Administration of Protamine Through Radial Arterial Access: A Prospective Observational Study.

Protamine is mainly used to reverse the anticoagulant effect of heparin after cardiopulmonary bypass (CPB). Unfortunately, it is associated with adverse clinical reactions ranging from minor cardiopulmonary instability to fatal cardiovascular collapse. In the present prospective observational study, effects of protamine administration through peripheral intra-arterial route, i.e., radial artery, were investigated. Copyright:

INTRODUCTION

Protamine sulfate, a polycation peptide, is mainly used to reverse the anticoagulant effect of heparin after cardiopulmonary bypass (CPB). Unfortunately, it is associated with adverse clinical reactions ranging from minor cardiopulmonary instability to fatal cardiovascular collapse.[12]

Pathophysiology for adverse reactions due to protamine cannot be explained by a single mechanism. Till date, the mechanism is unclear as the literature supports – protamine interaction with immunoglobulin and activation of complement pathway, triggering the release of wide variety of inflammatory mediators play a role in cardiac vasodilatation with an increase in cardiac output to acute pulmonary vasoconstriction, right ventricle (RV) dysfunction, and pulmonary arterial hypertension.[3456789] Patients who experience such adverse reactions has higher incidence of morbidity and mortality in the form of prolonged Intensive Care Unit (ICU) stay and even death.[4]

Recent advances in cardiovascular physiology and better understanding of pharmacokinetics, pharmacodynamics of drug protamine has enabled us to alter the dose, route, rate of administration which in turn affects the morbidity and mortality in cardiac surgery. To date, none of the prior studies could conclude that the rate or route of protamine administration through central vein, right atrium, left atrium, and ascending aorta could influence the incidence/severity of adverse protamine reactions probably due to poor designs or older studies.

Our prospective observational study investigated the effects of protamine administration through peripheral intra-arterial route, i.e., radial artery. The primary outcome was reduced amount of required dose to neutralize protamine, and changes in blood pressure. Secondary outcomes were reduced postoperative bleeding, no changes in pulmonary artery pressures, and no RV dysfunction.

METHODS

After receiving Institutional Ethical Committee approval and written informed consent, ninety patients undergoing elective on-pump coronary artery bypass grafting (CABG) surgery, mitral valve replacement (MVR), and aortic valve replacement (AVR) were included in the study (from July 2015 to July 2016). Exclusion criteria included emergency surgery, age group >80 years and <30 years, heparin allergy, preoperative inotropic support, on dialysis, and any hepatic disease.

Standard preoperative demographic data and EUROScore were collected. Standard anesthesia techniques of induction were followed as per institutional protocol. Large bore intravenous cannula and radial arterial line were secured under local anesthesia. Induction was done with intravenous midazolam (0.05 mg/kg), fentanyl (2–4 mcg/kg), and muscle relaxant pancuronium (0.1 mg/kg). After tracheal intubation, maintenance of anesthesia with inhalation agent isoflurane along with fentanyl infusion (1–2 mcg/kg/h) to maintain target BIS between 30 and 50. Central venous access with 9 Fr catheter and pulmonary artery catheter was secured under all aseptic precautions. Mechanical ventilation parameters standardized during data collection (tidal volume 6 ml/kg, rate 12/min, fraction of inspired oxygen 1.0, inspiratory-to-expiratory time ratio 1:2, and positive end-expiratory pressure 5 mmHg).

Median sternotomy was done and was supplemented with top-up dose of fentanyl (2–4 mcg/kg). Standard CPB protocol was followed for cannulation/initiation and maintenance as per the surgery performed. Data for baseline activated clotting time (ACT) were collected which was followed by heparin administration in the dose of 300 IU/kg. ACT above 480 obtained and was maintained throughout the CPB along with additional top-up dose of heparin (1 mg/kg) if required.

CPB flow rates between 2.4 and 2.8 L/min/m2 were maintained. CPB temperature was varying between 30°C and 34°C, mean arterial pressure (MAP) >60 mmHg, and BIS between 30 and 50 was maintained. After successful weaning from CPB, protamine was administered in the dose by the following formula to the nearest round off figure, i.e., (total dose of heparin/1.6), which is nearly 60%–63% of initial heparin dose.

Protamine was given directly in radial arterial line without dilution in span of 5 min. Baseline vital parameters such as heart rate (HR), MAP, pulmonary artery wedge pressure, oxygen saturation, central venous pressure, and airway pressures were recorded before protamine administration. After protamine administration, the same parameters were recorded at regular intervals of 5, 10, 15, and 30 minutes. Other parameters such as tricuspid annular plane systolic excursion (TAPSE) for RV dysfunction, ACT at 3 min postcompletion of protamine administration, 30 min, highest CPB ACT, and in ICU were also collected. CPB time and postoperative bleeding at 1st, 2nd, and 3rd hour were noted. TAPSE was calculated in deep transgastric view of transesophageal echocardiography using M-mode.

Additional protamine of 10 mg was given for ACT >160 up to 200. During and after protamine, adequate filling of left ventricle was maintained as assessed by transesophageal echocardiography (TEE). In case of hemodynamic instability, protamine was temporarily withheld and supported by vasopressors.

RESULTS

In the present observational study of 91 patients, mean age of the population was 54.08 years (standard deviation [SD] ±11.00) with a slight predominance of female gender [Figures 1 and 2]. Majority of the patients (58.24%) are in the weight group of 50–59 kg. The most common surgical procedure performed was on pump CABG surgery (63.74%), followed by MVR (24.18%) and AVR (12.09%) [Figure 3]. Mean value of baseline presurgery ACT was 101.01 (SD 12.97). After protamine administration, mean value of ACT measured at 5 min, 30 min, and after shifting patient to ICU was 137 (SD 18.26), 127.71 (SD 18.35), and 113.62 (SD 12.27), respectively [Figure 4].

Figure 1

Age-wise distribution of the study population

Figure 2

Male and female composition of the study population

Figure 3

Percentage of different surgeries performed on the patients

Figure 4

Trend of mean activated clotting time values from baseline to postprotamine activated clotting time at different intervals

Baseline MAP and mean HR were 65.81 mmHg and 85.93/min. After 5 min of protamine administration, mean MAP was 63 mmHg with compensatory rise in the mean HR of 92.03/min. At subsequent interval of 10, 15, and 30 min after protamine administration, mean MAP was 63.76, 64.12, and 64.62 mmHg and mean HR was 84.1, 82.28, and 81.21/min, respectively [Figure 5]. Mean value of TAPSE score was 16.52 mm (SD ± 1.34) which was suggestive of normal RV function [Figure 6]. The number of patients having TAPSE score more than 15 were 87 (95.60%). Only four patients have TAPSE score <15.

Figure 5

The trend of mean arterial pressure and heart rate from baseline to postprotamine administration at different intervals

Figure 6

Percentage of the patient having different tricuspid annular plane systolic excursion score group

Arterial saturation was always more than 99% at any point of time after protamine administration. Mean peak airway pressure was never more than 12 cm of H2O after protamine administration. Mean value of postoperative drainage was 30.34, 25.35, and 8.24 ml at 1st, 2nd, and 3rd hour after protamine administration, respectively [Figure 7].

Figure 7

Postoperative surgical drainage at 1st, 2nd, and 3rd hour after protamine administration

Statistical analysis

Statistical analysis was done using descriptive and inferential statistics using Student's paired t-test and software used in the analysis were SPSS 17.0 version and EPI-INFO 6.0 version and P < 0.05 is considered as the level of significance.

DISCUSSION

Protamine, a polypeptide which is isolated from salmon sperm, is used extensively to neutralize heparin following cardiac and vascular surgical procedures. The incidence of adverse reactions has been reported as varying from 0.06% to 10.6%.[10]

Protamine acts as an antigen and binds to the IgE antibodies. This process may lead to cross-linking with the antibody surfaces, which then initiates a process of cell degranulation. Adverse reactions may also be associated with the interaction between protamine and complement fixing antiprotamine IgG antibodies. Protamine-heparin complexes activate the classical complement cascade with subsequent generation of anaphylatoxins.[11] There are four basic types of adverse reactions of protamine: hypotension, anaphylactic reactions, anaphylactoid reactions, and catastrophic pulmonary hypertension.

The clinical implication of protamine reaction lies in the findings by different studies which suggested increased mortality rate. Kimmel et al. reported mortality of 2.7% in patients with mild protamine reaction and 8.3% in patients with severe reaction.[12] Welsby et al., in a large number of CABG patients, assessed hemodynamic “protamine reactions” (systemic hypotension/pulmonary hypertension) during the 30 min after protamine administration through peripheral vein.[13] Degree of systemic hypotension (odds ratio: 1.28) and pulmonary hypertension (odds ratio: 1.27) were related with increased mortality which was 2% in the study. Slower infusion of protamine can prevent associated adverse effects.[1415]

Prospective observational studies have suggested that protamine administration by bypassing right heart can give hemodynamic stability.[1617] However, most of such studies used left atrial or ascending aorta route, which can cause some inconvenience to surgical team by holding intra-aortic needle for at least 10 min. It also carries the risk of inadvertent air embolism. Hence, we preferred radial arterial route for protamine administration in our present study. To the best of our knowledge, protamine administration through radial route has not been evaluated in the literature. Traditionally, protamine is used to neutralize heparin after cardiac surgery in the ratio of 1:1 (1 mg of protamine for 100 units of heparin).[17] We have used 60% of the total calculated dose of protamine (i.e., protamine dose = total heparin dose/1.6).

Trend of ACT values from baseline to postprotamine administration at different interval clearly shows that intra-arterial protamine effectively neutralizes the heparin [Table 1]. There were only eight patients (8.8%) who required additional 10 mg protamine supplementation each. There was no significant postoperative drainage after the surgery. No patient in the study required blood or blood product transfusion which clearly suggests the absence of coagulopathy. Similar to our study, Chaney et al. showed in their study that the postprotamine ACT was comparable in all the groups where protamine was administered in routes such as central vein and ascending aorta.[18] However, the author used 70% of the calculated dose of protamine which is higher than that used in our study.

Table 1

Trends of ACT in perioperative period

ACT	n	Minimum	Maximum	Mean	Sth. deviation
Baseline ACT	91	70.00	156	101.01	12.97
Highest CPB ACT	91	541.00	999	756.14	145.21
Post protamine ACT	91	100.00	200	137.00	18.26
Post protamine ACT at 30 min	91	100.00	160	127.71	18.35
Post protamine ACT in ICU	91	100.00	156	113.62	12.27

The hemodynamic variables such as HR and mean arterial pressure studied after protamine administration did not show any significant change in the variables though there was a slight fall in mean arterial pressure after 5 min of protamine administration. HR after protamine administration 5 min later showed a slighter increase in HR which may be explained as reflex increase in HR due to transient hypotension. The intention of giving intra-arterial protamine was to reduce the occurrence of hypotension and other side effects. The mean decrease in MAP in our study was 2.81 ± 0.48 mmHg after 5 min of protamine administration.

Similarly, the peak airway pressure measured after induction and after protamine administration at various time intervals did not show any significant increase [Table 2]. Postoperative hypoxemia was not observed in our study. Protamine has been reported to cause histamine release causing pulmonary vasoconstriction subsequently. Pulmonary hypertension can potentially lead to RV dysfunction. In our study, we did not observe RV dysfunction in majority of study patients as indicated by TAPSE measurement by TEE. Four patients were having TAPSE value in the range of 13–14 mm [Table 3]. However, preoperative assessment in these patients suggested that patients were already having moderate pulmonary hypertension on transthoracic echocardiographic examination.

Table 2

Trends of peak airway pressure after protamine administration

Time period	n	Minimum peak airway pressure	Maximum peak airway pressure	Mean	Sth. deviation
1 Min	91	5	17	12.28	2.30
5 Min	91	9	17	12.40	2.13
10 Min	91	8	18	12.32	2.17
15 Min	91	9	17	12.39	2.11
30 Min	91	9	17	12.45	2.12

Table 3

TAPSE Score range among the patients

TAPSE Score	No. of patients	Percentage
13 to 14	4	4.40
15 to 16	44	48.35
17 to 18	36	39.56
19 to 20	7	7.69
Total	91	100.00
Mean±SD	16.52±1.34 (13-19)

Limitation of the present study is that it is not prospective comparative study. Systemic vascular resistance, pulmonary vascular resistance and cardiac output values were not calculated in this study.

CONCLUSION

Despite the study limitations, the authors found that protamine administration through radial artery route can effectively neutralize heparin without any significant coagulopathy and postoperative bleeding. We suggest using this derived low dose of protamine (total heparin dose/1.6) through radial arterial route can be practical and efficient to reverse the effect of heparin after cardiac surgery without using central route (ascending aorta or central venous line).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.