Case conference

CASE CONFERENCE Alan Jay Schwartz, MD, MSEd Frederick A. Hensley, Jr, MD Editors

CASE 4- 1990

Case Presentation A 66-year-old (59.5-kg, 142-cm) woman, with progressive exertional angina and inferior wall ischemia during stress thallium perfusion scan, was admitted to the Hospital of the University of Pennsylvania for cardiac catheterization. Daily medications included nitrates and one children’s aspirin (80 mg). Cardiac catheterization showed severe obstructions in the right and left anterior descending (LAD) coronary arteries, and a lesion in the first diagonal branch of the LAD. Inferobasal hypokinesis and normal hemodynamics were evident. There was no history or physical signs of a preexisting hemorrhagic diathesis. Results of preoperative coagulation studies including platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) were normal. The day following catheterization the patient developed rest angina that was refractory to the addition of diltiazem to her therapeutic to the coronary regimen. She was transferred care unit with ongoing rest angina, and continuous intravenous nitroglycerin and heparin infusions were started. On her fourth day in the hospital, the patient underwent emergency coronary artery bypass surgery. The continuous heparin infusion was discontinued 4 hours before the scheduled start of surgery. The activated clotting time (ACT) (Hemochron), measured in a prewarmed machine and tube, was 113 seconds in the operating room before induction of anesthesia. Heparin, 300 U/kg (18,000 U), was administered during dissection of the left internal mammary artery. An ACT drawn 5 minutes later was 475 seconds; 30 minutes after heparinization, a repeat ACT was 435 seconds. After aortic and

Journal of Cardiorhoracic Anesthesia, Vol4,

right atria1 cannulation, cardiopulmonary bypass (CPB) was started. CPB was conducted with a Biomedicus centrifugal flow pump, membrane oxygenator, and asanguineous prime (2,400 mL) containing 5,000 U of heparin. The patient was cooled to 26V. A saphenous vein was grafted to the distal right coronary artery and the left internal mammary artery was anastomosed to the LAD. The first diagonal branch of the LAD was explored, but found to be too small to graft. During CPB, an additional 5,000 U of heparin (total dose, 28,000 U) was administered when an ACT of 387 seconds was measured. The patient received 1,700 mL of crystalloid cardioplegia, and 1,300 mL of crystalloid was added to the CPB circuit intraoperatively. Two units of packed red blood cells (PRBCs) (500 mL) was also administered during bypass, in order to correct anemia. During CPB, urine output was 1,300 mL. After 1 hour 39 minutes of bypass and rewarming (nasopharyngeal (NP) temperature was 37.6V and rectal (R) temperature was 36.0°C), CPB was discontinued without event.

Frederick W. Campbell, MD. Department of Anesthesia. George S. Tyson, MD, Department of Surgery, Hospital of the University of Pennsylvania. Philadelphia, PA: Glenn P. Gravlee. MD, Department of Anesthesia. Wake Forest University Medical Center, Winston-Salem, NC: J.C. Horrow, MD, Department of Anesthesiology. Hahnemann University, Philadelphia, PA; Kenneth J. Tuman, MD, Department of Anesthesiology, Rush-Presbyterian-St Luke’s Medical Center, Chicago, IL. Address reprint requests to Frederick W. Campbell. MD, Department of Anesthesia, Hospital of the University of Pennsylvania. 3400 Spruce St, Philadelphia, PA 191044283.

No 4 (August), 1990: pp 499-5 17

0 1990 by W.B. Saunders Company.

0888-6296/90/0404-0015$03.00/0

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Sodium nitroprusside was initiated for the control of hypertension, and heparin was neutralized by the administration of protamine sulfate, 200 mg. Five minutes after administration of protamine, the ACT measured in an unwarmed machine and tube was 149 seconds. After warming the machine and a second tube, the test was repeated and was 120 seconds. Despite apparently complete heparin neutralization, the surgical field showed continued bleeding from multiple sites including skin edges, sternum, and the site of internal mammary artery harvest, and little clot was observed in the surgical field. Bleeding appeared excessive to both surgeons and anesthesiologists. The patient remained hemodynamically stable and volume losses were replaced with infusions of crystalloid (2,400 mL) and scavenged washed red blood cells (1,350 mL). Forty minutes after separation from CPB, repeated examination of the surgical field failed to demonstrate surgical bleeding sites. Chest tubes were placed in the inferior pericardial sac, anterior mediastinum, and left pleural space, and closure of the chest was started. At this time, the patient’s temperatures were 34.0°C (NP) and 35.2% (R). Blood samples were drawn for repeat ACT (126 seconds) and thromboelastograph (TEG) measurements. Positive end-expiratory pressure (PEEP) (10 cm H,O) was used after chest closure. Upon transfer to the surgical intensive care unit, 75 minutes after the termination of CPB, the patient was hemodynamically stable despite significant chest tube drainage. Blood samples were drawn for routine coagulation tests. Sodium nitroprusside was continued to control arterial blood pressure, and nitroglycerin, by continuous intravenous infusion, was instituted. PEEP (10 cm H,O) was maintained during ventilation. The patient’s rectal temperature was 34S”C, while a radiant heat lamp and warm blankets were applied for warming. Autotransfusions of shed blood, hetastarch, and 5% albumin solutions were administered to maintain the patient’s filling pressures and cardiac output (CO). After the first hour in the intensive care unit, the patient’s chest tube drainage was 625 mL. The chest tubes continued to drain and the routine coagulation test results were not yet available. The TEG tracing obtained in the operating room is shown in Fig 1.

Figl. TEG recording of the patient bleeding post-CPB obtained from a blood sample drawn 35 minutes after heparin neutralization. R = 12 min (normal, 7.5 to 15 mink K = 0 min (normal, 3 to 6 min), a = 52” (normal > 50’). MA = 46.5 mm (normal, 50 to 60 mm). A, = 45.0 mm (normal > 0.65 (MA)).

DISCUSSION

Etiologies of Post-Cardiopulmonary Hemorrhage*

Bypass

This case illustrates the clinical dilemma facing cardiac anesthesiologists and surgeons of the need for immediate treatment of postoperative bleeding in the absence of a laboratoryspecified diagnosis, which explains the etiology and guides therapy. The need for prompt correction of this patient’s bleeding is indicated by the volume of chest tube drainage in the first postoperative hour (>lO mL/kg), which exceeds the amount recognized by Kirklin and Barrett-Boyes as a criterion for reexploration of the chest.’ Empirical or “shotgun” approaches to the *Frederick

W. Campbell,

MD

CASE 4- 1990

treatment of bleeding have evolved because laboratory tests of hemostatic function, which are necessary to permit specific diagnosis-directed therapy, are neither available in a timely fashion, nor likely to accurately characterize the specific hemostatic defect(s) resulting in post-CPB bleeding. Shotgun treatment may not be wise in view of the risk of debilitating viral infection that may be acquired through unnecessary or excessive transfusion of blood products. Lacking a specific diagnosis, selection of therapy may be based on an understanding of the hemostatic abnormalities occurring in the cardiac surgical patient. Knowledge of the individual patient and the hemostatic consequences of the specific operative and perfusion techniques used may point to possible etiologies. Hemostatic abnormalities may be preexisting or acquired during surgery. Preexisting hemostatic abnormalities may often result from medications with primary or incidental anticoagulant effects. The patient reported in the case conference received aspirin for the prevention of platelet-related coronary thrombosis. An 80-mg dose is sufficient to inhibit platelet function, yet is believed to permit prostacyclin synthetase activity that preserves the nonthrombogenicity of vascular endothelium. Larger aspirin doses inhibit prostacyclin synthetase, thereby resulting in no net reduction in thrombogenicity. Although cardiac surgery may be safely performed in patients receiving aspirin, operative blood loss and transfusion requirements may be increased as a result of the drug’s inhibition of platelet function.2’3 The duration of platelet inhibition induced by aspirin is 7 to 10 days. This time period may be required for platelet function to normalize and the cardiac procedure to be performed without the risks associated with an increased transfusion requirement. The urgent nature of this patient’s surgical disease did not permit this option. Regardless of the presence of preexisting hemostatic abnormalities, acquired derangements in the vascular, platelet, coagulation, and fibrinolytic components of the hemostatic system are commonly induced during cardiac surgery.4-6 The specific defects observed following hypothermic CPB, listed in order of decreasing frequency, are: Loss of vascular integrity. Multiple breaks in vascular integrity are necessitated by

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the surgical procedure. No amount of blood components will stop bleeding that results from inadequate surgical hemostasis. When blood loss is confined to the surgical wound, in the absence of generalized oozing, surgical bleeding is likely. “Medical bleeding” resulting from hemostatic defect(s) may be distinguished from “surgical bleeding” on the basis of generalized oozing from previously dry skin edges (as observed in this case), vascular cannulation sites, and epistaxis. Platelet dysfunction. Qualitative (thrombocytopathy) and quantitative (thrombocytopenia) alterations in platelets occur during CPB as the result of interactions between the platelets and synthetic surfaces of the extracorporeal circuit, air-blood interfaces, and other factors (Table 1). Platelet interaction with the synthetic surfaces of the extracorporeal circuit is the major source of the alterations in platelet function.7-9 The largest area of synthetic surface in an extracorporeal circuit is a membrane oxygenator. Upon initiation of extracorporeal circulation, platelets adhere to a layer of fibrinogen on the circuit’s synthetic surface. Platelet adhesion, activation, and degranulation are triggered during this surface interaction. The platelet granule Table 1. Factors in Cardiac Surgery Causing Quantitative and Qualitative

Platelet Deficiencies

Mechanisms

and Their Possible

of Antiplatelet

Action

Thrombe

Platelet

cytopenia

Dysfunction

Pre-CPB

I

Preoperative antiplatelet therapy Pulmonary artery catheters

x?, a?

I I

Anesthetic drugs Cardiovascular drugs Heparin

s, a?

a?

CPB Hemodilution

d

Hypothermia

S

1

Membrane oxygenators

a

a

Bubble oxygenators

x, a

x. a

Cardiotomy suction

x. a

x.

Arterial filters

x.

a

a x. a

Post-CPB Protamine

s, a?

Cell washing

d

Transfusion

d

a7 -

Abbreviations: CPB, cardiopulmonary bypass; a, platelet activation triggered by interaction with synthetic surface or other agent; d, dilution of circulating platelets; i, direct inhibition of platelet cellular function; s, transient sequestration of platelets from circulation; x, mechanical platelet injury or destruction. Modified with permission.79

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contents liberated induce platelet aggregate formation. Surface adhesion and platelet-to-platelet aggregation result in a temporary reduction in circulating platelets. Return of platelets to the circulation occurs following their interaction with the fibrinogen-coated synthetic surface of extracorporeal circuits with membrane oxygenators. Available evidence indicates that a minority of platelets are fully activated, but, more importantly, the majority of platelets circulate with reduced function. The functional defect is not clearly defined but may result from a reduction of platelet membrane fibrinogen and (Y*-adrenergic receptors. During extracorporeal circulation with a bubble oxygenator, a direct platelet injury is superimposed upon the one that accrues from platelet-surface interaction. Blood-gas interfaces are known to denature plasma proteins and the mechanical destruction of platelets occurs at the interface. At the initiation of CPB with a bubble oxygenator, the platelet count declines, but more gradually than during CPB with a membrane oxygenator. This reflects the fact that the bubble oxygenator contains less synthetic surface area for synthetic surface-induced platelet adhesion and aggregate formation. However, in the bubble oxygenator circuit, the loss of circulating platelets is progressive and there is no return of platelets to the circulation, presumably reflecting platelet destruction. Cardiotomy suction systems, by returning blood from the operative field to the pump, provide blood-gas and blood-tissue interfaces at which platelet activation, injury, and destruction occur. The volume of blood aspirated by cardiotomy suction directly correlates with platelet loss. Hypothermia contributes to platelet dysfunction after cardiac surgery, the severity of dysfunction being directly related to the degree of hypothermia. In vitro platelet aggregation is abolished below 33OC. Bleeding times are prolonged when measured at hypothermic skin sites in viva.” Platelet count declines during CPB as a result of hemodilution, platelet interaction at blood-synthetic surface interfaces, and platelet destruction at blood-gas interfaces, in cardiotomy suction systems, and arterial and cardiotomy filters. During extracorporeal circulation with a bubble oxygenator, a progressive and permanent loss of circulating platelets results

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from their destruction at blood-gas interfaces, and occurs in addition to the reduction that is produced by hemodilution. In contrast, the decrease in platelet count, occurring during extracorporeal circulation with a membrane oxygenator, is largely the result of hemodilution alone. A reduction in platelet count results from dilution of the patient’s blood volume during CPB by priming solutions, which consist of crystalloid fluids or aged homologous blood, and by crystalloid cardioplegia solutions. Hemoconcentration achieved by urinary diuresis will moderate the dilutional reduction in platelet count. A transient reduction in circulating platelets by approximately one third occurs at the intravenous injection of protamine after CPB. This effect, probably caused by the protamine: heparin complex, lasts less than 1 hour and may result from temporary sequestration of platelets in the hepatic circulation. Although reductions in platelet counts occur frequently during cardiac surgery as a result of the factors described previously, the platelet count, per se, is generally not decreased enough to explain excessive postoperative bleeding. However, a large proportion of these platelets circulate with impaired function. Investigations demonstrate that average values for post-CPB platelet counts exceed the value, 50,000 to 70,0OO/c~L, normally required for hemostasis.5*6 Moreover, the occurrence of excessive postoperative hemorrhage does not usually correlate with platelet count. This suggests that alterations in platelet function are more important than reductions in platelet count in determining the contribution made by platelets to postoperative hemostasis. Fibrinolysis. Activation of the fibrinolytic system in the absence of active coagulation produces the condition of primary fibrin(ogen)olysis. The condition occurs when factors trigger plasminogen activation and increase plasmininduced lysis of fibrinogen and fibrin. Many investigators have demonstrated increased fibrinolytic activity during CPB. The resulting lysis of fibrinogen and fibrin generates fibrin(ogen) split products (FSPs). The bleeding diathesis, which may be caused by primary fibrinolysis, results from several FSP-induced hemostatic defects: lysis of formed fibrin and fibrinogen, coagulation factor degradation, and platelet inhibition. The incidence of primary fibrinolysis dur-

CASE 4- 1990

ing CPB varies depending on many clinical variables, as well as the method used to detect its presence. If elevated FSP titers are the criterion defining the occurrence of fibrinolysis, the incidence ranges from 0% to 85%. Studies finding modest reductions in plasminogen and fibrinogen levels that are attributable only to hemodilution and no elevations in FSPs suggest fibrinolysis is uncommon.5*6 In contrast, sensitive clot assay techniques detect the occurrence of increased fibrinolytic activity with a frequent incidence (up to 100%) even in the absence of significant plasminogen and fibrinogen reductions or FSP elevations.11*12 The measured fibrinolytic activity is shown to increase upon the initiation of CPB and resolve within minutes of CPB termination. In summary, it is likely that variable levels of primary fibrinolysis occur during CPB; however, this activity decreases to normal levels promptly after CPB and is infrequently associated with hypofibrinogenemia or elevated FSP titers in the post-CPB period. Disseminated intravascular coagulation (DIC) is a condition of uncontrolled systemic fibrin deposition and simultaneous fibrinolysis. A varying combination of thrombosis resulting from fibrin formation and hemostatic defects that result from fibrinolysis may ensue. DIC is an extremely rare occurrence during extracorporeal circulation and cardiac surgery. CPB-related thrombocytopenia, decreases in the levels of fibrinogen and other clotting factors, and/or the appearance of FSPs have been presumed to reflect the occurrence of DIC in early reports. Borderline or inadequate anticoagulation during CPB may result in low-grade activation of coagulation and produce secondary fibrinolysis. Reports concerning extensive DIC during CPB were published before the widespread acceptance by the mid1970s of the concept of heparin titration to a defined endpoint. The relative lack of reports describing DIC in the recent literature may be explained by uniform adequate anticoagulation preventing intravascular coagulation and secondary fibrinolysis. Procoagulant deficiency. Reductions in coagulation factor activity occur during CPB and parallel the reduction in hematocrit. Therefore, the decline in clotting factors, including fibrinogen, is generally the result of hemodilution. Factor V is an exception, decreasing to slightly

503

lower levels than predicted on the basis of hemodilution alone. The modest reductions in coagulation factor activities, resulting from routine CPB, will not be great enough to result in a bleeding diathesis. Coagulation guidelines have established that 5% to 20% is the minimum factor V level, and 10% to 40% is the minimum level for the other coagulation factors necessary for normal hemostasis. Clinically significant coagulation factor deficiencies may occur during cardiac surgery when certain patient-related variables and operative factors are present, ie, preexisting clotting factor deficiencies, excessive hemodilution, washing and concentration of large volumes of blood in cell washers, massive transfusion, or fibrinolysis. Residual heparin. Residual heparin effect may be observed after initial neutralization by protamine resulting from incomplete heparin neutralization, reinfusion of anticoagulated blood from the pump oxygenator, and heparin rebound. Incomplete heparin neutralization that results from administration of an insufficient protamine dose and heparin rebound are uncommon occurrences in modern practice when excessive heparin is avoided by titrating the dose to measured effect (ACT) before CPB and when adequate doses of protamine are administered following CPB. The selection of an appropriate protamine dose and monitoring of heparin neutralization are discussed below. After review of the patient and perfusionrelated circumstances of this coronary artery bypass procedure, the anesthesiologists believed that surgical bleeding sites, platelet abnormalities, and/or dilutional procoagulant deficiencies were the most likely causes of the bleeding diathesis. Fibrinolysis and residual heparin effect were considered less likely explanations. As soon as excessive bleeding was apparent, steps were taken to control hemorrhage and prevent secondary coagulation derangements. These included volume repletion to maintain hemodynamic stability, prevention of hypertension by the administration of sodium nitroprusside, efforts to maintain normothermia to prevent hypothermiarelated platelet dysfunction (although not effectively achieved in this case), and the addition of PEEP to controlled ventilation after chest closure. The first specific therapeutic action taken was a vigorous effort to identify and correct

504

CASE 4-1990

surgical sites because breaks in the vascular integrity were uniformly present. The presence of several factors altering platelet function, seen in the case presented, strongly suggested that a platelet deficiency, qualitative and/or quantitative, was a likely etiology of the patient’s post-CPB bleeding. Marked hemodilution producing thrombocytopenia resulted from the addition of a copious volume of asanguineous solution and packed red blood cells to a relatively small blood volume. The net addition of 4,600 mL (2,400 mL priming solution, 1,700 mL crystalloid cardioplegia, and 500 mL PRBCs less 1,300 mL urine output) to a patient with a 3,900 mL blood volume would be expected to reduce the concentration of circulating platelets to 46% of their pre-CPB number (225 x lo3 x 0.46 = 103 x 103/mL3). As expected, on the basis of the other predictable platelet losses described previously, the measured platelet count post-CPB (Table 2) was lower than that predicted by hemodilution alone. Furthermore, although the post-CPB platelet count observed marginally meets the value normally required for hemostasis, the vast majority are predicted to be dysfunctional. A defect in platelet function induced by preoperative aspirin therapy was superimposed on the platelet alterations known to occur during CPB. In addition, the relatively prolonged duration of chest closure in a cold operating room may have induced hypothermia-related platelet dysfunction. The net result of post-CPB infusion of sodium nitroprusside with its platelet-inhibiting effects is uncertain.13 Currently, the benefits resulting from the prevention of hypertension in a bleeding

patient are believed to outweigh the potential drawbacks that are related to the drugs’ demonstrated in vitro platelet inhibition. On the basis of these considerations, ordering platelet concentrates for transfusion to this bleeding patient, in the absence of laboratory-demonstrated platelet deficiencies, is rational and reasonable. The large degree of hemodilution occurring during CPB in this case might similarly explain the bleeding diathesis on the basis of a dilutional procoagulant deficiency. The marginal fibrinogen level measured post-CPB (Table 2) certainly resulted from hemodilution as well as fibrinogen loss during cell washing and to the surface of the extracorporeal circuit. Despite the anticipated dilution of clotting factors in this patient, empirical fresh frozen plasma (FFP) was not prescribed intraoperatively because the R value observed within the first several minutes of the TEG recording (Fig 1) was within normal limits. The role of fibrinolysis can only be the subject of speculation in the absence of an assay for fibrinogenolysis. The patient’s bleeding was not believed to be the result of fibrinolysis by the attending anesthesiologist, because of the lack of consistent substantiation of the clinical significance of the mild fibrinolytic activity generally measurable during CPB. Retrospectively, the post-CPB TEG tracing was not consistent with primary fibrinolysis. In this case, a “subtherapeutic” ACT (institutional minimum acceptable ACT is 400 seconds) was detected during CPB. This might lead to speculation that inadequate inhibition of coagulation could have precipitated low-grade coagu-

Table 2. Coagulation Test Results Preoperative Interval

Time studies obtained

PreheDarin

-4d

PostoDerative

HeDarinized

-Id

0

+0.5

h

+5h

+ld

PT (9.5 to 12.4 s)

10.7

11.4

18.6

14.7

12.9

aPTf (24 to 36 s)

26.8

87.5

68.0

39.9

37.9

Fibrinogen 99

(170 to 410 mg/dL)

6

12

n

68

66

I

11.3

FSP (pg/mL) 0

Platelet count (x 103/mL3) Hb (g/dL)

233 12.7

225 11.8

9.6

93 9.4

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CASE 4- 1990

lation during extracorporeal circulation. The resulting consumption of clotting factors and platelets, as well as secondary fibrinolysis, would explain a post-CPB coagulopathy. Although theoretically plausible, this explanation is highly unlikely. Despite numerous studies over the decades that CPB has been in clinical use, absolute criteria for prolongation of coagulation and the minimum acceptable ACT remain in question. In their heparin titration, the goal of Bull et al was to maintain the manual ACT between 300 and 480 seconds. I4 Young et al rep orted that keeping the automated ACT greater than 400 seconds would prevent microscopic coagulation, their endpoint was the appearance of fibrin monomer. l5 However, on the basis of a variety of investigational methodologies and/or clinical experience, ACT values less than 400 seconds have been shown to be safe by Jobes et al (300 seconds), l6 Metz and Keats (288 seconds),17 and Dauchot et al (266 seconds).” Moreover, the wide variability of ACT measurement of heparinized blood coagulation suggests that 387 seconds is not significantly different than 400 seconds.” Residual heparin effect was not believed to be contributing to the patient’s apparent coagulopathy, in view of the repeatedly normal ACT values that were obtained with the use of a consistent and appropriate measurement technique and the normal R time observed on TEG. In the case presented, empirical therapy, with platelet concentrates for aspirin- and CPBrelated platelet dysfunction and dilutional thrombocytopenia and/or FFP for clotting factor dilution, may have been justified on the basis of individual patient and CPB-related variables specific to the case. The TEG tracing (normal R, slightly prolonged K, normal (Y, borderline narrowing of MA, and normal A,,) was interpreted to depict a mild abnormality in platelet-fibrin interaction consistent with qualitative or quantitative platelet dysfunction. However, the anesthesiologists elected to manage the patient supportively until comprehensive hemostatic evaluation could be performed. Case Presentation

(Continued)

After failing to achieve intraoperative hemostasis and observing heavy chest tube drainage during the first postoperative hour, the pa-

tient’s chest tube drainage slowed in spite of the absence of specific hemostatic therapy. TWO hundred twenty-five milliliters of drainage was recorded in the second hour. After that, the hourly output was 50 to 75 mL. Volume requirements gradually decreased and the patient’s CO and filling pressures remained stable. The vasodilator infusions were continued and titrated to control blood pressure. The patient was weaned from ventilatory support, including PEEP. The routine coagulation studies, obtained at the conclusion of surgery, became available in the third postoperative hour (Table 2). In view of these results and despite the decreasing chest tube output and stable hemodynamics, FFP (2 U) was administered. Nine hours after admission to the intensive care unit, the patient’s total chest tube output was 1,450 mL. Volume replacement had consisted of 675 mL of autologous shed blood, 500 mL of 5% albumin, 500 mL of hetastarch, 400 mL of FFP, and 725 mL of crystalloid solution. The chest tubes were removed on the first postoperative day and the patient was transferred from the intensive care unit. The remainder of the patient’s postoperative course was uneventful. DISCUSSION (CONTINUED)

This case report demonstrates that routine laboratory coagulation tests must be interpreted with caution following cardiac surgery. Bleeding slowed during the second postoperative hour and was minimal thereafter, despite abnormalities in platelet count, PT, aPTT, and fibrinogen that persisted throughout the afternoon following surgery. Similar observations have been made by others. In one published series, 80% of 5 12 patients had elevations of PT after cardiac surgery, yet only 4% had clinically significant bleeding; all patients had factor II, V, VII, and X levels of 70% to 80%.20 In another series, excessive bleeding was observed in only one half of patients with abnormalities in a post-CPB laboratory coagulation profile consisting of platelet count, PT, aPTT, and fibrinogen level.21 In a third report, post-CPB bleeding occurred in only 5 of 40 cardiac surgical patients, each of whom had one or more abnormal laboratory coagulation test values.22 The extreme sensitivity of these coagulation tests to post-CPB alterations in hemostatic function, which are variable in their clinical significance, dictates that the anesthesiologist

506

CASE 4- 1990

should treat the patient, not the patient’s numbers. If a patient is not bleeding excessively despite abnormal laboratory coagulation values, any therapy offers only risks and no clinical benefit. Thus, the administration of FFP in this patient 1 hour after chest tube drainage had slowed to a minimal rate, despite abnormal coagulation studies, was neither indicated nor justifiable. The diminishing rate of chest tube drainage and the normal post-CPB ACT and TEG R values measured intraoperatively may suggest that the markedly prolonged PT and aPTT detected 30 minutes postoperatively were the result of heparin flush contamination of the blood sampled rather than procoagulant deficiency or residual systemic heparin effect. Furthermore, as this case illustrates, treatment of generalized oozing after cardiac surgery may not be necessary until diagnostic evaluation is complete and a trial of “tincture of time” is permitted, as long as hypovolemia or cardiac tamponade are avoided. Despite the generalized oozing observed intraoperatively in the surgical field, the rate of hemorrhage observed in the first postoperative hour caused the overestimation of the actual rate of bleeding. This might be suspected when hemodynamic stability was easily maintained in the face of apparently large volumes of chest drainage. Evacuation of blood previously accumulated in the left pleural space may have contributed to the volume of blood draining into the wound collection system in the immediate postoperative period. COMMENTARY

Protamine Dosing and Administration? Heparin induces anticoagulation principally by binding antithrombin III (AT III), thereby rendering it more receptive to thrombin.23 Because of its polycationic charge, protamine attracts the negatively charged polyanionic heparin so strongly that heparin abandons AT III to form heparin-protamine macromolecular cominteractions go, this is plexes. 23 As molecular fairly simple. Empirically it would seem best to provide enough protamine to overwhelm the heparin, leaving an abundance of protamine to spare. This line of reasoning has led some to

tGlenn P. Gravlee,

MD

choose initial protamine doses of 2 to 4 times the total heparin dose administered during CPB, measuring heparin and protamine in milligrams. This approach attained considerable popularity in the 197Os, sometimes resulting in initial protamine doses exceeding 1,000 mg. To some extent this therapeutic propensity was fueled by an influential 1971 study showing that substantial doses (600 to 800 mg) of intravenous protamine did not importantly prolong the Lee-White coagulation time or the partial thromboplastin time in unheparinized healthy volunteers.24 Similar effects were observed in cardiac surgical patients who were intentionally given 600 mg overdoses of protamine over 90 minutes.24 In 1975, Bull et al introduced the concept of heparin monitoring using the ACT.14,25 They recommended titrating heparin doses to a particular level of ACT (300 to 480 seconds). Along these same lines, they recommended using the ACT-based heparin dose-response relationship to select a protamine dose. This relationship assumed that any ACT prolongation during CPB was solely attributable to heparin and that 1.3 mg of protamine adequately neutralizes 1.0 mg (100 units for most commercial preparations) of heparin. Some subsequent investigations comparing ACT-based heparin and protamine management with empirical dosing protocols have shown reduced postoperative bleeding or intraoperative transfusion requirements with ACT-based management26-29; others have not.30*31 Some might attribute decreased post-CPB bleeding to the maintenance of adequate anticoagulation during CPB, therefore minimizing subclinical consumption of platelets and clotting factors during that period. However, in all of these studies, ACTbased management substantially reduced both the total protamine dose and the protamineheparin dose ratio when compared with the empirical protocol. Therefore, ACT-based management greatly alters both heparin and protamine dosing. Because both parameters have been varied, it is not possible to ascertain which one (if either) contributes more to improved post-CPB hemostasis. Guffin et al prospectively compared two methods of protamine dose calculation.32 One group of 30 patients empirically received 1 mg of protamine for each 1 mg of heparin given during

CASE

4-l 990

CPB. The other group of 30 patients received a protamine dose based on two assumptions: (1) heparin’s plasma elimination half-life during CPB is 2 hours, and (2) the optimal protamineheparin neutralization ratio is 1 mg of protamine to 1 mg of heparin. The patients in the latter group received much less protamine (105 -I- 4 v 334 k 20 mg) and experienced less postoperative bleeding (363 +- 29 v 702 k 85 mL of mediastinal drainage in the first 12 hours), less prolongation of automated plasma clotting times (PT, aPTT), and less reduction in platelet counts (P < 0.005 for all differences). The apparently contradictory findings of Guffin et a13* and Ellison et a124 can be reconciled. Subsequent work by Ellison et a133 demonstrated that the heparin-protamine interaction significantly impairs in vitro platelet function, whereas a comparable platelet inhibitory effect of protamine alone fell just short of statistical significance, probably because of a smaller sample size (6 v 12 volunteers). Kresowik et al used a canine model to show that platelets are more sensitive to protamine-induced impairment than are plasma coagulation factors.34 If their findings could be transferred directly to humans, clinically significant platelet functional impairment and platelet count reduction would result when the protamine dose exceeded the minimum requirement for heparin neutralization by 3 mg/ kg. In all likelihood, this level was attained in the higher protamine dose group in the study of Guffin et aL3* which probably accounted for the increased postoperative blood loss. Had Ellison et al performed an Ivy bleeding time in their 1971 study24 before and after administering 600 mg of protamine to unheparinized volunteers, perhaps they would have demonstrated substantial prolongation. The Lee-White coagulation time they selected more closely approximates an aPTT or ACT, therefore reflecting plasma coagulation function more than platelet function. Numerous approaches to protamine dose selection are used. Ideally, dose selection should balance complete neutralization of heparin with avoidance of possible protamine-induced coagulopathy. It appears that few clinicians actually plot the heparin dose-response curve as described by Bull et al. More commonly, a target ACT range for CPB is selected and maintained. In the absence of the linear plot, Bull’s method for

507

selecting a protamine dose becomes impractical. Consequently, clinicians tend to use one of the following approaches: (1) selecting a fixed ratio of protamine to the total CPB heparin dose (typically 0.75 to 2 mg of protamine per 1 mg or 100 units of heparin); (2) selecting a fixed ratio of protamine, usually 0.6 to 1.5 mg of protamine per 100 units of the initial (pre-CPB) heparin dose; or (3) using a protamine titration method to assess plasma heparin level, calculating the total mass of heparin in the bloodstream (using standard formulas to estimate blood volume), then administering a fixed ratio of protamine to the estimated amount of circulating heparin (usually 1 .l to 1.3 mg protamine per 100 units of heparin). Method 3 can be accomplished manually or with varying degrees of automation. All three methods have strengths and weaknesses. Method 1 holds the least appeal, because it has the greatest propensity to produce protamine doses far in excess of the amount needed to neutralize heparin. In addition to potentially causing or contributing to a coagulopathy, a recent animal study suggests that excessive protamine inhibits the breakdown of the complement-mediated anaphylatoxins produced by heparin-protamine complexes.35 Methods 2 and 3 seem more sensible, as does the original method proposed by Bull et al. An empirical approach with some appeal is the routine administration of 2 to 2.5 mg of protamine per kilogram of body weight. This approach simulates method 2, assuming a protamine/ heparin dose ratio of 0.67 to 0.80 mg/lOO U and an initial heparin dose of 300 U/kg. After infusing this dose of protamine, measuring an ACT assesses the adequacy of heparin neutralization. If the ACT remains substantially above its control level, subsequent 25- to 50-mg increments of protamine can be titrated as the ACT is followed. Few patients require protamine doses exceeding 2.5 mg/kg for heparin neutralization, and many require less than 2.0 mg/kg.24*3’,32 Subsequent protamine increments (25 to 50 mg) may be needed to treat heparin rebound. Zaidan et al showed that infusion of protamine over 30 minutes reduces the incidence of early heparin rebound (within 2 hours) when compared with a 5-minute infusion period.36 Slower infusion also decreases the incidence of hemodynamic disturbances.37 Based on these

508

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factors, it appears prudent to administer the initial protamine dose over a period of 15 minutes or more. Assessment

of heparin

neutralization.

Measuring the ACT following protamine offers the simplest approach to assuring adequate neutralization of heparin. This method might be described as crude but usually sufficient. The ACT suffers from suboptimal precision (varying somewhat among different automated ACT devices), susceptibility to operator-induced variability, baseline ACT variation during surgery, and insensitivity to low concentrations of heparin. ‘9~38-40 The presence of a normal ACT does not assure complete heparin neutralization.40*41 Elevated ACT values that remain within 1 to 2 standard deviations of the control level are compatible with aPTTs that are elevated to 1.3 to 2.0 times control levels.40 By the standards applied for treatment of deep vein thrombosis, a normal ACT may be consistent with therapeutic anticoagulation. The case presented here demonstrates this possibility. The ACT and TEG were normal after protamine when the aPTT was 68.0 seconds. This level of aPTT prolongation may have contributed to the patient’s bleeding, and probably contributed to the decision to administer fresh frozen plasma. Additional protamine alone might have corrected this abnormality. If residual unneutralized heparin contributed to the patient’s bleeding, the FFP may have been inappropriate for two reasons: (1) it was not the most direct solution to the problem, and (2) hemostasis had been restored at the time FFP was given (possibly because the heparin had worn off by then). Detecting clinically significant unneutralized heparin after CPB is difficult. If the ACT remains prolonged after protamine infusion, the differential diagnosis includes too little protamine, too much protamine, clotting factor deficiency, spurious ACT test result, excessive fibrinolytic activity, hemodilution, hypothermia, and markedly deficient platelet function (qualitative, If the patient exhibquantitative, or both). 30*42-46 its pathological bleeding, protamine, 25 to 50 mg, given empirically may normalize the ACT. If hemostasis on the surgical field appears satisfactory despite a moderately elevated ACT (150 to 200 seconds), pursuing this laboratory abnormality may be unnecessary. If an elevated ACT

fails to decrease after additional protamine, continuing to administer protamine will not help and will probably exacerbate any coagulopathy.34*46 However, as noted above, a normal ACT does not exclude the possibility that additional protamine is needed. If a normal ACT increases by more than 10 seconds following a supplemental protamine dose, additional protamine will not likely prove beneficial, Protamine titration presents a more scientific method for diagnosing residual unneutralized heparin. Two commonly used automated devices can perform this test, but the method may be no more sensitive to heparin than the ACT. The ideal test would be a fully automated bedside whole blood aPTT (or thrombin time) that could also accommodate protamine titration. This mechanism might also work with an ACT technique more sensitive to heparin than traditional ACTS. Such a method is now available, but has not yet been tested in this context. In the absence of tests that can serve as sensitive bedside heparin assays, clinicians should recognize the diagnostic limitations of the tests presently available. Desmopressin and AntiJibrinolytics as Hemostatic Agents After Cardiac Operations$

Pharmacological preparations used to control bleeding after CPB include desmopressin, antifibrinolytic drugs, and aprotinin. Aprotinin is a naturally occurring inhibitor of trypsin, plasmin, and kallikrein. Aprotinin inhibition of fibrinolysis occurs in low concentrations; intermediate concentrations inhibit platelet aggregation and activation.47 Aprotinin is available in Europe but not the United States. This commentary will concentrate on the other drugs available, desmopressin and lysine-analog antifibrinolytics. Desmopressin. Desmopressin, an analog of vasopressin lacking vasoconstrictor activity, alters coagulation by its effects on circulatory endothelial cells and platelets.48 In response to desmopressin, endothelial cells release prostacyclin, tissue plasminogen activator (t-PA), and the larger multimers of factor VIII:von Willibrand factor (vWF). A glycoprotein stored in endothelial cells, vWF circulates in various sizes, or “multimers,” in the blood. High molecular weight 3J.C. Horrow,

MD

CASE

4-l 990

multimers facilitate interaction of platelets with subendothelial elements.4g Desmopressin-induced release of these multimers accounts for its procoagulant activity in patients with structural or functional deficiency of vWF. Desmopressin also improves coagulation in patients with hemophilia, uremia, cirrhosis, and various platelet disorders.50 Postulating a desmopressin-remediable platelet defect during extracorporeal circulation, Salzman et a15’ administered desmopressin or placebo to 70 cardiac surgical patients following protamine infusion. The placebo group bled more (2,210 + 1,415 mL over 24 hours) than the group receiving desmopressin (1,3 17 f 486 mL). The excessive bleeding present in both groups cast doubts on the general applicability of these data.52V53Czer et al used desmopressin in place of transfusion therapy for 23 patients with excessive bleeding after cardiac surgery.54 Desmopressin was as successful as banked blood products in slowing bleeding in this nonrandomized and unblinded study. Because blood loss decreases steadily with time anyway, absence of a control group forces this author to wonder whether, if left alone, equivalent diminution of bleeding would have occurred. These reports51,54 stimulated interest in desmopressin as a hemostatic agent following CPB. Unfortunately, reproduction of the salutary effect of desmopressin in decreasing blood loss after cardiac operation has not been forthcoming. Rocha et al” gave desmopressin or placebo, in a randomized, double-blinded fashion, to 100 patients following CPB. Total blood loss did not differ between groups (458 v 536 mL/m’ over 72 hours). Seear et al studied 60 children.56 The desmopressin group (n = 30) bled 40 t 33 mL/kg over 24 hours compared with 31 _c 38 mL for the placebo group (n = 30, P = NS). Sarraccino et a157 also found no salutary effect of desmopressin following CPB in 13 pediatric patients compared with 13 placebo controls. Hackmann et al reported no hemostatic effect of desmopressin following CPB in an investigation of 150 patients undergoing elective cardiac operations.58 Drug and placebo groups bled similar amounts (median, 865 v 738 mL over 24 hours) and received similar volumes of blood products (1,025 v 860 mL). Current clinical data regarding the salu-

509

tary hemostatic effects of desmopressin in patients who take aspirin are sparse. Reduction of bleeding time was reported in a cohort of only two patients in one report5’ and in six volunteers in another.60 When this commentary was written, no published study documented that desmopressin reduces blood loss following CPB in patients with recent aspirin ingestion. The initial enthusiasm regarding desmopressin as a hemostatic agent has now subsided. What remains to be done is to identify a patient population that can benefit from the drug and find a rapid, inexpensive means of providing that identification. In summary, desmopressin appears to be a safe, but unfortunately an ineffective hemostatic agent following CPB, when administered to a typical population of adult or pediatric cardiac surgical patients. Whether the drug, administered prophylactically for operations associated with greater blood loss (ie, reoperation, multiple valve replacement), exerts a hemostatic action remains to be confirmed. Desmopressin decreases bleeding time, but not necessarily blood loss following CPB, in patients receiving aspirin or other antiplatelet medications. AntiJibrinolytic therapy. In contrast to desmopressin, antifibrinolytic medications have been available for decades. The plasma proteins fibrinogen and plasminogen circulate normally in the blood. “Kringles,” or outpouchings of the plasminogen molecule, contain binding sites for lysine residues on fibrinogen. Activation of the coagulation cascade eventually converts fibrinogen, with its attached plasminogen, to fibrin. Release of t-PA or administration of activator molecules such as streptokinase splits the bound plasminogen to plasmin. Plasmin then splits fibrin into fibrin split products (FSPs). Normally, small amounts of t-PA remodel and dissolve clots in a dynamic fashion; thus, a small amount of fibrinolysis always exists. FSPs in sufficient quantities interfere with future clot formation by intercalating into the protofibrils of fibrin during clot formation. Inhibitors of fibrinolysis, which are wamino-carboxylic acid analogs of lysine, bind to the kringles of plasminogen (or plasmin) at their lysine binding sites, displacing plasminogen from the fibrin molecular surface and, therefore, interfering with plasmin(ogen)‘s ability to split fibrinogen. t-Aminocaproic acid (Amicar, Led-

510

erle Laboratories, Wayne, NJ) achieves effective plasma concentrations with an IV loading dose of 100 to 150 mg/kg followed by an infusion of 10 to 15 mg/kg/h.61 Tranexamic acid (Cyclokapron, KabiVitrum, Inc, Franklin, OH), a congener approximately 10 times as potent as c-aminocaproic acid, provides more intense and sustained fibrinolytic activity in tissues compared with c-aminocaproic acid (cACA). Furthermore, the therapeutic index of tranexamic acid is more favorable than that of EACA. Fibrinolysis may commonly accompany CPB.“,‘* It is unclear whether heparin alone can completely suppress fibrin formation on foreign extracorporeal surfaces. Such extravascular coagulation may trigger an on-going fibrinolytic state during CPB. 62 Contact activation of factor XII may account for part of this lytic state by inducing thrombin formation through the coagulation cascade and by directly activating plasminogen.63 Initial efforts to decrease bleeding with antifibrinolytic therapy used study designs that lacked blinding, randomization, or controls.64-67 However, three double-blinded, randomized investigations do support a salutary effect of antifibrinolytics on bleeding after cardiac operations.68M70Twelve cyanotic children who received cACA bled 42% less after CPB than 18 controls who received placebo (35.8 v 62.2 mL/kg over 24 the hours). 68 Vander Salm et al investigated ability of cACA to decrease bleeding in patients following CPB for aortocoronary bypass grafts.6g The 31 CACA-treated patients bled less than 27 placebo-treated controls (273 f 19 v 332 * 2 mL over 12 hours, P = 0.04). Patients in both groups bled very little, accounting for the small difference in mean blood loss, 59 mL. Horrow et al investigated the hemostatic effect of tranexamic acid given before, during, and 10 hours following CPB in 18 patients compared with 20 placebo controls.” The drug group experienced decreased blood loss (496 f 228 v 750 * 314 mL/ 12 h, P = 0.0057) and less frequent presence of FSPs (4/18 v 17/20, P = 0.0002). Placebo patients received more FFP and platelets, but not red blood cells, than patients who received tranexamic acid. Preliminary data indicate that tranexamic acid may preserve platelet ADP content if it is given prior to CPB (unpublished data, G. Soslau and J. C. Horrow).

CASE 4- 1990

Although the theoretical risk of an increased systemic thrombotic tendency is superficially supported by anecdotal reports of intracranial and other vascular thromboses, controlled studies do not support this contention.” Exceptions are patients with disseminated intravascular coagulation, in whom formed intravascular clots remain inappropriately intact, and patients with bleeding in the kidneys or ureters, in whom upper urinary tract thrombosis follows urinary concentration of antifibrinolytic drug. Routine use of antifibrinolytics during cardiac surgery awaits additional confirmation of favorable costbenefit and risk-benefit ratios. Could the patient presented in this case conference have been helped by desmopressin or antifibrinolytic therapy? Routine administration of desmopressin generally appears ineffective. Specific use to counter the antiplatelet effects of aspirin should have decreased bleeding time, and might have decreased blood loss. The TEG showing no evidence of fibrinolysis suggests that antifibrinolytic therapy, given after significant hemorrhage developed, would likely have been ineffective. However, given prophylactically, antifibrinolytic therapy might have conferred additional platelet protection during ECC. Thromboelastograph Measurements§

and Sonoclot

TEG was performed when this patient developed hemostatic problems after CPB. Before discussing the application of TEG in the management of the patient bleeding after CPB, a brief explanation of this method of evaluating coagulation is necessary. TEG is performed by placing a small amount of whole blood in a metal cuvette, in which a piston is suspended from a torsion wire. The cuvette rotates a small amount and alterations in shear elasticity produced by the changing viscoelastic properties of the forming clot are transmitted through the torsion wire and measured on a recorder (Fig 2). Thus, TEG allows assessment of coagulation factor, fibrinogen, and platelet activity, as well as clot maturation and lysis, all from a single sample of blood.‘* TEG has been shown to be of clinical value in the evaluation of the hemostatic process during hepatic transplantation and cardiac surgery.2’,73*74 $Kenneth

J. Tuman,

MD

511

CASE 4- 1990

PRODUCTION OF NORMAL THROMBELASIOGRAM h 1

Fibrin strands /--50

mm J

Fig 2. Several parameters describe the TEG representation of whole blood coagulation. The reaction time (RI (normal R, 7.5 to 15 minutes) measures the time from placement in the cuvette until an amplitude of 1 mm is achieved, and is the time necessary for initial fibrin formation. The K value (normal K. 3 to 6 minutes) is the time interval from the end of the R value until the amplitude of the TEG is 20 mm, end is a meesure of the rapidity of fibrin buildup and cross-linking. The MA, or maximum amplitude (normal MA, 50 to 60 mm) is e reflection of the absolute strength of the fibrin clot and depends on platelet number and function, as well as fibrinogen levels. The (Y value (normal Q’, 60” to 60”) is the slope of the outside divergence of the tracing from the point of the Fl value and denotes the speed at which clot is being formed end cross-linked. The parameter A, denotes the amplitude 60 minutes after the MA is measured. The ratio A&MA (normal A,:MA > 0.861, as well as the F value (time from MA until the amplitude returns to zero) (normal F > 300 minutes), reflect loss of clot integrity over time. (Reprinted with

Given a normal R and K time, it is possible to get an initial evaluation of the onset of fibrin formation within 12 to 15 minutes after initiation of a TEG. An additional 20 minutes or more is required to obtain a good estimate of plateletfibrin function from the amplitude, and a variable amount of time beyond that is required to determine if significant fibrinolysis is occurring. Sonoclot analysis, another method to monitor viscoelastic properties of blood, is performed by placing a similar amount of whole blood (0.4 mL) into a cuvette in which a vertically vibrating probe is suspended. The changes in mechanical impedance, exerted upon the probe by the changing viscoelastic properties of the forming clot, are measured and a tracing such as in Fig 3 is produced. Sonoclot analysis is completed in a

somewhat shorter time frame than TEG, especially when celite activation is used. Characteristic tracings are produced with both TEG and Sonoclot analysis, and the parameters that may be quantified (Figs 2 and 3) are useful to differentiate etiologies for bleeding or hypercoagulable states. Viscoelastic parameters are interdependent and abnormalities in coagulation rarely present as single-parameter abnormalities. Thus, an algorithm may be developed for interpretation of abnormal TEG and Sonoclot data in order to better tailor therapy of coagulation abnormalities (Table 3). For example, when there are either inadequate numbers or function of platelets, a diminished MA (~50 mm) is seen, although the ratio A,,:MA is normal. When severe functional platelet deficiencies occur, not

512

CASE 4- 1990

P-

transducer disposable probe vibrating 1 p@ 200 Hz

.fibrin stran ds

whole bbod (0.4 ml)

.cuvette

-T, -I

Time

Fig 3. Sonoclot analysis of clot viscoelasticity. As fibrin strands form, impedance rises at various rates until a peek impedance is achieved. The onset time (T,) reflects the beginning of fibrin formation and the primary slope (R,) reflects further fibrin formation and the speed at which the clot is being formed. An inflection point is often seen where the platelets first start contracting the fibrin strands. The secondary slope WI,) reflects further fibrinogenesis and platelet-fibrin interaction. The peak impedance probably reflects completion of fibrin formation. A downward slope (R,) is produced as platelets induce contraction of the completed clot. Platelet functionality and number are key determinants of the peek impedance end R, values. Clot lysis can be determined by measuring the final impedance as a function of time (ie, severe fibrinolysis results in a final impedance close to that et the onset of clot formation). (Reprinted with permission.?

only will the MA be markedly diminished but there may be mild prolongation of both R and K values. Prolongation of the R value, and possibly of the K value, with normal MA and A,, values, is noted with factor deficiencies or moderate anticoagulation therapy. With near-complete heparinization or an extremely severe platelet deficiency, there will be markedly prolonged R and K values, and MA will diminish to less than 20 mm. In this setting, if heparin has been used, an in vitro protamine titration test may be carried out using whole blood and both channels of the TEG machine, in order to determine whether additional protamine is required or platelet therapy indicated. Full heparinization will result in a straight line TEG tracing with an infinite value for R and K, and an MA value of zero. This will occur not only with full heparinization, but also with afibrinogenemia. Primary fibrinolysis can be diagnosed with the TEG by the presence of nearly normal R and K values, but a diminished MA value and an A,,:MA ratio that is markedly diminished. In contrast, secondary fibrinolysis, which also may occur in a small number of patients after CPB, is associated with markedly prolonged R and K values, as well as severely diminished MA and A,,:MA ratios. Hypercoagulability may be related to plasma or platelet factors; shortened R and K values with MA

values less than 60 mm usually correspond to plasma-related hypercoagulability, while decreases in R and K values with large MA values exceeding 60 mm often reflect platelet-related hypercoagulability. Such hypercoagulability may occur after inappropriate shotgun treatment of patients after CPB with FFP and platelets, and may contribute to acute or subacute vein graft thrombosis or to perioperative myocardial infarction. TEG data have been compared with standard coagulation tests, and loose correlations exist between various TEG parameters and routine coagulation tests. 21 The lack of highly significant correlations between TEG parameters and more commonly used coagulation tests occurs because the TEG does not measure the same processes as routine coagulation tests. TEG examines whole blood coagulation and the interaction of the protein coagulation cascade, fibrinogen, and the platelet surface as a whole, whereas routine laboratory tests examine only isolated plasma protein samples and not the interaction of all coagulation components. Two separate studies have documented that TEG is a significantly better predictor (greater than 85% accuracy) of postoperative hemorrhage and need for reoperation than the activated clotting time or routine coagulation profile (33%

513

CASE 4- 1990

Table 3. Algorithm for Abnormal Coagulation Sondot

TEG Data

Normal R + K

Data

Status Therapy

Interpretation

Normal T, + R, Moderate functional platelet

MA<50

R,<

MA = A,,

R, < 6

MA<50

T, upper normal

R + K upper normal

R, lower normal R,<

15

DDAVP, platelets

deficiency Hypofibrinogenemia

Cryoprecipitate

Hyperfibrinolysis

t-Aminocaproic acid

Factor deficiency

Vitamin K, FFP

Moderate anticoagulation

Vitamin K, protamine, FFP

15,peak<50

MA<50

R, > 8

MA >> A,,

(initial-final) impedance < 20

Prolonged R + K

Prolonged T, + R,

MA and A,, WNL

R,<

R+++. K+ MA = A,,

T,+++. R,< 15

15

R+++.K+++

T,+++,R,---

30 > MA > 20

R,<

MA = A,,

(initial-final)

MA < 50

peak < 60

A,, = 0

R, > 8

R,therapy

15,R,<2

Severe functional platelet

DDAVP, platelets

deficiency

impedance z- 30 Abnormal coagulation with

Depends on clinical setting

secondary lysis

(initial-final) impedance < 20 Ma < 20

peak < 40

Near-complete hepariniza-

R,<10,R3=0

tion or severe platelet

Protamine or platelets

deficiency Ma = 0

Peak absent

R---,K-,MA
ShortenedT,

R--,K---, MA>60

+ R,

T,---,R,+,R,>30 R,<

10

T,--.R,++.R,>30 R,>

Protamine or cryoprecipitate

ogenemia

R, = 0 Decreased R + K

Full heparinization or afibrin-

10

Plasma-related hypercoagulability Platelet-related hypercoagulability

Heparin Warfarin Cyclo-oxygenase inhibition, prostacyclin, dipyridamole

Abbreviations: DDAVP, desmopressin acetate; FFP, fresh frozen plasma.

to 5 1% accuracy).2’v73 Sonoclot analysis is also a significantly better predictor of excessive postCPB bleeding. The majority of abnormalities in TEG and Sonoclot parameters after CPB are those reflective of abnormal platelet-fibrin interaction,73 and these viscoelastic determinants of clot strength are not well measured by routine coagulation tests. With specific reference to this case, a TEG tracing was obtained after CPB but, unfortunately, no baseline viscoelastic measures of coagulation were obtained before heparinization and CPB. The postbypass TEG tracing shows a normal R, slightly prolonged K, normal LX,slight narrowing of MA, and a normal MA:A,, ratio, consistent with a mild abnormality in plateletfibrin interaction. Although routine preoperative coagulation studies were normal, they provide no information about the functionality of the interaction of platelets and fibrinogen. As outlined previously, a variety of perioperative factors all

adversely affect the platelet-fibrin interaction. These include, not necessarily in order of importance, hypothermia, platelet dysfunction related to CPB itself, intravenous vasodilators with platelet-inhibiting effects, residual effects from preoperative aspirin therapy, marginal levels of fibrinogen and platelet counts resulting from hemodilution, as well as loss during cell washing and into the extracorporeal circuit. Because hypothermia contributes to platelet dysfunction and blood is warmed in the TEG machine to 37O, it is possible that in vitro platelet function is better than that occurring in vivo at hypothermia. It is possible to rheostatically control the TEG cuvette temperature to match that of in vivo conditions. Observing greater cx and MA values at normothermic conditions, when compared with that at hypothermia, would suggest that hemostasis could be improved simply by achieving normothermia in vivo. Comparison of viscoelastic measures of clot

514

strength not only requires knowledge of any in vivo to in vitro temperature gradients, but comparisons across time also require knowledge of the hematocrit at which the respective samples are measured. In vitro experiments have shown that decreases in red cell mass with constant platelet and plasma coagulation factor concentrations are associated with increases in (Yand MA values.75 Although the effect of hematocrit on the viscoelastic measurement of clot strength is minor, it may contribute to overestimation of the MA and (Yvalues when compared with prebypass measurements in cases where there is a large decline in red cell mass after CPB. If hemostasis remains a problem after achievement of normothermia, and the TEG appears as it did in this case, other therapeutic alternatives include the administration of desmopressin in order to augment the function of already circulating platelets or the transfusion of orthotopic platelets. Given the scenario of this case, inadequate platelet function would be the most likely cause of the TEG abnormality, associated with clinical bleeding. Hypofibrinogenemia may also have contributed to the diminishment of the MA value, but is not as likely given the relative normality of the remainder of the TEG. In this case, if desmopressin or sufficient quantities of platelets had been given without hemostatic success, cryoprecipitate could have been administered in order to increase the fibrinogen substrate available for clot formation. In any case, the normality of the R value (consistent with the postprotamine ACT values) suggests that procoagulant factor deficiency or inhibition is not likely to have played a major role in the hemostatic defect. Therefore, it is hard to recommend transfusion of FFP as the initial therapy in this case, and it should be used only if the measures just described had failed. It is most likely that achievement of normothermia and “tincture of time” would have resolved the hemostatic difficulties in this case without the use of FFP. The post-CPB TEG tracing offers no evidence of secondary or primary fibrinolysis and t-aminocaproic acid would also not appear to be indicated. In comparing the TEG values with the routine coagulation tests obtained postoperatively, the absolute platelet count and fibrinogen level, coupled with the probable mechanical and pharmacologically induced platelet dysfunction, are consistent with the mildly diminished MA.

CASE 4-l 990

The markedly prolonged PT and aPTT postoperative values are quite inconsistent with the R and K values of the TEG. Because the TEG is exquisitely sensitive to heparin as well as factor deficiencies, artifactual prolongation of R and K values are not uncommon if residual heparin is present either in the arterial catheter flush tubing or circulating in the patient. Conversely, artifactually shortened R and K values are extremely unusual, except in the case of inadvertent celite activation of the sample. Even inadvertent celite activation of the TEG sample would be insufficient alone to cause the degree of disparity observed between the R and K values of the TEG and the PT and aPTT. This suggests that the postoperative PT and aPTT may well have been artifactually elevated for unknown reasons that might include heparin contamination from arterial catheter flush systems, or an inadvertently hemodiluted sample. Regardless of the magnitude of discrepancy between routine coagulation testing and TEG parameters reflective of the plasma portion of the hemostatic process, this is usually not the primary abnormality present after CPB, and might prompt the clinician to repeat the laboratory test before beginning some form of transfusion therapy. Nonetheless, the marked prolongations in the routine measures of plasma coagulation factor activity (PT and aPTT) were probably the motivation for the surgical staff to transfuse FFP. This case points out the extreme complexities of evaluation of the hemorrhagic tendency after CPB. The need to correlate coagulation test abnormalities with the clinical picture is essential. Given the risks associated with most therapies for coagulopathies, it is important to remain cautious in reacting to abnormal laboratory values when clinical bleeding is minimal. Clotting is a dynamic process that is difficult to quantitate, especially when using the static end-points of routine coagulation tests, which provide only minimal information about the quality of the clot, the kinetics of its formation, and the interactions of the various components of the clotting process beyond the first stages of clotting. These limitations are responsible for the very high false-positive rate of prediction of postoperative hemorrhage by routine coagulation tests.73 Careful assessment of the factors that influence viscoelastic properties of blood, in conjunction with the clinical scenario, are necessary to maximize

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4-1990

the effectiveness of TEG in reducing uct use after cardiac surgery.

blood prod-

The Surgeon’s Perspective1 I Cardiac surgery requires total anticoagulation and exposure of the blood to the synthetic surfaces of the extracorporeal circuit. The result is some degree of coagulopathy in every patient and may lead to excessive bleeding in an occasional patient, as described in this case report. Irrespective of the exact cause, coagulopathic bleeding may become evident at any time after the reversal of heparin. Although the TEG has shown promise in the limited series available, there currently is no single laboratory technique that can differentiate a coagulopathy from “surgical” bleeding. Once protamine has been administered and the ACT returned to baseline, treatment of bleeding intraoperatively must begin with meticulous surgical technique. However, after all anastomoses, cannulation sites, and the mammary harvest site have been inspected and hemostasis has been achieved, there is little to be gained by spending lengthy periods of time cauterizing rasv surfaces. Maintenance of the open chest state generally will result in a worsening situation as the patient loses heat to the ambient environment. Specifically, coagulation will not return toward normal until the patient is warm. The shotgun approach should be avoided in general and is rarely necessary intraoperatively. The infusion of blood products, simply because the patient is bleeding, exposes the patient unnecessarily to an increased risk of transfusion reaction and viral infection. Many patients will exhibit a coagulopathy, which varies in the degree of II George S. Tyson, MD

severity but will reverse over the first several hours postoperatively as platelet function returns to normal. 76 Thus, sternal closure should be completed and further diagnosis and treatment of the coagulopathy should be undertaken in the intensive care unit. Routine coagulation studies should be obtained upon the patient’s arrival in the intensive care unit. Infusions of FFP or cryoprecipitate should be given only for a prolonged PTT or demonstrated hypofibrinogenemia, respectively. The decision regarding the administration of platelets is more difficult. The platelet count generally is not severely decreased. Although TEG ultimately may prove helpful, the assessment of platelet function is difficult in the intensive care setting. The platelet dysfunction induced by CPB will resolve over the initial hours postoperatively. However, excessive bleeding in a patient taking aspirin may be an indication for the administration of platelets. Most surgeons base the decision for reexploration on the amount of mediastinal drainage per hour, following the principles established by Kirklin. These absolute criteria may be modified in the presence of a strong suspicion of a coagulopathy, especially when all anastomoses and cannulation sites were carefully inspected and demonstrated to be hemostatic. The use of autotransfusion has also contributed to the willingness to modify these criteria for mediastinal exploration, because the transfusion requirement for homologous blood can be substantially decreased.77v78 In the typical patient whose platelets are dysfunctional following CPB, autotransfusion of shed mediastinal blood allows hemodynamic stability to be maintained while platelet function returns to the baseline preoperative state.

REFERENCES 1. Kirklin JW, Barratt-Boyes BG: Postoperative care, in Cardiac Surgery. New York, NY, Wiley, 1986, pp 139-176 2. Ferraris VA, Ferraris SP, Lough FC, Berry WR: Preoperative aspirin ingestion increases operative blood loss after coronary artery bypass grafting. Ann Thorac Surg 4571-74, 1988 3. Goldman S, Copeland J, Moritz T, et al: Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study. Circulation 77: 1324-1332,1988 4. Bick RL: Hemostasis defects associated with car-

disc surgery, prosthetic devices, and other extracorporeal circuits. Semin Thromb Hemost 11:249-280, 1985 5. Harker LA, Malpass TW, Branson HE, et al: Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: Acquired transient platelet dysfunction associated with selective o-granule release. Blood 56:824834,198O 6. Mammen EF, Koets MH, Washington BC, et al: Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost 11:281-292, 1985 7. Addonizio VP, Colman RW: Platelets and extracorporeal circulation. Biomaterials 3:9-l 5, 1982 8. Edmunds LH, Ellison N, Colman RW, et al:

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Platelet function during cardiac operation. Comparison of membrane and bubble oxygenators. J Thorac Cardiovasc Surg 83805-812, 1982 9. van den Dungen JJAM, Karliczek GF, Brenken U, et al: Clinical study of blood trauma during perfusion with membrane and bubble oxygenators. J Thorac Cardiovasc Surg 83:108-l 16, 1982 10. Valeri CR, Cassidy G, Khuri S, et al: Hypothermia-induced reversible platelet dysfunction. Ann Surg 205: 175-181, 1987 11. Kucuk 0, Kwann HC, Frederickson J, et al: Increased fibrinolytic activity in patients undergoing cardiopulmonary bypass operation. Am J Hematol23:223-229,1986 12. Stibbe J, Kluft C, Brommer EJP, et al: Enhanced fibrinolytic activity during cardiopulmonary bypass in open heart surgery in man is caused by extrinsic (tissue-type) plasminogen activator. Eur J Clin Invest 14:375-382, 1984 13. Hines R, Barash I? Infusion of sodium nitroprusside induces platelet dysfunction in vitro. Anesthesiology 70:611-615, 1989 14. Bull BS, Huse WN, Brauer FS, Korpman RA: Heparin therapy during extracorporeal circulation. II. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 69:685-689, 1975 15. Young JA, Kisker CT, Doty DB: Adequate anticoagulation during cardiopulmonary bypass determined by activated clotting time and the appearance of fibrin monomer. Ann Thorac Surg 26:231-240, 1978 16. Jobes DR, Schwartz AJ, Ellison N, et al: Monitoring heparin anticoagulation and its neutralization. Ann ThoracSurg31:161-166,198l 17. Metz S, Keats AS: Low activated coagulation time during cardiopulmonary bypass does not increase postoperative bleeding. Ann Thorac Surg 49:440-444, 1990 18. Dauchot PJ, Berzina-Moettus L, Rabinovitch A, Ankeney JL: Activated coagulation and activated partial thromboplastin times in assessment and reversal of heparininduced anticoagulation for cardiopulmonary bypass. Anesth Analg 62:710-719, 1983 19. Gravlee GP, Case D, Angert KC, et al: Variability of the activated coagulation time. Anesth Analg 67:469472,1988 20. Bachman F, McKenna R, Cole ER, Najafi H: The hemostatic mechanism after open heart surgery. I. Studies on plasma coagulation factors and fibrinolysis in 512 patients after extracorporeal circulation. J Thorac Cardiovast Surg 70:76-85, 1975 2 1. Spiess BD, Tuman KJ, McCarthy RJ, Ivankovich AD: Thromboelastography as an indicator of post-cardiopulmonary bypass coagulopathies. J Clin Monit 3:25-30, 1987 22. Moriau M, Masure R, Hurlet A, et al: Haemostasis disorders in open heart surgery with extracorporeal circulation. VOX Sang 32:41-51, 1977 23. Okajima Y, Kanayama S, Maeda Y, et al: Studies on the neutralizing mechanism of antithrombin activity of heparin by protamine. Thromb Res 24:21-29, 198 1 24. Ellison N, Ominsky AJ, Wollman H: Is protamine a clinically important anticoagulant? Anesthesiology 35:621-629, 1971 25. Bull BS, Korpman RA, Huse WM, Briggs BD: Heparin therapy during extracorporeal circulation. I. Prob-

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lems inherent in existing heparin vast Surg 69:674-684, 1975

protocols.

J Thorac

Cardio-

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