Patients undergoing cardiac surgery with and

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1 REVIEW ARTICLES 102 Raja et al. Desmopressin and Cardiac Surgery Annals of Cardiac Anaesthesia 2006; 9: Desmopressin for Haemostasis in Cardiac Surgery: When to Use? Shahzad G Raja, MRCS, Yaseer Shahbaz, MD Royal Hospital for Sick Children, Glasgow, United Kingdom and Department of Pathology, Lahore Medical College, Lahore, Pakistan Bleeding after cardiac surgery increases morbidity and exposes patients to the risks associated with blood transfusion. Desmopressin acetate, a synthetic vasopressin analogue, has been used in patients undergoing cardiac operations to reduce postoperative blood loss and transfusion requirements, although a benefit has not been demonstrated in large randomized controlled trials. Therefore, the routine use of desmopressin in uncomplicated cardiac operations is not recommended. This review article discusses the pharmacology of desmopressin as a haemostatic agent and evaluates available clinical evidence to determine current indications for desmopressin as a haemostatic agent in cardiac surgery. (Annals of Cardiac Anaesthesia 2006; 9: ) Key words: Desmopressin, Cardiac surgery, DDAVPartery bypass Postoperative complications, Pulmonary, Randomized controlled trials Patients undergoing cardiac surgery with and potentially without cardiopulmonary bypass (CPB) are at risk for excessive microvascular bleeding. 1 This bleeding often leads to transfusion of allogeneic blood and blood components as well as surgical re-exploration. Excessive bleeding after cardiac surgery occurs because of alterations in the haemostatic system pertaining to dilutional thrombocytopenia, excessive haemostatic activation, and exposure to long-acting antiplatelet or antithrombotic agents. 1 Pharmacological interventions may attenuate the alterations in haemostatic system during CPB in an attempt to reduce excessive bleeding, transfusion, and reexploration. 1 Desmopressin (DDAVP, 1-deamino-8-D-arginine vasopressin), a synthetic vasopressin derivative, has been used in patients with bleeding after cardiac surgery to reduce postoperative blood loss and transfusion requirements. Continuing experience unfortunately failed to show any effects to reduce the need for transfusions in the cardiac surgical patient. 3 This review focuses on the pharmacology of DDAVP as a haemostatic agent Address for Correspondence: Dr. Shahzad G. Raja, Department of Cardiac Surgery, Royal Hospital for Sick Children, Yorkhill NHS Trust, Dalnair Street, Glasgow, G3 8SJ United Kingdom, Tel: , Fax: drrajashahzad@hotmail.com and current indications for use in cardiac surgery. Pharmacology of DDAVP DDAVP structurally differs from the natural hormone by deamination of homocystein at position 1 on the molecule, and substitution of D- arginine for L-arginine at position 8. 4 This gives desmopressin both greater potency and a more prolonged duration of antidiuretic effect and markedly decreased pressor activity compared to vasopressin. 4 DDAVP was used for the first time in 1977 to treat patients with haemophilia A and von Willebrand disease (vwd), the most frequent congenital bleeding disorders, 5 following the observation that DDAVP increased circulating factor VIII and von Willebrand factor (vwf) in healthy individuals. 6,7 Haemostatic Effects and Mechanism of Action DDAVP increases plasma concentrations of factor VIII, vwf and tissue plasminogen activator. The increases are virtually immediate and are probably caused by release from endogenous reservoirs rather than increased synthesis. The proposed site of release of factor VIII is from the sinusoid liver endothelial cells and vwf from vascular endothelial cells

2 Annals of Cardiac Anaesthesia 2006; 9: Raja et al. Desmopressin and Cardiac Surgery 103 The increases in plasma levels of factor VIII and vwf occur not only in deficient patients, but also in healthy individuals and in patients who already have high levels of these factors. DDAVP shortens the prolonged activated partial thromboplastin time and bleeding time. 5,8 These effects probably result from the increases in factor VIII and vwf, which play a rate-accelerating role in these global tests of intrinsic coagulation and primary haemostasis. DDAVP has no effect on platelet count or aggregation, but enhances platelet adhesion to the vessel wall. 5,9 Release into plasma of large amounts of tissue plasminogen activator is another short-lived effect of DDAVP. 5-7 This released plasminogen activator generates plasmin in vivo, but most of the plasmin is quickly complexed to α 2 -antiplasmin and does not produce fibrinogenolysis in circulating blood. 5 Despite nearly 30 years of clinical use of DDAVP, mechanisms of action are still not completely understood. Two general classes of vasopressin receptors have been characterized; V 1 receptors which mediate smooth muscle contraction in the peripheral vasculature and glucose turnover in hepatocytes, and V 2 receptors which regulate water reabsorption in the collecting ducts of the kidney. 4 DDAVP is a strong V 2 receptor agonist, but has no effect on V 1 receptors. DDAVP s haemostatic effect seems to be mediated by its strong V 2 -receptor agonist activity, as patients with nephrogenic diabetes insipidus, who lack this receptor, manifest no increase in haemostatic variables in response to DDAVP. 4 The effect is not mediated via V 2 receptors in the kidneys, as anephric patients respond normally to DDAVP. 4,7 In contrast, patients with other rare forms of nephrogenic diabetes insipidus seem to manifest a normal clotting factor response to DDAVP. 4,5 It is postulated that activation of endothelial V 2 receptors results in camp-mediated exocytosis of vwf and tissue plasminogen activator from Weibel Palade bodies, where both are stored. The mechanism of action of DDAVP on factor VIII plasma levels remains to be elucidated. 10 Recently, aquaporin-1 water channels and caveolin proteins have been shown to contribute to modulate the haemostatic mechanisms of DDAVP. 11 However, the role of these additional cellular effects needs further confirmation. Pharmacokinetics DDAVP can be administered parenterally, by intravenous or subcutaneous injection, or intranasally in drop or spray form. Intravenous injection is the most common route in cases with haemostatic indications. In healthy volunteers, the maximal effect of DDAVP on factor VIII-C and vwf, with peak levels after about min, is achieved with an intravenous dosage of 0.3 µg/ Kg. 4 The response is not increased when the DDAVP dosage is increased to 0.4 µg/kg, even though the plasma concentration of DDAVP is dose-dependent. 4 The maximal biological response to DDAVP may be due to saturation at receptor sites. 4,12 The effect of subcutaneous administration of DDAVP on factor VIII/vWF is comparable to that of intravenous administration, except that the plasma concentrations of factor VIII-C do not peak until after about 2 hours. 4 The terminal half-life of DDAVP in plasma is about 4-5 hours, irrespective of the mode of administration. As the effect is of the hit-and-run type, the DDAVP disappearance curve is probably of minor importance for the haemostatic effects. It is, however, more important for the duration of antidiuretic effect, which is considered as a sideeffect when the drug is used for haemostatic indications. 4 The half-life of factor VIII in plasma after DDAVP administration has been calculated in several earlier studies. Most studies have found half-lives of about 4-5 hours in healthy volunteers after intravenous administration, which is significantly shorter than the half-life of factor VIII after injection of factor VIII concentrates. The reason for the short half-life after DDAVP is not known. It is probably not caused by increased proteolytic degradation, as DDAVP does not affect the half-life of factor VIII in plasma in patients given both factor VIII concentrate and DDAVP. 4,13 The short half-life may reflect redistribution of factor VIII from plasma to other compartments, possibly back to storage sites

3 104 Raja et al. Desmopressin and Cardiac Surgery Annals of Cardiac Anaesthesia 2006; 9: Adverse Effects, Cautions and Contraindications Adverse effects of DDAVP include mild facial flushing, headache, palpitations and hypotension. 14 Other adverse effects are the result of the potent antidiuretic effect of this agent, and include water retention and hyponatraemia. 14,15 In patients given more than one dose, plasma sodium and body weight should be measured daily and excessive administration of fluids avoided. 16 Several case reports on acute myocardial infarction after DDAVP infusion have been published 14,17 with a 2.4-fold increase in the risk of myocardial infarction reported by Cattaneo and Mannucci. 18 Cattaneo and Mannucci 18 pooled data from double-blind placebo-controlled trials that evaluated the haemostatic efficacy of DDAVP in cardiac, vascular, and orthopaedic surgery. Total thrombotic events (i.e., myocardial infarction, stroke, arterial thrombosis, venous thromboembolism) were reported in 3.4 percent of the DDAVP-treated patients and 2.7 percent of the placebo-treated patients (p = 0.38). The authors pooled data from 17 randomized controlled trials in cardiac (n = 15) and vascular (n = 2) surgery that specifically mentioned the presence or absence of thrombotic events. The incidence of myocardial infarction was 3.9 percent (28 of 716 patients) in the DDAVP-treated group and 3.1 percent (20 of 646 patients) in the placebo group for an odds ratio (OR) of 1.25 (95% CI, ; p = 0.43). A recent meta-analysis of 12 randomized controlled trials with DDAVP in cardiac surgery reported an incidence of myocardial infarction of 4.4 percent in the DDAVP-treated group versus 1.6 percent in the placebo-treated group (OR, 2.07; 95% CI, ; p= 0.19). 19,20 DDAVP should, therefore, be used with caution in patients with coronary artery disease. It is considered to be contraindicated in patients with unstable coronary artery disease. 15 DDAVP is also contraindicated in patients with polydipsia, and should be used with caution in cases of severe congestive heart disease because of its antidiuretic effect. 4 In vwd type 2B it is recommended that DDAVP should not be used because it causes platelet aggregation and thrombocytopenia. This has, however, been a matter of debate. 4 Routine Use of DDAVP in Cardiac Surgery: Current Best Available Evidence A search of MEDLINE, EMBASE, Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Science Citation Index, Current Contents, NHS Economic Evaluation Database, and International Network of Agencies for Health Technology Assessment databases from the date of their inception to the end of August 2005 using search terms meta-analysis, desmopressin and bleeding retrieved 4 meta-analyses and one Cochrane Systematic Review 25 which provide no convincing evidence for the routine use of DDAVP as a haemostatic agent in cardiac surgery (Table 1). Current Indications for DDAVP as a Haemostatic Agent in Cardiac Surgery With the latest boom in percutaneous intervention techniques, cardiologists prefer antiplatelet and anticoagulant drugs before percutaneous coronary intervention. These drugs including aspirin, ticlopidine, clopidogrel, and glycoprotein (GP) IIb/IIIa inhibitors have been shown to decrease the incidence of coronary occlusive events. However, at the same time a significant number of these patients may be sent directly for coronary artery surgery from the catheterization. As these patients have been on anticoagulation medication, there is a potential risk of increased postoperative bleeding and need for re-exploration and transfusion of blood products. 26 DDAVP can be beneficial in this group of patients Reiter et al 28 have shown that DDAVP accelerates normalization of the in-vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Part 1 of their study was an open, prospective trial in 10 healthy volunteers (group 1), who received DDAVP. Dose-response curves were established for the in-vitro platelet inhibition by eptifibatide, tirofiban, or abciximab together with a fixed concentration of aspirin before and after the increase in vwf activity induced by DDAVP. Part 2 was a randomized, placebocontrolled crossover study in 10 other healthy volunteers (group 2), who had not been part of group 1, receiving DDAVP and placebo. 104

4 Annals of Cardiac Anaesthesia 2006; 9: Raja et al. Desmopressin and Cardiac Surgery 105 Table 1. Meta-analyses of desmopressin usage in cardiac surgery Reference Design No. of Trials Primary End Point(s) Key Outcomes Fremes et al. Meta-analysis of 13 Postop chest tube loss DDAVP vs. placebo: 85.8 ml, placebo-controlled, (ml, mean ± SD) p = double-blind, randomized studies Cattaneo et al. Meta-analysis of 17 Postop chest tube loss DDAVP vs. placebo: OR = placebo-controlled, (OR, 95% CI) 0.91, 95% CI = 0.87 to 0.97 double-blind, Transfusion requirements DDAVP vs. placebo: p = NS randomized studies (p <0.05) Laupacis et al. Meta-analysis of 12 Patients receiving at least DDAVP vs. placebo: OR = placebo-controlled, 1RBC transfusion 0.98, 95% CI = 0.64 to 1.50 double-blind, (OR, 95% CI) randomized studies Levi et al. Meta-analysis of 16 Blood loss (WMD) DDAVP vs. placebo: WMD = placebo-controlled, ml, p= NS double-blind, Transfusion requirements DDAVP vs. placebo: OR = randomized studies (proportion of patients 0.79, 95% CI = 0.56 to 1.11 transfused OR, 95% CI) Reexploration rate DDAVP vs. placebo: OR = (OR, 95% CI) 0.67; 95% CI = 0.33 to 1.37 MI and mortality (p <0.05) DDAVP vs. placebo: p = NS Carless et al. Systematic review of 18* Perioperative allogeneic DDAVP vs. placebo: RR = placebo-controlled, RBC transfusion risk 0.95; 95%CI = 0.86 to 1.06 double-blind, (RR, 95% CI) randomized studies Blood loss (WMD) DDAVP vs. placebo: WMD = ml; 95% CI = to 30.2ml per patient Volume of RBC transfused (WMD) DDAVP vs. placebo: WMD = units; 95%CI = to 0.01 units Re-operation due to bleeding DDAVP vs. placebo: RR = (RR, 95% CI) 0.69 (95%CI = 0.26 to 1.83) Mortality (RR, 95% CI) DDAVP vs. placebo: RR = 1.72: 95%CI = 0.68 to 4.33 Non-fatal MI (RR, 95% CI) DDAVP vs. placebo: RR = 1.38: 95%CI = 0.77 to 2.50 * 15 cardiac surgery trials included. DDAVP = desmopressin; OR = odds ratio; CI = confidence interval; WMD = weighted mean difference; RR = relative risk; MI = myocardial infarction; NS = not significant; RBC = red blood cell; SD = standard deviation In group 1, all GPIIb/IIIa inhibitors prolonged collagen-epinephrine (CEPI) and collagenadenosine diphosphate (CADP) closure times (CTs), measured with the platelet function analyzer 100 (PFA-100). DDAVP caused a shift in the concentration response curves to the right for all 3 GPIIb/IIIa inhibitors. In group 2, DDAVP accelerated the normalization of CADP-CT and CEPI-CT after the discontinuation of eptifibatide infusion with a maximum effect at 1.5 to 2 hours. In contrast, CEPI-CT remained above normal in the placebo group for more than 4 hours. The same group of authors in a crossover study have tested the additive effects of platelet concentrates after DDAVP infusion in antagonizing the anti-platelet effects of GPIIb/IIIa inhibitors and aspirin. 27 After eptifibatide and aspirin infusion (at standard dosages), 10 healthy volunteers received DDAVP or placebo. Thereafter, increasing amounts of platelets from fresh single-donor apheresis concentrates were added in-vitro to blood samples of all volunteers to increase platelet counts by 30 x 10 9, 60 x 10 9, or 120 x 10 9 per litre. Adding platelets in-vitro further improved platelet function after DDAVP: it shortened collagen-adenosine diphosphate closure times (p < 0.01), to normal ranges. In contrast, normal platelet function could not be restored even when platelet counts were increased by 50 percent (120 x 10 9 /litre) in the placebo group. The authors concluded that combined use of platelets from fresh apheresis platelet concentrates and DDAVP additively enhances recovery of normal platelet function after eptifibatide infusion. Such a strategy may help to avoid excessive transfusion of platelet concentrates. 105

5 106 Raja et al. Desmopressin and Cardiac Surgery Annals of Cardiac Anaesthesia 2006; 9: Interestingly, contrary to the studies of Reiter et al, 27,28 in a recently published prospective, randomized, double-blinded, placebo-controlled, parallel group trial, Pleym et al 32 have shown that DDAVP does not reduce postoperative bleeding in coronary artery bypass grafting patients treated with aspirin until the day before surgery. In this study, 100 patients were included and divided into two groups. One group received DDAVP 0.3 µg/ Kg and the other received placebo (0.9% NaCl) after the neutralization of heparin with protamine sulfate. Postoperative blood loss was recorded for 16 hours. The mean ± SD bleeding was 606 ± 237 ml in the DDAVP group and 601 ± 301 ml in the placebo group (p=0.93), representing no significant difference (95% confidence interval, 107 to 117 ml). However, in this study tranexamic acid and transfusions of fresh frozen plasma and platelets were given as treatment for increased postoperative bleeding in addition to DDAVP and placebo at the discretion of the attending physician. This treatment may have reduced the postoperative bleeding and because more patients in the placebo group received such treatment, the difference in postoperative bleeding between the two groups could have been reduced. Lastly, DDAVP has been shown to improve acquired platelet dysfunction such as found in uraemia and liver cirrhosis and hence may be beneficial in patients with these disorders undergoing cardiac surgery. 5 Conclusion Although there is no evidence for routine use of DDAVP after cardiac surgery, DDAVP may be considered whenever bleeding is suspected to stem from GPIIb/IIIa inhibitors and other antiplatelet agents. A proposed algorithm to deal with bleeding due to GPIIb/IIIa inhibitors and other antiplatelet agents, based on the limited evidence available mainly from in-vitro studies, will be to: (1) stop the GPIIb/IIIa infusion and/or withdraw the offending drug; (2) obtain a platelet count and activated partial thromboplastin time; (3) if possible, measure the degree of platelet inhibition with a rapid bedside test; (4) administer a DDAVP infusion; and/or (5) transfuse platelet concentrates in case of major or life-threatening bleeding or urgent need for normalization of platelet function in case of surgery. However, it is extremely important that large clinical studies preferably randomized controlled trials are conducted in this specific patient population to evaluate the impact of DDAVP on transfusion rates so that its efficacy can be validated beyond doubt. References 1. Levy JH, Tanaka KA, Steiner ME. Evaluation and management of bleeding during cardiac surgery. Curr Hematol Rep 2005; 4: Salzman EW, Weinstein MJ, Weintraub RM, et al. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. A double-blind randomized trial. N Engl J Med 1986; 314: Kovesi T, Royston D. Pharmacological approaches to reducing allogeneic blood exposure. Vox Sang 2003; 84: Lethagen S. Desmopressin-a haemostatic drug: state-ofthe-art review. Eur J Anaesthesiol Suppl 1997; 14: Mannucci PM. Desmopressin (DDAVP) in the treatment of bleeding disorders: the first 20 years. Blood 1997; 90: Cash JD, Gader AM, da Costa J. Proceedings: The release of plasminogen activator and factor VIII to lysine vasopressin, arginine vasopressin, I-desamino-8-darginine vasopressin, angiotensin and oxytocin in man. Br J Haematol 1974; 27: Mannucci PM, Aberg M, Nilsson IM, Robertson B. Mechanism of plasminogen activator and factor VIII increase after vasoactive drugs. Br J Haematol 1975; 30: Mannucci PM, Pareti FI, Holmberg L, Nilsson IM, Ruggeri ZM. Studies on the prolonged bleeding time in von Willebrand s disease. J Lab Clin Med 1976; 88: Sakariassen KS, Cattaneo M, vd Berg A, Ruggeri ZM, Mannucci PM, Sixma JJ. DDAVP enhances platelet adherence and platelet aggregate growth on human artery subendothelium. Blood 1984; 64: Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost 2003; 1: Tyagi MG, Namboodri KV. Evaluation of vasopressin mediated effects on hemostatic mechanisms: relationship with aquaporins and caveolin proteins. Indian J Exp Biol 2005; 43: Lethagen S, Harris AS, Sjorin E, Nilsson IM. Intranasal and intravenous administration of desmopressin: effect on F VIII/vWF, pharmacokinetics and reproducibility. Thromb Haemost 1987; 58:

6 Annals of Cardiac Anaesthesia 2006; 9: Raja et al. Desmopressin and Cardiac Surgery McLellan DS, Knight S, McLellan HG, Wassef M, Aronstam A. The influence of DDAVP on the survival of factor VIII in severe haemophiliacs. Thromb Res 1985; 40: Porte RJ, Leebeek FW. Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs 2002; 62: Shepherd LL, Hutchinson RJ, Worden EK, Koopmann CF, Coran A. Hyponatremia and seizures after intravenous administration of desmopressin acetate for surgical hemostasis. J Pediatr 1989; 114: Mannucci PM. Hemostatic drugs. N Engl J Med 1998; 339: Lowe GD. Desmopressin and myocardial infarction. Lancet 1989; 1: Cattaneo M, Mannucci PM. Desmopressin and blood loss after cardiac surgery. Lancet 1993; 342: Levy JH. Novel intravenous antithrombins. Am Heart J 2001; 141: Levy JH. Hemostatic agents. Transfusion 2004; 44 (12 Suppl): 58S-62S 21. Fremes SE, Wong BI, Lee E, et al. Meta analysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg 1994; 58: Cattaneo M, Harris AS, Stromberg U, Mannucci PM. The effect of desmopressin on reducing blood loss in cardiac surgery-a meta-analysis of double-blind, placebocontrolled trials. Thromb Haemost 1995; 74: Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Anesth Analg 1997; 85: Levi M, Cromheecke ME, de Jonge E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999; 354: Carless PA, Henry DA, Moxey AJ, et al. Desmopressin for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2004; (1): CD Raja SG. Clopidogrel before coronary artery surgery: bleeding or no bleeding? Eur J Cardiothorac Surg 2004; 26: Reiter R, Jilma-Stohlawetz P, Horvath M, Jilma B. Additive effects between platelet concentrates and desmopressin in antagonizing the platelet glycoprotein IIb/IIIa inhibitor eptifibatide. Transfusion 2005; 45: Reiter RA, Mayr F, Blazicek H, et al. Desmopressin antagonizes the in vitro platelet dysfunction induced by GPIIb/IIIa inhibitors and aspirin. Blood 2003; 102: Gratz I, Koehler J, Olsen D, et al. The effect of desmopressin acetate on postoperative hemorrhage in patients receiving aspirin therapy before coronary artery bypass operations. J Thorac Cardiovasc Surg 1992; 104: Sheridan DP, Card RT, Pinilla JC, et al. Use of desmopressin acetate to reduce blood transfusion requirements during cardiac surgery in patients with acetylsalicylic-acid-induced platelet dysfunction. Can J Surg 1994; 37: Dilthey G, Dietrich W, Spannagl M, Richter JA. Influence of desmopressin acetate on homologous blood requirements in cardiac surgical patients pretreated with aspirin. J Cardiothorac Vasc Anesth 1993; 7: Pleym H, Stenseth R, Wahba A, et al. Prophylactic treatment with desmopressin does not reduce postoperative bleeding after coronary surgery in patients treated with aspirin before surgery. Anesth Analg 2004; 98: