Case Reports
19. BOfTSJ, MCCALLUM RW. Medication-induced esophageal injury-surveyof the literature. Med Toxicol1986;l :449-57. 20. FIEDOREK SC, CASTEEL HB. Pediatric medication-induced focal esophagitis. Clin Pediatr 1988;27:455-6. 21. MAHDY HA, BOSWELL GY. Captopril-induced esophagitis. Eur 1 Clin PhamuJcoI1988;34:95.
22. MAROY B, MOULLOf P. Esophageal bum due to chlorazepate dipotassium. Gastrointest Endosc 1986;32:240. 23. SCHREIBER 18. Aspirin-induced esophageal hemorrhage. lAMA 1988; 259: 1647-8. 24. COLLINS AJ, DAVIES J,DIXON ASJ. A prospective endoscopic studyofthe effect of Orudis and Oruvail on the upper gastrointestinal tract in patients withosteoarthritis. Br 1 RheumatoI1988;27: 106-9. 25. WONG RKH, KIKENDALLJW, DACHMAN AH. Quinaglute-induced esophagitis mimickingan esophageal mass. Ann Intern Med 1986; 105:62-3.
EXTRACTO Oxibutinina, utilizado en el manejo sintomatico de vejiga neurogenica, tiene menos actividad anticolinergica que el bromuro de propantelina. Por esta razon, oxibutinina es el farmaco prescrito mas frecuentemente en pacientes con alto riesgo de desarrollar
complicaciones por efectos adversos antimuscarinicos. Los autores reportan un caso de esofagitis por reflujo inducido por oxibutinina. Este efecto probablemente es resultado del efecto anticolinergico de oxibutinina, 10 cual disminuye el tono del esffnter del esofago inferior. Debido a que otros medicamentos prescritos comunmente pueden exacerbar 0 causar esofagitis por reflujo, los autores presentan un esquema para el manejo de los pacientes que desarrollan este efecto adverso. GISELLE RIVERA RESUME Puisque I'oxybutinine possede moins de proprietes anticholinergiques que Ie bromure de propantheline, elle est souvent preferee chez les patients presentant un risque accru de reactions adverses de type atropinique. Dans cet article, un cas d'oesophagite de reflux irnputee a l'oxybutinine est presente, II est probable que I'activite anti-muscarinique de I'oxybutinine ait reduit Ie tonus du sphinctere gastro-oesophagien inferieur, Les auteurs dressent ensuite une liste des medicaments pouvant causer une oesophagite de reflux ou une irritation oesophagienne et proposent une conduite pour rernedier a ce probleme d'origine rnedicamenteuse. MARC PARENT
ORAL ANTICOAGULATION IN PATIENTS WITH SHORT-BOWEL SYNDROME Julie Ponting Owens, Jay M. Mirtallo, and Christine C, Murphy
ABSTRACT: A 55-year-old woman was transferred to our institution from another hospital. The history of her present illness began 17days earlier with a right-sided cerebral vascular accident (CVA). Three days later she had a superior mesenteric artery (SMA) embolus with infarcted bowel. Her small bowel was resected leaving about 20-25 centimeters of small bowel. A cardiac echo on hospital day 6 documented the presence of a left ventricular embolus, which was considered to be the cause of her eVA and SMA embolus. The cardiologists recommended lifelong anticoagulation, preferably with warfarin when technically feasible. After one month of warfarin therapy, with doses as high as 25 mg/d, the patient's prothrombin times (PTs) were not changed from baseline; however, this was probably due to concomitant therapy with vitamin K. Heparin was incorporated into her total parenteral nutrition (TPN) in preparation for her discharge. Because the TPN was cycled, she required subcutaneous heparin twice daily while offTPN. This patient's clinical course while she was maintained on heparin therapy was complicated by bleeding episodes and extensive thigh and abdominal hematomas, which led to erratic heparin absorption and widely fluctuating partial thromboplastin times. Ten months after the initiation of anticoagulation the patient was again JULIE PONTING OWENS, Phann.D., isa Clinical Pharmacist, Metabolic Support Team, Department ofPharmacy, Providence Medical Center. 4805 NEGlisan. Portland, OR 97213; JAY M. MIRTALLO, M.S .. FASHP, FASCP, isa Clinical Pharmacist, Nutrition Support Service, Department ofPharmacy, The Ohio Stale University Hospitals, Clinical Associate Professor, Division ofPharmacy Practice, College ofPharmacy, and Adjunct Assistant Professor, Department ofSurgery, College ofMedicine. Ohio Stale University; and CHRISTINE C. MURPHY, B.S.Phann., isthe Clinical Manager, Clinical Phannacist Consultants, Inc.. Columbus, OH. Reprints: Julie Ponting Owens, Phann.D. Adapted from a poster presentation given atthe 23rd Annual Midyear Meeting ofthe American Society ofHospital Pharmacists, Dallas. TX, December 5.1988. We thank E.!. du Pont de Nemours and Company for financial support for travel and presentation-related expenses.
tried on an oral warfarin regimen. She was successfully titrated to achieve the desired PT ratio. This case led to a reviewof the literature of patients with short-bowel syndrome requiring anticoagulation. DICP Ann Pharmacother 1990;24:585-9.
THROMBOTIC OR EMBOLIC OCCLUSION of the superior mes-
enteric vessels is a major cause of intestinal infarction and subsequent short-bowel syndrome (SBS). Many of these patients may require home parenteral nutrition and prolonged anticoagulation therapy. According to the recommendations of the American College of Chest Physicians (ACCP), these patients may require anticoagulation for three months or a lifetime depending on whether the thromboembolic event was an isolated or recurrent phenomenon .' The initial thrombotic event is treated with intravenous heparin. However, continuation of heparin anticoagulation at home poses many obstacles because it is only available parenterally and repeated subcutaneous dosing is associated with a variety of risks. Home total parenteral nutrition (TPN) patients may incorporate heparin into the TPN, but if the patient is on a cycled solution supplemental heparin will be necessary because of heparin's short half-life. For patients requiring prolonged anticoagulation, oral anticoagulants are the drugs of choice as they provide the most convenient route of administration. Oral drug therapy in the patient with SBS may be handicapped because of the considerable lack of absorptive sur-
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face and subsequent reduced availability of most medications. Warfarin sodium is a water-soluble salt absorbed rapidly and completely from the stomach and proximal small intestine." Theoretically, then, absorption and availability of this agent should be excellent even in patients with SBS. The literature contains six reports of successful oral anticoagulation in II SBS patients.P" None of these reports, however, provides recommendations on the dosing of warfarin or the monitoring and education of these patients. The patient case below exemplifies many of the problems that m~y be encountered during anticoagulant therapy. Using this case as an example, a rational approach to anticoagulant therapy in this patient population is discussed. CASE REPORT A 55-year-old while woman wiIh a past medical history of hypertension (since 1986), hypothyroidism, and myocardial infarction (1974) was transferred to our hospital on July 8, 1987. from another hospital. The history of her present illness began on June 21 with admission to her local hospital for right-sided cerebral vascular accident (CVA). Three days later she experienced abdominal pain, hypotension, and melanotic stools. She was taken to the operating room (OR) for an emergent laparotomy and was found to have a superior mesenteric artery (SMA) embolus with infarcted sm~1l bowel. Her small bowel was resected leaving her With an end Jejunostomy (20 cm) and a mucous fistula ileostomy (2 ern). On July I she was taken to the OR again for Hickman catheter placement for TPN administration and a tracheostomy for failure to wean from the ventilator. The following day she developed clinical signs of sepsis and was returned to the OR. Findings included more necrosis of remaining small bowel requiring revision of ostomies and a double gastrostomy. The patient did not improve postoperatively and was transferred to our institution for further management. Baseline laboratory test results on admission were significant for a white blood cell count of 16.7 x 109/L, blood urea nitrogen of 21 mmol/L of urea (normal 3.0-6.5 mmol/L), serum creatinine of274lLmoUL (normal 50-110 urnol/L), and serum phosphorus of 2.9 rnmol/L (normal 0.80-1.60 mrnol/L), Heparin anticoagulation was started on July 13 after an echocardiograrn revealed a large embolus in her left ventricle (Ihis was thought to be Ihe source ofboIh herCVA and SMA embolus). Recommendations from Ihe cardiologists were to prepare her for lifelong anticoagulant therapy, ultimately wiIh oral warfarin sodium. Heparin was titrated to her partial thromboplastin time (PTT) to achieve 1.5-2.0 times Ihe control. By September 21Ihe patient's clinical condition had improved to the extent that discharge planning was in order. She had her tracheostomy removed and oral anticoagulant Iherapy was initiated. Warfarin was started at a dose of 10 mg/d. Prothrombin time (PT) was 9.7 seconds (control 9.5-12.5) and PTT was 74 seconds (control 23-35). One month later, at a warfarin dose of 25 rng/d, Ihe PT (10.4 seconds) was still not elevated. However, the patient was inadvertently receiving concomitant vitamin K 10 mg once per week which was the likely reason for the lack of response to warfarin. The patient was labeled refractive to oral anticoagulants "due to her short bowel syndrome" and all efforts at oral anticoagulation were discontinued at Ihis time. On October 13 all her heparin requirements were incorporated into Ihe TPN (running 24 hours daily). On October 23 she was put on a 12-hour TPN cycle to facilitate her physical rehabilitation. Heparin 10 000 units remained in the TPN. The rest of her heparin requirements were provided subcutaneously, 6000 units four hours after TPN stops and four hours before TPN starts. In response to wide swings in serum glucose concentrations and PTTs, herTPN schedule was changed toa 16-hourcycle (5 pm to 9 am) containing heparin 13500 units. She also received heparin 6000 units sc at 9 am, I pm, and 5 pm. On October 27 she was transferred to a physical rehabilitation facility, where the heparin
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dose was adjusted to maintain her PTT at 50-100 seconds (controI23-35). The patient received an inadequate trial of warfarin 10mg once daily for 1hreedays wiIh no response. Only 1hreedays were tried ~cause of a residual belief in her warfarin-resistant state. Upon discharge from Ihe rehabilitation facility she was maintained on Ihe same TPN solution containing heparin 13500 units. She also receiv~ 500 mL of a 10% iv fat emulsion twice weekly, heparin Unitssc (9 am, 12 noon), aluminum hydroxide gel 10mL po qid, and levoIhyroxine 10 lLg im twice weekly. The patient was educated in regard to foods containing vitamin K and the deleterious interaction wiIh her warfarin Iherapy. Three days following discharge she noticed a red clot in the end of her colostomy as well as red drainage. She was readmitted ?n December 25 for adjustment of her heparin dose. The heparin In her TPN was reduced to 8000 units. It was speculated Ihat an error may have been made in her heparin dose while at home. She w~ discharged January 8 to a long term care facility as her family believed her care was too complex. Her TPN formula remained Ihe ~am~ except for the reduced heparin dose. Her discharge medications were heparin 9000 units sc bid (8 am, 12 noon) and levoIhyroxine 0.1 mg im qam. Vitamin K 10 mg iv every week was incorporated into her regimen on January 22. Her clinical course from this time until March 1988 was uneventful, requiring only periodic adjustments of her heparin dose to maintain the PTT in the desired range. On March 10 blood was documented in her ostomy. The patient's PTTs were fluctuating from 31 to 195 seconds. The homecare nurse, evaluating the sc heparin sites (thighs and abdomen), found extensive areas of hematoma, and the fluctuating PTTs were attributed to erratic absorption from these sites. A literature review revealed that patients with SBS can indeed absorb warfarin. It was then decided to try warfarin therapy again. Vitamin K was discontinued on March 22 and warfarin therapy was to begin once PTTs were controlled. On April 14 heparin was discontinued from the TPN as well as su~utaneously. The plan was to stabilize Ihe patient on a heparin drip over seven days and start warfarin Iherapy once Ihe PTTs were in Ihe desired range. AlIhough Ihe final heparin drip adjustment was made on April 21 warfarin was not started for anoIher two weeks simply because of lack of a physician order to do so. Warfarin Iherapy was initiated May 4 at a dose of 5 mg/d. The PT and PTT were 13.8 and 53 seconds, respectively. The patient's cour:-e on warfarin is depicted in Figure I. Warfarin 5 rng/d was continued for eight days without change in Ihe patient's PT. On May 12 Ihe warfarin dose was increased to 10 mg and wiIhin a week .the PT was consistently in the target range. Although heparin ~ould have been discontinued at this time, it was not stopped until May 25, three weeks after oral anticoagulation was begun, purely for technical reasons. The patient did well on warfarin 10 mg/d with eventual dose adjustment to 7.5 mg/d after several monIhs of Iherapy.
9?00
Problems with intravenous (via TPN) and subcutaneous heparin therapy in this patient prompted her caregivers to reinvestigate oral anticoagulation in patients with SBS. Successful Warfarin Regimen
26 2.0 x control
24t-'-==:....---------------~22
'.5 v:control 1.3 x control
•
o 00
warfarin
9/13-15 Hold' 12.5 10
Discontinue heparin
510mg
~;4
20
so
6/9
19
29
7/9
19
29
818 18 Time (dl
28
Figure I. Patient's successful course on warfarin 1herapy.
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9/27 10
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Case Reports
The initial step in this process was to critically evaluate the literature to ascertain the reasons for success, or lack of success, of oral anticoagulation in this patient population.
Literature Review The current literature contains six reports of successful oral anticoagulation in II patients with SBS (Table I). All patients had between 12 and 100 cm of small intestine, and each patient's warfarin dose was individualized based on PT ratios (defined as the patient's PT in seconds divided by the control PT in seconds). The goal PT ratios were similar (1.5-2.5), when known, for all the studies. Warfarin resistance is defined as the inability to achieve a predetermined elevation in the PT (usually 1.2-2.0 times the control). These cases serve as a template upon which to base future use of oral anticoagulants in patients with SBS. The first reported use of warfarin in a patient with SBS was by Mitchell et al. in 1977. This patient had a long history of multiple peripheral and pulmonary emboli that finally resulted in a superior mesenteric artery infarction and necessitated the removal of all but 100 em of the small intestine. Warfarin therapy began seven days after heparin at a dose of to mg. The patient was discharged on a dose of 7.5 mg/d.:' The next successful series of oral anticoagulation in SBS patients did not appear in the literature until 1985. Lutomski et al. documented hypoprothrombinemic response to oral warfarin in five patients. Three of the patients had SBS as a result of infarcted bowels. They required long-term oral anticoagulation due to recurrent embolic events. The other two patients had SBS as a result of multiple bowel resections and their thromboembolic events occurred later in the clinical course. The extent of SBS was quantitated in only one patient (patient 5) with 12 em of residual small intestine. All patients were converted from intravenous heparin to oral warfarin therapy, except for one (patient 4) with anti-
Table I. Summary of Warfarin Dosage Regimens in SBS Patients REMAINING INTESTINE
INITIAL WARFARIN DOSE
DAILY WARFARIN DOSAGE RANGE
REF.
(em)
(rng)
(mg)
3 4
100
10 10 5 5 5
0-20 5-10 0-10 0-10 0-7.5
12
10
0-10
12-15 30
20 2
2-25 x I mo
50 40 12
8* 2.5 15
5 6,7 8
9
with lipid: 15 without lipid: 5-10
*Acenocoumarin dosages, not warfarin. SBS = short bowel syndrome.
ANAL WAFARIN DOSE
7.5 mg/d 10 mgld 2.5 mg qod 5 mg/d 2.5mgld x6d 1.25 mg/wk on 7th day 5 mg qod alternating with 2.5 mg qod 2.5 mg/d 5 mg/d 4 mg/d* 2.5 mg q3d* 2.5 mg/d 2 mg/d
thrombin III deficiency who was started directly on warfarin therapy. One patient (patient 3) was started on warfarin within one month of his small bowel resection. Six days of oral warfarin therapy failed to elevate his PT ratio and intravenous warfarin was required to achieve an appropriate hypoprothrombinemic response. One month later oral warfarin was successful in elevating this patient's PT ratio. In all other patients several months or more separated the small bowel resection from oral anticoagulant therapy. They all successfully attained PT ratios greater than 1.5 on individualized doses of warfarin. The authors also noticed a dramatic decrease in warfarin requirements over time in two patients (patients 2 and 3) receiving TPN without vitamin K supplementation. They attribute reduced warfarin requirements to depletion of endogenous vitamin K stores. The possibility of improved absorption from the gut may also explain this effect. 4 The previous reports adequately demonstrate the ability to achieve hypoprothrombinemic response in patients with SBS, but neither looked at serum concentrations or quantitative absorption of warfarin. Lehman et al. studied oral absorption, serum concentrations, and anticoagulant effect of warfarin in a patient with less than 15 ern of jejunum. Warfarin therapy was initiated with a 20-mg dose. The peak warfarin serum concentrations occurred at or before 0.5 hours and the elimination half-life was 12.1 hours. On two separate occasions, 24-hour jejunostomy drainage was collected following doses of 10 mg (day 2) and 2.5 mg (day 57, steady-state) to determine the extent of absorption. The calculated absorption of the IO-mg dose was 92.8 percent. At steady-state, the calculated absorption of the 2. 5-mg dose was 96.1 percent. The patient was discharged on warfarin 2.5 mg/d with a PT ratio of 1.6. 5 This is the first report in the literature documenting the rapid and near complete absorption of warfarin (using jejunostomy concentrations of warfarin and clinical effect) in a patient with SBS. Other data by Kearns et al. have also demonstrated bioavailability consistent with that in normal individuals. Their patient had only 30 cm of jejunum and was maintained on a dose of 2 mg/d to keep her PT ratio at 2.0. Nine months later she required replacement of her Broviac catheter for a superior vena caval thrombosis. Vitamin K 25 mg sc was given to bring PT values down to normal for the Broviac catheter placement. Four days later the patient was started back on warfarin, but doses as high as 25 mg/d failed to elevate her PT to greater than 14 seconds. After four weeks her PT began to prolong and at five weeks she had been titrated to a warfarin dose of 5 mg to achieve PTs in the range of 16-20 seconds. Decreased absorption was ruled out by normal bioavailability studies. The patient was on no medications that could enhance the metabolism for warfarin. Having ruled out decreased absorption and increased metabolism, the warfarin resistance was attributed to the vitamin K. Because the vitamin K was given subcutaneously, the authors hypothesized that a depot was formed which gradually released vitamin K over the month of warfarin resistance. 6.7 Gimmon reports on three patients with SBS receiving acenocoumarin and/or warfarin. One patient was receiving anticoagulants secondary to a prior cerebral vascular event and was currently experiencing exacerbation of Crohn 's disease. The other two received anticoagulants because of
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superior mesenteric artery infarcts resulting in SBS. 8 These results are similar to previous reports and are included here for completeness. Finally, Lutomski et al. report a possible interaction between continuous lipid infusions and warfarin in a patient with SBS, leading to warfarin resistance. They theorize that the egg phospholipid in the iv fat emulsions may accelerate the conversion of prothrombin to thrombin by providing a more efficient surface for the assembly and activation of the vitamin K-dependent clotting factors. The patient, however, had several factors that may have caused warfarin resistance, such as concurrent nafcillin therapy, fevers, and septicemia." In summary, this literature demonstrates that patients with SBS can absorb warfarin and be successfully anticoagulated with oral therapy. Patients with as little as 12 ern of intestine have responded to oral warfarin. However, patients may not respond to warfarin as rapidly as patients without SBS which may, in part, be due to the process of adaptation of the bowel. Thus, if patients do not respond to oral warfarin soon after bowel resection, it is possible that they may respond if oral warfarin is tried again several months postsurgery. Care should be taken to avoid labeling a patient as warfarin-resistant without an adequate trial of oral therapy. Furthermore, patients may have a decreased requirement for warfarin secondary to depletion of vitamin K stores, or improved absorption over time. Warfarin resistance may be ruled out by performing bioavailability studies.
Discussion This patient was committed to ten months of heparin therapy after a short course of warfarin failed to elevate the patient's PT. Her clinical course, while she was maintained on parenteral heparin therapy, was complicated by bleeding episodes and extensive thigh and abdominal hematomas, which quite likely led to erratic heparin absorption and widely fluctuating PTTs. Had her oral anticoagulation therapy been managed in a more rational and persistent manner, heparin therapy may have been discontinued much earlier. The necessary components for achieving successful and appropriate anticoagulation therapy are patient selection, medication profile review, anticoagulation dosage regimen design, consistent monitoring, and patient education. Patient selection for anticoagulation therapy is based on the recommendations from the ACCP conference on antithrombotic therapy. I These patients may require anticoagulation for three months or a lifetime depending on whether the thromboembolic event was an isolated or recurrent phenomenon. Our patient had two consecutive events resulting from a large left ventricular embolus. The cardiologists, in accordance with the ACCP guidelines, recommended lifelong anticoagulation for her. Once patients have been selected for therapy their medication profile should be closely scrutinized for any drug that may enhance or deter warfarin metabolism. Drugs most likely to increase warfarin resistance include vitamin K, estrogens, oral contraceptives, cholestyramine, colestipol, aluminum hydroxide, magnesium trisilicate, barbiturates, phenytoin, primidone, carbamazepine, ethchlorvynol, glutethimide, meprobamate, griseofulvin, rifampin, and nafciIIin. Drugs and conditions most likely to
588
increase sensitivity to warfarin include malabsorption and oral antibiotics (secondary to vitamin K deficiency), nonsteroidal antiinflammatory agents, sulfonylureas, naldixic acid, miconazole, chloramphenicol, clofibrate, tricyclic antidepressants, erythromycin, cimetidine, trimethoprim/ sulfamethoxazole, phenothiazine, quinine, quinidine, sulfisoxazole, vitamin E, anabolic steroids, and danazol.:" Our patient was receiving vitamin K during her first trial on warfarin therapy; therefore, this is the most likely explanation of her unresponsiveness to oral anticoagulants at that time. There are several alternative anticoagulant treatment regimens for patients with SBS. In order of preferred treatment options, they are: (I) continuous intravenous heparin":" followed by oral anticoagulation, recognizing in the immediate postoperative period there is potential for a delayed response to warfarin; (2) adjusted dose sc heparin with or without eventual oral anricoagulation.P?' (3) continuous heparin via TPN, which may not be suitable for cyclic TPN secondary to heparin's short half-life; and (4) combination regimens such as heparin in cyclic TPN plus adjusted sc heparin. The ACCP report recommends iv heparin or adjusted dose sc heparin, which should be dosed to prolong the PTT to 1.5-2.0 times the control. This therapy should extend five to ten days. Oral anticoagulants should be started during heparin therapy and these therapies should overlap for 4-5 days. The warfarin dose should be individualized to prolong the PT to an international normalized ratio of2-3. For North America, all PT reagents are made from rabbit brain thromboplastin, which is equal to the standard when the PT is prolonged to 1.3-1.5 times the control.':" The alternative is to continue adjusted-dose heparin. Patients should be closely monitored at the initiation of oral anticoagulant therapy. Initially, PTs should be measured daily. Once these are stabilized at 1.3-1.5 times control, the time between tests can be gradually increased to weekly and then monthly intervals.' In addition, patients should be monitored for any overt bleeding or bruising. The final component of successful and safe oral anticoagulation is counseling the patient on the importance of compliance, potential drug or food interactions with warfarin, and signs of bleeding. The manufacturer has available a patient's guide to anticoagulant therapy that may be a useful tool in patient education. 16 Summary
Patients with SBS are often assumed to have little or no absorptive capacity. This case report and other reports in the literature clearly show that warfarin is absorbed and can be used in SBS patients. This case provides an analysis of the complexities of anticoagulation therapy in this patient population and, in particular, highlights the hazards of long-term parenteral anticoagulation. Two of the reports in the literature highlight potential drug/nutrient interactions. The first documented warfarin resistance from vitamin K, ruling out all other possibilities. The second implicated lipid as a cause of warfarin resistance, although the evidence was less substantial as the resistance could easily have been caused by other drugs or the patient's clinical condition. Patients should remain on warfarin at least three months for an isolated episode of thromboembolism and indefi-
• DICP, The Annals of Pharmacotherapy • 1990 June, Volume 24
Case Reports
nitely if venous thromboembolism is recurrent. The warfarin dose should be individualized to attain a PT of 1.3-1.5 times the control. The PT should be monitored daily on initiation of therapy and less rigorously once therapy is stabilized. Before discharge from the hospital each patient should be educated on the importance of compliance with therapy, potential nutrient and drug interactions, and signs of bleeding or bruising. This case reinforces the existing literature documenting the successful use of oral anticoagulants in patients with short bowel syndrome.e> We thank Marci Abbruzzese forher secretarial services.
References I. HYERS TM, HULL RO, WEG JG. Antithrombotic therapy for venous thromboembolic disease. Chest 1989;95(suppl):37S-50S. 2. O'REILLY RA. Anticoagulant, antithrombotic, and thrombolytic drugs. In: Gilman AG, Goodman LS, Rail TW, Murad F, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985:1338-59. 3. MITCHELL JF, MAAS LC. BARGER RC.GELZAYO EA. Successful oral anticoagulant therapy in a patient with short bowel syndrome. Am 1 HospPharm 1977;34:171-2. 4. LUTOMSKI OM, LAFRANCE RJ, BOWER RH, FISCHER JE. Warfarin absorption after massive small bowel resection. Am 1 Gastroenterol 1985;80(2):99-102. 5. LEHMAN ME,KOLB KW, BARNHARTGR, WAGMAN LO,BARR WHo Warfarin absorption in a patient with short bowel syndrome. Clin Pharm 1985;4:325-6. 6. KEARNS RJ, O'REILLY RA. Bioavailability of warfarin in a patient with severe short bowel syndrome. lPEN 1 Parenter Enteral Nutr 1986; 10(1):100-1. 7. Warfarin resistance in a patient with short bowel syndrome. Nutr Rev 1987;45(7):208-11. 8. GIMMON Z. Oral anticoagulant therapy in patients who require nutritional support. lPEN 1 Parenter Enteral Nutr 1987;1/(1):102-3. 9. LUTOMSKI OM,PALASCAK JE, BOWER RH. Warfarin resistance associated with intravenous lipid administration. lPEN 1 Parenter Enteral Nutr 1987;JJ(3):316-8. 10. PETERSON CE, KWAAN He. Current concepts of warfarin therapy. Arch Intern Med 1986;146:581-4. 11. BENTLEY PG, KAKKAR VV, SCULLY MF, et al. An objective study of alternative methods of heparin administration. Thromb Res 1980; 18:177-87.
12. ANDERSSON G, FAGRELL B, HOLMGREN K,et al. Subcutaneous administrationof heparin: a randomised comparison with intravenousadministration of heparin to patients with deep-vein thrombosis. Thromb Res 1982;27:631-9. 13. HULL RO,RASKOB GE,HIRSH J,et aI. A double-blind randomized trial of intravenous versus subcutaneous heparin in the initial treatment of proximal-vein thrombosis; the therapeutic response. N Engl 1 Med 1986;3/5:1109-214.
14. DOYLE OJ, TURPIE AGG, HIRSH J, et aI. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial. Ann Intern Med 1987;107:441-5. 15. HIRSH 1. Is the dose of warfarin prescribed by American physicians unnecessarily high? Arch Intern Med 1987;147:769-71. 16. Anticoagulant therapy: a patient's guide. Wilmington, DE: E.1. duPont de Nemours & Co., 1984.
EXTRACTO Los autores reportan el caso de una mujer de 55 afios transferida de otro hospital. EI historial de la presente enfennedad comenz6 con un accidente cerebrovascular en ellado derecho. Tres dias mas tarde la paciente desarrollo un embole en la arteria mesenterica superior con infarto al intestino. Se extirpo el intestino delgado dejando alrededor de 20-25 em. Un ecocardiograma document6 la presencia de un embolo en el ventrfculo izquierdo, que se consider6 fue la causa de su accidente cerebrovascular y del embole en la arteria mesenterica superior. Los cardiologos recomendaron terapia con anticoagulantes de por vida, preferiblemente warfarina. Luego de un mes de comenzar terapia con warfarina administrando dosis tan altas como 25 mg diarios, el tiempo de protrombina se mantuvo igual, debido probablemente a terapia concurrente con vitamina K. La heparina se incorpor6 a la nutrici6n parentral total (TPN) al comenzar los preparativos para dar de alta al paciente. Como el TPN se administraba en ciclos, la paciente requeria heparina por via subcutanea dos veces al dia, los dias que no recibia TPN. EI curso clfnico de esta paciente mientras recibia heparina, se complic6 por episodios de sangramiento, extensos hematomas en el abdomen y el muslo, que llev6 a una absorci6n erratica de heparina y una fluctuaci6n amplia en el tiempo parcial de protrombina. Diez meses luego de haber comenzado la terapia con anticoagulantes, se trat6 nuevamente al paciente con warfarina. La terapia fue exitosamente titulada hasta alcanzar el tiempo de protrombina deseado. Este caso concuerda con otros casas reportados en la literatura donde el uso de anticoagulantes orales ha sido exitoso en pacientes con sindrome de intestino corto. ANNETTE PEREZ RESUME Les auteurs presentent Ie cas d'une femme de 55 ans hospitalisee Ie 21106/87 pour un accident cerebrovasculaire (ACY) du cote droit et transferee dans leur centre hospitalier Ie 08/07/87. Trois jours apres son ACY, elle avait une embolie de l'artere rnesenterique superieure (AMS) avec un infarctus intestinal. Apres resection, environ 20 a 25 em du petit intestin etaient conserves. Un echo cardiaque Ie 13/07/87 a revele la presence d'une embolie du ventricule gauche, qui etait sans doute la cause de I' ACY et de I'embolie de I' AMS. Les cardiologues ont recommandes une anticoagulation a vie, de preference avec la warfarine. Apres un mois de traitement avec la warfarine 25 mg/jr, les temps de prothrombine (TP) etaient toujours au niveau des valeurs de base; cependant, I'absence de reponse a la warfarine etait probablement due a la prise concomitante de vitamine K. La patiente a ete jugee refractaire aux anticoagulants oraux, et tous les efforts pour I'anticoagulation orale ont ete interrompus. De l'heparine a ete incorporee a son alimentation parenterale totale (APT). Puisque I' APT etait cyclique et que la demivie de l'heparine est courte, la patiente devait recevoir des doses supplernentaires d'heparine, en administration sous-cutanee deux fois par jour. Sous ce regime therapeutique, Ie suivi c1inique de la patiente a ete complique par des episodes de saignements et des hernatomes importants aux cuisses et a I'abdomen, ceux-ci ont entraine une absorption erratique de l'heparine et de larges fluctuations dans les temps de cephaline. Dix mois apres I'instauration de l'anticoagulation, I'administration de warfarine orale etait a nouveau essayee, Les valeurs du TP ont ete maintenus dans les ecarts souhaites. La presentation de ce cas est sui vie par une revue de litterature des patients avec un syndrome de I'intestin court qui necessitent une anticoagulation.
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19. BOfTSJ, MCCALLUM RW. Medication-induced esophageal injury-surveyof the literature. Med Toxicol1986;l :449-57. 20. FIEDOREK SC, CASTEEL HB. Pediatric medication-induced focal esophagitis. Clin Pediatr 1988;27:455-6. 21. MAHDY HA, BOSWELL GY. Captopril-induced esophagitis. Eur 1 Clin PhamuJcoI1988;34:95.
22. MAROY B, MOULLOf P. Esophageal bum due to chlorazepate dipotassium. Gastrointest Endosc 1986;32:240. 23. SCHREIBER 18. Aspirin-induced esophageal hemorrhage. lAMA 1988; 259: 1647-8. 24. COLLINS AJ, DAVIES J,DIXON ASJ. A prospective endoscopic studyofthe effect of Orudis and Oruvail on the upper gastrointestinal tract in patients withosteoarthritis. Br 1 RheumatoI1988;27: 106-9. 25. WONG RKH, KIKENDALLJW, DACHMAN AH. Quinaglute-induced esophagitis mimickingan esophageal mass. Ann Intern Med 1986; 105:62-3.
EXTRACTO Oxibutinina, utilizado en el manejo sintomatico de vejiga neurogenica, tiene menos actividad anticolinergica que el bromuro de propantelina. Por esta razon, oxibutinina es el farmaco prescrito mas frecuentemente en pacientes con alto riesgo de desarrollar
complicaciones por efectos adversos antimuscarinicos. Los autores reportan un caso de esofagitis por reflujo inducido por oxibutinina. Este efecto probablemente es resultado del efecto anticolinergico de oxibutinina, 10 cual disminuye el tono del esffnter del esofago inferior. Debido a que otros medicamentos prescritos comunmente pueden exacerbar 0 causar esofagitis por reflujo, los autores presentan un esquema para el manejo de los pacientes que desarrollan este efecto adverso. GISELLE RIVERA RESUME Puisque I'oxybutinine possede moins de proprietes anticholinergiques que Ie bromure de propantheline, elle est souvent preferee chez les patients presentant un risque accru de reactions adverses de type atropinique. Dans cet article, un cas d'oesophagite de reflux irnputee a l'oxybutinine est presente, II est probable que I'activite anti-muscarinique de I'oxybutinine ait reduit Ie tonus du sphinctere gastro-oesophagien inferieur, Les auteurs dressent ensuite une liste des medicaments pouvant causer une oesophagite de reflux ou une irritation oesophagienne et proposent une conduite pour rernedier a ce probleme d'origine rnedicamenteuse. MARC PARENT
ORAL ANTICOAGULATION IN PATIENTS WITH SHORT-BOWEL SYNDROME Julie Ponting Owens, Jay M. Mirtallo, and Christine C, Murphy
ABSTRACT: A 55-year-old woman was transferred to our institution from another hospital. The history of her present illness began 17days earlier with a right-sided cerebral vascular accident (CVA). Three days later she had a superior mesenteric artery (SMA) embolus with infarcted bowel. Her small bowel was resected leaving about 20-25 centimeters of small bowel. A cardiac echo on hospital day 6 documented the presence of a left ventricular embolus, which was considered to be the cause of her eVA and SMA embolus. The cardiologists recommended lifelong anticoagulation, preferably with warfarin when technically feasible. After one month of warfarin therapy, with doses as high as 25 mg/d, the patient's prothrombin times (PTs) were not changed from baseline; however, this was probably due to concomitant therapy with vitamin K. Heparin was incorporated into her total parenteral nutrition (TPN) in preparation for her discharge. Because the TPN was cycled, she required subcutaneous heparin twice daily while offTPN. This patient's clinical course while she was maintained on heparin therapy was complicated by bleeding episodes and extensive thigh and abdominal hematomas, which led to erratic heparin absorption and widely fluctuating partial thromboplastin times. Ten months after the initiation of anticoagulation the patient was again JULIE PONTING OWENS, Phann.D., isa Clinical Pharmacist, Metabolic Support Team, Department ofPharmacy, Providence Medical Center. 4805 NEGlisan. Portland, OR 97213; JAY M. MIRTALLO, M.S .. FASHP, FASCP, isa Clinical Pharmacist, Nutrition Support Service, Department ofPharmacy, The Ohio Stale University Hospitals, Clinical Associate Professor, Division ofPharmacy Practice, College ofPharmacy, and Adjunct Assistant Professor, Department ofSurgery, College ofMedicine. Ohio Stale University; and CHRISTINE C. MURPHY, B.S.Phann., isthe Clinical Manager, Clinical Phannacist Consultants, Inc.. Columbus, OH. Reprints: Julie Ponting Owens, Phann.D. Adapted from a poster presentation given atthe 23rd Annual Midyear Meeting ofthe American Society ofHospital Pharmacists, Dallas. TX, December 5.1988. We thank E.!. du Pont de Nemours and Company for financial support for travel and presentation-related expenses.
tried on an oral warfarin regimen. She was successfully titrated to achieve the desired PT ratio. This case led to a reviewof the literature of patients with short-bowel syndrome requiring anticoagulation. DICP Ann Pharmacother 1990;24:585-9.
THROMBOTIC OR EMBOLIC OCCLUSION of the superior mes-
enteric vessels is a major cause of intestinal infarction and subsequent short-bowel syndrome (SBS). Many of these patients may require home parenteral nutrition and prolonged anticoagulation therapy. According to the recommendations of the American College of Chest Physicians (ACCP), these patients may require anticoagulation for three months or a lifetime depending on whether the thromboembolic event was an isolated or recurrent phenomenon .' The initial thrombotic event is treated with intravenous heparin. However, continuation of heparin anticoagulation at home poses many obstacles because it is only available parenterally and repeated subcutaneous dosing is associated with a variety of risks. Home total parenteral nutrition (TPN) patients may incorporate heparin into the TPN, but if the patient is on a cycled solution supplemental heparin will be necessary because of heparin's short half-life. For patients requiring prolonged anticoagulation, oral anticoagulants are the drugs of choice as they provide the most convenient route of administration. Oral drug therapy in the patient with SBS may be handicapped because of the considerable lack of absorptive sur-
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face and subsequent reduced availability of most medications. Warfarin sodium is a water-soluble salt absorbed rapidly and completely from the stomach and proximal small intestine." Theoretically, then, absorption and availability of this agent should be excellent even in patients with SBS. The literature contains six reports of successful oral anticoagulation in II SBS patients.P" None of these reports, however, provides recommendations on the dosing of warfarin or the monitoring and education of these patients. The patient case below exemplifies many of the problems that m~y be encountered during anticoagulant therapy. Using this case as an example, a rational approach to anticoagulant therapy in this patient population is discussed. CASE REPORT A 55-year-old while woman wiIh a past medical history of hypertension (since 1986), hypothyroidism, and myocardial infarction (1974) was transferred to our hospital on July 8, 1987. from another hospital. The history of her present illness began on June 21 with admission to her local hospital for right-sided cerebral vascular accident (CVA). Three days later she experienced abdominal pain, hypotension, and melanotic stools. She was taken to the operating room (OR) for an emergent laparotomy and was found to have a superior mesenteric artery (SMA) embolus with infarcted sm~1l bowel. Her small bowel was resected leaving her With an end Jejunostomy (20 cm) and a mucous fistula ileostomy (2 ern). On July I she was taken to the OR again for Hickman catheter placement for TPN administration and a tracheostomy for failure to wean from the ventilator. The following day she developed clinical signs of sepsis and was returned to the OR. Findings included more necrosis of remaining small bowel requiring revision of ostomies and a double gastrostomy. The patient did not improve postoperatively and was transferred to our institution for further management. Baseline laboratory test results on admission were significant for a white blood cell count of 16.7 x 109/L, blood urea nitrogen of 21 mmol/L of urea (normal 3.0-6.5 mmol/L), serum creatinine of274lLmoUL (normal 50-110 urnol/L), and serum phosphorus of 2.9 rnmol/L (normal 0.80-1.60 mrnol/L), Heparin anticoagulation was started on July 13 after an echocardiograrn revealed a large embolus in her left ventricle (Ihis was thought to be Ihe source ofboIh herCVA and SMA embolus). Recommendations from Ihe cardiologists were to prepare her for lifelong anticoagulant therapy, ultimately wiIh oral warfarin sodium. Heparin was titrated to her partial thromboplastin time (PTT) to achieve 1.5-2.0 times Ihe control. By September 21Ihe patient's clinical condition had improved to the extent that discharge planning was in order. She had her tracheostomy removed and oral anticoagulant Iherapy was initiated. Warfarin was started at a dose of 10 mg/d. Prothrombin time (PT) was 9.7 seconds (control 9.5-12.5) and PTT was 74 seconds (control 23-35). One month later, at a warfarin dose of 25 rng/d, Ihe PT (10.4 seconds) was still not elevated. However, the patient was inadvertently receiving concomitant vitamin K 10 mg once per week which was the likely reason for the lack of response to warfarin. The patient was labeled refractive to oral anticoagulants "due to her short bowel syndrome" and all efforts at oral anticoagulation were discontinued at Ihis time. On October 13 all her heparin requirements were incorporated into Ihe TPN (running 24 hours daily). On October 23 she was put on a 12-hour TPN cycle to facilitate her physical rehabilitation. Heparin 10 000 units remained in the TPN. The rest of her heparin requirements were provided subcutaneously, 6000 units four hours after TPN stops and four hours before TPN starts. In response to wide swings in serum glucose concentrations and PTTs, herTPN schedule was changed toa 16-hourcycle (5 pm to 9 am) containing heparin 13500 units. She also received heparin 6000 units sc at 9 am, I pm, and 5 pm. On October 27 she was transferred to a physical rehabilitation facility, where the heparin
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dose was adjusted to maintain her PTT at 50-100 seconds (controI23-35). The patient received an inadequate trial of warfarin 10mg once daily for 1hreedays wiIh no response. Only 1hreedays were tried ~cause of a residual belief in her warfarin-resistant state. Upon discharge from Ihe rehabilitation facility she was maintained on Ihe same TPN solution containing heparin 13500 units. She also receiv~ 500 mL of a 10% iv fat emulsion twice weekly, heparin Unitssc (9 am, 12 noon), aluminum hydroxide gel 10mL po qid, and levoIhyroxine 10 lLg im twice weekly. The patient was educated in regard to foods containing vitamin K and the deleterious interaction wiIh her warfarin Iherapy. Three days following discharge she noticed a red clot in the end of her colostomy as well as red drainage. She was readmitted ?n December 25 for adjustment of her heparin dose. The heparin In her TPN was reduced to 8000 units. It was speculated Ihat an error may have been made in her heparin dose while at home. She w~ discharged January 8 to a long term care facility as her family believed her care was too complex. Her TPN formula remained Ihe ~am~ except for the reduced heparin dose. Her discharge medications were heparin 9000 units sc bid (8 am, 12 noon) and levoIhyroxine 0.1 mg im qam. Vitamin K 10 mg iv every week was incorporated into her regimen on January 22. Her clinical course from this time until March 1988 was uneventful, requiring only periodic adjustments of her heparin dose to maintain the PTT in the desired range. On March 10 blood was documented in her ostomy. The patient's PTTs were fluctuating from 31 to 195 seconds. The homecare nurse, evaluating the sc heparin sites (thighs and abdomen), found extensive areas of hematoma, and the fluctuating PTTs were attributed to erratic absorption from these sites. A literature review revealed that patients with SBS can indeed absorb warfarin. It was then decided to try warfarin therapy again. Vitamin K was discontinued on March 22 and warfarin therapy was to begin once PTTs were controlled. On April 14 heparin was discontinued from the TPN as well as su~utaneously. The plan was to stabilize Ihe patient on a heparin drip over seven days and start warfarin Iherapy once Ihe PTTs were in Ihe desired range. AlIhough Ihe final heparin drip adjustment was made on April 21 warfarin was not started for anoIher two weeks simply because of lack of a physician order to do so. Warfarin Iherapy was initiated May 4 at a dose of 5 mg/d. The PT and PTT were 13.8 and 53 seconds, respectively. The patient's cour:-e on warfarin is depicted in Figure I. Warfarin 5 rng/d was continued for eight days without change in Ihe patient's PT. On May 12 Ihe warfarin dose was increased to 10 mg and wiIhin a week .the PT was consistently in the target range. Although heparin ~ould have been discontinued at this time, it was not stopped until May 25, three weeks after oral anticoagulation was begun, purely for technical reasons. The patient did well on warfarin 10 mg/d with eventual dose adjustment to 7.5 mg/d after several monIhs of Iherapy.
9?00
Problems with intravenous (via TPN) and subcutaneous heparin therapy in this patient prompted her caregivers to reinvestigate oral anticoagulation in patients with SBS. Successful Warfarin Regimen
26 2.0 x control
24t-'-==:....---------------~22
'.5 v:control 1.3 x control
•
o 00
warfarin
9/13-15 Hold' 12.5 10
Discontinue heparin
510mg
~;4
20
so
6/9
19
29
7/9
19
29
818 18 Time (dl
28
Figure I. Patient's successful course on warfarin 1herapy.
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Case Reports
The initial step in this process was to critically evaluate the literature to ascertain the reasons for success, or lack of success, of oral anticoagulation in this patient population.
Literature Review The current literature contains six reports of successful oral anticoagulation in II patients with SBS (Table I). All patients had between 12 and 100 cm of small intestine, and each patient's warfarin dose was individualized based on PT ratios (defined as the patient's PT in seconds divided by the control PT in seconds). The goal PT ratios were similar (1.5-2.5), when known, for all the studies. Warfarin resistance is defined as the inability to achieve a predetermined elevation in the PT (usually 1.2-2.0 times the control). These cases serve as a template upon which to base future use of oral anticoagulants in patients with SBS. The first reported use of warfarin in a patient with SBS was by Mitchell et al. in 1977. This patient had a long history of multiple peripheral and pulmonary emboli that finally resulted in a superior mesenteric artery infarction and necessitated the removal of all but 100 em of the small intestine. Warfarin therapy began seven days after heparin at a dose of to mg. The patient was discharged on a dose of 7.5 mg/d.:' The next successful series of oral anticoagulation in SBS patients did not appear in the literature until 1985. Lutomski et al. documented hypoprothrombinemic response to oral warfarin in five patients. Three of the patients had SBS as a result of infarcted bowels. They required long-term oral anticoagulation due to recurrent embolic events. The other two patients had SBS as a result of multiple bowel resections and their thromboembolic events occurred later in the clinical course. The extent of SBS was quantitated in only one patient (patient 5) with 12 em of residual small intestine. All patients were converted from intravenous heparin to oral warfarin therapy, except for one (patient 4) with anti-
Table I. Summary of Warfarin Dosage Regimens in SBS Patients REMAINING INTESTINE
INITIAL WARFARIN DOSE
DAILY WARFARIN DOSAGE RANGE
REF.
(em)
(rng)
(mg)
3 4
100
10 10 5 5 5
0-20 5-10 0-10 0-10 0-7.5
12
10
0-10
12-15 30
20 2
2-25 x I mo
50 40 12
8* 2.5 15
5 6,7 8
9
with lipid: 15 without lipid: 5-10
*Acenocoumarin dosages, not warfarin. SBS = short bowel syndrome.
ANAL WAFARIN DOSE
7.5 mg/d 10 mgld 2.5 mg qod 5 mg/d 2.5mgld x6d 1.25 mg/wk on 7th day 5 mg qod alternating with 2.5 mg qod 2.5 mg/d 5 mg/d 4 mg/d* 2.5 mg q3d* 2.5 mg/d 2 mg/d
thrombin III deficiency who was started directly on warfarin therapy. One patient (patient 3) was started on warfarin within one month of his small bowel resection. Six days of oral warfarin therapy failed to elevate his PT ratio and intravenous warfarin was required to achieve an appropriate hypoprothrombinemic response. One month later oral warfarin was successful in elevating this patient's PT ratio. In all other patients several months or more separated the small bowel resection from oral anticoagulant therapy. They all successfully attained PT ratios greater than 1.5 on individualized doses of warfarin. The authors also noticed a dramatic decrease in warfarin requirements over time in two patients (patients 2 and 3) receiving TPN without vitamin K supplementation. They attribute reduced warfarin requirements to depletion of endogenous vitamin K stores. The possibility of improved absorption from the gut may also explain this effect. 4 The previous reports adequately demonstrate the ability to achieve hypoprothrombinemic response in patients with SBS, but neither looked at serum concentrations or quantitative absorption of warfarin. Lehman et al. studied oral absorption, serum concentrations, and anticoagulant effect of warfarin in a patient with less than 15 ern of jejunum. Warfarin therapy was initiated with a 20-mg dose. The peak warfarin serum concentrations occurred at or before 0.5 hours and the elimination half-life was 12.1 hours. On two separate occasions, 24-hour jejunostomy drainage was collected following doses of 10 mg (day 2) and 2.5 mg (day 57, steady-state) to determine the extent of absorption. The calculated absorption of the IO-mg dose was 92.8 percent. At steady-state, the calculated absorption of the 2. 5-mg dose was 96.1 percent. The patient was discharged on warfarin 2.5 mg/d with a PT ratio of 1.6. 5 This is the first report in the literature documenting the rapid and near complete absorption of warfarin (using jejunostomy concentrations of warfarin and clinical effect) in a patient with SBS. Other data by Kearns et al. have also demonstrated bioavailability consistent with that in normal individuals. Their patient had only 30 cm of jejunum and was maintained on a dose of 2 mg/d to keep her PT ratio at 2.0. Nine months later she required replacement of her Broviac catheter for a superior vena caval thrombosis. Vitamin K 25 mg sc was given to bring PT values down to normal for the Broviac catheter placement. Four days later the patient was started back on warfarin, but doses as high as 25 mg/d failed to elevate her PT to greater than 14 seconds. After four weeks her PT began to prolong and at five weeks she had been titrated to a warfarin dose of 5 mg to achieve PTs in the range of 16-20 seconds. Decreased absorption was ruled out by normal bioavailability studies. The patient was on no medications that could enhance the metabolism for warfarin. Having ruled out decreased absorption and increased metabolism, the warfarin resistance was attributed to the vitamin K. Because the vitamin K was given subcutaneously, the authors hypothesized that a depot was formed which gradually released vitamin K over the month of warfarin resistance. 6.7 Gimmon reports on three patients with SBS receiving acenocoumarin and/or warfarin. One patient was receiving anticoagulants secondary to a prior cerebral vascular event and was currently experiencing exacerbation of Crohn 's disease. The other two received anticoagulants because of
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superior mesenteric artery infarcts resulting in SBS. 8 These results are similar to previous reports and are included here for completeness. Finally, Lutomski et al. report a possible interaction between continuous lipid infusions and warfarin in a patient with SBS, leading to warfarin resistance. They theorize that the egg phospholipid in the iv fat emulsions may accelerate the conversion of prothrombin to thrombin by providing a more efficient surface for the assembly and activation of the vitamin K-dependent clotting factors. The patient, however, had several factors that may have caused warfarin resistance, such as concurrent nafcillin therapy, fevers, and septicemia." In summary, this literature demonstrates that patients with SBS can absorb warfarin and be successfully anticoagulated with oral therapy. Patients with as little as 12 ern of intestine have responded to oral warfarin. However, patients may not respond to warfarin as rapidly as patients without SBS which may, in part, be due to the process of adaptation of the bowel. Thus, if patients do not respond to oral warfarin soon after bowel resection, it is possible that they may respond if oral warfarin is tried again several months postsurgery. Care should be taken to avoid labeling a patient as warfarin-resistant without an adequate trial of oral therapy. Furthermore, patients may have a decreased requirement for warfarin secondary to depletion of vitamin K stores, or improved absorption over time. Warfarin resistance may be ruled out by performing bioavailability studies.
Discussion This patient was committed to ten months of heparin therapy after a short course of warfarin failed to elevate the patient's PT. Her clinical course, while she was maintained on parenteral heparin therapy, was complicated by bleeding episodes and extensive thigh and abdominal hematomas, which quite likely led to erratic heparin absorption and widely fluctuating PTTs. Had her oral anticoagulation therapy been managed in a more rational and persistent manner, heparin therapy may have been discontinued much earlier. The necessary components for achieving successful and appropriate anticoagulation therapy are patient selection, medication profile review, anticoagulation dosage regimen design, consistent monitoring, and patient education. Patient selection for anticoagulation therapy is based on the recommendations from the ACCP conference on antithrombotic therapy. I These patients may require anticoagulation for three months or a lifetime depending on whether the thromboembolic event was an isolated or recurrent phenomenon. Our patient had two consecutive events resulting from a large left ventricular embolus. The cardiologists, in accordance with the ACCP guidelines, recommended lifelong anticoagulation for her. Once patients have been selected for therapy their medication profile should be closely scrutinized for any drug that may enhance or deter warfarin metabolism. Drugs most likely to increase warfarin resistance include vitamin K, estrogens, oral contraceptives, cholestyramine, colestipol, aluminum hydroxide, magnesium trisilicate, barbiturates, phenytoin, primidone, carbamazepine, ethchlorvynol, glutethimide, meprobamate, griseofulvin, rifampin, and nafciIIin. Drugs and conditions most likely to
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increase sensitivity to warfarin include malabsorption and oral antibiotics (secondary to vitamin K deficiency), nonsteroidal antiinflammatory agents, sulfonylureas, naldixic acid, miconazole, chloramphenicol, clofibrate, tricyclic antidepressants, erythromycin, cimetidine, trimethoprim/ sulfamethoxazole, phenothiazine, quinine, quinidine, sulfisoxazole, vitamin E, anabolic steroids, and danazol.:" Our patient was receiving vitamin K during her first trial on warfarin therapy; therefore, this is the most likely explanation of her unresponsiveness to oral anticoagulants at that time. There are several alternative anticoagulant treatment regimens for patients with SBS. In order of preferred treatment options, they are: (I) continuous intravenous heparin":" followed by oral anticoagulation, recognizing in the immediate postoperative period there is potential for a delayed response to warfarin; (2) adjusted dose sc heparin with or without eventual oral anricoagulation.P?' (3) continuous heparin via TPN, which may not be suitable for cyclic TPN secondary to heparin's short half-life; and (4) combination regimens such as heparin in cyclic TPN plus adjusted sc heparin. The ACCP report recommends iv heparin or adjusted dose sc heparin, which should be dosed to prolong the PTT to 1.5-2.0 times the control. This therapy should extend five to ten days. Oral anticoagulants should be started during heparin therapy and these therapies should overlap for 4-5 days. The warfarin dose should be individualized to prolong the PT to an international normalized ratio of2-3. For North America, all PT reagents are made from rabbit brain thromboplastin, which is equal to the standard when the PT is prolonged to 1.3-1.5 times the control.':" The alternative is to continue adjusted-dose heparin. Patients should be closely monitored at the initiation of oral anticoagulant therapy. Initially, PTs should be measured daily. Once these are stabilized at 1.3-1.5 times control, the time between tests can be gradually increased to weekly and then monthly intervals.' In addition, patients should be monitored for any overt bleeding or bruising. The final component of successful and safe oral anticoagulation is counseling the patient on the importance of compliance, potential drug or food interactions with warfarin, and signs of bleeding. The manufacturer has available a patient's guide to anticoagulant therapy that may be a useful tool in patient education. 16 Summary
Patients with SBS are often assumed to have little or no absorptive capacity. This case report and other reports in the literature clearly show that warfarin is absorbed and can be used in SBS patients. This case provides an analysis of the complexities of anticoagulation therapy in this patient population and, in particular, highlights the hazards of long-term parenteral anticoagulation. Two of the reports in the literature highlight potential drug/nutrient interactions. The first documented warfarin resistance from vitamin K, ruling out all other possibilities. The second implicated lipid as a cause of warfarin resistance, although the evidence was less substantial as the resistance could easily have been caused by other drugs or the patient's clinical condition. Patients should remain on warfarin at least three months for an isolated episode of thromboembolism and indefi-
• DICP, The Annals of Pharmacotherapy • 1990 June, Volume 24
Case Reports
nitely if venous thromboembolism is recurrent. The warfarin dose should be individualized to attain a PT of 1.3-1.5 times the control. The PT should be monitored daily on initiation of therapy and less rigorously once therapy is stabilized. Before discharge from the hospital each patient should be educated on the importance of compliance with therapy, potential nutrient and drug interactions, and signs of bleeding or bruising. This case reinforces the existing literature documenting the successful use of oral anticoagulants in patients with short bowel syndrome.e> We thank Marci Abbruzzese forher secretarial services.
References I. HYERS TM, HULL RO, WEG JG. Antithrombotic therapy for venous thromboembolic disease. Chest 1989;95(suppl):37S-50S. 2. O'REILLY RA. Anticoagulant, antithrombotic, and thrombolytic drugs. In: Gilman AG, Goodman LS, Rail TW, Murad F, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985:1338-59. 3. MITCHELL JF, MAAS LC. BARGER RC.GELZAYO EA. Successful oral anticoagulant therapy in a patient with short bowel syndrome. Am 1 HospPharm 1977;34:171-2. 4. LUTOMSKI OM, LAFRANCE RJ, BOWER RH, FISCHER JE. Warfarin absorption after massive small bowel resection. Am 1 Gastroenterol 1985;80(2):99-102. 5. LEHMAN ME,KOLB KW, BARNHARTGR, WAGMAN LO,BARR WHo Warfarin absorption in a patient with short bowel syndrome. Clin Pharm 1985;4:325-6. 6. KEARNS RJ, O'REILLY RA. Bioavailability of warfarin in a patient with severe short bowel syndrome. lPEN 1 Parenter Enteral Nutr 1986; 10(1):100-1. 7. Warfarin resistance in a patient with short bowel syndrome. Nutr Rev 1987;45(7):208-11. 8. GIMMON Z. Oral anticoagulant therapy in patients who require nutritional support. lPEN 1 Parenter Enteral Nutr 1987;1/(1):102-3. 9. LUTOMSKI OM,PALASCAK JE, BOWER RH. Warfarin resistance associated with intravenous lipid administration. lPEN 1 Parenter Enteral Nutr 1987;JJ(3):316-8. 10. PETERSON CE, KWAAN He. Current concepts of warfarin therapy. Arch Intern Med 1986;146:581-4. 11. BENTLEY PG, KAKKAR VV, SCULLY MF, et al. An objective study of alternative methods of heparin administration. Thromb Res 1980; 18:177-87.
12. ANDERSSON G, FAGRELL B, HOLMGREN K,et al. Subcutaneous administrationof heparin: a randomised comparison with intravenousadministration of heparin to patients with deep-vein thrombosis. Thromb Res 1982;27:631-9. 13. HULL RO,RASKOB GE,HIRSH J,et aI. A double-blind randomized trial of intravenous versus subcutaneous heparin in the initial treatment of proximal-vein thrombosis; the therapeutic response. N Engl 1 Med 1986;3/5:1109-214.
14. DOYLE OJ, TURPIE AGG, HIRSH J, et aI. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial. Ann Intern Med 1987;107:441-5. 15. HIRSH 1. Is the dose of warfarin prescribed by American physicians unnecessarily high? Arch Intern Med 1987;147:769-71. 16. Anticoagulant therapy: a patient's guide. Wilmington, DE: E.1. duPont de Nemours & Co., 1984.
EXTRACTO Los autores reportan el caso de una mujer de 55 afios transferida de otro hospital. EI historial de la presente enfennedad comenz6 con un accidente cerebrovascular en ellado derecho. Tres dias mas tarde la paciente desarrollo un embole en la arteria mesenterica superior con infarto al intestino. Se extirpo el intestino delgado dejando alrededor de 20-25 em. Un ecocardiograma document6 la presencia de un embolo en el ventrfculo izquierdo, que se consider6 fue la causa de su accidente cerebrovascular y del embole en la arteria mesenterica superior. Los cardiologos recomendaron terapia con anticoagulantes de por vida, preferiblemente warfarina. Luego de un mes de comenzar terapia con warfarina administrando dosis tan altas como 25 mg diarios, el tiempo de protrombina se mantuvo igual, debido probablemente a terapia concurrente con vitamina K. La heparina se incorpor6 a la nutrici6n parentral total (TPN) al comenzar los preparativos para dar de alta al paciente. Como el TPN se administraba en ciclos, la paciente requeria heparina por via subcutanea dos veces al dia, los dias que no recibia TPN. EI curso clfnico de esta paciente mientras recibia heparina, se complic6 por episodios de sangramiento, extensos hematomas en el abdomen y el muslo, que llev6 a una absorci6n erratica de heparina y una fluctuaci6n amplia en el tiempo parcial de protrombina. Diez meses luego de haber comenzado la terapia con anticoagulantes, se trat6 nuevamente al paciente con warfarina. La terapia fue exitosamente titulada hasta alcanzar el tiempo de protrombina deseado. Este caso concuerda con otros casas reportados en la literatura donde el uso de anticoagulantes orales ha sido exitoso en pacientes con sindrome de intestino corto. ANNETTE PEREZ RESUME Les auteurs presentent Ie cas d'une femme de 55 ans hospitalisee Ie 21106/87 pour un accident cerebrovasculaire (ACY) du cote droit et transferee dans leur centre hospitalier Ie 08/07/87. Trois jours apres son ACY, elle avait une embolie de l'artere rnesenterique superieure (AMS) avec un infarctus intestinal. Apres resection, environ 20 a 25 em du petit intestin etaient conserves. Un echo cardiaque Ie 13/07/87 a revele la presence d'une embolie du ventricule gauche, qui etait sans doute la cause de I' ACY et de I'embolie de I' AMS. Les cardiologues ont recommandes une anticoagulation a vie, de preference avec la warfarine. Apres un mois de traitement avec la warfarine 25 mg/jr, les temps de prothrombine (TP) etaient toujours au niveau des valeurs de base; cependant, I'absence de reponse a la warfarine etait probablement due a la prise concomitante de vitamine K. La patiente a ete jugee refractaire aux anticoagulants oraux, et tous les efforts pour I'anticoagulation orale ont ete interrompus. De l'heparine a ete incorporee a son alimentation parenterale totale (APT). Puisque I' APT etait cyclique et que la demivie de l'heparine est courte, la patiente devait recevoir des doses supplernentaires d'heparine, en administration sous-cutanee deux fois par jour. Sous ce regime therapeutique, Ie suivi c1inique de la patiente a ete complique par des episodes de saignements et des hernatomes importants aux cuisses et a I'abdomen, ceux-ci ont entraine une absorption erratique de l'heparine et de larges fluctuations dans les temps de cephaline. Dix mois apres I'instauration de l'anticoagulation, I'administration de warfarine orale etait a nouveau essayee, Les valeurs du TP ont ete maintenus dans les ecarts souhaites. La presentation de ce cas est sui vie par une revue de litterature des patients avec un syndrome de I'intestin court qui necessitent une anticoagulation.
DICP, The Annals of Pharmacotherapy
CELtNE FISET
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1990 June, Volume 24
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589
