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Anesth Analg 2003;97:1756-1763
© 2003 International Anesthesia Research Society

CRITICAL CARE AND TRAUMA

The Effects of Vasopressin on Systemic and Splanchnic Hemodynamics and Metabolism in Endotoxin Shock

Tero J. Martikainen, Jyrki J. Tenhunen, MD PhD, Ari Uusaro, MD PhD, MHSc (Epid), and Esko Ruokonen, MD PhD

Department of Anesthesiology and Intensive Care, Kuopio University Hospital, Finland

Address correspondence and reprint requests to Esko Ruokonen, MD, PhD, Department of Anesthesiology and Intensive Care, University Hospital of Kuopio, P.O. Box 1777, FIN-70211 Kuopio, Finland. Address e-mail to esko.ruokonen{at}kuh.fi


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We compared the effects of vasopressin and norepinephrine on systemic and splanchnic circulation and metabolism in endotoxin shock in pigs. Twenty-one pigs were randomized to endotoxin shock (Escherichia coli endotoxin infusion) (n = 6), endotoxin and vasopressin (VASO; n = 6), endotoxin and norepinephrine (NE; n = 6), and controls (n = 3). Endotoxin infusion was increased to induce hypotension, after which vasopressin or norepinephrine was started to keep systemic mean arterial blood pressure >70 mm Hg. Regional blood flows and arterial and regional lactate concentrations were measured. Tonometers with microdialysis capillaries were inserted into the stomach, jejunum, and colon. Systemic mean arterial blood pressure >70 mm Hg was achieved in the VASO and NE groups. Vasopressin decreased cardiac output, superior mesenteric artery, and portal vein blood flow, whereas hepatic arterial blood flow increased. Arterial lactate concentration increased from 2.0 mM (1.6–2.1 mM) to 4.7 mM (4.7–4.9 mM) (P = 0.007). Systemic and mesenteric oxygen delivery and consumption decreased and oxygen extraction increased in the VASO group. Vasopressin increased mucosal-arterial PCO2 gradients in all three locations, whereas luminal lactate release occurred only in the jejunum. Animals in the NE group remained stable. Vasopressin reversed hypotension but decreased systemic and gut blood flow. This was associated with hyperlactatemia, signs of visceral dysoxia, and jejunal luminal lactate release.

IMPLICATIONS: Although vasopressin induces vasoconstriction in visceral region, its effects on splanchnic circulation and metabolism during septic-endotoxin shock are still poorly characterized. We evaluated the metabolic and hemodynamic effects of vasopressin and norepinephrine within the splanchnic area in porcine endotoxin shock.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
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Severe sepsis and septic shock are common in critically-ill patients, and they are associated with frequent mortality (1,2). In the United States, sepsis annually causes as many deaths as acute myocardial infarction (3). The main causes of death in septic shock are multiple organ failure and refractory hypotension. Inadequate splanchnic perfusion, with subsequent mucosal barrier breakdown and bacterial translocation, may be associated with development of organ failure and death (4). Hypovolemia, low perfusion pressure, myocardial dysfunction, and, possibly inappropriately distributed blood flow because of disturbed vasoregulation, may all impair tissue perfusion.

Vasopressin not only has a major role in the regulation of circulation by its antidiuretic effect, but also by its effect on vascular tone. Hypotension induces secretion of vasopressin from hypophysis contributing to the maintenance of perfusion pressure. With the progression of septic shock, the vasopressin concentration decreases to levels that are appropriate for the osmotic effect but too small for the maintenance of blood pressure. A small vasopressin concentration is a common finding in septic shock because of depletion of vasopressin stores in neurohypophysis (5).

Based on the role of vasopressin in the pathophysiology of septic shock, it is an attractive choice as a vasopressor. Although vasopressin reverses hypotension and decreases the need for other vasopressors in septic shock (6–8), the hemodynamic and metabolic effects of vasopressin/terlipressin in septic shock have not been well studied. More specifically, the effects of vasopressin on regional blood flow within the splanchnic area during septic-endotoxin shock are poorly characterized as opposed to responses under normal physiology or endotoxin shock (9,10).

The aim of this study was to compare the hemodynamic and metabolic effects of vasopressin and norepinephrine in endotoxin shock. Our particular focus was the splanchnic region.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The institutional animal use and care committee in the University of Kuopio approved the study protocol. Twenty-one domestic female pigs (28–31 kg) were used in the study. Animals were fasted for 48 h before the experiment with free access to water. The gastrointestinal tract was emptied with osmotic laxative (Colonsteril®, Orion, Espoo, Finland). For the experiment, the animals were sedated with IM injection of atropine 0.05 mg/kg and azaperone 8 mg/kg. The ear vein was cannulated, and the anesthesia was induced with sodium thiopentone 5–15 mg/kg. Anesthesia and analgesia were maintained with continuous infusions of sodium thiopentone 5 mg · kg-1 · h-1 and fentanyl 30 µg · kg-1 · h-1 during the surgical manipulation, after which fentanyl infusion was reduced to 5 µg · kg-1 · h-1. Tracheotomy was performed, and the lungs were ventilated with a tidal volume of 10–15 mL/kg to maintain normocapnia (arterial CO2, 4.5–5.5 kPa) and fraction of inspired oxygen was adjusted to keep arterial partial pressure of O2 more than 13.3 kPa. Positive end expiratory pressure of 5–10 cm H2O was applied during the experiment. Cefuroxime (Zinacef®, GlaxoSmithKline, Middlesex, United Kingdom; 750 mg) was given IV at the beginning of the surgical instrumentation. Neuromuscular blockade was achieved with continuous infusion of pancuronium (1–4 mg/kg).

The left femoral artery was cannulated for arterial blood sampling and for monitoring of systemic arterial blood pressure. Right jugular and subclavian veins were prepared and cannulated for pulmonary artery catheter and hepatic vein catheter to measure pulmonary artery occlusion pressure (PAOP) and to collect blood samples. Probes for electrocardiogram, O2 saturation, and peripheral temperature were inserted. A full midline laparotomy was performed, and the urinary bladder was catheterized and drained. The stomach was emptied with an oro-gastric drain. The position of the hepatic catheter was ensured manually.

The celiac trunk, hepatic artery, portal vein, superior mesenteric artery, and its colonic branch were prepared and visualized. Precalibrated ultrasonic flow probes were inserted around the vessels. Mesenteric, colonic, portal, and gastric veins were cannulated for regional blood sampling. Tonometers with microdialysis capillaries were inserted through antimesenteric incision into the colon and jejunum. A gastric tonometer with microdialysis capillaries was inserted orally, and its position was ensured with manual palpation.

Systemic and pulmonary arterial and hepatic and portal vein pressures were recorded with quartz pressure transducers and displayed continuously on a multimodular monitor and recorder (CS3, Datex-Ohmeda Instrumentarium, Helsinki, Finland). Automated data filtering (2-min median) was used when collecting the continuous variables (Deio Instrumentarium, Helsinki, Finland). Heart rate was measured from the electrocardiogram. PAOP was measured hourly. Cardiac output was measured by thermodilution technique (mean value of 3 measurements) with room temperature saline injectants of 5 mL.

Regional blood flows were measured with ultrasonic transit time flow probes (Transonic Systems Inc, Ithaca, NY) from the superior mesenteric artery, celiac trunk, hepatic artery, and portal vein. The signals were recorded by flowmeters (Flowmeters T108 and T208, Transonic Systems Inc). The flow data were stored with computer software (Windaq, DATAQ Instruments Inc, Akron, OH). In vivo zero flow signals were recorded at the end of each experiment.

The microdialysis capillaries were manufactured in our laboratory. The structure and principle of the capillary is described previously and it has been validated for lactate sampling both in vivo and in vitro (11). Two microdialysis capillaries were attached on the surface of tonometer balloon, which compresses capillaries on the gut mucosa. The time delay from the capillary to sample tube in ice bed was adjusted to 7 min with 2 µL/min of dialysate flow. The samples were collected continuously over 30 min and analyzed within 5 min (YSI 2300 Stat Plus, Yellow Springs Instruments Co Inc, Yellow Springs, OH). A gastrointestinal tonometer was used for measurement of mucosal partial tension of carbon dioxide. We used a semiautomated gas analyzer (Tonocap, Tonometrics, Espoo, Finland) every 10 min throughout the experiment.

For the maintenance fluid therapy, 5 mL · kg-1 · h-1 of saline 0.9% was infused throughout the experiment. Fluid resuscitation with Ringer’s acetate solution and hydroxyethyl starch 1:1 (Hemohes®, Braun, Melsungen, Germany) were given to achieve PAOP 5–7 mm Hg and a central venous pressure <16 mm Hg. In case the systolic mean arterial blood pressure (SAPm) was <50 mm Hg with PAOP 5–7 mm Hg, a fluid challenge of 100–200 mL was done aiming to PAOP of 8–9 mm Hg.

After the instrumentation, the animals were stabilized for 8–10 h, and they were randomized into one of the following groups: Group 1 = Escherichia coli endotoxin infusion (ETX; n = 6; lipopolysaccharide 0111:B4, Difco Laboratories, Detroit, MI) was started at the rate of 0.25 µg · kg-1 · h-1, and after 1–3 h, the infusion rate was doubled stepwise to achieve hypotension (SAPm <60 mm Hg). Hypotensive shock was achieved after 10–18 h of endotoxin infusion. After that, the endotoxin infusion was continued for 4 h. Group 2 = E. coli endotoxin was infused as above. When hypotensive shock was achieved, vasopressin (VASO; n = 6; Pitressin®, Parke-Davis, Karlsruhe, Germany) infusion was started at a rate of 0.04 IU/min and adjusted for 4 h aiming to SAPm >70 mm Hg. Group 3 = E. coli endotoxin was infused as above, and when hypotensive shock was achieved, norepinephrine (NE; n = 6; Levophed®, S.A. ABBOT NV, Belgium) infusion was started at a rate of 8 µg/min and adjusted for 4 h aiming to SAPm > 70 mm/Hg. Group 4 = time controls (control; n = 3). The only vasoactive drug allowed was a bolus injection of epinephrine (0.02 mg) in case of hemodynamic collapse (SAPm <60 mm Hg and pulmonary artery pressure >50 mm Hg) at the early (<2 h) stage of endotoxin infusion.

Arterial blood samples were drawn hourly for hemoglobin, arterial blood gases, glucose, and lactate measurements. Colonic, mesenteric, portal, hepatic, gastric, and mixed venous blood samples were collected at baseline and at 0, 2, 3, and 4 h of vasopressor infusions (shock 0–4 h), and hemoglobin concentration, blood gases, and lactate concentrations were analyzed. Arterial plasma endotoxin, interleukin (IL)-1ß, and IL-6 concentrations were measured at baseline and at the end of the experiment to verify the induction of inflammatory response in this experimental model.

All data are presented in medians with interquartile ranges. Within group analysis (changes from shock 0 h to shock 4 h) was done with nonparametric analysis of variance for repeated measurements (Friedman). Wilcoxon’s signed rank test was used for post hoc analysis when a statistical significance was detected by the Friedman test. The Kruskal-Wallis test was also used. A P value of <0.05 was used to indicate statistical significance.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Five animals in the ETX group and one animal in the VASO group died before the end of the experiment. The animals treated with norepinephrine survived the 4-h period of vasopressor infusion. Control animals remained stable throughout the experiment. The animals receiving endotoxin had normal IL-1ß and IL-6 concentrations at the baseline and increased substantially in response to endotoxin (data not shown), whereas there were no change in controls.

To maintain normovolemia, control animals received Ringer’s acetate solution and hydroxyethyl starch 5000 mL (4000–6000 mL) and 4000 mL (4000–5000 mL), the ETX group received 3000 mL (3000–4000 mL) and 3000 mL (2500–3500 mL), the VASO group received 4000 mL (3000–4000 mL) and 3500 mL (3500–4000 mL), and the NE group received 3000 mL (2000–3000 mL) and 3000 mL (2000–3000 mL), respectively. Control animals received more fluids (P = 0.042), but no difference was noticed between VASO and NE groups (P = 0.124).

After the initial infusion rates of 0.001 IU · kg-1 · min-1 (0.001–0.001) and 0.28 µg · kg-1 · min-1 (0.27–0.29) of vasopressin and norepinephrine, respectively, the median infusion rates of vasopressors required to reverse hypotension were 0.007 IU · kg-1 · min-1 (0.004–0.009) in the VASO group and 0.44 µg · kg-1 · min-1 (0.34–0.47) in the NE group. The total amounts of vasopressin and norepinephrine infused were 50 IU (30–60 IU) and 3.0 mg (2.3–3.8 mg).

Both vasopressin and norepinephrine effectively treated hypotension, whereas five animals in the ETX group died in profound hypotension before the end of the experiment. Vasopressin, but not norepinephrine, infusion decreased cardiac output (Fig. 1). Total splanchnic blood flow (sum of portal venous and hepatic arterial blood flows) decreased in proportion to decreasing cardiac output in the VASO group. Vasopressin infusion decreased superior mesenteric arterial and thereby portal venous blood flow but simultaneously increased hepatic arterial blood flow. In response to norepinephrine infusion, the celiac trunk blood flow increased, whereas superior mesenteric, hepatic arterial, and portal venous flows did not change. Vasopressin increased fractional celiac trunk and hepatic arterial blood flows but decreased fractional portal flow; the fractional superior mesenteric arterial blood flow did not change. In contrast, fractional celiac trunk, hepatic and superior mesenteric arterial, and portal vein flows did not change in response to norepinephrine (Fig. 2).



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  		Figure 1. Mean arterial blood pressure and cardiac output. (A) Systemic mean arterial blood pressure (SAPm); (B) Cardiac output (CO). Gray column = Escherichia coli endotoxin infusion (ETX; n = 6); white column = Escherichia coli endotoxin infusion with vasopressin (VASO; n = 6); dark gray column = Escherichia coli endotoxin infusion with norepinephrine (NE; n = 6); diagonal column = control (n = 3). *P < 0.05 and {dagger}P < 0.01.

 


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  		Figure 2. Absolute and fractional regional blood flows. (A) Superior mesenteric, (B) fractional superior mesenteric, (C) celiac trunk, (D) fractional celiac trunk, (E) hepatic arterial, (F) fractional hepatic arterial, (G) portal vein, and (H) fractional portal vein flows. White column = Escherichia coli endotoxin infusion with vasopressin (VASO; n = 6); gray column = Escherichia coli endotoxin infusion with norepinephrine (NE; n = 6). *P < 0.05.

 
In the VASO group, systemic oxygen delivery (DO2) as well as oxygen consumption (VO2) decreased and remained low during vasopressor infusion, whereas systemic oxygen extraction increased. Similar changes were observed in mesenteric DO2, VO2, and oxygen extraction; vasopressin did not change hepatic oxygen transport. Norepinephrine had no effect on systemic DO2, VO2, and oxygen extraction. Norepinephrine did not alter small intestinal or hepatic DO2, VO2, or oxygen extraction (Table 1).


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  		Table 1. Systemic and Regional Oxygen Delivery, Consumption, and Extraction
 
During the 4-h period of vasopressin infusion, arterial lactate increased from 2.0 mM (1.6–2.1 mM) to 4.7 mM (4.7–4.9 mM) (P = 0.007), whereas norepinephrine did not change the arterial lactate concentration. Gastric, colonic, and hepatic venous-arterial lactate gradients increased in animals treated with vasopressin. There were no changes in regional lactate gradients in the NE group (Table 2). Lactate exchange data are presented in Table 3. Luminal lactate release did not occur in the ETX, NE, or control groups. However, vasopressin infusion was associated with luminal lactate release in the jejunum. Lactate could not be detected at baseline, whereas at 4 h, the median luminal lactate concentration in the jejunum was 3.0 mM (1.6–4.4 mM; P < 0.001). There was no luminal lactate release in the stomach or colon in the VASO group. Vasopressin infusion was associated with increasing mucosal-arterial PCO2 gradients in the stomach, colon, and jejunum. Four-hour norepinephrine treatment had no effect on mucosal-arterial PCO2 gradients. Regional PCO2 data are presented in Figure 3.


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  		Table 2. Arterial Blood Lactate Concentration and Regional Lactate Gradients (venous - arterial)
 

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  		Table 3. Hepatic, mesenteric, and prehepatic lactate exchange
 


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  		Figure 3. Mucosal-arterial PCO2 gradients. (A) Gastric-arterial PCO2 gradient, (B) jejunal-arterial PCO2 gradient, and (C) colonic-Arterial PCO2 gradient. White column = Escherichia coli endotoxin infusion with vasopressin (VASO; n = 6); gray column = Escherichia coli endotoxin infusion with norepinephrine (NE; n = 6). *P < 0.05.

 

   Discussion
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 Introduction
 Methods
 Results
 Discussion
References
 
We found that large-dose vasopressin decreased cardiac output and selectively reduced superior mesenteric arterial blood flow, whereas celiac trunk blood flow was maintained. Thus, vasopressin induced redistribution of blood flow within the splanchnic area during endotoxin shock. This was associated with systemic hyperlactatemia despite increased hepatic lactate uptake, splanchnic (prehepatic) lactate release, intestinal luminal lactate release from the small bowel, and increased gut mucosal-arterial PCO2 gradients. Only a minor increase was observed in the gastric mucosal-arterial PCO2 gradient. In contrast, norepinephrine did not compromise either systemic or regional blood flow or tissue oxygenation.

In agreement with our results, several studies show that large-dose vasopressin decreases cardiac output (12–14). Based on a retrospective human study, it has been recommended that, for adults, infusion rates of 0.04 IU/min (largest dose used was 0.6 IU/min) should not be exceeded (14). Although comparison of human data to animal studies may not be fully justified, the maximum dose used in our study was large: 0.21 IU/min (0.007 IU · kg-1 · min-1). The large doses of vasopressin we used were required to reverse hypotension despite adequate fluid resuscitation. The infusion rates for norepinephrine were also rapid, but comparable deleterious changes in regional blood flow did not develop.

In the present experiment, total splanchnic blood flow (sum of portal venous and hepatic arterial blood flows) decreased in proportion to decreasing cardiac output in response to vasopressin infusion. Thus, we observed no selective reduction of total splanchnic blood flow. However, vasopressin selectively decreased superior mesenteric arterial and thereby portal vein blood flow but simultaneously increased hepatic arterial blood flow (and celiac trunk blood flow). In other words, vasopressin induced selective blood flow redistribution within splanchnic circulation. The response is comparable to the hepatic arterial buffer response, wherein hepatic arterial blood flow compensates acute reduction of portal venous blood flow to the liver (15,16). In contrast, with an equipotent vasopressor infusion rate of norepinephrine, both celiac trunk and superior mesenteric arterial blood flows were maintained, no redistribution of blood flow within the splanchnic bed occurred, and total splanchnic blood flow was maintained.

These findings are in accordance with a previous study by Träger et al. (17), who found that total splanchnic, portal, and hepatic arterial blood flows are preserved or increased during prolonged endotoxin shock treated with norepinephrine. Our results are also in agreement with data on the effects of vasopressin or its analog on splanchnic blood flow profile; in rats (18) and humans (19), hepatic arterial blood flow increased, whereas portal blood flow decreased. Others have described a biphasic response on hepatic arterial blood flow by vasopressin with a primary decrease followed by an increase in blood flow. It has been suggested that this increase is not related to decreasing portal blood flow but rather a characteristic response of the hepatic arterial bed to vasopressin (20).

We found that vasopressin induced arterial hyperlactatemia during endotoxin shock. Endotoxin shock per se did not cause prehepatic lactate release, whereas it tended to increase during vasopressin infusion. This is in accordance with the study by Krarup (21). Jejunal luminal lactate of 3 mM after four hours of vasopressin infusion is not explained by arterial hyperlactatemia of 4.7 mM (22). Surprisingly, mesenteric (jejunal) lactate production or mesenteric venous-arterial lactate gradient did not increase concomitantly. This indicates selective jejunal mucosal epithelial dysoxia associated with vasopressin as opposed to norepinephrine or 12-hour endotoxin shock alone. Tsuneyoshi et al. (23) detected a trend of decreasing serum lactate concentrations when vasopressin was used in septic shock. The lactate concentrations in that study were relatively large (5.7 mM) at the beginning of vasopressin infusion and also remained increased (4.4 mM) after 16 hours of vasopressin infusion. Taken together, our finding of selective (superior mesenteric artery versus celiac trunk) adverse effects of large-dose vasopressin may be important, assuming the association between poor splanchnic perfusion, mucosal barrier breakdown, and excess mortality and morbidity (4).

There are some limitations in our study. We infused fluids to keep PAOP at 5–7 mm Hg, and it is possible that the animals were hypovolemic. However, increases in pulmonary artery and central venous pressures set limits to fluid loading. Control animals received more fluids than the VASO, NE, and ETX animals because endotoxin decreased urine production. Vasopressin infusion rates were rapid, and therefore, it can be argued that we only observed the side effects of an excessive dosage of vasopressin. Vasopressin has beneficial effects, especially in catechola-mine-resistant septic shock. In our experiment, hypotension was also effectively reversed with norepinephrine, and thus, animals were not resistant to catecholamines. In addition, because we did not measure antidiuretic hormone (ADH) concentrations, we cannot confirm ADH-deficiency in our animals. In some previous studies, ADH deficiency has been confirmed, and our endotoxin model does not necessarily represent a clinical state of catecholamine resistant septic shock. However, the infusion rates of both vasopressors were adjusted to maintain the same mean arterial blood pressure of >=70 mm Hg. Therefore, we feel that our comparison between vasopressin and norepinephrine as a monotherapy in septic shock was relevant. It is reasonable to assume that combining vasopressin with inotropes might have counteracted the cardiac side effects of the vasopressin. However, the aim of the experiment was to focus on the effect of each vasoconstrictor separately. Extrapolating experimental data to the clinical setting has to be done with caution.

In conclusion, we found that vasopressin as a monotherapy effectively reversed hypotension in septic shock, but large doses were required. There is no clear recommendation of the dosage of vasopressin in septic shock. The results of the present study indicate that large-dose vasopressin, but not norepinephrine, may decrease systemic and selectively small intestinal blood flow. This is associated with the splanchnic lactate release, increased gut mucosal-arterial PCO2-gradient, increased jejunal luminal lactate, and systemic hyperlactatemia. Large-dose vasopressin in experimental endotoxin shock is associated with blood flow redistribution and heterogeneous metabolic changes within splanchnic tissues.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 2, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press