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Division of Pulmonary, Critical Care, and Sleep Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201
Submitted 8 January 2003 ; accepted in final form 17 April 2003
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ABSTRACT |
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vasopressors; resuscitation; blood flow
Therapy for septic shock typically includes administration of intravenous fluids, antibiotics, and vasopressor agents (33). However, development of adrenergic hyposensitivity with gradual loss of catecholamine pressor responsiveness resulting in refractory hypotension is a frequent clinical challenge (2, 21). Arginine vasopressin (AVP), a potent endogenous vasoconstrictor, has been proposed as a vasopressor alternative or adjuvant to conventional catecholamine treatment for management of septic shock (16, 23, 29). In this setting, AVP infusion improved mean arterial blood pressure, facilitated withdrawal of catecholamine vasopressor support, and improved some measures of renal function (16, 23, 29). However, organ-specific heterogeneity in the vascular responsiveness to AVP has been described. For example, AVP causes cerebral and pulmonary vasodilatation (9, 30), whereas increases in systemic vascular resistance and reduction of skeletal muscle and skin blood flow have been described as well (5). The effects of AVP on intestinal and renal blood flow during sepsis-induced circulatory shock remain largely unknown.
We conducted the present animal investigation to assess the systemic, splanchnic, and renal hemodynamic and metabolic effects of AVP infusion compared with norepinephrine (NE) administration during basal conditions and during resuscitation from endotoxic shock.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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40 Torr. A femoral vein
and artery were exposed by surgical dissection and cannulated with vascular
catheters for continuous intravenous infusions of pentobarbital sodium (0.06
mg · kg-1 · min-1) and normal saline
solution, as well as for continuous monitoring of mean arterial blood pressure
(Pao) and intermittent blood sampling for blood-gas, lactate, and hemoglobin
assays. A balloon-tipped, multilumen, continuous-thermodilution pulmonary
artery catheter (746HF8; Baxter Healthcare; Irvine, CA) was advanced through
the femoral vein and guided into the pulmonary artery by pressure waveform
analysis for measurement of cardiac output (
t),
central venous pressure (Pcv), pulmonary artery pressure (Ppa), and pulmonary
artery occlusion pressure (Ppao). After a midline laparotomy, the duodenum and
small intestine were displaced to expose the portal vein. After careful
dissection, an 8-mm ultrasonic transit-time flow probe (model 8RS; Transonic
Systems; Ithaca, NY) was placed around the vessel and secured with sutures to
the adjacent lymphatic tissue. A 7-Fr catheter was advanced through the
splenic vein to the portal vein for blood sampling and pressure (Ppv)
recording. Its position was confirmed by palpating the tip of the catheter
through the wall of the portal vein. Ileal mucosal blood flow was measured
continuously by laser-Doppler flowmetry. Through a second small ileostomy, a
laser-Doppler flow probe (type R; Transonic Systems) was sewn to the
antimesenteric mucosal surface, and the ileostomy was closed. The manufacturer
modified the probe so that it could be secured to the mucosa without
compromising perfusion in the area of interest. This methodology does not
provide measurements of microvascular perfusion in absolute terms, but it has
been validated previously as a reliable means of estimating relative changes
in mucosal perfusion (26). A
7-Fr curved-tip catheter was advanced though the femoral vein to the renal
vein for blood sampling and pressure (Prv) measurements. After identification
of the main renal artery (either side), a 2-mm ultrasonic flow probe (model
2RS; Transonic Systems) was placed around the vessel and secured with sutures
to the adjacent adipose tissue. After hemostasis was ensured, the laparotomy
was closed and the animals were allowed to stabilize for 45 min, during which
time minute ventilation was readjusted, if necessary, to maintain arterial
PCO2 at 40 Torr. Core temperature was monitored via
the thermistor of the pulmonary artery catheter and maintained at 38.0
± 0.5°C by use of heating pads and overhead infrared lamps as
necessary.
Measurements and calculations. Systemic arterial, mixed venous,
portal, and renal venous blood samples were analyzed for
PO2,PCO2, pH, and lactate
concentration by using an automated blood-gas analyzer (model 860; Bayer
Diagnostics; Medfield, MA). Total hemoglobin concentration and oxyhemoglobin
fraction were assayed spectrophotometrically by using a multiwavelength
oximeter calibrated for canine blood (OSM-3; Radiometer; Westlake, OH).
Cardiac output was measured by continuous thermodilution (Vigilance; Baxter
Healthcare) and indexed to body mass (l · kg-1 ·
min-1). Hemodynamic pressures (mmHg) were measured by fluid-coupled
electronic transduction (Transpac; Abbott Laboratories; North Chicago, IL).
Portal vein (;pv) and renal artery
(ra) blood flow were measured ultrasonically
(model T206; Transonic Systems) and indexed to total organ mass (ml ·
100 g-1 · min-1)
(20). Systemic arterial
(CaO2), mixed venous (CmvO2),
portal venous (CpvO2), and renal venous
(CrvO2) blood oxygen content; systemic, splanchnic, and
renal oxygen extraction (O2ex); and systemic, splanchnic, and renal
oxygen delivery (DO2) were calculated from gas tensions
(Torr) and fractional oxyhemoglobin saturations of systemic arterial
(PaO2 and SaO2, respectively),
pulmonary arterial (PmvO2 and
SmvO2, respectively), portal venous
(PpvO2 and SpvO2, respectively),
and renal venous blood (PrvO2 and
SrvO2, respectively) and total hemoglobin concentration
(Hb, g/dl) according to
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Experimental procedure. After two consecutive sets of baseline
measurements were obtained (vital signs; arterial, mixed venous, portal
venous, and renal venous blood-gas, acid-base, and lactate values; portal,
mucosal, and renal blood flow; and cardiac output), animals were assigned to
receive either NE (group 1) or AVP (group 2). The study
protocol consisted of two parts. During the first part, a continuous
intravenous infusion of NE (norepinephrine bitartrate; Abbott Laboratories) at
0.2 µg · kg-1 · min-1 or AVP (V0377;
Sigma-Aldrich; St. Louis, MO) at 0.08 U/min was started and maintained for 30
min, during which time measurements were obtained at 15-min intervals. The
vasopressor infusion was then discontinued, and a washout period of 45 min was
allowed to reverse the drug-induced hemodynamic changes. During this washout
period, a set of measurements was obtained at 15 and 45 min after drug
discontinuation. During the second part, the animals were subjected to
endotoxic shock by intravenous infusion of 4 mg/kg Escherichia coli
(serotype 0111:B4) lipopolysaccharide (LPS; Sigma-Aldrich) over 20 min
followed by a resuscitation period of 30 min. Animals in both groups were
resuscitated by use of an intravenous infusion of isotonic saline solution
titrated to maintain Ppao within ±1 mmHg of their initial baseline
value. In addition to fluid resuscitation, a continuous intravenous infusion
of NE (0.2 µg · kg-1 · min-1) was
restarted in group 1 animals, whereas a continuous intravenous
infusion of AVP (0.08 U/min) was restarted in group 2 animals. The
vasopressor doses remained fixed as long as Pao increased to 
80% of the
pre-LPS value or were otherwise increased as necessary to achieve that minimum
systemic arterial pressure. After the 30-min resuscitation period,
vasopressors were discontinued and the animals were followed for another 15
min. Measurements were obtained at 10-min intervals during and at 15-min
intervals after LPS infusion. Animals were then euthanized by intravenous
injection of a saturated solution of potassium chloride.
Statistical analysis. Summary values are expressed as means ± SE. One-factor repeated-measures analysis of variance (ANOVA) was used to compare sequential measurements for each tested variable obtained between baseline and the end of the washout period and between the end of washout period and the end of resuscitation. Dunnett's test was used to make further comparisons if ANOVA revealed significant differences. The control values for Dunnett's test were designated as the last measurement obtained at the end of the baseline period and the last measurement obtained at the end of the washout period. Two-way (one factorial and one repeated-measures factor) ANOVA was used to compare sequential measurements obtained between baseline and the end of the washout period and between the end of the washout period and the end of the experiment between the two groups. Probability values (2-tailed) of <0.05 were considered statistically significant. Statistical calculations were performed by using Excel (version 7.0; Microsoft; Redmond, WA) and SigmaStat (version 2.0; Jandel; San Rafael, CA) software.
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RESULTS |
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t and
a concomitant increase in Rsys during pre-LPS conditions. Although the trends
in these changes were more pronounced in animals receiving AVP, they were not
statistically different from animals receiving NE. Changes in
t during LPS infusion and resuscitation were
similar in both study groups. Changes in systemic DO2
were not significantly different between groups throughout the experiment.
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Changes in portal, intestinal mucosal, and renal blood flow are shown in
Fig. 1. Portal blood flow
decreased significantly shortly after AVP infusion was initiated and returned
to near baseline levels by the end of the washout period. Concomitantly, AVP
decreased portal venous pressure by 12 ± 9% and increased Rspl by 125
± 9%. Contrary to animals in group 2, NE infusion increased
portal venous pressure by 19 ± 5% and Rspl by 29 ± 13%
(P < 0.05 for both compared with AVP). On the other hand, changes
observed in portal blood flow and venous pressure and in Rspl post-LPS and
during resuscitation were comparable between study groups. Mucosal blood flow
changes paralleled changes in pv.
ra remained essentially unchanged during
pre-LPS conditions, irrespective of study group, and decreased by 60%
post-LPS. AVP resuscitation restored ra to near
pre-LPS levels in contrast to NE, which had no effect on
ra. NE significantly increased Prv and Rren
during resuscitation in comparison to AVP and end-of-washout levels.
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Table 2 shows the results of selected splanchnic variables throughout the experiment. Pre-LPS, AVP induced a significant reduction in splanchnic DO2. This coincided with a significant decrease in PpvO2 and an increase in splanchnic O2ex. Judging by the essentially unchanged PpvCO2 and portal lactate concentration, the drop in splanchnic delivery DO2 was not of sufficient magnitude to cause a detectable shift to anaerobic metabolism. On the other hand, observed changes in splanchnic variables during LPS administration and resuscitation were all comparable between groups.
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Selected renal variables are shown in Table 3. Similar to the effects noted on the splanchnic vasculature, AVP administration induced a significant increase in renal O2ex and a trend toward decreased PrvO2 during pre-LPS conditions. This occurred without an adverse affect on renal DO2, suggesting an increase in renal oxygen consumption. Post-LPS, AVP infusion restored renal DO2 to near basal levels and resulted in lower renal O2ex compared with NE. Despite restoration of renal DO2 in group 2, renal venous lactate levels remained above pre-LPS values in both study groups.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Except for a more pronounced drop in t and a
decrease in LVSW in animals receiving AVP, systemic circulatory effects during
basal conditions were comparable between the two study groups. Because of a
left shift of the heart rate-arterial pressure baroreflex curve, AVP is a weak
vasopressor agent in animals with intact autonomic nervous system
(15). This baroreflex effect
explains why, under physiological conditions, rate-related decreases in
t preclude vasoconstriction from yielding
proportional increases in blood pressure. However, pentobarbital anesthesia
and surgical stress can alter central nervous system reflexes and vascular
reactivity and enhance vascular sensitivity to exogenous AVP administration,
thus explaining the significant rise in Pao we observed after initiation of
AVP (3,
24). On the other hand, the
NE-induced increase in Pao pre-LPS was predictable because of its known
vasoconstrictor and inotropic effects. To our knowledge, the effects of AVP on
LVSW have not been previously described. During basal conditions, AVP induced
a significant decrease in LVSW compared with NE. Differences in Rsys and
t observed in our model can explain these
findings, although AVP-induced coronary vasoconstriction and myocardial
ischemia could also be involved
(9,
14). Although hypothetical,
the increase in renal oxygen extraction observed after AVP infusion could
represent increased metabolic expenditure associated with AVP-induced
activation of aquaporins in the distal nephron.
Attempting to avoid any confounding effects of drug titration on our results, our protocol allowed for fixed starting doses of either AVP or NE as long as Pao remained within 20% of pre-LPS values. The starting doses were chosen on the basis of previous clinical and experimental work (1, 14, 18, 19, 23, 29). Because the initial infusion dose increased Pao to the preselected target range, titration was not necessary in either group.
The effects of AVP administration on renal perfusion and oxygen transport were more striking during resuscitation from endotoxic shock. Although the renal effects of AVP are complex, the observed improvement in renal blood flow was likely secondary to nitric oxide-mediated afferent arteriolar vasodilatation and selective efferent arteriolar vasoconstriction (4, 25). However, with higher exogenous AVP doses, profound vasoconstriction and decreased renal blood flow should be expected (8). It could be postulated that a dose-response increase in renal blood flow might have been achieved if higher NE doses were used. Arguing against this, Treggiari and colleagues (28) demonstrated in a porcine model of endotoxin shock that the administration of NE to increase Pao to 20 mmHg above shock levels did not increase renal or splanchnic blood flows compared with lower doses. However, caution should be exercised in extrapolating this data to human sepsis.
Although the effects of AVP on pv and Ppv
have been previously studied, the comparative effects of AVP and NE on the
splanchnic circulation have not. During basal conditions, a significant
decrease in portal and mucosal blood flow was observed during AVP infusion.
This resulted in a marked reduction in splanchnic oxygen delivery accompanied
by a rise in gut O2ex. However, the absence of changes suggestive
of anaerobic metabolism, such as detectable increases in
PpvCO2 or portal venous lactate concentration place
these hemodynamic findings in perspective and imply that regional oxygen
delivery was not critically impaired. More importantly, during endotoxin shock
we did not find appreciable differences in the effects of the two drugs on the
splanchnic circulation at the doses studied.
Patterns of endogenous AVP release during clinical septic shock may differ from that observed in animal models. Although plasma levels of endogenous AVP appear to be inappropriately low in patients with septic shock, they remain persistently elevated for up to 12 h after shock induction in laboratory investigations (10, 27, 34). This difference may only reflect variations in the timing of AVP measurements with respect to the temporal stage of shock. Nevertheless, despite the likelihood that plasma levels of endogenous AVP were high in our model, we found that exogenous AVP administration has desirable vasoconstrictor effects in early endotoxic shock. Even in the presence of high endogenous AVP levels, this observation may be secondary to an AVP-induced enhancement of catecholamine-mediated vasoconstriction (7, 17). In addition, it is possible that AVP-induced dose-dependent blockade of K+-sensitive adenosine triphosphate channels may have helped to restore vascular tone in this model of septic shock (12, 32).
In summary, our data demonstrate that, in contrast to NE, exogenous AVP administration effectively restores renal blood flow and renal oxygen delivery with comparable systemic and splanchnic hemodynamic and metabolic effects in endotoxin-induced circulatory shock. These findings suggest that AVP alone, or perhaps in combination with other catecholamines, may enhance renal perfusion and facilitate the clinical management of septic shock.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) in portal, intestinal mucosal, and renal blood flow
during experiment. 
, Group 1; 
, group 2. Arrows
indicate periods of vasopressor infusion. Shading indicates duration of
endotoxin infusion. *P < 0.05 compared with baseline.
P < 0.05 compared with end of washout. 
P
< 0.05 between groups from time 0 to 85 min. 
P <
0.05 between groups from immediately preendotoxin to end of experiment.