Serum magnesium concentrations after repetitive magnesium cathartic administration

SerumMagnesium Concentrations After RepetitiveMagnesium CatharticAdministration

PETER G. LACOUTURE, Sever8 hyp8rmaQnesemla has been reported by several authors after multiple doses of magneslum-containingcathartic are administered during management of a toxic Ingestion. To evaluate the fnquency and magnitude of serum magnesium elevations aNer ths use of mpstltlve magnesium catharsis, we prospectively evaluated 102 patients who recelved multlple doses of magneslum citrate as a part of trsatment of an overdose. Commonly Ingested substances for which repetltlve catbartlc was admlnlstered wer8 trlcycllc antidepressants In 47%, aspirin In 17%, and phenytoln In 10%. For each case, serial etectmlytes, blood uresnltrogen, cmatlnlne, calcium and maQneslumwer8 obtalned. Mean Initial semm magnesium concentration was 1.6 f .03 mEqA. After a mean 960 ml of magnesium citrate (9.22 g magnesium), final mean semm magnesium concentrationwas 2.6 k .06 mEq/L. Forty-seven patlents (47%) developed an elevated (>2.4 mEq/L) serum magneslum concentration, with 12 > 3.0 mEql1. No correlation was found between total quantity 01 magfleslum Cltmt8 admlnlrtersd and the Increment In serum magnesium concsutntlon. Our data l8dlC8t8 that senrm magneslum COuC88tt8tlO8S conslSt88tly rlS8 after repetltlve magnesium citrate use. However, the m8Q8ltUd8 Of tbls rise appears UtOd8SLTb8 8l8V8tlO8 is serum magnaSIUIU COuC88b8tlOudO8S UOt CON818t8with the qU8utlty Of IU8Q88SlUUI edmlnltter8d. W8 COuClUd8that wltb Clot8 monltorlng, NIQ8tltlV8 maQneslum cltrats can be admInIStered without Inducing sever8 hypermagu8S8iUl8 (S8rtUU IU8Q88SlUUICOIIC88b8tlO8>6.0 mEq/L). (Am J Emerg

Med 1996;6:297-300. 0 1990 by W.B. Saunden Company.) Successful management of a patient after a toxic ingestion includes aggressive gastrointestinal decontamination. Typically, gastrointestinal decontamination has three components: evacuation of gastric contents (by gastric iavage or ipecac-induced emesis), administration of activated charcoal to absorb the drug before its absorption, and catharsis to enhance expulsion of the charcoal-drug complex. Multiple-dose activated charcoal has become a common therapeutic intervention for toxic ingestions. The repetitive administration of activated charcoal appears to enhance the elimination of three types of medications: (1) drugs with delayed absorption (anticholinergics, phenytoin, sustainedrelease tablets), (2) drugs with significant enterohepatic circulation (eg, thyroid hormone, digitoxin), and (3) drugs

From the *Massachusetts Poison Control System, the +Department of Pediatrics, Harvard Medical School, and the *Divisions of Clinical PharmacologyiToxicology and Emergency Medicine, The Children’s Hospital, Boston, MA. Manuscript received May 12, 1989; revision accepted August 9, 1989. Presented in part at the AAPCCIAACTIABMT Annual Meetings, October 1988. Baltimore, MD. Address reprint requests to Judith A. Woodard RN, BSN: MA Poison Control System, 300 Longwood Ave, Boston, MA 02115. Key Worcfs: Cathartics, hypermagnesemia. 0 1990 by W.B. Saunders Company. 0735-6757/90/0804-0006$5.00/0

JUDITH A. WOODARD, RN, BSN,* MICHAEL SHANNON, MD, MPH,*+* PHD,** ALAN WOOLF, MD, MPH*+*

whose elimination can be enhanced by gastrointestinal dialysis (aspirin, phenobarbital, theophylline).‘” As the use of multiple-dose activated charcoal for the treatment of acute poisoning has expanded, so has the use of multiple-dose cathartic. Although many authors have suggested that cathartics add little to the overall effectiveness of gastrointestinal decontamination, other studies have indicated that cathartics are useful in their ability to both facilitate expulsion of toxin and decrease the potential risk of charcoal impaction that may occur with the repetitive administration of activated charcoal.4d Cathartics also may enhance the efficacy of activated charcoal.7-9 Treatment with multiple-dose cathartic has been associated with many reports of adverse reactions.4~‘o~11 With repetitive administration of the cathartic sorbitol, hypematremic dehydration has been reported, particularly when it is used in infants.12 There are also case reports of severe hypermagnesemia after repetitive administration of magnesium-containing cathartics, often associated with lifethreatening clinical manifestations including electrocardiographic abnormalities, bradycardia, hypotension, coma, hypothermia, muscular paralysis, and respiratory depression.‘0*1’~‘3‘16Although these reports have consistently advised caution or discouraged the use of multiple-dose magnesium cathartic, they have been unable to identify the frequency or etiology of hypermagnesemia. The purpose of this study was to characterize the increases in serum magnesium concentration that occur after the repetitive administration of magnesium citrate and to identify potential risk factors other than renal disease for the development of hypermagnesemia. METHODS We prospectively followed 102 patients referred to the Massachusetts Poison Control System who received multiple-dose activated charcoal with magnesium citrate after a toxic ingestion. Patients were excluded if they had a past medical history of renal disease. Weight and past medical history were obtained on each patient. For each case, standard treatment was recommended. Activated charcoal was recommended at a dose of 1 gm/kg every 4 hours. A 300-mL dose of magnesium citrate (4 mL/kg for children) with each or alternate doses of activated charcoal were recommended. For all patients, a metabolic profile (electrolytes, calcium, magnesium, blood urea nitrogen [BUN], and creatinine) was recommended at admission and after every dose of magnesium citrate. Patients were monitored by twice-daily phone calls from the Poison Center until the last dose of cathartic was given. 297

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298

Laboratory values were obtained with each call. The normal

reference serum magnesium concentration used by all participating hospitals was 1.8 to 2.4 mEq/L.“*‘* STATISTICAL ANALYSIS Multiple comparisons were performed using analysis of variance with the Newman-Kuels procedure. Pretreatment and posttreatment serum magnesium concentrations were analyzed by the Student’s c test. Pearson’s product moment correlation coefficient was calculated with the assistance of the Statistical Program for the Social Sciences (SPSS) for personal computers. A P value of <.OS was considered significant. Values are expressed as mean ? SEM. RESULTS

DISCUSSION

The 102 patients ascertained for this study had a mean age of 27 years (range 2 to 61 years). The medications most commonly ingested were tricyclic antidepressants (47%), aspirin (15%), and phenytoin (10%). Multiple-dose activated charcoal/magnesium citrate therapy was continued over 24-48 hours in all patients (mean 14.4 ? 1.31 h). During this time, a median four doses of magnesium citrate with activated charcoal were administered (range 2 to 12 doses). The mean total magnesium citrate dose was 960 & 44 mL. All patients had a metabolic profile obtained on at least three occasions. No significant changes in serum BUN, creatinine, or calcium occurred during multiple-dose cathartic therapy. The mean baseline serum magnesium concentration was 1.8 f .03 mEq/L. In contrast, the mean final serum magnesium concentration was 2.5 + .05 mEq/L, which was significantly greater that the pretreatment magnesium concentration (P < .Ol). Forty-seven patients (47%) had a final serum magnesium concentration of >2.4 mEq/L after the last dose of cathartic. Of these, 35 had serum magnesium 2.5 to 2.9 mEq/L, 11 had a final serum magnesium of 3.0 to 3.9 mEq/L, and 1 had a final serum magnesium of 4.0 mEq/L. No patient had a decreased serum magnesium concentration during the treatment interval. The final serum magnesium concentration was always the highest value obtained. To determine if the increment in serum magnesium concentration (the difference between the final and initial serum magnesium concentration) was influenced by the quantity of cathartic administered, results were stratified into four groups based on the increment in serum magnesium concentration that had occurred (Table 1). Neither the total quantity of magnesium citrate nor quantity of magnesium citrate administered hourly were significantly different among groups. Because the final serum magnesium concentrations were obtained across a wide interval from the last dose of magTABLE1.

nesium citrate administered, data also were analyzed for a subset of 77 patients who had the final serum magnesium determination within 8 hours of the last dose of magnesium citrate. Again, no correlation was found between the quantity of magnesium administered and the final serum magnesium concentration. Univariate regression analysis also was performed using a correlation matrix which evaluated relationships between age (r = - .08), dose of magnesium citrate administered (r = .12), and dose of cathartic administered per hour (r = .08) with final serum magnesium concentration. No significant correlations were identified. A small (r = .45), but significant, correlation was found between initial and final serum magnesium concentration.

Serum magnesium concentration is maintained within a very narrow range by several homeostatic mechanisms. Magnesium absorption from the gastrointestinal tract is generally confined to 30 to 40% of daily intake.10*‘9 The fractional absorption of ingested magnesium decreases with hypermagnesemia by mechanisms that have not been completely characterized but are, in part, mediated by parathyroid hormone activity.” Magnesium is excreted almost exclusively by the kidneys, with magnesium ions freely filtered by the glomerulus. Tubular reabsorption, which determines the extent of magnesium conservation, is also influenced by parathyroid hormone activity.3*‘5*20,21 Several potential mechanisms of hypermagnesemia exist with respect to the physiological basis of magnesium balance. Excessive oral administration of magnesium may overwhelm the barriers to its absorption, leading to an increase in magnesium burden.” Positive magnesium balance has been associated with daily intakes of greater than 6 g. In gastrointestinal conditions associated with altered absorption, eg, enteritis or toxic megacolon, the fractional absorption of magnesium may increase in the face of normal daily magnesium intake. Because excretion of magnesium ion is dependent on normal renal function, any condition associated with changes in glomerular filtration or creatinine clearance may be associated with a limited ability to excrete magnesium.*’ Significant impairment in magnesium excretion occurs when creatinine clearance falls below 30 mL/min. ‘O,*’Therefore, conditions potentially leading to impaired magnesium excretion include chronic illnesses such as renal failure or congestive heart failure, and acute processes such as dehydration or hypotension.” The clinical consequences of hypermagnesemia have been well described. Depressed mental status and diminished deep tendon reflexes typically appear at serum magnesium

Relationship Between Increment in Serum Magnesium Concentration and Quantity of Magnesium Citrate Administered Increment in Serum Magnesium Concentration (mEq/L) 0 to0.5

N Mean cathartic dose (mL) mL Cathartic/h ABBREVIATIONS: N,

39

870 + 44 87 k 8

number of subjects; NS, not significant.

0.6to 1.0

26 1140288 93 2 5

1.1to 1.5

>1.5

P

6 1020 2 198 84i 14

5 1110 k 237 90 2 10

NS NS

WOODARD ET AL m REPETITIVE MAGNESIUM CATHARTIC

TABLE2.

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Published Reports of Cathartic-Induced Hypermagnesemia

Age (Y)

Renal Disease

Admission BUN/ Creatinine (mgldL)

67 61

+ +

65/l .6 610.6

2.3 1.5

77 50

+ -

? 1510.4

7

Fassler et all4 Jones et al” Gerard et al13$

39 56

+

Normal 1310.6

7 1.9 ?

Gren and Woolf’ Smilkstein et all5

19 56

-

610.7 610.4

1.6 7

Author(s) Garrelts et al” Weber and Santiago2’T

l

Admission Magnesium* (mEq/L)

Cathartic Mg citrate Mg citrate/ Mg sulfate Mg citrate Mg citrate/ Mg sulfate Mg citrate Mg citrate/ Mg sulfate Mg citrate Mg sulfate

Total Magnesium Administered (9)

Peak Magnesium (mEqlL)

5.76 55

5.3 6.9

2.90 99

10.3 13.2

56 1.94

11.4 19.0

5.76 45

9.6 21.3

Serum magnesium concentrations are expressed in the relatively interchangeable units of mgldl or mEq/L.‘7~18

t Also received intravenous magnesium. $ Ingested magnesium sulfate as part of an overdose.

concentrations of 24.0 mEq/L. Serum concentrations of ~5.0 mEq/L are associated with cardiac conduction abnormalities (particularly disturbances in the PR or QRS interval), often in association with hypocalcemia. Serum magnesium concentrations of >6.0 mEq/L may lead to coma, bradycardia, and hypotension. Complete heart block and respiratory arrest are seen when serum magnesium concentrations exceed 15.0 mEq/L. Death may occur with serum magnesium concentrations of 319.0 mEq/L.6~10~“~13-‘6*2~23 Existing reports of hypermagnesemia after repetitive magnesium cathartic use have described a heterogeneous group of patients and clinical circumstances (Table 2). These cases have included patients with preexisting cardiac or renal dysfunction as well as patients who ingested magnesium as part of an overdose or who received intravenous magnesium. In four of these cases, a pretreatment magnesium concentration is not reported. In the only systematic study of hypermagnesemia after repetitive cathartic use, Smilkstein et al reported that repeated administration of 30 g magnesium sulfate in 14 patients led to elevated serum magnesium (>2.1 mEq/L) in 9 of 14 patients. In their series, all patients with hypermagnesemia had a final serum magnesium of 2.2 to 5.0 mEq/L. I9 Our data suggest that severe hypermagnesemia (serum magnesium concentration 25.0 mEq/L) is an uncommon event after repetitive magnesium cathartic therapy, reinforcing the theories of magnesium homeostasis over a range of magnesium intake. The difference in our findings versus those of previous reports may be explained by our population, which received a lower total dose (mean 9.2 g [768 mEq]) of magnesium over 24 to 48 hours. Several limitations exist in our study that require caution in its interpretation. Most importantly, we did not obtain clinical correlates to the increases in serum magnesium concentration. The consequences of even mild elevations in serum magnesium concentration therefore can not be determined. However, severe magnesium toxicity has invariably been associated with serum magnesium concentrations of greater than 4.0 to 5.0 mEq/L.” This is in part owing to the heterogeneity encountered in doses of magnesium citrate ad-

ministered over varying periods of time. Also, our findings do not identify any mechanism or risk factor that is consistently associated with the development of hypermagnesemia. The data from this study cannot be used to predict the consequence of administering larger doses of magnesium citrate. Our study design involved repeated encouragement by the poison specialists for physicians to follow serum magnesium concentrations closely. In clinical settings where such prompting does not occur or in health care facilities where serum magnesium determinations are not as readily available, close monitoring may not be done, potentially increasing the risk of hypermagnesemia. Although the efftcacy of repetitive cathartic use has not been documented, it remains an accepted and commonly recommended modality of care. Close monitoring of serum magnesium concentrations should prevent the occurrence of severe hypermagnesemia and its clinical consequences. Use of multiple-dose magnesium cathartic for patients with renal insufficiency either as a result of chronic renal failure or dehydration is still not advised. REFERENCES 1. Derlet RW, Albertson TE: Activated charcoal-Past, present and future. West J Med 1966;145:493-496 2. Pond SM: Role of repeated oral doses of activated charcoal in clinical toxicology. Med Toxicol 1966;1:3-11 3. Jones J, McMullen MJ, Dougherty J, et al: Repetitive doses of activated charcoal in the treatment of poisoning. Am J Emerg Med 1967;5:305-310 4. Shannon MW, Fish SS, Lovejoy FJ Jr: Cathartics and laxatives-Do they still have a place in the management of the poisoned patient? Med Toxicol 1966;1:247-252 5. Mudge GH: Agents affecting volume and composition of body fluids. In Gilman GA, Goodman L, Rail TW, et al (eds): The Pharmacological Basis of Therapeutics. New York, NY, Macmillan, 1965, pp 646-676 6. Gren J, Woolf A: Hypermagnesemia associated with catharsis in a salicylate-intoxicated patient with anorexia nervosa. Ann Emerg Med 1969;16:200-203 7. Ryan CF, Spigiel RW, Zeldes G: Enhaned absorptive capac-

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ity of activated charcoal in the presence of magnesium citrate. Clin Toxicol 1980;17:457481 8. Curd-St-reed CD, Bordelon JG, Parks KS, et al: Effects of activated charcoal and sorbitol on sodium pentobarbital absorption in the rat. Clin Toxicol 1987;25:555-588 9. Gaudreault P, Friedman P, Lovejoy FH Jr: Efficacy of activated charcoal and magnesium citrate in the treatment of oral paraquat intoxication. Ann Emerg Med 1985;14:123-125 10. Garrelts JC, Watson WA, Holloway KD, et al: Magnesium toxicity secondary to catharsis during management oftheophvlline ooisonina. Am J Emera Med 1989:7:34-37 11. Jones J,-Heiselman 6, Doughterty J, et al: Catharticinduced magnesium toxicity during overdose management. Ann Emerg Med 1988;15:1214-1218 12. Farley TA: Severe hypernatremic dehydration after use of an activated charcoal-sorbitol suspension. J Ped 1988;109:719722 13. Gerard SK, Hernandez C, Khayam-Bashi H: Extreme hypermagnesemia caused by an overdose of magnesiumcontaining cathartics. Ann Emerg Med 1988;17:728-731 14. Fassler CA, Rodriguez M, Bodesch DB, et al: Magnesium toxicity as a cause of hypotension and hypoventilationOccurrence in patients with normal renal function. Arch Int Med 1985;145:1804-1805 15. Smilkstein MJ, Smolinske SC, Kulig KW, et al: Severe hy-

permagnesemia due to multiple-dose cathartic therapy. West J Med 1988;148:208-211 18. Rodis JF, Vintzileos AM, Campbell WA, et al: Maternal hypothermia: An unusual complication of magnesium sulfate therapy. Am J Obstet Gynecol 1987;158:435-438 17. Young DS: Implementation of SI units for clinical laboratory data. Ann Int Med 1987;108:114-129 18. Anon: Now read this-The SI units are here. JAMA 1988; 255:2329-2338 19. Smilkstein MJ, Steedle D, Kulig KW, et al: Magnesium levels after magnesium-containing cathartics. J Toxicol Clin Toxicol 1988;28:51-85 20. Wacker WEC, Parisi AF: Magnesium metabolism. N Engl J Med 1988;278:712-717 and 772-778 21. Weber CA, Santiago RM: Hypermagnesemia-A potential complication during treatment of theophylline intoxication with oral activated charcoal and magnesium-containing cathartics. Chest 1989;95:56-59 22. Oren S, Rapoport J, Zlotnik M, et al: Extreme hypermagnesemia due to ingestion of Dead Sea water. Nephron 1987;47: 199-201 23. Collinson PO, Burroughs AK: Severe hypermagnesaemia due to magnesium sulphate enemas in patients wGh hepatic coma. Br Med J 1986;293:1013-1014