- Email: [email protected]
An Adjusted Calculation Model of Reduced Heparin Doses in Cardiopulmonary Bypass Surgery in a Chinese Population
An Adjusted Calculation Model of Reduced Heparin Doses in Cardiopulmonary Bypass Surgery in a Chinese Population Yufeng Zhang, MD, Kai Liu, MD, Wei Li, MD, Qian Xue, MD, Jiang Hong, MD, Jibin Xu, MD, Lihui Wu, MD, Guangyu Ji, MD, Jihong Sheng, MD, and Zhinong Wang, MD Objective: To investigate the safety and efficacy of an adjusted regimen of heparin infusion in cardiopulmonary bypass (CPB) surgery in a Chinese population. Design: Prospective, single-center, observational study. Setting: University teaching hospital. Participants: Patients having cardiac surgery with CPB were selected for this study using the following criteria: 18 to 75 years of age, undergoing first-time cardiac surgery with conventional median sternotomy, aortic clamping time between 40 and 120 minutes, and preoperative routine blood tests showing normal liver, renal, and coagulation functions. The exclusion criteria include salvage cases, a history of coagulopathy in the family, and long-term use of anticoagulation or antiplatelet drugs. Interventions: Sixty patients were divided randomly into a control group (n ¼ 30) receiving a traditional heparin regimen and an experimental group (n ¼ 30) receiving an adjusted regimen. Measurements and Main Results: Activated coagulation time (ACT) was monitored at different time points, ACT 4480 seconds was set as the safety threshold of CPB. Heparin doses (initial dose, added dose, and total dose), protamine doses (initial dose, added dose, and
total dose), CPB time, aortic clamping time, assisted circulation time, sternal closure time, blood transfusion volume, and drainage volume 24 hours after surgery were recorded. There was no significant difference in achieving target ACT after the initial dose of heparin between the 2 groups; CPB time, aortic clamping time, assisted circulation time, postoperative complication rate, and drainage volume between the 2 groups were not significantly different (p 4 0.05). However, initial and total dosage of heparin, initial and total dosage of protamine, sternal closure time, and intraoperative blood transfusion volume in the experimental group were significantly lower (p o 0.05). Conclusions: Adjusted regimen of heparin infusion could be used safely and effectively in Chinese CPB patients, which might reduce the initial and total dosage of heparin and protamine as well as sternal closure time and intraoperative blood transfusion volume. & 2016 Elsevier Inc. All rights reserved.
T
calculate the initial dose of heparin12; this formula takes into account baseline ACT (bACT) and body weight. In the present study, bACT and target ACT 4480 seconds were taken into account to develop an adjusted formula. The main objective of the present study was to evaluate the safety and effectiveness of this adjusted formula in CPB.
HERE IS NO COMMONLY recognized regimen for heparin infusion in cardiac surgery with cardiopulmonary bypass (CPB).1 Heparin inadequacy could lead to failure of CPB or even thromboembolic events, whereas heparin overdose could cause excessive blood loss during sternal closure.2 In addition, rapid administration of protamine, used to neutralize excessive heparin, could cause life-threatening hemodynamic disturbance, along with histamine release and hypoxemia, especially at the end of CPB.3 Additional use of protamine after CPB also could increase allergy risks and bleeding.4 Currently, 300 IU/kg is used widely as the initial dosage of heparin administered before starting CPB. Activated coagulation time (ACT) is used as an indicator of the effectiveness of heparin intraoperatively, with ACT 4480 seconds as the safety threshold of CPB.5,6 In this regimen, heparin dosage calculation is based solely on patient body weight. The regimen may achieve target ACT quickly but often causes heparin overdosing. Moreover, heparin rebound after CPB may require additional protamine administration,7 especially in Chinese populations. Adjusted heparin regimens have been used in some research projects,8,9 but most subjects in these studies were European and American. According to the experience of the authors there are more bleeding than embolism events in Chinese populations during the process of anticoagulation compared with European and American populations.10,11 The hypothesis in the present study was that less heparin is needed in cardiac surgeries for Chinese people. Recently, Nakasuji et al developed an original formula, which had been proven effective to
KEY WORDS: individual administration, heparin, activated clotting time, cardiopulmonary bypass, transfusions, protamine, anticoagulation
MATERIAL AND METHODS
Patients who underwent cardiac surgery with CPB from January 2013 to December 2014 in the Department of Cardiothoracic Surgery in Changzheng Hospital were selected. Inclusion criteria were as follows: 18 to 75 years of age, undergoing first-time cardiac surgery with conventional median sternotomy, aortic clamping time between 40 and 120 minutes, and preoperative routine blood tests showing normal liver, renal, and coagulation function.
From the Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. Yufeng Zhang, Kai Liu, and Wei Li contributed equally to this work. This work was supported by the National Nature Science Foundation of China (No.81300102). Address reprint requests to Zhinong Wang, MD, Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. E-mail: [email protected] © 2016 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2016.04.005
Journal of Cardiothoracic and Vascular Anesthesia, Vol 30, No 5 (October), 2016: pp 1179–1183
1179
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ZHANG ET AL
Table 1. Preoperative Baseline Characteristics
Groups
Control Group
Experimental Group
p
(n ¼ 30)
(n ¼ 30)
Value
52.80 ⫾ 11.15 14 163.63 ⫾ 9.25 61.33 ⫾ 10.65
0.75 0.606 0.54 0.24
12 14 4 6 8 4 11.69 ⫾ 1.04 34.59 ⫾ 3.41 181.07 ⫾ 51.31
0.793 0.602 0.718 0.488 0.542 0.488 0.58 0.73 0.391
Age (year) 55.90 ⫾ 12.75 Sex (male) 16 Height (cm) 162.10 ⫾ 10.09 Weight (kg) 58.10 ⫾ 10.69 Heart function (NYHA) Class II 13 Class III 12 Class IV 5 Diabetes 4 Hypertension 6 COPD 6 Preoperative Hb (g/L) 11.85 ⫾ 1.22 Preoperative Hct (%) 34.90 ⫾ 3.59 Preoperative platelet 192.67 ⫾ 52.76 Count (c/mL)
NOTE. Values expressed as number, median (interquartile range), or mean ⫾ standard deviation. Abbreviations: NYHA, New York Heart Association; COPD, chronic obstructive pulmonary disease; Hb, hemoglobin; Hct, hematocrit value.
Exclusion criteria were: salvage cases, a history of coagulopathy in the family, and long-term use of anticoagulation or antiplatelet drugs due to atrial fibrillation, cerebral infarction, or unstable angina. All included patients signed informed consent forms meeting ethical standards of the Human Research Committee of Changzheng Hospital. All surgeries were performed by the same group of surgeons, anesthesiologists, and perfusionists. Groups With an alpha value of 0.05 and a desired power of 0.80, it was found that 27 participants were required for each group to address the primary aim of the study. The authors planned the study with 30 patients in each group. A total of 60 patients were enrolled and randomized into a control group (n ¼ 30) and an experimental group (n ¼ 30). A traditional regimen, with initial dose of heparin (units) ¼ body weight (kg) 300 U/lg, was used in the control group. An adjusted regimen, with initial dose of heparin (units) ¼ Body weight (kg) 300 U/kg (480 – bACT) / (480 –100), was used in the experimental group. Patients’ general information included name, sex, age, body weight, hospitalization number, and diagnosis. Perioperative states of heart, lung, liver, kidney, and coagulation function and information regarding history of diabetes or hypertension also were collected. Surgery information included the type, mode, and date of surgeries. Surgeons, anesthesiologists, and caregivers were blinded to this information. Anesthesia and Cardiopulmonary Bypass Anesthesia was induced with 0.1 mg/kg of midazolam, 1 to 2 mg/kg of sufentanil, and 0.2 mg/kg of vecuronium, and it was maintained with propofol, sufentanil, and vecuronium. Electrocardiogram, arterial pressure, central venous pressure, pulmonary artery pressure, and cardiac index, as well as nasopharyngeal
temperature, rectal temperature, and blood gas were monitored during the procedure. The circuit was primed with 1,000 mL of gelatin solution, 500 mL of Ringer’s acetate, 400 mL of mannitol, 160 mg of sodium chloride, and 2000 U of heparin. Myocardial protection was achieved by using cold (41C) crystalloid cardioplegia solution (St. Thomas Hospital cardioplegic solution No. 2; Plegisol W, Abbott Laboratories, Chicago, IL). The targeted mean perfusion pressure was 50 to 70 mmHg. Patient temperature was maintained between 341C and 361C, and blood flow was kept between 2.2 and 2.4 L/min/m2. A cell-saving device was used to process red blood cells during the whole procedure. The initial dose of heparin was administered according to 2 different regimens. ACT was measured 4 times before administration of heparin, and bACT was the mean of 4 numeric values. If required, additional doses of heparin (5000 U) were administered during CPB to maintain an ACT 4480 seconds. After termination of CPB, heparin was antagonized with protamine at a 1:1 ratio, and then ACT was measured to exclude residual heparin. Blood was transfused to maintain hemoglobin 47g/L and hematocrit 40.20. Evaluation of Adjusted Regimen ACT was monitored at 5 different time points, including T0 (before heparin infusion), T1 (3 minutes after initial heparin infusion), T2 (30 minutes after CPB), T3 (before protamine administration), and T4 (5 minutes after protamine administration). Initial, additional, and total dose of heparin and protamine; CPB time; aortic clamping time; assisted circulation time; sternal closure time (from termination of CPB to termination of surgery); blood transfusion volume; and chest drainage volume were recorded. Statistical Methods Categorical variables are presented as the number of observations. Continuous variables are presented as the mean ⫾ standard deviation. Statistical analysis was performed with the IBM SPSS 19 (SPSS, Inc, Armonk, New York). Data were compared by using one-way analysis of variance and χ2 test; p values o 0.05 were considered significant.
Table 2. Comparison of Surgery Types Between the 2 Groups
MVR þ TVP AVR MVR þ AVR þ TVP TVP ASD/VSD
Control Group
Experimental Group
p
(n ¼ 30)
(n ¼ 30)
Value
12 8 4 1 5
14 6 5 2 3
0.602 0.542 0.718 0.554 0.448
NOTE. Values expressed as number. Abbreviations: MVR þ TVP, mitral valve replacement and tricuspid valvuloplasty; AVR, aortic valve replacement; MVR þ AVR þ TVP, mitral valve replacement, aortic valve replacement, and tricuspid valvuloplasty; TVP, tricuspid valvuloplasty; ASD, atrial septal defect; VSD, ventricular septal defect.
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ADJUSTED CALCULATION MODEL OF REDUCED HEPARIN IN CPB
Table 3. Comparison of ACT Values Between the 2 Groups at Different Time Points
ACT Value (s)
T0 (bACT) T1 T2 T3 T4
Table 4. Comparison of Dosage of Heparin and Protamine Between the 2 Groups
Control Group
Experimental Group
p
Control Group
Experiment Group
p
(n ¼ 30)
(n ¼ 30)
Value
(n ¼ 30)
(n ¼ 30)
Value
153.40 ⫾ 20.11 703.10 ⫾ 127.57 887.67 ⫾ 90.70 820.77 ⫾ 138.14 140.10 ⫾ 12.84
153.67 ⫾ 21.91 623.03 ⫾ 127.33 799.73 ⫾ 139.24 712.63 ⫾ 182.21 142.63 ⫾ 17.05
0.96 0.02 0.005 0.012 0.518
174.30 ⫾ 32.06
156.67 ⫾ 29.99
0.029
195.97 ⫾ 33.48
178.37 ⫾ 34.70
0.048
293.85 ⫾ 50.24
260.88 ⫾ 53.32
0.017
NOTE. Values expressed as mean ⫾ standard deviation. Abbreviations: ACT, activated clotting time; bACT, baseline activated clotting time.
RESULTS
There were no significant differences in baseline characteristics or surgery types between the 2 groups, as shown in Tables 1 and 2. There also were no significant differences in bACT or success rate of achieving target ACT between the 2 groups, and only 1 patient required an additional dose of heparin before CPB. However, ACT in the experimental group was significantly lower than that of the control group at T1, T2, and T3, and ACT values returned to normal after infusion of protamine (T4), as shown in Table 3 and Figure 1. In addition, initial and total dose of heparin and total dose of protamine in the experimental group were significantly lower than in the control group (p o 0.05), as shown in Table 4. There were no significant differences in CPB time, aortic clamping time, or assisted circulation time between the 2 groups (p 4 0.05), but sternal closure time and blood transfusion volume during surgery in the experimental group were significantly lower (p o 0.05), as shown in Table 5. There were no deep vein thromboses, pulmonary embolism, cerebral infarction, renal failure, or other severe complications in either group. Drainage volume and blood transfusion volume
Initial dose of heparin (mg) Total dose of heparin (mg) Total dose of protamine (mg)
NOTE. Values expressed as mean ⫾ standard deviation.
after surgery in the experimental group were less than in the control group, but differences were not significant (p 4 0.05). Three patients in the control group and 4 patients in the experimental group suffered from delirium, but the difference was not significant, as shown in Table 6. DISCUSSION
Overdose of heparin in CPB is associated with increased blood loss and excessive use of protamine,13–15 and heparin rebound after surgery could cause greater drainage volume and a longer intensive care unit stay;16,17 whereas inadequacy of heparin could lead to thromboembolic and other risk events during CPB. An optimal regimen of heparin infusion should use a relatively small amount of heparin to ensure the safety of CPB. Most clinical research projects about heparin infusion were designed for European and American patients. According to the experience of the authors’ center, there were relatively more bleeding than embolic events in Chinese people during the coagulation process,18,19 and the authors also found that the traditional regimen of heparin transfusion could cause excessive oozing in the surgical field, which resulted in multiple ACT checks and additional protamine infusion after CPB. This study aimed to verify the effectiveness and safety of an
Fig 1. ACT values compared to CS group (p o 0.05). T0: before heparin infusion (bACT), T1: 3 minutes after initial heparin infusion, T2: 30 minutes after CPB, T3: before protamine administration, T4: 5 minutes after protamine administration. ACT, activated clotting time.
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ZHANG ET AL
Table 5. Comparison of Data of CPB Between the 2 Groups
Assisted circulation time (min) Aortic clamping time (min) CPB time (min) Sternal closure time (min) Blood transfusion volume during surgery (mL)
Table 6. Comparison of Complications Between the 2 Groups
Control Group
Experiment Group
p
(n ¼ 30)
(n ¼ 30)
Value
36.57 ⫾ 23.40
35.30 ⫾ 23.07
0.834
77.80 ⫾ 44.02
76.73 ⫾ 45.19
0.927
131.27 ⫾ 45.88 58.60 ⫾ 7.27
130.33 ⫾ 50.84 52.20 ⫾ 7.36
0.941 0.001
480.00 ⫾ 260.50
306.67 ⫾ 250.42
0.011
NOTE. Values expressed as mean ⫾ standard deviation.
p
Drainage volume (mL) Blood transfusion volume after surgery (mL) Delirium Deep vein thrombosis Pulmonary embolism Cerebral infarction Renal failure (eGFR o30mL/min/ 1.73m2)
Control (n ¼ 30)
Experiment (n ¼ 30)
Value
681.40 ⫾ 205.96 416.67 þ 313.03
645.33 ⫾ 204.30 333.33 þ 242.59
0.499 0.254
3 0 0 0 0
4 0 0 0 0
0.688 1 1 1 1
NOTE. Values expressed as number or mean ⫾ standard deviation.
adjusted regimen of heparin infusion during cardiac surgeries in a Chinese population. Comparing the effectiveness of the 2 regimens showed no significant difference in achieving target value and maintaining ACT value (4480 seconds), which indicated that the adjusted regimen was as effective as the traditional regimen. The authors’ results also showed that initial dosage, total dosage of heparin, and total dosage of protamine in the experimental group were significantly lower, and there was no significant difference in ACT value after protamine neutralization, which indicated that the adjusted regimen could effectively reduce the use of heparin and protamine. There were no significant differences in CPB time, aortic clamping time, and assisted circulation time, but sternal closure time in the experimental group was significantly shorter, which might have been attributed to less oozing in the surgical field and thus less time spent by surgeons dealing with active bleeding. Comparing the safety of the 2 regimens, the authors found no blood coagulation, thrombosis formation, tubing blockage, or other risk events in either group. There were no postoperative complications such as deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or renal failure in the experimental group, which indicated that the adjusted regimen was as safe as the traditional regimen. Three patients in the control group and 4 patients in the experimental group suffered from delirium, but no significant difference was shown. Intraoperative ACT values at T1 through T3 and blood transfusion volume during surgery in the experimental group were significantly lower, indicating that the adjusted regimen
could reduce intraoperative ACT and blood transfusion, which might be attributed to taking account of bACT and infusing less heparin in the adjusted regimen, especially for patients with high bACT. Postoperative drainage volume and blood transfusion volume in the experimental group were lower than in the control group, but the difference was not significant. This result indicated that factors other than heparin and protamine, such as CPB time and systematic inflammatory reaction, also could play parts in the postoperative recovery of the coagulation system. This study had some limitations. First, this study was a singlecenter trial; the validity of the adjusted regimen needs to be verified through larger multicenter clinical trials. Second, due to a relatively small sample size, few heparin resistances occurred. Whether the regimen is applicable to other Chinese populations still needs further research. Finally, to ensure consistency of the baseline, patients with abnormal liver, kidney, and coagulation function or patients taking anticoagulants preoperatively were excluded. When applying the adjusted regimen to these patients, extra attention was required because of potential heparin metabolic abnormality. CONCLUSION
This study verified an adjusted regimen of heparin infusion, which could be used safely and effectively in a Chinese population with CPB surgery. Moreover, this adjusted regimen could reduce sternal closure time and intraoperative blood transfusion volume.
REFERENCES 1. Shibasaki M, Nakajima Y, Kojima A, et al: How much dosage of heparin do you administer? The relationship between heparin dosage and activated coagulation time (ACT) value during cardiovascular surgery: A multicenter investigation. Jpn J Anesthesiol 59:535-539, 2010 2. Palmer K, Ridgway T, Al-Rawi O, et al: Heparin therapy during extracorporeal circulation: Deriving an optimal activated clotting time during cardiopulmonary bypass for isolated coronary artery bypass grafting. J Extra Corpor Technol 44:145-150, 2012 3. Lowenstein E, Johnston WE, Lappas DG, et al: Catastrophic pulmonary vasoconstriction associated with protamine reversal of heparin. Anesthesiology 59:470-472, 1983 4. Madani H, Sadiki EO, Bouziane M, et al: Anaphylaxis to protamine during cardiovascular surgery. Ann Pharm Fr 72: 143-145, 2014
5. Bull BS, Karpman RA, Huse WM, et al: Heparin therapy during extracorporeal circulation. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg 69:674-684, 1975 6. Bull BS, Huse WM, Brauer FS, et al: 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 7. Grieshaber P, Bakchoul T, Wilhelm J, et al: Platelet-activating protamine-heparin-antibodies lead to higher protamine demand in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg 150: 967-973, 2015 8. Vonk AB, Veerhoek D, van den Brom CE, et al: Individualized heparin and protamine management improves rotational thromboelastometric
ADJUSTED CALCULATION MODEL OF REDUCED HEPARIN IN CPB
parameters and postoperative hemostasis in valve surgery. J Cardiothorac Vasc Anesth 28:235-241, 2014 9. Kjellberg G, Sartipy U, van der Linden J, et al: An adjusted calculation model allows for reduced protamine doses without increasing blood loss in cardiac surgery. Thorac Cardiovasc Surg (in press). 10. Wang J, Ma HP, Ti AL, et al: Prothrombotic SERPINC1 gene polymorphism may affect heparin sensitivity among different ethnicities of Chinese patients receiving heart surgery. Clin Appl Thromb Hemost (in press). 11. Rao X, Xiao LQ, Chen W, et al: Comparison of two heparin doses during cardiopulmonary bypass surgery. Beijing Biomed Eng 31: 415-421, 2012 12. Nakasuji A, Matsushita S, Inaba H, et al: Evaluation of a new formula for calculating heparin dose for cardiopulmonary bypass patients. Open J Thorac Surg 4:32-38, 2014 13. John LC, Rees GM, Kovacs IB: Inhibition of platelet function by heparin. An etiologic factor in post bypass hemorrhage. J Thorac Cardiovasc Surg 105:816-822, 1993
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14. Galeone A, Rotunno C, Guida P, et al: Monitoring incomplete heparin reversal and heparin rebound after cardiac surgery. J Cardiothorac Vasc Anesth 27:853-858, 2013 15. Teoh KHT, Young E, Blackall MH, et al: Can extra protamine eliminate heparin rebound following cardiopulmonary bypass surgery? J Thorac Cardiovasc Surg 128:211-219, 2004 16. Shuhaibar MN, Hargrove M, Millat MH, et al: How much heparin do we really need to go on pump? A rethink of current practices. Eur J Cardiothorac Surg 26:947-950, 2004 17. Fromes Y, Daghildjian K, Caumartin L, et al: A comparison of low vs conventional-dose heparin for minimal cardiopulmonary bypass in coronary artery bypass grafting surgery. Anaesthesia 66:488-492, 2011 18. Jorgensen AL, Fitzgerald RJ, Oyee J, et al: Influence of CYP2C9 and VKORC1 on patient response to warfarin: A systematic review and meta-analysis. PLoS One 7:e44064, 2012 19. Yang J, Chen Y, Li X, et al: Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: A systematic review and meta-analysis. Int J Cardiol 168: 4234-4243, 2013
total dose), CPB time, aortic clamping time, assisted circulation time, sternal closure time, blood transfusion volume, and drainage volume 24 hours after surgery were recorded. There was no significant difference in achieving target ACT after the initial dose of heparin between the 2 groups; CPB time, aortic clamping time, assisted circulation time, postoperative complication rate, and drainage volume between the 2 groups were not significantly different (p 4 0.05). However, initial and total dosage of heparin, initial and total dosage of protamine, sternal closure time, and intraoperative blood transfusion volume in the experimental group were significantly lower (p o 0.05). Conclusions: Adjusted regimen of heparin infusion could be used safely and effectively in Chinese CPB patients, which might reduce the initial and total dosage of heparin and protamine as well as sternal closure time and intraoperative blood transfusion volume. & 2016 Elsevier Inc. All rights reserved.
T
calculate the initial dose of heparin12; this formula takes into account baseline ACT (bACT) and body weight. In the present study, bACT and target ACT 4480 seconds were taken into account to develop an adjusted formula. The main objective of the present study was to evaluate the safety and effectiveness of this adjusted formula in CPB.
HERE IS NO COMMONLY recognized regimen for heparin infusion in cardiac surgery with cardiopulmonary bypass (CPB).1 Heparin inadequacy could lead to failure of CPB or even thromboembolic events, whereas heparin overdose could cause excessive blood loss during sternal closure.2 In addition, rapid administration of protamine, used to neutralize excessive heparin, could cause life-threatening hemodynamic disturbance, along with histamine release and hypoxemia, especially at the end of CPB.3 Additional use of protamine after CPB also could increase allergy risks and bleeding.4 Currently, 300 IU/kg is used widely as the initial dosage of heparin administered before starting CPB. Activated coagulation time (ACT) is used as an indicator of the effectiveness of heparin intraoperatively, with ACT 4480 seconds as the safety threshold of CPB.5,6 In this regimen, heparin dosage calculation is based solely on patient body weight. The regimen may achieve target ACT quickly but often causes heparin overdosing. Moreover, heparin rebound after CPB may require additional protamine administration,7 especially in Chinese populations. Adjusted heparin regimens have been used in some research projects,8,9 but most subjects in these studies were European and American. According to the experience of the authors there are more bleeding than embolism events in Chinese populations during the process of anticoagulation compared with European and American populations.10,11 The hypothesis in the present study was that less heparin is needed in cardiac surgeries for Chinese people. Recently, Nakasuji et al developed an original formula, which had been proven effective to
KEY WORDS: individual administration, heparin, activated clotting time, cardiopulmonary bypass, transfusions, protamine, anticoagulation
MATERIAL AND METHODS
Patients who underwent cardiac surgery with CPB from January 2013 to December 2014 in the Department of Cardiothoracic Surgery in Changzheng Hospital were selected. Inclusion criteria were as follows: 18 to 75 years of age, undergoing first-time cardiac surgery with conventional median sternotomy, aortic clamping time between 40 and 120 minutes, and preoperative routine blood tests showing normal liver, renal, and coagulation function.
From the Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. Yufeng Zhang, Kai Liu, and Wei Li contributed equally to this work. This work was supported by the National Nature Science Foundation of China (No.81300102). Address reprint requests to Zhinong Wang, MD, Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China. E-mail: [email protected] © 2016 Elsevier Inc. All rights reserved. 1053-0770/2601-0001$36.00/0 http://dx.doi.org/10.1053/j.jvca.2016.04.005
Journal of Cardiothoracic and Vascular Anesthesia, Vol 30, No 5 (October), 2016: pp 1179–1183
1179
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ZHANG ET AL
Table 1. Preoperative Baseline Characteristics
Groups
Control Group
Experimental Group
p
(n ¼ 30)
(n ¼ 30)
Value
52.80 ⫾ 11.15 14 163.63 ⫾ 9.25 61.33 ⫾ 10.65
0.75 0.606 0.54 0.24
12 14 4 6 8 4 11.69 ⫾ 1.04 34.59 ⫾ 3.41 181.07 ⫾ 51.31
0.793 0.602 0.718 0.488 0.542 0.488 0.58 0.73 0.391
Age (year) 55.90 ⫾ 12.75 Sex (male) 16 Height (cm) 162.10 ⫾ 10.09 Weight (kg) 58.10 ⫾ 10.69 Heart function (NYHA) Class II 13 Class III 12 Class IV 5 Diabetes 4 Hypertension 6 COPD 6 Preoperative Hb (g/L) 11.85 ⫾ 1.22 Preoperative Hct (%) 34.90 ⫾ 3.59 Preoperative platelet 192.67 ⫾ 52.76 Count (c/mL)
NOTE. Values expressed as number, median (interquartile range), or mean ⫾ standard deviation. Abbreviations: NYHA, New York Heart Association; COPD, chronic obstructive pulmonary disease; Hb, hemoglobin; Hct, hematocrit value.
Exclusion criteria were: salvage cases, a history of coagulopathy in the family, and long-term use of anticoagulation or antiplatelet drugs due to atrial fibrillation, cerebral infarction, or unstable angina. All included patients signed informed consent forms meeting ethical standards of the Human Research Committee of Changzheng Hospital. All surgeries were performed by the same group of surgeons, anesthesiologists, and perfusionists. Groups With an alpha value of 0.05 and a desired power of 0.80, it was found that 27 participants were required for each group to address the primary aim of the study. The authors planned the study with 30 patients in each group. A total of 60 patients were enrolled and randomized into a control group (n ¼ 30) and an experimental group (n ¼ 30). A traditional regimen, with initial dose of heparin (units) ¼ body weight (kg) 300 U/lg, was used in the control group. An adjusted regimen, with initial dose of heparin (units) ¼ Body weight (kg) 300 U/kg (480 – bACT) / (480 –100), was used in the experimental group. Patients’ general information included name, sex, age, body weight, hospitalization number, and diagnosis. Perioperative states of heart, lung, liver, kidney, and coagulation function and information regarding history of diabetes or hypertension also were collected. Surgery information included the type, mode, and date of surgeries. Surgeons, anesthesiologists, and caregivers were blinded to this information. Anesthesia and Cardiopulmonary Bypass Anesthesia was induced with 0.1 mg/kg of midazolam, 1 to 2 mg/kg of sufentanil, and 0.2 mg/kg of vecuronium, and it was maintained with propofol, sufentanil, and vecuronium. Electrocardiogram, arterial pressure, central venous pressure, pulmonary artery pressure, and cardiac index, as well as nasopharyngeal
temperature, rectal temperature, and blood gas were monitored during the procedure. The circuit was primed with 1,000 mL of gelatin solution, 500 mL of Ringer’s acetate, 400 mL of mannitol, 160 mg of sodium chloride, and 2000 U of heparin. Myocardial protection was achieved by using cold (41C) crystalloid cardioplegia solution (St. Thomas Hospital cardioplegic solution No. 2; Plegisol W, Abbott Laboratories, Chicago, IL). The targeted mean perfusion pressure was 50 to 70 mmHg. Patient temperature was maintained between 341C and 361C, and blood flow was kept between 2.2 and 2.4 L/min/m2. A cell-saving device was used to process red blood cells during the whole procedure. The initial dose of heparin was administered according to 2 different regimens. ACT was measured 4 times before administration of heparin, and bACT was the mean of 4 numeric values. If required, additional doses of heparin (5000 U) were administered during CPB to maintain an ACT 4480 seconds. After termination of CPB, heparin was antagonized with protamine at a 1:1 ratio, and then ACT was measured to exclude residual heparin. Blood was transfused to maintain hemoglobin 47g/L and hematocrit 40.20. Evaluation of Adjusted Regimen ACT was monitored at 5 different time points, including T0 (before heparin infusion), T1 (3 minutes after initial heparin infusion), T2 (30 minutes after CPB), T3 (before protamine administration), and T4 (5 minutes after protamine administration). Initial, additional, and total dose of heparin and protamine; CPB time; aortic clamping time; assisted circulation time; sternal closure time (from termination of CPB to termination of surgery); blood transfusion volume; and chest drainage volume were recorded. Statistical Methods Categorical variables are presented as the number of observations. Continuous variables are presented as the mean ⫾ standard deviation. Statistical analysis was performed with the IBM SPSS 19 (SPSS, Inc, Armonk, New York). Data were compared by using one-way analysis of variance and χ2 test; p values o 0.05 were considered significant.
Table 2. Comparison of Surgery Types Between the 2 Groups
MVR þ TVP AVR MVR þ AVR þ TVP TVP ASD/VSD
Control Group
Experimental Group
p
(n ¼ 30)
(n ¼ 30)
Value
12 8 4 1 5
14 6 5 2 3
0.602 0.542 0.718 0.554 0.448
NOTE. Values expressed as number. Abbreviations: MVR þ TVP, mitral valve replacement and tricuspid valvuloplasty; AVR, aortic valve replacement; MVR þ AVR þ TVP, mitral valve replacement, aortic valve replacement, and tricuspid valvuloplasty; TVP, tricuspid valvuloplasty; ASD, atrial septal defect; VSD, ventricular septal defect.
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ADJUSTED CALCULATION MODEL OF REDUCED HEPARIN IN CPB
Table 3. Comparison of ACT Values Between the 2 Groups at Different Time Points
ACT Value (s)
T0 (bACT) T1 T2 T3 T4
Table 4. Comparison of Dosage of Heparin and Protamine Between the 2 Groups
Control Group
Experimental Group
p
Control Group
Experiment Group
p
(n ¼ 30)
(n ¼ 30)
Value
(n ¼ 30)
(n ¼ 30)
Value
153.40 ⫾ 20.11 703.10 ⫾ 127.57 887.67 ⫾ 90.70 820.77 ⫾ 138.14 140.10 ⫾ 12.84
153.67 ⫾ 21.91 623.03 ⫾ 127.33 799.73 ⫾ 139.24 712.63 ⫾ 182.21 142.63 ⫾ 17.05
0.96 0.02 0.005 0.012 0.518
174.30 ⫾ 32.06
156.67 ⫾ 29.99
0.029
195.97 ⫾ 33.48
178.37 ⫾ 34.70
0.048
293.85 ⫾ 50.24
260.88 ⫾ 53.32
0.017
NOTE. Values expressed as mean ⫾ standard deviation. Abbreviations: ACT, activated clotting time; bACT, baseline activated clotting time.
RESULTS
There were no significant differences in baseline characteristics or surgery types between the 2 groups, as shown in Tables 1 and 2. There also were no significant differences in bACT or success rate of achieving target ACT between the 2 groups, and only 1 patient required an additional dose of heparin before CPB. However, ACT in the experimental group was significantly lower than that of the control group at T1, T2, and T3, and ACT values returned to normal after infusion of protamine (T4), as shown in Table 3 and Figure 1. In addition, initial and total dose of heparin and total dose of protamine in the experimental group were significantly lower than in the control group (p o 0.05), as shown in Table 4. There were no significant differences in CPB time, aortic clamping time, or assisted circulation time between the 2 groups (p 4 0.05), but sternal closure time and blood transfusion volume during surgery in the experimental group were significantly lower (p o 0.05), as shown in Table 5. There were no deep vein thromboses, pulmonary embolism, cerebral infarction, renal failure, or other severe complications in either group. Drainage volume and blood transfusion volume
Initial dose of heparin (mg) Total dose of heparin (mg) Total dose of protamine (mg)
NOTE. Values expressed as mean ⫾ standard deviation.
after surgery in the experimental group were less than in the control group, but differences were not significant (p 4 0.05). Three patients in the control group and 4 patients in the experimental group suffered from delirium, but the difference was not significant, as shown in Table 6. DISCUSSION
Overdose of heparin in CPB is associated with increased blood loss and excessive use of protamine,13–15 and heparin rebound after surgery could cause greater drainage volume and a longer intensive care unit stay;16,17 whereas inadequacy of heparin could lead to thromboembolic and other risk events during CPB. An optimal regimen of heparin infusion should use a relatively small amount of heparin to ensure the safety of CPB. Most clinical research projects about heparin infusion were designed for European and American patients. According to the experience of the authors’ center, there were relatively more bleeding than embolic events in Chinese people during the coagulation process,18,19 and the authors also found that the traditional regimen of heparin transfusion could cause excessive oozing in the surgical field, which resulted in multiple ACT checks and additional protamine infusion after CPB. This study aimed to verify the effectiveness and safety of an
Fig 1. ACT values compared to CS group (p o 0.05). T0: before heparin infusion (bACT), T1: 3 minutes after initial heparin infusion, T2: 30 minutes after CPB, T3: before protamine administration, T4: 5 minutes after protamine administration. ACT, activated clotting time.
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ZHANG ET AL
Table 5. Comparison of Data of CPB Between the 2 Groups
Assisted circulation time (min) Aortic clamping time (min) CPB time (min) Sternal closure time (min) Blood transfusion volume during surgery (mL)
Table 6. Comparison of Complications Between the 2 Groups
Control Group
Experiment Group
p
(n ¼ 30)
(n ¼ 30)
Value
36.57 ⫾ 23.40
35.30 ⫾ 23.07
0.834
77.80 ⫾ 44.02
76.73 ⫾ 45.19
0.927
131.27 ⫾ 45.88 58.60 ⫾ 7.27
130.33 ⫾ 50.84 52.20 ⫾ 7.36
0.941 0.001
480.00 ⫾ 260.50
306.67 ⫾ 250.42
0.011
NOTE. Values expressed as mean ⫾ standard deviation.
p
Drainage volume (mL) Blood transfusion volume after surgery (mL) Delirium Deep vein thrombosis Pulmonary embolism Cerebral infarction Renal failure (eGFR o30mL/min/ 1.73m2)
Control (n ¼ 30)
Experiment (n ¼ 30)
Value
681.40 ⫾ 205.96 416.67 þ 313.03
645.33 ⫾ 204.30 333.33 þ 242.59
0.499 0.254
3 0 0 0 0
4 0 0 0 0
0.688 1 1 1 1
NOTE. Values expressed as number or mean ⫾ standard deviation.
adjusted regimen of heparin infusion during cardiac surgeries in a Chinese population. Comparing the effectiveness of the 2 regimens showed no significant difference in achieving target value and maintaining ACT value (4480 seconds), which indicated that the adjusted regimen was as effective as the traditional regimen. The authors’ results also showed that initial dosage, total dosage of heparin, and total dosage of protamine in the experimental group were significantly lower, and there was no significant difference in ACT value after protamine neutralization, which indicated that the adjusted regimen could effectively reduce the use of heparin and protamine. There were no significant differences in CPB time, aortic clamping time, and assisted circulation time, but sternal closure time in the experimental group was significantly shorter, which might have been attributed to less oozing in the surgical field and thus less time spent by surgeons dealing with active bleeding. Comparing the safety of the 2 regimens, the authors found no blood coagulation, thrombosis formation, tubing blockage, or other risk events in either group. There were no postoperative complications such as deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, or renal failure in the experimental group, which indicated that the adjusted regimen was as safe as the traditional regimen. Three patients in the control group and 4 patients in the experimental group suffered from delirium, but no significant difference was shown. Intraoperative ACT values at T1 through T3 and blood transfusion volume during surgery in the experimental group were significantly lower, indicating that the adjusted regimen
could reduce intraoperative ACT and blood transfusion, which might be attributed to taking account of bACT and infusing less heparin in the adjusted regimen, especially for patients with high bACT. Postoperative drainage volume and blood transfusion volume in the experimental group were lower than in the control group, but the difference was not significant. This result indicated that factors other than heparin and protamine, such as CPB time and systematic inflammatory reaction, also could play parts in the postoperative recovery of the coagulation system. This study had some limitations. First, this study was a singlecenter trial; the validity of the adjusted regimen needs to be verified through larger multicenter clinical trials. Second, due to a relatively small sample size, few heparin resistances occurred. Whether the regimen is applicable to other Chinese populations still needs further research. Finally, to ensure consistency of the baseline, patients with abnormal liver, kidney, and coagulation function or patients taking anticoagulants preoperatively were excluded. When applying the adjusted regimen to these patients, extra attention was required because of potential heparin metabolic abnormality. CONCLUSION
This study verified an adjusted regimen of heparin infusion, which could be used safely and effectively in a Chinese population with CPB surgery. Moreover, this adjusted regimen could reduce sternal closure time and intraoperative blood transfusion volume.
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