- Email: [email protected]
Reduction and elimination of systemic heparinization during cardiopulmonary bypass
Reduction and elimination of systemic heparinization during cardiopulmonary bypass After extensive experimental evaluation, heparin-coated perfusion equipment was clinically evaluated with low or no systemic heparinization in three different groups of patients (n = 47). In group 1, resection of descending thoracic aortic aneurysms (n = 24) was performed with heparin-coated equipment used for left heart bypass (n = 12) or partial cardiopulmonary bypass (n = 12) for proximal unloading and distal protection (heparin 5000 IV, autotransfusion). All devices remained functional throughout the procedures and no systemic emboli were detected. The sole death (1 of 24, 4 %) occurred in a patient with ruptured thoracoabdominal aortic aneurysm requiring operation in extremis. Paraparesis with spontaneous recovery occurred in one patient (1 of 24, 4 %). In group 2, coronary artery revascularization randomized for low (activated clotting time greater than 180 seconds) versus full (activated clotting time greater than 480 seconds) systemic haparinization was prospectively analyzed in 22 patients. All patients recovered without sequelae, and no myocardial infarction was diagnosed. Low dose of heparin (8041 ± 1270 IV versus 52,500 ± 17,100 IV; p < 0.0005) resulted in reduced protamine requirements (7875 ± 1918 IV versus 31,400 ± 14,000 IV; p < 0.0005~ reduced blood loss (831 ± 373 00 versus 2345 ± 1815 00; p < 0.01), reduced transfusion requirements of homologous blood products (281 ± 415 00 versus 2731 ± 2258 00; p < 0.001), and less patients transfused (5 of 12 versus 10 of 10; p < 0.05). Lower D-dimer levels in the group perfused with low systemic heparinization (0.50 ± 0.43 mg/L versus 1.08 ± 0.59 mg/L; p < 0.05) were attributed to the absence of cardiotomy suction in this group. In group 3, rewarming in accidental hypothermia by cardiopulmonary bypass was successfully performed without systemic heparinization in a patient with hypothermic cardiac arrest (23.3° C) and intracranial trauma. We conclude that systemic heparinization for clinical cardiopulmonary bypass can be reduced and eliminated in selected patients if perfusion equipment with improved biocompatibility is used. Bypass-induced morbidity can be reduced. (J THORAC CARDIOVASC SURG 1992;103:790-9)
Ludwig K. von Segesser, MDa (by invitation), Branko M. Weiss, MD,b Eligio Garcia, BN (by invitation), Arthur von Felten, MDC (by invitation), and Marco I. Turina, MD,a Zurich, Switzerland
Nowadays the polymer industry is able to provide a large scale of versatile materials from which all sorts of devices may be extruded. Polytetrafluoroethylene is used From the Clinic of Cardiovascular Surgery,' the Institute of Anesthesiology," and the Department of Medicine," University Hospital, Ziirich, Switzerland. Supported by the Swiss National Foundation for the Development of Scientific Research, grant 32-26271.89. Read at the Seventy-first Annual Meeting of the American Association for Thoracic Surgery, Washington, D.C., May 6-8,1991. Address for reprints: Ludwig K. von Segesser, MD, Clinic for Cardiovascular Surgery, University Hospital, CH-8091 Ziirich Switzerland.
12/6/34910
790
for vascular grafts and for clothes, polypropylene is used for microporous hollow fibers in oxygenators and for carpets, polyvinylchloride is used as tubings for perfusion and as garden hoses, and polyethylene is used for connectors and other parts in cardiopulmonary bypass (CPB) sets as well as for trash bags in waste management. None of the materials cited was primarily developed for medical application, and there is little surprise to see that the overall biocompatibility of today's perfusion equipment remains poor. Hence during perfusion with standard equipment we have still to induce so-called full systemic heparinization that equates the extremely pathologic condition of total incoagulability of the blood. Various approaches to improve the biocompatibility of
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79 I
Table 1.. Experimental evaluation of heparin-coated surfaces Model Roller pump LHBP (n = 20)
Canine, LA-aorta
LHBP (n = 20) Centrifugal pump LHBP (n = 10) Pulsatile device LVAD (n = 15) CPB Open chest (n = 40)
Closed chest (n
= 30)
Coating
Duration
Ref No.
6 hr
9
Bovine. LA-aorta
TDMAC, Duraflo II, CBAS Duraflo II, CBAS
6 hr
10
Bovine, LA-aorta
CBAS
6 hr
11
Bovine LA-aorta
CBAS
6 and 24 hr
12
Canine. bovine, RA-aorta
Duraflo II, CBAS
6 and 24 hr
Bovine, jugular veincarotid artery
Duraflo II, CBAS
6 hr with 7-day survival
13 14 15 16
LHPB, Left heart bypass; LA, left atrium; RA, right atrium; LVAD, left ventricular assist device; CPB, cardiopulmonary bypass. Suppliers: TDMAC: (tridodecylmethylammonium chloride), Sherwood Medical, St Louis, Mo.; Duraflo II, Baxter Healthcare Corporation, Irvine, Calif.; CBAS, Carmeda Bioactive Surface; Carmeda, Stockholm, Sweden.
Table II. Perfusion data for resection of descending thoracic aortic aneurysms n Coating Perfusion (min) Heparin (IU) Protamine (IU) ACT (sec) Baseline After heparin 10 min bypass 30 min bypass After protamine
LHBP
p<
Partial CPB
All
12 CBAS 35 ± 21 7813 ± 2915 5443 ± 860
NS
10 Duraflo II 41 ± 18 8963 ± 2208 7236 ± 3348
24
± ± ± ± ±
NS 0.05 0.05 NS NS
113 199 198 232 118
10 25 39 51 9
NS NS NS
124 286 442 288 131
± ± ± ± ±
25 67 301 105 30
38 ± 19 8283 ± 2524 6428 ± 2792 119 260 356 270 127
± ± ± ± ±
21 70 250 93 26
LHBP, Left heart bypass; CPB, cardiopulmonary bypass; CBAS, Carmeda Bioactive Surface; NS, not significant; ACT, activated clotting time.
blood-exposed surfaces are currently explored, including hybrid vascular grafts with endothelial cell lining, I textured surfaces allowing tissue ingrowth.? development of new polymers with active surface groups;' and bonding of heparin" or other substances to existing surfaces. The most sophisticated concept (and also a complex ethical issue) is probably the combination of all suggested approaches, that is, realization of hybrid artificial organs with textured surfaces exposing specific groups that allow solid anchoring of genetically modified cells secreting antithrombotic and, eventually, other drugs. At this time, however, the various heparin-bonding techniquesi" appear to be the most suitable approach to improve the thromboresistance of blood-exposed surfaces in existing disposable devices used for short-term application. We have systematically evaluated various heparin-coated surfaces in numerous experiments since 1985. The major steps in this evolution included left heart bypass with
heparin-coated tubing sets, left ventricular assist with heparin-coated devices, and CPB with heparin-coated oxygenators and tubing sets with USe of full, low, and no systemic heparinization as summarized in Table I. The data compiled from our own and other studies convinced us that heparin surface-coated perfusion equipment can be used in the clinical setting with reduced systemic heparinization,
Patients and methods Heparin-coated perfusion equipment was used clinically in three differentgroups of patients (n = 47), including resection ofdescending thoracicaorticaneurysms, coronaryartery revascularization, and rewarming in accidental deep hypothermia. Resection of descending thoracic aortic aneurysms. Heparin-coatedshunts for distal perfusion to protect the spinalcord during operation on the descending thoracic aorta have been available for many years.i For this study,a pump was added to the circuit to increase the shunt flow" for proximal unloading
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Table III. Results ofproximal unloading and distal protection during resection of descending thoracic and thoracoabdominal aortic aneurysms with use of heparin-coated perfusion equipment and low systemic heparinization Device LHBP Roller pump Centrifugal pump Part ial CPB Centrifugal pump Roller pump Mortality Parapareses
Coaling CBAS CBAS CBAS Duraflo II
n 4 8 2 10
Nonsurvivors
Parapareses
0 1
0 0
0 0 1/24 (4%)
0 1 1/24 (4%)
Fig. 1. CBAS heparin-coated centrifugal pump head rinsed after clinical perfusion with low systemic heparinization (5000 IV): clean device.
LHBP, Left heart bypass; CPB, cardiopulmonary bypass; CBAS, Carmeda Bioactive Surface.
and distal protection . Left heart bypass was realized with CBAS (Carmeda Bioactive Surface; Carmeda, Stockholm, Sweden) heparin-coated perfusion equipment with use of an inletpressure servocontrolled roller pump (Stockert, Munich, German y; n = 4) or a centrifugal pump (Bio-Medicus, Minneapolis, Minn.; n = 8) in 12 patients undergoing resection of descending thoracic and thoracoabdominal aortic aneurysms . A single dose of heparin (5000 IV ; Liquemin, Roche , Basel, Switzerland) was given to facilitate the use of a red cell washing device (Autotrans, Dideco, Mirandola , Italy). A CBAS heparin-coated oxygenator (Maxima, Medtronic, Anaheim, Calif.) was added to the perfusion circuit for patients with extremely poor respiratory function (n = 2) . After this experience, partial CPB with Duraflo II heparin-coated equipment (Baxter Healthcare Corp., Irvine, Calif.), including a hollow-fiber membrane oxygenator (BOS-CM 50) and low systemic heparinization (100 IU /kg body weight), was used routinely in 10 patients undergoing repair of descending thoracic and thoracoabdominal aortic aneurysms. Coronary artery revascularization. The positive results of partial CPB with low systemic heparinization encouraged us to perform a prospectively randomized study for evaluation of heparin-coated perfusion equipment during total CPB with low systemic heparinization. Twenty-two selected patients undergoing elective coronary artery revascularization were randoml y assigned to two groups perfused with heparin-coated CPB equipment and either low activated clotting time [ACT] greater than 180 seconds (Hemochron, International Technidyne, Edison, N.J.) or full (ACT> 480 seconds) systemic heparinization. The protocol used was accepted by the institutional review board , and informed consent was obtained from each patient included in the study . Inclusion criteria for this study were body weight greater than 50 kg, left ventricular ejection fraction greater than 35%, and expected hematocrit value during perfusion greater than 20%. Exclusion criteria were known coagulopathies, ongoing anticoagulation, and emergenc y procedures. Low versus full systemsic heparinization was defined as follows: heparin loading dose 100 IV /kg versus 300 IV /kg body weight, heparin priming dose 1000 IU/ L versus 5000 IV /L of priming fluid, ACT greater than 180 seconds versus greater than 480 seconds, protamine (Roche, Basel, Switzerland)
equivalent to the respective heparin loading dose, and shed blood recovery during the procedure by a red cell washing device versus cardiotomy suction. Duraflo II heparin-coated perfusion equipment, including coated cannulas, coated flexible venous reservoirs, coated heat exchanger/oxygenator structures (BOSCM 50, Baxter Healthcare Corp ., Irvine, Calif.) coated arterial filters, and coated tubings and connectors, were used in all patients. CPB was performed with clear priming fluid (Ringer's lactate solution), complete hemodilution, and moderate hypothermia. Coronary artery revascularization was realized under cardioplegic arrest of the heart (cold, high-potassium cardioplegie solution) as previously reported . A standard battery of blood samples was drawn before heparin, after heparin, and at regular intervals during as well as after CPB for hematologic analyses and coagulation studies. The latter included ACT , platelet counts, thrombin time (first dilution was performed with 4 V of thrombin per milliliter; Roche, Basel, Switzerland), activated partial thromboplastin time (PTT reagent; Behringwerke AG, Marburg, Germany), prothrombin time (Thromborel S, Behringwerke Marburg, Germany), and D-dimer levels (latex agglutination test with a monoclonal antibody : Boehringer, Mannheim GmbH, Germany). Rewarming in accidental deep hypothermia. Rewarming in accidental deep hypothermia is an accepted indication for CPB. However, systemic heparinization in hypothermic patients with polytrauma and especially craniocerebral trauma is contraindicated. Hence rewarming with CPB with use of heparin-coated perfusion equipment without systemic heparinization was selected in a hypothermic patient with a core temperature of 23.3° C, cardiac arrest, and severe craniocerebral trauma. For this purpose Duraflo II heparin-coated perfusion equipment was used as reported previously. No heparin was added to the priming fluid and no heparin was given systemically, however. Data analyses. Quantitative data are represented as the mean ± standard deviation. Student's t test and analysis of variance (GLM-ANOVA; Solo: BMDP Statistical Software Inc, Los Angeles, Calif.) were used for comparison of quantitative data where applicable . Fisher's exact test was used for comparison of nonparametric data. Statistical significance is confirmed by a probability value (p < 0.05).
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Reduction of systemic heparinization during CPB
0----0
Table IV. Basic parameters in patients undergoing coronary artery revascularization with use of heparin-coated CPB equipment with low versus full systemic heparinization Heparinization (ACT) Age (yr) Body weight (kg) Body surface area (m-) CPB duration (min) Crossclamp time (min) Number of bypasses ITA anastomoses Nonsurvivors Myocardial infarction
Low
Full
(>180 sec)
(>480 sec)
59 ± 9 72 ± 1.8 ± 69 ± 36 ± 2.9 ± 1.1 ±
9
0.1 16
12 0.8 0.8
0/12 0/12
56 ± 70 ± 1.8 ± 66 ± 35 ± 3.2 ± 0.9 ±
6 7
ACT
793
ACT~4BO
....--.. ACT>180
600
400
0.2 14 8 0.6 0.3
0/10 0/10
ACT. Activated clotting time; CPR, cardiopulmonary bypass; ITA. internal thoracic artery.
200
o L......JC--.---'_---'-_---'-_-----'-_--'-_ baseline heparin 10'
30'
45'
_____'__----'-_ _-'--_---'
60' protamine 50' post
Fig. 2. MeanACT ± standard deviations before, during,and after CPB with lowversus full systemic heparinization.
Results Resection of descending thoracic aortic aneurysms. Perfusion data for patients undergoing resection of descending thoracic and thoracoabdominal aortic aneurysms are given in Table II. Similar mean values were found in the two analyzed groups for perfusion time, heparin dose, protamine dose, as well as prebypass and postbypass ACT. ACT after heparin and after 10 minutes of bypass was higher in the group with partial CPB. The outcome of these first 24 patients, perfused with low systemic heparinization, is shown in Table III. The sole death in this series (1/24; 4%) occurred (unrelated to the technique) in a patient with ruptured thoracoabdominal aneurysm requiring an operation in extremis. Paraparesis with spontaneous recovery occurred in one patient (1/24; 4%). All devices remained functional throughout the procedures, and no systemic emboli were detected. After perfusion all devices were carefully analyzed. No macroscopic red clots were found. A heparin-coated centrifugal pump head, rinsed after clinical perfusion with low systemic heparinization, is shown in Fig. 1. It is absolutely clean. Coronary artery revascularization. Basic parameters like body weight, body surface area, perfusion time, crossclamp time, number of bypasses, and number of internal thoracic artery anastomoses were similar for the two groups (Table IV). All patients survived the procedure without sequelae, and no myocardial infarction was diagnosed by creatine kinase levels and electrocardiogram. Mean ACTs measured in the two analyzed groups are depicted in Fig. 2. The prebypass ACT moved from 117 ± 11 seconds to 241 ± 28 seconds after heparin for the group perfused with low systemic heparinization versus from 107 ± 13 seconds to 382 ± 86 seconds for full systemic heparinization. Throughout perfusion the mean
15'
Gradient
0-- --0
ACT~4BO
--
ACT>180
mmHg .-----
-----,
200
150
100
50
O'--'--'"--~-~-----'-~------'---'-""'------'-------'--~
Start
10'
15'
30'
45'
60'
End
CPS
Fig. 3. Mean oxygenator pressuregradient ± standard deviation during CPB with lowversus full systemic heparinization: not significant. values measured were between 240 and 277 seconds for low and between 382 and 570 seconds for full systemic heparinization. The lowest ACT observed in the group perfused with low systemic heparinization was 210 seconds. Hence no additional heparin was necessary in this group with a mean perfusion time above 60 minutes. In the control group, however, additional heparin was necessary in most cases to maintain the ACT above 480 seconds. The results of the coagulation studies are tabulated in Table V. Similar platelet levels were measured in the two analyzed groups. Throughout perfusion the thrombin time was above 200 seconds in both groups, and the latter was significantly higher early after protamine in the group perfused with full systemic heparinization. No difference was observed for the activated partial thromboplastin time during and after perfusion for the two groups.
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Table V. Coagulation studies in patients undergoing coronary artery revascularization with use of CPR with low versus full systemic heparinization Heparinization
Low
Full
(10 3j ,um3)
Platelets Baseline After heparin 10 min bypass 45 min bypass After protamine 24 hr Thrombin time (sec) Baseline After heparin During bypass After protamine 60 min after protamine Activated partial thromboplastin time (sec) Baseline After heparin 10 min bypass 45 min bypass After protamine 60 min after protamine Prothrombin time (%) Baseline After heparin 10 min bypass 45 min bypass After protamine 60 min after protamine D-dimers (mgjL) Baseline Heparin 10 min bypass 45 min bypass After protamine 60 min after protamine
266 225 130 140 153 131
± 71 ± 65 ± 36 ± 49 ± 59 ± 38
13.5 ± 1.4 >200 >200 25.2 ± 13.5 14.8 ± 5.0
293 227 142 140 141 133
± 88 ± 62 ± 37 ± 31 ± 32 ± 33
13.3 ± 1.0 >200 >200 111.2 ± 89.1 17.5 ± 5.7
p
NS NS NS NS NS NS NS NS NS <0.05
NS
39 43 61 55 45 44
± 4 ± 4 ± 9 ± 8 ± 6 ± 7
35 47 61 86 49 47
± 3 ± 8 ±7 ± 61 ±6 ±8
<0.05
97 73 46 49 64 73
± 7 ± 5 ± 3 ± 6 ± 6 ± 7
98 69 48 38 52 69
± ± ± ± ±
3 8 9 12 8 ± 10
NS NS NS
0.31 0.33 0.25 0.25 0.50 0.47
± 0.15 ± 0.19 ± 0.00 ± 0.00 ± 0.43 ± 0.42
0.25 0.60 0.50 0.42 1.08 1.17
± 0.00 ± 0.49 ± 0.25 ± 0.24 ± 0.59 ± 0.47
NS NS NS NS NS
<0.05 <0.05
NS
NS NS <0.05 <0.05 <0.05 <0.05
CPB. Cardiopulmonary bypass; NS. not significant.
Prothrombin time, however, remained significantly longer at the end of perfusion and early after protamine in the group perfused with full systemic heparinization. The D-dimer levels remained relatively low for both groups; however, they were significantly higher in the group perfused with full systemic heparinization. There was no difference for the pressure gradients measured throughout the perfusions between the blood inlet and outlet of the heat-exchanger/oxygenator structure (Fig. 3) perfused with low versus full systemic heparinization (final value at full flow, III ± 9 mm Hg for low versus 110 ± 16 for full; not significant). CPB with heparincoated equipment and low dose of heparin, 15% of control (8041 ± 1270 IV versus 52,500 ± 17,100 IV; p < 0.0005), resulted in reduced protamine requirements of only 25% of control (7875 ± 1918 IV versus 31,400 ± 14,000 IV; p < 0.0005), as shown in Fig. 4.
Mean blood loss (defined as total chest tube drainage) for low systemic heparinization was 35% of that for full systemicheparinization(831 ± 373 ml versus 2345 ± 1815 ml; p < 0.01), and transfusion requirements (defined as homologous blood and blood products) were 10%of those for full systemic heparinization (281 ± 415 ml versus 2731 ± 2258 ml; p < 0.001), as shown in Fig. 5. Fewer patients perfused with low systemic heparinization received blood or blood products (5/12 versus 10/10; p < 0.05). Mean hematocrit value is depicted in Fig. 6. The baseline values are 44% ± 3% for both groups. After mixing blood with the priming fluid, we measure 23% ± 3% for low systemic heparinization, and 22% ± 3% for full systemic heparinization, and at the seventh day the respective values are 32% ± 5% and 35% ± 3% (not significant). The only significant difference is observed 60 minutes after protamine, where we
Volume 103 Number 4 April 1992
Reduction of systemic heparinization during CPR
i.u, r - - - - - - - - - - - - - - - - - - - - - , 50'000
795
ml
Bloodloss
Heparin
3000
[I
Transfusion
40'000 30'000
2000
20'000 1000 10'000
o
0 ACT>180
ACT>480
Fig. 4. Totalheparinand protaminedoses (mean ± standard deviation) applied during coronary artery revascularization procedures with low and full systemic heparinization. measure 35% ± 3% for low systemic heparinization versus 26% ± 2% for full systemic heparinization (p < 0.0005). At the end of the procedure, all oxygenators, venous reservoirs, arterial filters, and tubings were carefully analyzed. Despite the fact that occasionally some degree of localized red staining could be observed in devices perfused with low systemic heparinization, there were no macroscopic red clots (Fig. 7). Rewarming in accidental hypothermia. After initiation of CPB without systemic heparinization under ongoing cardiac massage, cardiac activity resumed spontaneouslyafter 12 minutes of perfusion at a core temperature of 26° C. Weaning from CPB was feasible after 96 minutes at 35° C. However, reperfusion for another 42 minutes was necessary because of low cardiac output resulting from high serum potassium levels. Whereas perfusion of the patient without systemic heparinization lasted 138 minutes, perfusion of the pump-oxygenator system, including recirculation, totaled 182 minutes. As usual, the CPB equipment was carefully analyzed after the procedure. There were no macroscopic clots in the perfusion circuit, and the arterial filter was clean (Fig. 8). Progressive somatic and neurologic recovery of the patient followed after 3 weeks of intensive care including intracranial pressure monitoring, peritoneal dialysis, and mechanical ventilation. Discussion Systemic heparinization for CPB can be reduced and eliminated in selected applications if adequate equipment, perfusion techniques, and surgical skills are available. Improved thromboresistance of heparin-coated surfaces has been shown by many studies.r! and perfusion with heparin-coated equipment with low or no systemic heparinization was realized in canine and bovine experiments
ACT>480
ACT>180
Fig. 5. Mean bloodloss(defined as total chest tube drainage) and transfusions of homologous blood and blood products (± standarddeviation) forpatientsperfusedwithlowversus full systemic heparinization.
0----0 ACT>480 - - ACT>180
'l6r---------------------, 50
30
20
10
O'--"---'----.J~__.J
baseline heparin 10'
_
____'_
___I._
60' protamine 60' CPB post
___I._
24 h
___'__
48 h
___'__---'
7 days
Fig. 6. Mean hematocrit value ± standard deviation for patients perfused with lowversus full systemic heparinization. for left heart bypass with roller, centrifugal, and pulsatile pumps, high-flow open chest CPB, and prolonged lowflow CPB, as well as for closed chest CPB, in surviving animals, as has been shown herein. Other groups investigated similar protocols in bovine," ovine,18, 19 and canine" experiments. Improved thromboresistance of blood-exposed surfaces with heparin coating was documented by hematology, biochemistry, coagulation, immunology, and scanning electron microscopy.'"!" In the experimental setup, intact hemostasis during perfusion resulted in reduced blood loss and transfusion requirements, as well as superior hemodynamics.I" preserved renal function, and attenuated hormonal stimulation." Translation of the findings described into clinical practice was initiated many years ago by the introduction of the Gott shunt for resection of descending thoracic aortic aneurysms. Other
The Journal' of .
7 9 6 vonSegesser et al.
Fig. 7. Heparin-coated heat exchanger and oxygenator inlet gently rinsed after clinicalCPB with lowsystemic heparinization for coronary artery revascularization: no macroscopic deposits.
groups used standard perfusion equipment without systemic heparinization in patients with an impaired coagulation system, such as during liver transplantation.F Heparin-coated oxygenators and perfusion circuits were primarily used clinically for extracorporeal lung assist because of the well-known bleeding problems in this group of patients.P However, there are other groups of patients in the cardiovascular field with bleeding problems. Because of the latter, CPB was abandoned by most groups during resection of descending thoracic aortic aneurysms.i" and simple crossclamping of the aorta with rapid reanastomosis was advocated. The availability of heparin-coated perfusion equipment that can be used with low systemic heparinization allowed the reintroduction of efficient proximal unloading and distal perfusion during staged resection of large descending thoracic and thoracoabdominal aortic aneurysms. During the series operated on with left heart bypass, we
Thoracic and Cardiovascular Surgery
noted that additional heparin was necessary in some cases to avoid clots in the operating field if a loading dose of only 5000 IV was used. Hence a loading dose of 100 IVjkg body weight was applied in the series operated on with partial CPB. The results that have been presented include elective and emergency procedures and are with an in-hospital mortality and paraparesis rate of 4%, clearly superior to our previous experiences.P The fact that no device failures occurred during resection of descending thoracic and thoracoabdominal aneurysms and that bleeding was controllable in all cases encouraged us to explore further applications of perfusion with heparin-coated equipment and low systemic heparinization. Hence CPB with heparin-coated equipment with low (ACT> 180 seconds) versus full (ACT> 480 seconds) systemic heparinization was prospectively analyzed. Interestingly, the coagulation studies performed showed only few differences between the group perfused with low systemic heparinization and the group perfused with full systemic heparinization. During perfusion, all patients had thrombin times above 200 seconds, demonstrating significant anticoagulation in both analyzed groups (see Table V). The problems with heparin "neutralization" by means of protamine, however, are well demonstrated by prolonged thrombin times and prolonged prothrombin times in the group with full systemic heparinization after protamine application. These findings may also explain the superior blood loss in the group perfused with full systemic heparinization. We attribute the higher p-dirner levels observed in the group with full systemic heparinization to the use of cardiotomy suction in this group. Cardiotomy suction is known for significant blood trauma. 15 The results reported herein, namely, reduced heparin and protamine requirements, reduced bleeding and transfusion requirements, and a lesser number of patients requiring less homologous transfusions, speak for themselves and confirmed the results of our preliminary report-" It has to be mentioned here that the blood loss and transfusion requirements reported for the group perfused with full systemic heparinization do not represent our current practice, which includes routine application of aprotinin.i? CPB with heparin-coated equipment without systemic heparinization was finally realized in an extreme situation where no standard procedure appeared applicable. There can be no doubt about the fact that rewarming in accidental deep hypothermia without CPB is extremely difficult once cardiac arrest has occurred.f Although several recent reports questioned the necessity for so-called full systemic heparinization (ACT> 480 seconds is recommended by most oxygenator manufacturers) during CPB with standard equipment.P'" thereduc-
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Reduction of systemic heparinization during CPR
797
Fig. 8. Heparin-coated perfusionequipment after clinicalCPB without systemicheparinization for rewarming in deep accidental hypothermia: clean devices.
tions of systemic heparinization suggested in these studies are far less than those reported here for perfusion with heparin-coated equipment. Furthermore, we have shown that severe clotting can occur when standard equipment is used without systemic heparinization.v 14 We conclude from these and other data that heparin surface coating significantly improves the thromboresistance of existing perfusion equipment. Hence perfusion with low systemic heparinization can be realized in selected cases, and bypass-induced morbidity can be reduced. Reduced bleeding and transfusion requirements are also of increasing interest in patients refusing transfusion of homologous blood and blood products. At this time the main limitation for clinical application of heparin-coated perfusion equipment with low systemic heparinization appears to be the lack of a cardiotomy system functioning despite low systemic heparinization. It has to be repeated here that the lower systemic heparinization is the higher is the potential for clot formation . Furthermore, it is now known that the antithrombotic efficiency of heparin surface coating in perfusion equipment is strictly flow dependent. 20 Hence some basic rules have to be respected during perfusion with low systemic heparinization: (I) Blood stagnation (low flow) in the perfusion circuit must be avoided; (2) immediate recirculation through an arterio-
venous bridge close to the cannulas is necessary; and (3) venting of cannulas before starting perfusion is recommended. REFERENCES 1. Muller-Glauser W, Lehmann KH, Bittmann P, et al. A compliant small-diameter vascular prosthesis lined with functional venous endothelial cells. Trans Am Soc Artif Intern Organs 1988;34:528-31. 2. Dasse KA, Chipman SO, Sherman CN, et al. Clinical experiencewith textured blood contacting surfaces in ventricular assist devices. ASAIO J 1987;10:418-25. 3. Josefowicz M, Jozefonvicz J. New approaches to anticoagulationheparin likebiomaterials. ASAIO J 1985;8:218-22. 4. Gott VL, Whiffen JD, Datton RC. Heparin bonding on colloidal graphite surfaces. Science 1963;142:1297-8. 5. Cukingnan RA, Fee HJ , Carey JS. Repair oflesions ofthe descending thoracic aorta with the TDMAC-heparin shunt. J THORAC CARDIOVASC SURG 1978;75:227-31. 6. Kim SW, Ebert CD, Lin JY, et al. Nonthrombogenic polymers. Pharmaceutical approaches. ASAIO J 1983; 6:76-87. 7. Larm 0 , Larsson R, Olsson P. A new non-thrombogenic surface prepared by selective covalent binding of heparin via a modified reducing terminal residue. Biomater Med Devices Artif Organs 1983;11:161-73.
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8. Tong SD, Rolfs MR, Hsu LC. Evaluation of Duraflo II heparin immobilized cardiopulmonary bypass circuits. Trans Am Soc Artif Intern Organs 1990;36:M654-6. 9. von Segesser LK, Weiss BM, Turina MI. Perfusion with heparin-coated equipment: potential for clinical use. Semin Thorac Cardiovasc Surg 1990;2:373-80. 10. von Segesser LK, Weiss BM, Gallino A, et al. Superior hemodynamics in left heart bypass without systemic heparinization. Eur J Cardiothorac Surg 1990;4:384-9. II. von Segesser LK, Lachat M, Gallino A, et al. Performance characteristics of centrifugal pumps with heparin surface coating. Thorac Cardiovasc Surg 1990;34:224-8. 12. von Segesser LK, Weiss BM, Bisang B, Leskosek B, Turina MI. Ventricular assist with heparin surface coated devices.Trans Am Soc Artif Intern Organs 1991;37:H2789. 13. von Segesser LK, Turina MI. Heparin coated hollow fiber membrane oxygenator without systemic heparinization in comparison to classic membrane and bubble oxygenators. J Extracorp Technol 1988;76-80 [Proceedings issue]. 14. von Segesser LK, Turina M. Cardiopulmonary bypass without systemic heparinization: performance of heparin coated oxygenators in comparison with classic membrane and bubble oxygenators. J THORAC CARDIOVASC SURG 1989;98:386-96. 15. von Segesser LK, Turina M. Long term cardiopulmonary bypass without systemic heparinization. Int J Artif Organs 1990;13:687-91. 16. von Segesser LK, Lachat M, Leskosek B, et al. Cardiopulmonary bypass with low systemic heparinization: an experimental study. Perfusion 1990;5:267-76. 17. von Segesser LK. Arterial grafting for myocardial revascularization. 1st ed. Berlin: Springer, 1990:48-79. 18. Toomasian JM, Hsu LC, Hirschi RB, Heiss KF, Hultquist KA, Bartlett RH. Evaluation of Duraflo II heparin coating in prolonged extracorporeal membrane oxygenation. Trans Am Soc Artif Intern Organs 1988;34:410-4. 19. Mottaghy K, Oedekoven B, Schaich-Lester D, Poppel K, Kiipper W. Applications of surfaces with end-point attached heparin to extracorporeal circulation with membrane lungs. Trans Am Soc Artif Intern Organs 1989; 35:146-52. 20. Anander C, Olsson P. Influence of blood flowand the effect of protamine on the thromboresistant properties of a covalently bonded heparin surface. J Biomed Mater Res 1988;22:859-68. 21. Weiss BM, von Segesser LK, Vetter W, Gautschi K, Pasch T. Heparin coated left heart bypass: renal function and hormonal response. Int J Artif Organs 1990;13:565. 22. McSteen F, Hackett J, Rhoades W, et al. Heparinless bypass for liver transplantation. Proc Am Acad Cardiovasc Perfusion 1984;5:28-9. 23. Bindslev L, Eklund J, Norlander 0, et al. Treatment of acute respiratory failure by extracorporeal carbon dioxide elimination performed with a surface heparinized artificial lung. Anesthesiology 1987;67:117-20. 24. Livesay 11, Cooley DA, Ventimiglia RA, et al. Surgical
25.
26.
27.
28.
29.
30.
31.
experience in descending thoracic aneurysmectomy with and without adjuncts to avoid ischemia. Ann Thorac Surg 1985;39:37-46. von Segesser LK, Burki H, Schneider K, Siebenmann R, Schmid ER, Turina M. Outcome and risk factors in surgery of descending thoracic aortic aneurysms. Eur J Cardiothorae Surg 1988;2:100-5. von Segesser LK, Weiss HM, Garcia E, Gallino AS, Turina M. Reduced blood loss and transfusion requirements with low systemic heparinization: preliminary clinical results in coronary artery revascularization. Eur J Cardiothorac Surg 1990;4:639-43. von Segesser LK, Weiss BM, Leskosek B, von Felten A, Pei P, Turina M. Experimental evaluation of heparin coated cardiopulmonary bypass equipment with low systemic heparinization and high dose aprotinin. Thorac Cardiovasc Surg 1991;39:251-6. Schmid ER, von Segesser L, Hossli G, et al. Akzidentelle Hypothermie: Wiedererwarmung mit extrakorporaler Zirkulation. Anaesthesist 1989;38:120. Metz S, Keats AS. Low activated coagulation time during cardiopulmonary bypass does not increase postoperative bleeding. Ann Thorac Surg 1990;49:440-4. Gravlee GP, Haddon WS, Rothberger HK, et al. Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J THORAC CARDIOVASC SURG 1990; 99:518-27. Cardoso PFG, Yamazaki F, Keshavjee S, et al. A reevaluation of heparin requirements for cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1991;101:153-60.
Discussion Dr. Stefan Thelin (Uppsala, Sweden). The lack of biocompatibility in standard CPB circuits is one reason for morbidity after CPB. Our group in Uppsala, Sweden, have studied CPB circuits coated with end-point-attached heparin both experimentally and clinically. In our clinical studies we found that accepting ACTs down to 300 seconds had no effect on the postoperative blood loss. A further reduction of the heparin dose, accepting ACTs down to 200 seconds, resulted in a significant reduction in the postoperative blood loss (16 hours) from 735 ± 67 ml (control) to 578 ± 33 ml (heparin coated). However, independent of the heparin dose given, there was a significant reduction in the adherence and activation of blood cells illustrated in scanning electron micrographs from arterial filters. Coated filters from coated circuits showed a significant reduction in adherence of blood cells when compared with the control filters. Moreover, the groups treated with heparin-coated equipment also showed a significantly reduced release of the granulocyte factors lactoferrin and myeloperoxidase, indicating less activation of granulocytes. Do you have any indications for important differences in biocompatibility between different methods of heparin coating? What is your opinion on the use of heparin-coated circuits and normal doses of heparin during transplant operations to decrease the activation of the immunologic system? Dr. von Segesser. We think that for specific applications some coatings may have advantages over others. In some the
Volume 103 Number 4 April 1992
heparin is supposed to stay longer in its place. Even if there is some washout from the surface, however, this might have an advantage in situations where there is low flow. There cannot be one coating that is superior in any situation. We cannot say, in regard to the second question, if there is an advantage of coating in full systemic heparinization because of the wide variability in the parameters of immunologic activation that display a well-known lack of clinical correlates, and therefore we have not analyzed this approach. Dr. Delos M. Cosgrove (Cleveland, Ohio). Would you care to speculate about other potential uses for coating intravascular devices? Dr. von Segesser. We have evaluated pulsatile ventricular assist devices and have seen similar results. Dr. James L. Cox (St. Louis, Mo.). Could you explain the difference between this coating and the Carmeda coating process that is being used by the group in Uppsala? Dr. von Segesser. We have used both coatings in this series. The coating that was used in the coronary bypass study is an ionic coating provided by Baxter Healthcare Corporation; it is insoluble in water and has good properties for staying on the
Reduction of systemic heparinization during CPB
799
surface. We could not measure heparin washout in vivo when we tried to measure it. The Carmeda process, which was also used in our study for resection of aortic aneurysms, uses covalent bonding, which has superior adherence to the surface. From this point of view, it may have an advantage in long-term applications. Dr. Craig R. Smith (New York, NiY}. I am responding in particular to your experience with the patient you rewarmed. I think reduction in heparin with this approach would be particularly attractive in patients in whom we might have to resort to deep hypothermia and circulatory arrest and must often sequester some of the blood volume into the bypass circuit to produce a dry operative field. As you have said, low flow at normothermia may not be a good idea, but I wonder if you have studied this either experimentally or clinically under conditions of deep hypothermia. If you have, did you measure any of the parameters of coagulation under deep hypothermia to see if hypothermia alone might be protective? Dr. von Segesser. We know from other studies that coagulation is less active under deep hypothermia, but I cannot provide measurements for this special setup.
Ludwig K. von Segesser, MDa (by invitation), Branko M. Weiss, MD,b Eligio Garcia, BN (by invitation), Arthur von Felten, MDC (by invitation), and Marco I. Turina, MD,a Zurich, Switzerland
Nowadays the polymer industry is able to provide a large scale of versatile materials from which all sorts of devices may be extruded. Polytetrafluoroethylene is used From the Clinic of Cardiovascular Surgery,' the Institute of Anesthesiology," and the Department of Medicine," University Hospital, Ziirich, Switzerland. Supported by the Swiss National Foundation for the Development of Scientific Research, grant 32-26271.89. Read at the Seventy-first Annual Meeting of the American Association for Thoracic Surgery, Washington, D.C., May 6-8,1991. Address for reprints: Ludwig K. von Segesser, MD, Clinic for Cardiovascular Surgery, University Hospital, CH-8091 Ziirich Switzerland.
12/6/34910
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for vascular grafts and for clothes, polypropylene is used for microporous hollow fibers in oxygenators and for carpets, polyvinylchloride is used as tubings for perfusion and as garden hoses, and polyethylene is used for connectors and other parts in cardiopulmonary bypass (CPB) sets as well as for trash bags in waste management. None of the materials cited was primarily developed for medical application, and there is little surprise to see that the overall biocompatibility of today's perfusion equipment remains poor. Hence during perfusion with standard equipment we have still to induce so-called full systemic heparinization that equates the extremely pathologic condition of total incoagulability of the blood. Various approaches to improve the biocompatibility of
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Reduction of systemic heparinization during CPR
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79 I
Table 1.. Experimental evaluation of heparin-coated surfaces Model Roller pump LHBP (n = 20)
Canine, LA-aorta
LHBP (n = 20) Centrifugal pump LHBP (n = 10) Pulsatile device LVAD (n = 15) CPB Open chest (n = 40)
Closed chest (n
= 30)
Coating
Duration
Ref No.
6 hr
9
Bovine. LA-aorta
TDMAC, Duraflo II, CBAS Duraflo II, CBAS
6 hr
10
Bovine, LA-aorta
CBAS
6 hr
11
Bovine LA-aorta
CBAS
6 and 24 hr
12
Canine. bovine, RA-aorta
Duraflo II, CBAS
6 and 24 hr
Bovine, jugular veincarotid artery
Duraflo II, CBAS
6 hr with 7-day survival
13 14 15 16
LHPB, Left heart bypass; LA, left atrium; RA, right atrium; LVAD, left ventricular assist device; CPB, cardiopulmonary bypass. Suppliers: TDMAC: (tridodecylmethylammonium chloride), Sherwood Medical, St Louis, Mo.; Duraflo II, Baxter Healthcare Corporation, Irvine, Calif.; CBAS, Carmeda Bioactive Surface; Carmeda, Stockholm, Sweden.
Table II. Perfusion data for resection of descending thoracic aortic aneurysms n Coating Perfusion (min) Heparin (IU) Protamine (IU) ACT (sec) Baseline After heparin 10 min bypass 30 min bypass After protamine
LHBP
p<
Partial CPB
All
12 CBAS 35 ± 21 7813 ± 2915 5443 ± 860
NS
10 Duraflo II 41 ± 18 8963 ± 2208 7236 ± 3348
24
± ± ± ± ±
NS 0.05 0.05 NS NS
113 199 198 232 118
10 25 39 51 9
NS NS NS
124 286 442 288 131
± ± ± ± ±
25 67 301 105 30
38 ± 19 8283 ± 2524 6428 ± 2792 119 260 356 270 127
± ± ± ± ±
21 70 250 93 26
LHBP, Left heart bypass; CPB, cardiopulmonary bypass; CBAS, Carmeda Bioactive Surface; NS, not significant; ACT, activated clotting time.
blood-exposed surfaces are currently explored, including hybrid vascular grafts with endothelial cell lining, I textured surfaces allowing tissue ingrowth.? development of new polymers with active surface groups;' and bonding of heparin" or other substances to existing surfaces. The most sophisticated concept (and also a complex ethical issue) is probably the combination of all suggested approaches, that is, realization of hybrid artificial organs with textured surfaces exposing specific groups that allow solid anchoring of genetically modified cells secreting antithrombotic and, eventually, other drugs. At this time, however, the various heparin-bonding techniquesi" appear to be the most suitable approach to improve the thromboresistance of blood-exposed surfaces in existing disposable devices used for short-term application. We have systematically evaluated various heparin-coated surfaces in numerous experiments since 1985. The major steps in this evolution included left heart bypass with
heparin-coated tubing sets, left ventricular assist with heparin-coated devices, and CPB with heparin-coated oxygenators and tubing sets with USe of full, low, and no systemic heparinization as summarized in Table I. The data compiled from our own and other studies convinced us that heparin surface-coated perfusion equipment can be used in the clinical setting with reduced systemic heparinization,
Patients and methods Heparin-coated perfusion equipment was used clinically in three differentgroups of patients (n = 47), including resection ofdescending thoracicaorticaneurysms, coronaryartery revascularization, and rewarming in accidental deep hypothermia. Resection of descending thoracic aortic aneurysms. Heparin-coatedshunts for distal perfusion to protect the spinalcord during operation on the descending thoracic aorta have been available for many years.i For this study,a pump was added to the circuit to increase the shunt flow" for proximal unloading
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7 9 2 von Segesser et al.
Table III. Results ofproximal unloading and distal protection during resection of descending thoracic and thoracoabdominal aortic aneurysms with use of heparin-coated perfusion equipment and low systemic heparinization Device LHBP Roller pump Centrifugal pump Part ial CPB Centrifugal pump Roller pump Mortality Parapareses
Coaling CBAS CBAS CBAS Duraflo II
n 4 8 2 10
Nonsurvivors
Parapareses
0 1
0 0
0 0 1/24 (4%)
0 1 1/24 (4%)
Fig. 1. CBAS heparin-coated centrifugal pump head rinsed after clinical perfusion with low systemic heparinization (5000 IV): clean device.
LHBP, Left heart bypass; CPB, cardiopulmonary bypass; CBAS, Carmeda Bioactive Surface.
and distal protection . Left heart bypass was realized with CBAS (Carmeda Bioactive Surface; Carmeda, Stockholm, Sweden) heparin-coated perfusion equipment with use of an inletpressure servocontrolled roller pump (Stockert, Munich, German y; n = 4) or a centrifugal pump (Bio-Medicus, Minneapolis, Minn.; n = 8) in 12 patients undergoing resection of descending thoracic and thoracoabdominal aortic aneurysms . A single dose of heparin (5000 IV ; Liquemin, Roche , Basel, Switzerland) was given to facilitate the use of a red cell washing device (Autotrans, Dideco, Mirandola , Italy). A CBAS heparin-coated oxygenator (Maxima, Medtronic, Anaheim, Calif.) was added to the perfusion circuit for patients with extremely poor respiratory function (n = 2) . After this experience, partial CPB with Duraflo II heparin-coated equipment (Baxter Healthcare Corp., Irvine, Calif.), including a hollow-fiber membrane oxygenator (BOS-CM 50) and low systemic heparinization (100 IU /kg body weight), was used routinely in 10 patients undergoing repair of descending thoracic and thoracoabdominal aortic aneurysms. Coronary artery revascularization. The positive results of partial CPB with low systemic heparinization encouraged us to perform a prospectively randomized study for evaluation of heparin-coated perfusion equipment during total CPB with low systemic heparinization. Twenty-two selected patients undergoing elective coronary artery revascularization were randoml y assigned to two groups perfused with heparin-coated CPB equipment and either low activated clotting time [ACT] greater than 180 seconds (Hemochron, International Technidyne, Edison, N.J.) or full (ACT> 480 seconds) systemic heparinization. The protocol used was accepted by the institutional review board , and informed consent was obtained from each patient included in the study . Inclusion criteria for this study were body weight greater than 50 kg, left ventricular ejection fraction greater than 35%, and expected hematocrit value during perfusion greater than 20%. Exclusion criteria were known coagulopathies, ongoing anticoagulation, and emergenc y procedures. Low versus full systemsic heparinization was defined as follows: heparin loading dose 100 IV /kg versus 300 IV /kg body weight, heparin priming dose 1000 IU/ L versus 5000 IV /L of priming fluid, ACT greater than 180 seconds versus greater than 480 seconds, protamine (Roche, Basel, Switzerland)
equivalent to the respective heparin loading dose, and shed blood recovery during the procedure by a red cell washing device versus cardiotomy suction. Duraflo II heparin-coated perfusion equipment, including coated cannulas, coated flexible venous reservoirs, coated heat exchanger/oxygenator structures (BOSCM 50, Baxter Healthcare Corp ., Irvine, Calif.) coated arterial filters, and coated tubings and connectors, were used in all patients. CPB was performed with clear priming fluid (Ringer's lactate solution), complete hemodilution, and moderate hypothermia. Coronary artery revascularization was realized under cardioplegic arrest of the heart (cold, high-potassium cardioplegie solution) as previously reported . A standard battery of blood samples was drawn before heparin, after heparin, and at regular intervals during as well as after CPB for hematologic analyses and coagulation studies. The latter included ACT , platelet counts, thrombin time (first dilution was performed with 4 V of thrombin per milliliter; Roche, Basel, Switzerland), activated partial thromboplastin time (PTT reagent; Behringwerke AG, Marburg, Germany), prothrombin time (Thromborel S, Behringwerke Marburg, Germany), and D-dimer levels (latex agglutination test with a monoclonal antibody : Boehringer, Mannheim GmbH, Germany). Rewarming in accidental deep hypothermia. Rewarming in accidental deep hypothermia is an accepted indication for CPB. However, systemic heparinization in hypothermic patients with polytrauma and especially craniocerebral trauma is contraindicated. Hence rewarming with CPB with use of heparin-coated perfusion equipment without systemic heparinization was selected in a hypothermic patient with a core temperature of 23.3° C, cardiac arrest, and severe craniocerebral trauma. For this purpose Duraflo II heparin-coated perfusion equipment was used as reported previously. No heparin was added to the priming fluid and no heparin was given systemically, however. Data analyses. Quantitative data are represented as the mean ± standard deviation. Student's t test and analysis of variance (GLM-ANOVA; Solo: BMDP Statistical Software Inc, Los Angeles, Calif.) were used for comparison of quantitative data where applicable . Fisher's exact test was used for comparison of nonparametric data. Statistical significance is confirmed by a probability value (p < 0.05).
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Reduction of systemic heparinization during CPB
0----0
Table IV. Basic parameters in patients undergoing coronary artery revascularization with use of heparin-coated CPB equipment with low versus full systemic heparinization Heparinization (ACT) Age (yr) Body weight (kg) Body surface area (m-) CPB duration (min) Crossclamp time (min) Number of bypasses ITA anastomoses Nonsurvivors Myocardial infarction
Low
Full
(>180 sec)
(>480 sec)
59 ± 9 72 ± 1.8 ± 69 ± 36 ± 2.9 ± 1.1 ±
9
0.1 16
12 0.8 0.8
0/12 0/12
56 ± 70 ± 1.8 ± 66 ± 35 ± 3.2 ± 0.9 ±
6 7
ACT
793
ACT~4BO
....--.. ACT>180
600
400
0.2 14 8 0.6 0.3
0/10 0/10
ACT. Activated clotting time; CPR, cardiopulmonary bypass; ITA. internal thoracic artery.
200
o L......JC--.---'_---'-_---'-_-----'-_--'-_ baseline heparin 10'
30'
45'
_____'__----'-_ _-'--_---'
60' protamine 50' post
Fig. 2. MeanACT ± standard deviations before, during,and after CPB with lowversus full systemic heparinization.
Results Resection of descending thoracic aortic aneurysms. Perfusion data for patients undergoing resection of descending thoracic and thoracoabdominal aortic aneurysms are given in Table II. Similar mean values were found in the two analyzed groups for perfusion time, heparin dose, protamine dose, as well as prebypass and postbypass ACT. ACT after heparin and after 10 minutes of bypass was higher in the group with partial CPB. The outcome of these first 24 patients, perfused with low systemic heparinization, is shown in Table III. The sole death in this series (1/24; 4%) occurred (unrelated to the technique) in a patient with ruptured thoracoabdominal aneurysm requiring an operation in extremis. Paraparesis with spontaneous recovery occurred in one patient (1/24; 4%). All devices remained functional throughout the procedures, and no systemic emboli were detected. After perfusion all devices were carefully analyzed. No macroscopic red clots were found. A heparin-coated centrifugal pump head, rinsed after clinical perfusion with low systemic heparinization, is shown in Fig. 1. It is absolutely clean. Coronary artery revascularization. Basic parameters like body weight, body surface area, perfusion time, crossclamp time, number of bypasses, and number of internal thoracic artery anastomoses were similar for the two groups (Table IV). All patients survived the procedure without sequelae, and no myocardial infarction was diagnosed by creatine kinase levels and electrocardiogram. Mean ACTs measured in the two analyzed groups are depicted in Fig. 2. The prebypass ACT moved from 117 ± 11 seconds to 241 ± 28 seconds after heparin for the group perfused with low systemic heparinization versus from 107 ± 13 seconds to 382 ± 86 seconds for full systemic heparinization. Throughout perfusion the mean
15'
Gradient
0-- --0
ACT~4BO
--
ACT>180
mmHg .-----
-----,
200
150
100
50
O'--'--'"--~-~-----'-~------'---'-""'------'-------'--~
Start
10'
15'
30'
45'
60'
End
CPS
Fig. 3. Mean oxygenator pressuregradient ± standard deviation during CPB with lowversus full systemic heparinization: not significant. values measured were between 240 and 277 seconds for low and between 382 and 570 seconds for full systemic heparinization. The lowest ACT observed in the group perfused with low systemic heparinization was 210 seconds. Hence no additional heparin was necessary in this group with a mean perfusion time above 60 minutes. In the control group, however, additional heparin was necessary in most cases to maintain the ACT above 480 seconds. The results of the coagulation studies are tabulated in Table V. Similar platelet levels were measured in the two analyzed groups. Throughout perfusion the thrombin time was above 200 seconds in both groups, and the latter was significantly higher early after protamine in the group perfused with full systemic heparinization. No difference was observed for the activated partial thromboplastin time during and after perfusion for the two groups.
The Journal cif Thoracic and Cardiovascular Surgery
7 9 4 von Segesser et al.
Table V. Coagulation studies in patients undergoing coronary artery revascularization with use of CPR with low versus full systemic heparinization Heparinization
Low
Full
(10 3j ,um3)
Platelets Baseline After heparin 10 min bypass 45 min bypass After protamine 24 hr Thrombin time (sec) Baseline After heparin During bypass After protamine 60 min after protamine Activated partial thromboplastin time (sec) Baseline After heparin 10 min bypass 45 min bypass After protamine 60 min after protamine Prothrombin time (%) Baseline After heparin 10 min bypass 45 min bypass After protamine 60 min after protamine D-dimers (mgjL) Baseline Heparin 10 min bypass 45 min bypass After protamine 60 min after protamine
266 225 130 140 153 131
± 71 ± 65 ± 36 ± 49 ± 59 ± 38
13.5 ± 1.4 >200 >200 25.2 ± 13.5 14.8 ± 5.0
293 227 142 140 141 133
± 88 ± 62 ± 37 ± 31 ± 32 ± 33
13.3 ± 1.0 >200 >200 111.2 ± 89.1 17.5 ± 5.7
p
NS NS NS NS NS NS NS NS NS <0.05
NS
39 43 61 55 45 44
± 4 ± 4 ± 9 ± 8 ± 6 ± 7
35 47 61 86 49 47
± 3 ± 8 ±7 ± 61 ±6 ±8
<0.05
97 73 46 49 64 73
± 7 ± 5 ± 3 ± 6 ± 6 ± 7
98 69 48 38 52 69
± ± ± ± ±
3 8 9 12 8 ± 10
NS NS NS
0.31 0.33 0.25 0.25 0.50 0.47
± 0.15 ± 0.19 ± 0.00 ± 0.00 ± 0.43 ± 0.42
0.25 0.60 0.50 0.42 1.08 1.17
± 0.00 ± 0.49 ± 0.25 ± 0.24 ± 0.59 ± 0.47
NS NS NS NS NS
<0.05 <0.05
NS
NS NS <0.05 <0.05 <0.05 <0.05
CPB. Cardiopulmonary bypass; NS. not significant.
Prothrombin time, however, remained significantly longer at the end of perfusion and early after protamine in the group perfused with full systemic heparinization. The D-dimer levels remained relatively low for both groups; however, they were significantly higher in the group perfused with full systemic heparinization. There was no difference for the pressure gradients measured throughout the perfusions between the blood inlet and outlet of the heat-exchanger/oxygenator structure (Fig. 3) perfused with low versus full systemic heparinization (final value at full flow, III ± 9 mm Hg for low versus 110 ± 16 for full; not significant). CPB with heparincoated equipment and low dose of heparin, 15% of control (8041 ± 1270 IV versus 52,500 ± 17,100 IV; p < 0.0005), resulted in reduced protamine requirements of only 25% of control (7875 ± 1918 IV versus 31,400 ± 14,000 IV; p < 0.0005), as shown in Fig. 4.
Mean blood loss (defined as total chest tube drainage) for low systemic heparinization was 35% of that for full systemicheparinization(831 ± 373 ml versus 2345 ± 1815 ml; p < 0.01), and transfusion requirements (defined as homologous blood and blood products) were 10%of those for full systemic heparinization (281 ± 415 ml versus 2731 ± 2258 ml; p < 0.001), as shown in Fig. 5. Fewer patients perfused with low systemic heparinization received blood or blood products (5/12 versus 10/10; p < 0.05). Mean hematocrit value is depicted in Fig. 6. The baseline values are 44% ± 3% for both groups. After mixing blood with the priming fluid, we measure 23% ± 3% for low systemic heparinization, and 22% ± 3% for full systemic heparinization, and at the seventh day the respective values are 32% ± 5% and 35% ± 3% (not significant). The only significant difference is observed 60 minutes after protamine, where we
Volume 103 Number 4 April 1992
Reduction of systemic heparinization during CPR
i.u, r - - - - - - - - - - - - - - - - - - - - - , 50'000
795
ml
Bloodloss
Heparin
3000
[I
Transfusion
40'000 30'000
2000
20'000 1000 10'000
o
0 ACT>180
ACT>480
Fig. 4. Totalheparinand protaminedoses (mean ± standard deviation) applied during coronary artery revascularization procedures with low and full systemic heparinization. measure 35% ± 3% for low systemic heparinization versus 26% ± 2% for full systemic heparinization (p < 0.0005). At the end of the procedure, all oxygenators, venous reservoirs, arterial filters, and tubings were carefully analyzed. Despite the fact that occasionally some degree of localized red staining could be observed in devices perfused with low systemic heparinization, there were no macroscopic red clots (Fig. 7). Rewarming in accidental hypothermia. After initiation of CPB without systemic heparinization under ongoing cardiac massage, cardiac activity resumed spontaneouslyafter 12 minutes of perfusion at a core temperature of 26° C. Weaning from CPB was feasible after 96 minutes at 35° C. However, reperfusion for another 42 minutes was necessary because of low cardiac output resulting from high serum potassium levels. Whereas perfusion of the patient without systemic heparinization lasted 138 minutes, perfusion of the pump-oxygenator system, including recirculation, totaled 182 minutes. As usual, the CPB equipment was carefully analyzed after the procedure. There were no macroscopic clots in the perfusion circuit, and the arterial filter was clean (Fig. 8). Progressive somatic and neurologic recovery of the patient followed after 3 weeks of intensive care including intracranial pressure monitoring, peritoneal dialysis, and mechanical ventilation. Discussion Systemic heparinization for CPB can be reduced and eliminated in selected applications if adequate equipment, perfusion techniques, and surgical skills are available. Improved thromboresistance of heparin-coated surfaces has been shown by many studies.r! and perfusion with heparin-coated equipment with low or no systemic heparinization was realized in canine and bovine experiments
ACT>480
ACT>180
Fig. 5. Mean bloodloss(defined as total chest tube drainage) and transfusions of homologous blood and blood products (± standarddeviation) forpatientsperfusedwithlowversus full systemic heparinization.
0----0 ACT>480 - - ACT>180
'l6r---------------------, 50
30
20
10
O'--"---'----.J~__.J
baseline heparin 10'
_
____'_
___I._
60' protamine 60' CPB post
___I._
24 h
___'__
48 h
___'__---'
7 days
Fig. 6. Mean hematocrit value ± standard deviation for patients perfused with lowversus full systemic heparinization. for left heart bypass with roller, centrifugal, and pulsatile pumps, high-flow open chest CPB, and prolonged lowflow CPB, as well as for closed chest CPB, in surviving animals, as has been shown herein. Other groups investigated similar protocols in bovine," ovine,18, 19 and canine" experiments. Improved thromboresistance of blood-exposed surfaces with heparin coating was documented by hematology, biochemistry, coagulation, immunology, and scanning electron microscopy.'"!" In the experimental setup, intact hemostasis during perfusion resulted in reduced blood loss and transfusion requirements, as well as superior hemodynamics.I" preserved renal function, and attenuated hormonal stimulation." Translation of the findings described into clinical practice was initiated many years ago by the introduction of the Gott shunt for resection of descending thoracic aortic aneurysms. Other
The Journal' of .
7 9 6 vonSegesser et al.
Fig. 7. Heparin-coated heat exchanger and oxygenator inlet gently rinsed after clinicalCPB with lowsystemic heparinization for coronary artery revascularization: no macroscopic deposits.
groups used standard perfusion equipment without systemic heparinization in patients with an impaired coagulation system, such as during liver transplantation.F Heparin-coated oxygenators and perfusion circuits were primarily used clinically for extracorporeal lung assist because of the well-known bleeding problems in this group of patients.P However, there are other groups of patients in the cardiovascular field with bleeding problems. Because of the latter, CPB was abandoned by most groups during resection of descending thoracic aortic aneurysms.i" and simple crossclamping of the aorta with rapid reanastomosis was advocated. The availability of heparin-coated perfusion equipment that can be used with low systemic heparinization allowed the reintroduction of efficient proximal unloading and distal perfusion during staged resection of large descending thoracic and thoracoabdominal aortic aneurysms. During the series operated on with left heart bypass, we
Thoracic and Cardiovascular Surgery
noted that additional heparin was necessary in some cases to avoid clots in the operating field if a loading dose of only 5000 IV was used. Hence a loading dose of 100 IVjkg body weight was applied in the series operated on with partial CPB. The results that have been presented include elective and emergency procedures and are with an in-hospital mortality and paraparesis rate of 4%, clearly superior to our previous experiences.P The fact that no device failures occurred during resection of descending thoracic and thoracoabdominal aneurysms and that bleeding was controllable in all cases encouraged us to explore further applications of perfusion with heparin-coated equipment and low systemic heparinization. Hence CPB with heparin-coated equipment with low (ACT> 180 seconds) versus full (ACT> 480 seconds) systemic heparinization was prospectively analyzed. Interestingly, the coagulation studies performed showed only few differences between the group perfused with low systemic heparinization and the group perfused with full systemic heparinization. During perfusion, all patients had thrombin times above 200 seconds, demonstrating significant anticoagulation in both analyzed groups (see Table V). The problems with heparin "neutralization" by means of protamine, however, are well demonstrated by prolonged thrombin times and prolonged prothrombin times in the group with full systemic heparinization after protamine application. These findings may also explain the superior blood loss in the group perfused with full systemic heparinization. We attribute the higher p-dirner levels observed in the group with full systemic heparinization to the use of cardiotomy suction in this group. Cardiotomy suction is known for significant blood trauma. 15 The results reported herein, namely, reduced heparin and protamine requirements, reduced bleeding and transfusion requirements, and a lesser number of patients requiring less homologous transfusions, speak for themselves and confirmed the results of our preliminary report-" It has to be mentioned here that the blood loss and transfusion requirements reported for the group perfused with full systemic heparinization do not represent our current practice, which includes routine application of aprotinin.i? CPB with heparin-coated equipment without systemic heparinization was finally realized in an extreme situation where no standard procedure appeared applicable. There can be no doubt about the fact that rewarming in accidental deep hypothermia without CPB is extremely difficult once cardiac arrest has occurred.f Although several recent reports questioned the necessity for so-called full systemic heparinization (ACT> 480 seconds is recommended by most oxygenator manufacturers) during CPB with standard equipment.P'" thereduc-
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Fig. 8. Heparin-coated perfusionequipment after clinicalCPB without systemicheparinization for rewarming in deep accidental hypothermia: clean devices.
tions of systemic heparinization suggested in these studies are far less than those reported here for perfusion with heparin-coated equipment. Furthermore, we have shown that severe clotting can occur when standard equipment is used without systemic heparinization.v 14 We conclude from these and other data that heparin surface coating significantly improves the thromboresistance of existing perfusion equipment. Hence perfusion with low systemic heparinization can be realized in selected cases, and bypass-induced morbidity can be reduced. Reduced bleeding and transfusion requirements are also of increasing interest in patients refusing transfusion of homologous blood and blood products. At this time the main limitation for clinical application of heparin-coated perfusion equipment with low systemic heparinization appears to be the lack of a cardiotomy system functioning despite low systemic heparinization. It has to be repeated here that the lower systemic heparinization is the higher is the potential for clot formation . Furthermore, it is now known that the antithrombotic efficiency of heparin surface coating in perfusion equipment is strictly flow dependent. 20 Hence some basic rules have to be respected during perfusion with low systemic heparinization: (I) Blood stagnation (low flow) in the perfusion circuit must be avoided; (2) immediate recirculation through an arterio-
venous bridge close to the cannulas is necessary; and (3) venting of cannulas before starting perfusion is recommended. REFERENCES 1. Muller-Glauser W, Lehmann KH, Bittmann P, et al. A compliant small-diameter vascular prosthesis lined with functional venous endothelial cells. Trans Am Soc Artif Intern Organs 1988;34:528-31. 2. Dasse KA, Chipman SO, Sherman CN, et al. Clinical experiencewith textured blood contacting surfaces in ventricular assist devices. ASAIO J 1987;10:418-25. 3. Josefowicz M, Jozefonvicz J. New approaches to anticoagulationheparin likebiomaterials. ASAIO J 1985;8:218-22. 4. Gott VL, Whiffen JD, Datton RC. Heparin bonding on colloidal graphite surfaces. Science 1963;142:1297-8. 5. Cukingnan RA, Fee HJ , Carey JS. Repair oflesions ofthe descending thoracic aorta with the TDMAC-heparin shunt. J THORAC CARDIOVASC SURG 1978;75:227-31. 6. Kim SW, Ebert CD, Lin JY, et al. Nonthrombogenic polymers. Pharmaceutical approaches. ASAIO J 1983; 6:76-87. 7. Larm 0 , Larsson R, Olsson P. A new non-thrombogenic surface prepared by selective covalent binding of heparin via a modified reducing terminal residue. Biomater Med Devices Artif Organs 1983;11:161-73.
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8. Tong SD, Rolfs MR, Hsu LC. Evaluation of Duraflo II heparin immobilized cardiopulmonary bypass circuits. Trans Am Soc Artif Intern Organs 1990;36:M654-6. 9. von Segesser LK, Weiss BM, Turina MI. Perfusion with heparin-coated equipment: potential for clinical use. Semin Thorac Cardiovasc Surg 1990;2:373-80. 10. von Segesser LK, Weiss BM, Gallino A, et al. Superior hemodynamics in left heart bypass without systemic heparinization. Eur J Cardiothorac Surg 1990;4:384-9. II. von Segesser LK, Lachat M, Gallino A, et al. Performance characteristics of centrifugal pumps with heparin surface coating. Thorac Cardiovasc Surg 1990;34:224-8. 12. von Segesser LK, Weiss BM, Bisang B, Leskosek B, Turina MI. Ventricular assist with heparin surface coated devices.Trans Am Soc Artif Intern Organs 1991;37:H2789. 13. von Segesser LK, Turina MI. Heparin coated hollow fiber membrane oxygenator without systemic heparinization in comparison to classic membrane and bubble oxygenators. J Extracorp Technol 1988;76-80 [Proceedings issue]. 14. von Segesser LK, Turina M. Cardiopulmonary bypass without systemic heparinization: performance of heparin coated oxygenators in comparison with classic membrane and bubble oxygenators. J THORAC CARDIOVASC SURG 1989;98:386-96. 15. von Segesser LK, Turina M. Long term cardiopulmonary bypass without systemic heparinization. Int J Artif Organs 1990;13:687-91. 16. von Segesser LK, Lachat M, Leskosek B, et al. Cardiopulmonary bypass with low systemic heparinization: an experimental study. Perfusion 1990;5:267-76. 17. von Segesser LK. Arterial grafting for myocardial revascularization. 1st ed. Berlin: Springer, 1990:48-79. 18. Toomasian JM, Hsu LC, Hirschi RB, Heiss KF, Hultquist KA, Bartlett RH. Evaluation of Duraflo II heparin coating in prolonged extracorporeal membrane oxygenation. Trans Am Soc Artif Intern Organs 1988;34:410-4. 19. Mottaghy K, Oedekoven B, Schaich-Lester D, Poppel K, Kiipper W. Applications of surfaces with end-point attached heparin to extracorporeal circulation with membrane lungs. Trans Am Soc Artif Intern Organs 1989; 35:146-52. 20. Anander C, Olsson P. Influence of blood flowand the effect of protamine on the thromboresistant properties of a covalently bonded heparin surface. J Biomed Mater Res 1988;22:859-68. 21. Weiss BM, von Segesser LK, Vetter W, Gautschi K, Pasch T. Heparin coated left heart bypass: renal function and hormonal response. Int J Artif Organs 1990;13:565. 22. McSteen F, Hackett J, Rhoades W, et al. Heparinless bypass for liver transplantation. Proc Am Acad Cardiovasc Perfusion 1984;5:28-9. 23. Bindslev L, Eklund J, Norlander 0, et al. Treatment of acute respiratory failure by extracorporeal carbon dioxide elimination performed with a surface heparinized artificial lung. Anesthesiology 1987;67:117-20. 24. Livesay 11, Cooley DA, Ventimiglia RA, et al. Surgical
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experience in descending thoracic aneurysmectomy with and without adjuncts to avoid ischemia. Ann Thorac Surg 1985;39:37-46. von Segesser LK, Burki H, Schneider K, Siebenmann R, Schmid ER, Turina M. Outcome and risk factors in surgery of descending thoracic aortic aneurysms. Eur J Cardiothorae Surg 1988;2:100-5. von Segesser LK, Weiss HM, Garcia E, Gallino AS, Turina M. Reduced blood loss and transfusion requirements with low systemic heparinization: preliminary clinical results in coronary artery revascularization. Eur J Cardiothorac Surg 1990;4:639-43. von Segesser LK, Weiss BM, Leskosek B, von Felten A, Pei P, Turina M. Experimental evaluation of heparin coated cardiopulmonary bypass equipment with low systemic heparinization and high dose aprotinin. Thorac Cardiovasc Surg 1991;39:251-6. Schmid ER, von Segesser L, Hossli G, et al. Akzidentelle Hypothermie: Wiedererwarmung mit extrakorporaler Zirkulation. Anaesthesist 1989;38:120. Metz S, Keats AS. Low activated coagulation time during cardiopulmonary bypass does not increase postoperative bleeding. Ann Thorac Surg 1990;49:440-4. Gravlee GP, Haddon WS, Rothberger HK, et al. Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J THORAC CARDIOVASC SURG 1990; 99:518-27. Cardoso PFG, Yamazaki F, Keshavjee S, et al. A reevaluation of heparin requirements for cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1991;101:153-60.
Discussion Dr. Stefan Thelin (Uppsala, Sweden). The lack of biocompatibility in standard CPB circuits is one reason for morbidity after CPB. Our group in Uppsala, Sweden, have studied CPB circuits coated with end-point-attached heparin both experimentally and clinically. In our clinical studies we found that accepting ACTs down to 300 seconds had no effect on the postoperative blood loss. A further reduction of the heparin dose, accepting ACTs down to 200 seconds, resulted in a significant reduction in the postoperative blood loss (16 hours) from 735 ± 67 ml (control) to 578 ± 33 ml (heparin coated). However, independent of the heparin dose given, there was a significant reduction in the adherence and activation of blood cells illustrated in scanning electron micrographs from arterial filters. Coated filters from coated circuits showed a significant reduction in adherence of blood cells when compared with the control filters. Moreover, the groups treated with heparin-coated equipment also showed a significantly reduced release of the granulocyte factors lactoferrin and myeloperoxidase, indicating less activation of granulocytes. Do you have any indications for important differences in biocompatibility between different methods of heparin coating? What is your opinion on the use of heparin-coated circuits and normal doses of heparin during transplant operations to decrease the activation of the immunologic system? Dr. von Segesser. We think that for specific applications some coatings may have advantages over others. In some the
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heparin is supposed to stay longer in its place. Even if there is some washout from the surface, however, this might have an advantage in situations where there is low flow. There cannot be one coating that is superior in any situation. We cannot say, in regard to the second question, if there is an advantage of coating in full systemic heparinization because of the wide variability in the parameters of immunologic activation that display a well-known lack of clinical correlates, and therefore we have not analyzed this approach. Dr. Delos M. Cosgrove (Cleveland, Ohio). Would you care to speculate about other potential uses for coating intravascular devices? Dr. von Segesser. We have evaluated pulsatile ventricular assist devices and have seen similar results. Dr. James L. Cox (St. Louis, Mo.). Could you explain the difference between this coating and the Carmeda coating process that is being used by the group in Uppsala? Dr. von Segesser. We have used both coatings in this series. The coating that was used in the coronary bypass study is an ionic coating provided by Baxter Healthcare Corporation; it is insoluble in water and has good properties for staying on the
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surface. We could not measure heparin washout in vivo when we tried to measure it. The Carmeda process, which was also used in our study for resection of aortic aneurysms, uses covalent bonding, which has superior adherence to the surface. From this point of view, it may have an advantage in long-term applications. Dr. Craig R. Smith (New York, NiY}. I am responding in particular to your experience with the patient you rewarmed. I think reduction in heparin with this approach would be particularly attractive in patients in whom we might have to resort to deep hypothermia and circulatory arrest and must often sequester some of the blood volume into the bypass circuit to produce a dry operative field. As you have said, low flow at normothermia may not be a good idea, but I wonder if you have studied this either experimentally or clinically under conditions of deep hypothermia. If you have, did you measure any of the parameters of coagulation under deep hypothermia to see if hypothermia alone might be protective? Dr. von Segesser. We know from other studies that coagulation is less active under deep hypothermia, but I cannot provide measurements for this special setup.