CARDIAC ARREST DUE TO HYPERKALEMIA FOLLOWING THERAPY FOR ACUTE LYMPHOBLASTIC

LEUKEMIA DEBORAH WILSON, MD, ALAN STEWART, MD, JAMES SZWED, MD

AND LAWRENCE H. EINHORN, MD

A patient with acute lymphoblastic leukemia with a large tumor burden is presented. Following successful chemotherapy, the patient experienced a car- diac arrest presumably due to hyperkalemia in association with hyperuricemia. The implication of these findings for patients with responsive hematological malignancies is discussed.

Cancer 39:2290-2293, 1977.

YPERURICEMIA ASSOCIATED WITH RENAL H failure is a known complication of leu- kemia and lymphoma due wholly or in part to the rapid turnover of neoplastic cells. "vl'

Chemotherapy has been shown to exacerbate this complication as a result of the accelerated breakdown of tumor cells. 12 .798 Hyperkalemia has also been observed following chemotherapy in patients with Burkitt's lymphoma and radio- therapy in a patient with chronic lymphocytic leukemia and may be responsible for sudden death due to cardiac arrhythmia. ','*'The follow- ing case report describes a patient with acute lymphoblastic leukemia who had a cardiac ar- rest secondary to hyperkalemia shortly after in- itiation of anti-leukemic therapy.

CASE REPORT

A 17-year-old male was referred to the Hema- tology-Oncology service at Indiana University Medi- cal Center (IUMC) on May 16, 1975, for treatment of acute lymphoblastic leukemia (ALL). He was well until one week prior to admission when he com- plained of fronto-occipital headaches, fever to 37.8OC, fatigue, and enlarged lymph nodes. A hemogram re- vealed a white brood count (WBC) of 150,000/mms, predominantly lymphoblasts. The uric acid was 13 mg/100 ml and the latic dehydrogenase (LDH) was greater than 1000 I.U. He was anemic and throm-

From the Hematology-Oncology and Nephroloqy Depart- ments, Indiana University Medical Center, Indianapolis, Indiana.

Addrt-ss for reprints: Lawrence H. Einhorn, MD, Indiana University Medical Center. Hematology-Oncology, 1100 Wrst Michigan. Emerson Hall Room 435, Indianapolis, IN 46202.

Accepted for publication August 10, 1976.

bocytopenic and packed red blood cells and platelets were given prior to transferring him to IUMC. The only medication prior to transfer was allopurinol 100 mg tid which he received for three days prior to initiation of chemotherapy at IUMC.

O n admission to IUMC, be was a healthy appear- ing young male with a blood pressure of 118/50 and a regular pulse of 68/minute. His temperature was 36.7"C and the respiratory rate was 12/min. There were numerous lymph nodes palpable to 3 cm in the anterior and posterior cervical chains, several 1-cm supraclavicular and submental nodes, and multiple large axillary and inguinal nodes. The chest was clear, there was sternal tenderness to palpation, and a grade 2/6 systolic ejection murmur was present. The liver was percussed to 15 cm and was easily palpable below the right costal margin. The spleen was pal- pable 4 cm below the left costal margin.

The hemoglobin was 11.7 mg/100 ml the hem- atocrit 34 mg/100 ml, and the WBC 207,900 with 81% lymphoblasts. T h e platelet count was 70,000/mm3. The sodium was 142 mEq/L, the potas- sium 3.6 mEq/L. the chloride 102 mEq/L and the bicarbonate 32 mEq/L. The blood urea nitrogen (BUN) was 13 mg/100 ml, the serum creatinine 1.1 mg/ 100 ml, the serum glucose 110 mg/100 ml, serum calcium 10.8 mg/lOO ml, phosphorus 3.2 mg/100 ml, and uric acid 9.1 mg/ 100 ml. The prothrombin time was 14 seconds with a control of 11 seconds, the LDH 531 I.U., the serum glutamic oxalacetic transaminase (SGOT) 137 I.U. The urine pH was 7.0, the specific gravity 1.016, and it was negative for protein, glucose, and ketones; there were 0-3 white blood cells/hpf, no red cells, and there was calcium oxalate crystals but no uric acid crystals present. The EKG (Fig. 1A) and the chest x-ray were normal. A bone marrow aspirate confirmed the diagnosis with 95-9970 lymphoblasts present.

The allopurinol was continued at 100 mg tid and the patient was begun on prednisone 75 mg per day in divided doses (40 mg/M2/d). The afternoon of admis-

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No. 5 HYPERKALEMIA IN ACUTE LEUKEMIA Wilson et al. 2291

FIG. 1. Electrocardiographs (EKGs). A. (Top) Admission EKC, B. (Bottom) EKG following cardiac arrest.

sion he was treated with Daunomycin 150 mg (80 mg/m2) and vincristine 2.8 mg. (1.5 mg/MZ) in- travenously. Seventeen hours after chemotherapy had begun he had a cardiorespiratory arrest and was suc- cessfully resuscitated. Immediately following the ar- rest the serum chemistries were: sodium 135 mEq/L, potassium 6.8 mEq/L, chloride 94 mEq/L, bicarbo- nate 10 mEq/L, BUN 70 mg/100 ml, serum creati- nine 4.5 mg/100 ml, serum glucose 480 mg/100 ml, uric acid 21 mg/100 ml, prothrombin time 29 sec- onds, and the serum lactate 20 mg/100 ml. The he- moglobin was 10.4 mg/ 100 ml, the WBC 85,000/mm3 with 58% lymphoblasts, and the platelet count was 35,000/mmS. The arterial PO, on 40% oxygen was 350 mmHg, the pCOz 31 mmHg, the p H 7.16. Blood cultures were drawn and were subsequently negative. The patient’s vital signs were stable, however the

EKG throughout the remainder of the day showed progressively widening QRS complexes and peaked T-waves (Fig. 1B). The serum potassium rose to a maximum of 8.8 mEq/L despite the administration of Kayexalate enemas, insulin, calcium chloride, and sodium bicarbonate. The serum clacium was 6.7 mg/ 100 ml, the phosphorus 14.1 mg/ 100 ml, and the uric acid rose to 28 mg/100 ml. Furosemide 240 mg was given slowly as a n intravenous infusion over 30 minutes and the patient remained anuric. The small amount of urine produced was packed with red blood cells and amorphous debris but not uric acid crystals were seen.

Hemodialysis was begun twelve hours postarrest and resulted in a fall of the potassium to 3.4 mEq/L and the uric acid to 20 mg/100 ml. Five hours later the uric acid was 36.9 mg/ 100 ml, the serum calcium

TABLE 1. Clinical Course

Hospital BUN Creatinine Uric acid Potassium Calcium/ day Hemoglobin WBC Platelets (mg/100ml) (mg/100 mi) (rng/100 mi) (mEq/L) phosphorus

1 11.7 207,900 70,000 13 1.1 9.1 3.6 10.8/32 2 10.4 46,000 35.000 72 4.6 28 8.8 6.7/ 14.1 3 8 .3 2,100 20,000 100 4.9 36.9 4.9 5.7/ 18.3 4 7.6 1,700 40,500 78 5.1 14.3 4.3 5.9/ 14.2 6 7.5 544 57,000 164 13.3 9.1 4.3 __

16 6.9 3,500 67,500 1 so 10.6 8.0 5.5 __ 25 7.1 3,000 61,000 37 3.7 6.4 3.9 ~

33 9.5 16,000 200,000 24 0.9 4.3 4.3 9.0/4.1

2292 CANCER May 1977 Vol. 39

peripheral white blood cell count and the reduc- tion in the size of the extramedullary tumor mass resulted in the release of potassium into the circulation. A rise in serum potassium can be expected with metabolic acidosis due to cellu- lar shifts of hydrogen and potassium. However, according to a nomogram" which correlates ar- terial p H with serum potassium concentration, a level of 5.5 mEq/L would be expected at p H 7.16 with normal total body potassium. A level of 6.8 mEq/L indicates a total body excess of approximately 670, which is not only a result of the release of potassium from the lysis of leu- kemic cells but to the inability to excrete the extra load in renal failure. Very few cases of hyperkalemia following the treatment of lym- phocytic leukemia have been reported although hyperkalemia has resulted from the treatment of Burkitt's lymphoma. b q 6 These patients also had large tumor burdens similar to that of our patient. Fennelly et al.' calculated that the amount of potassium released from a certain mass of tumor tissue could account for the level of hyperkalemia they observed post-cardiac ar- rest. According t o Rigas13 a serum potassium rise of 0.3 mEq/l day is the maximum expected with complete renal shutdown without excessive catabolism. Although pseudohyperkalemia has been reported in patients with myeloprolifera- tive disorders, the blood specimens from our patient were not incubated long enough to ac- count for the hyperkalemia.

Kjellstrand' noted hyperphosphatemia in sev- eral of the patients in his study, all of whom had received chemotherapy. I n our patient, the mag- nitude of the hyperphosphatemia and reciprocal hypocalcemia also were not compatible with the degree of renal failure, and the etiology is thought to be the release of phosphorus from tumor cells. There is also the added danger of precipitation of calcium phosphate as well as uric acid in the kidney of these patients which may cause further nephropathy.

No source of infection or bleeding could be found in this patient to account for the cardiac arrest. We therefore believe that this case is unique in that hyperuricemia and renal failure were complicated by hyperkalemia, extreme hy- perphosphatemia, and marked hypocalcemia and severe metabolic acidosis. Hyperkalemia was probably the cause of the cardiac arrest. The successful diagnosis and treatment of a hy- perkalemia-induced cardiac arrest is a rare and fortuitous event. However, hyperkalemia may be the cause of sudden unexplained deaths in leu- kemia and lymphoma patients shortly after the initiation of effective cytolytic therapy.

was 5.7 mg/100 ml and the phosphorus was 18.3 mg/100 ml. Extubation and elimination of oxygen therapy were accomplished 24 hours after the arrest. There were no neurologic deficits and the adenopathy and hepatosplenomegaly were remarkably reduced. During the first 48 hours after chemotherapy was begun the WBC dropped to ZlOO/mm?

A total of 12 hemodialysis treatments were required over the ensuing 19 days with the plasma creatinine reaching a maximum of 13.3 mg/100 ml on hospital day 8 before renal function began to improve. The serum uric acid remained below 10 mg/100 ml after the fourth day of hemodialysis. The patient was anuric or oliguric for 18 days but gradually the renal function returned to normal. O n the 14th hospital day, a bone marrow aspirate was normal with no leukemic lymphoblasts, and on the 33rd hospital day the patient was discharged with a BUN of 24 mg/100 ml and a plasma creatinine of 0.9 mg/100 ml. Sub- sequently, he has been followed as an outpatient and is presently receiving maintainance chemotherapy consisting of methotrexate and 6-mercaptopurine. He has received prophylactic whole brain radiotherapy and intrathecal methotrexate. He remains in a com- plete remission with normal renal function and nor- mal neurologic status five months following his car- diac arrest, and he has returned to school.

DISCUSSION

Elevation of serum uric acid is frequently seen in young patients with ALL due to rapid cell turnover, 14,10 and resulting uric acid nephro- pathy with renal shutdown has been described previously. 12,',8,10 Several proposed modes of pre- vention and treatment have also been described which include intravenous hydration, acetazola- mide, mannitol, furosemide, ethacrynic acid, and sodium bicarbonate to ensure a good diur- esis and alkalinization of the urine to enhance clearance of uric acid. 12,6-8*2-11 Allopurinol is also used in large doses to block the conversion of hypoxanthine and xanthine to uric acid.'" Kjellstrand' found these methods unreliable for the prevention or the cure of uric acid nephro- pathy, although there are reports of possible reversal of impending renal failure with the above methods 12~e,16 and peritoneal dialysis. The treatment of choice in urate nephropathy is hernodialysis because the clearance of uric acid is 10 to 20 times greater with hemodialysis than with peritoneal dialysis. 723 Most of the patients in Kjellstrand's study diuresed promptly after the serum uric acid was lowered to 10-20 mg/ 100 ml which supports the hypothesis that renal damage may occur secondary to tubular obstruction in urate nephropathy.

W e believe that the rapid lysis of leukemic cells as evidenced by the precipitous fall in the

No. 5 HYPERKALEMIA I N ACUTE LEUKEMIA Wilson et al. 2293

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