CASE REPORT cathartics, and magnesium toxicity; magnesium, toxicity, from cathartics; overdose, management, complication

Cathartic-Induced Magnesium Toxicity During Overdose Management

A 39-year-old women was admitted to the hospital followmg a large inges- tion of a tricylic antidepressant. The administration of magnesium citrate in repeated doses w~th activated charcoal resulted in a striking increase in serum magnesium levels followed by acute neuromuscular deterioration and respiratory depression. The patient required dialysis for control of hyper- magnesemia. Her clinical condition improved slowly without further com- plication and she was discharged to a rehabilitation center. [Jones J, Heiselman D, Dougherty J, Eddy A: Cathartic-induced magnesium toxicity during overdose management. Ann Emerg Med October I986;15:1214-1218.]

I N T R O D U C T I O N Cathartics are used widely as a means of removing poison from the gas-

trointestinal tract. Because they are effective and relatively free of toxic ef- fects, magnesium citrate or magnesium sulfate (Epsom salts) traditionally are administered following instillation of activated charcoal. There is a paucity of reports of serious electrolyte disorders resulting specifically from the use of these agents. 1

We report a case of magnesium toxicity occurring during the treatment of a tricyclic overdose with pulse doses of charcoal and magnesium citrate. After 72 hours of therapy the patient developed prerenal azotemia with sub- sequent hypermagnesemia (11.4 mEq Mg + +/L). The toxic levels of magne- sium caused acute neuromuscular deterioration followed by respiratory de- pression.

C A S E R E P O R T A 39-year-old woman with a history of chronic depression ingested approx-

imately 400 tablets of amoxapine 100 mg (Ascendin ®) and was brought to the emergency department by her husband. At the time of presentation she was obturided with minimal respirations. Admission vital signs were as follows: blood pressure, 128/82 mm Hg; pulse, 130; respirations, 12 and shallow; and temperature, 37.6 C. Physical examination revealed a comatose woman with dilated reactive pupils. The patient responded only to deep pain and had a weak gag reflex. The remainder of the physical examination was unremark- able. There were no anticholinergic signs or focal neurological deficits.

Emergency treatment included 2 L IV crystalloids, 2 mg naloxone, 25 g dextrose, and 100% oxygen. Soon after arrival, the patient had two gener- alized tonic-clonic seizures and received 20 mg IV diazepam, 100 mEq so- dium bicarbonate, and 2 mg physostigmine. She subsequently was intubated, lavaged using a large-bore tube, and given activated charcoal with 300 mL magnesium citrate (containing 3.3 g magnesium).

Complete and differential blood counts were normal, as were the blood levels of electrolytes, creatinine, urea nitrogen, and glucose. Serum magne- sium was 1.9 mEq/L on admission. Urinalysis revealed no abnormalities. The initial serum amoxapine level was 1,700 ng/mL five hours after ingestion (therapeutic levels, 30 to 120 ng/mL). 2 The level fell to 640 ng/mL and 180 ng/mL at 30 and 48 hours, respectively, after ingestion. Toxicological screen- ing was negative for other drugs. The initial ECG demonstrated a sinus tachycardia (140 beats per minute) with normal PR and QRS intervals (Figure 1). Repeated ECGs were unchanged during the patient's hospital course.

The patient was admitted to the intensive care unit and treated with W

Jeffrey Jones, MD* Darell Heiselman, DO, FACA ~r James Dougherty, MD, FACEP* Andrew Eddy, MD¢ Akron, Ohio

From the Departments of Emergency Medicine* and Internal Medicine:l and the Division of Critical Care Medicine,t Northeastern Ohio Universities College of Medicine, Akron General Medical Center, Akron, Ohio.

Received for publication March 13, 1986. Accepted for publication June 2, 1986.

Address for reprints: Jeffrey Jones, MD, Department of Emergency Medicine, Akron General Medical Center, 400 Wabash Avenue, Akron, Ohio 44307.

15:10 October 1986 Annals of Emergency Medicine 1214/121

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FIGURE 1. ECG demonstrating sinus tachycardia.

FIGURE 2. The clinical course and f luc tuat ion of serum magnes ium. Boxes m a r k the t ime periods of Mg + + citrate therapy and dialysis (D). The normal range of serum mag- nesium is shaded.

sodium bicarbonate 44 mEq/250 mL DsW for alkaline diuresis with 50 g charcoal and 300 mL magnesium cit- rate by nasogastric tube every four hours. Twenty-four hours after admis- sion, she was responsive to verbal stimuli and deep tendon reflexes were intact. Spontaneous respirations were present, but the patient remained ven- tilator dependent. Charcoal and mag- nesium therapy was continued, al- though the serum magnes ium level was 3.3 mEq/L. Adequate catharsis re- quired repeated enemas and bisacodyl suppositories because of poor bowel motility. Repeat urinalysis and elec- trolytes remained normal.

Seventy-two hours after admission the p a t i e n t d e v e l o p e d p r e r e n a l azotemia (fractional excretion of so- dium < 1) secondary to the alkaline diuresis. Physical examination at this t ime revealed marked hyporeflexia, no response to painful stimuli, paralytic ileus, and loss of spontaneous respira-

12

11

10

9

8 SERUM Mg*"

(mEq/L) Z

6

S

4

3

2

1

Enemas

~1~ + Cit T~[apy

\\\\\

. . . . \ ~ Adm 24 48 76 ao 84 88 92 96 100 104 108 112 116 120

Time (Hours after admission)

tions. Laboratoy values were as fol- lows: serum calcium, 6.5 mg/dL; so- dium, 158 mEq/L; po tass ium, 3.3 mEq/L; creatinine, 2.3 mg/dL; urea ni- trogen, 37 mg/dL; and serum magne- sium, 11.4 mEq/L (Figure 2). The pa- tient had received approximately 58 g (5,017 mEq) of m a g n e s i u m by nasogastric tube over 72 hours. Imme-

diate therapy included IV 0.9% saline, 40 mg furosemide, and 10 mEq cal- cium gluconate infusion while main- taining mechanical ventilation. Serial enemas were administered to elimi- nate m a g n e s i u m remain ing in the bowel.

Seventy-six hours after admission the patient underwent hemodialysis

122/1215 Annals of Emergency Medicine 15:10 O c t o b e r 1986

TABLE. Clinical manifestat ions of hypermagnesemia& 1°,13

Level

Normal serum level Nausea, vomiting, cutaneous flushing Decrease in deep tendon reflexes,

drowsiness, unsteadiness, diaphoresis ECG changes (QRS widening, PR prolongation) Somnolence, bradycardia, hypotension Absent deep tendon reflexes, voluntary muscle

paralysis Complete heart block, respiratory paralysis Asystole

Serum Mg + + (mEq/L)

1.4-2.0 3.0

4.0 5.0

6.0-7.0

10.0 15.0

17.0-20.0

to reduce the magnesium level during renal insufficiency. Dialysis therapy decreased serum magnesium from 9.9 to 5.1 mEq/L in approximately four hours.

At this t ime the patient had re- covered sufficiently to respond to sim- ple commands of arm and leg move- ment ; reflexes were normal and spontaneous respirations were 18 per minute. Twenty-four hours later, her serum magnesium level was 3.0 mEq/ L, and creatinine was 1.1 mg/dL. Her clinical condition improved slowly without further complication and she was discharged to a rehabilitation cen- ter three weeks after admission.

DISCUSSION Magnesium has been advocated in a

wide variety of disorders, including neonatal tetany, hyperuricemia, lith- ium toxicity, hyperthyroidism, pancre- atitis, hepatitis, arrhythmias, and digi- talis intoxication. 3 Magnesium sulfate and magnesium citrate are used in the treatment of acute poisoning after gas- tric emptying. The rationale for ca- tharsis is to decrease intestinal transit time, thus minimizing the availability of both absorbed and nonabsorbed tox- in for gut absorption. Although some controversy exists concerning the safety and efficacy of these agents, they are recommended increasingly for use with activated charcoal. 4 Re- cent evidence indicates that magne- sium citrate may enhance the ad- sorptive capacity of charcoal, s

The recommended dose of magne- sium citrate is 100 to 200 mL in adults and 50 to 100 mL in childrenJ The standard dose of magnesium sulfate is 250 mg/kg of body weight to a limit of 30 g.1 The dose of either cathartic

should be repeated at three- to four- hour intervals if necessary until pas- sage of a charcoal stool appears. Con- t ra indicat ions to the use of mag- nesium cathartics are shown (Figure 3).

Repeated administrat ion of acti- vated charcoal and cathartics recently has emerged as a potentially valuable new modality to increase the elimina- tion of certain agents. This treatment not only adsorbs drugs within the gas- trointestinal tract, but also enhances elimination of drugs already absorbed that may be secreted into the gastroin- testinal tract or enterohepatic circula- tion. 6-9 Further invest igat ions are needed to characterize fully the safety and efficacy of this "gastrointestinal dialysis.'6,9

Clinical ly impor tan t hypermag- nesemia is rare and is usually iatro- genic in originJ o The kidney is the principal organ in the homeostasis of the magnesium ion. Renal tubular Mg + + reabsorption is controlled by a transport system regulated by para- thyroid hormone (PTH)3 o Hypermag- nesemia inhibits PTH secretion and the kidney is extremely effective in preventing elevations of magnesium to dangerous levels. Normal indi- viduals can excrete more than 6 g/day (500 mEq) of magnesium, u Some de- gree of .hypermagnesemia invariably accompanies acute renal failure. The plasma level becomes elevated as the glomerular filtration rate approaches 30 mL/min, and peaks at about 2.5 mEq/L of Mg+ + as the renal func- tion nears zero. 1~ Clinically important hypermagnesemia usually is attributa- ble to administration of Mg-contain- ing products to patients with coexist- ing renal failure. 13

The efficacy and safety of catharsis

Annals of Emergency Medicine

Adynamic ileus Severe diarrhea Abdominal trauma Intestinal obstruction Renal failure or insufficiency Heart block Need for prolonged catharsis

(repetitive charcoal therapy) 3

FIGURE 3. Contraindications to mag- nes ium cathartics, is

has been challenged, t4 Toxic patients who are comatose, especially those in- gesting drugs with anticholinergic ac- tivity, have poor bowel motility, and attempts at catharsis often are futile and may cause serious electrolyte im- balances. 14 Ia t rogenic hypermag- nesernia with respiratory depression has been reported in at least one pa- tient with normal renal function who received large doses of magnesium sulfate for ingestion of an unknown toxin.l]

The diagnosis of magnesium tox- icity can be difficult. Mild to moder- ate hypermagnesemia may remain un- no t i c ed un less a high index of suspicion exists or a plasma magne- sium concentrat ion is determined. The initial presentation of drowsiness, lethargy, and weakness is nonspecific, and can be attributed easily to other causes. 13 There is a correlation be- tween increasing blood levels and spe- cific clinical signs (Table). 3 However, there is a great variability in the liter- ature among patients with similar blood levels. Conditions that exagger- ate a patient's sensitivity to hyper- magnesemia include coexisting renal failure, is old age, 12 hypothyroidism, m and Addison's disease. 3

Drowsiness, lethargy, diaphoresis, nausea, cutaneous flushing, and un- steadiness are common initial symp- toms of most patients as the plasma magnesium rises above 4 mEq/L (Ta- ble).12,13 Deep tendon reflexes become depressed, usually disappearing above levels of 10 mEq/L. Somnolence is seen at 6 to 7 mEq/L and paralysis of voluntary muscles at 10 mEq/L or more.13 The latter may impair respira- tory function, causing apnea during severe magnesium intoxication. ECG changes (prolonged P-R, QRS, and Q-T intervals) may begin with plasma con-

15:10 October 1986 1216/123

MAGNESIUM TOXICITY Jones et al

4

Hypermagnesemia (> 2 mEq/L)

1 Eliminate MG + + source

I If patient is symptomatic

1 5 to 10 mEq IV CA ++

1 Watch for ECG changes ,

hypotension, respiratory depression

1 Renal function

tests normal?

I Yes

1 40 mg furosemide IVP

0.9% saline IV

Check calcium and phosphate levels

Im

Symptomatic treatment

No

Consider peritoneal or hemodialysis

FIGURE 4. F]ow diagram for treat- ment of hypermagnesemia.

cen t r a t i ons as low as 5 mEq/L and p roceed to c o m p l e t e h e a r t b lock . 3 M a g n e s i u m has a d i r ec t effect on b l o o d v e s s e l s and is a g a n g l i o n i c b locker p roduc ing v a s o d i l a t i o n and hypotens ionJ o Higher concentrat ions inhibi t cardiac contract ions and de- crease membrane excitability. L~

H y p e r m a g n e s e m i a m a y lower the serum ca lc ium by suppressing PTH sec re t ion or decreas ing the respon- siveness of end organs to PTH/6 The resulting hypocalcemia may delay es- tabl ishing the correct diagnosis, but may lead to the correct t rea tment (ie, IV calcium).

Treatment ini t ial ly is directed at re- m o v i n g the exogenous m a g n e s i u m source and then administer ing IV cal- c i um (Figure 4). Pa t i en t s w i th poor bowel mo t i l i t y may require enemas

and/or bowel s t imulants to e l iminate magnes ium remaining in the gastroin- testinal tract. Once the source is elim- inated, the rapid fall of magnes ium leve l s a l l e v i a t e s t h e need for di- alysis. H Calc ium acts as a direct an- tagonist to magnes ium and may readi- ly reverse a po ten t ia l ly le thal respi- ratory depression or cardiac arrhyth- mia. 9 The exact m e c h a n i s m of the ca l c ium a n t a g o n i s m is no t known, but may be related to the abil i ty of the calcium ion to displace magnesium on cell membranes, causing transient re- versal of symptoms. 17 The usual dose is 5 to 10 mEq IV calcium (equal to 4.7 mL of a 10% CaC1 solution, or 10 to 20 mL of a 10% calcium gluconate so- lution)J 2

If r e n a l f u n c t i o n is adequa te , IV fu rosemide should be a d m i n i s t e r e d and urine volume replaced with 0.9N saline, is Th is approach ensures con- t inuing ur ine output and prevents vot-

ume depletion. Support of blood pres- sure and vent i la t ion may be necessary un t i l the e levated m a g n e s i u m level subsides. As a general guideline, when the deep tendon reflexes are absent, r e s p i r a t i o n s s h o u l d be m o n i t o r e d closely. The absence of reflexes indi- cates magnes ium toxici ty (blood level of at least 10 mEq/L. I3 If renal func- tion is impaired, the pat ient may re- qui re p e r i t o n e a l d i a ly s i s or h e m o - dia lys is . D ia lys i s aga ins t a magne- s ium-f ree d ia lysa te wi l l rap id ly and effectively lower the p lasma magne- s ium concentra t ionJ 3

S U M M A R Y In pa t ien t s who are receiving fre-

quent, r epe t i t i ve dosages of magne- s ium cathartics, we recommend care- ful m o n i t o r i n g of the deep t endon reflexes, bowel mot i l i ty , rena l func- tion, serum calcium, and magnes ium levels . T h e s e c a t h a r t i c s s h o u l d be

124/1217 Annals of Emergency Medicine 15:10 October 1986

used judiciously during the treatment of acute poisoning wi th drugs that might decrease bowel motility, affect renal function, or require prolonged catharsis because of a long half-life or significant enterohepatic circulation.

REFERENCES 1. Epstein FB, Eilers MA: Poisoning, in Rosen P, Baker FJ, Braen GR, et al (eds): E m e r g e n c y Medic ine : Concep t s and Clinical Practice. St Louis, CV Mosby, 1980, pp 215-253.

2. Package insert, formulary information on amoxapine (Ascendin®). Pearl River, New York, Lederle Laboratories, 1980.

3. Mordes JP: Excess magnesium. Pharm Rev 1978;29:273-300.

4. Easom JM, Lovejoy FH: Efficacy and safety of gastrointestinal decontamina- tion in the treatment of oral poisoning. Pediatric Clin North A m 1979;26:827- 836.

5. Ryan CF, Spigiel RW, Zeldes G: En- hanced absorptive capacity of activated charcoal in the presence of magnesium citrate. Clin Toxicol 1980;17:457-461.

6. Krenzelok EP, Keller R, Stewart RD: Gastrointestinal transit times of cathar- tics combined with charcoal. Ann Emerg Med 1985;14:1152-1155.

7. Berg MJ, Berlinger WG, Goldberg MJ, et al: Acceleration of the body clearance of phenobarbital by oral activated charcoal. N Engl J Med 1982;307:642-644.

8. Eisenberg MS, Copass MK: Emergency Medical Therapy. Philadelphia, WB Saun- ders, 1982, p 193.

9. Levy G: Gastrointestinal clearance of drugs with activated charcoal. N Engl J Med 1982;307:676-678.

10. Chernow B, Zaloga G: Ions for society members (sulfate, chloride, calcium, mag- nesium), in Shoemaker WC (ed): Critical Care: State of the Art, vol 5. Fullerton, California, Society of Critical Care Medi- cine, 1984, pp 1-43.

11. Fasler CA, Rodriguez M, Badesch DB, et al: Magnesium toxicity as a cause of hypotension and hypoventilation. Arch Intern Med 1985;145:1604-1606.

12. Ratzon RM, Chapron DJ, Mumford D, et al: Uncovering magnesium toxicity. Geriatrics 1980;35:75-86.

13. Rude RK, Singer FR: Magnesium defi- c i ency and excess . A n n Rev M e d 1981;32:245-259.

14. Kunkel DB: A critical look at gut de- con tamina t ion . Emerg Med 1985;17: 179-186.

15. Randall RE, Cohen MD, Spray CC, et al: Hypermagnesemia in renal failure: Etiology and toxic manifestations. Ann Intern Med 1964;61:73-88.

16. Garcia-Webb P, Bhagat C: Hypermag- nesaemia and hypophosphataemia after ingestion of magnesium sulphate. Br Med ] 1984;288:759.

17. Jenny DB, Goris GB, Urwiller MD, et al: Hypermagnesemia following irrigation of r e n a l pe l v i s . J A M A 1978;240: 1378-1379.

18. Alfrey AC: Disorders of magnesium metabolism in man, in Schrier RW (ed): Renal and Electrolyte Disorders. Boston, Little Brown & Co, 1980, pp 299-319.

19. Goldfrank LR, F lomenbaum NE, Weisman RS: General management of the poisoned and overdosed patient, in Gold- frank LR (ed): Toxicologic Emergencies. New York, Appleton-Century-Crofts, 1982, pp 3-18.

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