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Splanchnic Circulation in Shock
Vo!' 52, No.2, Part 2 Printea in U.S.A.
GASTROENTEROLOGY
Copyright © 1967 by The Williams & Wilkins Co.
SPLANCHNIC CIRCULATION IN SHOCK FOUAD
A.
BASHOUR, M.D., AND ROBERT MCCLELLAND, M.D.
Departments of Medicine and Surgery, University of Texas Southwestern Medical School, Dallas, Texas
Shock refers to a complex clinical picture manifested by signs and symptoms which result from an inadequate blood supply to the various organs of the body. A number of factors contribute to this clinical picture, but the main contenders for the site of the "central lesion" of shock are the splanchnic organs (intestines and liver) and the heart. It is, therefore, not surprising that so many investigators have stressed the vascular and anatomical changes in the splanchnic bed. In the normal state, the splanchnic bed plays an important role in the over-all circulatory adjustment in both human beings and animals. This bed, in general, receives 20% of the cardiac output and constitutes 25% of the total blood volume. In this regard, the liver and the portal vein function as blood reservoirs. The liver is endowed with specialized anatomical structures (sphincters) that control the outflow of blood from this reservoir.! Clinically and experimentally, the small intestines have been implicated in endotoxin shock. Penner and Bernheim2 noted that congestion, edema, and hemorrhage appeared in the submucosa, with hemorrhagic necrosis as a later complication of endotoxin shock in man. Similarly, extensive hemorrhagic congestion and edema of the intestines were common findings in dogs but were not seen in the monkey. In the monkey, endotoxin resulted in a gradual and progressive fall in the systemic blood pressure. 3 The close, phylogenetic proximThis work is supported by Grants HE-07739 and HE-09318 from the United States Public Health Service. The authors acknowledge the technical assistance of Mr. Gary Coffman, Constantine Kousari des, Willie McFarland, Paul Parker, and W. F. Howard. 461
ity of monkey to man would indicate that all the hemodynamic findings in dogs are probably not applicable to man. The behavior of the splanchnic vascular bed in dogs with endotoxin shock is different from that in hemorrhagic shock. We would like to review the observed hemodynamic and some of the metabolic changes that follow a sublethal dose of Escherichia coli endotoxin (2 mg per kg) and to contrast some of these changes with those seen in hemorrhagic shock. Our observations were made in fasting, adult mongrel dogs (12 to 20 kg) that were anesthetized with pentobarbital and paralyzed with succinylcholine. Their respira~ tory rate and tidal volume were controlled throughout the experiment by an electrically driven respirator. All of these studies were performed while the animals were breathing room air. Hepatic blood flow was estimated by the clearance and extraction method of Bradley, with either p31-ros e Bengal or Bromsulphalein dye as the extractable substance. A simultaneous measurement of the cardiac output was made by the dye dilution method using cardiogreen dye. Splanchnic blood volume was determined from the mean circulation time and the estimated hepatic blood flow immediately before and 30 to 40 min after the intravenous injection of endotoxin. All pressure measurements were simultaneously recorded on heat-sensitive paper (PolyvisoSanborn). The hepatic vein and wedge pressures were obtained by introducing two cardiac catheters into the external jugular veins, and under fluoroscopic guidance each catheter was placed in a separate lobe of the liver. The hepatic wedge, or sinusoidal, pressure approximated the portal vein pressure, and the changes that are seen in the former paralleled those of the portal vein. All of
462
B A SHOUR AND McCLELLAND
these circulatory parameters were determined b efore and at regular intervals of 10 min (labeled as period) after endotoxin administration, whereas the metabolic measurements were recorded once before and once after (30 to 60 min) endotoxin was given. Hemodynamic Changes in the Splanchnic Circulation
Changes in the hepatic wedge, vein, and systemic arterial pressures. After the injection of endotoxin and 5 to 10 sec before the drop in the systemic arterial pressure, a rise in the hepatic wedge pressure occurred (fig. 1). The rise in the hepatic wedge pressure reached a peak in the first few minutes after endotoxin was given and returned gradually toward the baseline. At the 60th min, the hepatic wedge pressure averaged 118% of the control in a group of 9 dogs. The observed changes in the hepatic wedge pressure paralleled those seen in the mean portal vein pressure (fig. 2). The hepatic venous pressure, on the other hand, decreased in the immediate period following injection of endotoxin, reaching 88% of the control value 5 min later. In most instances, the hepatic vein pressure rose slightly above the control level at the 20th min, and it continued at this level for the rest of the period of observation.
Vol. 52, No.2, Part 2
The maximal drop in the systemic arterial pressure occurred 2 to 3 min after endotoxin and averaged 45% of the control pressure. A gradual return of the systemic pressure became noticeable by the 5th to the 8th min and reached 70% of the control level by the end of 60 min of observation. Figure 3 represents a composite picture of the pressure changes that follow the administration of a sublethal dose of endotoxin in dogs. Hemorrhagic shock, on the other hand, decreased the systemic arterial, hepatic venous, and wedge pressures. 5 Changes in the total splanchnic (or the estimated hepatic) blood flow. In hemorrhagic shock, a marked reduction in the total splanchnic blood flow was reported by a number of observers,5. 6 but few observations have been made concerning the changes in the total splanchnic flow during endotoxin shock. The estimated hepatic blood flow was observed to increase after a pyrogenic febrile reaction,4 2 to 3 hI' after the administration of sub febrile doses of bacterial pyrogens, at a time when the cardiac output showed no significant change. 7 During endotoxin shock in the experimental animal, we found that both the cardiac output and the estimated hepatic blood flow (EHBF) dropped. The EHBF
Femoral Artery
Hepatic Wedge
Hepatic Vein
FIG. 1. Effect of endotoxin on splanchnic circulation (dog 503 a). Simultaneous recording of the femoral arterial pressure, hepatic wedge, and vein pressures before and after the injection of endotoxin (2 mg per kg).
463
SPLANCHNIC CIRCULATION IN SHOCK
February 1967 min I/g
Hepatic Wedge
mmHg
Portal Vein
mmHg
Femoral Artery
10:~
:~:
F
Superior
Mesenteric
Artery Flow
mllmin --Continued---+-
Effect Of Endotoxin On Superior Mesentery Arterial Blood Flow
Dog #
401
(a)
FIG. 2. Simultaneous recording of the hepatic wedge, portal vein, femoral arterial pressures, and superior mesenteric arterial blood flow before and after the injection of endotoxin (2 mg per kg).
averaged 502 ml per min and corresponded to 19% of the cardiac output during the control period. In the first 10 min after endotoxin was given, the average EHBF dropped to 194 ml per min, which corresponded to 29% of the cardiac output. In the subsequent periods, the EHBF rose to 312, 314, and 288 ml per min during the 2nd, 3rd, and 6th period, respectively, after the administration of endotoxin. The fraction of the cardiac output represented by the EHBF remained above the control level in 5 of the 9 dogs, and it averaged
23% in the 6th period (50 to 60 min) after endotoxin. It would appear that during endotoxin shock the total splanchnic bed received a larger fraction of the reduced total cardiac output, resulting in a further decrease of the blood flow to other parts of the body. The changes that occurred in the hepatic arterial inflow during endotoxin shock were studied in 4 dogs with end to side portacaval shunts with gradual occlusion of the inferior vena cava just above the shunt. The inferior vena cava was gradually
464
BASHOUR AND McCLELLAND
:'....
(n: 9 d.ogs)
, ....
I
......
II
HEPATIC WEDGE
.................... ...
((Sinusoidal) _________ •
,
'-- HEP. VEIN \'SYSTEMIC ARTERIAL
+EnC1oic;l
--~!~~!~~~!~~!~'I'J--~!~-5
15
25
Minu./;es
35
60
FIG. 3. Effect of endotoxin on splanchnic circulation. Changes in the hepatic wedge, hepatic vein, and systemic arterial mean pressures during endotoxin shock.
................... .... ...,
75
1
• He{?a;fic At'ter>iaL (PC Shunt) o Total I-Iepa-l:ic
........... ---------.
50~
+E'1dotO;l
"I~/1<'?',)
31<:0 6 TH ------ PERIODS - - - - - 1ST
2ND
FIG. 4. Effect of endotoxin on splanchnic circulation. Changes in the total hepatic and hepatic arterial blood flows during endotoxin shock.
occluded by slow thrombosis by placing a hollow Tygon tube within it, cephalad to the shunt at the time that the shunt was made. In these dogs, the hepatic arterial inflow was greater than in simple portacaval shunt and averaged 15 to 18% of the cardiac output. s The hepatic arterial blood flow was estimated by the extraction and clearance method of Bradley. In figure 4, we represented graphically the mean changes of the hepatic arterial inflow in portacaval shunt dogs and compared it with the total hepatic blood flow in normal dogs following endotoxin. In the first period, the mean hepatic arterial inflow increased slightly to 103%, and the total hepatic blood flow decreased to 39% of the control. In the 2nd, 3rd, and 6th periods, the decrease in the hepatic arterial inflow was 9, 17, and 22%, respectively, and, in the total hepatic blood flow, 38, 37, and 43%.
Vol. 52, No.2, Part 2
Elsewhere in this symposium, Fine discussed the intestinal circulation in shock. 9 Longerbeam et al.1° demonstrated previously that the superior mesenteric arterial (SMA) blood flow decreased promptly and markedly after the injection of endotoxin. The findings illustrated in figure 2 confirmed their observation and pointed to the marked reduction in the SMA blood flow, particularly in the early postendotoxin period. Changes in the peripheral, total splanchnic, and postsinusoidal resistances. The systemic as well as the splanchnic resistances increased after the injection of E. coli endotoxin, as diagrammed in figure 5. Although these resistances behaved in a similar fashion, differences in the magnitude of the change were apparent. The increase in the peripheral resistance, as compared to the control level, was consistently greater than the relative increase that was observed in the total splanchnic resistance. The average increase in a group of 9 dogs in the peripheral resistance was 196, 153, and 147% during the 1st, 3rd, and 6th period, respectively, after endotoxin infusion, as compared to the 128, 147, and 128% for the same periods for the total splanchnic resistance. Similar relationships between these two resistances were noted in hemorrhagic shock. 5 The postsinusoidal resistance, a venous resistance, contributed a little to the overall splanchnic resistance. This resistance, RESISTANCES
r-"------,
<.
0
«~
~ld
J1
41 ~.--.300
J.~~ .!!d ~ \. ~ ;j
~ u}.~
~r:ri'~
CONTROL
1 ST
3 RD
- - - - - - PERIODS - - - - -
FIG. 5. Effect of endotoxin on splanchnic circulation. Changes in the total peripheral, total splanchnic, and postsinusoidal resistances during endotoxin shock.
February 1967
465
SPLANCHNIC CIRCULATION IN SHOCK HW-HV EHBF
where HW (hepatic wedge pressure) and HV (hepatic venous pressure) were measured in millimeters of mercury and EHBF in liters per minute, rose markedly after endotoxin. The increase was most marked in the 1st lO-min period, and it was maintained between 300 and 328% of the control level during the remaining periods, tending to decrease gradually in some instances. The finding of an increased postsinusoidal resistance is due to constriction of the outlet (sphincter) of the liver sinusoids. 1 Splanchnic blood volume. In hemorrhagic shock, the reduction in splanchnic blood volume 6 suggested a restricted portal vascular volume or liver volume, or both, and confirmed the observation made roentgenographically by Friedman et alY of -collapsed hepatic venules and sinusoids. In dogs with endotoxin shock, MacLean ·et aP2 observed a mean increase of 140 g (range, 80 to 350 g) in the weight of the liver and estimated the mean total storage {)f fluid in the entire small intestine in 6 dogs to be 261 ml (range, 70 to 770 ml). Our own observations (table 1) of an increase in both the splanchnic blood volume and the ratio of the splanchnic to the total blood volume suggested hepatosplanchnic blood pooling and confirmed the direct observation made by MacLean et al. In our study, with one exception, (dog 811), endotoxin increased splanchnic blood volume by only 89 to 139 ml. The quantitative difference between these two studies suggested, perhaps, that some extravasation of the blood plasma occurred, which is reflected in a larger increase in the weight of the organ than in the measurement of its intravascular blood volume. It was not possible to determine from the present observation whether the portal venous or the hepatic venous system, or both, contributed to the increased splanchnic blood volume. MacLean et al. observed that the weight of the intestines rose after the weight of the liver and the portal vein pressure had returned to normal, suggesting that, perhaps 30 to 40 min after the administration of endotoxin, the increased
1. Effect of endotoxin on the splanchnic blood volume in dogs
TABLE
Control
SBV/. TBVb
SBV·
30 min
SBV·
--- - -
SBV/. TBVb
Endotoxin c
725 727 809 811 817
Mean
618 140 235 245 420 332
22.2 8.9 16.5 15.5 20.0 16.6
757 278 324 939 520 564
31. 7 16.3 19.3 37.0 24.8 25.8
311 288 386 470 364
18.6 22.4 19.4 27.4 22.0
362 275 428 479 386
19.4 21.6 25.6 29.1 23.9
Normal
1 2 3 4 Mean
I
• Splanchnic blood volume, in milliliters. b Ratio of SBV to total blood volume. c Dose, 2 mg per kg.
splanchnic volume was the result of an increase in the volume of the portal venous system. Comments on the Hemodynamics of Endotoxin Shock
The drop of the total splanchnic blood flow in the 1st period after the administration of endotoxin was the most marked. This finding, coupled with the early drop in the hepatic venous pressure and the rise in the sinusoidal pressure, is the result of pooling of the blood in the hepatosplanchnic bedP The subsequent moderate increase in the splanchnic blood flow in the 2nd and 3rd periods after endotoxin can be explained by the release of the pooled blood from the hepatosplanchnic reservoir; this was associated with the gradual return of the systemic blood pressure toward the control level. In the last period of observation, the 6th period, the systemic blood pressure, the sinusoidal pressure, and the splanchnic blood flow tended to decline. The postsinusoidal resistance increased markedly after endotoxin injection, the result of the immediate and maximal constriction of the vascular apparatus that controls the outflow of blood from the
466
BASHOUR AND McCLELLAND Sys-ternic
vo.,..r.o.l Vein
I-Iepcxi:.ic V~';T')
7>=9
n=5
n=9
Artery
N
S
N
S
N
S
::~ddd L in Tn~/100-m7.
FIG. 6. Splanchnic circulation in endotoxin. Changes in the lactate concentration and the lactate-pyruvate (LIP) ratio in the systemic arterial, portal, and hepatic venous blood. N and S represent average values of these two parameters during control and shock periods, respectively. Blood lactate concentration is reported in milligrams per 100 ml and LIP ratio in units. n represents the number of dogs in each study.
liver sinusoids, and it is responsible for the trapping of the blood in the splanchnic bed. The release of the trapped blood in the 2nd period and thereafter is consistent with the partial release of the constriction of these sphincters. The cardiac output dropped after endotoxin administration; it was probably solely the result of a decreased venous return subsequent to pooling of the blood in the splanchnic vascular bedP The fall in the blood pressure followed shortly the rise in the hepatic wedge pressure; it is believed to be primarily the result of a decreased cardiac output, not arteriolar dilation. This was demonstrated by Weil et al. 13 in dogs with total body perfusion; they observed no fall in the blood pressure after endotoxin. Had it been that arteriolar dilation followed endotoxin at the constant cardiac output, systemic arterial pressure would have fallen. The observed rise in calculated total peripheral resistance (or the state of the vascular resistance) could not be interpreted in the presence of a low cardiac output. In the normal state, the hepatic arterial inflow contributes 30 to 40% of the total hepatic blood flow, and the portal venous inflow, the rest, 60 to 70%. If, in dogs with portacaval shunt and common hepatic
Vol. 52, No.2, Part 2
vein, the hepatic arterial inflow reacted to endotoxin in the same manner as in the normal dog, the 20% reduction in the hepatic arterial inflow in the face of a 40% reduction in the total hepatic blood flow would suggest that the portal venous inflow was comparatively and more markedly reduced by endotoxin. This is corroborated by the observation that the mesenteric arterial flow is markedly reduced in endotoxin shock, and it could conceivably represent the initiating factor in the irreversibility of shock. H , 15 From the observed hemodynamic changes, it was felt that, of the two splanchnic organs (the liver or the intestines), the "key organ" in endotoxin shock is the intestines. Further evidences supporting this contention were gathered from the behavior of the lactate-pyruvate metabolism in these two organs. In endotoxin shock, the concentration of lactate increased in the systemic arterial, portal, and hepatic venous blood (fig. 6). During the control period, the concentration of lactate varied slightly in these three sites; it averaged 23.2, 28.4, and 22.9 mg per 100 ml, respectively. After endotoxin, the mean lactate concentration in the hepatic venous blood was lower than in the other two sites, indicating that lactate is still being utilized by the liver (fig. 6). The lactate-pyruvate (LIP) ratio at these three sites behaved in a similar fashion. During the control period, the LIP ratio averaged 21.1, 27.6, and 19.5 in the systemic arterial, portal, and hepatic venous blood, respectively. During endotoxin shock, the ratio at these sites increased to 28, 38, and 24.4, respectively (fig. 6). An increase in the LIP ratio is an indicator of the presence and severity of hypoxia; therefore, the finding of a relatively lower LIP ratio in the hepatic venous blood as compared to that in the systemic arterial and portal venous blood would indicate that the liver most probably is less hypoxic than the intestines. The observations are consistent with those of Ballinger et aJ.16 in dogs with hemorrhagic shock. They found that the liver continued to remove lactate from the portal venous and the arterial blood until very low systemic ar-
February 1967
SPLANCHNIC CIRCULATION IN SHOCK
terial pressure was attained. The point of departure of the liver from aerobic to anaerobic metabolism coincided with the drop in the splanchnic oxygen consumption. The mechanism responsible for endotoxin shock is complex. The hemodynamic change in the early phase of endotoxin shock is on a humoral basis. The similarity of these changes to those seen in anaphylaxis suggested the possibility that histamine and 5-hydroxytryptamine may play a role in the genesis of these changes,17 Epinephrine and norepinephrine have also been shown to play a role in the endotoxin reaction. An increased level of circulating catecholamines was demonstrated by Von Euler 18 and confirmed by Rosenberg and his group.19 REFERENCES 1. Knisely, M., F. Harding, and H. Debacker, 1957. Hepatic sphincters. Science 125: 1023-1025. 2. Penner, A., and A. Bernheim. 1939. Acute
postoperative enterocolitis study of pathologic nature of shock. Arch. Path. (Chicago) 27: 966-972. 3. Kuida, H., R Gilbert, L. Hinshaw, J. Brunson, and M. Visscher. 1961. Species differences in effect of gram-negative endotoxin on circulation. Amer. J. Physio!. 2QO: 1197-1200. 4. Bradley S. and J. Conan. 1947. Estimated
hepatic blood flow and Bromsulphalein extraction in normal man during the pyrogenic reactions. J. Clin. Invest. 26: 11751183.
5. Bashour, F. A., A. Nafrawi, and R McClelland. 1965. Splanchnic hemodynamics and carbohydrate metabolism in hemorrhagic shock, p. 265. In Shock and hypotension. Grune and Stratton, Inc., New York. 6. Reynell, P., P. Marks, C. Chidsey, and S. Bradley. 1955. Changes in splanchnic blood volume and splanchnic blood flow in dogs after hemorrhage. Clin. Sci. 14: 407-414.
467
7. Hamrick, L., and J. Myers. 1955. The effect of
8.
9. 10.
11.
12.
subfebrile doses of bacterial pyrogens on splanchnic metabolism and cardiac output. J. Clin. Med. (Shanghai) 35: 568-574. Bashour, F. A., and R McClelland. 1966. Portal venous-hepatic arterial reflex mechanism. Clin. Res. 14: 38-46. Fine, J. 1966. The intestinal circulation in shock. Gastroenterology 52: 454-458. Longerbeam, J., R. Lillehei, W. Scott, and J. Rosenberg. 1962. Visceral factors in shock. J. A. M. A. 181: 878-880. Friedman, E., H. Frank, and J. Fine. 1951. Portal circulation in experimental hemorrhagic shock; in vivo roentgen-ray studies. Ann. Surg. 134: 10-17. MacLean, L., M. Weil, W. Spink, and M. Visscher. 1956. Canine intestinal and liver weight changes induced by E. coli endotoxins. Proc. Soc. Exp. BioI. Med. 92: 602-
604. 13. Weil, M., L. MacLean, M. Visscher, and W. Spink. 1956. Studies on the circulatory
changes in the dog produced by endotoxin from gram-negative micro-organisms. J. Clin. Invest. 35: 1191-1200. 14. Lillehei, R 1957. The intestinal factor in irreversible hemorrhagic shock. Surgery 42: 1043-1050. 15. Lillehei, R,
and L. MacLean. 1958. The intestinal factor in irreversible endotoxin shock. Ann. Surg. 148: 513-519. 16. Ballinger, W., H. Vollenweider, and E. Montgomery. 1961. The response of the canine liver to anaerobic metabolism induced by hemorrhagic shock. Surg. Gynec. Obstet. 112: 19-27. 17. Hinshaw, L., J. Vick, C. Carlson, and Y. Fan. 1960. Role of histamine in endotoxin shock. Proc. Soc. Exp. BioI Med. 104: 379-381. 18. Von Euler, U. 1927. Uber Hyperadrenalinamie bei Fieberzustanden. Arch. Ges. Physio!. 217 : 699-717. 19. Rosenberg
J., R Lillehei, J. Longerbeam, and B. Zimmerman. 1961. Studies on hemorrhagic and endotoxin shock in relation to vasomotor changes and endogenous circulating epinephrine, norepinephrine and serotonin. Ann. Surg.154: 611-620.
GASTROENTEROLOGY
Copyright © 1967 by The Williams & Wilkins Co.
SPLANCHNIC CIRCULATION IN SHOCK FOUAD
A.
BASHOUR, M.D., AND ROBERT MCCLELLAND, M.D.
Departments of Medicine and Surgery, University of Texas Southwestern Medical School, Dallas, Texas
Shock refers to a complex clinical picture manifested by signs and symptoms which result from an inadequate blood supply to the various organs of the body. A number of factors contribute to this clinical picture, but the main contenders for the site of the "central lesion" of shock are the splanchnic organs (intestines and liver) and the heart. It is, therefore, not surprising that so many investigators have stressed the vascular and anatomical changes in the splanchnic bed. In the normal state, the splanchnic bed plays an important role in the over-all circulatory adjustment in both human beings and animals. This bed, in general, receives 20% of the cardiac output and constitutes 25% of the total blood volume. In this regard, the liver and the portal vein function as blood reservoirs. The liver is endowed with specialized anatomical structures (sphincters) that control the outflow of blood from this reservoir.! Clinically and experimentally, the small intestines have been implicated in endotoxin shock. Penner and Bernheim2 noted that congestion, edema, and hemorrhage appeared in the submucosa, with hemorrhagic necrosis as a later complication of endotoxin shock in man. Similarly, extensive hemorrhagic congestion and edema of the intestines were common findings in dogs but were not seen in the monkey. In the monkey, endotoxin resulted in a gradual and progressive fall in the systemic blood pressure. 3 The close, phylogenetic proximThis work is supported by Grants HE-07739 and HE-09318 from the United States Public Health Service. The authors acknowledge the technical assistance of Mr. Gary Coffman, Constantine Kousari des, Willie McFarland, Paul Parker, and W. F. Howard. 461
ity of monkey to man would indicate that all the hemodynamic findings in dogs are probably not applicable to man. The behavior of the splanchnic vascular bed in dogs with endotoxin shock is different from that in hemorrhagic shock. We would like to review the observed hemodynamic and some of the metabolic changes that follow a sublethal dose of Escherichia coli endotoxin (2 mg per kg) and to contrast some of these changes with those seen in hemorrhagic shock. Our observations were made in fasting, adult mongrel dogs (12 to 20 kg) that were anesthetized with pentobarbital and paralyzed with succinylcholine. Their respira~ tory rate and tidal volume were controlled throughout the experiment by an electrically driven respirator. All of these studies were performed while the animals were breathing room air. Hepatic blood flow was estimated by the clearance and extraction method of Bradley, with either p31-ros e Bengal or Bromsulphalein dye as the extractable substance. A simultaneous measurement of the cardiac output was made by the dye dilution method using cardiogreen dye. Splanchnic blood volume was determined from the mean circulation time and the estimated hepatic blood flow immediately before and 30 to 40 min after the intravenous injection of endotoxin. All pressure measurements were simultaneously recorded on heat-sensitive paper (PolyvisoSanborn). The hepatic vein and wedge pressures were obtained by introducing two cardiac catheters into the external jugular veins, and under fluoroscopic guidance each catheter was placed in a separate lobe of the liver. The hepatic wedge, or sinusoidal, pressure approximated the portal vein pressure, and the changes that are seen in the former paralleled those of the portal vein. All of
462
B A SHOUR AND McCLELLAND
these circulatory parameters were determined b efore and at regular intervals of 10 min (labeled as period) after endotoxin administration, whereas the metabolic measurements were recorded once before and once after (30 to 60 min) endotoxin was given. Hemodynamic Changes in the Splanchnic Circulation
Changes in the hepatic wedge, vein, and systemic arterial pressures. After the injection of endotoxin and 5 to 10 sec before the drop in the systemic arterial pressure, a rise in the hepatic wedge pressure occurred (fig. 1). The rise in the hepatic wedge pressure reached a peak in the first few minutes after endotoxin was given and returned gradually toward the baseline. At the 60th min, the hepatic wedge pressure averaged 118% of the control in a group of 9 dogs. The observed changes in the hepatic wedge pressure paralleled those seen in the mean portal vein pressure (fig. 2). The hepatic venous pressure, on the other hand, decreased in the immediate period following injection of endotoxin, reaching 88% of the control value 5 min later. In most instances, the hepatic vein pressure rose slightly above the control level at the 20th min, and it continued at this level for the rest of the period of observation.
Vol. 52, No.2, Part 2
The maximal drop in the systemic arterial pressure occurred 2 to 3 min after endotoxin and averaged 45% of the control pressure. A gradual return of the systemic pressure became noticeable by the 5th to the 8th min and reached 70% of the control level by the end of 60 min of observation. Figure 3 represents a composite picture of the pressure changes that follow the administration of a sublethal dose of endotoxin in dogs. Hemorrhagic shock, on the other hand, decreased the systemic arterial, hepatic venous, and wedge pressures. 5 Changes in the total splanchnic (or the estimated hepatic) blood flow. In hemorrhagic shock, a marked reduction in the total splanchnic blood flow was reported by a number of observers,5. 6 but few observations have been made concerning the changes in the total splanchnic flow during endotoxin shock. The estimated hepatic blood flow was observed to increase after a pyrogenic febrile reaction,4 2 to 3 hI' after the administration of sub febrile doses of bacterial pyrogens, at a time when the cardiac output showed no significant change. 7 During endotoxin shock in the experimental animal, we found that both the cardiac output and the estimated hepatic blood flow (EHBF) dropped. The EHBF
Femoral Artery
Hepatic Wedge
Hepatic Vein
FIG. 1. Effect of endotoxin on splanchnic circulation (dog 503 a). Simultaneous recording of the femoral arterial pressure, hepatic wedge, and vein pressures before and after the injection of endotoxin (2 mg per kg).
463
SPLANCHNIC CIRCULATION IN SHOCK
February 1967 min I/g
Hepatic Wedge
mmHg
Portal Vein
mmHg
Femoral Artery
10:~
:~:
F
Superior
Mesenteric
Artery Flow
mllmin --Continued---+-
Effect Of Endotoxin On Superior Mesentery Arterial Blood Flow
Dog #
401
(a)
FIG. 2. Simultaneous recording of the hepatic wedge, portal vein, femoral arterial pressures, and superior mesenteric arterial blood flow before and after the injection of endotoxin (2 mg per kg).
averaged 502 ml per min and corresponded to 19% of the cardiac output during the control period. In the first 10 min after endotoxin was given, the average EHBF dropped to 194 ml per min, which corresponded to 29% of the cardiac output. In the subsequent periods, the EHBF rose to 312, 314, and 288 ml per min during the 2nd, 3rd, and 6th period, respectively, after the administration of endotoxin. The fraction of the cardiac output represented by the EHBF remained above the control level in 5 of the 9 dogs, and it averaged
23% in the 6th period (50 to 60 min) after endotoxin. It would appear that during endotoxin shock the total splanchnic bed received a larger fraction of the reduced total cardiac output, resulting in a further decrease of the blood flow to other parts of the body. The changes that occurred in the hepatic arterial inflow during endotoxin shock were studied in 4 dogs with end to side portacaval shunts with gradual occlusion of the inferior vena cava just above the shunt. The inferior vena cava was gradually
464
BASHOUR AND McCLELLAND
:'....
(n: 9 d.ogs)
, ....
I
......
II
HEPATIC WEDGE
.................... ...
((Sinusoidal) _________ •
,
'-- HEP. VEIN \'SYSTEMIC ARTERIAL
+EnC1oic;l
--~!~~!~~~!~~!~'I'J--~!~-5
15
25
Minu./;es
35
60
FIG. 3. Effect of endotoxin on splanchnic circulation. Changes in the hepatic wedge, hepatic vein, and systemic arterial mean pressures during endotoxin shock.
................... .... ...,
75
1
• He{?a;fic At'ter>iaL (PC Shunt) o Total I-Iepa-l:ic
........... ---------.
50~
+E'1dotO;l
"I~/1<'?',)
31<:0 6 TH ------ PERIODS - - - - - 1ST
2ND
FIG. 4. Effect of endotoxin on splanchnic circulation. Changes in the total hepatic and hepatic arterial blood flows during endotoxin shock.
occluded by slow thrombosis by placing a hollow Tygon tube within it, cephalad to the shunt at the time that the shunt was made. In these dogs, the hepatic arterial inflow was greater than in simple portacaval shunt and averaged 15 to 18% of the cardiac output. s The hepatic arterial blood flow was estimated by the extraction and clearance method of Bradley. In figure 4, we represented graphically the mean changes of the hepatic arterial inflow in portacaval shunt dogs and compared it with the total hepatic blood flow in normal dogs following endotoxin. In the first period, the mean hepatic arterial inflow increased slightly to 103%, and the total hepatic blood flow decreased to 39% of the control. In the 2nd, 3rd, and 6th periods, the decrease in the hepatic arterial inflow was 9, 17, and 22%, respectively, and, in the total hepatic blood flow, 38, 37, and 43%.
Vol. 52, No.2, Part 2
Elsewhere in this symposium, Fine discussed the intestinal circulation in shock. 9 Longerbeam et al.1° demonstrated previously that the superior mesenteric arterial (SMA) blood flow decreased promptly and markedly after the injection of endotoxin. The findings illustrated in figure 2 confirmed their observation and pointed to the marked reduction in the SMA blood flow, particularly in the early postendotoxin period. Changes in the peripheral, total splanchnic, and postsinusoidal resistances. The systemic as well as the splanchnic resistances increased after the injection of E. coli endotoxin, as diagrammed in figure 5. Although these resistances behaved in a similar fashion, differences in the magnitude of the change were apparent. The increase in the peripheral resistance, as compared to the control level, was consistently greater than the relative increase that was observed in the total splanchnic resistance. The average increase in a group of 9 dogs in the peripheral resistance was 196, 153, and 147% during the 1st, 3rd, and 6th period, respectively, after endotoxin infusion, as compared to the 128, 147, and 128% for the same periods for the total splanchnic resistance. Similar relationships between these two resistances were noted in hemorrhagic shock. 5 The postsinusoidal resistance, a venous resistance, contributed a little to the overall splanchnic resistance. This resistance, RESISTANCES
r-"------,
<.
0
«~
~ld
J1
41 ~.--.300
J.~~ .!!d ~ \. ~ ;j
~ u}.~
~r:ri'~
CONTROL
1 ST
3 RD
- - - - - - PERIODS - - - - -
FIG. 5. Effect of endotoxin on splanchnic circulation. Changes in the total peripheral, total splanchnic, and postsinusoidal resistances during endotoxin shock.
February 1967
465
SPLANCHNIC CIRCULATION IN SHOCK HW-HV EHBF
where HW (hepatic wedge pressure) and HV (hepatic venous pressure) were measured in millimeters of mercury and EHBF in liters per minute, rose markedly after endotoxin. The increase was most marked in the 1st lO-min period, and it was maintained between 300 and 328% of the control level during the remaining periods, tending to decrease gradually in some instances. The finding of an increased postsinusoidal resistance is due to constriction of the outlet (sphincter) of the liver sinusoids. 1 Splanchnic blood volume. In hemorrhagic shock, the reduction in splanchnic blood volume 6 suggested a restricted portal vascular volume or liver volume, or both, and confirmed the observation made roentgenographically by Friedman et alY of -collapsed hepatic venules and sinusoids. In dogs with endotoxin shock, MacLean ·et aP2 observed a mean increase of 140 g (range, 80 to 350 g) in the weight of the liver and estimated the mean total storage {)f fluid in the entire small intestine in 6 dogs to be 261 ml (range, 70 to 770 ml). Our own observations (table 1) of an increase in both the splanchnic blood volume and the ratio of the splanchnic to the total blood volume suggested hepatosplanchnic blood pooling and confirmed the direct observation made by MacLean et al. In our study, with one exception, (dog 811), endotoxin increased splanchnic blood volume by only 89 to 139 ml. The quantitative difference between these two studies suggested, perhaps, that some extravasation of the blood plasma occurred, which is reflected in a larger increase in the weight of the organ than in the measurement of its intravascular blood volume. It was not possible to determine from the present observation whether the portal venous or the hepatic venous system, or both, contributed to the increased splanchnic blood volume. MacLean et al. observed that the weight of the intestines rose after the weight of the liver and the portal vein pressure had returned to normal, suggesting that, perhaps 30 to 40 min after the administration of endotoxin, the increased
1. Effect of endotoxin on the splanchnic blood volume in dogs
TABLE
Control
SBV/. TBVb
SBV·
30 min
SBV·
--- - -
SBV/. TBVb
Endotoxin c
725 727 809 811 817
Mean
618 140 235 245 420 332
22.2 8.9 16.5 15.5 20.0 16.6
757 278 324 939 520 564
31. 7 16.3 19.3 37.0 24.8 25.8
311 288 386 470 364
18.6 22.4 19.4 27.4 22.0
362 275 428 479 386
19.4 21.6 25.6 29.1 23.9
Normal
1 2 3 4 Mean
I
• Splanchnic blood volume, in milliliters. b Ratio of SBV to total blood volume. c Dose, 2 mg per kg.
splanchnic volume was the result of an increase in the volume of the portal venous system. Comments on the Hemodynamics of Endotoxin Shock
The drop of the total splanchnic blood flow in the 1st period after the administration of endotoxin was the most marked. This finding, coupled with the early drop in the hepatic venous pressure and the rise in the sinusoidal pressure, is the result of pooling of the blood in the hepatosplanchnic bedP The subsequent moderate increase in the splanchnic blood flow in the 2nd and 3rd periods after endotoxin can be explained by the release of the pooled blood from the hepatosplanchnic reservoir; this was associated with the gradual return of the systemic blood pressure toward the control level. In the last period of observation, the 6th period, the systemic blood pressure, the sinusoidal pressure, and the splanchnic blood flow tended to decline. The postsinusoidal resistance increased markedly after endotoxin injection, the result of the immediate and maximal constriction of the vascular apparatus that controls the outflow of blood from the
466
BASHOUR AND McCLELLAND Sys-ternic
vo.,..r.o.l Vein
I-Iepcxi:.ic V~';T')
7>=9
n=5
n=9
Artery
N
S
N
S
N
S
::~ddd L in Tn~/100-m7.
FIG. 6. Splanchnic circulation in endotoxin. Changes in the lactate concentration and the lactate-pyruvate (LIP) ratio in the systemic arterial, portal, and hepatic venous blood. N and S represent average values of these two parameters during control and shock periods, respectively. Blood lactate concentration is reported in milligrams per 100 ml and LIP ratio in units. n represents the number of dogs in each study.
liver sinusoids, and it is responsible for the trapping of the blood in the splanchnic bed. The release of the trapped blood in the 2nd period and thereafter is consistent with the partial release of the constriction of these sphincters. The cardiac output dropped after endotoxin administration; it was probably solely the result of a decreased venous return subsequent to pooling of the blood in the splanchnic vascular bedP The fall in the blood pressure followed shortly the rise in the hepatic wedge pressure; it is believed to be primarily the result of a decreased cardiac output, not arteriolar dilation. This was demonstrated by Weil et al. 13 in dogs with total body perfusion; they observed no fall in the blood pressure after endotoxin. Had it been that arteriolar dilation followed endotoxin at the constant cardiac output, systemic arterial pressure would have fallen. The observed rise in calculated total peripheral resistance (or the state of the vascular resistance) could not be interpreted in the presence of a low cardiac output. In the normal state, the hepatic arterial inflow contributes 30 to 40% of the total hepatic blood flow, and the portal venous inflow, the rest, 60 to 70%. If, in dogs with portacaval shunt and common hepatic
Vol. 52, No.2, Part 2
vein, the hepatic arterial inflow reacted to endotoxin in the same manner as in the normal dog, the 20% reduction in the hepatic arterial inflow in the face of a 40% reduction in the total hepatic blood flow would suggest that the portal venous inflow was comparatively and more markedly reduced by endotoxin. This is corroborated by the observation that the mesenteric arterial flow is markedly reduced in endotoxin shock, and it could conceivably represent the initiating factor in the irreversibility of shock. H , 15 From the observed hemodynamic changes, it was felt that, of the two splanchnic organs (the liver or the intestines), the "key organ" in endotoxin shock is the intestines. Further evidences supporting this contention were gathered from the behavior of the lactate-pyruvate metabolism in these two organs. In endotoxin shock, the concentration of lactate increased in the systemic arterial, portal, and hepatic venous blood (fig. 6). During the control period, the concentration of lactate varied slightly in these three sites; it averaged 23.2, 28.4, and 22.9 mg per 100 ml, respectively. After endotoxin, the mean lactate concentration in the hepatic venous blood was lower than in the other two sites, indicating that lactate is still being utilized by the liver (fig. 6). The lactate-pyruvate (LIP) ratio at these three sites behaved in a similar fashion. During the control period, the LIP ratio averaged 21.1, 27.6, and 19.5 in the systemic arterial, portal, and hepatic venous blood, respectively. During endotoxin shock, the ratio at these sites increased to 28, 38, and 24.4, respectively (fig. 6). An increase in the LIP ratio is an indicator of the presence and severity of hypoxia; therefore, the finding of a relatively lower LIP ratio in the hepatic venous blood as compared to that in the systemic arterial and portal venous blood would indicate that the liver most probably is less hypoxic than the intestines. The observations are consistent with those of Ballinger et aJ.16 in dogs with hemorrhagic shock. They found that the liver continued to remove lactate from the portal venous and the arterial blood until very low systemic ar-
February 1967
SPLANCHNIC CIRCULATION IN SHOCK
terial pressure was attained. The point of departure of the liver from aerobic to anaerobic metabolism coincided with the drop in the splanchnic oxygen consumption. The mechanism responsible for endotoxin shock is complex. The hemodynamic change in the early phase of endotoxin shock is on a humoral basis. The similarity of these changes to those seen in anaphylaxis suggested the possibility that histamine and 5-hydroxytryptamine may play a role in the genesis of these changes,17 Epinephrine and norepinephrine have also been shown to play a role in the endotoxin reaction. An increased level of circulating catecholamines was demonstrated by Von Euler 18 and confirmed by Rosenberg and his group.19 REFERENCES 1. Knisely, M., F. Harding, and H. Debacker, 1957. Hepatic sphincters. Science 125: 1023-1025. 2. Penner, A., and A. Bernheim. 1939. Acute
postoperative enterocolitis study of pathologic nature of shock. Arch. Path. (Chicago) 27: 966-972. 3. Kuida, H., R Gilbert, L. Hinshaw, J. Brunson, and M. Visscher. 1961. Species differences in effect of gram-negative endotoxin on circulation. Amer. J. Physio!. 2QO: 1197-1200. 4. Bradley S. and J. Conan. 1947. Estimated
hepatic blood flow and Bromsulphalein extraction in normal man during the pyrogenic reactions. J. Clin. Invest. 26: 11751183.
5. Bashour, F. A., A. Nafrawi, and R McClelland. 1965. Splanchnic hemodynamics and carbohydrate metabolism in hemorrhagic shock, p. 265. In Shock and hypotension. Grune and Stratton, Inc., New York. 6. Reynell, P., P. Marks, C. Chidsey, and S. Bradley. 1955. Changes in splanchnic blood volume and splanchnic blood flow in dogs after hemorrhage. Clin. Sci. 14: 407-414.
467
7. Hamrick, L., and J. Myers. 1955. The effect of
8.
9. 10.
11.
12.
subfebrile doses of bacterial pyrogens on splanchnic metabolism and cardiac output. J. Clin. Med. (Shanghai) 35: 568-574. Bashour, F. A., and R McClelland. 1966. Portal venous-hepatic arterial reflex mechanism. Clin. Res. 14: 38-46. Fine, J. 1966. The intestinal circulation in shock. Gastroenterology 52: 454-458. Longerbeam, J., R. Lillehei, W. Scott, and J. Rosenberg. 1962. Visceral factors in shock. J. A. M. A. 181: 878-880. Friedman, E., H. Frank, and J. Fine. 1951. Portal circulation in experimental hemorrhagic shock; in vivo roentgen-ray studies. Ann. Surg. 134: 10-17. MacLean, L., M. Weil, W. Spink, and M. Visscher. 1956. Canine intestinal and liver weight changes induced by E. coli endotoxins. Proc. Soc. Exp. BioI. Med. 92: 602-
604. 13. Weil, M., L. MacLean, M. Visscher, and W. Spink. 1956. Studies on the circulatory
changes in the dog produced by endotoxin from gram-negative micro-organisms. J. Clin. Invest. 35: 1191-1200. 14. Lillehei, R 1957. The intestinal factor in irreversible hemorrhagic shock. Surgery 42: 1043-1050. 15. Lillehei, R,
and L. MacLean. 1958. The intestinal factor in irreversible endotoxin shock. Ann. Surg. 148: 513-519. 16. Ballinger, W., H. Vollenweider, and E. Montgomery. 1961. The response of the canine liver to anaerobic metabolism induced by hemorrhagic shock. Surg. Gynec. Obstet. 112: 19-27. 17. Hinshaw, L., J. Vick, C. Carlson, and Y. Fan. 1960. Role of histamine in endotoxin shock. Proc. Soc. Exp. BioI Med. 104: 379-381. 18. Von Euler, U. 1927. Uber Hyperadrenalinamie bei Fieberzustanden. Arch. Ges. Physio!. 217 : 699-717. 19. Rosenberg
J., R Lillehei, J. Longerbeam, and B. Zimmerman. 1961. Studies on hemorrhagic and endotoxin shock in relation to vasomotor changes and endogenous circulating epinephrine, norepinephrine and serotonin. Ann. Surg.154: 611-620.