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*Division of General and Surgical Intensive Care Medicine, Department of Anesthesia and Critical Care Medicine; and Department of Medical Biostatistics, The Leopold Franzens University of Innsbruck, Innsbruck, Austria
Address correspondence and reprint requests to Walter R. Hasibeder, MD, Division of General and Surgical Intensive Care Medicine, Department of Anesthesia and Critical Care Medicine, The Leopold Franzens University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. Address e-mail to Walter.Hasibeder@ uibk.ac.at.
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Abstract |
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Implications: In this retrospective analysis, the influence of a continuous infusion of anendogenous hormone (arginine vasopressin) on systemic hemodynamics andlaboratory variables was assessed in patients with vasodilatory shockunresponsive to conventional therapy. Arginine vasopressin was effective inreversing systemic hypotension. However, adverse effects on gastrointestinalperfusion and coagulation cannot beexcluded.
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Introduction |
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Vasopressor catecholamines are the only drugs available for the management of severe hypotension in SS and PS. However, development of adrenergic hyposensitivity with loss of catecholamine pressor effects, resulting in refractory hypotension, is a well known clinical dilemma (3). Further enforcing catecholamine therapy, intensivists often enter a vicious circle in which the significant toxicity of catecholamine administration (e.g., excessive pulmonary hypertension and development of tachyarrhythmias) may contribute to further clinical deterioration and subsequent outcome. Therefore, alternative vasopressor drugs devoid of major systemic side effects would be of vital benefit in advanced states of vascular failure. Arginine vasopressin (AVP) is a potent vasoconstrictor in various hypotensive states, including cardiac arrest, the late phase of hemorrhagic shock, and orthostatic or hemodialysis-induced hypotension (4–7). In addition, in smaller studies (8), AVP has been successfully used to treat hypotension in volume-resuscitated critically ill patients with sepsis and after cardiopulmonary bypass.
Between January 1998 and May 2000, we administered AVP to 60 critically ill patients with catecholamine-resistant SS or PS and severe multiple-organ dysfunction syndrome. This retrospective analysis demonstrates the effects of continuous AVP infusion on systemic hemodynamics, acid/base status, and single-organ variables. This is the largest study reporting on the application of AVP in critically ill patients.
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Methods |
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Catecholamine-resistant shock was defined as the failing effect of a stepwise increase of norepinephrine by 0.2 µg · kg-1 · min-1 over a 2-h period on mean arterial pressure (MAP). All patients were volume-resuscitated according to the response of stroke volume index to volume loading. Normovolemia was assumed if a trial of further volume loading with colloids produced no effect on stroke volume index. The pulmonary capillary wedge and central venous pressure where stroke volume index was maximal was used as the therapeutic target for additional volume resuscitation. An AVP infusion was given continuously, with doses ranging from 4 to 6 U/h. No bolus injections were used. After initiating AVP infusion, norepinephrine therapy was targeted to maintain MAP 
70 mm Hg in all patients. When MAP exceeded 70 mm Hg, norepinephrine infusion was stepwise decreased according to MAP. Norepinephrine was not completely withdrawn in any patient. AVP infusion was continuously reduced and tapered off when norepinephrine requirements decreased <0.3–0.4 µg · kg-1 · min-1. In this situation, weaning from AVP occurred first and individually according to the patient’s response to a stepwise decrease in AVP. In patients successfully weaned from AVP, further weaning from norepinephrine occurred individually according to the response of MAP to small stepwise reductions in norepinephrine infusion. During the observation period, 80% of the study patients were on continuous venovenous hemofiltration with constant ultrafiltration rates between 20 and 30 mL/min.
The following data were collected from all patients: demographics (including age, sex, admission diagnosis, and length of ICU stay), multiple-organ dysfunction score (MODS) (Appendix 1), ICU mortality, and length of AVP administration.
Hemodynamic data, including heart rate, MAP, mean pulmonary arterial pressure, and norepinephrine requirements, were obtained before; 30 min after; and 1, 4, 12, 24, 48, and 72 h after the start of AVP infusion. Arterial acid/base status and arterial lactate concentrations (Rapidlab 860; Chiron Diagnostics, Medfield, MA), as well as pulmonary artery catheter measurements—including cardiac index, stroke volume index, and pulmonary capillary wedge pressure—were measured before and 1–3, 4–8, 12–16, 24 ± 5, 48 ± 5, and 72 ± 5 h after the start of AVP infusion. Systemic vascular resistance was calculated from recorded data.
In all patients, laboratory examinations to evaluate hepatic, renal, and hematologic organ systems, as well as creatine kinase MB (CK-MB) and troponin I (TROP) serum concentrations were obtained at least once daily.
The primary study end point was the assessment of changes in systemic hemodynamics during continuous infusion of AVP in catecholamine-resistant SS and PS. To evaluate possible differences at baseline and during AVP infusion, patients were further separated into survivors and nonsurvivors and into patients with SS or PS.
The secondary study end point was to compare alterations in acid/base status and single-organ laboratory variables during AVP infusion in survivors and nonsurvivors.
Demographic data were compared with the use of Student’s t-tests, 
2 tests, or Mann-Whitney U-tests, as appropriate. Repeated measurements were analyzed with a mixed-effects model (SAS PROC MIXED; SAS Institute, Cary, NC) to account for death-related dropouts (9). Variables that did not meet normality assumptions (systemic vascular resistance, aspartate aminotransferase, and alanine aminotransferase; bilirubin, lactate, CK-MB, and TROP serum concentrations; and thrombocyte count) were log-transformed. If trends were significant, comparisons with baseline were performed with the same model. Because of the explorative character of the study, no corrections for multiple comparisons were used. P values <0.05 were regarded as statistically significant. Data are given as mean ± SD.
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Results |
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Characteristics of study subgroups are shown in Table 1. There were no significant differences in age and MODS between survivors and nonsurvivors. ICU stay was significantly longer in survivors. We found no differences in MODS, ICU stay, and mortality between SS and PS patients. Patients with PS were significantly older and demonstrated nearly 20% less ICU mortality when compared with SS patients.
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Discussion |
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The pharmacologic mechanisms of AVP-mediated increases in arterial pressure are still a matter of speculation. However, four molecular pathways have already been discussed. First, stimulation of vascular smooth muscle V1-receptors by AVP increase cytoplasmic ionized calcium via the phosphatidyl-inositol-bisphosphate cascade, leading to arteriolar vasoconstriction (8). Second, blockage of activated ATP/potassium channels within the muscle cell membrane facilitates myocyte depolarization and thus vasoconstriction (10). Third, under pathophysiologic conditions, AVP attenuates endotoxin and interleukin-1ß-stimulated generation of nitric oxide and its second messenger, cyclic guanosine monophosphate, thus inhibiting excessive arteriolar vasodilatation (11). Fourth, during endotoxemia, AVP enhances adrenergic responsiveness through stimulation of smooth muscle V1-receptors (12). The last three mechanisms may be especially important in counteracting excessive vasodilatation in shock caused by sepsis or after major surgery.
Because similar dosages of AVP usually demonstrate no pressor effect in normotensive subjects, several authors have postulated that AVP deficiency in critically ill patients is probably mediated by a defective baroreflex system with subsequent development of compensatory "AVP pressor hypersensitivity" (13,14). However, in acute hypotensive states (i.e., cardiac arrest, hypotension during combined general and epidural anesthesia, or phosphodiesterase inhibitor-induced hypotension) in which primary AVP deficiency seems to be unlikely, AVP is also a potent arterial vasoconstrictor (4,15,16). Argenziano et al. (17) demonstrated a reversal of vasodilatory shock with AVP regardless of AVP plasma concentrations before administration. In addition, in normotensive subjects, AVP-induced vasoconstriction is accompanied by a reflectory decrease in heart rate and cardiac output, preventing any increase in MAP (18). Furthermore, in critically ill patients, partial restoration of adrenergic hyporesponsiveness could imitate AVP hypersensitivity. These findings suggest that hypotension per se, rather than an impaired baroreflex system or AVP deficiency, is a precondition for the pressor effect of AVP.
In this study, we observed a significant decrease in mean pulmonary arterial pressure during infusion of AVP; such a decrease has not been described in humans before. This decrease was already present four hours after the start of AVP infusion, suggesting a causal relationship with AVP administration. Experimental studies in animals have demonstrated that AVP-induced pulmonary vasodilatation is probably mediated by a nitric oxide-dependent mechanism (19,20). However, in our patients, the simultaneous significant reduction in norepinephrine requirements during AVP infusion may have contributed to the observed decrease in mean pulmonary arterial pressure.
AVP proved to be equally effective in reversing hypotension caused by SS or PS with an almost identical hemodynamic response. Reversal of hypotension was accompanied by a decrease in heart rate and mean pulmonary arterial pressure without any change in myocardial performance (assessed by stroke volume index), despite a simultaneous significant reduction in norepinephrine requirements. The latter observation is of particular interest because AVP, in contrast to norepinephrine, is devoid of major positive inotropic effects on the myocardium (18). Perhaps AVP improved myocardial perfusion and thus prevented any deterioration in myocardial performance, either by increasing myocardial perfusion pressure or by inducing selective coronary vasodilatation at dosages used in these patients. Coronary vasodilatation, probably caused by stimulation of various V1- and V2-receptors, has been demonstrated in animal experiments (21). We observed no new myocardial ischemic events during AVP administration in this study. Increased concentrations of serum CK-MB and TROP at baseline significantly decreased during the observation period in both survivors and nonsurvivors. Although four patients developed new onset supraventricular tachyarrhythmias, we observed eight other patients spontaneously converting into sinus rhythm during application of AVP. Decreased adrenergic myocardial stimulation because of a significant reduction in norepinephrine requirements and a possible improvement of myocardial perfusion may have contributed to this observation.
Nonsurvivors demonstrated more severe lactic acidosis, most likely as a consequence of a more pronounced deterioration of tissue perfusion when compared with survivors. Survivors showed a progressive improvement in acid/base status throughout the observation period. Because 80% of patients were on continuous venovenous hemofiltration, no differences in serum creatinine concentrations were observed.
A significant increase in liver enzymes and bilirubin concentrations occurred in all patients during the observation period. Because AVP is a potent gastrointestinal vasoconstrictor, this finding might indicate adverse effects on gastrointestinal perfusion (22). However, the observed increases in liver enzymes and bilirubin concentration may have also been a consequence of shock-associated hepatic dysfunction.
We noted a significant decrease in platelet count during this study that was almost identical in survivors and nonsurvivors. Although disseminated intravascular coagulation with increased platelet consumption is a common finding in patients with shock, the observed decrease in circulating platelets may in part be related to the infusion of AVP; in animal experiments, AVP facilitates platelet adhesion and aggregation as a consequence of V1-receptor stimulation, with subsequent platelet calcium loading (23,24).
In conclusion, AVP proved to be a powerful vasopressor in patients with catecholamine-resistant SS or PS and severe multiple-organ dysfunction syndrome. AVP consistently led to a significant increase in MAP and a decrease in heart rate, mean pulmonary arterial pressure, and norepinephrine requirements, without any change in myocardial performance. Because negative side effects on gastrointestinal perfusion and coagulation cannot be excluded, we suggest that the administration of AVP should still be restricted to patients with catecholamine-resistant vasodilatory shock. Future studies should focus on the influence of AVP on single-organ functions and its effect on overall mortality in these critically ill patients.
APPENDIX
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