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Ann Thorac Surg 2000;70:1923-1930
© 2000 The Society of Thoracic Surgeons

Original article: cardiovascular

Desmopressin does not reduce bleeding and transfusion requirements in congenital heart operations

William C. Oliver, Jr, MDa, Paula J. Santrach, MDb, Gordon K. Danielson, MDc, Gregory A. Nuttall, MDa, Darrell R. Schroeder, MSd, Mark H. Ereth, MDa

a Department of Anesthesiology, Division of Transfusion Medicine, Mayo Foundation, Rochester, Minnesota, USA
b Department of Laboratory Medicine and Pathology, Division of Cardiovascular Surgery, Mayo Foundation, Rochester, Minnesota, USA
c Department of Surgery, Mayo Foundation, Rochester, Minnesota, USA
d Department of Biostatistics, Mayo Foundation, Rochester, Minnesota, USA

Accepted for publication July 10, 2000.

Address reprint requests to Dr Oliver, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905
e-mail: oliver.william{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Desmopressin (DDAVP) has been evaluated in many randomized clinical trials as a means to reduce blood loss and transfusion of allogeneic blood in cardiac operation requiring cardiopulmonary bypass. Desmopressin reduces blood loss in adult patients with excessive bleeding after cardiac operation. Its usefulness in patients undergoing complex congenital heart repair with cardiopulmonary bypass is unproved.

Methods. Sixty patients younger than 40 years of age scheduled for complex congenital heart operation (44 redo, 16 primary) were enrolled in this prospective, randomized, double-blind trial. Desmopressin 0.3 µg/kg or placebo was administered 10 minutes after protamine administration. Transfusion requirements and postoperative blood loss were recorded. Differences were analyzed using analysis of variance with a p value of 0.05 or less used to denote statistical significance.

Results. There were no differences in demographic or surgical characteristics between the DDAVP or placebo groups. There was no difference in blood loss and transfusion requirements between the DDAVP and placebo groups. During the intraoperative postinfusion time period, the median blood loss for redo patients was 343 versus 357 mL/m2 for placebo versus DDAVP, respectively, and for primary patients, the median blood loss was 277 versus 228 mL/m2.

Conclusions. The prophylactic use of DDAVP to reduce excessive bleeding or transfusion requirements in patients undergoing complex congenital heart operations is not warranted.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Advances in congenital heart operation have led to an increasing number of adults as well as children undergoing operation for complex congenital heart disease. These patients, particularly infants and children, are at great risk for excessive bleeding and allogeneic blood transfusion [1–3], which has been shown to significantly increase the morbidity and mortality of cardiac operation [4, 5]. Among the congenital heart operation population, cyanotic heart disease, prolonged duration of cardiopulmonary bypass (CPB), profound hypothermia and circulatory arrest, complex surgical procedures, severe hemodilution, and prior sternotomy further increase the risk of excessive blood loss and transfusion [1, 4, 6–9].

Desmopressin (DDAVP) is a vasopressin analogue that increases circulating levels of coagulation factor VIII (FVIII) and von Willebrand factor (vWF) [10]. It improves hemostasis in patients with certain congenital or acquired disorders of platelet function [11]. Salzman and coworkers [12] reported significant reductions in blood loss and transfusion requirements following CPB with prophylactic DDAVP administration in cardiac surgical patients, yet subsequent investigations have yielded mixed results [13–15]. Recently, Cattaneo and coworkers [16] performed a meta-analysis of 17 randomized, double-blind, placebo-controlled clinical trials of DDAVP in cardiac operation. In these studies, if the patients’ 24-hour postoperative blood losses were within the upper third of the blood loss distribution (687 to 1,108 mL), there was a 34% reduction in postoperative blood loss if they received DDAVP compared with placebo. Desmopressin had no apparent benefit in the patients that had lesser degrees of blood loss.

Certain factors and clinical situations may influence the efficacy of blood conservation interventions. Identification of these factors may enable clinicians to optimize the perioperative blood conservation strategy, thus limiting transfusion and the expense to patients undergoing cardiac operation. This double-blinded, prospective, randomized trial was designed to determine if prophylactic DDAVP administered immediately after CPB reduced blood loss and transfusion requirements in young adults and children undergoing complex congenital heart operations.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Following Institutional Review Board approval and informed consent, 60 patients less than 40 years of age scheduled for complex congenital heart operation requiring CPB were recruited. Patients were excluded if the operation was anticipated to have minimal blood loss as in closure of an isolated atrial septal defect or if they had a preexisting bleeding disorder.

Anesthesia and surgical techniques
Anesthesia was induced in children less than 12 years of age by spontaneously inhaling 1% to 1.5% halothane and 50% nitrous oxide and oxygen until loss of consciousness when a peripheral intravenous catheter was placed. The halothane and nitrous oxide were replaced with 100% oxygen and 50 µg/kg fentanyl, 0.1 mg/kg midazolam, and 0.1 mg/kg pancuronium. All other patients received 50 µg/kg fentanyl, 0.1 mg/kg midazolam, and 0.1 mg/kg pancuronium, and 100% oxygen after insertion of a peripheral intravenous catheter. Anesthesia was maintained in all patients with isoflurane (0.25% to 0.5%) and 100% oxygen and supplemental fentanyl, midazolam, and pancuronium. All patients were cared for by one of two staff anesthesiologists.

Standard surgical and CPB techniques for adults and children were used. Antifibrinolytic agents were not administered to any patients during the study. Porcine heparin (Elkins-Sinn Inc, Cherry Hill, NJ) was administered at a dose of 300 U/kg for anticoagulation and the activated clotting time (Hemochron 400, International Technidyne, Edison, NJ) was maintained above 480 seconds with additional heparin as required. The extracorporeal circuit included a bubble oxygenator (Bentley C 12, Baxter Healthcare, Irvine, CA) and roller pump (Sarnes Inc, Ann Arbor, MI) with 40-micron arterial filter (Paul-Biomedical, Glencoe, NY). The priming volume for the CPB circuit included lactated Ringers solution, sodium bicarbonate, mannitol, and heparin. CPB was established at a flow of 2.4 L · min-1 · m-2. The lowest temperature achieved during CPB was between 18° and 32°C. Circulatory arrest was used in some patients. Following complete rewarming to a nasal temperature of 37°C and bladder temperature of 35°C, CPB was discontinued and protamine, 1.3 mg/100 U heparin (Elkins-Sinn Inc, Cherry Hill, NJ) was administered. All patients were under the surgical and perioperative care of one cardiothoracic surgeon (G.K.D.).

Ten minutes after protamine administration and a return of the activated clotting time to within 10% of the base line value, either placebo or DDAVP, 0.3 µg/kg, was given over 20 to 30 minutes. Only the pharmacist was aware of the solution’s identity. The solution was prepared in either 50 mL of normal saline or if the patient weighed less than 10 kg, in 10 mL of 0.2 normal saline. Electrolytes were monitored for 24 hours to detect severe hyponatremia, a rare complication of DDAVP due to water retention [17].

All blood and blood components were administered in accordance with the following guidelines. If the hemoglobin (Hgb) was estimated to be less than 6.5 g/dL upon initiation of CPB, packed red blood cells (PRBC) were included in the priming volume of the extracorporeal circuit. During hypothermia of 18° to 26°C, PRBC were given for a Hgb less than 6.5 g/dL. Packed red blood cells were given for a Hgb less than 7.5 g/dL during the period of rewarming. Platelets, fresh frozen plasma (FFP), and cryoprecipitate were administered at the discretion of the staff anesthesiologist and cardiothoracic surgeon based on evidence of microvascular bleeding in the surgical field. Postoperatively, all transfusions were directed by the staff cardiothoracic surgeon based on the mediastinal chest tube drainage (MCTD) and laboratory tests: Hgb, prothrombin time (PT), activated partial thromboplastin time (APTT), and platelet count.

Blood from the surgical field was collected throughout the intraoperative period for the purpose of autotransfusion. After the infusion of the study drug began, blood collected from the surgical field was kept separate from blood collected before infusion of the study drug for analysis. Blood was collected in a dedicated canister and subsequently processed by intraoperative autotransfusion with a cell salvage instrument (Medtronics AT-1000, Parker, CO). A standardized volume (225 mL/bowl) and hematocrit (HCT) (55%) were used to calculate intraoperative blood loss defined as RBC volume (mL)/body surface area (BSA) (m2). Any blood remaining in the venous reservoir of the extracorporeal circuit was either returned to the patient before removal of the cannulas or identified and processed by intraoperative autotransfusion. Cell-salvaged autologous blood was transfused based on the same criteria as for transfusion of PRBC. Postoperatively, blood loss was determined by obtaining a HCT on the MCTD collected over the initial 24 hours in the cardiac surgical intensive care unit (ICU) and expressed as RBC (mL)/BSA (mL/m2). The surgical field was characterized by the surgeon as either dry, moderate, or wet immediately before study drug infusion and 90 and 180 minutes after infusion of the study drug.

Characteristics recorded on each patient included: height, weight, gender, cardiac diagnoses, surgical procedures, medications, previous cardiac operation, duration of operation, aortic cross-clamp duration, CPB duration, lowest temperature during CPB, duration of circulatory arrest, time to extubation, intraoperative and 24-hour postoperative urine output, and time to discharge from ICU. All intraoperative fluids and blood products were recorded.

Blood pressure and heart rate were recorded during and after the infusion of the study drug. A decrease in the blood pressure of greater than 20% from the baseline blood pressure for 50 minutes or more was defined as "prolonged hypotension." Specific postoperative events such as surgical reexploration, cardiac tamponade, cardiac arrest, MCTD totaling more than 1 mL · kg-1 · h-1, seizures, death, stroke, or thrombosis were monitored and recorded.

Laboratory methods
Preoperative Hgb, HCT, platelet count, PT, and APTT were obtained by venipuncture within 72 hours before the operation. After induction of anesthesia and placement of an arterial catheter, a baseline thromboelastogram (TEG) was obtained. All subsequent blood samples were obtained from the indwelling arterial catheter after 10 mL of blood had been withdrawn. Following the termination of CPB and protamine administration but before and 90 minutes after the initiation of the study drug, blood was obtained for a Hgb, HCT, platelet count, PT, APTT, fibrinogen, TEG, FVIII level, and ristocetin cofactor activity of vWF (FVIII:RCo). Three hours after the study drug was administered, a Hgb, HCT, platelet count, PT, APTT, fibrinogen, and TEG were obtained. At 12 and 24 hours after the study drug was given, a Hgb, HCT, and platelet count were obtained. All laboratory tests were performed using standard referenced laboratory methods.

Statistical analysis
Sample size was calculated a priori based on a retrospective analysis of 69 patients who underwent repair of congenital heart defects and met all of the inclusion criteria for the current investigation. The patients’ intraoperative salvaged blood, expressed as a function of the BSA (mL/m2), was used to estimate blood loss and analyzed using a log transformation. For this investigation, a decrease in blood loss of approximately 200 mL (35% difference) was considered clinically relevant because this amount would produce a great enough decrease to potentially decrease the transfusion of allogeneic RBC. Using a two-sided test with {alpha} = 0.05, a total sample size of 60 patients (30 DDAVP and 30 control) would provide 90% power to detect a 35% (or 200 mL) decrease in blood loss in patients who would receive DDAVP.

Patients were randomized into one of two treatment groups (DDAVP or placebo) in blocks of six using a random number table with stratification on the basis of previous sternotomy (Redo) or not (Primary). The primary endpoint for this investigation was blood loss, which was expressed as RBC volume (mL)/BSA (m2) analyzed using a log transformation. Blood loss was summarized for the following time periods: intraoperative before infusion of study drug, intraoperative after infusion of study drug, and the initial 8 and 24 hours in the ICU.

The analysis was performed using a two-factor analysis of variance model. For this model, the dependent variable was log (blood loss) and the independent variables were treatment (DDAVP versus placebo) and strata (Primary versus Redo). The treatment by strata interaction term was included in the model to assess whether the effect of DDAVP was dependent on prior cardiac operation status. A p value of 0.05 or less was considered statistically significant.

Hematologic and TEG data were analyzed using a two-factor repeated measures analysis of variance approach. In all cases, the hematologic or TEG measure was the dependent variable; treatment group (DDAVP versus placebo) was the independent cross-stratification factor; and time was the repeated factor. Baseline patient and procedural characteristics were compared between treatment groups using the rank sum test for continuous variables and the {chi}-square test for categorical variables. The frequency of complications was compared between treatment groups using Fischer’s exact test. In all cases, two-sided tests were used with p values of 0.05 or less to denote statistical significance.

To assess the exposure to allogeneic blood products, an analysis of transfusion requirements was performed using analysis of variance in which the dependent variable was log (units + 1). In addition, a logistic regression analysis was performed with a dichotomous dependent variable indicating whether any of the given blood product was required (any versus none). In all cases the independent variables were treatment (DDAVP versus placebo) and strata (Primary versus Redo). The treatment by strata interaction term was included to assess whether the effect of DDAVP was dependent on prior cardiac operation status. To adjust for potential differences due to patient size, BSA was included as a covariate in all analyses. To assess whether the effect of DDAVP was dependent on cyanotic versus acyanotic congenital heart disease, post hoc analyses were performed that included independent variables for the presence of cyanosis and the treatment by cyanosis interaction.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
There were no significant demographic and surgical characteristic differences between the patients that received DDAVP or placebo (Table 1). The primary surgical procedures are listed in Table 2. Some patients underwent more than one major cardiac surgical procedure during their operation. Four patients were taking aspirin (3 DDAVP, 1 placebo) and 4 patients were taking coumadin (2 DDAVP, 2 placebo) before operation.


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  		Table 1. Demographic and Surgical Characteristics

 

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  		Table 2. Surgical Procedures

 
Blood loss (mL/m2) was analyzed for three periods (intraoperative postinfusion study drug and the first 8 and 24 hours in the ICU) as a function of previous sternotomy (Redo or Primary) and study drug (DDAVP or placebo) (Figure 1). Desmopressin did not significantly reduce blood loss during any of these intervals. For Redo patients, the median blood loss was 343 versus 357 mL/m2 for placebo versus DDAVP, respectively, during the intraoperative postinfusion time period; 18 versus 30 mL/m2 for the first 8 hours in the ICU; and 26 versus 43 mL/m2 for the first 24 hours in the ICU. For primary patients, the median blood loss was 277 versus 229 mL/m2, 13 versus 12 mL/m2, and 23 versus 24 mL/m2 for placebo versus DDAVP at the respective time periods. There was no evidence of any significant treatment by strata interaction to suggest the efficacy of DDAVP was related to previous cardiac operation. Blood loss in Redo patients was greater intraoperatively during the pre- and postinfusion study drug periods (p = 0.008 and p < 0.001, respectively) compared with Primary patients. Although not statistically significant (p = 0.051), Redo patients bled more than Primary patients during the first 8 hours in the ICU. Redo and Primary patients did not differ with respect to blood loss during the first 24 hours in the ICU. Because evidence suggesting that FVIII activity was lower in the DDAVP patients before the study drug infusion, the analysis was repeated with preinfusion factor VIII included as a covariate. In all cases, the findings remained unchanged. Desmopressin was not found to significantly reduce blood loss during any of the time intervals. The effectiveness of DDAVP in reducing blood loss was not affected by whether the patient had cyanotic or acyanotic congenital heart disease. There was no evidence that DDAVP improved the hemostatic condition of the surgical field at 90 and 180 minutes after infusion.



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  		Fig 1. Each dot represents a patient’s blood loss (mL/m2) intraoperatively after the study drug infusion, during the first 8 hours in the ICU, and during the first 24 hours in the ICU. The data are represented as median and interquartile ranges. The patients were divided into two groups, either previous sternotomy (Redo) or Primary. Desmopressin (DDAVP) did not significantly reduce blood loss during any of the time periods. Blood loss was greater intraoperatively during the postinfusion study drug period (p < 0.001) in Redo patients compared with Primary patients. (Intraop = intraoperative; ICU = intensive care unit.)

 
There were no differences in the percentage of patients requiring blood products or the total number of blood products administered to DDAVP and placebo patients (Figure 2). Desmopressin did not affect transfusion requirements in either Redo or Primary patients. However, there were differences in transfusion requirements between Redo and Primary patients. Redo patients received more RBCs (p = 0.04) during the preinfusion study drug interval than Primary patients. Redo patients also received more FFP (p = 0.002) and platelets (p = 0.002) than Primary patients during the intraoperative postinfusion study drug period. The presence of cyanosis did not affect the efficacy of DDAVP at reducing transfusion requirements.



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  		Fig 2. Each dot represents a single patient’s total postinfusion transfusion requirements (U) for the corresponding blood product. The data are represented as median and interquartile ranges. Patients were divided into two groups, either previous sternotomy (Redo) or Primary. There were no differences in the total number of blood products administered to patients receiving desmopressin (DDAVP) versus placebo. Redo patients received more fresh frozen plasma (p = 0.044) and platelets (p = 0.03) than Primary patients during the total postinfusion study drug period.

 
There was no difference between DDAVP and placebo patients concerning hematologic variables for the preinfusion study drug interval except with respect to FVIII activity (Table 3). After CPB before the study drug infusion, FVIII activity was significantly lower in the DDAVP patients compared with those receiving placebo (p = 0.029). Both FVIII and FVIII:RCo activity increased 90 minutes after infusion of either DDAVP or placebo. When analyzed using repeated measures of variance, all hematologic variables in Table 3 were found to change significantly across time (p < 0.003 in all cases). From the repeated measures analysis, no effect of DDAVP was detected for any hematologic variable with the exception of the MA + 30 where there was some evidence of a significant treatment by time interaction (p = 0.021) indicating that the effect of DDAVP is dependent on time. This interaction appears to be due to the differential changes in the TEG measurement MA + 30 from 90 minutes postinfusion to 180 minutes postinfusion. There was also some evidence (p = 0.018) that the TEG measurement R+K was lower at 180 minutes postinfusion study drug in patients receiving DDAVP versus placebo.


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  		Table 3. Comparison of Hematologic and Coagulation Data

 
The urine output was similar intraoperatively for DDAVP and placebo patients before study drug infusion (3.8 ± 2.9 and 3.9 ± 2.0 mL · kg-1 · h-1, respectively) and after study drug infusion (4.9 ± 6.0 and 5.9 ± 4.8 mL · kg-1 · h-1, respectively). The 24-hour urine output in the ICU for DDAVP and placebo patients was not significantly different (2.81 ± 1.16 and 2.77 ± 1.07 mL · kg-1 · h-1, respectively). The serum sodium of patients receiving DDAVP was slightly increased (141.2 ± 3.2 and 139.5 ± 2.5 mEq/L, respectively, p = 0.026) after the infusion but before leaving the operating room compared with those receiving placebo; however, there were no other significant differences in the electrolytes between the groups.

There was no difference in the frequency of prolonged hypotension, reexploration for bleeding, cardiac tamponade, cardiac arrest, and hospital death between patients who received DDAVP or placebo (Table 4).


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  		Table 4. Perioperative Complications

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Prophylactic DDAVP did not result in a reduction in intraoperative or ICU blood loss or transfusion requirements in either Primary or Redo pediatric or adult patients who underwent operation for congenital heart disease. There was significantly more blood loss intraoperatively after CPB in Redo patients than in Primary patients who received either DDAVP or placebo. Redo patients also bled more than Primary patients in the first 8 hours in the ICU, approaching statistical significance (p = 0.051) irrespective of whether they received DDAVP or placebo. Redo patients received significantly more FFP and platelet transfusions intraoperatively than Primary patients. The results suggest that patients were stratified correctly as to their risk of bleeding and transfusion, but DDAVP did not confer any hemostatic benefit to either Redo or Primary patients.

The benefit of DDAVP as a prophylactic blood conservation technique in cardiac operation appears limited. Initially, Salzman and coworkers [12] reported a 40% reduction in early postoperative blood loss in patients undergoing complex cardiac surgical procedures requiring CPB who received DDAVP compared with placebo. Subsequently, several randomized, double-blind trials of DDAVP in adults [13, 18] or children [19, 20] undergoing CPB did not demonstrate reduced blood loss or transfusion requirements. However, statistical significance may often be difficult to achieve in a smaller study population unless the drug’s hemostatic effect is very strong [16, 18]. A post hoc analysis restricted to Redo patients demonstrated that the current investigation provided statistical power of greater than 95% to detect a difference in intraoperative postinfusion blood loss of 200 mL between treatment groups. We believe that any difference of less than 200 mL would be of questionable clinical relevance because it would not be great enough to decrease transfusion of allogeneic RBC. It has also been noted that previous DDAVP studies concerning cardiac operation did not include patients with severe platelet dysfunction, excessive blood loss, and increased transfusion requirements, so clinical evidence of improved platelet function after DDAVP was less likely [21]. In support of that statement, DDAVP reduced transfusion requirements by 48% compared with placebo in patients who underwent coronary artery bypass grafting (CABG) who were taking aspirin preoperatively. Aspirin can induce significant platelet dysfunction in patients who require CPB [21, 22].

Recently, Cattaneo and coworkers [16] performed a meta-analysis of all double-blind, placebo-controlled, and randomized trials of DDAVP in cardiac operation from 1986 to 1993. With 17 trials involving 1,171 patients (579 DDAVP and 592 placebo patients), a statistically significant reduction in blood loss of 9% was found in DDAVP patients. More importantly, DDAVP reduced blood loss most effectively if a patient’s blood loss was in the upper third of the blood loss distribution (more than 1,100 mL/24 hours). These patients had a 34% reduction in blood loss with DDAVP compared with placebo, but the investigators were unable to make a statement about the corresponding transfusion requirements. They concluded that DDAVP is effective prophylactically in cardiac operation to reduce post-CPB bleeding but clinically relevant only in patients who bleed excessively. Cattaneo and coworkers [16] and Hackmann and coworkers [13] called for additional studies evaluating DDAVP in patients at risk for excessive bleeding after CPB. Patients undergoing congenital heart repair, with or without previous sternotomy, are considered to be at increased risk of excessive bleeding [3, 8]. These patients would be expected to more likely demonstrate a clinically significant hemostatic benefit with DDAVP in contrast to patients undergoing CABG for the first time [16], but our results do not support this expectation.

The few studies evaluating DDAVP to reduce bleeding and transfusion requirements in patients undergoing congenital heart repair included only children [19, 20] Reynolds and coworkers [20] observed no difference in 24-hour blood loss or transfusion requirements between DDAVP and placebo infants undergoing congenital heart repair with CPB. Although previous sternotomy was a characteristic in 33% and 46% of DDAVP and placebo patients, respectively, in their study, the use of fresh whole blood in the CPB priming volume may have weakened the classification of their patients as excessive bleeders compared with the children in our study. The lack of benefit of DDAVP in both Reynolds and coworkers [20] and the present study may be attributed to a reduced capacity of children and infants to release vWF and FVIII from storage sites. Reynolds and coworkers [20] were unable to demonstrate an increase in the FVIII and FVIII:RCo activity at any time following DDAVP administration, which corresponds to an extent with our results. Consequently, children and infants may be poor candidates for DDAVP regardless of the risk of excessive bleeding.

In addition to certain factors that may increase the likelihood of excessive bleeding after CPB [1, 4, 8], the TEG has been reported to predict excessive bleeding after CPB [23]. Mongan and coworkers [14] demonstrated a reduction in blood loss and transfusion requirements with DDAVP compared with placebo in connection with specific postbypass TEG values. This relationship was examined in the present study. Post hoc analysis of TEGs at four different time periods was performed to assess whether the effect of DDAVP was dependent on preinfusion study drug post-CPB TEG values. A separate analysis was performed for each TEG value with the dependent variable as blood loss and the independent variables treatment, strata, and preinfusion study drug TEG values. The higher preinfusion study drug TEG R value and lower preinfusion study drug TEG angle were associated with greater intraoperative blood loss, but there was no correlation between the effectiveness of DDAVP and any preinfusion study drug TEG value as in Mongan and coworkers [14]. The TEG was unable to identify patients undergoing congenital heart repair that might respond favorably to DDAVP. The TEG MA + 30 value was improved 90 minutes after CPB with DDAVP and worsened significantly with placebo. It may represent improved hemostasis due to DDAVP, but standard coagulation results did not support such a conclusion.

The hemostatic benefit of DDAVP is attributed to reduced platelet dysfunction after CPB [12, 15]. Administration of DDAVP increases the large vWF multimers and FVIII from endogenous endothelial storage sites. High molecular weight multimers of FVIII occur immediately after DDAVP is given and vWF peaks 30 to 60 minutes later. These factors remain elevated 6 hours [24]. By facilitating the binding of platelet glycoprotein Ib receptors, larger vWF multimers augment platelet adhesion and potentially platelet aggregation [25]. A measure of the functional activity of vWF is FVIII:RCo activity, which is the ability of the intermediate and larger vWF multimers to agglutinate with fixed, normal platelets in the presence of the antibiotic, ristocetin. There is a strong negative correlation with 24-hour blood loss and FVIII:RCo activity in patients undergoing repeat or primary aortic or mitral valve replacement supporting the importance of vWF in hemostasis [26]. In our study with patients undergoing congenital heart operation at risk for excessive bleeding and Hackman and coworkers [13] with primary CABG patients, there was no difference in the FVIII and FVIII:RCo activity between DDAVP and placebo patients. The effectiveness of DDAVP may depend on a vWF response that neither Hackman and coworkers [13] or our study detected. There may be hemostatic effects due to DDAVP that are independent of released vWF [27] such as a platelet-stimulating action [28].

A single dose of DDAVP as given in our study may be insufficient to generate a hemostatic benefit. Desmopressin does have a short serum half-life, and results have been mixed regarding efficacy of single-dose DDAVP [13, 14, 18, 20, 29]. Most studies have concluded there was no benefit of repeated doses of DDAVP over a single dose [30].

A major criticism of our study is a lack of strict transfusion guidelines, which are often cited as a cause for great variation in transfusion practice. There is now debate about the advisability of strict laboratory guidelines for transfusion [31, 32]. Our study did not have strictly enforced guidelines for transfusion; however, institutional transfusion guidelines were available. In an effort to minimize transfusion variability, the number of individuals involved in transfusion decisions during this study was limited. Intraoperative transfusion decisions were made by only one of two anesthesiologists. Postoperative transfusions were under the sole direction of the cardiovascular surgeon and senior author (G.K.D.). Transfusion in this manner is considered more reflective of actual clinical practice [23].

The side effects associated with DDAVP infusion include mild vasodilation and hypotension [18], hyponatremia [17], and decreased urine output. Desmopressin allows the renal collecting ducts to become more permeable to water thereby concentrating the urine and decreasing the serum sodium. Hyponatremia is usually secondary to multiple doses of DDAVP in small children [17]. No evidence of those perioperative complications was found in this study.

In conclusion, conservation efforts to reduce transfusion requirements in cardiac operation have often proved more beneficial in adults [14, 33, 34] than children [2, 6, 19, 20] and in acquired rather than congenital heart disease. Although some patients at risk for excessive bleeding may benefit from the administration of DDAVP, the drug does not reduce blood loss and transfusion requirements in pediatric and adult patients undergoing CPB for congenital heart operation. Routine use of DDAVP for this purpose might best be abandoned and efforts redirected to the use of hemofiltration, antifibrinolytic agents, and platelet-sparing therapies.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We thank Gail Schumacher and Debra Kirtz, of the Mayo Clinic, Rochester, Minnesota, for their excellent secretarial assistance in the preparation of this manuscript.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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