Prolonged toxicity following acute phenytoin overdose in a child

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S B T s to assess antibiotics in osteomyelitis

acute staphylococcal osteomyelitis (ASO), Pediatr Res 9:339, 1975. TetzlaffTR, McCracken GH, and Nelson JD: Oral antibiotic therapy for skeletal infections of children. II. Therapy of osteomyeiitis and suppurative arthritis, J PBDIATR 92:485, 1978. Kienitz M: Cephalosporin antibiotics in the treatment of acute osteomyelitis in children, Postgrad Med J Suppl:87, 1971. Feigin RD, Pickering LK, Anderson D, Kenney, RE, and Shackleford PG: Clindamycin treatment of osteomyelitis and septic arthritis in children, Pediatrics 55:213, 1975. Geddes AM, Dwyer NSJ, Ball AP, and Amos RS: Clindamycin in bone and joint infections, J Antimicrob Chem0ther 3:501, 1977. Pien FD, Williams RD, and Vosti KL: Comparison of broth and human serum as the diluent in the serum bactericidal test, Antimicrob Agents Chemother 7:113, 1975. Blazevic DJ, Hall CT, and Wilson ME: Practical quality control procedures for the clinical microbiology laboratory, Cumitech 3:1, 1976. Barry AL: The antimicrobic susceptibility test: Principles and practices, Philadelphia, 1976, Lea & Febiger, Publishers. Reller LB, and Stratton CW: Serum dilution test for bactericidal activity. II. Standardization and correlation with antimicrobial assays and susceptibility tests, J Infect Dis 136:196, 1977.

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14. Blockey NH, and McAllister TA: Antibiotics in acute osteomyelitis in children, J Bone Joint Surg 54B:299, 1972. 15. Walker SH: Staphylococcal osteomyelitis in children. Success with Cephaloridine-Cephalexin therapy, Clin Pediatr 12:98, 1973. 16. Mollan RAB, and Piggot J: Acute osteomyelitis in children, J Bone Joint Surg 59B:2, 1977. 17. Ek J: Acute hematogenous osteomyelitis in infancy and childhood. Early clinical diagnosis and effect of treatment, Clin Pediatr 10:377, 1971. 18. Dich VQ, Nelson JD, and Haltalin KC: Osteomyelitis in infants and children. A review of 163 cases, Am J Dis Child 129:1273, 1975. 19. Sabath LD, Garner C, Wilcox C, and Finland M: Effect of inoculum and of beta-lactamase on the anti-staphylococcal activity of thirteen penicillins and cephalosporins, Antinaicrob Agents Chemother 8:344, 1975. 20. Jawetz E, and Brainerd HD: Staphylococcal endocarditis: Results of combined antibiotic therapy in fourteen consecutive cases (1956-1959), Am J Med 32:17, 1962. 21. Carrizosa J, Kaye D: Antibiotic concentrations in serum, serum bactericidal activity, and results of therapy of streptococcal endocarditis in rabbits, Antimicrob Agents Chemother 12:479, 1977.

Brief clinical and laboratory observations Prolonged toxicity following acute phenytoin overdose in a child John T. Wilson, M.D., F.A.A.P.,* John G. Huff, M.D., and Anthony W. Kilroy, M.D., M.R.C.P., Nashville, Tenn.

THE MAJORITY o f reports characterize the toxic m a n i festations o f acute p h e n y t o i n overdose as b e i n g relatively b r i e f in d u r a t i o n . O n s e t of s y m p t o m s is usually within one to two h o u r s a f t e r ingestion. 1-3 T h e m a j o r manifestations From the Division o f Pediatric Clinical Pharmacology, Departments o f Pediatrics, Pharmacology, and Neurology, Vanderbilt Medical Center. *Reprint address: Section on Clinical Pharmacology, Department of Pharmacology and Therapeutics, Louisiana State University, School of Medicine in Shreveport, Shreveport, LA 71130.

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o f D P H toxicity usually persist for a b o u t four to five days. In one report 3 toxic effects w a n e d c o n c o m i t a n t with a decline in D P H p l a s m a levels over a period of four days. T h e most p r o m i n e n t effects were seen in the first three Abbreviations used DPH: phenytoin VCH: Vanderbilt Children's Hospital days, a n d were associated with p l a s m a levels over 45 /~g/ml. M o r t a l i t y - p l a s m a level correlates are unavailable, b u t r e p o r t e d deaths h a v e occurred within 34 to 53 hours ~-~

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Brief cfinical and laboratory observations

The Journal of Pediatrics July 1979

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Figure, Acute poisoning with phenytoin in a 6-year-old child. after a n overdose. D u r a t i o n of t o x i c effects does n o t a p p e a r to b e related to dose of D P H ingested. Previous reports o f D P H overdose thus imply that the d u r a t i o n of major toxic effects is one week or less a n d that clinical i m p r o v e m e n t is to b e expected c o n c o m i t a n t with falling p l a s m a levels of the d r u g d u r i n g this period. This r e p o r t describes a n atypical course for D P H toxicity in a 6-year-old child. T h e d u r a t i o n of s y m p t o m s was p r o l o n g e d c o r n c o m i t a n t with protracted b u t relatively low levels o f D P H in plasma. CASE REPORT A 6-year-old white girl was admitted to Vanderbiit Children's Hospital because of deteriorating neurologic status following phenytoin (Dilantin, DPH) overdose. Three days prior to transfer to VCH the child was found to be weak, unsteady, and delirious. An empty bottle of Dilantin (25 tablets of 50 mg each, estimated 1,500 mg total) was found. (We estimate 8 PM as time of ingestion, arbitrarily denoted as day zero of the illness.) Ipecac-induced emesis and gastric lavage were performed .at a local hospital. Activated charcoal was given orally. A magnesium sulfate enema was administered, These procedures were performed approximately four hours after the overdose. On

admission she was stuporous, with diminished reflexes. Her condition deteriorated during the next few hours until she became responsive only to deep pain. Spontaneous and repetitive opisthotonic posturing and intermittent disconjugate position of the eyes were noted. Forty-eight hours following the overdose she was first noted to have a generalized tonic spasm ("seizure"); blood gas analysis showed a Pao~ of 22 mm Hg, Pco~ 57 mm Hg, and the pH was 7.33. With additional oxygen her PAD._,increased only to 48 mm Hg. During transfer by helicopter to VCH on day 3, she had a first episode of apnea and required oxygen delivered by pressure assist. On admission to VCH she had spontaneous opisthotonic movements with extensor posturing of the legs and flexion of the arms, either spontaneous or elicited by a mild stimulus, The test for deep pain response provoked a generalized flexion withdrawal response. The eyes were disconjugate intermittently; cold caloric tests were normal. Respiratory pattern was irregular. All deep tendon reflexes were present; right ankle clonus was noted. Babinsk~ reflex was present bilaterally. The admission serum electrolytes, complete blood count, and liver function tests were normal. A drug screen of a urine was positive for phenytoin. Her course was marked in the first 24 hours (day 3-4) by coma and a respiratory pattern which showed intermittent spontaneous respirations while on the respirator. The opisthotonic posturing

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persisted but with decreased frequency and severity. Her response to deep pain changed to one mainly of flexion. Her reflexes continued to be abnormally brisk, with bilateral ankle clonus and positive Babinski reflex. Over days 4 and 5, the posturing gradually decreased in frequency but she remained comatose, with a decorticate response to deep pain. Respirator assist was discontinued on day 6; In response to deep pain there was now facial grimacing but there was no response to voice commands. The posturing subsequently ceased, but the reflexes continued to be hyperactive, associated with clonus and Babinski reflexes. An electroencephalogram showed generalized 1 to 3 cps slowing with no focal discharges. By day 10 she was more alert and fixed her eyes on the examiner. She would obey simple commands to hand-squeeze and fixate. Her reflexes returned to normal and the previous clonus and Babinski reflexes were absent. Tremors and lethargy remained. Her neurologic examination was normal by day 14. The elimination profile of plasma DPH in regard to clinical findings and treatment regimens is summarized in the Figure. A plasma DPH level of 52 ,ag/ml was obtained about four hours after ingestion. The highest level (65 /~g/ml) was obtained at about 72 hours. From day 3 to 5 her clinical condition remained unchanged and very little change in plasma DPH levels were observed. For comparison, a T50% for DPH decay 2in plasma was calculated and found to be 532 hours during this period. Diazepam was used intermittently to control opisthotonic posturing and tremors. Hemodialysis was considered on day 6 but postponed when the DPH plasma level fell to 35 /~g/ml. Little change in level of plasma DPH was seen over the next two days so that dialysis was again considered, especially in view of the unexplained prolonged course of clinical symptoms. By day 8, however, a consistent downward trend in DPH plasma levels was observed on day 6 and on day 8, not accompanied by a change in the percent of DPH bound to plasma protein. A T50% = 112 hours was found for days 6 to 12. During this slow elimination phase of plasma DPH (from 35 to 15 /~g/ml) clinical improvement was seen, especially apparent on days 8 to 10 when DPH levels Were 35 to 25/xg/ml. The terminal elimination of DPH was seen on days 12 and 13, with a plasma half-life of 16 hours. Signs of DPH toxicity did not abate until the plasma level fell to 3 /~g/ml by day 13. DISCUSSION Toxicity during chronic treatment with DPH is seen when plasma levels exceed 30 ~g/ml. Toxic effects are better related to the free concentration of D P H and are more prevalent at > 5 t~g/ml of free drug. 7 Minor signs of intoxication are encountered when free D P H levels are 1.5 to 3.5 /~g/ml. Our patient had a free D P H plasma concentration of 4.9/~g/ml on day 2 and 1.9/~g/ml on day 8. Major clinical manifestation s of toxicity were present at both times. The m a x i m u m plasma level of total D P H (65 t~g/ml) in our patient is lower than in two previously reported cases of severe acute intoxication '' 3 and certain cases of chronic

Brief clinical and laboratoJy observations

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intoxication with m a x i m u m levels of 92 to 100/xg/ml? 9" Major manifestations of D P H toxicity were not seen when plasma levels reached 17/~g/ml, usually about 4 to 6 days after either an overdose or discontinuation of the drug?, Our patient had a persistent elevation of D P H in plasma, but the levels were not appropriately high with regard to the severe toxicity observed. Complete recovery was not apparent until D P H levels reached 3/~g/ml, 13 days after the overdose. Thus, an acute overdose of D P H can be followed by a prolonged period of toxicity associated with comparatively low plasma levels of the drug. The prolonged toxicity apparently resulted from slow elimination of D P H and was not a consequence of abnormal protein binding of the drug. Data are not available to rule out the possibility of a toxic D P H metabolite, the formation and clearance of which could be more closely associated with the observed severe and prolonged clinical course. That certain unknown but toxic metabolites occur with an acute and high body burden of D P H can be inferred from skin toxicity observed in children given loading doses of DPH. 1~ ~1 The prolonged clinical course in this patient raised the q u e s t i o n about measures to eliminate phenytoin. Dialysis is predictably of limited value in accelerating the removal of D P H from the circulation. D P H is about 89 to 91% plasma protein-bound, and only an estimated 6% of the body burder~ resides in the plasma compartment. Some reports, however, have implied that dialysis may be useful. In one case the D P H plasma level fell from about 150 to 30 t~g/ml during 35 hours of peritoneal dialysisl~; an estimated 775 m g of D P H was recovered in the dialysate. If one assumes a 70 kg m a n with a volume of distribution = 0.61/kg for total D P H , this amount would correspond to 18.5/~g/ml rather than the observed 120 ~ g / m l decrease in plasma level. In another patient, hemodialysis was initiated 138 hours after ingestion and performed for 96 hours? Plasma levels of D P H fell from 50 to 4/~g/ml; D P H was not detected in the dialysate even though 1.9 gm of D P H should have been removed to produce such a fall in plasma levels. In another patient, plasma D P H levels declined from 112 to 3.5/~g/ml after 40 hours of peritoneal dialysis, begun 74 hours after an overdose of D P H 5 Only trace levels of DPH, however, were found in the dialysis fluid. In reported instances of dialysis, matched controls were not used. Our experience demonstrates the misinterpretation which can follow from lack of such control data. Consideration of dialysis on days 6 and 8 was followed by a decline in plasma levels which surely would have been attributed to dialysis had it been undertaken. An apparent accelerated decline in plasma D P H with dialysis has been

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B r i e f clinical and laboratory observations

seen in other instances of acute intoxication 3 as well as in chronic intoxication?. 9. ~a This pattern is a result of saturation kinetics operative for D P H elimination in children. 19. . . . . :~D P H is metabolized to para-hydroxyphenytoin (about 80% of a dose) and other metabolites, and little is excreted unchanged in the urine. That previous studies have not reported significant amounts of D P H in dialysis fluid is indicative of metabolic clearance occurring concurrently with dialysis. The apparent clinical improvement reported to occur "immediately" during or after dialysis may be fortuitous or due to removal of an active D P H metabolite. Thus, until a series of D P H intoxicated patients are dialysed and compared with nondialysed controls, each group having excretion studies of D P H and para-hydroxyphenytoin in urine and dialysis fluid, dialysis should be considered only as an investigative procedure. REFERENCES 1. Tenckhoff H, Sherrard DJ, Hickman RO, et al: Acute diphenylhydantoin intoxication, Am UDis Child 116:422, 1968. 2. Thiel GB, Richter, RW, Powell MR, et al: Acute Dilantin poisoning, Neurology 11:138, 1961. 3. Holcomb R, Lynn R, Harvey B, Sweetman BJ, and Gerber N: Intoxication with 5,5-diphenylhydantoin (Dilantin), J PEDIATR80:627, 1972.

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Schmeiser M: Totliche vergiftung mit zentopil beim kind, kinderasrztl, Praxis 20:158, 1952. Tichner JB, and Enselberg CD: Suicidal Dilantin (sodium diphenylhydantoin) poisoning, N Engl J Med 245:723, 1951. Petty CS, Muellings RJ, and Sindell W: Accidental fatal poisoning with diphenylhydantoin (Dilantin), J Forensic Sci 2:279, 1957. Booker HE, and Darcey B: Serum concentrations of free diphenylhydantoin and their relationship to clinical intoxication, Epilepsia (Amsterdam) 14:177, 1973. Gerber N, Lynn R, and Oates J: Acute intoxication with 5,5-diphenylhydantoin (Dilantin) associated with impairment of biotransformation, Ann Intern Med 77:765, 1972. Pruitt AW, Zwiren GT, Patterson JH, et al: A complex pattern of disposition of phenytoin in severe intoxication, Clin Pharmacol Ther 18:112, Wilson JT, Hojer B, and Rane A: Loading and conventional dose therapy with phenytoin in children: Kinetic profile of parent drug and main metabolite "in plasma, Clin Pharmacol Ther 20:'48, 1976. Wilson JT, Hojer B, Thomson G, Rane A, and Sjoqvist F: High incidence of a concentration dependent skin reaction in children treated with phenytoin, Br Med J 1:1583, 1978. Blair AAD, Hallpike JF, Lascelles PT, et al: Acute diphenylhydantoin and primidone poisoning treated by peritoneal dialysis, J Neurol Neurosurg Psychiatry 31:520, 1968. Garrettson LK and Jusko WJ: Diphenylhydantoin elimination kinetics in overdosed children, Clin Pharmacol Ther 17:481, 1975.

Acute hepatic failure in severe iron poisoning Wallace A. Gieason, Jr., M.D.,* Daphne E. deMello, M.D., Fernando J. deCastro, M.D., and James J. Connors, M.D., St. Louis, Mo.

A L T H O U G H PERIPORTAL NECROSIS 1 has been described in both h u m a n beings and experimental animals dying from iron intoxication, clinical and biochemical expressions of such lesions are largely limited to reports of jaundice occurring 24 to 48 hours after iron ingestion. ~ Covey ~ described hepatic failure as a late complication of iron poisoning, and suggested acute hepatic failure as p h a s e III of the clinical course Of patients with iron intoxication, with phase IV (pyloric stenosis) and a speculative stage V (cirrhosis) as late From the Departments of Pediatrics and Pathology, St. Louis University School of Medicine and Cardinal Glennon Memorial Hospital for Children. *Reprint address: Division of Gastroenterology, Department of Pediatrics, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284.

complications. Acute hepatic failure, the clinical syndrome due to severe hepatic dysfunction or massive hepatic necrosis, is not c o m m o n l y recognized as a part of the clinical syndrome of iron poisoning. This report describes such a patient. CASE REPORT Patient E. B., an 18-month-old boy, was transferred from another hospital eight hours after ingestion of 50 to 60 ferrous sulfate tablets (3,200 to 3,900 mg elemental iron). He was obtunded, hypotensive, and had bloody diarrhea. The blood pressure was restored with infusions of albumin, whole blood, and fluids. Therapy was instituted with parenteral desferrioxamine, gastric lavage, and instillation of magnesium sulfate. The serum iron concentration was 3,630 /~g/dl and rose to 13,585 /~g/dl three hours later (11 hours after ingestion). A doublevolume exchange transfusion was performed, after which the serum iron value was 1,148 /zg/dL SGPT on admission was 58

0022-3476/79/070138 +03500.30/0 9 1979 The C. V. Mosby cO.