hemodynamic and morphologic alterations after experimental administration of protamine sulfate

Hemodynamic and Morphologic Alterations After Experimental Administration of Protamine Sulfate

Julian Alvarez, MD, Barcelona, Spain, Lourdes Alvarez, MD, Cristina Escudero, MD, Fernando Gilsanz, MD,

Santiago de Oya, MD, and Jose Luis Castillo-Olivares, MD, Madrid, Spain

T h e admin is t ra t ion of p ro t amine sulfate produces i m p o r t a n t h e m o d y n a m i c and p u l m o n a r y a l ter - at ions which can be summar ized as hypotension; pu lmona ry hyper tens ion with a u g m e n t e d pu lmona ry vascular resistances, an increase in the oxygen alveolar-ar ter ia l gradient , an increase in in t rapul - monary shun t pressure , an increase in a i rway resistance, and a decrease of pu lmona ry compliance; and anaphylac t ic shock [11-15]. Disregarding the ad- vantage of injecting p ro t amine sulfate into an a r te ry or vein, we s tudied the h e m o d y n a m i c a l tera t ions and morphologic repercussions t ha t its admin i s t ra - t ion produces in the lungs, left ventricle, and r ight ventr ic le a f te r the i m p l e m e n t a t i o n of d i f fe ren t types of ex t racorporea l circulation [8,16].

Mater ia l and M e t h o d s

Twenty-eight healthy mongrel dogs were divided into six groups. The animals were anesthetized with thiopen- tal (Pentothal | 20 mg/kg body weight) by intravenous injection. Tracheal intubation was performed in every case with a no. 9 Magill tube, with no need for muscle relaxants, and the dogs were subsequently connected to a respirator (Bird-Mark II| which maintained mechanical ventilation at 12 to 14 cycles/min and a current volume of 15 to 20 ml/kg body weight as measured with a Wright spirometer: Throughout the operation, each animal re- ceived diazepam (0.8 to 1 mg/kg body weight), fentanyl (0.05 to 0.08 mg/kg body weight) and pancuronium bro- mide (0.4 mg/kg weight). By means of implanted subcuta- neous electrodes, the 0ne-dimensional, two-dimensional, and three-dimensional derivations of the peripheral e!ec-

From the Experimental Surgery Laboratories, Clinica Puerta de Hierro, Madrid, Spain. Supported in part by a grant from the Fund for Health Investigation of the Spanish Social Security System (project no. 663182).

Requests for reprints should be addressed to Julian Alvarez, MD, Servi- cio de Anestesiologia y Reanimacibn, Hospital de la Santa Cruz y San Pablo, C.--San Antonio M a Claret. 167, 08028 Barcelona, Spain.

trocardiogram were monitored using an Electronics for Medicine VR-8 register system. Cannulization of the left femoral artery permitted the monitoring of arterial pressure using a Bentley Trantec model 800 register system connected to a Knott SMG 43 oscilloscope. The right femoral vein was catheterized for administration of drugs and liquids and for determination of the central venous pressure. A Swan-Ganz 7 F. hemodilution catheter connected to a KT6 Lexington Cardiac Output Computer was introduced through the left femoral vein, reaching the pulmonary artery. Recording of pressure in both ventricles and the left atrium was obtained by direct puncture and connection to the VR-8 register system.

The parameters obtained in each study were heart rate (beats/min); mean arterial pressure, mean pulmonary pressure, pulmonary capillary pressure, right atrial pressure, left ventricular end diastolic pressure, and right ventricular end diastolic pressure (mm Hg); systemic and pulmonary vascular resistance (dynes/s/cm-5); cardiac output (liters/min); stroke volume (ml/beat); left and right ventricular work (kg/m/min); and left and right ventricular rate of pressure development (dp/dt).

The computations of systemic vascular resistance, pulmonary vascular resistance, left ventricular work, right ventricular work, and stroke volume were carried o u t

using the following formulas: SVR = [(MAP - RAP)/CO] • 79.96; PVR = [(MPP - LAP)/CO] x 79.96; LVW = (CO x MAP • 0.0135); RVW = (CO • MPP • 0.0135); and SV = [CO (ml)/HR], where CO indicated cardiac output, HR indicated heart rate, LAP indicated left atrial pressure; LVW indicated left ventricular work, MAP indicated mean arterial pressure, MPP indicated mean pulmonary pressure, PVR indicated pulmonary vascular resistance, RAP indicated right atrial pressure, RVW indicated right ventricular work, and SV indicated stroke volume.

At the time of each hemodynamic study, blood samples were obtained for platelet count by a Coulter Plus II | All of the determinations were carried out in the basal state,

Volume 155, June 1988 735

Alvarez et al

TABLE I Group i Parameters*

Parameters Basal After Heparin After Protamine

Heart rate (beats/min) 166.66 4- 26.25 Mean arterial pressure (mm Hg) 96.08 4- 6.42 Mean pulmonary pressure (ram Hg) 11.50 4- 2.25 Systemic vascular resistance (dynes/s/cm -s) 2746.83 4- 525.21 Pulmonary vascular resistance (dynes/s/ore -s) 199.16 4- 57.39 Pulmonary vascular resistance to systemic vascular resistance 7.24 4- 2.53

(%) Right atrial pressure (mm Hg) 4.33 4- 0.51 Left ventricular end diastolic pressure (mm Hg) 2.50 -I- 0.54 Right Ventricular end diastolic pressure (ram Hg) 2.66 4- 0.51 Cardiac output (liters/min) 2.73 4- 0.41 Stroke volume (ml/beat) 16.89 4- 4.49 Left ventricular work (kg/m/min) 3.53 4- 0.54 Right ventricular work (kg/m/min) 0.42 4- 0.13 Right ventricuiar work to left ventricular work (%) 11.97 4- 2.17 Left ventricular dp/dt 1529 4- 197.77 Right ventricular dp/dt 547.16 4- 73.01 Platelet count 249 4- 73.53

166.83 4- 26.61 143.83 4- 18.20 t5 96.08 4- 6.42 71.66 4- 6.50 T5 11.50 4- 2.25 18.50 4- 4.53 t5 2724 4- 628.69 1942.16 4- 247.7115

200.83 4- 60.64 508.33 4- 132.43 t t 7.45 4- 2.93 26.57 4- 7.63 t5

4.33 4- 0.51 8.33 2.50 4- 0.54 5 2.66 4- 0.51 5.50 2.73 4- 0.46 2.65

16.89 4- 4.63 18.76 3.53 4- 0.59 2.58 0.42 4- 0.12 0.79

11.78 4- 2.09 31 1613.33 4- 182.07 1345.50 546.50 4- 63.45 463.83 251.16 4- 74.24 134.16

4- 1.03tt 4- 0.89 t t 4- 1.04t5 4- 0.45 4- 5.87 4- 0.62 4- 0.27 t~t 4- 4.83 t$ 4- 147.68 tt 4- 61.52 t$ 4- 18~t

* Values indicate mean 4- standard deviation. T Comparison with the basal level; p <0.05.

Comparison between postheparin and postprotamine sulfate; p <0.05.

20 minutes after intravenous administration of heparin (3 mg/kg body weight) in the control group and after extracorporeal circulation in the rest of the animals, and 10 minutes after intravenous administration of protamine sulfate (5 mg/kg body weight). Later, samples of lung, left ventricle, and right ventricle were taken for microscopic study with the heart beating. These samples were obtained from parts that had been macroscopically resected.

For optical microscopic studies, the specimens were fixed in formaldehyde for subsequent staining with hema- toxylin-eosin and silver carbonate. For electron microscopic studies, the specimens were fixed in glutaralde- hyde to be stained later with osmium tetroxide and visualized under a Phillips 300 | electron microscope. In animals subjected to extracorporeal circulation, cannula- tion of both vena cavas and the right femoral artery was performed. Each group of animals was characterized as follows: In Group I (si x dogs), extracorporeal circulation was not performed; In Group II (six dogs), extracorporeal circulation was maintained for 20 minutes without appli- cation of hypothermia, an aortic clamp, or cardioplegic solution: In Group III (six dogs), after implementation of extracorporeal circulation, the animals underwent hypothermia (body temperature 25 ~ C), aortic clamping for 20 minutes, and administration of a single dose of cardioplegic solution (30 mEq/liter of potassium, body temperature 4~ Rewarming was carried out slowly over a period of 40 to 45 minutes. In Group IV (six dogs), the procedure was identical to that in Group III, except that rewarming time was 10 to 15 minutes. In these four groups, heparin and protamine sulfate were administered at the afore- mentioned doses. In Groups V and VI (two dogs per group), the same procedure was employed as in Groups III and IV, respectively, but protamine sulfate was not administered.

During hemodynamic study, the dogs were maintained at a constant left atrial pressure, which was similar to basal levels, in order not to distort the results correspond- ing to contractility. Statistical analysis was performed with a Digital PDP 11-55 | computer. The mean and standard deviation of each sample were computed, and analysis of variance, Kolmogoroffs test, and Shapiro and Wilk's test were carried out to determine whether the data fol- lowed a normal distribution, when they did, the paramet- ric contrasts of analysis of variance and the Student's t test were applied, an d when they did not, the Mann- Whitney U test with Friedman contrast was applied in cases of single samples and the Wilcoxon signed-rank test with Kruskat-Wallis contrast for paired results.

R e s u l t s

In regard to the hemodynamic and hematologic values, there were no significant differences in basal states between the groups, and thus they were com- parable among themselves (Tables I and II). Mean arterial pressure decreased significantly af ter extracorporeal c i rculat ion in Groups III and IV. After injection of p ro tamine sulfate, this decrease was produced in Groups I, II, II!, and IV, being especially pronounced in Group IV as compared with the other three groups (p <0.05). In regard to systemic vascular resistance, in none of the groups was a significant difference between the basal values and the postext racorporeal circulat ion Values observed. The adminis t ra t ion of p ro tamine sulfate p roduced a statistically significant decrease in comParison with basal values which, however, was not significant when comparison Was made among the groups. T h e mean p u lm o n a ry pressure was n o t s ignif icant ly modif ied after adminis t ra t ion of hepar in or extra-

736 The American Journal of Surgery

Hemodynamics and Morpho log ic A l te ra t ions With Pro tamine Sul fa te

TABLE II Hemodynamic and Hematologic Values Between Groups II, III, & IV*

Parameters Basal After ECC After Protamine

Group II

Heart rate (beats/min) Mean arterial pressure (ram Hg) 106.66 4- 7.84 Mean pulmonary pressure (ram Hg) 16 4- 2.28 Systemic vascular resistance (dynes/s/cm -5) Pulmonary vascular resistance (dynes/s/cm -s) 266 4- 89.83 Pulmonary vascular resistance to systemic vascular resistance 7.39 4- 1.45

(%) Right atrial pressure (mm Hg) 4.50 4- 1.22 Left ventricular end diastolic pressure (mm Hg) 3.66 4- 1.50 Right ventricular end diastolic pressure (ram Hg) 2.50 4- 0.83 Cardiac output (liters/rain) 2.36 4- 0.48 Stroke volume (ml/beat) 15.97 4- 4.76 Left ventricular work (kg/m/min) 3.42 4- 0.86 Right ventricular work (kg/m/min) 0.53 4- 0.15 Right ventricular work to left ventricular work (%) 16.68 4- 2.87 Left ventricular dp/dt 1596 4- 99.61 Right ventricular dp/dt 538.16 4- 74.05 Platelet count 251.16 4- 85.55

152 4- 22.41 157 4- 37.02 127 4- 37.38 t t 100 -4- 7.30 76.41 4- 9.57 t t

17.50 4- 2.60 21.85 4- 1.27 t t 3569.16 4- 756.44 3494 4- 760.27 2595.83 -I- 475.87tt

316.83 4- 94.03 503.83 4- 126.11 t t 9.12 4- 2.53 19.53 4- 3.521.~

5 4- 0.89 6 4- 1.78 Tt 5 4- 1.26 7.25 4- 2.31 t t

3.66 4- 0.21 4.83 4- 2.13 t~ 2.23 4- 0.44 2.21 4- 0.43

14.67 4- 5.56 19.16 4- 8.90 3.02 4- 0.68 2.28 4- 0.60 t t 0.53 4- 0.15 0.65 4- 0.141.t

19.16 4- 2.29 t 29.17 4- 4.481.~ 1483.33 4- 125.59 1285.66 4- 97.161.t

494.16 4- 73.18 438.50 4- 57.96 t t 182.50 4- 44.241. 91.66 4- 16.631.t

Group III

Heart rate (beats/min) 160.66 4- 23.41 145 4- 19.61 128.33 4- 13.33 t t Mean arterial pressure (mm Hg) 106.50 4- 10.52 92.16 4- 8.181. 76 4- 6.19 t t Mean pulmonary pressure (mm Hg) 13.33 4- 2.06 16.66 4- 3.83 21.50 4- 3.56 t t Systemic vascular resistance (dynes/s/cm -s) 3445.25 4- 408.25 3353.50 4- 580.50 2493.83 4- 180.04 t$ Pulmonary vascular resistance (dynes/s/cm -5) 250.66 4- 124.41 344 4- 104.14 537 4- 178.77 t t Pulmonary vascular resistance to systemic vascular resistance 7.11 4- 2.89 10.94 4- 3.621. 23.84 4- 7.53 t~

(%) Right atrial pressure (mm Hg) 5.66 4- 1.03 6.16 4- 0.75 10.66 4- 1.21 t~t Left ventricular end diastolic pressure (mm Hg) 2.66 4- 0.51 3.50 4- 0.54 t 4.83 4- 1.16 t t Right ventricular end diastolic pressure (ram Hg) 2.66 -4- 0.81 3 4- 0.89 5 4- 1.671.t Cardiac output (liters/min) 2.40 4- 0.17 2.15 4- 0.181. 1.15 4- 0.101.t Stroke volume (ml/beat) 14.91 4- 1.83 15.13 4- 2.30 16.90 4- 1.97 Left ventricula r work (kg/m/min) 3.37 4- 0.45 2.69 4- 0.36 2.24 4- 0.25 t t Right ventricular work (kg/m/min) 0.42 4- 0.05 0.48 4- 0.12 0.62 4- 0.111.t Right ventricular work to left ventricular work (%) 12.68 4- 1.41 18.19 4- 4.311. 26.96 4- 4.931.t Left ventricular dp/dt 1579.66 4- 213.65 1338.33 4- 183.971 1046 4- 105.591.t Right ventricular dp/dt 539.83 4- 59.99 499.66 4- 62.01 420.33 4- 32.04 t t Platelet count 253.83 4- 40.98 179.16 4- 29.05 t 92.50 4- 19.17 t t

Group IV

Heart rate (beats/min) 133.33 4- 6.28 Mean arterial pressure (ram Hg) 103.83 4- 7.67 Mean pulmonary pressure (mm Hg) 12.50 4- 1.51 Systemic vascular resistance (dynes/s/cm -5) 3143.83 4- 653.67 Pulmonary vascular resistance (dynes/s/cm -s) 193.66 4- 60.15 Pulmonary vascular resistance to systemic vascular resistance 6.51 4- 2.48

(%) Right atrial pressure (mm Hg) 6.33 4- 1.03 Left ventricular end diastolic pressure (mm Hg) 2.50 4- 0.54 Right ventricular end diastolic pressure (mm Hg) 2.50 4- 0.54 Cardiac output (liters/min) 2.36 4- 0.29 Stroke volume (ml/beat) 17.81 4- 1.92 Left ventricular work (kg/m/min) 3.27 4- 0.58 Right ventricular work (kg/m/min) 0.39 4- 0.05 Right ventricular work to left ventricular work (%) 12.68 4- 1.41 Left ventricutar dpldt 1648.16 4- 186.93 Right ventricular dp/dt 551 4- 39.90 Platelet count 262 4- 44.56

147.66 4- 23.64 115.83 4- 23.82 t$ 87.16 4- 7.25 t 54.83 4- 6.61 t t 18.16 4- 1.321 27.38 4- 5.131.t

3109.83 4- 85.47 2263.66 4- 166.501.t 414.16 4- 61.96 t 1086.33 4- 320.12 ~t

13.31 4- '1.78 t 48.35 4- 14.98 t t

8.50 -4- 0.54 14 -I- 1.091.t 3.66 -4- 0.511. 6.66 -I- 1.03t$ 4.16 -I- 0.981. 8.66 4- 0.811.t 2.02 4- 0.201. 1.45 • 0.251.;

14.16 -I- 1.77 12.72 -I- 2.07 2.44 4- 0.40 1.08 4- 0.331.$ 0.50 4- 0.05 0.54 4- 0.17

18.19 4- 4.311 49.96 -I- 14.931.t 1292.33 4- 195.02 t 991.33 4- 158.22 t$

423.33 4- 35.43 t 305.33 4- 39t t 101.66 4- 10.32 t 26.33 4- 12.111.~

* Values indicate mean -I- standard deviation. t Comparison with the basal level; p <0.05.

Comparison between postextracorporeal circulation and postprotamine sulfate; p <0.05. ECC = extrac0rporeai circulation.


Alvarez et al

Figure 1. Right ventricular edema In a dog in Group IV. (Magnification X 25, reduced by 51 percent.)

corporeal circulation in Groups I, II and III, but it was in Group IV. In all four groups, the injection of protamine sulfate increased the mean pulmonary pressure significantly. The pulmonary vascular resistances evolved in a similar manner, without mod- ifications after extracorporeal circulation except in Group IV. After protamine sulfate administration, they increased significantly, especially in Group IV when compared with the other groups (p <0.05).

The left ventricle dp/dt underwent a decrease after extracorporeal circulation which did not prove statistically significant when compared with basal values in Groups I and II, although the decrease was statistically significant in Groups III and IV when compared with basal levels and with Group I (p <0.05). The injection of protamine sulfate decreased this value significantly in all groups compared with previous levels. The decrease was also significant when Groups III and IV were compared with Groups I and II (p <0.05). The right ventricle dp/dt was not modified in a significant way after extracorporeal circulation except in Group IV. With the administration of protamine sulfate, the value decreased from the previous level in all groups, and in Group IV, it was lower when compared with the other three groups (p <0.05). The end diastolic pressure increased in both ventricles in a manner similar to that of the dp/dt. At no time was the cardiac output modified in Groups I and II. In Groups III and IV, it diminished significantly after extracorporeal circulation and especially after protamine sulfate administration; however, no differences were observed between these two groups. The heart rate remained stable after extracorporeal circulation, but decreased significantly after administration of protamine sulfate. There were no statistical

differences among the groups. Stroke volume remained unchanged throughout the entire study period in all of the groups. The right atrial pressure was significantly augmented in all groups after protamine sulfate administration. In a comparison between groups, this increase was most marked in Groups III and IV in comparison with Groups I and II (p <0.05). After extracorporeal circulation, the number of circulating platelets decreased significantly, this descent being most notable in Group IV (p <0.05). The injection of protamine sulfate produced a further significant reduction in the number of platelets compared with previous determinations, including those in Group I.

Optical microscopic examination of samples from the lungs and both ventricles did not show any alterations. With the electron microscope, observations of the lungs and left ventricle proved normal, but there was evidence of right ventricle edema in half of the Group I dogs, in five of six dogs in Groups II and III, and in all dogs in Group IV. The edema had intracellular and extracellular localization and was considered slight since it respected the intracellular organelles, including mitochondria (Figure 1). Worthy of mention is the fact that in Groups V and VI, no alterations were observed in any of the dogs.

Comments The administration of protamine sulfate pro-

duces a decrease in the mean pulmonary pressure by means of two different mechanisms: peripheral vasodilation and depression of myocardial contractility [1-9,16]. Protamine sulfate causes vasodilation with diminished systemic vascular resistance and pulmonary vasoconstriction with increased pulmonary vascular resistance. Its mechanism of action is


Hemodynamics and Morphologic Alterations With Protamine Sulfate

indirect and mediated by platelet activation [2,14]. The liberation of the vasoactive mechanisms of adenosine diphosphate and adenosine triphosphate generates peripheral vasodilation, and serotonin and prostaglandin F2a produce pulmonary vasoconstriction and bronchoconstriction [17-20]. This is in accordance with the alterations in the airway and pulmonary functions found by Jastrzebski et al [3] after protamine sulfate administration.

Our findings agreed with these affirmations, as we observed a decrease in the mean arterial pressure by peripheral vasodilation and an increase in the mean pulmonary pressure due to an increase in the pulmonary vascular resistances after protamine sulfate injection. These alterations were more notable in the group subjected to rapid rewarming. On the other hand, we observed a marked decrease in the number of circulating platelets after administration of protamine sulfate regardless of whether or not extracorporeal circulation was performed; however, we did not investigate the intimate mechanism that relates this finding to the vascular resistance modi- fications. The depression in myocardial contractility seems to be related to the movement of calcium across the membranes since hypocalcemia has been demonstrated after protamine sulfate administration and subsequent calcium injection improves contractility [9,21]. We observed that this depression of contractility affects both ventricles, but although the postload of the left ventricle is diminished due to peripheral vasodilation, that of the right ventricle is increased due to pulmonary vasoconstriction. This determines the increase in right ventricular work and the right ventricular work and left ventricular work quotient, as well as the diminution of cardiac output. The stroke volume does not vary, which may be attributed to concomitant bra- dycardia. This effect in the right ventricle could justify the appearance of edema in that ventricle, it being the result and not the cause of the hemodynamic alterations. In this regard, five patients were described with severe pulmonary vasoconstriction and fatal right ventricular insufficiency who had been subjected to extracorporeal circulation, having undergone subsequent protamine sulfate administration [10].

In our experience, the ventricular morphologic alterations appear only in the right ventricle, and their frequency augments in a pattern similar to that of the hemodynamic results. In Group IV, all of the dogs had edema of the right ventricle, whereas in Group VI, there was no edema. The only difference between the two groups was the administration of protamine sulfate. The assessment of the edema was exclusively qualitative as the wet weight to dry weight ratio was not measured, nor were extracellular and intracellular markers used to arrive at a quantitative analysis. The hemodynamic, hemato-

logic, and morphologic alterations were more important in Group III and most important in Group IV.

According to our observations, we were able to conclude that under experimental conditions, protamine sulfate produces some hemodynamic effects which manifest themselves fundamentally in the circulation of the right side, given that the overall depression of contractility is added to the increase in the right ventricular pressures, which exert their influence on the normal functioning of the right ventricle.

Summary The hemodynamic, hematologic, and morpholog-

ic effects induced by protamine sulfate have been studied in 28 dogs divided into 6 groups. All of the groups were given heparin (3 mg/kg body weight) and Groups I, II, III, and IV were given protamine (5 mg/kg body weight). Group I (control group) was not subjected to extracorporeal circulation. The other groups had the following interventions: Group II, cardiopulmonary bypass without aortic clamp, hypothermia, or cardioplegia; Groups III and V, hypothermia of 25~ aortic clamping for 25 minutes, administration of cardioplegic solution, and slow rewarming; and Groups IV and VI, the same as Groups III and V, but with rapid rewarming. After injection of protamine sulfate, there was a decrease in mean arterial pressure due to peripheral vasodilation and an increase in the mean pulmonary pressure due to increased pulmonary vascular resistance; marked diminution of the number of circulating platelets aside from the extracorporeal circulation; a decrease in the contractility of both ventricles with augmented right ventricular work and decreased cardiac output; and right ventricular edema in Groups I, II, III, and IV. These alterations were most evident in Groups III and IV.

Acknowledgment: We thank M. Messman for her translation and preparation of the manuscript.

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hemodynamic and morphologic alterations after experimental administration of protamine sulfate

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