Con: Desmopressin is not of value in the treatment of post-cardiopulmonary bypass bleeding

Con: Desmopressin Is Not of Value in the Treatment Post-Cardiopulmonary Bypass Bleeding Thomas

Hackmann,

MD, FRCPC, and Sheldon

T

RADITIONALLY, cardiac surgery has been an area of high blood product use. In recent years, fear of transmission of infectious diseases has stimulated efforts to reduce the need for homologous blood products.’ Research has focused on several ways of minimizing blood loss and eliminating the need for blood transfusion including improved surgical technique, salvaging of blood intraoperatively and postoperatively, using techniques of autologous blood donations, and pharmacological interventions to improve hemostasis.2 Desmopressin (DDAVP) has recently been promoted as a useful therapeutic agent in reducing blood loss associated with cardiac surgery and the need for transfusion.‘.g DDAVP, a synthetic vasopressin analog, has long been known not only to possess antidiuretic activity but also to improve hemostasis in mild to moderate cases of hemophilia and von Willebrand’s disease. Its role as a useful hemostatic agent has been extended to include other congenital and acquired platelet defects and has been reviewed in detail elsewhere.’ Its mechanism of action has not been fully elucidated, but it was found to shorten bleeding time and increase levels of factor VIII coagulant activity and von Willebrand factor. The release of vWF was documented in several ways: an increase in vWF-related antigen and an increase in ristocetin cofactor activity, an index of the platelet reactivity of vWF. Using electrophoretic techniques, increases in the multimers of vWF were shown, especially the high molecular weight subunits thereof that are important in primary hemostasis by facilitating platelet aggregation. A number of factors may play a role in the increased bleeding tendency encountered after operations with extracorporeal circulation. Some of the explanations quoted in the older literature such as increased platelet destruction, inadequate heparin reversal, heparin rebound, dilution of coagulation factors, and increased fibrinolysis may be considered of lesser importance now because of improved perfusion technology, closer monitoring of coagulation during bypass, or because some of these theories were refuted.6.7 Much attention has been paid to the study of the acquired qualitative platelet dysfunction, which is observed during and after cardiopulmonary bypass (CPB), and a variety of alterations of platelet physiology, function, and morphology have been described.7~9 Hence, it seemed logical to investigate in cardiac surgery the use of DDAVP,

From the Depattment of Anaesthesia, University of Alberta Hospitals, Edmonton, Alberta, Canada, and the Division of Hematopathologv, Vancouver General Hospital, Vancouver, British Columbia, Canada. Address reprint requests to Thomas Hackmann, MD, FRCPC, Department of Anaesthesia, WMC 3 B.232, Universi@ of Alberta Hospitals, 8440-112 St, Edmonton, Alberta T6G 287, Canada. Copyright Q 1991 by W.B. Saunders Company 1053-0770/9110503-0019$03.00/0 290

of

C. Naiman, MD, FRCPC

which corrected abnormalities.

several

congenital

and acquired

platelet

DDAVP IN CARDIAC SURGERY

The purpose of this review is to present the knowledge to date on the use of DDAVP in cardiac surgery in chronological order. This information will serve to build an argument against its use in this area. Each of the studies that will be discussed can be examined under two aspects: (1) what were the changes with regards to coagulation studies and platelet function studies if these were performed?; and (2) was there a decrease in blood loss; if so, of what magnitude. and did this result in less transfusion of homologous blood products? Whereas answering the first question is of scientific merit and may increase understanding of the coagulation system, the second set of questions is obviously of greater therapeutic and economic relevance. Two groups reported first on the use of DDAVP for treatment of bleeding after surgery with CPB. Salzman et al” performed a randomized, double-blind study of 70 patients who underwent a variety of cardiac operations that included valve replacement, combined valve replacement and coronary artery bypass grafting (CABG), and repeat CABG. Primary CABG was excluded. DDAVP or placebo was given after protamine reversal of heparin. These investigators observed reductions of blood loss in the treatment group intraoperatively and in the first 24 hours postoperatively (total blood Ioss 1,317 * 487 mL treatment in 2,210 +- 1,415 mL placebo), which resulted in concomitant decreases in red-cell transfusions. Another interesting observation was that patients who had lower preoperative factor VIII/vWF levels tended to have higher blood loss. This article raised a number of questions, the most important being whether these results could be generalized to all patients who underwent operations with CPB and whether this would reduce overall transfusion requirements in those patients.“’ It was also speculated whether patients who had a potential for greater postoperative blood loss could be identified preoperatively by measuring vWF. The issue was raised that intraoperative blood loss after the study drug had been given appeared unexpectedly high.” Czer et al,’ who were among the first to report beneficial effects of DDAVP in cardiac surgical patients, followed a different approach. They established a set of criteria defining excessive hemorrhage in the postoperative period (abnormal bleeding time, chest tube output > 100 mL/h). In the first year of the study 16 consecutive patients met these criteria and formed the control group. They received blood products according to a standardized protocol and underwent reexploration for hemorrhage if these measures failed. The treatment group consisted of 23 consecutive patients who fulfilled the definition of excessive hemorrhage in the second year of the study and were given DDAVP. No blood products were given for 1 hour after the desmopressin infusion and then patients were treated the same as the previous control patients. The patients who had

Journalof Cardiothoracicand VascularAnesthesia,

Vol

5, No 3

(June), 1991: pp 290.293

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CON: DDAVP AND BLEEDING

Table 1. Overview of Studies on DDAVP in Cardiac Surgeryt Investigation

Study Design Randomized, double-

Salzman et al3

PatientSelection

70

Valve replacement, valve

J lntraoperative and

+ CABG, repeat opera-

1 postoperative

blind, placebo-controlled

Transfusion & Red cells

tions

Case-control

Czer et al’

Blood Loss

No. of Patients

39

t Postoperative bleed-

1 Postoperative

& Red cells 4 Platelets

ing, CABG, valve replacement, valve + CABG, repeat operations Randomized, double-

Rocha et al’*

100

Valve replacement or

J Intraoperative, no dif-

repair, ASD closure

ference postoperative

blind, placebo-con-

No difference

trolled Hackmann at all3

Randomized, double-

150

CABG, valve replace-

blind, placebo-con. trolled Brown et all6

No difference

No difference

ment, valve + CABG, repeat operations

Randomized, double-

20

CABG

No difference

No difference

62

CABG, repeat CABG

No difference

No difference

19

CABG

No difference

No difference

60

Infants and children

No statistical difference

Not reported

blind, placebo-controlled Hedderich et al”

Randomized, doubleblind, placebo-controlled

Anderson et al’*

Randomized, doubleblind, placebo-controlled

Seear et aI*?

Randomized, doubleblind, placebo-con-

(see text)

trolled NOTE. Not included are studies reported in abstract form or as letters to the editor (see references 19-21,23,24). Abbreviations:

1, decreased;

t, increased; CABG, coronary artery bypass grafting; valve + CABG, combined valve replacement and coronary

artery bypass grafting, ASD, atrial septal defect.

received DDAVP required significantly fewer blood products, especially platelets, than the control patients. The bleeding times shortened significantly after desmopressin, and factor VIII coagulant activity and vWF, which were measured only in the treatment patients, increased significantly from preoperative values. A significantly higher number of patients in the control group (75%) required reexploration for hemorrhage as compared with the treatment group (9%). However, 10 of the 14 patients who underwent reexploration were found to have an identifiable bleeding source. The authors concluded that DDAVP reduced transfusion requirements and blood loss in patients with severe bleeding after CPB. This study design is flawed because of possible observer and treatment bias. Therefore, no general conclusions can be made from this study of highly selected patients. Since these early optimistic reports of the benefits of DDAVP in reducing blood loss and transfusion in patients who underwent cardiac surgery with CPB, further studies were performed that expanded on the patient selection and surprisingly reported different results from the previous studies (Table 1). Rocha et al’* performed a randomized, double-blind, placebo-controlled trial of 100 patients undergoing valve replacement or repair. The patients who had received DDAVP bled less intraoperatively, but the total blood loss up to 72 hours postoperatively was not statistically different between treatment and placebo group (458 2 206 mL/m* DDAVP v 536 2 304 mL/m’ placebo). Similarly, replace-

ment with red cells was not significantly different between the two groups (1,642 + 705 mL DDAVP v 1,574 t 645 mL placebo). Coagulation studies performed 90 minutes after the infusion of the study drugs showed statistically significant higher levels of factor VIII and factor VIII:vWF and less prolongation of the bleeding time in the treatment group, but these differences disappeared 24 hours later. In another, similarly designed trial of 150 consecutive, unselected patients who underwent elective cardiac surgery, no differences between the DDAVP or the placebo group were observed with regard to blood loss after the infusion of study drug intraoperatively or up to 24 hours postoperatively.r3 This was mirrored by the fact that the intraoperative and postoperative replacement was similar in treatment and placebo groups with respect to the amounts transfused as well as how many patients required any of the products. Patients undergoing primary CABG comprised 69% of the study population. With respect to the coagulation system, Hackmann et al observed an increase in ristocetin cofactor and increases in multimers of vWF in both groups after infusion of DDAVP or placebo, which the authors interpreted as a stress response.13 It is important to note that these findings are consistent with a follow-up study of the original patients of Salzman et al in which further analyses ofvWF showed increases of high-molecularweight multimers of vWF regardless of DDAVP infusion.14 This can be interpreted in support of the theory that vWF levels increase with various forms of stress or, alternatively, one has to postulate a different, yet undefined, hemostatic

HACKMANN AND NAIMAN

mechanism of action of DDAVP for which there is some evidence in the literature.‘5 Three more studies that included only patients undergoing CABG with or without internal mammary grafts, failed to show hemostatic benefits of DDAVP.‘6”R These studies have several features in common other than patient selection: they were randomized, double-blinded studies in which DDAVP or placebo was administered after protamine had been given. Total blood loss tended to be smaller than in the control group of Salzman et al, and duration of extracorporeal circulation was shorter. All three concluded that the use of DDAVP in routine CABG was not warranted. Other reports that appeared in abstract form showed similar results in the same type of patients.“.” Because only relatively small sample sizes were reported (range, 19 to 70 patients), these studies lack sufficient statistical power to conclusively rule out a beneficial effect of DDAVP on blood loss or transfusion of blood products but cumulatively support the findings of Rocha et al” and Hackmann et al.” An important subgroup of patients requiring cardiac surgery are children with congenital lesions, whose response to DDAVP was reported by Seear et al.” Sixty infants and children were studied in the same fashion as reported by Salzman et al. No statistically significant differences were found between the placebo and DDAVP groups with respect to postoperative blood loss, postoperative bleeding time, or other coagulation studies. These results were confirmed by another group in 26 acyanotic children with congenital heart disease.‘” In the study by Seear et al, another surprising observation was made. Although not statistically significant, blood loss was approximately 30% higher in the children who had received DDAVP than in the placebo group. This raises the issue of whether treatment with DDAVP may not only be ineffective but in fact detrimental. This question prompted LoCicero and Massad to review their experience with DDAVP in 74 patients having elective CABG and to compare them with a group of age- and sex-matched controls.” Postoperative blood loss in the patients who had received DDAVP was strikingly higher than in the historic controls (1,306 I~I89 mL v 896 ? 33 mL, P < 0.0001) and transfusion requirements were also considerably higher. Although reservations apply to the validity of such a retrospective analysis, these results certainly support the conclusions of all of the follow-up studies to Salzman et al that the prophylactic use of DDAVP given at the termination of CPB after protamine does not reduce bleeding or transfusion requirements. SIDE EFFECTS OF DDAVP

Based on previous experience in other bleeding conditions, side effects of treatment with DDAVP are considered relatively minor. They include facial flushing, transient headache, increases in heart rate, and slight decreases in blood pressure. Tachyphylaxis occurs with repeated doses over a short time period.5 Side effects from the administration of DDAVP were not reported in the first studies on the

use of this drug in cardiac surgery. There was concern that a hypercoagulable state might be created after the use of DDAVP, which might lead to thrombosis and premature graft closure in CABG.’ Indeed, there have been several isolated case reports of myocardial infarction or cerebral thrombosis in patients who had received DDAVP? A recent studg’ found more perioperative myocardial infarctions, although not statistically significant, in a group of patients undergoing CABG who received two doses of DDAVP after termination of CPB as compared with patients who received only one dose or placebo. However, Mannucci and Lusher surveyed the literature on the use of DDAVP in cardiac surgery in 1989; using information provided by the drug manufacturer, they concluded that there was “no clear evidence indicating that desmopressin carries a high risk of thrombosis.“‘6 A case was reported of a child with tetralogy of Fallot who developed a “tet spell” after the infusion of DDAVP to correct postoperative bleeding.17 It was believed that the vasodilatation induced by DDAVP increased right-to-left shunting and was responsible for this episode of cyanosis and dyspnea. Similarly, Brown et al,” in their series of patients undergoing CABG, noted hypotension requiring treatment in 4 of 20 patients who had received DDAVP compared with none of the placebo patients. Severe hyponatremia with serious clinical sequelae was reported in 4 patients who had received multiple doses of DDAVP for treatment of coagulopathies. Thus, serious reactions to intravenous DDAVP do occur, albeit rarely. USE IN SELECTED PATIENTS

Anesthesiologists and cardiac surgeons may have had the occasional patient who bled severely after a procedure with CPB and in whom DDAVP almost miraculously stopped bleeding after everything else had failed. In fact, four cases were reported of patients who bled profusely under such circumstances, three of whom had received aspirin before their surgery.28 Such case reports are interesting observations and should stimulate interests in further research; unfortunately, they do not establish a cause and effect relationship. Moreover, a substantial number of patients who had received aspirin and/or dipyridamole preoperatively were included in three of the previously published clinical trials, and no differences between treatment and placebo groups were observed.‘2.‘6~‘7 Differences in patient selection and in the type of surgeries performed were seen as a likely explanation for the different results of the earlier two trials and subsequent studies. Thus, in patients who undergo uncomplicated surgeries such as valve replacement or repair, or primary CABG, major blood loss may not be expected and no beneficial effect of DDAVP may be observed. As noted previously, blood loss in several of these studies was indeed smaller and CPB times were shorter than in the first report by Salzman et al.” Yet when the number of patients in the Salzman et al series undergoing complex surgeries (16 repeat CABG, 12 combined valve replacement and CABG, 1 resection of ventricular aneurysm) are compared with the

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CON: DDAVP AND BLEEDING

Hackmann et al series (4 repeat CABG, 10 combined valve replacement and CABG, 3 resection of ventricular aneurysm, 7 repeat valve replacement), differences in patient selection appear less impressive.3s13A convincing explanation for these contradictory results is still lacking. SUMMARY

Following two early promising reports that treatment with intravenous DDAVP was helpful in reducing postoperative hemorrhage and the amount of transfusion with homologous blood products in patients who had undergone

cardiac surgery with CPB, these results were not repeated in any of the follow-up studies (Table 1). At the present time, the routine prophylactic use of DDAVP in cardiac surgery cannot be recommended for patients undergoing closure of atria1 septal defect, valve repair or replacement, primary CABG, or in children requiring cardiac surgery. The use of DDAVP in complicated procedures or for control of severe postoperative bleeding remains controversial. In the authors’ opinion, DDAVP should not be used in cardiac surgery except in patients with a presurgical DDAVP-responsive coagulopathy.

REFERENCES

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