BRIEF REPORTSevere Dactinomycin Overdose in an 18-Month-Old Child

Thomas V. Brogan, MD,1* James D. Mellema, MD,2 and David S. Jardine, MD1

Key words: multiorgan system failure; hypotension; neurologic sequelae; toxicity

Dactinomycin is an antineoplastic antibiotic used inthe treatment of a variety of tumors, including Wilmstumor, soft-tissue sarcomas, testicular cancer, lympho-mas, and breast cancer [1–3]. The reported extrahemato-poetic toxicities are mild and include nausea, vomiting,ulcers of the gastrointestinal mucosa, and elevation ofliver enzymes. Reports of severe toxicity with therapeu-tic doses [3] or overdoses [4] of dactinomycin are un-common. Choonara et al. [4] describe a case of a 17-year-old boy who received a total dose of 3.3 mg/m2 (0.1mg/kg) who had severe and prolonged myelosuppres-sion, electrolyte abnormalities, generalized seizures, andskin rash. Our experience with an 18-month-old boy whoreceived an overdose of dactinomycin is of interest be-cause of the massive amount administered, the severeacute toxicity affecting many organs, and the prolongedcomplications.

CASE REPORT

The patient was found to have a stage I peritesticularrhabdomyosarcoma and was transferred to the PICU atour institution with respiratory distress, oliguria, andpancytopenia following an inadvertent overdose of dacti-nomycin. For each of the first 3 days of the inductionphase of chemotherapy, he received a tenfold overdose ofdactinomycin (0.15 mg/kg/day rather than 0.015 mg/kg/day). The error was discovered after the third day oftreatment, and no further dactinomycin was adminis-tered. By day 5 after initiation of therapy, the child ex-perienced pancytopenia, severe mucositis, hepatic insuf-ficiency, pancreatitis, hyponatremia, hypocalcemia, re-spiratory distress, and melena.

He was transferred to our PICU on day 6. He wasfebrile and irritable but had an otherwise normal neuro-logic examination. He required supplemental oxygen,and chest radiography revealed extensive, bilateral, al-veolar–interstitial infiltrates. Initial therapy included broad-spectrum antibiotics, granulocyte colony-stimulatingfactor, and transfusion of blood products. Blood culturesobtained on day 5 were positive forStaphylococcus au-

reus. On day 7, his trachea was intubated and he wasstarted on conventional mechanical ventilation. He de-veloped pneumomediastinum with subcutaneous emphy-sema and was changed to high-frequency oscillatory ven-tilation on day 8. On day 9, he became anuric and wassupported with continuous venovenous hemofiltration(CVVH), for 14 days. Because his PT and PTT wereprolonged, heparin therapy was not required for CVVH.

On day 11, he developed hypotension refractory todopamine and epinephrine therapy. Cerebrospinal fluidand repeated blood, urine, and tracheal cultures revealedno pathogens. Broad-spectrum antibiotics were contin-ued, and amphotericin B was added. Echocardiographyrevealed good cardiac function. Cardiac index was mea-sured at 6.7 l/min/m2, and a systemic vascular resistanceindex (SVRI) was calculated to be 350–450 dyne-sec/cm5/m2. A phenylephrine infusion did not change theSVRI, but a norepinephrine infusion at 1.4mg/kg/minincreased the SVRI to 700 dyne-sec/cm5/m2.

Because of concerns of possible hypoadrenalism, ad-renocorticotropic hormone (ACTH) and cortisol levelswere drawn and the patient was started on stress doses ofhydrocortisone (40 mg/m2/day). Twelve hours followinginitiation of the hydrocortisone, the patient achieved nor-mal hemodynamic stability, and all inotropic and vaso-pressor support was discontinued. The initial serum cor-tisol was 9.9mg/dl (normal 7–20), but an ACTH assaywas not performed at that time owing to a technical error.A repeat ACTH level performed 4 hr after the first cor-tisone dose was <5 pg/ml (normal 9–52 pg/ml; adultvalues). A cosyntropin stimulation test 3 days after

1Children’s Hospital and Regional Medical Center and University ofWashington School of Medicine, Seattle, Washington2Sacred Heart Medical Center, Spokane, Washington

*Correspondence to: Thomas V. Brogan, MD, Department of Anes-thesia and Critical Care, Children’s Hospital and Regional MedicalCenter, P.O. Box 5371, Seattle, WA 98105.

Received 23 February 1999; Accepted 9 April 1999

Medical and Pediatric Oncology 33:506–507 (1999)

© 1999 Wiley-Liss, Inc.

completion of the 5-day hydrocortisone regimen revealednormal adrenal function, and an abdominal ultrasoundwas normal.

On day 20, neuromuscular blockade was discontinuedand the patient demonstrated choreoathetoid movementsof all extremities and weakness of the right arm. MRI ofthe brain revealed bilateral periventricular and frontalwhite matter bright T1 and T2 signals, T2 hyperintensityof the head of the left caudate, and hyperintense regionsof the cerebellar white matter. There was also a large leftparietal lesion involving primarily the cerebral cortex,consistent with an infarct in the area of the left middlecerebral artery.

Renal failure, coagulopathy, and pancytopenia all re-solved by day 22. He was successfully weaned frommechanical ventilation on day 28 but was found to bedysarthric. There was residual right arm weakness at thetime of discharge from the ICU, but the choreoathetosishad improved. The dysarthria also gradually improved,and he was discharged from the hospital on day 50.

He resumed vincristine and dactinomycin chemo-therapy several days following discharge. The patient didwell and finished his chemotherapy approximately 1 yearafter discharge. He has had normal psychosocial devel-opment following the overdose and no learning disabili-ties have been identified. Four years following the over-dose, the patient is normal except for slightly diminishedfunction of his right arm.

DISCUSSION

We document the survival of a child with only minorlong-term sequelae following a massive overdose ofdactinomycin that was much larger than any previouslyreported. The most commonly reported toxicities ofdactinomycin include mucositis, bone marrow suppres-sion, hepatic dysfunction, and erythematous rashes [1–4].These side effects are usually dose-dependent and tran-sient. Our patient suffered hematologic, circulatory, re-spiratory, pancreatic, liver, and renal failure requiring aprolonged stay in the intensive care unit. Although mul-tiple organ system failure often results in high mortality,this experience indicates that the injury produced by

dactinomycin overdose can be successfully treated withmeasures directed at supporting the failing physiologicsystems.

The patient’s shock was far more severe and persistentthan is usually observed in fulminant bacterial sepsis.Although we failed to demonstrate adrenal insufficiency,the patient promptly responded to corticosteroid therapyafter several days of severe hypotension. His responsesuggests that a trial of steroids should be administered inthe presence of severe, persistent hypotension followingdactinomycin overdose.

Choreoathetosis, dysarthria, and right arm weaknesswere observed after discontinuation of the neuromuscu-lar blocking agents. The lesions in the central nervoussystem seen on MRI were not typical of lesions causedexclusively by ischemia. No previous reports on dacti-nomycin have noted a direct toxic effect of the drug onneural tissue, but this possibility cannot be excluded,given the magnitude of the overdose. The patient’s neu-rologic function was slowly improving at the time ofdischarge and he appears to have developed normallysince discharge.

There were no extenuating circumstances surroundingthis overdose, which was reported to the FDA. The hos-pital protocols were reviewed and found to be appropri-ate and intact. This case does, however, demonstrate theimportance of continual review of quality-control proto-cols designed to prevent such errors in the administrationof therapeutic agents.

REFERENCES

1. Grimm RA, Muss HB, White DR, et al. Actinomycin D in thetreatment of advanced breast cancer. Cancer Chemother Pharma-col 1980;4:195–197.

2. Petrilli ES, Twiggs LB, Blessing JA, et al. Single-dose actinomy-cin-D, treatment for nonmetastatic gestational trophoblastic dis-ease. A prospective phase II trial of the gynecologic oncologygroup. Cancer 1987;60:2173–2176.

3. Petrilli ES, Morrow CP. Actinomycin-D toxicity in nonmetastatictrophoblastic disease: A cost effective chemotherapy. GynecolOncol 1983;16:190–195.

4. Choonara IA, Kendall-Smith S, Bailey CC. Accidental actinomy-cin-D overdosage in man, a case report. Cancer Chemother Phar-macol 1988;21:173–174.

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