phenytoin may have bleeding tendencies during the first day of life that are

related

decreased levels of vitamin K dependent clotting can be prevented by parenteral vitamin K administration at birth. No other neonatal problems have been encountered when using intravenous phenytoin in status epilepticus in pregnancy.40 Breast-feeding in the presence of therapeutic maternal phenytoin levels is not thought to be a major hazard, because very low plasma concentrations of phenytoin are found in the newborn to

factors.39 This

baby.41 Other than a cephalohaematoma in a vaginally delivered infant of 34 weeks’ gestation, all other problems in our series were probably related to prematurity (less than 32 weeks’ gestation). No baby over 35 weeks required admission to the special-care unit after delivery, in contrast to babies who may be sleepy and hypotonic after maternal sedative therapy and therefore require careful observation. None of our infants had neurological abnormalities which might have indicated drug withdrawal effects after birth. Whilst diazepam remains the drug of choice for the short-term control of seizures, phenytoin, given as a high-dose infusion, is an appropriate anticonvulsant for use in seizure prophylaxis in severe pre-eclampsia, and avoids the potentially dangerous maternal and neonatal sedative effects of other regimens. Phenytoin should be compared with other drugs in larger trials in pre-eclampsia and

eclampsia. We thank the staff of the central delivery unit, St Mary’s Hospital, Manchester, for their assistance, and Dr A. H. Gowenlock and the technical staff of the Manchester Royal Infirmary biochemistry department for analysis of plasma phenytoin.

Correspondence should be addressed to R. M. S., Department of Anaesthetics, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL. REFERENCES Health and Social Security. Report on confidential enquiries into maternal deaths in England and Wales in 1979-81. London: HM Stationery Office, 1986. 2. Gilman AG, Goodman LS. The pharmacological basis of therapeutics. 7th ed. New York: Macmillan. 1985: 450-54. 3. Woodbury DM, Swinyard EA. Diphenhydantoin: Absorption, distribution and excretion. In: Woodbury DM, Penry JK, Schmit RP, eds. Antiepileptic drugs. New York: Raven Press, 1972: 113-23. 4. Cranford RE, Leppik IE, Patrick B, Anderson CB, Kostick B. Intravenous phenytoin: Clinical and pharmacokinetic aspects. Neurology 1978; 28: 874-80. 5. Wilder BJ, Ramsay E, Willmore LJ, Feussner GF, Perchalski RJ, Shumate JB. Efficacy of intravenous phenytoin in the treatment of status epilepticus: Kinetics of central nervous system penetration. Ann Neurol 1977; 1: 511-18. 6. Wallis W, Kutt H, McDowell F. Intravenous diphenylhydantoin in treatment of acute repetitive seizures. Neurology 1968; 18: 513-24. 7. Cloyd JC, Gumnit RJ, McLain LW. Status epilepticus: the role of intravenous phenytoin. JAMA 1980; 244: 1479-81. 8. Rubin PC. Management of hypertension in pregnancy. Prescribers J 1985, 25: 19-25. 9. American College of Obstetricians and Gynecologists Committee on Terminology. In: Hughes EC, ed. Obstetric-gynecologic terminology. Philadelphia: FA Davis, 1972: 442-43. 10. Redman CWG, Beilin LJ, Bonnar J, Wilkinson RH. Plasma-urate measurements in predicting fetal death m hypertensive pregnancy. Lancet 1976; i: 1370-73. 11. D’Souza SW, John RW, Richards B, Milner RDG. Fetal distress and birth scores in newborn infants: Arch Dis Child 1975; 50: 920-26. 12. Benedetti TJ, Quilligan EJ. Cerebral edema in severe pregnancy-induced hypertension. Am J Obstet Gynecol 1980; 137: 860-62. 13. Seager SJ, MacDonald R. Laryngeal oedema and preclampsia Anaesthesia 1980; 35: 360-62. 14. Rowlatt RJ. Effect of maternal diazepam on the newborn. Br Med J 1978; i: 985. 15. Scher J, Hailey DM, Beard RW. The effects of diazepam on the fetus. J Obstet Gynaecol Br Commonw 1972; 79: 635-38. 16. Owen JR, Irani SF, Blair AW. Effect of diazepam administered to mothers during labour on temperature regulation of the neonate. Arch Dis Child 1972; 47: 107-10. 1.

17.

Department of

McCarthy GT, O’Connell B, Robinson AE. Blood levels of diazepam in infants of two mothers given large doses of diazepam in labour. J Obstet Gynecol Br Commonw 1973, 80: 349-52 JE, Meyer J, Hailey DM. Diazepam in labour: its metabolism and effect on the

18. Cree

clinical condition and thermogenesis of the newborn Br Med J 1973; iv: 251-55. 19. Patrick MJ, Tilstone WJ, Reavy P. Diazepam and breast-feeding. Lancet 1972; i: 542. 20. Duffus GM, Tunstall ME, MacGillivray I. Intravenous chlormethiazole in preexclamptic toxaemia m labour. Lancet 1968; i: 335-37. 21. Hibbard BJ, Rosen M. The management of severe preeclampsia and eclampsia. Br J Anaesth 1977; 49: 3-9.

1421 METHODS

Nutrition INADEQUATE SUPPLIES

OF POTASSIUM AND MAGNESIUM IN RELIEF FOOD— IMPLICATIONS AND COUNTERMEASURES

Samples were obtained by one of us from relief shelters, feeding centres, and stores in Addis Ababa, Wollo, Hararghe, and Sidamo, all places where the League of Red Cross Societies (LORCS) was engaged in relief work. All samples were homogenised in 5 % trichloroacetic acid with a high-speed rotating knife (’Ultra-Turrax’, Janke and Kunkel, Staufen,West Germany). After centrifugation at 2000 rpm (1500 g) for 10 min,

KIM FLEISCHER MICHAELSEN*

Department of Pediatrics, Hvidovre Hospital, Denmark TORBEN CLAUSEN Institute of Physiology, Aarhus

University, 8000 Århus C, Denmark

Analyses of relief food used in Ethiopia showed that, because of food refinement, 6 out of 10 samples of cereals contained too little potassium and magnesium to cover daily needs. Malnutrition is often associated with gastrointestinal infections, which lead to further deficiency of these electrolytes. Potassium and magnesium are required for protein synthesis, growth, and

Summary

tissue repair. Since protein supplies are often marginal, relief food should contain sufficient potassium and magnesium to allow optimum utilisation of dietary nitrogen sources. This may be achieved by using coarse qualities of cereals, by supplementing cereals with legumes, and by avoiding cooking procedures that extract these salts from the cereals. INTRODUCTION

THE relief food distributed by international agencies consists of a large variety of products, the major source of calories being cereal. Although there is general agreement that the core items in the relief food basket should be cereals, legumes, and oil, often the reality is that, because of limited resources, only cereals or cereals and oil are distributed. Since some cereals have a low content of potassium (K) and magnesium (Mg), deficiency of these two electrolytes may result. K deficiency leads to poor utilisation of dietary nitrogen sources,l.2 thereby reducing the benefit from the already limited supplies of protein. Furthermore, Mg deficiency favours the net loss of K, and K deficiency may not be corrected unless Mg balance is restored. We therefore examined relief food samples for their K and Mg content. The samples were collected during the droughtrelief operation in Ethiopia, May-August, 1985. *Former medical

coordinator, League of Red Cross Societies, Addis

Ababa, Ethiopia.

an extract was

obtained that could be diluted for flame

photometry. The K content was determined with an FLM flame photometer with lithium as internal standard (’Radiometer’, Copenhagen, Denmark). Magnesium was determined by atomic absorption (’5000 Perkin Elmer’, Norwalk, Connecticut, USA). Control experiments showed that wet ashing of the samples in 65% HN03 gave the same values for Mg and K as the trichloroacetic acid extracts. To classify the wheat samples as whole-meal, brown, or white flour, the ash content was measured after being heated to 500°C in

a

furnace. RESULTS

K content

As shown in the accompanying table, the K content varied from around 25 to 400 mmol/kg dry wt. The cereals fell into two categories, the more refined, including white wheat and polished rice, had a low K content, and the other, of coarser quality, had 2-4 times as much K. The ash content of the wholemeal flour (sample nos 1 and 2) was 1 ’5—1 -7%, and that of the white flour samples (nos 3-6) was 0-4-05%. The minimum daily K requirement for an adult is around 20 mmol,4 corresponding approximately to 800 mg. Typically, the basic daily ration of relief food consists of 500 g of cereal, and if this were the only K source, the K content of the relief food should be above 40 mmol/kg to cover the minimum requirements. Obviously, this minimum requirement was not met by 6 of the 10 cereal samples tested. In contrast, milk powder and fish meal are rich sources of K.

Mg Content In most of the food samples there seemed to be a rough correlation between K and Mg content. An adult requires 10-15 mmol (240-360 mg) Mg daily,5,6and the same 6 cereals that were inadequate sources of K would also provide too little Mg in daily rations of 500 g. Again, coarse flour, soybean-enriched flour, or oatmeal seemed to supply sufficient amounts. However, coarser qualities of flour also contain more phytate, which interfere with the intestinal absorption of Mg and other vital divalent metal ions (eg,

Ca", Fe++, Zn++).

JA. The use of magnesium sulphate in preeclampsia-eclampsia. J Reprod Med 1979; 23: 107-14. 32. Pritchard JA. The use of the magnesium ion in the management of eclamptogenic toxemias. Surg Gynecol Obstet 1955; 100: 131. 33. Stone SR, Pritchard JA. Effect of maternally administered magnesium sulphate on the neonate. Obstet Gynecol 1970; 35: 574-78. 34. Lipsitz PJ. The clinical and biochemical effects of excess magnesium in the newborn. Pediatrics 1971; 47: 501-05. 35. Chadwick D. Pharmacokinetics of anticonvulsants. Br J Hosp Med 1983; 30: 421-24. 36. Sherwin AL, Eisen AA, Sokolowski CD. Anticonvulsant drugs in human epileptogenic brain. Arch Neurol 1973; 29: 73-77. 37. Symonds EM. Fits and hypertension in pregnancy. Hosp Update 1986; 12: 103-08. 38. Cloyd JC, Bosch DE, Sawchuck RJ. Concentration-time profile of phenytoin after admixture with small volumes of intravenous fluids. AmJ Hosp Pharm 1978; 35: 31. Pntchard

22. Pentikainen PJ, Valtonen W, Miettinen TA. Deaths in connection with chlormethiazole (Heminevrin) therapy. Int Clin Pharmacol Biopharm 1976; 14: J 225-30. 23. Scott DB. Chlormethiazole as a sleep cover for regional anaesthesia. Acta Psychiatr Scand 1986; 73 (suppl 329): 182-84 24. Wood C, Renou P. Sleepy and hypotonic neonates. Med J Aust 1978; ii: 73. 25. Johnson RA. Adverse neonatal reaction to maternal administration of intravenous chlormethiazole and diazoxide. Br Med J 1976; i 943. 26. Tunstall ME, Campbell DM, Dauson BM, Jostell KG. Chlormethiazole treatment and breast feeding. Br J Obstet Gynaecol 1979; 86: 793-98. 27. Pritchard JA, Cunningham FG, Pntchard SA. The Parkland Memorial Hospital protocol for the treatment of eclampsia: Evaluation of 245 cases Am J Obstet Gynecol 1984; 148: 951-60. 28. Sibai BM, McCubbin JH, Garland DA, Lipshitz J, Dilts PV. Eclampsia I: Observations from 67 recent cases. Obstet Gynecol 1981; 58: 609-13. 29. Sibai BM, Spinnato JA, Watson DL, Lewis JA, Anderson GD. Effect of magnesium sulphate on electroencephalographic findings in preeclampsia-eclampsia. Obstet Gynecol 1984; 64: 261-66. 30. Hilmy MI, Somjen GG. Distribution and tissue uptake of magnesium related to its pharmacological effects. Am J Physiol 1968, 214: 406.

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