ORIGINAL ARTICLE

 

Standardization of the sodium heparin dose used in off-pump myocardial revascularization surgery

 

 

José Glauco Lobo Filho; Maria Cláudia Leitão; Roberto Augusto Mesquita Lobo; José Mário de Lima Júnior; João Paulo Aguiar Ribeiro; Fernanda Cavalcante; Glício Rebouças; Allison Borges; Dadson Leandro Sales; Newton Teles Júnior

Correspondence

 

 

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ABSTRACT

OBJECTIVE: To evaluate a methodology of anticoagulation during off-pump coronary artery bypass surgery (CABS) that promotes safe anticoagulation during the procedure (Activated Coagulation Time (ACT) > 200 seconds), using an initial dose of 1 mg of sodium heparin/kg weight.
METHOD: 40 patients (30 men and 10 women), with ages ranging from 41 to 85 years, were submitted to off-pump CABS, using an initial sodium heparin dose of 1mg/kg of weight. Ten minutes after the drug was administered, if the ACT was = 200 seconds, we initiated the revascularization procedure. If not, we administered an additional dose of 0.5mg/kg heparin. During the surgery, the ACT was measured at 30 minute intervals. After revascularization, heparin reversal was achieved with a dose of protamine chloride equal do the total heparin dose infused during the procedure (1:1).
RESULTS: The mean ACT at 10 minutes after heparinization was 372.2 (± 104.31) seconds, without significant statistical difference between gender and age groups (p>0.05). The ACT values at 30 and 60 minutes remained greater than 200 seconds in all patients. The ACT at 30 minutes showed a significant statistical difference between age groups and gender (p<0.05). After heparin reversal using protamine, all patients returned to their initial hemostasis level (ACT < 200s).
CONCLUSION: The results show the safety and effectiveness of an initial sodium heparin dose of 1 mg/kg of weight during off-pump CABS maintaining safe ACTs (> 200s) even after 60 minutes of heparinization, independently of age and gender.

Descriptors: Myocardial Revascularization; Heparin; Whole Blood Coagulation Time

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INTRODUCTION

Sodium heparin is the anticoagulant normally used in heartsurgery. Pharmacologically, it allows an adequate control of theanticoagulation and the prevention of thromboembolic events, andis responsible for the great development of surgical techniques.However, an adequate and rigorous control of the levels ofanticoagulation is necessary, in order to minimize its adverseeffects [1,2].

The use of large-dose endovenous sodium heparin in on-pumpcoronary artery bypass surgery is already well established. Dueto the prothrombotic effects induced by the blood circulation ina artificial environment [3], the anticoagulant doses used arehigh, with levels of up to 3 to 4 mg (300 to 400 IU) of heparinper kg of body weight [1], to reach a safe activated coagulationtime (ACT) of over than 480 seconds [2,4].

The technical use of off-Pump coronary artery bypass grafting(OPCABG) surgery reduces the incidence of a series ofpostoperative complications and the time of hospitalization iscomparable to the on-pump procedure [5-7], without damaging theanastomoses [7-8]. Thus, we have seen an increase in the use ofoff-Pump CABG.

In spite of OPCABG becoming a common technique, there is stillno consensus about the ideal dose of heparin to be utilized inthis new context [3]. Consequently, the heparinization ofpatients in this type of surgery has been empirically performedby many surgeons. Some even utilize anticoagulation in dosessimilar to those employed in on-pump CABG, which may beresponsible for the high risk of bleeding in the postoperativeperiod thereby increasing the in-hospital time [9-12].Additionally, proportionally greater doses of protamine must beutilized to revert this heparinization, making the dose-dependentdeleterious effects of protamine, such as hypotension, myocardialdepression and non-cardiogenic pulmonary edema, possible[12,13].

Remembering that in OPCABG surgery the induction ofprothrombotic events is less frequent than in on-pump CABG [3],patients submitted to this surgical procedure should, thus,receive differentiated trans-operative anticoagulation, at lowerdoses.

Based on the fact that OPCABG from the physiological,hemodynamical and functional viewpoints, is similar to peripheralvascular surgery, it has been suggested that the use of heparindoses in OPCABG should be similar to those universally acceptedin peripheral vascular surgical techniques. As ACT levels over200 seconds are considered safe in peripheral vascularprocedures, according to current publications [12,14,15], ourprotocol adopted this ACT level as appropriate for patientsundergoing anticoagulation in OPCABG.

Consequently, we present a protocol of a safe method of anticoagulation that can be routinely utilized in this type of intervention. We stress that due to individual variations in the necessities of heparin and the risks involved with small doses, monitoring of the anticoagulant activity of heparin during the surgical procedure is essential [16-19].

 

METHOD

Forty patients (30 men and 10 women) with ages between 41 and85 years (mean: 64.02 ± 11.14 years), participated in thestudy after signing written informed consent forms. The patientswere consecutively submitted to elective OPCABG surgery fromJanuary to June 2005.

This is an observational-type study, with exclusion criteriaof previous coagulopathies, patients submitted to reoperationsand those that did not accept to participate in the study. Theresearch was approved by the Ethics Committees of the serviceswhere the surgical procedures were performed, according to theprotocol as follows:

1. All ACT measurements were performed using the 2000®MCA apparatus (Adib Jatene Foundation). In all measurements 3-mLsamples of whole blood collected from a peripheral venous vesselwas utilized.

2. Before induction of anesthesia, the ACT of the patient(Initial ACT) was determined.

3. After obtaining the initial ACT, EV sodium heparin in bolusat a dose of l mg/kg of body weight was infused.

4. Another ACT measurement was made 10 minutes after heparininfusion (ACT₁₀). If the determined ACT at this timewas 200 seconds or greater, CABG would be initiated. If the ACTwas less than 200 seconds, an extra dose of sodium heparin of 0.5mg/kg of body weight in bolus was administrated EV, aiming atachieving an ACT of more than 200 seconds, defined as safe.

5. At thirty-minute intervals, ACT values were determined(ACT₃₀ and ACT₆₀) and, when they were lessthan 200 seconds, extra doses of sodium heparin (0.5 mg/kg) wereadministrated in order to maintain the ACT at over 200seconds.

6. At the end of CABG, circulating heparin was neutralized byendovenous administration of protamine hydrochloride, controlledusing a continuous infusion pump, at a proportion of 1 mgprotamine to 1 mg of total heparin administrated. A maximum doseof 50 mg of protamine was administered in each ten minutes.

Ten minutes after the end of protamine infusion, the ACT was measured again (ACT_FINAL).

 

RESULTS

Statistical analysis of the ACT values was made. All thevalues are in seconds and are reported as arithmetical means,followed by the standard deviation (between parentheses).

To evaluate a possible variation in response between thegenders and different age groups to anticoagulation with heparin,we proceeded in the following manner: we obtained mean ACT valuesof patients from both genders, comparing them and after weutilizing the non-paired t-test. In respect to the analysis ofthe differences in response according to the age of the patient,we subdivided our sample into three age groups: from 40 to 54years, from 55 to 69 years and greater than 70 years. For eachgroup the mean value of ACT was obtained and these values werecompared among each other utilizing the one-way analysis ofvariance test (ANOVA). In both tests, a p-value = 0.05 wasconsidered statistically significant (CI=95%).

The mean of the initial ACT values of studied patients was127.8 (± 30.57) seconds demonstrating its basal level ofhemostatic response. Comparing the mean basal ACT values amongthe male patients (122.4 ± 29.41) and female patients(143.9 ± 29.66), we obtained a borderline value of p (p=0.0532), but without significant difference. In the analysis ofthe basal ACT in the different age groups, we obtained meanvalues of 134.9 (± 37.47) seconds in the group of 40 to 54year-olds, 132.4 (± 24.09) seconds in group of 55 to 69years year-olds and 119.3 (± 30.89) seconds in the groupof over 70 year-olds. Comparing the mean values, there is nostatistically significant difference among age groups (p=0.3603).

When the ACT₁₀ values were analysed, we observed a mean value of 372.2 (± 104.31) seconds. It was verified that there was no statistically significant variation between the ACT₁₀ of male patients (360.8 ± 106.2) and female patients (406.5 ± 95.13) (p=0.2346) (Figure 1).

 

 

To analyze if the ACT₁₀ values presented significant variations among the different age groups, we obtained the following values: from 40 to 54 years (371.1 ± 128.3), from 55 to 69 years (395.9 ± 116.1) and over 70 years (352.2 ± 76.1). Comparing these values, we verified that there were no statistically significant variations among the ACT₁₀ measurements of the different age groups (p= 0.5315) (Figure 2).

 

 

In respect to the mean ACT₃₀ value, we calculated it to be 342.27 (± 87.14) seconds. It was thus demonstrated that the heparin dose utilized maintained the patients safely anticoagulated in the thirtieth minute after its administration. Comparing the mean values among male patients (319.2 ± 75.15) and female patients (403.9 ± 90.28), we verified that there was a statistically significant variation, with levels of response to the anticoagulation greater in the female group than those obtained in male group (p-value = 0.0067) (Figure 3).

 

 

Comparing the ACT₃₀ among the three aforementioned age groups, we obtained the following values: from 40 to 54 years _ 287.3 (± 67.99), from 55 to 69 years – 396.8, (± 87.79) and over 70 years – 314.7 (± 73.7). Statistically significant differences were identified with the levels of anticoagulation among the different age groups (p-value = 0.0047) (Figure 4). Using the Newman-Keuls test for multiple comparisons, we observed that this difference occurs only between the 55- to 69-year-old Group and the other two groups. Between the 40- to 54-year-old Group and over 70-year-old Group, there was no statistically significant difference.

 

 

For those patients who were still in surgery for coronaryanastomoses at 60 minutes after the initial heparinization (13patients), a new measurement of the ACT was performed. In thesepatients the mean ACT value was 324.61 (± 98.80) seconds,thus still within safe levels. Again, there was no statisticallysignificant variations between the ACT₆₀ of malepatients (321.1 ± 78.3) and female patients (330.3± 150.5) (p-value = 0.8979). In respect to an analysisamong the different age groups, from 40 to 54 years, from 55 to69 years and more than 70 years, we obtained the following means,259.0 (± 78.39), 427.7 (± 123.1) and 316.8(± 61.6) respectively. There was also no statisticallysignificant difference between these values (p= 0.0645).

In respect to the additional heparinization, only one patientpresented with an ACT₁₀ less than the minimum of 200seconds. An extra dose of 0.5 mg/kg of weight of sodium heparinwas administrated to this patient. After this dose, the patient'sACT increased from 168 seconds (ACT₁₀) to 403seconds.

Completing the surgical time corresponding to coronary anastomoses and the protamine infusion the ACT_FINAL was checked. At this moment, the mean time was from 120.47 (± 22.83) seconds, demonstrating adequate neutralization of the circulating heparin and an efficient return to the initial levels of hemostasis for the patients. Comparing male and female patients, the mean values were 116.4 (± 22.65) and 132.7 (± 19.6) seconds respectively, giving a statistically significant difference between genders (p-value = 0.0492) (Figure 5). When comparing the values among the three age groups, the mean ACTs were 123.8 (± 29.71), 124.9 (± 22.5) and 114.6 (± 18.01), respectively. No statistically significant differences between the ACT_FINAL values and the different age groups were identified (p-value = 0.417) (Figure 6).

 

 

 

 

DISCUSSION

With the growing use of the OPCABG, the number of scientificpublications, both national and international, related to the useof this surgical technique has increased considerably. However,there are the several gaps in the scientific literature about themost adequate heparin doses to be employed in this procedure.Through this study, our group aimed at maintaining the levels ofanticoagulation of patients submitted to OPCABG to reduced dosesof heparin of 1 mg/kg of body weight, similar to the dosesutilized in the peripheral vascular surgery.

A concern at the start of the study was about individualvariations among patients who could respond heterogeneously tothe standard heparin dose, as has already been reported inpublished studies [16-19]. To try to get around this problem, weadopted the practice of intraoperative monitoring of the ACT,attempting to continuously measure the response of each patientto the heparinization and to immediately increase the dose ifpatients did not present adequate anticoagulation for theprocedure [20,21]. Accordingly, we determined a safety level toperform the surgery with an ACT of at least 200 seconds.

Only one patient presented an unsatisfactory ACT of less than200 seconds at 10 minutes after heparinization, but the ACTincreased immediately to a safe level with an additional dose of0.5 mg heparin/kg of body weight.

In the other patients, the proposed heparinization gave aneffective ACT level, with mean values of 372.2 (± 104.31)seconds after administration, well over the pre-establishedminimum of 200 seconds, a level at which there is surely nointravascular coagulation [16]. We also demonstrated that,independently of gender or age the ACT₁₀ level wasalways greater than the acceptable minimum. That is, even takinginto account individual variations, differences in gender andage, the utilization of this heparin dose is capable of inducinga safe anticoagulation level, well above the minimum of 200seconds stipulated by previous studies [12,14,15].

This level of heparinization was even adequate 30 minutesafter heparin infusion, as the mean ACT₃₀ was 342.27(± 87.14) seconds. At this time interval, variables suchas gender and age influenced the degree of response toheparinization. However, even responding differently, allpatients remained above the safety level.

In those patients in which anastomoses were still beingperformed 60 minutes after the initiation of heparinization, theACT was, on average, 324.61 (± 98.80) seconds, stillconsidered an adequate level. At this point we can affirm thatpatients submitted to OPCABG using doses of 1 mg of sodiumheparin per kilogram of body weight are safely maintainedanticoagulated during all the period necessary to perform thecoronary anastomosis procedure.

At the end of the anastomoses, reversal of the heparin wasinitiated using protamine hydrochloride at a proportion of 1:1.This total reversal at the end of OPCABG, is known to avoidcomplications such as excessive postoperative bleeding, and theconsequent need of blood derivatives and their inherent risks[8,18]. Ten minutes after the end of the infusion of theprotamine, the TCA_FINAL had a mean value of 120.47(± 22.83) seconds. At this moment, there was a slightdifference between the genders, again with women having higherACTs. However, differences among age groups were notidentified.

Nevertheless, even with possible individual variations, the heparin reversal protocol brought all patients back to safe hemostasis states – practically similar states to those obtained before the start of the surgical procedure, where the mean ACT was 127.8 (± 30.57) seconds (p-values = 0.2284).

The results presented in this study demonstrate the safety and efficacy of anticoagulation of patients who will be submitted to OPCABG utilizing low doses of sodium heparin – 1 mg/kg of body weight. In all patients the response was satisfactory with safe ACTs, adequate to complete the procedure. We also demonstrated that this response lasts for at least 30 minutes or even 60 minutes after initiation of heparinization, maintaining the patient safely anticoagulated throughout.

The efficiency of heparin reversal with protamine at a proportion of 1:1 (total reversion), is also evident, returning the hemostasis of the patients at the end of the surgical procedure to levels similar to the basal level (Figure 7).

 

 

It was also clear that, independently of variables such asgender and age, heparinization at the proposed dose allowsadequate levels of anticoagulation to be achieved. Even when theresponse was statistically different between the genders or agegroups, as seen with the ACT₃₀ and theACT_FINAL, this does not put the patient at risk,because the ACTs remain at adequate levels.

Finally, we believe that according to the results presented in this study, the efficiency of the anticoagulation using 1 mg of sodium heparin/kg of body weight for patients submitted to OPCABG was proven, maintaining the ACTs at safe levels (200 seconds), minimizing the adverse effects resulting from heparinization.

 

ACKNOWLEDGEMENTS

We wish thank to the anesthesiology staff, composed of Dr. Fernando Lima Verde, Dr. Júlio Alexandre and Dr. Geraldo Silva, for the invaluable help they gave in the exact monitoring of the trans-operative ACT levels. We also wish to thank Dr. Ausonius Saraiva, resident physician in our service, who was willing to help us in all surgical procedures and to the secretary Patrícia Queiroz de Sousa, always ready to offer us assistance during all the study period.

 

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Correspondence to
ICORP – Instituto do Coração e Pulmão
Rua Dr José Lourenço, 625, Aldeota
Fortaleza (CE), Brazil, CEP 60115-280
Telephone: (85) 3244-1711
Fax: (85) 3261-0816
E-mail: glaucolobo@uol.com.br, jmljmed@yahoo.com.br

Article received in May, 2005
Article accepted in August, 2005

 

 

Work performed in the Cardiac Surgery Department of ICORP; Hospital Regional da Unimed; Hospital Monte Klinikum; Hospital Universitário Walter Cantídio (HUWC) of the Ceará Federal University (UFC), Fortaleza, CE, Brazil.