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Anesth Analg 2004;99:878-885
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000131970.54062.1C

CRITICAL CARE AND TRAUMA

Dopexamine Reverses the Vasopressin-Associated Impairment in Tissue Oxygen Supply but Decreases Systemic Blood Pressure in Ovine Endotoxemia

Martin Westphal, MD, Andreas Wilhelm Sielenkämper, MD, Hugo Van Aken, MD PhD, FRCA, FANZCA, Henning Dirk Stubbe, MD, Fritz Daudel, MD, Ralf Schepers, Simone Schulte, and Hans-Georg Bone, MD

Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany

Address correspondence and reprint requests to Martin Westphal, MD, Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany. Address e-mail to Martin. Westphal{at}gmx.net


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Since arginine vasopressin (AVP) may reduce cardiac output and, in proportion, oxygen delivery, we studied the efficacy of dopexamine (DPX) as an adjunct to AVP infusion. After 1 h of continuous AVP infusion (0.04 U/min) in healthy sheep (n = 7), DPX was additionally administered in incremental doses (1, 5, and 10 µg · kg–1 · min–1; each dose for 30 min). After a 24-h period of recovery, endotoxin was continuously infused in the same sheep to induce and maintain a hypotensive/hyperdynamic circulation. After 16 h of endotoxemia, AVP and DPX were given as described previously. AVP infusion increased systemic vascular resistance index and decreased cardiac index in both healthy and endotoxemic conditions (P < 0.001 each). This was accompanied by an augmented pulmonary vascular resistance index in endotoxemia (159 ± 13 dynes · cm–5 · m–2 versus 202 ± 16 dynes · cm–5 · m–2) and a decrease in oxygen delivery index (health: 842 ± 66 mL · min–2 · m–2 versus 475 ± 38 mL · min–2 · m–2; endotoxemia: 1073 ± 49 mL · min–2 · m–2 versus 613 ± 44 mL · min–2 · m–2) and mixed venous oxygen content (health: 63% ± 2% versus 47% ± 2%; endotoxemia: 68% ± 2% versus 51% ± 3%; P < 0.001 each). Small doses of DPX (1 and 5 µg · kg–1 · min–1) improved not only the AVP-associated depressions in cardiac index, oxygen delivery index, and mixed venous oxygen content, but also the pulmonary vasopressive effect in both groups. While large-dose DPX (10 µg · kg–1 · min–1) also reduced mean pulmonary arterial pressure in endotoxemia (27 ± 1 mm Hg versus 23 ± 1 mm Hg; P < 0.05 versus baseline), mean arterial blood pressure decreased (105 ± 4 mm Hg versus 80 ± 3 mm Hg) and heart rate increased (84 ± 4 bpm versus 136 ± 9 bpm; P < 0.001 versus AVP alone), thereby limiting its therapeutic use.

IMPLICATIONS: Because vasopressin decreases cardiac output and oxygen delivery, we investigated the use of dopexamine as an adjunct to vasopressin infusion. During experimental endotoxemia, small doses of dopexamine reversed the arginine vasopressin-linked depression in cardiac index, thereby improving oxygen supply. Although large-dose dopexamine (10 µg · kg–1 · min–1) improved the pulmonary circulation, systemic hypotension and tachycardia occurred.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The early stage of septic shock is characterized by a hypotensive/hyperdynamic circulation that possibly contributes to organ hypoperfusion, multiple organ dysfunction syndrome, or even death. In clinical practice, current treatment strategies include a calculated antimicrobial therapy and early goal-directed hemodynamic support, aiming at the maintenance of adequate systemic blood flow and tissue oxygenation (1). When fluid substitution fails to restore systemic blood pressure, catecholamines are often needed to ensure sufficient organ perfusion. The dilemma, however, is that during sepsis, excessive nitric oxide (NO) formation, resulting from activation of the inducible form of NO synthetase (iNOS), leads not only to vasodilation, but also to vascular hyporeactivity against adrenoceptor agonists, thereby complicating hemodynamic support (2).

Arginine vasopressin (AVP) has been investigated as an alternative nonadrenergic vasopressor effectively reversing vasodilation secondary to septic shock (3,4). Acting via vasopressinergic V1 receptors, AVP causes considerable constriction of vascular smooth muscle cells and thus is useful to restore the impaired tone of resistance vessels, even in catecholamine-refractory shock states (3–6). However, it has to be taken into consideration that AVP causes a leftward shift of the heart rate (HR)/mean arterial blood pressure (MAP) baroreflex curve, thereby reducing cardiac index (CI) and, in proportion, oxygen delivery (DO2) (7). This may be especially problematic during hyperdynamic sepsis, in which CI is characteristically increased to compensate for increased metabolic demands (8).

We hypothesized that it could be advantageous to administer dopexamine (DPX) as an adjunct during hemodynamic support with AVP. DPX is a synthetic catecholamine that acts predominantly via dopaminergic (dopamine-1 and -2) and ß2-adrenergic receptors. In addition, DPX exhibits agonistic effects at cardiac ß1 receptors (9). In vivo, DPX causes vasodilation on both the systemic and pulmonary levels. Further, DPX possesses positive inotropic and chronotropic properties and thus increases HR, contractility, and cardiac output (10). In clinical practice, DPX is primarily given to patients with left ventricular failure to improve cardiac performance (11).

The purpose of this study was to compare the effects of AVP with and without a concurrent DPX infusion on hemodynamics and global oxygen transport under physiologic (healthy) and pathologic (endotoxemic) conditions. Specifically, our hypothesis was that with an infusion of AVP, MAP can be increased and that the anticipated reduction in CI and DO2 may be reversed by a simultaneous DPX infusion. Because we have already demonstrated that AVP infusion is accompanied by a pulmonary vasopressive effect (12), it was an additional objective to investigate whether DPX may be useful to mitigate or reverse this condition.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by the Government Animal Research Committee, 9 adult sheep were instrumented for chronic study as described previously (12–15). During the first 14 h of endotoxemia, 2 sheep died and were excluded from the study. The entire experiment was performed in 7 ewes with an average weight of 42 ± 3 kg.

After the induction of anesthesia with IM ketamine (20–25 mg/kg KetanestTM; Parke-Davis Ltd. Berlin, Freiburg, Germany), the ewes were chronically instrumented with a thermodilution pulmonary artery catheter positioned percutaneously through an introducer sheath via the right jugular vein (8.5F Catheter Introducer Set; pvb Medizintechnik GmbH, Kirchseeon, Germany; and 7.5F Edwards Swan-GanzTM catheter; Baxter Critical Care Division, Irvine, CA). In addition, an arterial catheter (18-gauge Leader Cath; Vygon Ltd., Aachen, Germany) was inserted into the left femoral artery. During the instrumentation, anesthesia was maintained with a continuous infusion of propofol 120–180 mg/h (DisoprivanTM; AstraZeneca, Schwetzigen, Germany). After the instrumentation, the ewes received a single infusion of 2 g of ceftriaxone (RocephinTM; Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany) and a continuous infusion of lactated Ringer’s solution (2 mL · kg–1 · h–1).

After a 24-h period of recovery, catheters were connected to pressure transducers (DTXTM pressure transducer kit; Ohmeda Ltd. and Co. KG, Erlangen, Germany) and a physiological recorder (Hellige ServomedTM; Hellige Ltd., Freiburg, Germany) to monitor HR, MAP, mean pulmonary artery pressure (MPAP), central venous pressure (CVP), and pulmonary artery occlusion pressure (PAOP). Cardiac output was obtained with the thermodilution technique by using the mean of triplicate 10-mL injections of cold (2°C–5°C) saline solution (9520 A cardiac output computer; Edwards Laboratories, Irvine, CA). CI, systemic vascular resistance index (SVRI), pulmonary vascular resistance index (PVRI), stroke work index (SVI), left ventricular stroke work index (LVSWI), and right ventricular stroke work index (RVSWI) were calculated with standard equations:


{41MM1}



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{41MM4}



{41MM5}



{41MM6}

Mixed venous and arterial blood was drawn to determine oxygen saturation, hemoglobin, oxyhemoglobin saturation, hematocrit (Hct), acid-base status, and lactate concentrations. All blood samples were analyzed at the measured body temperature with an ABL 620 (Radiometer; Copenhagen, Denmark). DO2 index (DO2I) was calculated as 0.136 · arterial · Hb · SaO2 + 0.03 · PaO2) · CI (mL · min–2 · m–2), and oxygen extraction rate (O2-ER) as arteriovenous oxygen content difference/arterial oxygen content. Core body temperature was measured with the thermistor of the Swan-Ganz catheterTM.

All measurements were performed in awake, spontaneously breathing animals, which were housed and studied in metabolic cages with water and food ad libitum throughout the experiment. During the endotoxemic part of the study, lactated Ringer’s solution was adjusted as a continuous fluid resuscitation, aiming to keep CVP and PAOP at their baseline level ±3 mm Hg.

Animals were included in the study only if body temperature was >38.5°C and <40°C, HR was <100 bpm, and MPAP was <25 mm Hg. After a baseline measurement (T0), healthy sheep received AVP (PitressinTM; Parke-Davis Ltd. Berlin) as a continuous infusion (0.04 U/min). One hour later (T1), DPX (DopacardTM; Speywood Pharmaceuticals, Berkshire, UK) was additionally administered in incremental doses (1 µg · kg–1 · h–1 [T2], 5 µg · kg–1 · h–1 [T3], and 10 µg · kg–1 · h–1[T4]), each dose for 30 min. After the titration period of 90 min, all drug infusions were stopped. Hemodynamic variables and key variables of oxygen transport were analyzed before and 1 h after AVP infusion and 30 min after each dose of DPX.

After a 24-h period of recovery, endotoxemia was induced and maintained in the same sheep by a continuous infusion of Salmonella typhosa endotoxin (10 ng · kg–1 · min–1; Sigma Chemicals, Deisenhofen, Germany) for the next 18.5 h. In the animals that survived 16 h of endotoxin challenge (n = 7), measurements were repeated according to the same study protocol that was used in the healthy state. Because the same animals were studied in healthy and endotoxemic conditions, they served as their own controls (n = 7 per group). At the end of the experiment, the surviving ewes were deeply anesthetized with propofol (4 mg/kg Disoprivan) and killed with an overdose of 100 mL of potassium chloride (7.4%).

Data are presented as mean ± SEM. For statistical analysis, SigmaStat 2.03 software (SPSS Inc., Chicago, IL) was used. After testing for normal distribution (Kolmogorov-Smirnov test), Student’s t-test was used to compare the differences between healthy and endotoxemic sheep. With a two-way analysis of variance for repeated measurements and a Student-Newman-Keuls post hoc test for multiple comparisons, effects of the treatments in healthy and endotoxemic conditions were calculated. For all statistical tests, P < 0.05 was regarded as significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
After 16 h of endotoxemia, all surviving sheep (n = 7) exhibited a hypotensive/hyperdynamic circulation with a decrease in SVRI and MAP (Fig. 1) and an increase in HR and CI (P < 0.001 each; Fig. 2). In addition, all sheep demonstrated an increase in PVRI, MPAP (Fig. 1), and RVSWI (Table 1), as well as a decrease in LVSWI (Table 1; P < 0.001 each). These hemodynamic changes were associated with an increase in DO2I (P < 0.01) and a decrease in O2-ER (P < 0.05; Fig. 3). Endotoxin infusion was also linked with a loss in bases and an increase in both lactate (Table 2) and core body temperature (39.3°C ± 0.1°C versus 41.3°C ± 0.2°C; P < 0.001 versus baseline). Compared with the healthy state, there were no changes in CVP, PAOP (Table 1), or Hct (Table 2).



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  		Figure 1. Mean arterial blood pressure (MAP) and mean pulmonary arterial pressure (MPAP) before (T0) and 1 h after continuous infusion of arginine vasopressin at 0.04 U/min (T1) and with simultaneous infusion of dopexamine at 1 µg · kg–1 · min–1 (T2), 5 µg · kg–1 · min–1 (T3), and 10 µg · kg–1 · min–1 (T4) in healthy controls and endotoxemic sheep.{OV0060} = controls (n = 7);{OV0051} = sheep after 16 h of endotoxemia (n = 7). Data are expressed as mean ± SEM. *P < 0.05, control versus endotoxemia; §P < 0.05 versus T0 in controls; $P < 0.05 versus T1 in controls; #P < 0.05 versus T0 in endotoxemia; +P < 0.05 versus T1 in endotoxemia.

 


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  		Figure 2. Heart rate (HR) and cardiac index (CI) before (T0) and 1 h after sole vasopressin infusion (0.04 U/min; T1) and with simultaneous infusion of dopexamine at 1 µg · kg–1 · min–1 (T2), 5 µg · kg–1 · min–1 (T3), and 10 µg · kg–1 · min–1 (T4) in healthy controls and endotoxemic sheep.{OV0060} = controls (n = 7);{OV0051} = sheep after 16 h of endotoxemia (n = 7). Data are expressed as mean ± SEM. *P < 0.05, control versus endotoxemia; §P < 0.05 versus T0 in controls; $P < 0.05 versus T1 in controls; #P < 0.05 versus T0 in endotoxemia; +P < 0.05 versus T1 in endotoxemia.

 

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  		Table 1. Effect of Arginine Vasopressin and Dopexamine on Hemodynamic Variables
 


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  		Figure 3. Oxygen delivery index (DO2I) and oxygen extraction rate (O2-ER) before (T0) and 1 h after sole vasopressin infusion (0.04 U/min; T1) and with simultaneous infusion of dopexamine at 1 µg · kg–1 · min–1 (T2), 5 µg · kg–1 · min–1 (T3), and 10 µg · kg–1 · min–1 (T4) in healthy controls and endotoxemic sheep.{OV0060} = controls (n = 7);{OV0051} = sheep after 16 h of endotoxemia (n = 7). Data are expressed as mean ± SEM. *P < 0.05, control versus endotoxemia; §P < 0.05 versus T0 in controls; $P < 0.05 versus T1 in controls; #P < 0.05 versus T0 in endotoxemia; +P < 0.05 versus T1 in endotoxemia.

 

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  		Table 2. Effects of Arginine Vasopressin and Dopexamine on Oxygen Saturation, Hematocrit, Acid-Base Balance, and lactate
 
AVP infusion increased MAP (Fig. 1) and SVRI (Table 1; P < 0.001 each) and led to a substantial decrease in HR and CI in both healthy and endotoxemic conditions (P < 0.001 each; Fig. 2). In the endotoxemic condition, however, the increase in MAP was more pronounced than in the healthy state ({Delta}MAP: 22.1% versus 11.5%; P < 0.001; Fig. 1). During endotoxemia, AVP decreased HR to baseline values and reduced CI to even less than baseline in the healthy state (P < 0.05; Fig. 2). In both conditions, this was associated with a significant decrease in DO2I (P < 0.001) and an increase in O2-ER (P < 0.001; Fig. 3). In both healthy and endotoxemic animals, AVP infusion also depressed mixed venous oxygen content (SvO2) to values less than baseline (P < 0.001; Fig. 4). Interestingly, AVP administration did not alter the pulmonary circulation in the healthy state but did increase PVRI during endotoxemia (P < 0.01; Table 1). Although AVP infusion did not affect LVSWI, it reduced RVSWI in healthy (P < 0.05) and endotoxemic (P < 0.001; Table 1) conditions. After AVP infusion, there were no changes in acid-base balance or Hct (Table 2).



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  		Figure 4. Systemic venous oxygen saturation (SvO2) before (T0) and 1 h after sole vasopressin infusion (0.04 U/min; T1) and after additional administration of dopexamine at 1 µg · kg–1 · min–1 (T2), 5 µg · kg–1 · min–1 (T3), and 10 µg · kg–1 · min–1 (T4) in healthy controls and endotoxemic sheep.{OV0060} = controls (n = 7);{OV0051} = sheep after 16 h of endotoxemia (n = 7). Data are expressed as mean ± SEM. *P < 0.05, control versus endotoxemia; §P < 0.05 versus T0 in controls; $P < 0.05 versus T1 in controls; #P < 0.05 versus T0 in endotoxemia; +P < 0.05 versus T1 in endotoxemia.

 
In a dose-dependent manner, DPX restored the AVP-linked depression in HR and CI in health and endotoxemia (Fig. 2). Adding DPX to AVP infusion successively increased DO2I and SvO2 and decreased O2-ER in both conditions (Figs. 3 and 4). Dose-dependently, DPX also blunted the AVP-associated increase in MAP (Fig. 1) and SVRI (Table 1) in healthy and endotoxemic sheep. With DPX doses ≥5 µg · kg–1 · h–1, MAP and SVRI returned to baseline values in healthy conditions. In endotoxemia, large-dose DPX (10 µg · kg–1 · h–1) decreased SVRI to baseline and MAP to even less than baseline. Compared with baseline in healthy sheep, DPX infusion did not affect MPAP or PVRI. In endotoxemic sheep, however, DPX infusion ≥5 µg · kg–1 · h–1 reversed the AVP-associated increase in PVRI, and DPX at 10 µg · kg–1 · h–1 also decreased MPAP to less than baseline in endotoxemia (P < 0.05; Table 1). In this study, DPX infusion had no effect on LVSVI in either group, but it restored the AVP-associated decrease in RVSVI in healthy sheep. Adding DPX to AVP led not only to a dose-dependent loss in bases but also to an increase in blood lactate levels (Table 2).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study we investigated the effects of exogenous AVP with and without a concomitant DPX infusion on hemodynamics and key variables of global oxygen transport. The major finding was that during endotoxemia, small doses of DPX ameliorated the AVP-related depression in CI, DO2I, and SvO2 but decreased systemic blood pressure.

In an established and clinically valid ovine model (11–17), systemic inflammation was induced and maintained by a continuous endotoxin infusion and resulted in a hypotensive/hyperdynamic circulation. This was to be expected, because endotoxin upregulates iNOS, which produces large amounts of NO (18). In addition, vascular adenosine 5'-triphosphate-regulated potassium channels are activated in endotoxemia and lead to a reduced entry of Ca2+ ions through voltage-gated Ca2+ channels (19). Both mechanisms ultimately contribute to significant relaxation of resistance vessels and myocardial depression, with resultant decreases in SVRI and contractility (20). The associated reduction in afterload typically leads to a reflectory increase in CI and DO2. The observed vasodilation in this study (decrease in SVRI by 35%) is usually found in this sheep model (12–15), which is one of the most frequently used large-animal models to investigate vasoactive drugs for the treatment of vasodilatory shock (17). Although the mortality rate of 22% may appear not to be very high, it is similar to that found in postoperative intensive care patients with systemic inflammation. The occurrence of pulmonary hypertension in this model has to be ascribed to increased thromboxane and endothelin plasma levels (21) and is similar to the pathophysiology seen in clinical practice (22). Most likely, the observed increase in core body temperature has to be attributed to increased metabolic demands. Notably, the changes in hemodynamics and oxygen transport after 16 hours of endotoxemia observed in this study are similar to those found in previous experiments using the same animal model without AVP and DPX treatment before the induction of endotoxemia (11,16). Accordingly, infusion of these vasoactive drugs before the administration of endotoxin did not affect the hemodynamic response to endotoxin.

AVP infusion led to a rapid and significant increase in MAP and SVRI both in stressed and unstressed conditions. During endotoxemia, however, the increase in systemic blood pressure was greater than in healthy conditions. These findings are in full agreement with previous experimental and clinical studies showing a vasopressin pressor hypersensitivity in vasodilatory septic shock (3–6,12). This hypersensitivity to exogenous AVP may be explained by exhausted endogenous vasopressin stores and, subsequently, low plasma levels (5), which in turn may increase the affinity of V1 receptors against exogenous AVP. Because AVP plays a key role in the regulation and preservation of cardiovascular homeostasis, inappropriately low vasopressin plasma levels have been identified as a causative factor that contributes to the vasodilation in septic shock (6). Because infusion of small-dose AVP (0.01–0.04 U/min) improves cardiovascular functions in human septic shock (5–6), vasopressin substitution has been suggested as a rational therapy (23).

Currently, AVP is increasingly used for hemodynamic support in different kinds of shock states. The potential problem, however, is that exogenous AVP may exhibit negative chronotropic (4,12) and inotropic (24) effects that, most likely, have to be attributed to interactions with cardiac and central nervous V1 receptors (7,25). Our findings that the increase in MAP was linked to a decrease in HR and CI (Fig. 1) are in full agreement with this assumption. A reduction in systemic blood flow in a state of increased oxygen demand—i.e., systemic inflammatory response syndrome—may carry the risk of inappropriate tissue oxygenation and, therefore, lead to cellular or organ dysfunction (2). An AVP-associated decrease in systemic DO2I was also observed in our study. In response to the decrease in DO2I, systemic O2-ER increased to compensate for increased oxygen requirements. However, the observed tendency of an increased SvO2 in endotoxemia suggests that this mechanism failed over time. Alternatively, the increase in SvO2 may have resulted from increases in CI, DO2I (26), and/or arteriovenous shunt (27). Because AVP, when given in vasoactive doses, may exert unfavorable effects on the splanchnic microcirculation (28), it may also be that microcirculatory disturbances caused this impairment in SvO2. However, these results are especially important, since Rivers et al. (1) demonstrated that keeping SvO2 within physiologic ranges is essential to improve survival in patients with sepsis. When these results are viewed together, our data imply that infusion of vasopressor drugs to correct moderate hypotension in sepsis is not necessarily beneficial, because this may impair systemic blood flow and, in proportion, tissue oxygen supply.

Interestingly, infusion of AVP alone had no influence on the acid-base balance, whereas adding DPX to AVP led to a dose-dependent loss in bases and an increase in blood lactate levels. Because DPX infusion was associated with an improvement in both systemic blood flow and DO2I, it is unlikely that lactate was generated because of inappropriate tissue oxygenation. Notably, an increase in lactate does not necessarily have to be ascribed to an imbalance between oxygen demand and supply but may be the result of ß2-adrenoceptor activation (9,10,29). Alternatively, one may speculate whether AVP infusion contributed to microregional acidosis that was initially masked by postcapillary vasoconstriction. Adding DPX may have resulted in splanchnic vasodilation (30), with a subsequent liberation of lactate into the systemic circulation.

However, DPX restored the AVP-associated decrease not only in SvO2, but also in DO2I. Most likely, this improvement in oxygen supply can be explained by increases in systemic and microvascular blood flow, a hypothesis that is supported by previous experimental and clinical studies (30–33). Using intravital microscopy, Sack et al. (31) demonstrated that DPX attenuated intestinal microvascular perfusion injury in pigs subjected to extracorporeal circulation. A DPX-associated improvement in ileal and jejunal blood flow has also been demonstrated in rabbits undergoing cardiopulmonary bypass (32). Similarly, Smithies et al. (30) confirmed that DPX improves gastric intramucosal pH and oxygenation in patients with sepsis.

Since Bucher et al. (34) demonstrated that cytokines may downregulate vasopressinergic V1 receptors in septic rats, we performed another study to investigate whether long-term administration of AVP is associated with a reduced efficacy in our model. Using the same AVP dose (0.04), we found that in endotoxemic sheep, hemodynamics remained unchanged for a longer observation period than that investigated in the current study (Table 3). Therefore, it is unlikely that the hemodynamic changes seen in association with DPX were due to tachyphylaxis against exogenous AVP.


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  		Table 3. Effects of Arginine Vasopressin Infusion on Hemodynamics in Endotoxemia
 
Fluid challenge is one of the cornerstones in the treatment of patients with sepsis (1). In the endotoxemic period of this study, we therefore adjusted the infusion rate to keep CVP and PAOP at baseline. The fact that Hct remained unchanged in endotoxemic sheep confirms adequate volume substitution. This approach, nevertheless, failed to maintain hemodynamics in normal ranges and resulted in a hypotensive/hyperdynamic circulation. This condition, however, mimics the clinical setting, where vasoconstrictors are usually administered to augment MAP. Despite increasing SVRI, AVP infusion did not alter LVSWI. Because SVI also remained constant in endotoxemia, the changes in CI were obviously due to changes in HR and afterload rather than to an improvement in contractility. Interestingly, AVP even decreased RVSWI (Table 1), a finding that is supported by Leather et al. (24): in a canine model of acute pulmonary hypertension, they showed that AVP exerted a negative inotropic effect on the right ventricle, thereby impairing ventriculoarterial coupling.

In the common setting of systemic inflammatory response syndrome, pulmonary hypertension often occurs (2,13). An increase in MPAP and PVRI was also observed in this study. As reported previously, AVP infusion alone further augmented the pulmonary vasoconstrictive response in endotoxemia; this is possibly explained by upregulation of pulmonary V1 receptors (12). Because the pulmonary circulation does not necessarily follow Ohm’s law and PVRI is inversely related to CI (13,35), it is also possible that the decrease in PVRI was linked to the increase in CI. However, because of its pulmonary vasodilatory effect (10,11), DPX infusion reversed this condition. While large-dose DPX (10 µg · kg–1 · min–1) also decreased MPAP, systemic hypotension and tachycardia occurred, thereby limiting its therapeutic use. Since DPX caused systemic vasodilation in a dose-dependent manner, only DPX at small doses may be useful to improve cardiovascular functions during hemodynamic support with AVP. In our study, DPX at 5 µg · kg–1 · min–1 was associated with the most favorable hemodynamic effects.

To improve hemodynamics of patients with sepsis, current treatment strategies aim to maintain or reestablish an adequate perfusion pressure, assuming that this approach ensures sufficient tissue oxygenation. In this study, AVP reversed the hyperdynamic circulation—as indexed by an increase in MAP and SVRI and a decrease in HR and CI—but nevertheless resulted in a decrease in systemic DO2I and SvO2. In a dose-dependent manner, DPX infusion decreased systemic blood pressure, most likely through stimulation of cardiovascular ß2 receptors (9). At the same time, however, key variables of oxygen transport were ameliorated, suggesting that an increase in perfusion pressure is not necessarily associated with an improvement in tissue oxygen supply. The ideal hemodynamic profile, which is characterized by a simultaneous improvement in perfusion pressure and tissue oxygenation, was reached neither with AVP infusion alone nor with a combination of AVP and DPX.

This study has limitations that we want to acknowledge. First, we did not study a control group that received no treatment. In this regard, however, it is noteworthy that we have already demonstrated in untreated animals that hemodynamics remain stable for an observation period of 19 hours (12). It also remains unanswered whether the effects of AVP and DPX differ in more severe models. Whether or not the combination of both drugs has the potential to improve survival remains to be investigated in future studies. In addition, the pathophysiologic changes that occur during ovine endotoxemia may differ from those of human sepsis. However, all sheep exhibited a hypotensive/hyperdynamic circulation and changes in oxygen transport comparable to those observed in patients with severe sepsis (1).

In summary, this is the first study to investigate the effects of a simultaneous AVP and DPX infusion on hemodynamics and key variables of oxygen transport. Despite decreasing perfusion pressure, small doses of DPX reversed the AVP-related depression in CI, DO2I, and SvO2. Although large-dose DPX also attenuated pulmonary hypertension, systemic hypotension and tachycardia occurred. Additional preclinical studies may be required to determine the effects of AVP and DPX on oxygen transport and microvascular blood flow in greater detail.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Rivers E, Nguyen B, Havstad S. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345: 1368–77.[Abstract/Free Full Text]
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Accepted for publication March 2, 2004.




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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