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Effect of sodium polystyrene sulfonate on lithium bioavailability
ORIGINAL CONTRIBUTION lithium sodium polystyrene sulfonate
Effect of Sodium Polystyrene Sulfonate on Lithium Bioavailability
From the Departments of Pharmacy Services* and Emergency Medicine, ~ Ottawa General Hospital, Ottawa, Ontario, Canada. Received for publication October 16, 1990. Revisions received September 9, 1991, and March 2, 1992. Accepted for publication July 23, 1992.
Denis R Belanger, BSc, Pharm* Michael G Tierney, MSc Garth Dickinson,MD, FRCPCt
Study objective: To examine the effect of a single dose of sodium polystyrene sulfonate and sorhitol on lithium absorption. Design: Prospective, randomized, crossover. Setting: University teaching hospital. Type o f p a r t i c i p a n t s : Healthy volunteers.
Interventions: Subjects ingested 600 mg lithium carbonate on two occasions, with and without 30 g concomitant sodium polystyrene sulfonate. Blood samples were drawn up to 24 hours after ingestion and assayed for serum lithium concentration. Measurements and main results: Compared with control, sodium polystyrene sulfonate and sorbitol reduced the area under the lithium serum concentration-time curve by 11.33%, reduced the mean observed peak serum lithium concentration 0.07 +0.08 mme[/L, and delayed the time to the mean Observed peak serum lithium concentration by 2.04 + 2.40 hours.
Conclusion: Sodium polystyrene sulfonate and sorbitol may be used in patients immediately or shortly after ingestion of a significant acute overdose of lithium in situations in which hemodialysis cannot be instituted promptly. [BOlanger DR, Tierney MG, Dickinson G: Effect of sodium polystyrene sulfonate on lithium bioavailability. Ann EmergMeal November 1992;21:1312-I 315.]
20/1312
ANNALS OF EMERGENCYMEDICINE 21:11 NOVEMBER1992
LITHIUM B I O A V A I L A B I L I T Y
Bdlanger, Tierney & Dickinson
INTRODUCTION
Lithium carbonate is used on a widespread basis in the treatment of manic-depressive and schizo-affective psychiatric disorders. Lithium has a n a r r o w therapeutic index; its therapeutic range is 0.6 to 1.5 mmol/L. At post-distribution serum concentrations of more than 1.5 retool/L, adverse drug reactions such as muscle twitching, ataxia, weakness, drowsiness, and thirst frequently occur. Post-distribution serum concentrations of more than 2.5 mmol/L can cause confusion, convulsions, dehydration, and coma, whereas cardiovascular collapse is known to occur at concentrations of more than 4 mmol/L. 1 F o r any given serum lithium concentration, the toxicity associated with chronic intoxication is greater than that for a single acute ingestion. Presently, hemodialysis, which increases elimination, is the treatment of choice for severe lithium intoxication. Very little can be done to prevent lithium absorption because activated charcoal does not adequately bind lithium. 2 This presents a great problem for facilities without dialysis equipment or in which there is a long delay before dialysis can be accomplished. Another p r o b l e m is the potential intoxication with sustained-release lithium products, which would be absorbed over a lengthened period of time, creating the need for repeat dialysis. Recently, whole-bowel irrigation has been shown to reduce lithium absorption in healthy volunteers.3 Animal and in vitro studies have indicated that sodium polystyrene sulfonate may be useful as an adsorbent in the treatment of lithium intoxication. Linalds et al performed an animal study examining lithium binding and concluded that sodium polystyrene sulfonate significantly lowered serum lithum concentrations in a dose-related manner compared with the control ~onp. a It also appeared that repetitive sodium polystyrene sulfonate doses increased lithium elimination, a An in vitro study showed a binding capacity of 0.7 rnmol lithium for every gram of sodium polystyrene sulfonate at both p H 7 and p H 1.5 The objective of this experiment was to examine the effects of sodium polystyrene sulfonate and sorbitol on the relative bioavailability of lithium in healthy volunteers. MATERIALS
AND
METHODS
Twelve healthy volunteers age 21 to 35 years participated in this study. The study was approved by the human experimental procedures committee of our institution, and all subjects were required to give written informed consent. ECGs and serum chemistry were performed on each volunteer, and they were required to complete a medical history form. The results of the above were reviewed by a physician for the presence of any of the following exclusion criteria: hypokalemia; hypertension; congestive heart failure; arrhythmias; thyroid disorders; renal disease; diabetes; sodium-restricted diet; serum sodium outside the normal range (135 to 145 mmol/L); and concomitant use of diuretics, acetazolamide, anti-inflammatory agents, anticonvulsants, annpsychotic agents, or potassium supplements. Women of child-bearing age who were not using an effective form of birth control were also excluded.
NOVEMBER1992
21:11 ANNALSOF EMERGENCYMEDICINE
The design was a single-dose crossover study of lithium with or without sodium polystyrene sulfonate. The o r d e r of treatment was randomized with the use of r a n d o m - n u m b e r tables. After an overnight fast, each volunteer ingested 600 mg (16.24 retool) lithium as the carbonate salt (two 300-mg tablets). One group of participants concomitantly consumed 30 g sodium polystyrene sulfonate (120 mL of sodium polystyrene sulfonate 15 g/60 mL) whereas the other group consumed an equivalent volume of water. The sodium polystyrene sulfonate p r e p a r a t i o n also contained 28.2 g sorbitol. The subjects were required to fast for at least two hours after the lithium dose; thereafter, they were allowed to eat without restriction. After a one-week washout period, the procedure was repeated, but the group that initially had consumed the sodium polystyrene sulfonate was administered water, and the members of the other group were administered sodium polystyrene sulfonate. Before commencing the study, trained personnel placed IV lock devices in each subject. Blood samples of 5 to 10 mL were collected in evacuated tubes at zero, 0.33, 0.66, one, 1.5, two, three, four, six, eight, ten, and 24 hours after lithium ingestion. During the course of the experiment, the subjects were asked to report any untoward events. This was accomplished through periodic questioning during the treatment period and by supplying each subject with an extensive list of adverse drug reactions and signs of toxicity. The subjects were required to complete a special form describing any reactions. Before being analyzed, the blood samples were centrifuged, and the plasma was collected and stored at - 2 0 C in polystyrene tubes until analysis for lithium content. The samples drawn at zero, six, and 24 hours also were analyzed for sodium and potassium content. Lithimn assay was performed by a potentiometric method with ion-selective electrodes using the AVL 985-S Electrolyte Analyzer (AVL Scientific Corporation, Roswell, Georgia). A three-point calibration of the instrumentation was performed before and after each subject's analysis to ensure standardization. The assay is sensitive to lithium concentrations as low as 0.01 mmol/L and the s t a n d a r d deviation is less than or equal to 0.02 nmlol/L over the range of 0.01 to 9.90 mmol/L. 6 F r o m the obtained data, relative bioavailabilities were compared by the area under the concentration time curve (AUC) to 24 hours calculated by the trapezoidal rule for each arm of the study for each volunteer. Peak observed plasma lithium concentration (C . . . . ) and time to peak observed lithium concentration (t . . . . ) were obtained directly from the serum concentration-time curves. The AUC results were evaluated with the two-tailed Student's t-test for p a i r e d observations with an a e r r o r of .05. Sample size was calculated using an c~e r r o r of 5% for a two-tailed test and a B e r r o r of 15% for a one-tailed test to detect a 20% difference between the two t r e a t m e n t s / C m a ~ and tma,~ results were compared using the two-tailed Wilcoxon sign r a n k test.
1313/21
LITHIUM BIOAVAILABILITY Bdlanger, Tierney & Dickinson
RESULTS
DISCUSSION
Of the initial 12 volunteers, one was excluded due to an abnormal ECG (Wolff-Parkinson-White syndrome), leaving 11 volunteers to continue with the study. The serum concentration-time data for oral lithium carbonate given with water and with sodium polystyrene sulfonate are shown (Figure). Individual and mean Cmax, t . . . . , and AUC values for both arms of the study are given (Table). Ten of the 11 subjects had increased t . . . . and reduced C . . . . in the sodium polystyrene sulfonate arm of the study. Paradoxically, one subject had an unexplained decrease in tma× and increase in C..... in the sodium polystyrene sulfonate arm. Analysis of these variables revealed a mean reduction in AUC of 11.33 + 5.87% from 5.63 _+1.32 to 5.03 + 1.38 mmol.hr/L (P < .001), a reduced observed peak concentration of lithium (P < .05), and a delay in attaining peak lithium concentration (P < .05) in the sodimn polystyrene sulfonate arm compared with the placebo arm of the trial. Mean individual decrease in C..... was 0.07 + 0.08 mmol/L, and mean increase in tm~x was 2.04 + 2.40 hours in the sodium polystyrene sulfonate arm. No significant changes in serum sodium and potassium concentrations between the two treatments were found at six and 24 hours after ingestion. The more frequently reported adverse effects in the placebo arm were unsteadiness and drowsiness in four subjects, whereas five subjects reported abdominal cramping and/or diarrhea during the sodium polystyrene snlfonate treatment. None of the adverse effects was severe enough to require removal from the study or prompt the subject to seek medical attention.
This study demonstrated that sodium polystyrene sulfonate and sorbitol given concomitantly with lithium caused statistically significant decreases in bioavailability and C..... and an increase in t m a x. Although the changes in AUC and C. . . . were found to be statistically significant, these decreases of 11% and 13%, respectively, would not change the clinical course of lithium intoxication. However, the two-hour delay in absorption of lithium observed with administration of sodium polystyrene sulfonate may be of clinical use in certain cases. For example, if a person ingested a toxic dose of lithium and dialysis could not be initiated quickly for geographic or technical reasons, efforts to delay or reduce absorption using sodium polystyrene sulfonate and/or whole-bowel lavage should be considered. Re-equilibration is a potential explanation for the apparent delay in absorption without a large change in bioavailability. Initially, the sodium polystyrene sulfonate would be exposed to a high concentration of lithium ions. An exchange takes place between the lithium and sodium ions causing a large decrease in free lithium ions available for absorption. Later, as the lithium-sodium polystyrene sulfonate complex moves down the gastrointestinal tract, the complex would no longer be exposed to an environment of high lithium ion concentration. Hence, a new equilibration process occurs in which the lithium ion is exchanged for the u n b o u n d cations normally found in the gastrointestinal tract (sodium and potassium). These unbound lithium ions are absorbed quickly. It is possible that repeat sodium polystyrene sulfonate doses would prevent this re-equilibration and cause a more profound decrease in lithium bioavailability, but this theory requires evaluation. This concept of desorption and re-equilibration has been proposed for the salicylate-activated charcoal interaction.8,9
Figure. M e a n s e r u m l i t h i u m c o n c e n t r a t i o n v e r s u s time Serum lithium concentration (mmol/L) 0.5-A
Table. "
Lithium
Individual lithium absorption variables
Sodium Polystyrene Sulfonate
O.41
Subject 0"3 I
0.2
0.1
0.0
O
22/1314
I
I
I
I
I
2
4
6
8
10
] ,
I
12 14 Time (hr)
I
]
I
I
I
16
18
20
22
24
AUC Cmax (mmol.hr/L)* (mmol/Lp
Control
tmax
AUC
(hr) t
(mmol,hr/L)
Cmax (mmol/L)
tma× (hr)
7.28 5.59 6.65 3.47 3.97 6.11 527 5.97 5.17 7.63 4.31
0.62 0.58 0.49 0.36 0.46 0.39 0.58 0.82 0.51 0.61 0.62
3.01 1,50 2.98 1.08 2.99 7.98 1.48 0.65 1.98 2.00 1,50
1 7.08 0.51 6.03 2 4.87 0.52 6.02 3 5.93 0.41 8.00 4 2.71 0,32 3.00 5 3.58 0.40 3.01 6 5,65 0.51 5.96 7 5.12 0,51 2,95 8 5.21 0.58 1.47 9 4.07 0,42 3.20 10 7.08 0,55 8,03 11 4.03 0,51 1.99 *P< .001 compared with control (Student's t-test).
t p < .05 compared with control (Wilcoxon sign rank test).
ANNALS OF EMERGENCYMEDIC]NE
21:11
NOVEMBER1992
LITHIUM BIOAVAILABILITY
B~langer, Tierney & Dickinson
Mthough the sodium polystyrene sulfonate preparation contained sorbitol, we believe that it is unlikely that the inclusion of sorbitol affected the results. The dose of sorbitol used (28.2 g) was relatively small, and no subject reported severe diarrhea associated with sodium polystyrene sulfimate and sorbitol administration. Nevertheless, this study was not designed to isolate the relative contributions of sodium polystyrene sulfonate and sorbitol. A limitation of this study is the relatively few bloodsampling times between ten and 24 hours to characterize the serum lithium concentration-tbne relationship. The sampling times were chosen based on the prediction that sodium polystyrene sulfonate would decrease AUC without delaying absorption. However, due to the delayed absorption, the rehability of the C . . . . and t . . . . in the sodium polystyrene sulfonate arm can be questioned. Between four to ten hours after lithium ingestion, blood samples were drawn every two hours, and it is possible that the observed mean t ..... was slightly less than the actual t ..... " A further consideration in interpretation of our results is that the sodium polystyrene sulfonate and sorbitol were administered concurrently with lithium. Therefore, one cannot necessarily extrapolate the results to the clinical situation in which patients typically present up to several hours after ingestion.
REFERENCES 1. Ellenhorn MJ, Barceloux DG: Medical Toxicology: Diagnosis and Treatment of Human Poisoning. New York, Elsevier, 1988,p 1042-1046. 2. Favin FD, Klein-Schwartz W, Oderda GM, et al: In vitro study of lithium carbonate absorption by activated charcoal. Clin Toxico11988;26:443-450. 3. Smith SW, Ling LJ, Halstenson CE: Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 1991;20:536-539. 4. Linakis LG, Lacouture PG, Eisenberg MS, et al: Multiple-dose sodium polystyrene sulfonate in lithium intoxication: An animal modeI. VetHum Toxico11989;31:364. 5. Welch WW, Driscoll JL, Lewander W J, et al: In vitro lithium binding with sodium polystyrene sulfonate. Vet Hum Toxico11987;29:472. 6. AVL 985-SOwner's Manual Roswell, Georgia, AVL Scientific Corporation, 1988. 7. Colten T: Statistics in Medicine. Boston, Little, Brown & Co, 1974; p 142-144. 8. Filippone GA, Fish SS, Lacouture P6, et al: Reversible absorption (desorption) or aspirin from activated charcoal. Arch Intern Med 1987;147:1390-1392. 9. Keller RE, Schwab RA, Krenzelok EP: Contribution of sorbitol combined with activated charcoal in prevention of salicy[ate absorption. Ann Emerg Med 1990;19:654-656. Address for reprints: Michael G Tierney, MSc Department of Pharmacy Ottawa General Hospital 501 Smyth Road Ottawa, Ontario, Canada K1 H 8L8
CONCLUSION
Based on the results of this study-, which demonstrates a significant and consistent delay in lithium absorption, it would be acceptable to recommend that sodium polystyrene sulfonate be given to patients immediately or soon after ingestion of a significant acute overdose of lithium in situations in which hemodialysis cannot be instituted promptly. Studies of the effects of repeat doses of sodium polystyrene sulfonate on lithium pharmacokinetics must be conducted before repeat doses can be recommended to reduce absorption in lithium intoxication.
NOVEMBER 1992 2 1 : 1
ANNALS OF EMERGENCY MEDICINE
1315/23
Effect of Sodium Polystyrene Sulfonate on Lithium Bioavailability
From the Departments of Pharmacy Services* and Emergency Medicine, ~ Ottawa General Hospital, Ottawa, Ontario, Canada. Received for publication October 16, 1990. Revisions received September 9, 1991, and March 2, 1992. Accepted for publication July 23, 1992.
Denis R Belanger, BSc, Pharm* Michael G Tierney, MSc Garth Dickinson,MD, FRCPCt
Study objective: To examine the effect of a single dose of sodium polystyrene sulfonate and sorhitol on lithium absorption. Design: Prospective, randomized, crossover. Setting: University teaching hospital. Type o f p a r t i c i p a n t s : Healthy volunteers.
Interventions: Subjects ingested 600 mg lithium carbonate on two occasions, with and without 30 g concomitant sodium polystyrene sulfonate. Blood samples were drawn up to 24 hours after ingestion and assayed for serum lithium concentration. Measurements and main results: Compared with control, sodium polystyrene sulfonate and sorbitol reduced the area under the lithium serum concentration-time curve by 11.33%, reduced the mean observed peak serum lithium concentration 0.07 +0.08 mme[/L, and delayed the time to the mean Observed peak serum lithium concentration by 2.04 + 2.40 hours.
Conclusion: Sodium polystyrene sulfonate and sorbitol may be used in patients immediately or shortly after ingestion of a significant acute overdose of lithium in situations in which hemodialysis cannot be instituted promptly. [BOlanger DR, Tierney MG, Dickinson G: Effect of sodium polystyrene sulfonate on lithium bioavailability. Ann EmergMeal November 1992;21:1312-I 315.]
20/1312
ANNALS OF EMERGENCYMEDICINE 21:11 NOVEMBER1992
LITHIUM B I O A V A I L A B I L I T Y
Bdlanger, Tierney & Dickinson
INTRODUCTION
Lithium carbonate is used on a widespread basis in the treatment of manic-depressive and schizo-affective psychiatric disorders. Lithium has a n a r r o w therapeutic index; its therapeutic range is 0.6 to 1.5 mmol/L. At post-distribution serum concentrations of more than 1.5 retool/L, adverse drug reactions such as muscle twitching, ataxia, weakness, drowsiness, and thirst frequently occur. Post-distribution serum concentrations of more than 2.5 mmol/L can cause confusion, convulsions, dehydration, and coma, whereas cardiovascular collapse is known to occur at concentrations of more than 4 mmol/L. 1 F o r any given serum lithium concentration, the toxicity associated with chronic intoxication is greater than that for a single acute ingestion. Presently, hemodialysis, which increases elimination, is the treatment of choice for severe lithium intoxication. Very little can be done to prevent lithium absorption because activated charcoal does not adequately bind lithium. 2 This presents a great problem for facilities without dialysis equipment or in which there is a long delay before dialysis can be accomplished. Another p r o b l e m is the potential intoxication with sustained-release lithium products, which would be absorbed over a lengthened period of time, creating the need for repeat dialysis. Recently, whole-bowel irrigation has been shown to reduce lithium absorption in healthy volunteers.3 Animal and in vitro studies have indicated that sodium polystyrene sulfonate may be useful as an adsorbent in the treatment of lithium intoxication. Linalds et al performed an animal study examining lithium binding and concluded that sodium polystyrene sulfonate significantly lowered serum lithum concentrations in a dose-related manner compared with the control ~onp. a It also appeared that repetitive sodium polystyrene sulfonate doses increased lithium elimination, a An in vitro study showed a binding capacity of 0.7 rnmol lithium for every gram of sodium polystyrene sulfonate at both p H 7 and p H 1.5 The objective of this experiment was to examine the effects of sodium polystyrene sulfonate and sorbitol on the relative bioavailability of lithium in healthy volunteers. MATERIALS
AND
METHODS
Twelve healthy volunteers age 21 to 35 years participated in this study. The study was approved by the human experimental procedures committee of our institution, and all subjects were required to give written informed consent. ECGs and serum chemistry were performed on each volunteer, and they were required to complete a medical history form. The results of the above were reviewed by a physician for the presence of any of the following exclusion criteria: hypokalemia; hypertension; congestive heart failure; arrhythmias; thyroid disorders; renal disease; diabetes; sodium-restricted diet; serum sodium outside the normal range (135 to 145 mmol/L); and concomitant use of diuretics, acetazolamide, anti-inflammatory agents, anticonvulsants, annpsychotic agents, or potassium supplements. Women of child-bearing age who were not using an effective form of birth control were also excluded.
NOVEMBER1992
21:11 ANNALSOF EMERGENCYMEDICINE
The design was a single-dose crossover study of lithium with or without sodium polystyrene sulfonate. The o r d e r of treatment was randomized with the use of r a n d o m - n u m b e r tables. After an overnight fast, each volunteer ingested 600 mg (16.24 retool) lithium as the carbonate salt (two 300-mg tablets). One group of participants concomitantly consumed 30 g sodium polystyrene sulfonate (120 mL of sodium polystyrene sulfonate 15 g/60 mL) whereas the other group consumed an equivalent volume of water. The sodium polystyrene sulfonate p r e p a r a t i o n also contained 28.2 g sorbitol. The subjects were required to fast for at least two hours after the lithium dose; thereafter, they were allowed to eat without restriction. After a one-week washout period, the procedure was repeated, but the group that initially had consumed the sodium polystyrene sulfonate was administered water, and the members of the other group were administered sodium polystyrene sulfonate. Before commencing the study, trained personnel placed IV lock devices in each subject. Blood samples of 5 to 10 mL were collected in evacuated tubes at zero, 0.33, 0.66, one, 1.5, two, three, four, six, eight, ten, and 24 hours after lithium ingestion. During the course of the experiment, the subjects were asked to report any untoward events. This was accomplished through periodic questioning during the treatment period and by supplying each subject with an extensive list of adverse drug reactions and signs of toxicity. The subjects were required to complete a special form describing any reactions. Before being analyzed, the blood samples were centrifuged, and the plasma was collected and stored at - 2 0 C in polystyrene tubes until analysis for lithium content. The samples drawn at zero, six, and 24 hours also were analyzed for sodium and potassium content. Lithimn assay was performed by a potentiometric method with ion-selective electrodes using the AVL 985-S Electrolyte Analyzer (AVL Scientific Corporation, Roswell, Georgia). A three-point calibration of the instrumentation was performed before and after each subject's analysis to ensure standardization. The assay is sensitive to lithium concentrations as low as 0.01 mmol/L and the s t a n d a r d deviation is less than or equal to 0.02 nmlol/L over the range of 0.01 to 9.90 mmol/L. 6 F r o m the obtained data, relative bioavailabilities were compared by the area under the concentration time curve (AUC) to 24 hours calculated by the trapezoidal rule for each arm of the study for each volunteer. Peak observed plasma lithium concentration (C . . . . ) and time to peak observed lithium concentration (t . . . . ) were obtained directly from the serum concentration-time curves. The AUC results were evaluated with the two-tailed Student's t-test for p a i r e d observations with an a e r r o r of .05. Sample size was calculated using an c~e r r o r of 5% for a two-tailed test and a B e r r o r of 15% for a one-tailed test to detect a 20% difference between the two t r e a t m e n t s / C m a ~ and tma,~ results were compared using the two-tailed Wilcoxon sign r a n k test.
1313/21
LITHIUM BIOAVAILABILITY Bdlanger, Tierney & Dickinson
RESULTS
DISCUSSION
Of the initial 12 volunteers, one was excluded due to an abnormal ECG (Wolff-Parkinson-White syndrome), leaving 11 volunteers to continue with the study. The serum concentration-time data for oral lithium carbonate given with water and with sodium polystyrene sulfonate are shown (Figure). Individual and mean Cmax, t . . . . , and AUC values for both arms of the study are given (Table). Ten of the 11 subjects had increased t . . . . and reduced C . . . . in the sodium polystyrene sulfonate arm of the study. Paradoxically, one subject had an unexplained decrease in tma× and increase in C..... in the sodium polystyrene sulfonate arm. Analysis of these variables revealed a mean reduction in AUC of 11.33 + 5.87% from 5.63 _+1.32 to 5.03 + 1.38 mmol.hr/L (P < .001), a reduced observed peak concentration of lithium (P < .05), and a delay in attaining peak lithium concentration (P < .05) in the sodimn polystyrene sulfonate arm compared with the placebo arm of the trial. Mean individual decrease in C..... was 0.07 + 0.08 mmol/L, and mean increase in tm~x was 2.04 + 2.40 hours in the sodium polystyrene sulfonate arm. No significant changes in serum sodium and potassium concentrations between the two treatments were found at six and 24 hours after ingestion. The more frequently reported adverse effects in the placebo arm were unsteadiness and drowsiness in four subjects, whereas five subjects reported abdominal cramping and/or diarrhea during the sodium polystyrene snlfonate treatment. None of the adverse effects was severe enough to require removal from the study or prompt the subject to seek medical attention.
This study demonstrated that sodium polystyrene sulfonate and sorbitol given concomitantly with lithium caused statistically significant decreases in bioavailability and C..... and an increase in t m a x. Although the changes in AUC and C. . . . were found to be statistically significant, these decreases of 11% and 13%, respectively, would not change the clinical course of lithium intoxication. However, the two-hour delay in absorption of lithium observed with administration of sodium polystyrene sulfonate may be of clinical use in certain cases. For example, if a person ingested a toxic dose of lithium and dialysis could not be initiated quickly for geographic or technical reasons, efforts to delay or reduce absorption using sodium polystyrene sulfonate and/or whole-bowel lavage should be considered. Re-equilibration is a potential explanation for the apparent delay in absorption without a large change in bioavailability. Initially, the sodium polystyrene sulfonate would be exposed to a high concentration of lithium ions. An exchange takes place between the lithium and sodium ions causing a large decrease in free lithium ions available for absorption. Later, as the lithium-sodium polystyrene sulfonate complex moves down the gastrointestinal tract, the complex would no longer be exposed to an environment of high lithium ion concentration. Hence, a new equilibration process occurs in which the lithium ion is exchanged for the u n b o u n d cations normally found in the gastrointestinal tract (sodium and potassium). These unbound lithium ions are absorbed quickly. It is possible that repeat sodium polystyrene sulfonate doses would prevent this re-equilibration and cause a more profound decrease in lithium bioavailability, but this theory requires evaluation. This concept of desorption and re-equilibration has been proposed for the salicylate-activated charcoal interaction.8,9
Figure. M e a n s e r u m l i t h i u m c o n c e n t r a t i o n v e r s u s time Serum lithium concentration (mmol/L) 0.5-A
Table. "
Lithium
Individual lithium absorption variables
Sodium Polystyrene Sulfonate
O.41
Subject 0"3 I
0.2
0.1
0.0
O
22/1314
I
I
I
I
I
2
4
6
8
10
] ,
I
12 14 Time (hr)
I
]
I
I
I
16
18
20
22
24
AUC Cmax (mmol.hr/L)* (mmol/Lp
Control
tmax
AUC
(hr) t
(mmol,hr/L)
Cmax (mmol/L)
tma× (hr)
7.28 5.59 6.65 3.47 3.97 6.11 527 5.97 5.17 7.63 4.31
0.62 0.58 0.49 0.36 0.46 0.39 0.58 0.82 0.51 0.61 0.62
3.01 1,50 2.98 1.08 2.99 7.98 1.48 0.65 1.98 2.00 1,50
1 7.08 0.51 6.03 2 4.87 0.52 6.02 3 5.93 0.41 8.00 4 2.71 0,32 3.00 5 3.58 0.40 3.01 6 5,65 0.51 5.96 7 5.12 0,51 2,95 8 5.21 0.58 1.47 9 4.07 0,42 3.20 10 7.08 0,55 8,03 11 4.03 0,51 1.99 *P< .001 compared with control (Student's t-test).
t p < .05 compared with control (Wilcoxon sign rank test).
ANNALS OF EMERGENCYMEDIC]NE
21:11
NOVEMBER1992
LITHIUM BIOAVAILABILITY
B~langer, Tierney & Dickinson
Mthough the sodium polystyrene sulfonate preparation contained sorbitol, we believe that it is unlikely that the inclusion of sorbitol affected the results. The dose of sorbitol used (28.2 g) was relatively small, and no subject reported severe diarrhea associated with sodium polystyrene sulfimate and sorbitol administration. Nevertheless, this study was not designed to isolate the relative contributions of sodium polystyrene sulfonate and sorbitol. A limitation of this study is the relatively few bloodsampling times between ten and 24 hours to characterize the serum lithium concentration-tbne relationship. The sampling times were chosen based on the prediction that sodium polystyrene sulfonate would decrease AUC without delaying absorption. However, due to the delayed absorption, the rehability of the C . . . . and t . . . . in the sodium polystyrene sulfonate arm can be questioned. Between four to ten hours after lithium ingestion, blood samples were drawn every two hours, and it is possible that the observed mean t ..... was slightly less than the actual t ..... " A further consideration in interpretation of our results is that the sodium polystyrene sulfonate and sorbitol were administered concurrently with lithium. Therefore, one cannot necessarily extrapolate the results to the clinical situation in which patients typically present up to several hours after ingestion.
REFERENCES 1. Ellenhorn MJ, Barceloux DG: Medical Toxicology: Diagnosis and Treatment of Human Poisoning. New York, Elsevier, 1988,p 1042-1046. 2. Favin FD, Klein-Schwartz W, Oderda GM, et al: In vitro study of lithium carbonate absorption by activated charcoal. Clin Toxico11988;26:443-450. 3. Smith SW, Ling LJ, Halstenson CE: Whole-bowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 1991;20:536-539. 4. Linakis LG, Lacouture PG, Eisenberg MS, et al: Multiple-dose sodium polystyrene sulfonate in lithium intoxication: An animal modeI. VetHum Toxico11989;31:364. 5. Welch WW, Driscoll JL, Lewander W J, et al: In vitro lithium binding with sodium polystyrene sulfonate. Vet Hum Toxico11987;29:472. 6. AVL 985-SOwner's Manual Roswell, Georgia, AVL Scientific Corporation, 1988. 7. Colten T: Statistics in Medicine. Boston, Little, Brown & Co, 1974; p 142-144. 8. Filippone GA, Fish SS, Lacouture P6, et al: Reversible absorption (desorption) or aspirin from activated charcoal. Arch Intern Med 1987;147:1390-1392. 9. Keller RE, Schwab RA, Krenzelok EP: Contribution of sorbitol combined with activated charcoal in prevention of salicy[ate absorption. Ann Emerg Med 1990;19:654-656. Address for reprints: Michael G Tierney, MSc Department of Pharmacy Ottawa General Hospital 501 Smyth Road Ottawa, Ontario, Canada K1 H 8L8
CONCLUSION
Based on the results of this study-, which demonstrates a significant and consistent delay in lithium absorption, it would be acceptable to recommend that sodium polystyrene sulfonate be given to patients immediately or soon after ingestion of a significant acute overdose of lithium in situations in which hemodialysis cannot be instituted promptly. Studies of the effects of repeat doses of sodium polystyrene sulfonate on lithium pharmacokinetics must be conducted before repeat doses can be recommended to reduce absorption in lithium intoxication.
NOVEMBER 1992 2 1 : 1
ANNALS OF EMERGENCY MEDICINE
1315/23