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mSdicamenteuse. Ce type de rein artificiel a servi au traitement de trois malades .... sluggishly to light, and the gag reflex, deep pain response and bowel sounds were ..... bon, Trans Am Soc Artif Intern Organs 18: 473, 1972. 21. NEALON TF ...
ORIGINAL ARTICLES

Microcapsule artificial kidney: treatment of patients with acute drug intoxication Thomas M.S. Chang, m.d., ph.d., f.r.c.p.[c], John F. Coffey, m.d., Paul Barre, m.d., Andrew Gonda, m.d., f.r.c.p.[c], John H. Dirks, m.d., f.r.c.p.[c], Mortimer Levy, m.d., f.r.c.p.[c] and Colin Lister, aist, Montreal

Summary: The microcapsule artificial kidney was used in the treatment of three patients with acute drug intoxication. The apparatus contains 300 g. of microencapsulated activated charcoal with a total membrane area available for diffusion of more than 2m.2 The membrane thickness is only 500 A. These properties make possible a compact artificial kidney whose efficiency for the removal of uremic metabolites and drugs is much higher than standard hemodialysis apparatus. The microcapsules are made blood-compatible by coating with human albumin. A roller pump was used to propel the blood through the microcapsule artificial kidney at a flow rate of 300 ml./min. for two to three hours. The clearance values for glutethimide, methyprylon and methaqualone were much higher than those achieved by standard hemodialysis. Hemoperfuston quickly lowered the drug level in the blood with resulting clinical improvement. Resume: Rein artificiel sous forme d'une microcapsule pour traiter les cas dintoxication aigue d'origine mSdicamenteuse. Ce type de rein artificiel a servi au traitement de trois malades souffrant d'intoxication aigue d'origine mediacamenteuse. L'appareil renferme 300 g de charbon vegetal active, a l'etat de particules microscopiques encapsulees. La membrane de diffusion a une superficte totale depassant 2 m2. L'epaisseur de la membrane n'est que de 500 unites Angstrom. Grace a ces proprietes, on dispose d'un rein artificiel peu encombrant dont I'efficacite pour I'elimination des medicaments toxiques et des metabolites uremiques est nettement plus elevee que celle de I'hemodialyseur classique. Les particules microscopiques ont ete enrobees d'albumine humaine pour les rendre compatibles avec le sang. Une pompe speciale a ete utilis6e pour propulser le sang a travers le rein artificiel a un rythme de 300 ml/min. et ce, durant une pe>iode de deux a trois heures. Les taux de clearance pour le glutethimide, la methyprylone et la methaqualone ont 6te beaucoup plus eleves que ceux r6alises par I'hemodialyse conventionnelle. Cette hemoperfusion a rapidement diminue la concentration du medicament dans le sang et s'est traduite par une amelioration clinique.

Since the experimental demonstration1 and clinical ap¬ plication2 of hemodialysis, its efficiency for the removal of certain drugs in patients with acute intoxication has been well documented.3 However, in many centres, es¬ pecially the smaller ones, the availability of the hemodialysers, the bulkiness of the machine, the length of treatment required, the possible fluctuation in extracorporeal blood volume and the specialized personnel required may be obstacles to the more frequent use of hemodialysis for the treatment of drug intoxication. A new type of artificial kidney based on the use of microcapsules has been developed4"7 and tested clinical¬ ly for the treatment of patients with chronic renal failure.6,810 It consists essentially of 300 g. of semiultrathin semipermeable permeable microcapsules membranes enveloping adsorbents. The microcapsules are contained in an extracorporeal shunt chamber 10 cm. in diameter and 8 cm. in height (internal dimensions), where they are retained by screens. Blood can circulate freely through the chamber and come in direct contact with the semipermeable microcapsules, This permits permeant exogenous toxins to cross the semi¬ permeable membrane to be removed by the microen¬ capsulated adsorbent. The membranes are less than 500 A in thickness and constitute a total surface area of more than 2 m.2 compared to the total membrane area of 1 m.2 and membrane thickness of 50,000 A of the standard hemodialysers. Therefore, the microcap¬ sule artifical kidney has a potential transport capacity which is at least 100 times greater. In addition to the ultrathin membranes and the large surface-to-volume relationship, there is the added advantage that the .

From the Department of Physiology, Faculty of Medicine, McGill University and Royal Victoria Hospital, Montreal. Reprint requests to: Dr. T. M. S. Chang, Professor of Physiology, 10th Floor, Mclntyre Medical Sciences Building,

McGill University, Montreal, P.Q. C.M.A. JOURNAL/FEBRUARY 17, 1973/VOL. 108 429

of adsorbents for the removal of permeant toxins makes unnecessary the large volume of dialysate re¬ quired in standard hemodialysers. This means that a very compact and simple artificial kidney is available. After testing different types of adsorbents and en¬ zymes,6 the first agent to be used clinically for the microencapsulation was activated charcoal.8"10 When perfused by blood, free activated charcoal granules in a column can efficiently remove many drugs and uremic metabolites.11'14 Unfortunately, in the free form the charcoal granules release powder, causing embolism and adversely affecting platelets.1214 Microencapsula¬ tion of the activated charcoal within a highly permeable and blood-compatible membrane prevents both these adverse effects while allowing permeant toxins to be rapidly removed from circulating blood at a rate com¬ parable to that of free charcoal granules.5"8 The proved safety and efficiency of this system for use in patients with chronic renal failure, on both a short-term and long-term basis,8"10 and the laboratory demonstration of its efficiency for the removal of drugs in animals with acute intoxication,6,7 led to the present study of its clinical use for the treatment of acute drug intoxication in humans. use

Methods

microcapsule artificial kidney (Fig. 1) was pre¬ pared in this laboratory as previously described.6 In the present study each apparatus contained 300 g. of microencapsulated activated charcoal. The membrane was formed by coating the activated charcoal granules with cellulose nitrate, then with albumin.6'7 The total membrane area was 2.25 m.2 and the priming volume 300 ml. The afferent tubing to the artificial kidney was connected to the patient's femoral artery with a 14gauge Intracath introduced by percutaneous puncture. The efferent tubing was inserted into a forearm vein with a 16-gauge Intracath. In one case an external arteriovenous shunt was used for blood access. Heparin, 1000 units, was injected into the priming liquid of the shunt, followed by 4000 units intravenously into the patient 10 minutes before the treatment was started. A roller pump was used to circulate blood from the pa¬ tient through the artificial kidney at a flow rate of 300 ml./min. The Lee-White clotting time was main¬ tained between 30 and 40 minutes during the twoto three-hour hemoperfusion periods by supplementary injections of 1000 units of heparin into the shunt every 45 to 60 minutes. Clearance of the drug was measured by estimations on afferent and efferent blood samples taken simultaneously from the artificial kidney. The blood glutethimide level was determined by colorimetric methods;15 methyprylon and methaqualone levels were measured by gas chromatography. Gas chromato¬ graphy was also used as a screening test for the presence of other in The

drugs

infused. Twenty-four hours after admission her con¬ dition was unchanged. Her rectal temperature was 87°F., blood pressure 90/50, and she still required isoproterenol and ventilatory support. At this time she had clinical and x-ray signs of bilateral bronchopneumonia. Her blood glutethimide level was 7 mg./lOO ml. At 27 hours after admission she was treated by hemoperfusion through 300 g. of the ACAC microcapsules for two hours. In the course of the hemoperfusion her blood pressure rose from 90/50 to 120/80 in 30 minutes without isoproterenol in¬ fusion. Her blood glutethimide level fell to 3 mg./lOO ml. was

but 10 hours after completion of the hemoperfusion it 5 mg./lOO ml. Except for a very slight pupillary reflex and gag reflex, she remained comatose. Her blood pressure was 110/55. A second hemoperfusion with an¬ other 300 g. of ACAC microcapsules was carried out. Within one hour a 2+ patellar reflex and a slight plantar reflex could be elicited. After one and one-half hours of hemoperfusion, her tidal volume increased from 250 ml. (pretreatment) to 475 ml. In addition, she exhibited some spontaneous limb movements. Her blood pressure in¬ creased to 130/75. The posthemoperfusion blood glute¬ thimide level was 1.5 mg./lOO ml. Two hours after com¬ pletion of the second hemoperfusion she no longer re¬ quired ventilatory support. She was fully conscious and answering questions 72 hours after admission. She was up and about the following day. Case 2: A 27-year-old man was admitted after ingesting a mixture of medications. He was comatose and unre¬ sponsive to painful stimuli and required ventilatory as¬ sistance. Blood pressure was 100/70, pulse was 50 with sinus rhythm and central venous pressure was 11 cm. rose to

the blood.

Case reports Case 1: A

26-year-old woman was admitted after ingesting 1.The ACAC Microcapsule Artificial Kidney, large amount of glutethimide. She was comatose and FIG. showing blood inlet and outlet tubing with air trap. Rheostat areflexic. Her blood pressure was 90/60 and she required next to chamber controls temperature of heating tape ventilatory support. Six hours after admission her systolic wrapped around the chamber, thereby controlling temperature blood pressure was less than 70 mm. Hg and isoproterenol of blood in extracorporeal circulation. Scale in inches. a

430 C.M.A. JOURNAL/FEBRUARY 17, 1973/VOL. 108

of water.

Pupils

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unresponsive. Corneal,

gag, plantar and abdominal reflexes were absent, but tendon reflexes were present in the arms and hyperactive in the legs with bilateral ankle clonus. Bowel sounds were absent. Temperature was 84°F. Urine output was 60 ml./hr. Gastric lavage was carried out and forced diuresis started. Eight hours after admission his blood methyprylon level was 18.3 mg./lOO ml., far above the "dangerous" level of 6 mg./lOO ml.16 A 60-minute ACAC hemoperfu¬ sion was carried out at a blood flow rate of 300 ml./min. Blood pressure fell slightly initially, but in 10 minutes was 110/85. One hour after hemoperfusion blood pressure increased to 140/90, resulting in profuse blood leakage from the femoral artery puncture sites which required blood replacement. The methyprylon level fell to 12.9 mg./lOO ml. after the 60-minute treatment and by 32 hours after admission was 9.0 mg./lOO ml. A second ACAC hemoperfusion, given over a period of two hours with a blood flow rate of 300 ml./min., lowered the methyprylon level to 5.9 mg./lOO ml. At this time an"»9% 8

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FIG. 2.Summary of laboratory and clinical data in case (glutethimide intoxication). Shaded area under ACAC represents period of hemoperfusion. Solid line shows the change in arterial blood glutethimide level.

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other drug, methaqualone, was detected in the patient's blood at a concentration of 6.5 mg./lOO ml. At 48 hours the levels were 1.8 mg./lOO ml. of methyprylon and 2.7 mg./lOO ml. of methaqualone. By now his pupils reacted sluggishly to light, and the gag reflex, deep pain response and bowel sounds were present. He experienced a number of short tonic convulsions. At 96 hours his breathing was independent; all reflexes were normal. By 130 hours after admission he was oriented, rational and up and about. Case 3: A 50-year-old woman, previously treated for de¬ pression, was admitted after taking several drugs. She was comatose and her blood pressure was 90/60, pulse 80/ min. and regular, respiration 12/min. and temperature 98.4°F. Corneal reflexes were absent. She was treated by intubation followed by gastric lavage containing activated charcoal. Heparin, 5000 units IV q4h, was started since pulmonary embolism was suspected. Four hours later two cardiac arrests occurred and were reversed with cardiac massage and direct current electroshock. A subsequent chest x-ray showed fracture of four ribs. Ventilatory as¬ sistance was required. Ten hours after admission her blood pressure could not be determined by auscultation. At this time her blood methyprylon level was 9.4 mg./lOO ml. and six hours later it was 9.6 mg./lOO ml. Direct mea¬ surement of arterial blood pressure from the AV shunt gave a systolic pressure of 80 mm. Hg. Hemoperfusion was carried out. For the first 20 minutes the systolic blood pressure was maintained at 90-100 mm. Hg with levarterenol. Then the levarterenol was discontinued and the pressure remained at 130-150 mm. Hg throughout the three hours of hemoperfusion. The arterial blood methy¬ prylon level reached a low of 4.1 mg./lOO ml. after 120 minutes of hemoperfusion. Voluntary respiration became more regular and increased to 40/min. with tidal volume increasing to 325 ml. during hemoperfusion. Corneal re¬ flexes and voluntary eye opening and blinking returned and response to painful stimuli appeared. The prehemoperfusion schedule of 5000 units heparin IV q4h was con¬ tinued. Gastrointestinal hemorrhage occurred 23 hours after admission and was treated by transfusion and discontinuation of heparin. Limb movements were detected 27 hours after admission and four hours later the patient responded to verbal commands. She no longer required ventilatory assistance and started talking four hours later.

Results and discussion

The first case demonstrates a rapid improvement in the patient's clinical condition after treatment with the mi¬ crocapsule artificial kidney. Changes in blood glutethi¬ mide levels with hemoperfusion are shown in Fig. 2. Since glutethimide has a high lipid coefficient a large part of the drug is accumulated in lipoid tissue. The rebound in its level after hemoperfusion likely reflects a redistribution of glutethimide from the lipoid tissue into the bloodstream. The second hemoperfusion quick¬ ly brought this patient out of coma. At a blood flow of 300 ml./min. the glutethimide clearance of the micro¬ capsule artificial kidney was 150 ml./min. Data from the second case are summarized in Fig. 3. The clearance for methyprylon in the first hemoperfu¬

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20 15 25 30 35 TIME AFTER ADMISSION (hrs)

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FIG. 3.Summary of the laboratory and clinical data in case 2 (methyprylon and methaqualone intoxication). Solid line represents arterial blood level of methyprylon. Dotted line represents arterial blood level of methaqualone. Shaded area represents period of ACAC hemoperfusion.

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210 ml./min. for the first 15 minutes, 225 ml./min. ml./min. at 60 min¬ utes. For comparison, methyprylon clearance by the coil hemodialyser is 80 ml./min.16 In the second hemo¬ perfusion the clearance of methyprylon was 275 ml./ min. in the first 15 minutes, 203 ml./min. at 30 minutes, 171 ml./min. at 60 minutes, 177.5 ml./min. at 90 was

at 30 minutes and 161

C.M.A. JOURNAL/FEBRUARY 17, 1973/VOL. 108 431

minutes and 152 ml./min. at 120 minutes. The two hemoperfusions removed 2.85 g. of methyprylon, lowering its level from three times the dangerous level to just below the dangerous level. Despite this, there was no marked immediate improvement in the patient's clinical condition. This could be explained partly by the blood level of 6.5 mg./100 ml. of the second drug, methaqualone, at this time, a level which is more than twice the dangerous level of 2.5 mg./100 ml. The patient showed the typical signs of methaqualone intoxication: tonic convulsions, hypotension, cardiac failure, myoclonia, bleeding tendency and hypothermia.'7 The clearance for methaqualone in this patient, calculated for the second hemoperfusion procedure, was 263 ml./ min. in the first 15 minutes, 232 ml./min. at 30 minutes, 218 ml./min. at 60 minutes, 213 ml./min. at 90 minutes and 186 ml./min. at 120 minutes. This represents the removal of 1.83 g. of methaqualone in two hours of hemoperfusion at 300 ml./min. It should be pointed out that using standard hemodialysis, the clearance for methaqualone is 29 ml./min.,"8 equivalent, at the same blood level, to a removal of 0.27 g. in two hours; in the case of peritoneal dialysis the clearance is only 8 ml./min.,"8 equivalent to a removal of .07 g. in two hours. Fig. 4 summarizes the data for case 3. With only one 3-hour hemoperfusion the methyprylon concentration was lowered from 9.6 to a low of 4.1 mg./100 ml., below the dangerous level of 6 mg./100 ml. An initial clearance of 250 ml./min. was obtained. As in case 1, only one drug was involved; the recovery was dramatic and straightforward. It should be emphasized that these initial clinical trials on the treatment of drug intoxication were carried out only in patients who were seriously intoxicated or who had serious complications requiring rapid recovery from the effects of drugs. In one case a combined intoxication existed - the methyprylon level was three times, and the methaqualone level at least twice, the dangerous level. In another case, before treatment the patient had had cardiac arrest on two occasions and possible pulmonary embolism requiring heparinization. mg % 15

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We acknowledge the nursing and technical assistance of Miss Anna Stark, R.N. and Mrs. T. Lee-Bums, R.N., the technical assistance of Miss Emma Taroy, B.Sc. and Miss Margriet Migchelsen, R.T., the help of the staff of the cardiorespiratory intensive care unit, and the preparation of the illustrations by Mr. Karl Holeczek. This work is supported by the Medical Research Council of Canada by a grant (MRC-SP-2) to T.M.S. Chang.

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