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Ertmer, Christian*; Bone, Hans-Georg*; Morelli, Andrea; Van Aken, Hugo*; Erren, Michael; Lange, Matthias*; Traber, Daniel L.§; Westphal, Martin*

doi: 10.1097/01.shk.0000235140.97903.90
Basic Science Aspects

Tachyphylaxis against catecholamines often complicates hemodynamic support in patients with septic shock. Recent experimental and clinical research suggests that the hemodynamic response to exogenous arginine vasopressin (AVP) infusion may also be blunted. The purpose of the present study was therefore to clarify whether the efficacy of a continuous AVP infusion (0.04 U · min−1) decreases over time in ovine endotoxemia. An additional objective was to determine whether the anticipated hyporesponsiveness can be counteracted by corticosteroids. Fourteen adult ewes (37 ± 1 kg) were instrumented for chronic hemodynamic monitoring. All ewes received a continuous endotoxin infusion that contributed to a hypotensive-hyperdynamic circulation. After 16 h of endotoxemia, the sheep were randomized to receive either AVP (0.04 U · min−1) or the vehicle (normal saline; n = 7 each). After 6 h of AVP or placebo infusion, respectively, methylprednisolone (30 mg · kg−1) was injected. Arginine vasopressin infusion increased mean arterial pressure and systemic vascular resistance index at the expense of a reduced cardiac index (P < 0.05 each). Supraphysiologic AVP plasma levels in the treatment group (298 ± 15 pg · mL−1) were associated with increased surrogate parameters of liver, mesenterial, and myocardial dysfunction. After 6 h of continuous AVP infusion, the vasopressor effect was significantly reduced. Interestingly, a bolus infusion of methylprednisolone (30 mg · kg−1) reestablished mean arterial pressure by increasing both cardiac index and systemic vascular resistance index. The present study demonstrates that in endotoxemia, (a) the vasopressor effect of AVP infusion may be reduced, (b) corticosteroids may potentially be useful to increase the efficacy of AVP infusion, and (c) even moderate AVP doses may potentially impair myocardial and hepatic function.

*Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany; Department of Anesthesiology and Intensive Care, University of Rome "La Sapienza," Rome, Italy; Department of Laboratory Medicine, University of Muenster, Muenster, Germany; and §Investigational Intensive Care Unit, University of Texas Medical Branch, Galveston, Texas

Received 31 May 2006; first review completed 15 Jun 2006; accepted in final form 24 Jul 2006

Address reprint requests to Priv.-Doz. Dr. Martin Westphal, Department of Anesthesiology and Intensive Care, University of Muenster, Albert-Schweitzer-Str. 33, 48149 Muenster, Germany. E-mail:

This study was funded by the Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany.

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Severe sepsis and septic shock are leading causes of morbidity and mortality in noncoronary intensive care unit patients (1). Death mainly results from multiple organ failure and protracted arterial hypotension hyporesponsive to catecholamines, contributing to tissue hypoperfusion of vital organs (2). In this specific patient population, mortality approaches 60% (3).

Therapeutic strategies to prevent tissue hypoperfusion and hypoxia in septic patients aim at the maintenance of a sufficient perfusion pressure and a balance between oxygen delivery and oxygen consumption (4). When aggressive volume challenge and inotropic therapy fail to improve the pressure-flow relationship, vasopressor agents have to be administered to prevent irreversible organ dysfunction or even death (5, 6).

Because of adrenergic receptor and signaling abnormalities in sepsis, the efficacy of catecholamines often gradually decreases over time (7). Excessive liberation of nitric oxide and inadequate opening of adenosine triphosphate (ATP)-dependent potassium channels play a pivotal role in this regard (7). In addition, it has been reported that arginine vasopressin (AVP) plasma levels are inadequately low in human septic shock (8) and that exogenous substitution of low-dose AVP (0.01-0.067 U · min−1) (8-10) or analogues (11, 12) increases mean arterial pressure (MAP) while allowing weaning from exogenous catecholamines.

However, recent studies suggest that cytokines, such as interleukin 1β, tumor necrosis factor α, and interferon γ may also contribute to a reduced efficacy of exogenous AVP by receptor downregulation (13-15) and impairment of the post-receptor signaling pathway (16, 17). The purpose of the present study was therefore to explicitly clarify whether the efficacy of a continuous AVP infusion (0.04 U · min−1) gradually decreases in an established and clinically relevant ovine model of endotoxic shock (18-22). Since corticosteroids have been shown to reverse tachyphylaxis against exogenous catecholamines (23, 24), it was an additional objective to determine whether corticosteroids may also be suitable to stabilize MAP in endotoxemic sheep treated with a continuous AVP infusion. Methylprednisolone was chosen as a proper substance to maximize glucocorticoid effects while minimizing mineralocorticoid potency.

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Fourteen adult ewes weighing 37 ± 1 kg were instrumented for chronic hemodynamic monitoring using an established protocol (18-22). Study approval was conferred by the local animal research committee.

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Animal preparation

Anesthesia was induced by i.m. injection of xylazine 2% (Xylazin, 0.15 mg · kg−1; CEVA Tiergesundheit GmbH, Düsseldorf, Germany) and S-ketamine (Ketanest 50, 15 mg · kg−1; Parke-Davis, Berlin, Freiburg, Germany) and maintained with a continuous i.v. propofol infusion (Disoprivan, 4 - 6 mg · kg−1 · h−1; AstraZeneca, Schwetzingen, Germany). The unconscious, spontaneously breathing ewes were instrumented with a left femoral arterial catheter (18-gauge Leader Cath; Vygon, Aachen, Germany) and an indwelling pulmonary artery catheter, which was inserted via the right jugular vein through an introducer sheath (8.5-F Catheter Introducer Set; pvb Medizintechnik GmbH, Kirchseeon, Germany; 7.5-F Edwards Swan Ganz; Edwards Critical Care Division, Irvine, Calif). Urine output was monitored by a balloon catheter inserted into the urinary bladder (Porgès S.A., Le Plessis-Robinson Cedex, France). As postsurgical infection prophylaxis, the ewes received a single dose of 1 g ceftriaxone (Rocephin; Homann-La Roche AG, Grenzach-Wyhlen, Germany). Infection prophylaxis was performed to guarantee that the hypotensive-hyperdynamic circulation induced by endotoxin infusion was independent from potential bacterial contamination. Instrumentation was followed by a 24-h recovery period. During this time, all sheep received a continuous i.v. infusion of lactated Ringer solution (2 mL · kg−1 · h−1) to prevent postoperative dehydration.

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Measurement equipment and determined variables

To monitor hemodynamic variables, the catheters were connected to a physiological recorder (Hellige Servomed; Hellige, Freiburg, Germany) via pressure transducers (DTX pressure transducer; Ohmeda, Erlangen, Germany). Hemodynamic monitoring included MAP, mean pulmonary arterial pressure (MPAP), central venous pressure, and pulmonary arterial occlusion pressure. In addition, heart rate (HR) was determined by calculating the mean frequency of arterial pressure curve peeks. Core body temperature (T) was continuously measured by the thermistor at the tip of the pulmonary artery catheter. The thermodilution technique (9520A cardiac output computer; Edward Lifescience, Irvine, Calif) was applied to measure cardiac output by threefold central venous injection of 10 mL physiological saline solution at a temperature of 2°C to 5°C. Cardiac index (CI), systemic vascular resistance index (SVRI), and pulmonary vascular resistance index were determined using standard equations (21).

Arterial and mixed venous blood samples (0.5 mL) were collected in heparinized tubes designed to determine blood gases (Sarstedt; Nümbrecht, Germany). Partial pressures of O2 and CO2 (Po2, Pco2) and pH were determined using an ABL 725 blood gas analyzer with SAT 100 calibration (Radiometer Copenhagen, Copenhagen, Denmark). In addition, hemoglobin concentration, arterial and mixed venous oxygen saturation (Sa/vo2), blood glucose, and arterial lactate concentrations were assessed. Standard bicarbonate (HCO3 ) and base excess were calculated from Pco2 and pH. Oxygen delivery index (Do2I), oxygen consumption index (V˙O2I), and oxygen extraction rate (O2-ER) were determined using standard formulas (21).

Furthermore, arterial serum and plasma samples were collected to measure AVP plasma levels (Vasopressin RIA; Bühlmann, Allschwill, Switzerland), troponin I serum levels (Troponin I-Immulite FC-EIA; Bühlmann), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and lipase activity as well as serum concentrations of bilirubin, creatinine, potassium, and sodium (Hitachi 747 Automatic Analyzer; Böhringer, Mannheim, Germany). EDTA plasma samples for AVP determination were immediately centrifuged, aliquoted, and stored at −20°C until radioimmunoassay was performed (25). Urine samples were analyzed for creatinine, potassium, and sodium concentrations. All measurements were performed according to the experimental protocol.

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Experimental protocol

Inclusion criteria for the present study were an initial HR of less than 100 beats · min−1; blood temperature, less than 39.8°C; MPAP, less than 20 mmHg; and arterial lactate, 1 mmol · L−1 or less.

During the experiment, animals were housed in metabolic cages with free access to water and food. All ewes were spontaneously breathing and studied in a conscious state.

Following a baseline measurement in the healthy state (BL1), the ewes were randomized into two equally sized groups, that is, AVP group and control group (n = 7 each). Thereafter, a hypotensive-hyperdynamic circulation was induced and maintained by a continuous central venous infusion of Salmonella typhosa endotoxin (10 ng · kg−1 · min−1; Sigma Chemicals, Deisenhofen, Germany) diluted with lactated Ringer solution (4 mL · kg−1 · h−1) for the next 24 h. After 16 h of endotoxemia, a second baseline measurement (BL2) was performed and followed by the 8-h study protocol. The AVP group was treated with a continuous central venous infusion of AVP (0.04 U · min−1); the control group received only the vehicle (isotonic sodium chloride solution). After 6 h, a central venous injection of methylprednisolone (30 mg · kg−1) was administered in both study groups.

After the last measurement had been performed, the ewes were deeply anesthetized with a bolus injection of propofol (4 mg · kg−1, Disoprivan; AstraZeneca) and killed with a lethal dose of 100 mL potassium chloride (7.45%).

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Statistical analysis

Data are expressed as means ± SEM. Sigma Stat 2.03 software (SPSS, Chicago, Ill) was used for statistical analysis. After confirming normal distribution of all variables (Kolmogorov-Smirnov), differences within and between groups were analyzed using a two-way analysis of variance for repeated measurements. Because there were significant group differences over time, appropriate post hoc comparisons (Student-Newman-Keuls) were performed. For all statistical tests, an error probability of P less than 0.05 was regarded as statistically significant.

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Effects of endotoxin infusion

All ewes (n = 14; body weight, 37 ± 1 kg) met the including criteria for the present study. Baseline hemodynamic and metabolic variables before endotoxin infusion (BL1) are presented in Figures 1-4 and Tables 1-4. There were no statistical differences between groups, neither at BL1 nor at BL2.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Fig. 4

Fig. 4

Table 1

Table 1

Table 2

Table 2

Table 3

Table 3

Table 4

Table 4

Endotoxin infusion increased core body temperature (Table 3) and arterial lactate concentration (from 0.6 ± 0.1 to 1.3 ± 0.3 mmol · L−1; BL1 vs BL2; P < 0.05) (Fig. 3). All sheep exhibited a hypotensive-hyperdynamic circulation, characterized by an elevated CI and HR and a reduced MAP, SVRI, and LVSWI (all P < 0.05) (Fig. 1, Table 1).

In addition, all sheep showed signs of pulmonary arterial hypertension, as indicated by an increase in MPAP (P < 0.05) (Fig. 2).

After 16 h of endotoxin infusion, V˙o2I remained constant, whereas Do2I was increased (P < 0.05), and O2-ER decreased (P < 0.05) (Fig. 3).

Endotoxin infusion also increased bilirubin and creatinine serum concentrations (Table 4). Arginine vasopressin plasma levels were not significantly different from BL1 (4.7 ± 1.2 vs 3.8 ± 1.3 pg · mL−1; BL1 vs BL2; P = 0.14) (Fig. 4).

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Effects of AVP infusion

Arginine vasopressin infusion significantly increased MAP and SVRI, whereas CI and HR decreased (all P < 0.05) (Fig. 1). Peak values of MAP and SVRI were reached at 3 and 1 h, respectively. In the sequel, both variables decreased until hour 6 (P < 0.05 for MAP and SVRI, 6 vs 1 h) (Fig. 1).

Except for an initial increase in pulmonary vascular resistance index (1 h vs BL2, P < 0.05), AVP infusion had no effect on pulmonary hemodynamics (Fig. 2).

Whereas Do2I and Svo2 decreased, O2-ER was markedly elevated after 6 h of AVP infusion (6 h vs BL2; all P < 0.05) (Fig. 3).

With respect to organ function, AVP significantly increased serum activities of ALT, AST, and LDH (Table 4). In the AVP group, troponin I and bilirubin serum concentrations were elevated as compared with the control group (Table 4). Arterial lactate levels tended to increase in the AVP group (Fig. 3). However, these changes did not reach statistical significance (1.7 ± 0.4 vs 1.2 ± 0.4 mg · dL−1; AVP vs control; P = 0.2).

Exogenous AVP infusion increased AVP plasma levels to supraphysiologic values (298 ± 15 vs 4.6 ± 1.4 pg · mL−1; AVP vs control; P < 0.05) (Fig. 4).

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Effects of methylprednisolone injection

Methylprednisolone injection resulted in a rapid and significant increase in MAP in the AVP group (Fig. 1). Apart from decreases in CI and HR (Fig. 1), there were no changes in hemodynamic variables in the control group.

Methylprednisolone significantly decreased core body temperature in both groups (Table 3).

Pulmonary hemodynamics, global oxygen transport, and parameters of organ function were not affected by methylprednisolone. In addition, AVP plasma levels remained unchanged in both groups (Fig. 4).

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In the present study, the effects of a methylprednisolone bolus infusion on hemodynamics, global oxygen transport, and organ function were investigated in endotoxemic sheep with and without preceding 6 h of AVP infusion.

The major findings are that (1) the efficacy of exogenous AVP infusion (0.04 U · min−1) gradually diminished over time, as indicated by decreases in MAP and SVRI; (2) methylprednisolone reestablished MAP secondary to an increase in CI and SVRI; and (3) even moderate doses of AVP caused increases in surrogate parameters of organ dysfunction, such as liver aminotransferases, LDH, bilirubin, and troponin I.

All measurements were performed in a clinically valid, large-animal model, which closely mimics hemodynamic and metabolic changes seen in human septic shock (18). After 16 h of endotoxemia, all animals showed signs of systemic inflammation, such as increases in core body temperature and arterial lactate levels, and exhibited a hypotensive-hyperdynamic circulation. These hemodynamic and metabolic alterations are similar to those found in previous studies using the same (21, 22) or similar sepsis models (19). The fact that sheep are used to slightly higher blood pressure than human beings explains the quite high MAP of approximately 85 mmHg after 16 h of endotoxemia. However, endotoxin infusion decreased the SVRI by approximately 30%, which reflects severe vasodilation as compared with the healthy state. Therefore, measurements were performed in a condition where vasopressor agents are indicated.

The fact that AVP plasma levels after 16 h of endotoxemia did not significantly differ from the values determined before injury is in harmony with previous clinical studies. In this context, it is noteworthy that Sharshar et al. (26) demonstrated that in acute human sepsis, AVP plasma levels reach peak values within the first 8 h and decline thereafter in proportion to the time from onset of septic shock. Likewise, Landry et al. reported that septic shock patients have low AVP levels of approximately 3 pg · mL−1 at 1 to 2 days after the onset of septic shock (8).

Notably, in the present study, AVP was not used as endocrine support but as a vasopressor to restore MAP. However, the increases in MAP and SVRI occurred at the expense of decreases in CI and HR. These findings are well documented in previous experimental and clinical investigation evaluating the role of AVP in sepsis (21, 27, 28). The increase in SVRI reflects vasoconstriction, mainly due to activation of vascular V1 receptors (29), inhibition of nitric oxide-mediated release of cyclic guanosyl monophosphate (30), and reduction of the opening probability of potassium channels (31). The observed decrease in CI is in line with some clinical and most animal research studies (21, 27, 28) and might be due to V1-mediated activation of baroreceptors resulting in reflex bradycardia (29). In a recent retrospective study of 316 patients treated with AVP (0.067 U · min−1), no significant overall reduction in CI was found (32). In the subpopulation of patients with a hyperdynamic circulation (CI, >3.6 L · min−1 · m−2), however, CI was significantly reduced by AVP infusion.

In addition, AVP infusion was associated with increases in surrogate parameters of organ dysfunction, such as ALT, AST, LDH, bilirubin, and troponin I. Elevations of bilirubin concentration and aminotransferases activity have also been observed in three clinical studies of Dünser et al. (10, 27) and Luckner et al. (32) and may reflect ischemic liver injury. Importantly, in the most recent study by Luckner et al. (32), the rise in bilirubin levels was significantly associated with increased mortality.

It is still unclear whether mesenterial and hepatic vasoconstriction and hypoperfusion represent general risks of AVP therapy in sepsis or do only appear with high supraphysiologic AVP plasma levels (33). In this context, Landry et al. (8) suggested that AVP infusion in septic shock should be aimed to establish plasma concentrations of approximately 20 to 30 pg · mL−1, which reflect the levels found in patients with cardiogenic (nonseptic) shock, where endogenous AVP release is not suppressed. To date, no optimal AVP plasma levels for hemodynamic support in septic shock have been evaluated. Inasmuch as Van Haren et al. (34) reported that high plasma levels (>50 pg · mL−1) proportionally correlate with mucosal hypoperfusion, it may well be that the biochemical markers of organ injury in the present study were related to high AVP plasma levels (298 ± 15 pg · mL−1). In contrast, AVP increased urinary output and improved renal function in endotoxemic ewes. These results are in accordance with previous experimental and clinical findings (21, 28, 35) and can be explained by V1-mediated selective constriction of efferent glomerular vessels and downregulation of renal V2 receptors (28, 29, 36, 37).

Patil et al. (38) were the first to describe a tachyphylaxis against AVP in healthy dogs. Notably, a progressively decreasing efficacy of exogenous AVP in sepsis or endotoxemia has not yet been reported, neither in experimental nor in clinical research. The fact that hemodynamics remained constant in the control group throughout the entire period of endotoxin infusion indicates that there was no progress of the endotoxin-induced SIRS. Vice versa, hyporesponsiveness against exogenous AVP appears suitable to explain the progressive reduction of MAP and SVRI in the AVP group. High AVP plasma levels in the present study may have resulted in V1-receptor desensitization or downregulation. This assumption is supported by the study of Bucher et al. (13), showing that high endogenous AVP levels are associated with a cytokine-mediated V1-receptor downregulation in acute endotoxemia. As AVP hyporesponsiveness in the present study was reversed by methylprednisolone, the underlying mechanism appears to be similar to catecholamine tachyphylaxis in sepsis and endotoxemia (i.e., receptor downregulation and desensitization, impairment of post-receptor signaling pathway and inducible nitric oxide synthase induction) (39-41). However, methylprednisolone administration in critically ill patients having septic shock remains controversial as a multicenter study showed no reduction in overall mortality in the subgroup of patients treated with methylprednisolone (30 mg · kg−1) (42). In the subgroup of patients with increased creatinine plasma concentrations, significantly more patients died because of secondary infections. However, lower doses of methylprednisolone (10 mg · kg−1) seem to provide beneficial effects on hemodynamics and adrenergic receptor physiology in patients with septic shock treated with high doses of catecholamines (43). Although the latter study was not adequately powered to determine mortality, it appears that lower doses of methylprednisolone may have similar beneficial effects in septic shock as hydrocortisone.

Because the pathophysiology of AVP hyporesponsiveness is complex and still not fully understood, future research should focus on the impact of glucocorticoids on AVP receptor physiology in the setting of AVP infusion in sepsis or endotoxemia, respectively.

The present study is limited by using an animal model. However, the model used in the present study closely reflects hemodynamic reactions in human septic diseases (18), and response to exogenous AVP application also equals clinical experience (8, 9, 21, 28). Thus, the results of our experiments can probably be translated into clinical practice. In addition, we attempted to explain the hemodynamic effects of AVP hyporesponsiveness, but did not perform analyses on receptor physiology. Because we did not perform multiple measurements of AVP plasma levels during the onset of endotoxemia, it remains unclear whether circulating AVP levels followed the characteristic profile of human septic shock as described by Sharshar et al. (26). Furthermore, the study period was limited to 8 h. The long-term effects of steroid application on AVP efficacy in endotoxemic or septic shock, respectively, should be focused in future studies. Finally, we infused 30 mg · kg−1 methylprednisolone to revert AVP hyporespon siveness. The current guidelines on septic shock treatment, however, recommend the daily use of 200 to 300 mg hydrocortisone, which is 13 to 20 times lower (5, 6, 44). In this regard, it is noteworthy that we intentionally departed from the international recommendations on the use of corticosteroids in septic shock for two reasons:

  1. To only analyze the effects of glucocorticoid receptor agonism on AVP tachyphylaxis, we chose a substance, which performs only marginal intrinsic activity on mineralocorticoid receptors, that is, methylprednisolone.
  2. Some of the acute glucocorticoid effects are only apparent with very high exogenous doses. These effects may be independent from glucocorticoid receptors and are possibly related to interferences with the cell membrane itself or membrane-bound receptors (45). These specific effects would possibly have been masked when using (only) stress-dose hydrocortisone. Notably, Bone et al. (42) reported that high steroid doses negatively affect long-term survival of septic shock patients mainly due to infectious complications. As survival was not an end point of the present study and the intention was to clearly demonstrate the effects of maximal glucocorticosteroidal agonism, we chose to apply a dose as high as 30 mg · kg−1 methylprednisolone. However, the impact of a stress-dose hydrocortisone therapy on AVP efficacy in endotoxemia or septic shock, respectively, should be determined in future studies. This is especially true because the present study shows that glucocorticoids do have a significant impact on AVP pressor response.

In summary, this is the first study showing that infusion of 0.04 U · min−1 AVP over 6 h is linked to a reduced vasopressor effect in ovine endotoxemia and that methylprednisolone (30 mg · kg−1) is suitable to partially reverse AVP hyporesponsiveness. As a multicenter study is currently evaluating the efficacy and safety of AVP in human septic shock (46), the presence of a hyporesponsiveness against exogenous AVP is of particular interest for clinical practice.

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Blood pressure; corticosteroids; endotoxemia; sepsis; septic shock

©2007The Shock Society