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Cardiac anaesthesia

Identifying optimal heparin management during cardiopulmonary bypass in obese patients

A prospective observational comparative study

Haas, Emmanuel; Fischer, François; Levy, François; Degirmenci, Su-Emmanuelle; Grunebaum, Lelia; Kindo, Michel; Collange, Olivier; Mertes, Paul-Michel; Steib, Annick

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European Journal of Anaesthesiology: June 2016 - Volume 33 - Issue 6 - p 408-416
doi: 10.1097/EJA.0000000000000431
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Abstract

Introduction

Obesity constitutes a real public health problem with an increased risk of morbidity and mortality related to cardiovascular diseases. The number of obese patients undergoing cardiac surgery has increased constantly over the past 10 years.

From a pharmacological point of view, obesity is usually accompanied by pharmacokinetic changes, therefore requiring adjustment of the dosage of drugs.

During cardiac surgery, contact of blood components with the cardiopulmonary bypass (CPB) circuit induces activation of coagulation. Potent anticoagulation by injection of UFH is therefore necessary to prevent thrombosis in the circuit. There is currently no consensus concerning the modalities of use of UFH in cardiac surgery and the optimal anticoagulation target assessed intraoperatively by activated clotting time (ACT). In a recent review, Finley et al.1 considered it necessary and sufficient to have an ACT target at least 350 s to carry out CPB under safe conditions. A plasma heparin concentration at least 4 IU ml−1 allows the management of all situations, including heparin resistance.1

In the majority of heparin protocols, the dose of heparin injected is calculated according to the patient's total body weight (UFH 300 IU kg−1 TBW). However, there is marked interindividual variability in the response to a fixed dose of heparin, requiring repeated intraoperative monitoring. This variability is also observed in obese patients in whom the usual heparin therapy protocols, based on TBW, present a number of limitations for the treatment of venous thromboembolic disease.2–7 Inappropriate doses of heparin may result in intraoperative and postoperative bleeding. To our knowledge, only one study, involving 27 patients, has addressed the appropriateness of heparin doses in the obese during cardiac surgery.8 These authors suggested adjustment of the initial dose of heparin for CPB according to lean body mass (LBM) rather than TBW. However, anticoagulation was monitored by measuring ACT alone without intraoperative plasma heparin assays.

The aim of this study was to evaluate changes in heparin concentrations and ACT during CPB by comparing obese and nonobese populations undergoing cardiac surgery and to calculate the optimal heparin regimen for obese patients.

Methods

This observational study was approved on 6 February 2013 by the Strasbourg Faculty of Medicine Ethics Committee, 4 rue Kirschleger, 67085 Strasbourg Cedex, France (reference AMK/BG/2013-15, Chairperson Professor B. Geny) and was declared to the Commission Nationale de l’Informatique et des Libertés (CNIL: registration number Vtr05679028). Written informed consent was obtained from all patients before surgery.

The study started on 27 February 2013 and was carried out over a period of 9 months. The primary objective of the study was to compare the effects of a standard heparin injection based on TBW during cardiac surgery on both the intraoperative plasma heparin concentrations and the ACT in obese and non-obese patients. The secondary objectives were to evaluate the relationship between plasma heparin concentration and ACT in each group of patients and, at different time points during CPB, to compare the incidence of bleeding, intraoperative blood transfusion and complications in the two groups of patients. An additional objective was to calculate the optimal heparin regimen for obese patients according to their ideal body weight (IBW), which is easy to assess according to the formula of Lorentz.9

The patients included in the study were at least 18 years of age and were scheduled for cardiac surgery (coronary artery bypass graft or valve surgery) under CPB. Exclusion criteria included preoperative heparin therapy (UFH or low molecular weight heparin), emergency surgery, redo surgery, heart transplantation, surgery for circulatory assistance, and heparin allergy.

In all patients, general anaesthesia consisted of a combination of etomidate, sufentanil, cisatracurium, sevoflurane and propofol during CPB. The heparin protocol consisted of the injection of UFH 300 IU kg−1 TBW before CPB with a target ACT value of at least 400 s. Additional boluses of UFH (50 to 100 IU kg−1 TBW) were injected if ACT, measured every 30 min during CPB, was insufficient.

Priming of the CPB circuit included 800 ml of Ringer's Lactate solution, 500 ml of 6% hydroxyethyl starch (HES) 130/0.4 in 0.9% normal sodium chloride solution (Voluven, Fresenius Kabi, Germany) and 7500 IU of unfractionated heparin (UFH). In patients with chronic renal failure, HES was replaced by 500 ml of 4% human albumin solution. For patients with a TBW less than 60 kg, CPB priming was reduced to 500 ml of Ringer's Lactate solution, 500 ml of HES and a reduced dose of UFH (5000 IU). Retrograde autologous priming was used to reduce the priming volume, resulting in less marked haemodilution. Cardioplegia was a cold (5°C) crystalloid solution with potassium chloride and magnesium sulphate. A volume of 400 ml was usually administered.

Surgery was performed under normothermia or mild hypothermia. Tranexamic acid was used in all patients at the usual antifibrinolytic dosage (an initial bolus of 12.5 mg kg−1, and then 6.5 mg kg−1 h−1 until the end of surgery). At the end of CPB, the residual effects of heparin were reversed by injection of protamine, based on the total heparin dose (1 : 1). The cut-off for transfusion was defined as a postoperative haemoglobin concentration of 10 g dl−1 or less. The study protocol is summarised in Fig. 1.

Fig. 1
Fig. 1:
Study flow chart. ACT, activated clotting time; CPB, cardiopulmonary bypass; UFH, unfractionated heparin.

Blood samples were taken intraoperatively at the following times: T0, at the start of the operation, measurement of baseline ACT (Hemochron Signature Elite, Gamida, Paris, France); T1, 3 min after injection of UFH, measurement of ACT, plasma heparin and antithrombin concentrations; T2, at the end of cardioplegia, measurement of ACT, heparin and antithrombin concentrations. ACT measurements were then performed every 30 min during CPB, with maintenance of the target value of at least 400 s; T3, before administration of protamine, measurement of ACT, heparin and antithrombin concentrations, as described above; T4, ACT was measured 10 min after the injection of protamine.

Plasma heparin concentration was measured in the haemostasis laboratory using a chromogenic method (STA-Rotachrom, Diagnostica Stago Inc., Parsippany, New Jersey, USA). The area of linearity for UFH was between 0.10 and 0.70 IU ml−1.

All patients were transferred to the ICU postoperatively. Clinical and laboratory parameters were monitored regularly, with blood samples taken on admission to ICU (H0), and then at 6 h (H6) and 24 h (H24). Multimodal analgesia was provided and adapted to each patient.

The data collected for each patient included: the characteristics, use, or discontinuation of antiplatelet agents; type of surgery; CPB and aortic clamping times; data concerning the heparin protocol and its monitoring; results of intraoperative assays (heparin and antithrombin); intraoperative transfusions, cell saver use; results of laboratory tests on admission to ICU, and then at H6 and H24; blood loss from chest drains (H6 and H24); postoperative transfusions of blood products or factor concentrates; total number of days spent in the ICU; postoperative complications; need for reoperation.

For each patient, we calculated the BMI, the IBW according to the formula of Lorentz9 and the LBM according to the formula of James,10 with weight expressed in kilograms and height in centimetres.

IBW women = (height − 100) − ((height − 150)/2.5)

IBW men = (height − 100) − ((height − 150)/4)

LBM women = (1.07 × weight) − (148 × (weight/height)2)

LBW men = (1.1 × weight) − (128 × (weight/height)2)

Statistical analysis

Sample size was designed to obtain 90% power to detect a plasma heparin concentration difference of 0.7 IU ml−1 at T1 (the mean difference of plasma heparin concentration at time 1 found in our preliminary study, including 17 obese patients and 33 nonobese patients), with a 5% alpha error risk. A total of 50 patients were required in each group. All patients were included in the statistical analysis. Tests were performed using R software version 2.12.0 (R Foundation for Statistical Computing, Vienna, Austria). Student's t test and Wilcoxon test were used to compare quantitative variables. The χ2 test was used to evaluate the relationship between two qualitative variables and Fisher's exact test was used when the contingency table consisted of small sample sizes. The correlation between two quantitative variables was tested using Pearson's correlation coefficient or Spearman's correlation coefficient. Linear regression and multiple regression analysis were used to test the relationships between several quantitative or qualitative variables, and analysis of covariance and analysis of variance were used for repeated measures. The limit of significance was set at P less than 0.05.

The ideal dose of heparin was calculated in terms of heparin dose per kilogram TBW in relation to each patient's IBW. The relationship between heparin concentration at T1 and heparin dose per kilogram IBW can be represented by a linear curve, but also by several nonlinear regression curves. Curve equations are shown below with plasma heparin concentration at T1 (y) and heparin dose per kilogram IBW (x).

Exponential equation: y = 14.59 (1 − 1.59e−0.109x)

Isotherm equation: y = 1.704x0.799

Michaelis-Menten equation: y = (6.27x/(1.52 + x))

Sigmoid equation: y = 7.3/(1 + 11.22e−0.879x)

These curves can be used to calculate the heparin dose per kilogram IBW to be injected to obtain a target plasma heparin concentration at T1 ranging from 3.5 to 4.5 IU ml−1. This range includes the mean target plasma heparin concentration of 4 IU ml−1, allowing management of all situations, including heparin resistance, as described by Finley et al.1

Results

The study population included 50 obese patients (BMI ≥ 30 kg m−2) and 50 nonobese patients (BMI < 30 kg m−2). The preoperative characteristics of patients in the control group are shown in Table 1. Obese patients had a significantly higher incidence of diabetes mellitus (P = 0.04) and obstructive sleep apnoea syndrome (P = 0.007). Preoperative values of haemoglobin concentration and haematocrit were significantly higher in obese patients (14.6 ± 0.3 vs. 13.3 ± 0.2 g dl−1, P < 0.001; 43.0 ± 0.8 vs. 39.7 ± 0.6%, P = 0.001). The intraoperative characteristics of the two groups of patients are shown in Table 2. The two groups were not significantly different in terms of CPB time or aortic clamping time, type of surgery, or intraoperative transfusions of blood products or factor concentrates.

Table 1
Table 1:
Preoperative characteristics of the study population
Table 2
Table 2:
Intraoperative data

The characteristics of heparin therapy and its use during surgery are shown in Table 3. The initial and total doses of heparin, as well as the total dose of protamine, were significantly higher in obese patients (P < 0.001). The number of additional boluses of heparin required during CPB to maintain the target ACT was similar in the two groups. Obese patients had significantly higher heparin concentrations at all times during CPB (Fig. 2) (at T1, 5.91 ± 0.22 vs. 4.48 ± 0.18 IU ml−1, P < 0.0001).

Table 3
Table 3:
Intraoperative haemostatic data
Fig. 2
Fig. 2:
Time course of plasma heparin concentration (anti-Xa activity). T1, 3 min after injection of heparin; T2, end of cardioplegia; T3, before protamine. * P < 0.05.

ACT was significantly lower (114.9 ± 1.8 vs. 121.9 ± 2.1 s, P = 0.006) in obese patients at T0. At T1, 3 min after injection of the first dose of heparin, ACT was significantly higher in obese patients (514.5 ± 10.4 vs. 489.8 ± 10.7 s, P = 0.0369). At all other times, ACT was not significantly different between the two groups. ACT values were correlated with heparin concentration, but a poor correlation was observed for ACT values greater than 400 s. The relationship between ACT and heparin concentration at T1 may be adjusted statistically by a linear regression curve or a nonlinear regression curve. These two adjustments were not significantly different. However, adjustment by the linear curve is not clinically relevant; with linear adjustment, the ACT value of 400 s corresponds to a negative heparin concentration of −0.15 IU ml−1. At T1, after the heparin bolus, the relationship between heparin concentration and ACT followed an asymptotic regression curve (Fig. 3).

Fig. 3
Fig. 3:
Activated clotting time as a function of plasma heparin concentration at T1 (3 min after injection of heparin). ACT, activated clotting time. Regression curve plotted according to the equation:
Fig. 1
where y is the value of ACT, x is plasma heparin concentration, with a = 335.44, b = 0.6657 and c = 118.0.

On admission to the ICU, obese patients had a significantly lower prothrombin time (P = 0.022), a lower activated partial thromboplastin time ratio (P = 0.013) and a significantly higher fibrinogen concentration (2.67 ± 0.09 vs. 2.42 ± 0.08 g l−1, P = 0.036), which remained higher postoperatively at H6 and H24. Antithrombin concentrations remained higher than 60% in both groups during surgery (Table 3). Laboratory variables are shown in Table 4.

Table 4
Table 4:
Perioperative laboratory data

Blood loss at H6 and H24 was similar in both groups. No significant difference was observed between the groups in terms of postoperative transfusions of blood products (Table 5). However, the mean differences between preoperative and immediate postoperative haemoglobin concentration and haematocrit were significantly higher in the obese group compared with the control group (ΔHb 3.8 ± 0.24 vs. 2.8 ± 0.16 g dl−1, P < 0.001).

Table 5
Table 5:
Postoperative events

The length of ICU stay was similar in the two groups with a mean of 3.68 ± 0.47 days for all patients. The incidence of postoperative complications and the reoperation rate for bleeding were also similar. No deaths occurred in either group.

Optimal dose of heparin

Calculated optimal doses of heparin per kilogram IBW to obtain the various target heparin concentrations are shown in Table 6. The relationship between heparin concentration at T1 and heparin dose per kilogram IBW can be represented by a linear curve, but also by several nonlinear regression curves. Curve equations are shown in the statistical section. These curves showed similar results for each target heparin concentration. An initial bolus dose of UFH of 340 IU kg−1 IBW instead of 300 IU kg−1 TBW would therefore achieve a mean plasma heparin value of 4.5 IU ml−1, which was observed in this study in nonobese patients at initiation of CPB. This value is slightly higher than the target value proposed by Finley et al.1 (4.0 IU ml−1), allowing the management of all situations, including heparin resistance, under good CPB safety conditions.

Table 6
Table 6:
Calculated optimal doses of unfractionated heparin per kg ideal body weight

Discussion

To our knowledge, this prospective observational and comparative study, carried out on 100 patients, is the first to evaluate the adequacy of heparin doses in obese patients undergoing cardiac surgery, based on simultaneous ACT and heparin assays. This study shows that the current heparin regimen based on TBW leads to an overdose of heparin in obese patients compared with nonobese patients at all times during CPB. This overdose is because of the administration of excessive initial and total doses of heparin and could not be linked to differences in antithrombin concentrations, which remained higher than 60% in both groups throughout the procedure.

The higher heparin concentration in obese patients could not be detected by measuring ACT, which showed a similar time course in the two groups. The relationship between ACT and heparin concentration was not linear 3 min after injection. ACT tends towards a plateau after a marked increase in heparin dose. Similar results have been described with loss of the correlation between heparin concentration and ACT beyond 500 s.12–15 Measurement of ACT indicates whether anticoagulation is sufficient to carry out CPB, but is a poor predictor of heparin concentration when heparin doses are excessive, especially in obese patients. Furthermore, the correlation between heparin concentration and ACT was poorer during CPB (T2 and T3) in both groups of patients, which can be explained by the fact that ACT measures overall coagulation time and is influenced by factors other than heparin concentration that are frequently observed during CPB: haemodilution, hypothermia, clotting factor deficiencies, activation and alteration of platelet function and decreased haematocrit.16 Many authors have demonstrated the poor correlation between ACT and heparin concentration during CPB.15,17–20

Our obese patients presented significantly higher preoperative haemoglobin concentration and haematocrit values than patients in the control group. On admission to the ICU, these values were comparable in the two groups.

Significant intraoperative reductions of haemoglobin concentration and haematocrit occurred in the obese group, without reaching the cut-off for transfusion. As the priming volume was the same in all but six lean patients, this more marked decrease in haemoglobin concentration in obese patients could reflect more extensive intraoperative bleeding, which is difficult to quantify during cardiac surgery. This could be related to excessive intraoperative heparin concentrations predisposing to bleeding, as recently demonstrated in invasive procedures for acute coronary syndromes21 and in mechanical circulatory support.22 Several authors have reported a higher risk of postoperative bleeding when high heparin doses are used during CPB.23–27 Dercksen et al.28 showed that the use of high doses of heparin and protamine was responsible for defective postoperative coagulation. Moreover, complete reversal of excessive heparin anticoagulation requires an excessive dose of protamine sulphate, which has been associated with increased bleeding and inhibition of platelet glycoprotein Ib von Willebrand factor, increased expression of P-selectin, blockade of calcium-release channels and negative inotropic effects.29,30 Chest drain blood loss measured postoperatively at H6 and H24 was not increased in obese patients and transfusion and reoperation rates were similar in the two groups. This absence of differences could be related to the specific characteristics of obesity. Obesity is associated with a higher risk of postoperative laboratory inflammatory syndrome, described by Kindo et al.31. These authors demonstrated a significant increase in plasma fibrinogen concentration on admission to the ICU and for the first 24 h after surgery in obese patients. Fibrinogen is an important coagulation factor, and its transformation to fibrin by the action of thrombin allows clot formation.32 The procoagulant effect of sufficient quantities of fibrinogen limits postoperative bleeding in obese patients. Obese patients may therefore present several factors that decrease postoperative bleeding.33,34

Another study has investigated the adequacy of heparin doses in obese patients during cardiac surgery under CPB.8 In 2005, Baker et al.8 carried out a comparative study of 27 patients divided into two groups: one group of 14 patients with a mean BMI of 32 kg m−2 and another group of 13 patients with a mean BMI of 31 kg m−2. The first group received UFH 300 IU kg−1 according to TBW and the second group received the same dose according to LBM. The results demonstrated that CPB was conducted under good conditions in ‘LBM’ patients, with the use of heparin doses 25% lower. Monitoring of anti-coagulation during CPB was carried out using ACT alone and heparin was not assayed.

By extrapolating the relationship between heparin concentration and heparin dose according to IBW injected at T1, our study provided a more accurate calculation of the optimal dose of heparin to obtain target heparin concentrations at the start of CPB. We used IBW, which was easy to calculate and was not different from mean LBM in our obese patients. We therefore propose the use of an initial loading dose of heparin of 340 IU kg−1 IBW in patients with a BMI of at least 30 kg m−2 to obtain a target plasma heparin concentration of 4.5 IU ml−1. This target corresponds to the mean heparin concentration observed in the control group in our study and allows the management of all situations, including heparin resistance, as reported by Finley et al.1, under good CPB safety conditions. These data are interesting and open the way to optimal adjustment of heparin therapy in obese patients according to pharmacokinetic data.

Our study has a number of limitations. First, this was a nonrandomised study, including only a limited number of obese patients. Second, the sample size was calculated to demonstrate a significant difference in heparin concentrations, but was insufficiently powered to demonstrate other differences (e.g. blood loss, transfusions). Third, other factors such as the surgical technique and the surgeon's experience could influence postoperative bleeding rates. However, surgery was performed by senior surgeons with extensive experience in cardiac surgery. Fourth, we did not measure haematocrit just before the heparin bolus, as the study was not designed to assess blood volume and the total blood volume between different time points before and after onset of CPB. Such a study would provide a better understanding of the pharmacokinetics and volume of distribution of heparin in obese patients and would require further investigation.

In conclusion, our prospective observational and comparative study showed that calculation of the heparin dose based on TBW leads to an overdose in obese patients at all times during CPB. ACT, which has a nonlinear relationship with heparin concentration and tends toward a plateau with higher doses of heparin, does not correctly assess this excess of heparin, which could be responsible for increased perioperative bleeding. The use of UFH based on IBW in obese patients at an initial dose of 340 IU kg−1 would achieve a similar heparin concentration to that observed in nonobese patients at initiation of CPB. A new prospective study should be carried out to validate this heparin regimen.

Acknowledgements relating to this article

Assistance with the study: we would like to thank Mrs Treger for her assistance with the study.

Financial support and sponsorship: none.

Conflicts of interest: MK received speaker honoraria from LFB. AS received honoraria from Sanofi-Aventis, consulted for Sanofi-Aventis, received honoraria from LFB, consulted for LFB, received honoraria from Bayer, consulted for Bayer, received honoraria from Boehringer-Ingelheim, received honoraria from BMS and consulted for BMS.

Presentation: none.

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