magnesium toxicity secondary to catharsis during management of theophylline poisoning

Magnesium Toxicity Secondary to Catharsis During Management of Theophylline Poisoning

JAMES C. GARRELTS, PHARMD,*t

WILLIAM A. WATSON, PHARMD,$§ KELLY D. HOLLOWAY, MD,”

DONNA E. SWEET, MDT

Multiple doses of oral activated charcoal are used increasingly to promote elimination of toxins that have already reached the bloodstream: thls Is often referred to as gastmintestlnal dialysis. Cathartics usually am used In conjunction to hasten transit of the charcoal-adsorbed toxin. In the pmsent case, a regimen of activated charcoal and magneslum citrate was used to tmat a patient with theophylline poisoning. It was effective in lowering the patient’s serum theophylline concentration but produced an elevated magnesium level associated with decreased msponslve- ness, confusion, and diminished deep tendon reflexes. Magne- sium citrate may not be the optimal cathartic for use in gastmlntestinal dialysis, at least in selected patients. Sorbltol has been shown to produce a more rapid catharsis without dis- turbing magneslum serum concentrations. Therefore, the use of sorbltol In place of magnesium citrate, at least in selected patients, may be preferred. (Am J Emerg Med 1989;7:34-37. 0 1989 by W.8. Saunders Company.)

Activated charcoal is currently enjoying expanded use because of recognition of its ability to remove toxins that have already reached the bloodstream.1‘3 Ca- thartics usually are administered concurrently to hasten transit of charcoal-adsorbed drugs from the gastrointestinal tract.4’5 A regimen of activated charcoal plus a cathartic has been shown to be effective in hastening elimination of theophylline from the bloodstream.6-‘0

The combination of activated charcoal and a cathartic is usually considered a relatively safe method of treating toxic ingestions. However, an accumulating number of reports indicate that this may not be the case for magnesium-containing cathartics. ‘t-l4 We re-

From the *Department of Pharmacy, St Francis Regional Medi- cal Center and the tuniversity of Kansas School of Medicine- Wichita, Wichita, KS; the *Clinical Pharmacokinetics Labora- tory, Millard Fillmore Hospital and the 9Department of Anesthe- sia, School of Medicine, SUNY at Buffalo, Buffalo, and the “H.C.A. Wesley Medical Center, Wichita, KS.

Manuscript received December 9, 1987; revision accepted Jan- uary 12, 1988.

No reprints available.

Key Words: Magnesium, magnesium citrate, cathartics, magnesium toxicity, theophylline poisoning, activated charcoal.

0 1989 by W.B. Saunders Company.

07356757/89/0701-0008$500/O

34

port a case in which activated charcoal and magnesium citrate were used to treat theophylline toxicity, result- ing in symptomatic hypermagnesemia.

CASE REPORT

An 87-year-old white man presented to the emergency department (ED) at approximately 9:30 AM with a chief com- plaint of a two-day history of anorexia, nausea, vomiting, occasional “rapid heartbeat,” fatigue, and increased irrita- bility. He had been seen several times in the ED during the past week for complaints of shortness of breath. Physical examination revealed a thin, elderly appearing man with a temperature of 98°F; a pulse 140 beats/minute, which was irregular with frequent premature beats; respirations 26 per minute; and a supine BP of 150/80 mmHg. The skin was warm and dry with decreased turgor; the mucous mem- branes of the oropharynx were also dry. Examination of the lungs revealed t-ales in the right base with diffuse expiratory wheezing and poor air exchange. The cardiovascular examination was remarkable for a rapid ventricular rate with frequent premature ventricular contractions. The extremities revealed 2 + pitting edema to the ankles. The remainder of the physical examination was noncontributory.

Laboratory values obtained in the ED were serum sodium, 130 mEq/L; potassium, 4.2 mEq/L; chloride, 91 mEq/L; car- bon dioxide, 27 mEq/L; magnesium 2.3 mg/dL; phosphorus, 3.1 mg/dL; glucose, 264 mg/dL; creatinine, 1.8 mg/dL; and BUN, 65 mg/dL. Hemoglobin was 11.7 gm/dL, hematocrit was 34.8%, and WBC count was 25,300lp.L with 4% bands, 83% segmented neutrophils, 1% lymphocytes, 11% mono- cytes, and 1% metamyelocytes. Results of urinalysis were unremarkable. Two blood cultures were negative. Lactate dehydrogenase was elevated, at 276 U/L, and uric acid was 14.1 mg/dL. Arterial blood gases on room air revealed a pH of 7.48; PO,, 62 mmHg; and PCO,, 38 mmHg. The remainder of the laboratory tests were unremarkable. Chest x-ray showed diffuse bilateral chronic changes and hyperaeration consistent with chronic obstructive pulmonary disease, as well as a possible infihrate in the right lower lobe.

The patient had a long history of chronic obstructive pulmonary disease, for which he received home oxygen therapy. His medications included sustained-release theophylline (Slo-Bid; Rorer, Ft Washington, PA), 300 mg twice daily; metaproterenol, 0.2 cc by inhalation four times daily; prednisone, 20 mg by mouth every morning; and a beclom- ethasone inhaler which he used four times daily. In addition, he received digoxin, 0.125 mg every day, for a history of atrial flutter. He had a history of hypertension, for which he

GARRELTS ET AL I CATHARTIC-INDUCED MAGNESIUM TOXICITY

received one Maxzide (Lederle, Wayne, NJ) tablet daily, and peptic ulcer disease which was treated with ranitidine, 150 mg by mouth twice daily.

Hospital Course

Admission blood collection measured a serum theophylline concentration of 75 mg/L (Fig 1). Additional questioning of the patient and his wife revealed that he had ingested “several” extra theophylline tablets that morning in an ef- fort to resolve his shortness of breath. The patient was im- mediately transferred to a cardiac unit and continuous ECG monitoring was instituted. The heart rate at this time was 130 beats/min, and a 1Zlead ECG demonstrated atrial flutter with variable AV block. A 40-g initial dose of activated charcoal (Liqui-Char; Jones Medical, St Louis) was administered along with 4 oz of magnesium citrate (2:OO PM). Activated charcoal, 25 g, was repeated every two hours, and an additional 4 oz magnesium citrate was administered with every other dose of activated charcoal. The patient received a total of nine doses of activated charcoal and five doses of magnesium citrate over a ldhour period (Fig 1). There was no evidence that this regimen resulted in dehydration of the patient.

This regimen was effective in lowering the serum theophylline concentration. The patient reverted to normal sinus rhythm at approximately 4 AM the day after admission. At 6 AM, the theophylline serum concentration had fallen to 10 mg/L. However, the patient was noted to be much less responsive than he had been upon admission, and he was disoriented and unable to answer questions appropriately. Deep tendon reflexes were diminished bilaterally. Serum magnesium concentration was measured and was found to be mark- edly elevated at 5.3 mg/dL, increased from 2.3 mg/dL on admission ~24 hours earlier (Fig 1).

On the third hospital day, the patient remained disoriented and less responsive. He could be awakened occasionally, but slept most of the time. A computed tomographic (CT) scan of the head was performed to rule out a CNS cause for lethargy and confusion, CT revealed a left cerebellar infarct and a small lacunar right caudate nucleus infarct, both inter- preted as having occurred some time ago. Blood cultures

FIGURE 1. Serum theophylline (+ ) and magnesium concentrations (*) plotted against time following treatment with oral activated charcoal and magnesium citrates. 0, administration of both activated charcoal and magnesium citrate; X,

administration of activated charcoal alone.

were also repeated, and remained negative with no growth. Serum magnesium concentration had decreased to 4.2 mg/ dL the evening of the third hospital day. By the morning of hospital day 4, the patient was easily arousable. He was alert throughout most of the day and was able to answer questions appropriately. Serum magnesium concentration was 3.8 mg/ dL. Deep tendon reflexes were increased from those noted previously.

Throughout the remainder of his hospitalization, the patient continued to slowly improve. Serum magnesium concentration was 1.1 mg/dL on hospital day 7. Renal function improved, with serum creatinine decreasing from 1.8 mg/dL on admission to 1.3 mg/dL on day 2. This decrease corre- sponded to an increase in calculated creatinine clearance from 29 to 41 ml/mm/70 kg. By hospital day 6, the serum creatinine had fallen to 1.0 mg/dL (53 mL/min/70 kg), where it remained stable throughout the rest of his hospitalization.

DISCUSSION

It is well established that activated charcoal plus a cathartic will hasten the removal of theophylline from the bloodstream. The mean theophylline elimination half-life has ranged from 3.3 hours to 5.6 hours in both subjects and patients receiving this regimen, compared with eight hours in healthy, nonsmoking adults.“” Those who initially have the longest elimination half- life appear to benefit the most from this form of gastrointestinal dialysis.* Notably, sorbitol in combination with activated charcoal is significantly more effective than activated charcoal alone when administered following ingestion of sustained-release theophylline. lo

The majority of board-certified toxicologists recom- mend the use of cathartics in the management of toxic ingestions. 475 Saline cathartics are generally preferred over sorbitol or others. However, recent evidence in- dicates that sorbitol produces a charcoal-laden stool more quickly than either magnesium citrate or magne-

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AMERICAN JOURNAL OF EMERGENCY MEDICINE n Volume 7, Number 1 H January 1989

sium sulfate; the mean times to appearance were 1.3, 4.1, and 16.7 hours, respectively.15

Magnesium-containing cathartics may not be the optimal agents to use with activated charcoal for safety reasons, at least in selected patients. A common mis- understanding is that magnesium is not significantly absorbed from the gastrointestinal tract when administered as a cathartic. However, approximately 30% of an ingested dose is absorbed, primarily in the small intestine.16 Therefore, hypermagnesemia can occur, especially in the face of renal failure. Elevated magnesium levels may result in diminished or absent deep tendon reflexes, ECG changes, somnolence, bradycardia, hypotension, voluntary muscle paralysis, apnea, and asystole. “J~-~ Accumulation of magnesium secondary to exogenous administration is most likely to occur when creatinine clearance falls below 10 to 30 mL/min. 16,”

The present case demonstrates the problems that may occur even with moderate degrees of magnesium toxicity. Following administration of 6.6 g magnesium as magnesium citrate over 16 hours, the patient be- came confused and somnolent, with greatly diminished deep tendon reflexes. This was associated with a magnesium level of 5.3 mg/dL. Signs and symptoms of magnesium toxicity are reported to begin when the magnesium level exceeds 4 mg/dL.16-” Life- threatening complications usually ensue when the magnesium level exceeds 10 mg/dL. In this patient, a diagnostic work-up was needed to search for the cause of sudden deterioration, and his hospital stay was un- doubtedly prolonged as well.

Jones et al reported a similar case of magnesium toxicity developing during treatment of an amoxapine overdose.” Magnesium toxicity ensued after the de- velopment of prerenal azotemia; however, their patient received approximately 175 oz magnesium citrate (58 g magnesium) over 72 hours, while ours received only 20 oz (6.6 g magnesium) over 16 hours. Their patient had a magnesium level of 11.4 mEq/L (1 mg/dL = 0.83 mEq/L), losing spontaneous respirations and requiring treatment with calcium and hemodialysis. Fassler et al also encountered severe magnesium toxicity during magnesium catharsis for a suspected toxic ingestion.” After receiving 90 g magnesium over an 18-hour period, their patient experienced somnolence, bradycardia, and a respiratory arrest that was associated with a serum magnesium level of 13.2 mEq/L. Interestingly, the patient had normal renal function, with a serum creatinine level of 0.9 mg/dL.

Theophylline toxicity is capable of producing nu- merous metabolic abnormalities.‘8-20 It is unlikely that theophylline toxicity contributed to the hypermagnesemia in our patient, as Hall et al reported hypo- magnesemia in three of their four patients in whom magnesium levels were measured. ‘*

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Although iatrogenic magnesium toxicity is usually encountered during administration of magnesium to patients in acute renal failure, the present case demonstrates that repeated doses administered to patients with borderline renal insufficiency may produce the same result. The calculated creatinine clearance in our patient was 29 mL/min/70 kg on admission; however, before discharge the calculated creatinine clearance had increased to 53 mL/min/70 kg. The initially low creatinine clearance probably reflected prerenal azotemia secondary to dehydration, as the ratio of the BUN to serum creatinine at that time was 36:l. Fol- lowing rehydration and improvement in the calculated creatinine clearance, the ratio of BUN to serum creatinine fell to 15: 1.

CONCLUSION

With greater awareness of the potential benefits of gastrointestinal dialysis using activated charcoal and a cathartic, the potential for serious magnesium toxicity will increase. Iatrogenic magnesium toxicity has been thought to occur primarily in the presence of acute renal failure. However, this case and other recent reports indicate that hypermagnesemia can be precipi- tated in the presence of mild renal insufficiency or even normal renal function. Potential solutions to this problem include (1) using a different cathartic, such as sorbitol, or (2) monitoring magnesium levels fre- quently during administration of magnesium-containing cathartics. The first option is attractive because sorbitol has been shown to produce a more rapid catharsis than magnesium preparations.” However, sorbitol did produce abdominal discomfort in this study, while magnesium citrate and sulfate did not. Sorbitol has been shown not to effect serum electro- lytes when a single dose is administered.2’ However, sorbitol is not without risks, with at least one case of severe dehydration reported in an infant.22 The second option appears less desirable; frequent monitoring could place manpower and financial burdens on health care facilities. A third option would be administration of one or two doses of magnesium citrate. However, this may not achieve the desired therapeutic endpoint. Therefore, the use of sorbitol in place of magnesium citrate, at least in patients at high risk for magnesium toxicity, is recommended.

The authors express their appreciation for the excellent techni- cal assistance provided by Vannessa Petersen in the preparation of this manuscript.

REFERENCES

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magnesium toxicity secondary to catharsis during management of theophylline poisoning

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