Underlying factors influencing the development of the post-thrombotic limb

Underlying factors influencing the development of the post-thrombotic limb Ann M. O Shaughnessy, MSc, RVT, AVT, a,b and Dermot E. FitzGerald, MD, PhD, MSc, a Dublin, Ireland Purpose: This study was designed to determine whether patients having underlying venous disease in their contralateral limbs indicates a more severe long-term clinical outcome in the ipsilateral limb after a deep vein thrombosis (DVT) and to determine what other factors may influence the long-term outcome. Methods: An acute DVT was initially diagnosed by means of duplex ultrasound scanning. Follow-up clinical examinations and bilateral duplex reflux studies were performed for a mean period as long as 3 years. The patients were divided into two groups: group I, those with no history of a contralateral DVT, and group II, those with a history of a contralateral DVT. The patients were classified at their final examination according to the Clinical, Etiology, Anatomic, Pathophysiologic (CEAP) classification, and the ipsilateral and contralateral limbs were compared. Predisposing factors were compared with the final clinical outcome. Results: Sixty-three patients were monitored in a mean follow-up period of 3 years. There was a significant difference in the incidence of symptoms between the ipsilateral limbs (P <.01) and the contralateral limbs (P <.001) for both groups. There was no significant difference between the incidence of superficial reflux between the ipsilateral and contralateral limbs, but the deep venous system and perforator veins were involved more often in the ipsilateral limbs. In group I, only six patients (10%) had no evidence of venous dysfunction (CEAP = 0) in their ipsilateral or contralateral limbs at the time of the final examination, and all patients had reversible risk factors. Of patients who had a mild clinical outcome (CEAP score, 1 to 3), 64% had a healthy contralateral limb, and the remaining 36% had mild to moderate disease. Eighty percent of patients with the most severe clinical outcome (CEAP > 3) had mild to moderate venous disease in their contralateral limb and had nonreversible risk factors. Conclusion: There are a significant number of patients with an acute DVT who had an underlying venous disease in the uninvolved contralateral limb. An ipsilateral post-thrombotic limb is more likely to develop in patients with primary venous reflux after an acute DVT. The level of venous dysfunction in the contralateral limb is an indication of the severity of disease developing in the ipsilateral limb. The initial risk factors of the patients have an influence on the final clinical outcome. (J Vasc Surg 2001;34:247-53.) The post-thrombotic syndrome (PTS) is one of the most serious long-term complications of deep venous thrombosis (DVT) in the lower limb. The PTS occurs in 60% to 70% of cases in which patients are monitored for between 5 and 10 years after conservative treatment of DVT. 1-3 However, 20% to 30% of limbs have no signs or symptoms after DVT, and 32% of the contralateral limbs, without DVT, have positive signs and symptoms. 4-6 It is unknown why some patients have a post-thrombotic limb, whereas others remain without symptoms. It is well established that valvular incompetence in the deep venous systems and in the perforating veins is the predominant factor in the development of chronic venous insufficiency (CVI). 1,2,7-10 The site and extent of venous reflux are important in the clinical severity of CVI. 7,8,10 Venous incompetence can occur because of damage to the From the Vascular Medicine Unit, James Connolly Memorial Hospital, a and the Department of Anatomy, Trinity College. b Competition of interest: nil. Supported in part by an education grant from Leo Laboratories, Ireland. Reprint requests: Ann M. O Shaughnessy, Vascular Medicine Unit, James Connolly Memorial Hospital, Blanchardstown, Dublin 15, Ireland (e-mail: defvmu@iol.ie). Copyright 2001 by The Society for Vascular Surgery and The American Association for Vascular Surgery. 0741-5214/2001/$35.00 + 0 24/1/115811 doi:10.1067/mva.2001.115811 valves caused by venous thrombosis or as a result of underlying degenerative changes in the venous wall, as in the case of varicose veins. It is, therefore, important to include the contralateral limb in long-term studies to determine whether the patient has an underlying venous disease affecting the overall outcome. 11 This study was designed to examine the long-term clinical outcome after acute DVT. The clinical results of the ipsilateral and contralateral limbs were compared to determine whether the presence of an underlying venous disease is a prediction of a more severe clinical outcome and to examine what other factors may play a part in the pathogenesis of CVI. METHODS AND MATERIALS A total of 100 consecutive above-knee acute DVTs at our vascular laboratory were examined. The presence of an acute DVT was diagnosed with bilateral venous duplex scanning. 12 The patients underwent follow-up examinations at 1 week, 1 month, 6 months, 1 year, and then yearly for a mean period of 3 years. The study was approved by the Institutional Review Board, and each patient gave informed consent before participating in the study. Bilateral reflux studies were performed at follow-up examinations by the use of the distal cuff deflation technique to determine the level of reflux, obstruction, or 247

248 O Shaughnessy and FitzGerald August 2001 Fig 1. Percentage of initial predisposing factors of patient population. both in the superficial, perforator, and deep venous systems. 13,14 The early results of this study have been reported. 15-17 At yearly examinations, the patients were also examined clinically, and symptoms were recorded. The patients were divided into two groups: group I consisted of those without a history of a contralateral DVT, and group II consisted of those with a history of a contralateral DVT. The patient symptoms, venous systems involved (ie, deep, superficial, or perforator), and anatomical site of venous dysfunction were compared in the ipsilateral and contralateral limbs for the two groups. The Clinical, Etiology, Anatomic, Pathophysiologic (CEAP) classification system was used to classify and grade the severity of the clinical findings at the final examination. 18 An overall subjective venous dysfunction CEAP score that was composed of a clinical severity score, an anatomical severity score, and a disability severity score as experienced by the patient was given for each limb (Table I). For simplicity, the anatomical score was given for overall superficial, deep, or perforator system involvement and not for the individual anatomical sites. The two groups of patients were subdivided according to their total CEAP score on the ipsilateral limb, and the ipsilateral and contralateral limbs were then compared. The subdivisions were (1) total CEAP score ipsilateral limb = 0, no venous disease; (2) total CEAP score ipsilateral limb = 1 to 3 inclusive, mild to moderate venous disease; and (3) total CEAP ipsilateral limb score more than 3, severe venous disease. The initial predisposing factors for the patients were then compared with their final CEAP classification. RESULTS There were initially 100 proximal DVTs in 89 patients (11 bilateral thromboses). At 1 year, 14 patients had died, and 23 patients were lost to follow-up. The causes of death were cancer (10), pulmonary embolism (3), and heart disease (1). The long-term results of the remaining 63 patients are presented in this report. None of these 63 patients initially had a bilateral DVT. The 63 patients included 34 men and 29 women, with a mean age of 62 years (range, 22-94 years). The mean follow-up period was 3 years (range, 2-6 years). The patients were treated by their referring physicians, with no therapeutic recommendations from the vascular laboratory. The therapeutic regimen consisted of heparin (either subcutaneous or intravenous) for a period of 5 to 7 days, followed by at least 3 months of orally administered warfarin. Compression stockings were supplied, but compliance of use was low, and only 20 patients wore the stockings as instructed. Most patients initially had a combination of risk factors. Two patients were proven to have an abnormality in the coagulation system (ie, factor V Leiden carriers). However, because only a small number of patients in this study had a thrombophilia screen, coagulation abnormalities that may have been present in this patient population could not be included in the risk factor assessment. Three patients had a history of an earlier bilateral DVT. A total of 16 limbs (25%) had a history of an ipsilateral DVT, and 17 limbs (27%) had a history of a contralateral DVT. The predisposing factors of the patient population are shown in Fig 1. There were 46 patients in group I and 17 patients in group II. Patients with symptoms at the final examination generally had a combination of symptoms that included aching, pain, edema, and ulcers (all healed at the time of the final examination). Only one patient complained of pain in both lower extremities. No underlying cause (eg, arterial disease) was established for this. The symptoms on follow-up in the ipsilateral and contralateral limb for group I and group II are shown in Table II. There is a significant difference between group I and group II in the number of patients with symptoms in their ipsilateral limb (P <.01) and the number of patients with symptoms in their contralateral limb (P <.001). Sites of reflux and obstruction in the ipsilateral and contralateral limbs were identified by means of duplex ultrasound scanning (Table III). There was no significant difference between the percentage of abnormalities in the ipsilateral limbs in group I and group II; however, there was a significant difference in the percentage of abnormalities present in the contralateral limbs between the two groups (P <.001). The anatomical sites of venous dysfunction involving the superficial, perforator, and deep venous systems in the ipsilateral and contralateral limbs for both groups are shown in Table IV. In group I, there was no significant difference in the incidence of superficial system involvement between the ipsilateral and contralateral limbs; however, there was a significant difference in the incidence of deep venous system and perforator vein involvement (P <.001 and P <.05, respectively). For group II, there was no significant difference in the involvement of the superficial or perforator system between the ipsilateral and contralateral limbs, but there was a significant difference in the incidence of deep venous system involvement (P <.04). In the comparison of group I and group II, there was no signifi-

Volume 34, Number 2 O Shaughnessy and FitzGerald 249 Table I. The CEAP scoring system of chronic venous dysfunction based on an anatomic score, clinical score, and disability score Anatomical score (1 point each) Clinical score (none = 0; mild/moderate = 1; severe = 2) Disability Superficial Deep Perforator Pain Edema Venous claudication Pigmentation Lipodermatosclerosis Ulcer size Ulcer duration Ulcer recurrence Ulcer number Asymptomatic = 0 Symptomatic, can function without support device = 1 Can work 8-hour d only with support device = 2 Unable to work = 3 Total score Subtotal Subtotal Subtotal Table II. The percentage of patients in group I and group II with symptoms on follow-up in the ipsilateral and contralateral limb Ipsilateral Contralateral Ipsilateral Contralateral Percentage of total with symptoms 56% 2% 88% 71% No. of patients with pain 0 0 1 0 No. of patients with edema 32 3 14 10 No. of patients with pigmentation 14 4 11 8 No. of patients with ulcer 3 0 0 0 Most patients had a combination of symptoms, and the number of patients with pain, edema, pigmentation, and history of an ulcer is also shown. There is a significant difference in the percentage of patients with symptoms in their ipsilateral limbs (P <.01) and the percentage of patients with symptoms in their contralateral limbs (P <.001) between group I and group II. Table III. The number of ipsilateral and contralateral limbs with reflux, obstruction, both reflux and obstruction, or no venous abnormalities for both groups (N = 46) (N = 17) None Reflux Obstruction Both None Reflux Obstruction Both Ipsilateral 6 15 1 24 0 9 0 8 Contralateral 26 18 2 0 2 11 4 0 There was no significant difference between the number of abnormalities in the ipsilateral limbs between groups I and II; however, there was a significant difference in the number of abnormalities present when the two contralateral limbs are compared (P <.001).

250 O Shaughnessy and FitzGerald August 2001 Fig 2. Percentage of predisposing factors in relation to total CEAP score on ipsilateral limb. cant difference between the incidences of venous dysfunction in the ipsilateral limbs, but in the contralateral limbs, there was a higher incidence of deep venous and perforator system involvement for group II. The anatomical sites of venous incompetence or obstruction in the ipsilateral and contralateral limbs are shown in Table V. Because of the difficulty of imaging the inferior vena cava, the common iliac, and internal iliac veins, these sites were not included in many patients. Most patients had multiple sites of reflux, obstruction, or both. The most frequent anatomical sites involved in both the ipsilateral and contralateral limbs for both groups were the long saphenous veins, the superficial femoral veins, the popliteal veins, and the calf perforator veins. The two groups of patients were divided according to their total CEAP score in the ipsilateral limb (Table I). The CEAP scores of the ipsilateral and contralateral limbs were compared for group I and group II and are shown in Table VI. The initial predisposing factors were compared with the classification according to the CEAP score, and this comparison is shown in Fig 2. DISCUSSION Post-thrombotic manifestations develop as a result of combined deep and superficial venous reflux, the extent of venous reflux, recurrent deep venous thrombotic events, and persistent deep venous occlusion. 2,4,10,19 After a DVT, post-thrombotic symptoms develop in many patients; however, reflux may not develop in as many as 50% of venous segments that recanalize, and the initial location and extent of a thrombus may not relate to the long-term sequelae. 3,4,7,11,20 We studied a consecutive series of 100 acute DVTs for a mean period as long as 3 years to examine the factors influencing post-thrombotic development. The mortality rate of the patients was 14% at 1 year. Most deaths were from cancer, and only 3% were caused by pulmonary embolism. This is a similar rate to that of other studies that report a mortality range as high as 15% during the first year, primarily because of an underlying disease such as cancer. 21,22 One of the long-term complications of DVT is recurrence. The risk of recurrent venous thrombosis has been reported to be as high as 20%. 17,21,23,24 Of the 63 patients available for long-term follow-up, 25% had a history of an ipsilateral DVT and 27% had a history of a contralateral DVT (5% bilateral). These histories were not always confirmed by means of objective testing. Also, the history of an occult DVT cannot be ruled out in either limb. The patients were divided into two groups, those without a history of a contralateral DVT and those with a history of a contralateral DVT (or bilateral post-thrombotic limbs). The clinical manifestations of the post-thrombotic syndrome are hyperpigmentation, edema, pain, and ulceration. There was a significant difference in the incidence of symptoms in the contralateral limbs between group I and group II (P <.001). This is not surprising, because the contralateral limbs in group II were post-thrombotic. However, in the ipsilateral limbs, there was also a significant difference in the incidence of symptoms between group I and group II (P <.01), indicating that symptoms are more likely to develop during follow-up in patients with bilateral disease. Symptomatic chronic venous disease results primarily from venous valvular insufficiency. 7,8,10,19 The presence of reflux, obstruction, or both was confirmed by means of duplex scanning and reflux studies. In both groups, the ipsilateral limbs had a higher incidence of combined reflux and obstruction (because of residual thrombus) than the contralateral limbs. However, the contralateral limbs in group I had an incidence of reflux similar to that in the ipsilateral limbs. Because these patients had no clinical history of DVT in their contralateral limb, degenerative changes not related to the DVT were the most likely cause for the development of reflux. It has been reported that the sites of venous dysfunction are not always related to the sites of DVT. 7,8,10,19,25 CVI can result from a primary as well as a post-thrombotic cause, although occult thrombosis cannot be excluded. For both groups of patients, in the ipsilateral and contralateral limbs, the most common sites of venous dysfunction were the long saphenous veins, the superficial femoral veins, the popliteal veins, and the perforator veins. The anatomical site of reflux is important because the most severe symptoms are found in patients with incompetence in the distal deep and superficial veins. 7,25-28 Superficial venous incompetence may occur in the postthrombotic limb because of concurrent thrombosis, increased venous pressure resulting from proximal venous obstruction or reflux, pressure transmission through incompetent perforator veins, or degenerative changes occurring in the superficial veins that are unrelated to the thrombotic event. 27,29 Meissner et al 27 have reported that approximately 22% of limbs with DVT have related concurrent superficial thrombosis that may account for the development of reflux in some of the long saphenous veins. However, there was no significant difference in the

Volume 34, Number 2 O Shaughnessy and FitzGerald 251 Table IV. The number of ipsilateral and contralateral limbs involving the superficial, deep, and perforator venous systems in both groups on follow-up Superficial Deep Perforator Superficial Deep Perforator Ipsilateral 22 41 22 8 15 10 Contralateral 17 8 12 7 12 10 P value NS <.001 <.05 NS <.04 NS In group I, there was a significant difference between the ipsilateral and contralateral limb in the incidence of involvement of the deep and perforator systems (P <.001 and P <.05). In group II, there was a significant difference in the incidence of involvement of the deep venous system only (P <.04). NS, Not significant. Table V. The number of anatomical sites of venous dysfunction (either incompetence or obstruction) in the contralateral and ipsilateral limbs for both groups No. of limbs Ipsilateral Contralateral Ipsilateral Contralateral Telangiectase/reticular veins 2 (4%) 1 (2%) 1 (6%) 1 (6%) LSV AK 17 (37%) 10 (22%) 6 (35%) 8 (47%) LSV BK 10 (22%) 6 (13%) 7 (41%) 5 (29%) SSV 8 (17%) 0 0 0 Nonsaphenous 1 (2%) 0 0 0 Iliac external 1 (2%) 0 0 0 Femoral common 4 (9%) 2 (4%) 3 (18%) 0 Femoral deep 2 (4%) 1 (2%) 1 (6%) 0 Femoral superficial 27 (59%) 7 (15%) 15 (88%) 9 (53%) Popliteal 32 (70%) 10 (22%) 16 (94%) 10 (59%) Cureal 8 (17%) 1 (2%) 1 (6%) 1 (6%) Muscular 7 (15%) 1 (2%) 2 (12%) 1 (6%) Perforator thigh 3 (6%) 2 (4%) 1 (6%) 0 Perforator calf 20 (43%) 15 (33%) 10 (59%) 7 (41%) LSV AK, Long saphenous vein above the knee; LSV BK, long saphenous vein below the knee; SSV, short saphenous vein. Table VI. The CEAP total score for the ipsilateral and contralateral limb on follow-up for the two groups Contralateral limb Ipsilateral limb 0 1 2 3 4 5 6 0 1 2 3 4 5 6 CEAP score 0 (N = 6) 6 1-3 (N = 22) 14 3 1 1 1 1 1 > 3 (N = 35) 7 5 4 3 0 2 1 1 1 1 4 3 3 incidence of superficial venous system involvement between the ipsilateral and contralateral limbs in group I, suggesting an underlying venous disease may more likely be the cause of reflux. Long saphenous reflux in the uninvolved extremity contralateral to a DVT develops at a background rate of approximately 15% in 8 years, which is likely related to degenerative changes within the vein because it has a similar rate of the prevalence of reflux in the general population. 27 All limbs with a history of DVT had a higher incidence of deep venous system involvement. The CEAP classification provides a uniform means of classifying and grading the severity of the clinical findings and is a useful method in any long-term study. 18 The clas-

252 O Shaughnessy and FitzGerald August 2001 sification addresses the clinical, etiologic, anatomic, and pathophysiologic mechanisms and requires objective testing to support these diagnoses. In group II, there was a similar distribution of CEAP scoring between the ipsilateral and contralateral limbs. In group I, six limbs had a CEAP score of 0 on both sides. Of the patients who had mild to moderate disease in the ipsilateral limb (CEAP 1 to 3), 64% had a healthy contralateral limb, and the remaining 36% had mild to moderate disease. Of the patients with severe venous disease (CEAP score > 3), only 20% had healthy contralateral limbs, and the remaining 80% had mild to severe disease. This means that the severity of the disease on the contralateral limb was related to the severity of the post-thrombotic changes recorded on the ipsilateral limb. These results indicate that symptoms in the ipsilateral limb are more likely to develop in patients with nonthrombotic venous disease in the contralateral limb. The CEAP scoring system does not take into account the history of the patient; however, risk factors play an important part in the long-term prognosis. Patients with temporary risk factors (eg, recent surgery and trauma) have an excellent long-term prognosis. 21 Thrombosis manifests itself as a multicausal disease and generally develops with a combination of risk factors. 30,31 Few patients in this study had only a single risk factor. The risk of developing a post-thrombotic limb is higher for patients with permanent risk factors than for patients who have had trauma or undergone surgery. 21 The six patients who had bilateral healthy venous systems on follow-up all had reversible risk factors. Patients with a history of varicose veins or a history of earlier DVT, either contralateral or ipsilateral, had a higher final CEAP score. Of those patients with a history of earlier DVT, only five had this as a single risk factor. The clinical manifestations of CVI are often referred to as the PTS. Patients with recurrent DVTs are at high risk for the development of the PTS. 21 However, an earlier episode of DVT is not a prerequisite for the development of the syndrome. 19 Venous hypertension, which is a universal element of the syndrome, can derive from primary as well as post-thrombotic venous reflux. The presence of reflux in the uninvolved contralateral limb without a history of an earlier DVT suggests an underlying venous disease and can lead to a more severe clinical outcome for the patient. Other factors also play a role in the pathogenesis of CVI. The initial risk factors for the development of a DVT have a strong influence on the long-term outcome. In conclusion, a significant number of patients with an acute DVT had an underlying venous disease in the uninvolved contralateral limb. An ipsilateral post-thrombotic limb was more likely to develop after an acute DVT in patients with primary venous reflux, and the level of venous dysfunction on the contralateral limb was an indication of the severity of disease developing in the ipsilateral limb. However, the numbers in this study, especially in group II (n = 17), were small, and these findings require further investigation in a larger study. REFERENCES 1. Meissner MH. The effect of recanalisation of venous thrombi on valve function. Vasc Med 1995;6:143-52. 2. O Shaughnessy AM, FitzGerald DE. Natural history of proximal deep vein thrombosis assessed by duplex ultrasound. Int Angiol 1997; 16:45-9. 3. Saarinen J, Sisto T, Laurikka J, Salenius JP, Tarkka M. Late sequelae of acute deep venous thrombosis; evaluation five and ten years after. Phlebotomy 1995;10:106-9. 4. Meissner MH, Manzo RA, Bergelin RO, Markel A, Strandness DE Jr. Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vasc Surg 1993;18:596-608. 5. Taheri SA, Weaver TA, Schultz RO. Genetic alterations in chronic venous insufficiency. Int Angiol 1993;12:1-4. 6. Heldal M, Seem E, Sandset PM, Abildgaard U. Deep vein thrombosis: a 7 year follow-up study. J Intern Med 1993;234:71-5. 7. Johnson BF, Manzo RA, Bergelin RO, Strandness DE Jr. The site of residual abnormalities in the leg veins in long term follow-up after deep vein thrombosis and their relationship to the development of the post-thrombotic syndrome. Int Angiol 1996;15:14-9. 8. Welch HJ, Young CM, Semegran AB, Iafrati MD, Mackey WC, O Donnell TF Jr. Duplex assessment of venous reflux and chronic venous insufficiency: the significance of deep venous reflux. J Vasc Surg 1996;24:755-62. 9. Killewich LA, Bedford GR, Beach KW, Strandness DE Jr. Spontaneous lysis of deep venous thrombi: rate and outcome. 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O Shaughnessy AM, Fitzgerald DE. The value of computer analysis in predicting the long-term outcome of deep vein thrombosis. Int Angiol 2000;19:308-13. 17. O Shaughnessy AM, Fitzgerald DE. An audit of the clinical and subclinical changes in the first year following an acute DVT. Int Angiol. In press 2000. 18. Beebe HG, Bergan JJ, Bergovist D, Eklof B, Eriksson I, Goldman MP, et al. Classification and grading of chronic venous disease in the lower limb. Int Angiol 1996;14:197-200. 19. Lapropoulos N, Giannoukas AD, Nicholaides AN, Veller M, Leon M, Volteas N. The role of venous reflux and calf muscle pump function in non-thrombotic chronic venous insufficiency: correlation with severity of signs and symptoms. Arch Surg 1996;131:403-6. 20. Browse NL, Clemenson G, Thomas ML. Is the postphlebitic leg always postphlebitic? Relation between phlebographic appearances of deep-vein thrombosis and late sequelae. BMJ 1980;281:1167-70. 21. Prandoni P, Lensing AWA, Rrins MR. 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Volume 34, Number 2 O Shaughnessy and FitzGerald 253 anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-7. 25. LeSiege CJ, McKean SCW, Persson AV. Importance of valvular incompetence after acute deep venous thrombosis. J Cardiovasc Surg 1992;33:710-3. 26. Strandness DE Jr, Langlois Y, Cramer M, Randlett AN, Thiele BL. Long-term sequelae of acute venous thrombosis. JAMA 1983;250: 1289-92. 27. Meissner MH, Caps MT, Zierler BK, Bergelin RO, Manzo RA, Strandness DE Jr. Deep venous thrombosis and superficial venous reflux. J Vasc Surg 2000;32:48-56. 28. Meissner MH. The effect of recanalization of venous thrombi on valve function. Vasc Med 1995;6:143-52. 29. Taheri SA, Weaver TA, Schultz RO. Genetic alterations in chronic venous insufficiency. Int Angiol 1993;12:1-4. 30. Motykie GD, Caprini JA, Arcelus JI, Zebala LP, Lee CE, Finke MN, et al. Risk factor assessment in the management of patients with suspected deep venous thrombosis. Int Angiol 2000;19:47-51. 31. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1993;353:1167-73. Submitted May 24, 2000; accepted Mar 2, 2001. BOUND VOLUMES AVAILABLE TO SUBSCRIBERS Bound volumes of the Journal of Vascular Surgery for 2001 are available to subscribers only. They may be purchased from the publisher at a cost of $119.00 for domestic, $147.66 for Canadian, and $138.00 for international subscribers for Vol 33 (January to June) and Vol 34 (July to December). Price includes shipping charges. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mosby, Subscription Customer Service, 6277 Sea Harbor Dr, Orlando, FL 32887; phone 800-654-2452 or 407-345-4000. Subscriptions must be in force to qualify. Bound volumes are not available in place of a regular Journal subscription.