Protamine Administration Via the Ascending Aorta May Prevent Cardiopulmonary Instability

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Protamine Administration Via the Ascending Aorta May Prevent Cardiopulmonary Instability Mark A. Chaney MD, J. Devin Roberts MD, Kristen Wroblewski MS, Sajid Shahul MD, MPH, Ross Gaudet MD, Valuvan Jeevanandam MD

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S1053-0770(15)00948-9 http://dx.doi.org/10.1053/j.jvca.2015.11.014 YJCAN3484

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Journal of Cardiothoracic and Vascular Anesthesia

Cite this article as: Mark A. Chaney MD, J. Devin Roberts MD, Kristen Wroblewski MS, Sajid Shahul MD, MPH, Ross Gaudet MD, Valuvan Jeevanandam MD, Protamine Administration Via the Ascending Aorta May Prevent Cardiopulmonary Instability, Journal of Cardiothoracic and Vascular Anesthesia, http://dx.doi.org/10.1053/j. jvca.2015.11.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Protamine Administration Via The Ascending Aorta May Prevent Cardiopulmonary Instability Mark A. Chaney, MD Professor Department of Anesthesia and Critical Care University of Chicago Medical Center 5841 S. Maryland Ave, MC 4028 Chicago, IL 60637 Telephone: 773-702-5951 Fax: 773-834-0063 Email: [email protected] J. Devin Roberts, MD Assistant Professor Department of Anesthesia and Critical Care University of Chicago Medical Center 5841 S. Maryland Ave, MC 4028 Chicago, IL 60637 Telephone: 773-702-8621 Fax: 773-702-3535 Email: [email protected] Kristen Wroblewski, MS Sr. Biostatistician Department of Public Health Sciences University of Chicago Medical Center 5841 S. Maryland Ave, MC 2000 Chicago, IL 60637 Telephone: 773-702-1979 Fax: 773-702-1979 Email: [email protected] Sajid Shahul, MD, MPH Associate Professor Department of Anesthesia and Critical Care University of Chicago Medical Center 5841 S. Maryland Ave, MC 4028 Chicago, IL 60637 Telephone: 773-702-6700 Fax: 773-702-3535 Email: [email protected] Ross Gaudet, MD CA-3, PGY-4, Chief Resident 2015-2016 Department of Anesthesia and Critical Care

University of Chicago Medical Center 5841 S. Maryland Ave, MC 4028 Chicago, IL 60637 Telephone: 773-702-6700 Fax: 773-702-3535 Email: [email protected] Valuvan Jeevanandam, MD Professor, Chief, Cardiac and Thoracic Surgery Department of Cardiac and Thoracic Surgery The University of Chicago Medical Center 5841 S. Maryland Ave, MC 5040 Chicago, IL 60637 Telephone: 773-702-2500 Fax: 773-702-4187 Email: [email protected]

Corresponding Author: Mark A. Chaney, MD Professor Department of Anesthesia and Critical Care University of Chicago Medical Center 5841 S. Maryland Ave, MC 4028 Chicago, IL 60637 Telephone: 773-702-5951 Fax: 773-834-0063 Email: [email protected] Introduction Protamine is standard therapy for reversing heparin anticoagulation in patients following cardiac surgery. Unfortunately, it is associated with adverse clinical reactions ranging from minor cardiopulmonary instability to fatal cardiovascular collapse.1,2 While mechanistic understanding is still unclear, interaction with immunoglobulins3,4 and activation of the complement pathway, 5-8 triggering release of a wide variety of inflammatory mediators are thought to play central roles in the cardiac (vasodilation, hypotension, arrhythmias) and pulmonary (bronchospasm, pulmonary hypertension) pathophysiology observed. 8,9

Patients experiencing adverse protamine events exhibit higher in-hospital mortality and those patients suffering severe events have the highest mortality.10,11 Additionally, the degree/duration of systemic hypotension and pulmonary hypertension within the first thirty minutes following protamine administration increases risk of in-hospital mortality and proximity of the response to protamine administration strengthens the relationship, which persists after exclusion of major hemodynamic disturbances.10 Thus, altering method (dose/route/rate) of protamine administration in such a way to attenuate cardiopulmonary instability may potentially decrease morbidity and mortality in patients following cardiac surgery. Prior studies indicate that rate and/or route of protamine administration (peripheral vein, central vein, right atrium, left atrium, ascending aorta) may potentially influence incidence/severity of adverse protamine reactions. 12-26 Intraaortic protamine (bypasses right heart and lungs) may 23,26 or may not 16-18,24

promote cardiopulmonary stability. However, it is difficult to arrive at reasonable conclusions

from these studies for a wide variety of reasons (old studies, animal models, poorly-designed, etc.). Our prospective, randomized clinical study will investigate three different methods of protamine administration (two via central vein, one via ascending aorta) on cardiopulmonary function in patients undergoing elective cardiac surgery. Primary outcome will be changes in blood pressure and secondary outcome will be changes in pulmonary oxygenation.

Methods Following Institutional Review Board approval and written informed consent, 95 patients undergoing elective coronary artery bypass grafting (CABG) and/or single valve repair/replacement with cardiopulmonary bypass (CPB) were prospectively studied (Feb 2012 to May 2014). Exclusion criteria included emergent surgery, extremes of age (< 18 yrs, > 90 yrs), pregnancy, heparin allergy, preoperative hemodynamic support (intravenous vasoactive medications, intra-aortic balloon pump [IABP]), preoperative supplemental oxygen/mechanical ventilation, preoperative renal dialysis, and/or evidence of substantial hepatic disease. Patients were preoperatively randomized via a random numbers table into one

of three groups (no blinding). Group Central Vein Control (CVC) had protamine administered via central vein over ten min, Group Central Vein (CV) had protamine administered via central vein over two min, and Group Ascending Aorta (AA) had protamine administered via ascending aorta over two min. Standard preoperative demographic data and Euroscore information (Appendix) was collected. The intraoperative anesthetic technique was standardized and consisted of intravenous midazolam/fentanyl/muscle relaxant/inhaled isoflurane consistent with tracheal extubation 2-4 hours following Intensive Care Unit (ICU) arrival. All underwent central venous cannulation via the right internal jugular vein or left subclavian vein (MAC two-lumen central venous access set, 9 French, Arrow International, Inc., Reading, PA) and insertion of a continuous cardiac output pulmonary artery catheter (Swan-Ganz CCOmbo CCO/SvO2/VIP, 8 French, Edwards Lifesciences, LLC, Irvine, CA). Mechanical ventilation parameters were standardized at every data collection time (tidal volume 6 ml/kg, rate 12/minute, FIO2 1.0, I:E ratio 1:2, PEEP + 5). All underwent median sternotomy and routine cannulation/initiation of CPB via ascending aorta and vena cava. Technique of CPB was standardized. After obtaining a baseline activated clotting time (ACT), an initial dose of heparin (300 units/kg) was administered. Supplemental heparin was given throughout CPB in order to maintain the ACT above 480 seconds. Target CPB flow was 2.4 – 2.8 L/min/m2 and target pressure was above 60 mmHg. CPB temperature was at the discretion of the cardiac surgeon. Protamine was administered following successful weaning from CPB (hemodynamic support, typically dobutamine, was administered at the discretion of the cardiac anesthesiologist/surgeon). Initial dose of protamine was 70% of initial heparin dose; thus 0.7 mg protamine per 100 units heparin. Group CVC and CV had protamine administered via central venous cannula over ten min and two min, respectively. Group AA had protamine administered via small gauge needle (inserted and held by cardiac surgeon) directly into the ascending aorta over two min. In all, if hemodynamic instability occurred, protamine administration was slowed/temporarily stopped. Post-protamine pharmacologic hemodynamic support was given at the discretion of the cardiac anesthesiologist (ephedrine/calcium for mild/moderate hypotension, epinephrine/vasopressin for moderate/severe hypotension). During and following protamine

administration, euvolemia was maintained with the assistance of transesophageal echocardiography. Most of our cardiac anesthesiologists try to maintain a mean arterial pressure of above 60 mmHg, while optimizing volume, contractility, and systemic vascular resistance via pharmacologic support (if required) based on clinical information from observing the heart in the surgical field and/or information obtained from transesophageal echocardiography. Supplemental protamine, if required, was administered via central venous cannula in all approximately 15 min post-protamine end. Heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), mean pulmonary artery pressure (MPAP), pulmonary artery occlusive pressure (PAOP), cardiac output (CO), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), and mixed venous oxygen saturation (SVO2) were documented at seven intraoperative timepoints:

1.

Baseline (Post-Induction / Intubation, Pre-Incision)

2.

Post-CPB Separation / Pre-Protamine

3.

2 Min Post-Protamine Start

4.

5 Min Post-Protamine Start

5.

10 Min Post-Protamine End

6.

30 Min Post-Protamine End

7.

Post-Chest Closure

Arterial blood gas analysis (pH, pCO2, pO2, hemoglobin level, lactate level), alveolar-arterial (A – a) gradient, and peak airway pressure (PAP) was documented at four intraoperative timepoints:

1.

Baseline (Post-Induction / Intubation, Pre-Incision)

2.

Post-CPB Separation / Pre-Protamine

3.

10 Min Post-Protamine End

4.

Post-Chest Closure

Routine postoperative data was collected, including postoperative hemodynamic support, tracheal extubation time, in-hospital mortality, ICU length of stay (LOS), and hospital LOS. Statistical Analysis Preoperative, intraoperative, and postoperative data were compared across Groups using chi-square tests for categorical variables and one-way analysis of variance (ANOVA) for continuous variables. If there was evidence of non-normality, Kruskal-Wallis test was used. Assessment of changes over time in hemodynamic and pulmonary parameters across Groups used repeated measures ANOVA with Group (CVC, CV, and AA) as between-subject factor and time (with either 4 or 7 timepoints depending on the parameter) as within-subject factor. Greenhouse-Geisser correction was used to account for possible violations of the sphericity assumption. Of particular interest was the Group-by-time interaction; a significant interaction would indicate that the change over time varied depending on how protamine was administered. This analysis was followed by between- and within-Group comparisons of changes between specific timepoints of interest using one-way ANOVA and paired t-tests, respectively, as appropriate. Statistical analyses were performed using Stata 13 (StataCorp, College Station, TX). Sample Size Computation Sample size calculations were based on our primary outcome measure, MAP. A total sample of 90 (30 per Group) would achieve approximately 90% power to detect a minimum detectable difference between any two Groups of 5 mmHg in the change over time (standard deviation = 6) with a two-sided alpha of 0.05.

Results Thirty-three patients were randomized into Group CVC, 32 into Group CV, and 30 into Group AA. Preoperative demographics and intraoperative data were similar between the Groups (Tables 1 and 2). The reason for “expansion” of surgery outside of original inclusion criteria (elective CABG and/or single

valve) was that in some patients, post-induction transesophageal echocardiography exam revealed new pathology (not detected preoperatively) that was subsequently surgically addressed. One Group AA patient had protamine administered over 3 min (not in required time) because of technical issues (problems with de-airing infusion line), not because of hemodynamic instability. One patient (Group CV) received ephedrine and five patients (3 Group CVC, 2 Group AA) received calcium for mild/moderate hypotension. In Group CVC, one patient received 6 units total vasopressin (no previous protamine exposure, discharged postoperative day [POD] #9) and one received 5 g total epinephrine (no previous protamine exposure, discharged POD #24). In Group CV, one patient received 5 units total vasopressin (previous protamine exposure, discharged POD #8) and one received 1 unit total vasopressin (no previous protamine exposure, discharged POD #14). In Group AA, one patient received 2 units total vasopressin and 5 g total epinephrine (previous protamine exposure, died POD #5 of cardiogenic shock), one received 1 unit total vasopressin (no previous protamine exposure, discharged POD #4), and one received 1 unit total vasopressin (no previous protamine exposure, discharged POD #5). Table 3 presents intraoperative hemodynamic data. Repeated measures ANOVA indicated there were significant differences between the three Groups regarding intraoperative changes in MAP (p = 0.02; Figure 1). Between-Group analysis revealed that changes in MAP were significantly different between the three Groups between timepoints 2 and 5 (p = 0.05) and timepoints 2 and 6 (p < 0.01). Within-Group changes in MAP between timepoints 2 and 6 were statistically significant in Group AA (mean increase 6.5 mmHg, p = 0.01) yet not in Group CVC (mean decrease 3.1 mmHg, p = 0.13) nor Group CV (mean decrease 4.3 mmHg, p = 0.14). Group-by-time interaction from repeated measures ANOVA revealed that the three Groups behaved similarly regarding intraoperative changes in HR (p = 0.40), CVP (p = 0.78), MPAP (p = 0.26), CO (p = 0.49), SVR (p = 0.98), and SVO2 (p = 0.81). Regarding PAOP, Group-bytime interaction yielded a p value of 0.02, which appears to be primarily detecting the changes observed from timepoints 1 to 2, prior to protamine administration. Between-Group analysis via ANOVA between timepoints 2 and 5 (p = 0.53) and timepoints 2 and 6 (p = 0.07) revealed that the Groups behaved

similarly. Regarding PVR, Group-by-time interaction yielded a p value of 0.04. Between-Group analysis between timepoints 2 and 5 (p = 0.09) and timepoints 2 and 6 (p = 0.19) revealed that the Groups behaved similarly regarding intraoperative changes in PVR at key timepoints of interest, although Group AA did have the largest decreases on average. Table 4 presents intraoperative arterial blood gas analysis and peak airway pressure data. The average pO2 change from baseline to timepoint 5 or 7 was smallest for Group AA. Between timepoints 1 and 7 Group CVC had a mean decrease of 61 mmHg (p = 0.003), Group CV had a mean decrease of 34 mmHg (p = 0.06), and Group AA had a mean decrease of 7 mmHg (p = 0.80). Similarly, between timepoints 1 and 5, Group CVC had a mean decrease of 85 mmHg (p < 0.001), Group CV had a mean decrease of 47 mmHg (p = 0.009), and Group AA had a mean decrease of 8 mmHg (p = 0.82). A similar pattern of changes was observed for A – a gradient. Between timepoints 1 and 7 Group CVC had a mean increase of 61 mmHg (p = 0.002), Group CV had a mean increase of 35 mmHg (p = 0.05), and Group AA had a mean increase of 6 mmHg (p = 0.80). Between timepoints 1 and 5, Group CVC had a mean increase of 84 mmHg (p < 0.001), Group CV had a mean increase of 50 mmHg (p = 0.006), and Group AA had a mean increase of 9 mmHg (p = 0.80). Group-by-time interaction from repeated measures ANOVA revealed that the Groups behaved similarly regarding intraoperative changes in pH (p = 0.53), pCO2 (p = 0.57), pO2 (p = 0.23), A – a gradient (p = 0.23), PAP (p = 0.17), hemoglobin (p = 0.47), and lactate (p = 0.24). Table 5 presents postoperative data. One Group CVC patient underwent complex aortic valve/ascending aorta/myocardial revascularization surgery and died on POD #4 from excessive bleeding (no postprotamine pharmacologic hemodynamic support required). One Group CV patient underwent re-do double valve surgery and died on POD #36 of multiple organ system failure (no post-protamine pharmacologic hemodynamic support required). One Group AA patient underwent aortic valve surgery and died on POD #40 of right heart failure, renal failure, and sepsis (no post-protamine pharmacologic hemodynamic support required). The second Group AA patient who died underwent re-do aortic

valve/myocardial revascularization surgery and died on POD #5 of cardiogenic shock. In this patient, 2 units total vasopressin and 5 g total epinephrine were required post-protamine. Discussion Our results indicate that administration of protamine via the ascending aorta may be the preferred route in patients following cardiac surgery. Both Groups of patients receiving protamine via central vein experienced moderate decreases in blood pressure while patients receiving the drug via ascending aorta exhibited moderate increases in blood pressure. Furthermore, post-protamine oxygenation (pO2, A – a gradient) was unchanged when compared to baseline in patients receiving the drug via ascending aorta and was worsened in patients receiving protamine via central vein. The differences between the two routes, while moderate, were statistically significant. The potential ability of administering protamine via the ascending aorta (bypassing the right heart and lungs) in preventing cardiopulmonary instability deserves further clinical investigation. Adverse reactions to protamine vary dramatically and may be fatal. 27-31 While mechanistic understanding is still not fully understood, there are thought to be four basic types. 1,2 Anaphylactic reactions are quite rare, likely mediated through heparin-protamine complex interaction with immunoglobulins, and result in rapid cardiovascular collapse. Anaphylactoid reactions are thought to involve complement system activation yet may involve immunoglobulin interaction and result in hypotension from systemic vasodilation. Pulmonary vasoconstriction is rare, likely mediated through complement mediated C5a – induced thromboxane A2 generation, and results in increased pulmonary artery pressure, increased right ventricular/right atrial pressures, and systemic hypotension. Lastly, simple hypotension, likely from mast cell release of histamine, decreasing systemic vascular resistance, is somewhat common. While some investigations have hinted at myocardial depression,32 this entity is not thought to be a major factor. Traditionally, patients receiving protamine-containing insulin preparations, who had previous exposure to protamine, who had a vasectomy, and who had a true vertebrate fish allergy were thought to be at

increased risk. 1,2,29,33-37 However, incidence of anaphylactic reactions is so rare and there are so many complicating factors that most clinicians feel that protamine is not contraindicated in any patient, even those with traditional risk factors. 2,38 One group of investigators revealed initially in dogs 39 and then in a small group of humans 40 that an initial pre-treatment dose of protamine given prior to heparinization may attenuate the adverse clinical effects of intravenously administered protamine. Two retrospective clinical investigations indicate that patients who experience adverse cardiopulmonary reactions to protamine have increased risk of in-hospital mortality. 10,11 Kimmel and associates compared 53 patients with an “adverse protamine event” with 223 patients without an event. 11 “Adverse protamine events” occurred within thirty minutes of protamine initiation, lasted longer than the infusion, and met one or more of the following criteria: (a) decrease in blood pressure ≥ 25% or ≥ 10% requiring inotropes, reinitiation of CPB, IABP support; (b) increase in pulmonary artery pressure ≥ 25% resulting in hypotension; (c) noncardiogenic pulmonary edema, oxygenation issues; (d) bronchospasm. Mortality was 2.7% in the 223 patients without an event yet 8.3% in the 36 with a mild event and 23.5% in the 17 with a severe event. Similarly, Welsby and associates evaluated 6921 patients undergoing CABG to test the hypothesis that hemodynamic “protamine reactions” (systemic hypotension/pulmonary hypertension) are associated with increased mortality.10 Following a 20 mg test-dose, protamine was typically administered (3.0 – 3.5 mg/kg) via peripheral vein slowly over a ten min. Degree/duration of systemic hypotension (< 100 mmHg) and pulmonary hypertension (> 30 mmHg) during the thirty min after administration were assessed. Overall mortality was 2% and greater degrees of systemic hypotension (odds ratio 1.28) and pulmonary hypertension (odds ratio 1.27) were associated with increased mortality. Proximity of the response to protamine administration strengthened the relationship, which persisted after exclusion of major hemodynamic disturbances. Tests for linearity confirmed an association even at the lowest range of values. These authors conclude that their “evidence suggests that strategies that avoid or attenuate these reactions may improve patient care.” Table 6 presents animal and human studies investigating influence of rate and/or route of protamine administration on incidence/severity of adverse reactions.12-26 All are old and most are small and poorly

designed. However, taken together, they seem to indicate that more rapid administration of protamine leads to more profound systemic hypotension/pulmonary hypertension and that bypassing the right heart and lungs via ascending aorta/left atrial administration may confer certain benefits. Our clinical study was designed to investigate the potential cardiopulmonary benefits of bypassing the right heart and lungs via the ascending aorta. We chose our rate of intraaortic administration (2 min) because previous clinical studies have suggested that this rate via the ascending aorta is hemodynamically safe (Table 6) and we did not want to inconvenience the surgical team for a prolonged period of time (holding intraaortic needle). One comparison cohort (Group CV) and a control cohort (Group CVC) were chosen as well. Regarding hemodynamic function, our study indicates that protamine administration via the ascending aorta may initiate less systemic hypotension. When post-CPB separation/pre-protamine values were compared to 30 min post-protamine values, Group AA patients exhibited a mean increase of 6.5 mmHg yet Group CVC patients and Group CV patients exhibited mean decreases of 3.1 mmHg and 4.3 mmHg, respectively (Figure 1). The differences in blood pressure between the two routes of administration (ascending aorta/central vein) are even more impressive/clinically relevant when one considers the number of patients in each Group who were on hemodynamic support (typically intravenous dobutamine) at the time of CPB separation (and protamine administration). While not statistically significant, substantially more patients in Group CVC and CV (20, 19, respectively) were on hemodynamic support at this time than Group AA patients (9). Furthermore, there were no differences between the Groups regarding administration of intravenous medications (ephedrine, calcium, epinephrine, vasopressin) to treat protamine-induced hypotension. Regarding pulmonary function, our study indicates that protamine administration via the ascending aorta may attenuate postoperative hypoxemia. When baseline values were compared to 10 min post-protamine values, Group AA patients exhibited a mean decrease of 8 mmHg yet Group CVC patients and Group CV patients exhibited mean decreases of 85 mmHg and 47 mmHg, respectively. However, these moderate differences in oxygenation did not lead to an earlier tracheal extubation time nor ICU LOS (Table 5).

There are limitations to our study. Blood pressure changes following protamine administration are a result of numerous factors (other than protamine). While we rigidly standardized technique of cardiopulmonary bypass (yet temperature was at discretion of cardiac surgeon), heparin/protamine administration, and timing of cardiopulmonary assessment, our inability to reasonably standardize postcardiopulmonary bypass and post-protamine pharmacologic hemodynamic support may have contributed to the differences observed between Groups. While the differences between Groups were not statistically significant, fewer patients in Group AA had a history of previous protamine exposure when compared to Group CVC and Group CV (2 versus 5, 8, respectively). Patients who have had previous exposure to protamine are thought to be at increased risk for developing an adverse reaction. This minor difference between Groups regarding previous protamine exposure may have potentially influenced results. Also, method of determining cardiac output via continuous cardiac output pulmonary artery catheter (slow response time) may have contributed to our inability to demonstrate substantial changes within the three Groups regarding CO, SVR, and PVR. Our inability to demonstrate substantial changes within the Groups regarding SVR and PVR (detected via some previous clinical investigations) may have been due to the small number of patients studied coupled with the fact that post-protamine pulmonary vasoconstriction is quite rare (approximately 1%). Lastly, our sample size calculation may have been a bit optimistic (our observed blood pressure standard deviations were about twice that quoted in our sample size calculation). Thus, a larger sample size might have been necessary. In conclusion, despite study limitations and the moderate yet statistically significant differences between Groups, we found that when compared to central vein administration, ascending aorta administration of protamine may prevent hypotension and may be associated with less hypoxemia. Because post-protamine cardiopulmonary instability has been linked to increased in-hospital mortality, the potential ability of administering the drug via the ascending aorta in preventing cardiopulmonary instability in patients undergoing cardiac surgery deserves further clinical investigation.

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Figure Legend

Figure 1. Intraoperative changes in mean arterial pressure between the three Groups. Error Bars represent 95% confidence intervals.

TABLE 1 PREOPERATIVE DEMOGRAPHICS

Group CVC (n = 33)

Group CV (n = 32)

Group AA (n = 30)

Age (years)

60.3  14.3

62.8  11.7

65.0  12.7

Gender

24M / 9F

23M / 9F

19M / 11F

Height (cm)

173.0  11.6

173.8  9.1

169.0  11.1

Weight (kg)

81.9  23.2

83.6  16.2

78.8  15.2

BMI (kg/m2)

26.8  6.6

27.6  4.8

27.7  4.6

Previous Cardiac Surgery

4

6

1

Previous Protamine Exposure

5

8

2

Beta-Blockers

16

16

20

Angiotension Converting Enzyme Inhibitors

12

9

8

Angiotensin Receptor Blockers

6

4

3

Calcium Channel Blockers

6

9

5

Nitrates

2

5

Diuretics

8

13

9

Digoxin

1

2

2

Insulin

1

2

4

Oral Hypoglycemic

1

4

1

Euroscore

3.6  3.4

4.5  4.9

4.0  3.9

4

Results are presented as mean  one standard deviation or absolute number of patients. CVC = Central Vein Control CV = Central Vein AA = Ascending Aorta M = Male F = Female BMI = Body Mass Index

TABLE 2 INTRAOPERATIVE DATA

Group CVC (n = 33)

Group CV (n = 32)

Group AA (n = 30)

CABG Surgery

6

7

8

Valve Surgery

21

20

18

CABG + Valve Surgery

6

5

4

Baseline ACT (Seconds)

110.1  12.5

110.4  12.5

109.9  13.5

Post-Heparin ACT (Seconds)

547.5  160.7

490.5  72.3

484.8  121.4

Highest CPB ACT (Seconds)

647.0  155.9

668.8  175.5

625.9  144.3

Lowest CPB Temperature (Degrees)

31.8  1.2

32.0  1.1

32.1  1.0

CPB Time (Minutes)

154.2  46.3

142.6  64.1

130.6  49.3

CPB Separation Hemodynamic Support

20

19

9

Total CPB Heparin (Units)

41.2  17.2

43.5  12.0

44.0  12.6

Initial Protamine Dose (mg)

183.7  55.9

187.3  51.0

174.2  56.6

Protamine Administered In Required Time

33

32

29

Post-Protamine Pharmacologic Hemodynamic Support

5

3

5

Post-Protamine ACT (Seconds)

128.4  14.4

131.9  25.1

138.1  51.2

Supplemental Protamine

17

13

12

Results are presented as mean  one standard deviation or absolute number of patients. CVC = Central Vein Control CV = Central Vein CABG = Coronary Artery Bypass Grafting AA = Ascending Aorta ACT = Activated Clotting Time CPB = Cardiopulmonary Bypass

TABLE 3 INTRAOPERATIVE HEMODYNAMIC DATA

Timepoint

1

2

3

4

5

6

7

HR (beats/min) 65.9 

86.3 

86.3 

87.2 

89.8 

87.5 

85.5 

Group CV

10.6

13.7

15.1

13.4

13.0

12.6

11.3

Group AA

66.2 

88.5 

90.0 

90.2 

90.2 

87.4 

86.1 

13.7

13.3

13.9

12.9

15.4

14.5

15.0

65.4 

87.4 

86.2 

85.6

85.1 

85.9 

87.6 

14.7

12.0

11.6

11.5

11.6

12.4

11.9

80.9 

77.8 

82.3 

79.8 

74.8 

74.8 

Group CV

12.4

12.8

14.6

14.5

13.2

12.9

76.4  9.3

Group AA

79.9 

79.6 

78.3 

78.5 

74.5 

76.1 

79.9 

11.4

15.0

14.5

14.2

11.2

13.1

14.3

83.5 

75.0 

76.8 

82.9 

79.6  9.6

81.6 

81.2 

10.2

12.6

11.9

11.5

8.9

11.1

10.6 

10.0 

10.2  4.9

9.8  5.2

10.3  4.8

11.2 

Group CV

4.8

5.5

11.0  4.1

11.1 

10.1  4.6

5.0

Group AA

10.3 

10.9 

12.7  5.1

4.8

12.1  6.2

11.2 

4.1

4.1

12.8 

4.5

12.0  5.4

12.1 

12.2 

5.2

12.8 

12.2  3.9

4.0

4.9

5.6

13.2  5.7

Group CVC

MAP (mmHg) Group CVC

CVP (mmHg) Group CVC

MPAP (mmHg) 22.9 

21.0 

22.0  6.3

21.8 

21.5  7.6

21.9 

Group CV

6.5

6.0

24.1  6.8

7.0

22.3  6.8

6.3

Group AA

23.1 

23.4 

24.9  7.6

23.1 

22.7  6.7

22.6 

6.9

5.7

6.8

5.7

22.5  6.6

25.8 

24.2 

25.1 

23.1 

24.4  4.6

6.7

6.6

6.4

6.2

24.3  6.3

18.1 

15.8 

16.3  5.9

15.7 

15.5  6.6

16.7 

Group CV

5.4

6.0

17.3  5.6

6.6

16.6  5.7

6.0

17.4  6.1

Group AA

16.5 

17.8 

20.3  5.7

17.4 

17.7  5.4

16.5 

18.2  5.1

5.1

4.9

6.1

4.7

19.1  5.2

18.7 

18.8 

19.7 

18.1 

5.7

5.0

5.0

5.0

Group CVC

4.9  1.7

5.3  1.9

5.2  1.9

5.3  2.2

5.2  1.8

5.1  1.7

4.9  1.7

Group CV

4.6  1.4

5.1  2.2

5.1  2.3

5.0  1.8

5.1  1.5

5.1  1.3

5.0  1.3

Group AA

4.4  1.3

4.3  1.7

4.0  1.0

4.2  1.1

4.5  1.0

4.8  1.7

4.3  1.2

1249 

1159 

1240 

1242 

1123 

1145 

1182 

531

478

492

591

477

619

434

1273 

1309 

1303 

1229 

1120 

1100 

1168 

457

701

734

530

458

429

440

1365 

1352 

1381 

1423 

1240 

1255 

1341 

Group CVC

PAOP (mmHg) Group CVC

CO (L/min)

SVR(dynes·sec·cm5 ) Group CVC Group CV Group AA

494

PVR (dynes · sec · cm-5)

Group CVC Group CV

540

481

462

410

366

403

90  53

92  52

100  55

113 

104  57

95  69

91  50

122  91

102  61

127  76

103

97  58

105  66

102  52

142  94

123 

99  83

102  67

95  57

95  51

103  49

Group AA 117 

102

104 SVO2 (%) 84.0 

78.7 

80.0  6.3

79.8 

80.1  6.6

81.1 

Group CV

6.7

6.7

79.0  8.2

6.4

79.0  9.1

5.9

Group AA

83.7 

77.3 

79.0  6.4

78.7 

78.9  8.5

79.7 

6.2

10.7

9.7

8.2

81.4  5.5

82.8 

78.0 

80.0 

79.6 

81.3  7.4

5.1

7.4

6.2

7.2

79.9  6.8

Group CVC

Results are presented as mean  one standard deviation. 1 = Baseline (Post-Induction/Intubation, Pre-Incision) 2 = Post – CPB Separation / Pre – Protamine 3 = 2 Minutes Post – Protamine Start 4 = 5 Minutes Post – Protamine Start 5 = 10 Minutes Post – Protamine End 6 = 30 Minutes Post – Protamine End 7 = Post – Chest Closure CVC = Central Vein Control CV = Central Vein AA = Ascending Aorta HR = Heart Rate

MAP = Mean Arterial Pressure CVP = Central Venous Pressure MPAP = Mean Pulmonary Artery Pressure PAOP = Pulmonary Artery Occlusive Pressure CO = Cardiac Output SVR = Systemic Vascular Resistance PVR = Pulmonary Vascular Resistance SVO2 = Mixed Venous Oxygen Saturation

TABLE 4 INTRAOPERATIVE ARTERIAL BLOOD GAS ANALYSIS/ PEAK AIRWAY PRESSURE DATA

Timepoint

1

2

3

4

pH Group CVC

7.38  0.05

7.40  0.04

7.35  0.07

7.35  0.06

Group CV

7.37  0.05

7.40  0.04

7.36  0.06

7.36  0.05

Group AA

7.39  0.04

7.42  0.07

7.38  0.05

7.36  0.05

Group CVC

44  6

39  5

45  7

44  6

Group CV

44  6

37  3

42  6

42  5

Group AA

43  7

39  9

42  5

43  5

Group CVC

407  98

312  150

322  147

346  122

Group CV

376  113

303  129

329  122

339  114

Group AA

366  131

335  118

358  137

359  104

Group CVC

252  97

352  148

335  143

313  118

Group CV

282  110

363  129

332  122

321  115

Group AA

294  129

330  114

303  136

300  102

Group CVC

18.1  6.1

17.0  6.1

17.3  5.4

19.1  7.2

Group CV

18.3  3.6

18.2  3.9

18.6  4.4

19.5  3.3

pCO2 (mmHg)

pO2 (mmHg)

A – a Gradient (mmHg)

Peak Airway Pressure (cmH20)

18.5  4.2

17.8  3.4

17.8  4.0

19.0  4.3

Group CVC

12.5  1.5

8.8  1.1

8.8  1.1

10.1  1.5

Group CV

11.8  1.9

8.6  0.9

8.6  1.0

10.0  1.2

Group AA

12.2  2.1

8.9  1.0

9.1  1.0

10.4  1.3

Group CVC

0.9  0.4

2.1  1.4

2.0  1.4

1.9  1.7

Group CV

1.0  0.3

2.0  0.8

1.9  0.8

1.8  0.8

Group AA

1.0  0.5

1.7  0.7

1.6  0.7

1.6  0.8

Group AA Hemoglobin (g/dL)

Lactate (mmol/L)

Results are presented as mean  one standard deviation. 1 = Baseline (Post-Induction/Intubation, Pre-Incision) 2 = Post – CPB Separation / Pre – Protamine 3 = 10 Minutes Post – Protamine End 4 = Post – Chest Closure CVC = Central Vein Control CV = Central Vein AA = Ascending Aorta

TABLE 5 POSTOPERATIVE DATA

Group CVC (n = 33)

Group CV (n = 32)

Group AA (n = 30)

Hemodynamic Support ICU Arrival

15

12

7

Extubation Time (Hours)

15.2  21.5

10.3  8.0

10.5  8.4

Hemodynamic Support 24 Hours Post-ICU Arrival

13

9

8

ICU LOS (Days)

4.0  2.5

3.8  3.9

4.1  3.0

Hospital LOS (Days)

8.8  4.8

9.8  12.1

9.2  4.2

In-Hospital Death

1

1

2

Results are presented as mean  one standard deviation or absolute number of patients. CVC = Central Vein Control CV = Central Vein AA = Ascending Aorta ICU = Intensive Care Unit LOS = Length Of Stay

TABLE 6 STUDIES INVESTIGATING INFLUENCE OF RATE AND/OR ROUTE OF PROTAMINE ADMINISTRATION ON INCIDENCE/SEVERITY OF ADVERSE REACTIONS

Study

Design

Comunale[12] 2003

1497 humans prospective randomized observational 32 humans prospective randomized observational

Ovrum[13] 1992

Protamine Administration central venous versus peripheral venous central venous versus ascending aorta

Conclusions

Remarks

site did not influence incidence of pulmonary vasoconstriction systemic hypotension in both groups pulmonary hypertension less pronounced in ascending aorta group most rapid infusions associated with most severe adverse effects site did not influence hemodynamic alterations

protective effect of aspirin ingestion within a week of surgery? ascending aorta administration associated with less pulmonary hypertension?

Morel[14] 1990

6 chronically instrumented sheep

various rates via right atrium

slower infusion may avoid adverse reactions?

Suwanchinda[15] 1989

100 humans prospective randomized observational

left atrium versus peripheral venous

Katz[16] 1987

68 humans prospective randomized observational

site did not influence hemodynamic alterations

immediate hypotension only in ascending aorta patients?

Blanco[17] 1987

21 humans prospective observational

right atrium versus left atrium versus ascending aorta right atrium versus aortic arch

systemic hypotension only in aortic arch patients

Procaccini[18] 1987

20 humans prospective

right atrium versus

systemic hypotension only in

right atrial administration promotes hemodynamic stability? right atrial administration

only heart rate, arterial blood pressure, and central venous pressure assessed

observational

aortic arch

aortic arch patients

Taylor[19] 1986

9 chronically instrumented dogs

Intravenous versus intraaortic

Frater[20] 1984

17 humans prospective randomized observational 5 humans clinical reports

right atrium versus left atrium

site did not influence cardiovascular effects systemic hypotension only in right atrium patients

Lowenstein[21] 1983

Rogers[22] 1983

14 chronically instrumented pigs

Pauca[23] 1983

80 humans prospective observational

Milne[24] 1983

10 humans prospective randomized observational 22 humans prospective observational

Shapira[25] 1982

Aris[26] 1981

40 humans prospective observational

Rapid peripheral vein right atrium Intravenous versus ascending aorta all patients via ascending aorta Intravenous versus intraaortic various rates via peripheral vein (?) all patients via aortic root

rapid administration initiates severe, precipitous hypotension site did not influence incidence of hemodynamic abnormalities hemodynamically stable if intravascular volume maintained systemic hypotension only in intraaortic patients various rates did not influence hemodynamic abnormalities only mild systemic hypotension observed

promotes hemodynamic stability? no effect on myocardial contractility

histamine released as protamine traverses lungs? pulmonary vasoconstriction the culprit? both sites associated with pulmonary hypertension clinical benefits if lungs bypassed?

intravenous route better than intraaortic?

substantial hypotension in all patients

rapid intraaortic administration safe?