Control of bleeding in severely uremic patients undergoing oral surgery

Control of bleeding in severely uremic patients undergoing oral surgery David J. Buckley, B.D.S.,* Anthony P. Barrett. B.D.Sc.. Ph.D.,** Jerry Koutts, M.D., B.S., F.R.A.C.P., F.R.C.P.A.,*** and John H. Stewart, A4.B.Ch.B.. F.R.C.P.. F.R.A.C.P.,**** Westmead, New South Wales, Australia WESTMEAD

HOSPITAL

The roles

of hemodialysis

DENTAL

and

CLINICAL

SCHOOL

I-deamino-8-D-arginine

AND

DEPARTMENT

vasopressin

OF MEDICINE

(DDAVP)

in the control

of hemorrhage

following oral surgery in a severely uremic patient are described. (ORAL SURC. ORAL MED. ORAL PATHOL. 61546-549, 1986)

P

CASEREPORT

*Registrar, Oral Diagnosis. **Staff Specialist, Oral Diagnosis. ***Head of Unit (Clinical Hematology). ****Head of Unit (Renal Medicine).

A 38-year-old white man was referred to the Westmead Hospital Dental Clinical School for assessment in preparation for cadaveric renal transplantation. One year previously the patient experienced the onset of progressive renal failure due to reflux nephropathy. Maintenance hemodialysis therapy with a cuprophane hollow-fiber dialyzer began 5 weeks prior to referral. Vascular access was via a surgically constructed forearm arteriovenous fistula. Systemic anticoagulation involved adjustment of the whole blood partial thromboplastin time to one and one half times that of established laboratory controls. This was achieved with an initial loading dose of 1,500 IU heparin and maintained by heparin infusion at a rate of approximately 1,500 IU per hour. Current medication included hydralazine hydrochloride, 50 mg, labetalol hydrochloride, 200 mg, and aluminum hydroxide, 600 mg twice daily, as well as calcium carbonate, 1.2 g three times daily. The patient’s medical history was otherwise unremarkable. Physical examination revealed significant pallor of the skin and mucosae, reflecting a severe underlying chronic anemia (Hb:5.9g/dl at initial presentation). The patient was partially dentate, and his oral hygiene was poor. Radiographic evidence of bony changes,9 commonly reported in long-term hemodialysis patients, was not evident. Nine extractions were performed in three stages, following induction of local anesthesia with lignocaine hydrochloride 2% with 1:200,000 epinephrine. Each extraction session was planned for 14 hours following dialysis. Immediately prior to and 24 hours after each extraction session, a full blood count and skin bleeding time (SBT) determination (by the Simplate II method) were performed. Since there is evidence to suggest that DDAVP may encourage hemostasis through the elevation of various factor VIII levels*, the following standard assays for factor VIII activity were performed: (1) factor VIII coagulant activity

rolonged bleeding is commonly encountered in patients requiring hemodialysis for the severe uremia of end-stage renal failure. There are three key factors that predispose to this bleeding tendency. First, the anticoagulation involved in the procedure of hemodialysis-and in the outpatient maintenance of prosthetic shunt patency-is generally considered to provoke bleeding following oral surgery.’ Indeed, the role of anticoagulation appears to be the principal concern expressed in the dental literature. Second, it is significant that approximately 10% of patients with severe uremia have mild (or occasionally severe) thrombocytopenia as a result of impaired platelet production.2 Furthermore, significant thrombocytopenia may be associated with the procedure of hemodialysis itself.’ Third, abnormal platelet function is now well established as an important factor in most patients with severe uremia.4,5 Although dialysis remains the mainstay for the prevention of prolonged bleeding in uremia, it is not always effective.6 Adjunctive measures may need to be employed to secure hemostasis. The synthetic analogue of the antidiuretic hormone vasopressin, 1-deamino-8-D-arginine vasopressin (DDAVP), has previously been recommended in the management of bleeding in severe uremia. ‘38 The aim of this article is to examine the role of hemodialysis and DDAVP in the prevention of bleeding following sequential dental extractions in a severely uremic patient.

546

Volume

6I

Number

6

Control

of bleeding in severely uremic oral surgery

patients

547

I. Key parameters measured

Table

Skin bleeding Stage Sesiitm

of treatment

V1II.C

VIII:

assay

7rnre sirw

(U/d11

VWF

VIlItAg

Urea (mmol/li

C’reatinint,

dial~~.si.c

(mmol/l)

(/VI

(I hr) (24 hr)

10 6.5 >I5

240 230 228

180 260 150

68 105 94

180 195 205

18 19.8 24.3

x43 886 1100

14 I5 3x

6 (24 hr)

>I5

237 224

120 I48

85 95

I80 I85

17.6 26.3

818 III9

I4 3x

5 9.5

261 204

I65 160

89 82

125 210

20.0 29.2

861 1093

14 ix

>I5 2-9.5

212 150-400

170 50-150

100 50-150

172 50-150

33.9 2.5-6.5

II54 ho- 125

40

II

Pre-extraction Postextraction Session

Platelets (X 10~////)

VIII

I

Pre-DDAVP Post-DDAVP Post-DDAVP Sessiorl

time (min)

Facror

111

Pre-extraction Postextraction (24 hr) (pre-DDAVP) Post-DDAVP (I hr) Normal range of values

(F VIII:C), (2) factor VIII-related antigen (F VIII:Ag), and (3) factor VIII von Willebrand (F VIILVWF) (Table I). Multiple biochemicalanalyses(MBA12) were also performedand includedserumurea and serumcreatinine levels. Prothrombin time and activated partial thromboplastin times were determinedsimilarly throughout and were within normal limits. Prior to the first extraction session,the SBT was 10 minutes-marginally above the upper limit of normal in this laboratory (range, 2 to 9.5 minutes). DDAVP was administeredin 50 ml of isotonic saline solution (by intravenous infusion over 30 minutes) at a dose of 0.3 pg/kg. One hour following the administrationof DDAVP, and immediatelyprior to surgery, thesetestswererepeated. The SBT was reduced to 6.5 minutes. Four teeth (upper left first and third molarsand lower left first and secondpremolars)wereextracted and the socketssecured with mattresssutures,as were all subsequentextraction sockets.Abnormal postoperativebleedingdid not occur. Prior to the secondextraction session,which includedtwo teeth (lower left first and secondmolars), the SBT was within normal limits (6 minutes)and, therefore, DDAVP was not administered.Abnormal postoperativebleeding did not occur. Twenty-four hours following eachof these extraction sessions, the SBT was>15 minutes. Prior to the third session-whenthree teeth (upper left lateral incisorand cuspidand upper right first molar) were extracted-the SBT was again within normal limits (5 minutes)and DDAVP wasnot administered.However,the socketsbeganto bleedfreely 18 hoursafter extraction (32 hours after dialysis). Six hours following the onset of bleeding,the patient returned. The socketsof the three recently extracted teeth were bleeding freely, with no evidenceof clot formation, despite seeminglyadequate localpressure.Eventhoughthe SBT at this stage(38 hours after dialysis) wasonly at the upper limit of normal (9.5 minutes), the decisionwas made to initiate DDAVP as previously described.Bleeding did not cease,however, following the infusionof DDAVP-the SBT having actu-

ally risen (SBT > 15 minutes) 1 hour following infusion. Hemodialysiswasreinstituted. Bleedingfrom all sockets ceasedabruptly 3 hourslater. Ten hoursfollowingcompletion of hemodialysis,there wasno evidenceof bleedingor soft tissuehematoma.Subsequenthealingwasuneventful, as with all other extractions. DISCUSSION

This report clearly demonstrates the potential for patients with end-stage renal disease to bleed postoperatively following dental surgery. Of the three key factors that predispose to the bleeding tendency in uremia, heparinization and thrombocytopenia did not appear important in this patient. First, the anticoagulant effect of heparinization was unlikely to provoke postoperative bleeding, as each extraction session was scheduled for 14 hours following hemodialysis, and the duration of action of heparin is reported to be on the order of 2 to 4 hours only.‘O As heparinization is the principal concern expressed in the dental literature, it is generally recommended that invasive dental and oral surgical procedures be performed on the day following hemodialysis. In the present case, however, effective hemostasis occurred during active anticoagulation with heparin. This probably reflects, in part, the increasingly precise control of anticoagulation possible during contemporary hemodialysis,” which tends to overcome the past complications of less efficient heparinization. Second, platelet counts throughout the study were never below 200 X 109/1. Therefore, as with the anticoagulation effects of heparin, thrombocytopenia appeared similarly unimportant. By exclusion, platelet dysfunction appeared to be the most likely cause of postoperative bleeding in the present case.

548

Buckley et al.

The precise pathogenesis of the platelet dysfunction in uremia is unclear, but it is considered to be associated with a number of factors, including retention of platelet toxins6 and abnormal factor VIII activity. I2 The retention of dialyzable platelet toxins, normally excreted by the kidney, has long been considered a cause of platelet dysfunction.6B’3 From Table I it is clear that rising levels of serum urea and creatinine are related to time following completion of hemodialysis. Therefore, it appears reasonable that a similar time-related increase in the concentration of platelet toxins could be anticipated. This may be reflected in the increased SBT, seen on each occasion 24 hours following extractions (38 hours following hemodialysis). The observation that the postoperative bleeding in this patient ceased once dialysis was instituted further supports a role of dialyzable platelet toxins in uremia. The von Willebrand portion of the factor’VII1 complex is essential for normal platelet function. A deficiency of this factor, as seen in von Willebrand’s disease, is characterized by a prolongation of the SBT and decreased platelet adhesiveness.14 A possible pathogenic role of factor VIII in the etiology of platelet dysfunction in uremia is suggested, but it has yet to be clearly demonstrated.5, I2 In fact, factor VIII activity in persons with renal failure is generally normal or increased.15 DDAVP has been used successfully to facilitate hemostasis in mild to moderate von Willebrand’s disease by increasing factor VIIIrelated activity and, therefore, apparently correcting platelet dysfunction. K” It has been proposed that boosting factor VIII activity above normal in uremia may similarly facilitate hemostasis.‘,* In one study by Mannucci and colleagues,8 major surgery was made possible in uremic patients with a hemorrhagic tendency. Infusion of DDAVP was associated with an increased factor VIII-related activity and a shortened SBT. A similar effect was seen during the first extraction session in this study when DDAVP was administered 14 hours after hemodialysis (Table I). A study performed by Vincente and colleagues,18 however, failed to demonstrate these effects. Following the third extraction session in the reported case, DDAVP-this time administered 38 hours after hemodialysis-failed to significantly boost factor VIII-related activity. The SBT was not shortened, and the patient continued to bleed. The reason for this apparently inconsistent action of DDAVP is unclear, but it is probably influenced by a number of factors, particularly the levels of dialyzable platelet toxins. Other possible factors may include lowered hematocrit19 and increased prostacyclin activity.*O In conclusion, we propose that the major cause of

Oral Surg. June, 1986

postoperative bleeding in the present case was due to disordered platelet function resulting from the increased accumulation of dialyzable platelet toxins following hemodialysis. We recommend, therefore, that in cooperation with the renal physician and hematologist, the dentist or oral surgeon perform invasive dental and oral surgical procedures 2 to 4 hours following hemodialysis, to allow for elimination of any potential residual influence of heparin. As the SBT is acknowledged to be the most valuable test for demonstrating platelet dysfunction,*’ it should be performed routinely prior to treatment. If it is prolonged following hemodialysis, DDAVP may be beneficial in reducing it to normal levels prior to surgery. If the SBT is not reduced-or if postoperative bleeding occurs, as seen following the third extraction session reported here-then further hemodialysis should be instituted. We wish to acknowledge the cooperation and excellent technical assistance of Mrs. Mary Sartor, Department of Hematology, Institute of Clinical Pathology and Medical Research, Westmead Hospital.

REFERENCES 1. Sowell SB: Dental care for patients with renal failure and renal transplants. J Am Dent Assoc 104: 171-177, 1982. 2. Stewart JH: Platelet numbers and life span in acute and chronic renal failure. Thromb Diath Haemorrh 17: 532-542. 1967. 3. Vicks SL, Gross ML, Schmitt GW: Massive hemorrhage due to hemodialysis-associated thrombocytopenia. Am J Nephrol 3: 30-33, 1983. 4. Castaldi PA, Rozenberg MC, Stewart JH: The bleeding disorder of uremia-a qualitative platelet disorder. Lancet 2: 66-69, 1966. 5. Deykin D: Uremic bleeding. Kidney Int 24: 698-705, 1983. JH, Castaldi PA: Uraemic bleeding: A reversible 6. Stewart platelet defect corrected by dialysis. Q J Med 30: 409-423, 1967. 1. Watson AJS, Keogh JAB: Effect of I-deamino-8-D-arginine vasopressin on the prolonged bleeding time in chronic renal failure. Nephron 32: 49-52, 1982. 8. Mannucci PM, Remuzzi G, Pusineri F, Lombardi R, Valsecchi C, Mecca G, Zimmerman TS: Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 308: 8-12, 1983. MK, Simon JHS, Gorman JT: Radio9. Kelly WH, Mirahmadi graphic changes of the jawbones in end-stage renal disease. ORAL SURG ORAL MED ORAL PATHOL 50: 372-38 I, 1980. GJ: Dental considerations 10. Precious DS, Laba JP, Hinrichsen for patients on chronic dialysis and renal transplant recipients. Can Dent Assoc J 9: 595-599, 1981. 11. Farrell PC, Ward RA, Schindhelm K, Gotch FA: PreciZe anticoagulation for routine hemodialysis. J Lab Clin Med 92: 164-176, 1978. 12. Kazatchkine M, Sultan Y, Caen JP, Bariety J: Bleeding in renal failure: a possible cause. Br Med J 2: 612-615, 1976. 13. Horowitz HI: Uremic toxins and platelet function. Arch Intern Med 126: 823-826, 1970. 14. Mammen EF: Congenital coagulation disorders. Semin Thromb Hemost 9: 22-27, 1983. E, Gruninger U, Furlan M, Beck EA. Hodler J, 15. Wegmuller

Volume Number

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17.

18. 19.

Control of bleeding in severely uremic oral surgery

61 6

Reubi FC: Factor VIII activity in chronic renal disease. Nephron 28: 157-162, 1981. Mannucci PM, Ruggeri ZM, Pareti Fl, Capitanio A: Ideamino-8-D-arginine vasopressin: a new pharmacological approach to the management of haemophilia and van Willebrand’s disease. Lancet 1: 869-872, 1977. Menon C, Berry EW, Ockelford P: Beneficial effect of D.D.A.V.P. on bleeding time in von Willebrand’s disease. Lancet 2: 743-744, 1978. Vincente V, Alberta I, Macias JF, Lopez Borrasca A: DDAVP in uremia. Nephron 36: 145-146, 1984. Livio M. Gotti E, Marchesi D, Mecca G, Remuzzi G, De Gaetano G: Uraemic bleeding: role of anaemia and beneficial

BOUND

VOLUMES

AVAILABLE

effect of 20. Remuzzi Gaetano failure. 21. Steiner uremia: Hematol

patients

549

red cell transfusions. Lancet 2: 1013-1015, 1982. G, Cavenaghi AE, Mecca G, Donati MB, De G: Prostacyclin-like activity and bleeding in renal Lancet 2: 1195-I 197, 1977. RW, Coggins C, Carvalho ACA: Bleeding time in a useful test to assess clinical bleeding. Am J 7: 107-I 17, 1979.

Reprint requests to: Dr. D.J. Buckley Westmead Hospital Dental Clinical School Westmead, New South Wales, 2145, Australia

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