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Role of serotonin and serotonin antagonist on pulmonary hemodynamics and microcirculation in hemorrhagic shock
Role of serotonin and serotonin antagonist on pulmonary hemodynamics and microcirculation in hemorrhagic shock Previous studies showed that pulmonary pathological changes after hemorrhagic shock are similar to those after continuous (2 hours) serotonin infusion. Both conditions produce congestive atelectasis, interstitial and intra-alveolar edema and hemorrhage, and red cell aggregation. Studies in 25 dogs compared pulmonary hemodynamics during 2 hours of hemorrhagic hypotension (40 mm. Hg) with methysergide (serotonin antagonist), without methysergide, and with serotonin (75 meg. per kilogram per minute) alone. During serotonin infusion in normovolemia, both pulmonary artery (PA) and pulmonary vein wedge (PV W) pressure rose. The pulmonary arteriolar and small pulmonary venous (SPV) constriction were statistically and physiologically significant. Pretreatment with methysergide prior to hypovolemia prevented the SPV pressure rise. Lung changes, grossly, microscopically, and by cinemicroscopy, were greatly reduced by administration of methysergide. These results suggest that serotonin-possibly released by the hypoxic intestine, hypoxic brain, or unstable platelets-plays a significant role in the pulmonary changes secondary to hypovolemic hypotension.
Katsuyuki Kusajima, M.D., 1. Ayhan Ozdemir, M.D., Watts R. Webb, M.D., Stennis D. Wax, M.D., and Frederick B. Parker, Jr., M.D., Syracuse, N. Y.
HemorrhagiC hypotension to forty millimeters of mercury for two hours, followed by reinfusion of shed blood, produces the full pathological picture of shock lung with patchy atelectasis, congestion, and interstitial and intra-alveolar edema and hemorrhage." Our pressure studies show the initial vascular response to be constriction of the small pulmonary veins (SPV). Subsequently, during hypovolemia and particularly after reinfusion, an additional gradient develops across the alveolar capillary bed due to alveolar and interstitial edema and aggregation of intravascular blood cells.' Serotonin is known to induce pulmonary From the Department of Surgery, State University of New York, Upstate Medical Center, Syracuse, N. Y. 13210. Supported by a Grant from the Upstate Heart Association. Received for publication March I, 1974.
908
hypertension, interstitial and intra-alveolar edema, and whole blood cell aggregation in the pulmonary bed.' 1" The similarity of these findings to those during hemorrhagic shock" 1S suggests the possible participation of serotonin, but its relationship in the shock lung syndrome has not been previously investigated. By studying the pulmonary hemodynamics and microcirculation with serotonin administration and with antiserotonin during hemorrhagic shock, we have evaluated the relationship between shock lung syndrome and serotonin-induced pulmonary injury. Methods
Twenty-five adult mongrel dogs, weighing 15 to 25 kilograms, were anesthetized
Volume 67
Hemorrhagic shock
Number 6 June, 1974
with intravenously administered pentobarbital and ventilated with room air. A Harvard mechanical respirator, adjusted to maintain arterial blood gases within normal physiological ranges, was used.. A positive end-expiratory pressure of 5 em. of water was maintained. The animals were given 3 mg. per kilogram of heparin prior to the experiment. A left femoral arterial (FA) cannula was inserted for monitoring pressure and a left femoral venous cannula was inserted for infusions. Another cannula was inserted into the right FA and attached to an airless plastic reservoir. The lung was exposed through the left fifth intercostal space, and a No. 8 Fr. catheter was inserted via the left jugular vein into the left pulmonary artery (PA) and advanced to the pulmonary artery wedge (PAW) position. Synthetic catheters with an outside diameter of 1.4 mm. were inserted into the main PA and the pulmonary vein wedge (PW) via the left atrium (LA) through a needle puncture. No. 10 Fr. catheters were inserted into the LA via the appendage. For measurement of pressure in the SPY, a polyvinyl catheter with an outside diameter of 0.9 mm. was passed through a large silicone rubber sheath into the LA and guided into the left lower lobe vein. The catheter was advanced into the PVW position and then withdrawn slightly; again, pressure changes were used to accomplish proper positioning. The experimental animals were divided into three groups (Fig.
GROUP (12)
HEMORRHAGIC SHOCK
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GROUP (8 )
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9
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3 Hrs.
"L-Methysergide 75 microgram / kg
Fig. 1. The experimental animals were divided into three groups.
tonin, dissolved in 100 c.c. of lactated Ringer's solution, was infused continuously through the right atrium for 2 hours at a rate of 75 meg. per kilogram per minute .. Pressures were recorded before infusion, three times (20, 60, and 120 minutes) during infusion, and three times (l0, 20, and 30 minutes) after serotonin infusion. Group III (8 dogs). The dogs were bled and reinfused as in Group I. These dogs were given 75 meg. per kilogram of antiserotonin (methysergide) after bleeding (at the onset of shock). The same pressure studies were performed as in Group I. Pulmonary microcirculation was studied with cinemicroscopy at 150 to 450 power with the method developed in our laboratory.
1).
Results
Group I (12 dogs). After baseline control values were obtained, the dogs were bled to shock levels within 15 minutes with the reservoir adjusted to maintain mean arterial pressure at 40 mm. Hg. After 2 hours the blood was reinfused over a 20 minute period. Pressures were recorded before shock, three times during shock (20, 60, and 120 minutes), and twice in the recovery period (20 and 60 minutes) after reinfusion. Group II (5 dogs). A venous cannula was inserted and advanced to the right atrium. Via this cannula, 100 mg. of sero-
Group I. It was necessary to withdraw approximately 50 c.c. of blood per kilogram to lower and maintain the arterial pressure at 40 mm. Hg. All pressures fell initially with hemorrhage, and all gradually rose during late shock, except that in the LA. The control gradient of 0.76 mm. Hg between the Spy and LA rose in midshock to 2.97 mm. Hg (p < 0.01). The gradient remained at this level until after reinfusion, when it fell slightly. Within 60 minutes after reinfusion of the shed blood, pressures in the FA,
The Journal of
9 10
Kusajima et al.
Tuorccic and Cardiovascular Surgery
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Fig. 2. Mean pressure changes in pulmonary circulation during continuous infusion of serotonin (Group II). PAW, Pulmonary artery wedge. SPV, Small pulmonary vein. LA, Left atrium. PA, Pulmonary artery. PVW, Pulmonary vein wedge. FA, Femoral artery.
PVW, SPY, and LA returned to near base-line control levels, whereas the PA and PAW pressures increased significantly above base-line levels. Thus the pressure gradients between the PAW and SPY increased significantly from 0.3 to 2.4 mm. Hg after reinfusion (p < 0.01). A gradient also developed between the PA and PVW during late shock; this gradient increased further in the recovery period (3.91 mm. Hg compared to 0.93 mm. Hg control) (p < 0.01). Group II. The systemic pressure increased immediately after the serotonin infusion was started, but within 5 minutes it decreased to 65 per cent of the base-line control value. However, the PA and PVW pressures increased significantly 60 per cent
above the base-line control. The PAWand SPY pressures increased slightly above the base-line control levels, whereas the LA pressure decreased. There was an increase in the pressure gradient between the SPY and the LA from 1.80 mm. Hg base line to 8.63 mm. Hg 120 minutes after the serotonin infusion (p < 0.02), suggesting Spy constriction. During the continuous serotonin infusion, the pressure gradients between the PA and PVW and between the PAW and the Spy showed slight but insignificant increases. When the infusion of serotonin was discontinued after 120 minutes, all pressures and pressure gradients quickly returned almost to control values and remained at those levels (Fig. 2).
Volume 67
Hemorrhagic shock
Number 6
9I1
June, 1974
26
(mean! S.E .) mm Hg
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Fig. 3. Mean pressure changes during hemorrhagic shock with methy sergide injected just before hemorrhage (Group III). For abbreviations, see Fig. 2.
Group III. Approximately 60 c.c. of blood per kilogram was withdrawn from each dog in this group to lower and maintain the arterial pressure at 40 mm. Hg. The methysergide infusion was started with the onset of shock. All pressures fell initially with hemorrhage (Fig. 3). During late hypovolemia, the LA pressure decreased slightly, the SPY pressure remained low, and the PAW pressure rose very minimally but not to base-line values. This is in contrast to shock alone, in which the PAW and Spy rose to higher than the control values. However, a slight but insignificant gradient (from 0.4 mm. Hg for control animals to 2.3 mm. Hg for those
Fig. 4. The characteristic histologic alteration of the lung. Top, After serotonin infusion: interstitial and intra-alveolar edema, cellular infiltration, and thrombus. Bottom, Hemorrhagic shock lung: interstitial and intra-alveolar edema and cellular filtration. (Original magnifications: top x215; bottom xI60.)
in late shock) did develop between the PAW and the SPY. The pressure gradient between the Spy and the LA changed only 0.71 mm. Hg (from 1.76 mm. Hg in early shock to 2.47 mm. Hg in late shock). During hypovolemia no significant change in pressure gradient developed between the PA and the PYW, though the gradient between the PAW and Spy increased to 2.5 mm. Hg from 0.4 mm. Hg in the control period (p < 0.005). After reinfusion of shed blood, a gradient of 3.2 mm. Hg developed between the PA and the PYW: this gradient had been only 2.1 mm. Hg in the control period. Histologic and cine.,icroscopic findings The characteristic 'histologic findings were seen in the hemorrhagic shock lung, i.e., interstitial and intra-alveolar edema, intra-
The Journal of
9 12
Kusajima et al.
vascular congestion, and cellular infiltration. The addition of methysergide did not change the histologic picture seen in the hemorrhagic shock lung. Serotonin infusion in the normovolemic animal caused interstitial and intra-alveolar edema, blood cell aggregations, and thrombi (Fig. 4). Pulmonary microcirculation was greatly reduced in hemorrhagic shock, but the circulation was slightly improved in the methysergide-treated animals. 20 Discussion
For many years it has been noted that clotted blood releases humoral substances which are capable of producing severe cardiovascular depression. The active humoral substance, serotonin (5-hydroxytryptamine), was isolated by Rapport and Colleagues':' in 1948. More recently many investigators have shown that serotonin is present mainly in the intestinal argentaffin cells, the platelets, and the brain. The circulatory effects of serotonin are constriction of coronary vessels by excitation of the coronary chemoreflex; activation of a pressor reflex to the atrium and great vessels in the thorax, through stimulation of the carotid sinus (baroreceptor and chemoreceptor) and vagus fibers; and a direct constrictive action on the great veins, trachea, and bronchi. More recently, the relation between serotonin, pulmonary vascular hypertension, and pulmonary embolism was studied.': 7 The pulmonary arterioles appeared to be more sensitive to the constrictor action of serotonin" than are the systemic vessels. The present pressure study shows that continuous infusion of serotonin (75 meg. per kilogram per minute) causes a decrease in systemic blood pressure and LA pressure. However, there is a significant increase in the PA and PVW pressures. The PAW and Spy pressures remain almost identical to the preinfusion levels. There is a significant increase in the pressure gradient between the Spy and the LA, but the pressure gradients between the PAW and the Spy show only insignificant physiological
Thoracic and Cardiovascular Surgery
changes. These data suggest that serotonin causes constriction of both the arterioles and the SPY but little or no blockage of the capillary bed, since no gradient develops across the capillary bed. Little work has been done previously to determine the role of serotonin in hemorrhagic shock. Swank 1 7 has shown that the pressure required to pass a sample of fresh blood through a filter with pores 20 by 20 po is 35 torr (1 torr = 1 mm. Hg). After hemorrhagic or traumatic shock, the filtration pressure progressively increases, reaching 200 torr after a loss of about 65 per cent of blood volume. When wool glass was interposed in the system in front of the micropore filter, the filtration pressure was only slightly elevated above prehemorrhagic values. Microscopic examination of the glass wool, after the wool had been gently washed free of red cells, showed platelets and leukocytes attached. From this evidence, it may be assumed that platelets and leukocytes aggregate intravascularly during hemorrhagic shock." Many investigators have presented evidence for altered hemostasis in hemorrhagic shock in experimental animals. A state of hypercoagulability may be present initially, followed by hypocoagulability. Following hemorrhage or traumatic shock, a state of hypercoagulability develops due to an increase in release of platelets by the spleen. Platelets and leukocytes become adhesive and/or aggregate." Serotonin inhibitor (methysergide) prevented serotonin-induced pulmonary hypertension'> in experimental animals. From each animal treated with methysergide, approximately 60 c.c. per kilogram of blood was withdrawn to lower and maintain the arterial pressure at 40 mm. Hg; however, loss of only 50 c.c. per kilogram of blood was necessary in Group I. Thus the Group III animals were subjected to a greater degree of hypovolemia than were those in the simple hemorrhage group, and yet they exhibited less hemodynamic and pulmonary deleterious effects. Of particular import was the absence of SPY constriction.
Volume 67
Hemorrhagic shock
Number 6 June, 1974
Our previous studies show that the characteristic hemodynamic changes of the pulmonary microcirculation in hemorrhagic shock include development of a gradient between the Spy and the LA during hypovolemia. During late shock and particularly after reinfusion, gradients develop between the PA and PYW and between the PAW and SPY. This suggests that the initial lesion is SPY constriction. Subsequently, during late hypovolemia and particularly after reinfusion, an additional gradient develops across the alveolar capillary bed." Many investigations concerning pathogenesis of the shock lung have been conducted." :J, fL ' " Sugg and co-workers> have succeeded in preventing the pulmonary changes secondary to hypovolemia by removal and reimplantation of the lung. Their results suggest that acute congestive atelectasis is at least in part neurally mediated. Moss and associates!" demonstrated that cerebral hypoxia (Po" 35 ± 5 mm. Hg for 2 hours) caused the full picture of pulmonary congestive atelectasis, including atelectasis of hyaline membranes. This phenomenon also could be prevented by pulmonary denervation (reimplantation), again confirming the importance of neural factors in pulmonary circulation." Levine and associates" suggested that the increased pulmonary vascular resistance in hypovolemic shock resulted from intrapulmonary effects of decreased pulmonary blood flow and from the effects of humoral factors on the lung. The SPY constriction characteristic of severe hypovolemia was prevented by methysergide: This fact implies that serotonin may play a significant role in the pulmonary changes. Serotonin is released by hypoxic intestine, hypoxic brain, or by unstable platelets, especially those that aggregate in the lung and are destroyed; ultimately after reinfusion, a blockage of the pulmonary capillary bed develops comparable to that of untreated animals. Thus undoubtedly other factors are of importance as well.
9 13
REFERENCES Allardyce, 8., Hamit, H. F., Matsumoto, T., and Moseley, R. V.: Pulmonary Vascular Changes in Hypovolemic Shock: Radiography of the Pulmonary Microcirculation and Possible Role of Platelet Embolism in Increasing Vascular Resistance, J. Trauma 9: 403, 1969. 2 Attar, S., Kirby, W. H., Jr., and Masaitis, C.: Coagulation Changes in Clinical Shock: I. Effect of Hemorrhagic Shock on Clotting Time in Humans, Ann. Surg, 164: 34, 1969. 3 Cook, W. A., and Webb, W. R.: Pulmonary Changes in Hemorrhagic Shock, Surgery 64: 85, 1968.
4 Daicoff, G. R., Chaves, F. R., Anton, A. H., and Swenson, E. W.: Serotonin-Induced Pulmonary Venous Hypertension in Pulmonary Embolism, J. THORAe. CARDIOVASe. SURG. 56: 810, 1968.
5 Gilbert, R. P., Hinshaw, L. B., Kuida, H., and Visscher, M. B.: Effect of Histamine, 5Hydroxytryptamine and Epinephrine on Pulmonary Hemodynamics With Particular References to arterial and Venous Segment Resistances, Am. J. Physiol. 194: 165, 1958. 6 Hardaway, R. M.: The Role of Intravascular Clotting in the Etiology of Shock, Ann. Surg. 155: 325, 1962. 7 Jacobsen, D. C., Soden, K. J., Allen, P. D., and Daicoff, G. R.: Humoral Blockade on Lethal Pulmonary Embolism in the Awake Dog, Surg. Forum 22: 209, 1971. 8 Kusajima, K., Wax, S. D., Webb, W. R., and Parker, F. B.: The Hemodynamic Effects of Atropine, Lasix, and Methylprednisolone on Pulmonary Microcirculation in Shock, Surg. Gynec. Obstet. In press. 9 Levine, F. H., Hollingsworth, 1. E., Coskle, D. M., and Reis, R. L.: Mechanism of the Pulmonary Vascular Response to Hypovolemic Shock, Surg. Forum 22: 34, 1971. 10 Moss, G., Staunton, c., and Stein, A. A.: Cerebral Hypoxia as the Primary Event in the Pathogenesis of the "Shock Lung Syndrome," Surg. Forum 22: 211, 1971. II Staunton, C., Stein, A. A., and Moss, G.: Cerebral Etiology of the Respiratory Distress Syndrome: Universal Response With Prevention by Unilateral Pulmonary Denervation, Surg. Forum 24: 229, 1973. 12 Murakami, T., Wax, S. D., and Webb, W. R.: Pulmonary Microcirculation in Hemorrhagic Shock. Surg. Forum 21: 25, 1970. 13 Parker, 8. M., Steiger, B. W., and Friedenberg, M. J.: Serotonin-Induced Pulmonary Venous Spasm Demonstrated by Selective Pulmonary Phlebography, Am. Heart Jr. 69: 521, 1965. . 14 Rapport, M. M., Green, A. A., and Page,
9 14
15
16
17
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I. H.: Serum Vasconstrictor (Serotonin); Isolation and Characterization, J. BioI. Chern. 176: 1243, 1948. Smith, D. J., and Coxe, J. W.: Reaction of Isolated Pulmonary Blood Vessels to Anoxia, Epinephrine, Acethylcholine and Histamine, Am. J. PhysioI. 167: 732, 1951. Sugg, W. L., Webb, W. R., Nakae, S., Theodorides, T., Gupta, D. N., and Cook, W. A.: Congestive Atelectasis: An Experimental Study, Ann. Surg. 168: 234, 1968. Swank, R. L., and Edwards, M. J.: Microvascular Occlusion by Platelet Emboli After Transfusion and Shock, Microvasc. Res. 1: 15, 1968. Swank, R. L., Hissen, W., and Fellman, J. H.:
The Journol of Thorocic ond Cordiovosculor Surgery
5-Hydroxytryptamine (Serotonin) in Acute Hypotensive Shock, Am. J. PhysioI. 207: 215, 1964. 19 Swank, R. L., Fellman, J. H., and Hissen, W. W.: Aggregation of Blood Cells by 5-Hydroxytryptamine (Serotonin), Circ. Res. 13: 392, 1963. 20 Webb, W. R., Wax, S. D., Kusajima, K., Parker, F. B., Kamiyama, T. M., and Murakami, T.: Cinemicroscopy of the Pulmonary Microcirculation in Shock. Presented at the National Conference on Research Animals in Medicine, Washington, D. c., January 28-30, 1972, National Heart and Lung Institute, p. 75.
Katsuyuki Kusajima, M.D., 1. Ayhan Ozdemir, M.D., Watts R. Webb, M.D., Stennis D. Wax, M.D., and Frederick B. Parker, Jr., M.D., Syracuse, N. Y.
HemorrhagiC hypotension to forty millimeters of mercury for two hours, followed by reinfusion of shed blood, produces the full pathological picture of shock lung with patchy atelectasis, congestion, and interstitial and intra-alveolar edema and hemorrhage." Our pressure studies show the initial vascular response to be constriction of the small pulmonary veins (SPV). Subsequently, during hypovolemia and particularly after reinfusion, an additional gradient develops across the alveolar capillary bed due to alveolar and interstitial edema and aggregation of intravascular blood cells.' Serotonin is known to induce pulmonary From the Department of Surgery, State University of New York, Upstate Medical Center, Syracuse, N. Y. 13210. Supported by a Grant from the Upstate Heart Association. Received for publication March I, 1974.
908
hypertension, interstitial and intra-alveolar edema, and whole blood cell aggregation in the pulmonary bed.' 1" The similarity of these findings to those during hemorrhagic shock" 1S suggests the possible participation of serotonin, but its relationship in the shock lung syndrome has not been previously investigated. By studying the pulmonary hemodynamics and microcirculation with serotonin administration and with antiserotonin during hemorrhagic shock, we have evaluated the relationship between shock lung syndrome and serotonin-induced pulmonary injury. Methods
Twenty-five adult mongrel dogs, weighing 15 to 25 kilograms, were anesthetized
Volume 67
Hemorrhagic shock
Number 6 June, 1974
with intravenously administered pentobarbital and ventilated with room air. A Harvard mechanical respirator, adjusted to maintain arterial blood gases within normal physiological ranges, was used.. A positive end-expiratory pressure of 5 em. of water was maintained. The animals were given 3 mg. per kilogram of heparin prior to the experiment. A left femoral arterial (FA) cannula was inserted for monitoring pressure and a left femoral venous cannula was inserted for infusions. Another cannula was inserted into the right FA and attached to an airless plastic reservoir. The lung was exposed through the left fifth intercostal space, and a No. 8 Fr. catheter was inserted via the left jugular vein into the left pulmonary artery (PA) and advanced to the pulmonary artery wedge (PAW) position. Synthetic catheters with an outside diameter of 1.4 mm. were inserted into the main PA and the pulmonary vein wedge (PW) via the left atrium (LA) through a needle puncture. No. 10 Fr. catheters were inserted into the LA via the appendage. For measurement of pressure in the SPY, a polyvinyl catheter with an outside diameter of 0.9 mm. was passed through a large silicone rubber sheath into the LA and guided into the left lower lobe vein. The catheter was advanced into the PVW position and then withdrawn slightly; again, pressure changes were used to accomplish proper positioning. The experimental animals were divided into three groups (Fig.
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HEMORRHAGIC SHOCK
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Fig. 1. The experimental animals were divided into three groups.
tonin, dissolved in 100 c.c. of lactated Ringer's solution, was infused continuously through the right atrium for 2 hours at a rate of 75 meg. per kilogram per minute .. Pressures were recorded before infusion, three times (20, 60, and 120 minutes) during infusion, and three times (l0, 20, and 30 minutes) after serotonin infusion. Group III (8 dogs). The dogs were bled and reinfused as in Group I. These dogs were given 75 meg. per kilogram of antiserotonin (methysergide) after bleeding (at the onset of shock). The same pressure studies were performed as in Group I. Pulmonary microcirculation was studied with cinemicroscopy at 150 to 450 power with the method developed in our laboratory.
1).
Results
Group I (12 dogs). After baseline control values were obtained, the dogs were bled to shock levels within 15 minutes with the reservoir adjusted to maintain mean arterial pressure at 40 mm. Hg. After 2 hours the blood was reinfused over a 20 minute period. Pressures were recorded before shock, three times during shock (20, 60, and 120 minutes), and twice in the recovery period (20 and 60 minutes) after reinfusion. Group II (5 dogs). A venous cannula was inserted and advanced to the right atrium. Via this cannula, 100 mg. of sero-
Group I. It was necessary to withdraw approximately 50 c.c. of blood per kilogram to lower and maintain the arterial pressure at 40 mm. Hg. All pressures fell initially with hemorrhage, and all gradually rose during late shock, except that in the LA. The control gradient of 0.76 mm. Hg between the Spy and LA rose in midshock to 2.97 mm. Hg (p < 0.01). The gradient remained at this level until after reinfusion, when it fell slightly. Within 60 minutes after reinfusion of the shed blood, pressures in the FA,
The Journal of
9 10
Kusajima et al.
Tuorccic and Cardiovascular Surgery
I
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Fig. 2. Mean pressure changes in pulmonary circulation during continuous infusion of serotonin (Group II). PAW, Pulmonary artery wedge. SPV, Small pulmonary vein. LA, Left atrium. PA, Pulmonary artery. PVW, Pulmonary vein wedge. FA, Femoral artery.
PVW, SPY, and LA returned to near base-line control levels, whereas the PA and PAW pressures increased significantly above base-line levels. Thus the pressure gradients between the PAW and SPY increased significantly from 0.3 to 2.4 mm. Hg after reinfusion (p < 0.01). A gradient also developed between the PA and PVW during late shock; this gradient increased further in the recovery period (3.91 mm. Hg compared to 0.93 mm. Hg control) (p < 0.01). Group II. The systemic pressure increased immediately after the serotonin infusion was started, but within 5 minutes it decreased to 65 per cent of the base-line control value. However, the PA and PVW pressures increased significantly 60 per cent
above the base-line control. The PAWand SPY pressures increased slightly above the base-line control levels, whereas the LA pressure decreased. There was an increase in the pressure gradient between the SPY and the LA from 1.80 mm. Hg base line to 8.63 mm. Hg 120 minutes after the serotonin infusion (p < 0.02), suggesting Spy constriction. During the continuous serotonin infusion, the pressure gradients between the PA and PVW and between the PAW and the Spy showed slight but insignificant increases. When the infusion of serotonin was discontinued after 120 minutes, all pressures and pressure gradients quickly returned almost to control values and remained at those levels (Fig. 2).
Volume 67
Hemorrhagic shock
Number 6
9I1
June, 1974
26
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Fig. 3. Mean pressure changes during hemorrhagic shock with methy sergide injected just before hemorrhage (Group III). For abbreviations, see Fig. 2.
Group III. Approximately 60 c.c. of blood per kilogram was withdrawn from each dog in this group to lower and maintain the arterial pressure at 40 mm. Hg. The methysergide infusion was started with the onset of shock. All pressures fell initially with hemorrhage (Fig. 3). During late hypovolemia, the LA pressure decreased slightly, the SPY pressure remained low, and the PAW pressure rose very minimally but not to base-line values. This is in contrast to shock alone, in which the PAW and Spy rose to higher than the control values. However, a slight but insignificant gradient (from 0.4 mm. Hg for control animals to 2.3 mm. Hg for those
Fig. 4. The characteristic histologic alteration of the lung. Top, After serotonin infusion: interstitial and intra-alveolar edema, cellular infiltration, and thrombus. Bottom, Hemorrhagic shock lung: interstitial and intra-alveolar edema and cellular filtration. (Original magnifications: top x215; bottom xI60.)
in late shock) did develop between the PAW and the SPY. The pressure gradient between the Spy and the LA changed only 0.71 mm. Hg (from 1.76 mm. Hg in early shock to 2.47 mm. Hg in late shock). During hypovolemia no significant change in pressure gradient developed between the PA and the PYW, though the gradient between the PAW and Spy increased to 2.5 mm. Hg from 0.4 mm. Hg in the control period (p < 0.005). After reinfusion of shed blood, a gradient of 3.2 mm. Hg developed between the PA and the PYW: this gradient had been only 2.1 mm. Hg in the control period. Histologic and cine.,icroscopic findings The characteristic 'histologic findings were seen in the hemorrhagic shock lung, i.e., interstitial and intra-alveolar edema, intra-
The Journal of
9 12
Kusajima et al.
vascular congestion, and cellular infiltration. The addition of methysergide did not change the histologic picture seen in the hemorrhagic shock lung. Serotonin infusion in the normovolemic animal caused interstitial and intra-alveolar edema, blood cell aggregations, and thrombi (Fig. 4). Pulmonary microcirculation was greatly reduced in hemorrhagic shock, but the circulation was slightly improved in the methysergide-treated animals. 20 Discussion
For many years it has been noted that clotted blood releases humoral substances which are capable of producing severe cardiovascular depression. The active humoral substance, serotonin (5-hydroxytryptamine), was isolated by Rapport and Colleagues':' in 1948. More recently many investigators have shown that serotonin is present mainly in the intestinal argentaffin cells, the platelets, and the brain. The circulatory effects of serotonin are constriction of coronary vessels by excitation of the coronary chemoreflex; activation of a pressor reflex to the atrium and great vessels in the thorax, through stimulation of the carotid sinus (baroreceptor and chemoreceptor) and vagus fibers; and a direct constrictive action on the great veins, trachea, and bronchi. More recently, the relation between serotonin, pulmonary vascular hypertension, and pulmonary embolism was studied.': 7 The pulmonary arterioles appeared to be more sensitive to the constrictor action of serotonin" than are the systemic vessels. The present pressure study shows that continuous infusion of serotonin (75 meg. per kilogram per minute) causes a decrease in systemic blood pressure and LA pressure. However, there is a significant increase in the PA and PVW pressures. The PAW and Spy pressures remain almost identical to the preinfusion levels. There is a significant increase in the pressure gradient between the Spy and the LA, but the pressure gradients between the PAW and the Spy show only insignificant physiological
Thoracic and Cardiovascular Surgery
changes. These data suggest that serotonin causes constriction of both the arterioles and the SPY but little or no blockage of the capillary bed, since no gradient develops across the capillary bed. Little work has been done previously to determine the role of serotonin in hemorrhagic shock. Swank 1 7 has shown that the pressure required to pass a sample of fresh blood through a filter with pores 20 by 20 po is 35 torr (1 torr = 1 mm. Hg). After hemorrhagic or traumatic shock, the filtration pressure progressively increases, reaching 200 torr after a loss of about 65 per cent of blood volume. When wool glass was interposed in the system in front of the micropore filter, the filtration pressure was only slightly elevated above prehemorrhagic values. Microscopic examination of the glass wool, after the wool had been gently washed free of red cells, showed platelets and leukocytes attached. From this evidence, it may be assumed that platelets and leukocytes aggregate intravascularly during hemorrhagic shock." Many investigators have presented evidence for altered hemostasis in hemorrhagic shock in experimental animals. A state of hypercoagulability may be present initially, followed by hypocoagulability. Following hemorrhage or traumatic shock, a state of hypercoagulability develops due to an increase in release of platelets by the spleen. Platelets and leukocytes become adhesive and/or aggregate." Serotonin inhibitor (methysergide) prevented serotonin-induced pulmonary hypertension'> in experimental animals. From each animal treated with methysergide, approximately 60 c.c. per kilogram of blood was withdrawn to lower and maintain the arterial pressure at 40 mm. Hg; however, loss of only 50 c.c. per kilogram of blood was necessary in Group I. Thus the Group III animals were subjected to a greater degree of hypovolemia than were those in the simple hemorrhage group, and yet they exhibited less hemodynamic and pulmonary deleterious effects. Of particular import was the absence of SPY constriction.
Volume 67
Hemorrhagic shock
Number 6 June, 1974
Our previous studies show that the characteristic hemodynamic changes of the pulmonary microcirculation in hemorrhagic shock include development of a gradient between the Spy and the LA during hypovolemia. During late shock and particularly after reinfusion, gradients develop between the PA and PYW and between the PAW and SPY. This suggests that the initial lesion is SPY constriction. Subsequently, during late hypovolemia and particularly after reinfusion, an additional gradient develops across the alveolar capillary bed." Many investigations concerning pathogenesis of the shock lung have been conducted." :J, fL ' " Sugg and co-workers> have succeeded in preventing the pulmonary changes secondary to hypovolemia by removal and reimplantation of the lung. Their results suggest that acute congestive atelectasis is at least in part neurally mediated. Moss and associates!" demonstrated that cerebral hypoxia (Po" 35 ± 5 mm. Hg for 2 hours) caused the full picture of pulmonary congestive atelectasis, including atelectasis of hyaline membranes. This phenomenon also could be prevented by pulmonary denervation (reimplantation), again confirming the importance of neural factors in pulmonary circulation." Levine and associates" suggested that the increased pulmonary vascular resistance in hypovolemic shock resulted from intrapulmonary effects of decreased pulmonary blood flow and from the effects of humoral factors on the lung. The SPY constriction characteristic of severe hypovolemia was prevented by methysergide: This fact implies that serotonin may play a significant role in the pulmonary changes. Serotonin is released by hypoxic intestine, hypoxic brain, or by unstable platelets, especially those that aggregate in the lung and are destroyed; ultimately after reinfusion, a blockage of the pulmonary capillary bed develops comparable to that of untreated animals. Thus undoubtedly other factors are of importance as well.
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REFERENCES Allardyce, 8., Hamit, H. F., Matsumoto, T., and Moseley, R. V.: Pulmonary Vascular Changes in Hypovolemic Shock: Radiography of the Pulmonary Microcirculation and Possible Role of Platelet Embolism in Increasing Vascular Resistance, J. Trauma 9: 403, 1969. 2 Attar, S., Kirby, W. H., Jr., and Masaitis, C.: Coagulation Changes in Clinical Shock: I. Effect of Hemorrhagic Shock on Clotting Time in Humans, Ann. Surg, 164: 34, 1969. 3 Cook, W. A., and Webb, W. R.: Pulmonary Changes in Hemorrhagic Shock, Surgery 64: 85, 1968.
4 Daicoff, G. R., Chaves, F. R., Anton, A. H., and Swenson, E. W.: Serotonin-Induced Pulmonary Venous Hypertension in Pulmonary Embolism, J. THORAe. CARDIOVASe. SURG. 56: 810, 1968.
5 Gilbert, R. P., Hinshaw, L. B., Kuida, H., and Visscher, M. B.: Effect of Histamine, 5Hydroxytryptamine and Epinephrine on Pulmonary Hemodynamics With Particular References to arterial and Venous Segment Resistances, Am. J. Physiol. 194: 165, 1958. 6 Hardaway, R. M.: The Role of Intravascular Clotting in the Etiology of Shock, Ann. Surg. 155: 325, 1962. 7 Jacobsen, D. C., Soden, K. J., Allen, P. D., and Daicoff, G. R.: Humoral Blockade on Lethal Pulmonary Embolism in the Awake Dog, Surg. Forum 22: 209, 1971. 8 Kusajima, K., Wax, S. D., Webb, W. R., and Parker, F. B.: The Hemodynamic Effects of Atropine, Lasix, and Methylprednisolone on Pulmonary Microcirculation in Shock, Surg. Gynec. Obstet. In press. 9 Levine, F. H., Hollingsworth, 1. E., Coskle, D. M., and Reis, R. L.: Mechanism of the Pulmonary Vascular Response to Hypovolemic Shock, Surg. Forum 22: 34, 1971. 10 Moss, G., Staunton, c., and Stein, A. A.: Cerebral Hypoxia as the Primary Event in the Pathogenesis of the "Shock Lung Syndrome," Surg. Forum 22: 211, 1971. II Staunton, C., Stein, A. A., and Moss, G.: Cerebral Etiology of the Respiratory Distress Syndrome: Universal Response With Prevention by Unilateral Pulmonary Denervation, Surg. Forum 24: 229, 1973. 12 Murakami, T., Wax, S. D., and Webb, W. R.: Pulmonary Microcirculation in Hemorrhagic Shock. Surg. Forum 21: 25, 1970. 13 Parker, 8. M., Steiger, B. W., and Friedenberg, M. J.: Serotonin-Induced Pulmonary Venous Spasm Demonstrated by Selective Pulmonary Phlebography, Am. Heart Jr. 69: 521, 1965. . 14 Rapport, M. M., Green, A. A., and Page,
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I. H.: Serum Vasconstrictor (Serotonin); Isolation and Characterization, J. BioI. Chern. 176: 1243, 1948. Smith, D. J., and Coxe, J. W.: Reaction of Isolated Pulmonary Blood Vessels to Anoxia, Epinephrine, Acethylcholine and Histamine, Am. J. PhysioI. 167: 732, 1951. Sugg, W. L., Webb, W. R., Nakae, S., Theodorides, T., Gupta, D. N., and Cook, W. A.: Congestive Atelectasis: An Experimental Study, Ann. Surg. 168: 234, 1968. Swank, R. L., and Edwards, M. J.: Microvascular Occlusion by Platelet Emboli After Transfusion and Shock, Microvasc. Res. 1: 15, 1968. Swank, R. L., Hissen, W., and Fellman, J. H.:
The Journol of Thorocic ond Cordiovosculor Surgery
5-Hydroxytryptamine (Serotonin) in Acute Hypotensive Shock, Am. J. PhysioI. 207: 215, 1964. 19 Swank, R. L., Fellman, J. H., and Hissen, W. W.: Aggregation of Blood Cells by 5-Hydroxytryptamine (Serotonin), Circ. Res. 13: 392, 1963. 20 Webb, W. R., Wax, S. D., Kusajima, K., Parker, F. B., Kamiyama, T. M., and Murakami, T.: Cinemicroscopy of the Pulmonary Microcirculation in Shock. Presented at the National Conference on Research Animals in Medicine, Washington, D. c., January 28-30, 1972, National Heart and Lung Institute, p. 75.