Cathartic-induced magnesium toxicity during overdose management

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 ingestion 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 hypermagnesemia. Her clinical condition improved slowly without further complication 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.] INTRODUCTION

Cathartics are used widely as a means of removing poison from the gastrointestinal tract. Because they are effective and relatively free of toxic effects, 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 subsequent hypermagnesemia (11.4 mEq Mg + +/L). The toxic levels of magnesium caused acute neuromuscular deterioration followed by respiratory depression.

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.

CASE REPORT

A 39-year-old woman with a history of chronic depression ingested approximately 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 m m 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 unremarkable. 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 generalized tonic-clonic seizures and received 20 mg IV diazepam, 100 mEq sodium 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 magnesium 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 screening 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 15:10 October 1986

Annals of Emergency Medicine

1214/121

MAGNESIUM J o n e s e t at

llllII

IllIIII'I

"IIlll

TOXICITY

"I""IIU'IIIIIII"IIIIII

"I I' ,l .| ,I,| h I "I ,",|,| ,| ,| I, l| I"I'I| ,' I | " ' "h", 'IlI"l l| I' |I ll lhlI' l"h| l . . , . l l I I I , i . ,

II

i!!!iiiiiiiiiii!i!!i! ii1111ili!!!iiiliiiii

IIIIIIIIIIIIIIIIIIIIIIIIIIIUIIIIIIIIIIIIIIIIIIIIII IIllIIllllIIIIllllII:l IIIIIIIIiIIIIIIiIIIIIiIIIIIIIIIIinIIIIlIIIIIiIIIII II!IIIIIIIIIIIF!!III iii!iilh!!iiii|!!!!hiiUiii!ihii!ii!|!ii!!|!!!!i IIIIIIIIIIIIIII|IIIIl

||m|||||i||nnlHi" |||||||||||'|| ||" "|||||r|"||'|= ,~!~!|!ii~i!iiiiiiiill •::::::::::::::::::::::::::::::::::::::::::::::::::: | ' " " l ....... ........ |"|'"='=""='=|"|" lll|IIIi||l|li::ihliiIl ,,,,°,,,,,,=,,,.,,..,,

iiiii!liiiilliil!iiiii!iliiiiiii!pi!iiiii!iii!ii!l IIIhIIIIII hIIIIUIIIIIIIIIIIII,I,~IIIIIIIIII,III ;iUIiii!!TIUIiiiiiII~ :::::::::::::::::::::: l~!ir||~|||l~l!llllllh~lllllllll~I|l~,ll|l!IilllH~II III!I!=IIIIIIIIIIIIUl iIIIi||||||hII~iillli~Iliiiii!ilIiIiiiIl|Ik|i||I~: ,Ill||ill||Ill|Ill|I| ,, I• I"II n,r.' =I' fl 'l ll ,I , • l"l"l 'hJ.i.l l |l" I I 'l=l l' l"l'l"l Ihl .l ", l' l"l"' "I 'l lIlll ||=h| :::::::::::::::::::::::::::::::::::::::::::: !!iiii:iiiiii!hhill I IIIIII!!IIIIFIIIIII, iiiil!=iiiiiiiiiiiiiii!iUiiiiiii!!iiiUi!!iii!iill =|ul'.|||||u==|||a||~=|||||||i|||||.|m.|||||||.|=

I

FIGURE 1. ECG demonstrating sinus tachycardia.

122/1215

|

~

I

Enemas ~1~ + Cit T~[apy 12

FIGURE 2. The clinical course and f l u c t u a t i o n of serum m a g n e s i u m . Boxes m a r k the t i m e periods of Mg + + citrate therapy and dialysis (D). The normal range of serum magnesium is shaded. sodium bicarbonate 44 mEq/250 mL DsW for alkaline diuresis with 50 g charcoal and 300 mL magnesium citrate by nasogastric tube every four hours. Twenty-four hours after admission, she was responsive to verbal stimuli and deep tendon reflexes were intact. Spontaneous respirations were present, but the patient remained ventilator dependent. Charcoal and magnesium therapy was continued, although the serum m a g n e s i u m level was 3.3 mEq/L. Adequate catharsis required repeated enemas and bisacodyl suppositories because of poor bowel motility. Repeat urinalysis and electrolytes remained normal. Seventy-two hours after admission the patient developed prerenal azotemia (fractional excretion of sodium < 1) secondary to the alkaline diuresis. Physical examination at this time revealed marked hyporeflexia, no response to painful stimuli, paralytic ileus, and loss of spontaneous respira-

I

11 10 9

SERUM Mg*" (mEq/L)

8 Z 6 S

4

3 2

\\\\\

1

. . . . Adm

24

\~ 48

76

ao

84 88 92 96 Time (Hoursafter admission)

tions. Laboratoy values were as follows: serum calcium, 6.5 mg/dL; sodium, 158 mEq/L; p o t a s s i u m , 3.3 mEq/L; creatinine, 2.3 mg/dL; urea nitrogen, 37 mg/dL; and serum magnesium, 11.4 mEq/L (Figure 2). The patient had received approximately 58 g (5,017 m E q ) of m a g n e s i u m by nasogastric tube over 72 hours. ImmeAnnals of Emergency Medicine

100

104

108

112

116

120

diate therapy included IV 0.9% saline, 40 mg furosemide, and 10 mEq calcium gluconate infusion while maintaining mechanical ventilation. Serial enemas were administered to eliminate m a g n e s i u m r e m a i n i n g in the bowel. Seventy-six hours after admission the patient underwent hemodialysis 15:10 O c t o b e r 1986

TABLE. Clinical manifestations of hypermagnesemia& 1°,13 Level

Serum Mg + + (mEq/L)

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 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 time the patient had recovered sufficiently to respond to simple commands of arm and leg movem e n t ; reflexes were n o r m a l 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 center three weeks after admission.

DISCUSSION Magnesium has been advocated in a wide variety of disorders, including neonatal tetany, hyperuricemia, lithium toxicity, hyperthyroidism, pancreatitis, hepatitis, arrhythmias, and digitalis intoxication. 3 Magnesium sulfate and magnesium citrate are used in the treatment of acute poisoning after gastric emptying. The rationale for catharsis is to decrease intestinal transit time, thus minimizing the availability of both absorbed and nonabsorbed toxin for gut absorption. Although some c o n t r o v e r s y exists c o n c e r n i n g the safety and efficacy of these agents, they are recommended increasingly for use with activated charcoal. 4 Recent evidence indicates that magnesium citrate may enhance the adsorptive capacity of charcoal, s The recommended dose of magnesium 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

15:10October 1986

1.4-2.0 3.0 4.0 5.0 6.0-7.0 10.0 15.0 17.0-20.0

should be repeated at three- to fourhour intervals if necessary until passage of a charcoal stool appears. Cont r a i n d i c a t i o n s to the use of magnesium cathartics are shown (Figure 3). Repeated administration of activated charcoal and cathartics recently has emerged as a potentially valuable new modality to increase the elimination of certain agents. This treatment not only adsorbs drugs within the gastrointestinal tract, but also enhances elimination of drugs already absorbed that may be secreted into the gastrointestinal tract or enterohepatic circulation. 6-9 Further investigations are needed to characterize fully the safety and efficacy of this "gastrointestinal dialysis.'6,9 Clinically i m p o r t a n t hypermagnesemia is rare and is usually iatrogenic in originJ o The kidney is the principal organ in the homeostasis of the m a g n e s i u m ion. Renal tubular Mg + + reabsorption is controlled by a transport system regulated by parathyroid hormone (PTH)3 o Hypermagnesemia inhibits PTH secretion and the kidney is extremely effective in preventing elevations of magnesium to dangerous levels. N o r m a l individuals can excrete more than 6 g/day (500 mEq) of magnesium, u Some degree 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 function nears zero. 1~ Clinically important hypermagnesemia usually is attributable to administration of Mg-containing products to patients with coexisting 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 magn e s i u m cathartics, is has been challenged, t4 Toxic patients who are comatose, especially those ingesting drugs with anticholinergic activity, have poor bowel motility, and attempts at catharsis often are futile and may cause serious electrolyte imbalances. 14 I a t r o g e n i c h y p e r m a g nesernia with respiratory depression has been reported in at least one patient with normal renal function who received large doses of magnesium sulfate for ingestion of an unknown toxin.l] The diagnosis of magnesium toxicity can be difficult. Mild to moderate hypermagnesemia may remain unn o t i c e d u n l e s s a high i n d e x of suspicion exists or a plasma magnesium concentration 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 between increasing blood levels and specific clinical signs (Table).3 However, there is a great variability in the literature among patients with similar blood levels. Conditions that exaggerate a patient's sensitivity to hypermagnesemia include coexisting renal failure, is old age, 12 hypothyroidism, m and Addison's disease. 3 Drowsiness, lethargy, diaphoresis, nausea, cutaneous flushing, and unsteadiness are common initial symptoms of most patients as the plasma magnesium rises above 4 mEq/L (Table).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 respiratory function, causing apnea during severe magnesium intoxication. ECG changes (prolonged P-R, QRS, and Q-T intervals) may begin with plasma con-

1216/123

MAGNESIUM TOXICITY Jones et al

Hypermagnesemia (> 2 mEq/L)

1 Eliminate MG + + source

Check calcium and phosphate levels

Im

I

If patient is symptomatic

1 5 t o 10 mEq IV CA ++

1 Watch for ECG changes, hypotension, respiratory depression

Symptomatic treatment

1

Renal function tests normal?

No

I

Yes

1 40 mg furosemide IVP 0.9% saline IV

Consider peritoneal or hemodialysis

4

F I G U R E 4. F]ow diagram for treatment of hypermagnesemia. c e n t r a t i o n s as low as 5 m E q / L and p r o c e e d to c o m p l e t e h e a r t b l o c k . 3 M a g n e s i u m h a s a d i r e c t effect on b l o o d v e s s e l s a n d is a g a n g l i o n i c b l o c k e r p r o d u c i n g v a s o d i l a t i o n and h y p o t e n s i o n J o Higher concentrations inhibit cardiac contractions and decrease m e m b r a n e excitability. L~ H y p e r m a g n e s e m i a m a y lower t h e s e r u m c a l c i u m by suppressing PTH s e c r e t i o n or d e c r e a s i n g the responsiveness of end organs to P T H / 6 The resulting hypocalcemia m a y delay establishing the correct diagnosis, but m a y lead to the correct treatment (ie, IV calcium). Treatment initially is directed at removing the exogenous magnesium source and then administering IV calc i u m (Figure 4). P a t i e n t s w i t h poor bowel m o t i l i t y m a y require enemas 124/1217

and/or bowel stimulants to eliminate m a g n e s i u m remaining in the gastrointestinal tract. Once the source is eliminated, t h e rapid fall of m a g n e s i u m l e v e l s a l l e v i a t e s t h e n e e d for dialysis. H C a l c i u m acts as a direct antagonist to m a g n e s i u m and m a y readily reverse a p o t e n t i a l l y lethal respiratory depression or cardiac arrhythmia. 9 T h e exact m e c h a n i s m of the c a l c i u m a n t a g o n i s m is n o t k n o w n , but m a y be related to the ability of the calcium ion to displace magnesium on cell membranes, causing transient reversal 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 solution)J 2 If r e n a l f u n c t i o n is a d e q u a t e , IV f u r o s e m i d e s h o u l d be a d m i n i s t e r e d and urine volume replaced with 0.9N saline, is T h i s approach ensures continuing urine output and prevents votAnnals of Emergency Medicine

ume depletion. Support of blood pressure and ventilation m a y be necessary u n t i l t h e e l e v a t e d m a g n e s i u m level subsides. As a general guideline, w h e n 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 indicates m a g n e s i u m toxicity (blood level of at least 10 mEq/L. I3 If renal function is impaired, the patient m a y req u i r e p e r i t o n e a l d i a l y s i s or h e m o dialysis. D i a l y s i s a g a i n s t a m a g n e s i u m - f r e e d i a l y s a t e will r a p i d l y and effectively lower the p l a s m a magnesium concentrationJ 3

SUMMARY In p a t i e n t s who are receiving frequent, r e p e t i t i v e dosages of m a g n e sium cathartics, we r e c o m m e n d careful m o n i t o r i n g of t h e deep t e n d o n reflexes, b o w e l m o t i l i t y , r e n a l function, serum calcium, and m a g n e s i u m levels. T h e s e c a t h a r t i c s s h o u l d be 15:10 October 1986

used judiciously during the treatment of acute p o i s o n i n g w i t h 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 M e d i c i n e : C o n c e p 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 decontamination in the treatment of oral poisoning. Pediatric Clin North A m 1979;26:827836. 5. Ryan CF, Spigiel RW, Zeldes G: Enhanced absorptive capacity of activated charcoal in the presence of magnesium citrate. Clin Toxicol 1980;17:457-461.

15:10 October 1986

6. Krenzelok EP, Keller R, Stewart RD: Gastrointestinal transit times of cathartics 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 Saunders, 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, magnesium), in Shoemaker WC (ed): Critical Care: State of the Art, vol 5. Fullerton, California, Society of Critical Care Medicine, 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.

Annals of Emergency Medicine

13. Rude RK, Singer FR: Magnesium defic i e n c y and e x c e s s . A n n R e v M e d 1981;32:245-259. 14. Kunkel DB: A critical look at gut dec o n t a m i n a t i o n . Emerg M e d 1985;17: 179-186. 15. Randall RE, Cohen MD, Spray CC, et al: Hypermagnesemia in renal failure: Etiology and toxic manifestations. A n n Intern Med 1964;61:73-88. 16. Garcia-Webb P, Bhagat C: Hypermagnesaemia 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 p e l v i s . J A M A 1 9 7 8 ; 2 4 0 : 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 l o m e n b a u m NE, Weisman RS: General management of the poisoned and overdosed patient, in Goldfrank LR (ed): Toxicologic Emergencies. New York, Appleton-Century-Crofts, 1982, pp 3-18.

1218/125