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Purpose: To evaluate the association between concomitant arginine-vasopressin (AVP)/hydrocortisone therapy and mortality in severe septic shock patients., Methods: This retrospective study included severe septic shock patients treated with supplementary AVP. To test the association between concomitant AVP/hydrocortisone use and mortality, a multivariate regression and Cox model (adjusted for admission year, initial AVP dosage and the Sepsis-related Organ Failure Assessment score before AVP) as well as a propensity score-based analysis were used. In both models, intensive care unit (ICU) and 28-day mortality served as outcome variables., Results: One hundred fifty-nine patients were included. Hydrocortisone was administered to 76 (47.8%) at a median daily dosage of 300 (200-300) mg. In the multivariate logistic regression model, concomitant use of AVP and hydrocortisone was associated with a trend towards lower ICU (OR, 0.51; CI 95%, 0.24-1.08; p = 0.08) and 28-day (HR, 0.69; CI 95%, 0.43-1.08; p = 0.11) mortality. The probability of survival at day 28, as predicted by the regression model, was significantly higher in patients treated with concomitant AVP and hydrocortisone compared to those receiving AVP without hydrocortisone (p = 0.001). In a propensity score-based analysis, ICU (45 vs. 65%; OR, 0.69; CI 95% 0.38-1.26; p = 0.23) and 28-day mortality (35.5 vs. 55%; OR, 0.59; CI 95%, 0.27-1.29; p = 0.18) was not different between patients treated with (n = 40) or without concomitant hydrocortisone (n = 40)., Conclusion: Concomitant AVP and hydrocortisone therapy may be associated with a survival benefit in septic shock. An adequately powered, randomised controlled trial appears warranted to confirm these preliminary, hypothesis-generating results.

Concomitant hydrocortisone and arginine vasopressin therapy increases arginine vasopressin plasma levels and may improve survival in septic shock. The objective of this post hoc analysis of a prospective study was to determine whether hydrocortisone therapy increases arginine vasopressin plasma levels in patients with septic shock. Forty-five patients were included into the study, of whom 23 (51.1%) received a hydrocortisone infusion because of escalating vasopressor dosages. Median arginine vasopressin plasma levels did not differ between patients treated with and without hydrocortisone therapy [4.2 (2.2-6.2) vs. 4.3 (2.7-6.1) pmol/L] both in a bivariate (p = 0.43, Mann-Whitney U-test) and a logistic regression model adjusted for differences in disease severity (p = 0.38). No association was further detected between hydrocortisone therapy and arginine vasopressin plasma levels in an adjusted linear regression model [β-coefficient, -0.57 (-1.86-0.73), p = 0.39]. We conclude that increased arginine vasopressin plasma levels during concomitant arginine vasopressin and hydrocortisone therapy in septic shock result from reduced arginine vasopressin clearance and not increased arginine vasopressin secretion or interaction of hydrocortisone with the arginine vasopressin assay.

Background: Plasma copeptin levels before and during exogenous arginine vasopressin infusion (AVP) were evaluated, and the value of copeptin levels before AVP therapy to predict complications during AVP therapy and outcome in vasodilatory shock patients was determined., Methods: This prospective, observational study was nested in a randomized, controlled trial investigating the effects of two AVP doses (0.033 vs. 0.067 IU/min) on the hemodynamic response in patients with advanced vasodilatory shock due to sepsis, systemic inflammatory response syndrome or after cardiac surgery. Clinical data, plasma copeptin levels and adverse events were recorded before, 24 hours after and 48 hours after randomization., Results: Plasma copeptin levels were elevated before AVP therapy. During AVP, copeptin levels decreased (P<0.001) in both groups (P=0.73). Copeptin levels at randomization predicted the occurrence of ischemic skin lesions (AUC ROC, 0.73; P=0.04), a fall in platelet count (AUC ROC, 0.75; P=0.01) during AVP and intensive care unit mortality (AUC ROC, 0.67; P=0.04). Twenty-five patients (64.1%) exhibited a decrease in copeptin levels. Patients experiencing a decrease in copeptin levels were older (P=0.04), had a higher Sequential Organ Failure Assessment score count before (P=0.03) and during AVP therapy (P=0.04), had a longer intensive care unit stay (P<0.001) and required AVP therapy longer (P=0.008) than patients without a decrease in copeptin levels during AVP., Conclusion: Plasma copeptin levels are elevated in patients with advanced vasodilatory shock. During exogenous AVP therapy, copeptin levels decrease, suggesting suppression of the endogenous AVP system.

Purpose: To compare the effects of two arginine vasopressin (AVP) dose regimens on the hemodynamic response, catecholamine requirements, AVP plasma concentrations, organ function and adverse events in advanced vasodilatory shock., Methods: In this prospective, controlled, open-label trial, patients with vasodilatory shock due to sepsis, systemic inflammatory response syndrome or after cardiac surgery requiring norepinephrine >0.6 microg/kg/min were randomized to receive a supplementary AVP infusion either at 0.033 IU/min (n = 25) or 0.067 IU/min (n = 25). The hemodynamic response, catecholamine doses, laboratory and organ function variables as well as adverse events (decrease in cardiac index or platelet count, increase in liver enzymes or bilirubin) were recorded before, 1, 12, 24 and 48 h after randomization. A linear mixed effects model was used for statistical analysis in order to account for drop-outs during the observation period., Results: Heart rate and norepinephrine requirements decreased while MAP increased in both groups. Patients receiving AVP at 0.067 IU/min required less norepinephrine (P = 0.006) than those infused with AVP at 0.033 IU/min. Arterial lactate and base deficit decreased while arterial pH increased in both groups. During the observation period, AVP plasma levels increased in both groups (both P < 0.001), but were higher in the 0.067 IU/min group (P < 0.001) and in patients on concomitant hydrocortisone. The rate of adverse events and intensive care unit mortality was comparable between groups (0.033 IU/min, 52%; 0.067 IU/min, 52%; P = 1)., Conclusions: A supplementary AVP infusion of 0.067 IU/min restores cardiovascular function in patients with advanced vasodilatory shock more effectively than AVP at 0.033 IU/min.

Further information on the endogenous arginine vasopressin (AVP) response in patients with postoperative systemic inflammatory response syndrome (SIRS) and vasodilatory shock would provide more insight into the pathophysiology of SIRS-associated cardiovascular failure and help indicate AVP therapy. Patients after uncomplicated abdominal surgery without SIRS (n = 10), critically ill patients after noncardiac surgery with SIRS (n = 9), and patients with SIRS plus vasodilatory shock (n = 22) were included in this prospective trial. Plasma AVP (radioimmunoassay) and copeptin (immunoluminometric assay) concentrations together with clinical parameters were documented daily during the first 7 days postoperative. The AVP response significantly differed between the three groups. Patients without SIRS had lower AVP concentrations than SIRS patients with (P = 0.001) or without shock (P = 0.003). Patients with SIRS and shock had higher AVP levels than patients with SIRS alone (P < 0.001). Arginine vasopressin decreased over time (P = 0.007) in all groups. At day 28, nonsurvivors had higher AVP levels than did survivors (P < 0.001). In SIRS patients without shock, serum osmolarity was indirectly associated with AVP levels, whereas mean arterial blood pressure and serum osmolarity were associated with AVP in SIRS patients with shock. Arginine vasopressin and copeptin correlated significantly with each other (P < 0.001; r = 0.76). In patients without hemofiltration, copeptin levels predicted 28-day mortality with high sensitivity and specificity. The postoperative AVP response in noncardiac surgery patients seems well maintained. The possibility that AVP plays a contributory role in the failure to restore vascular tone in patients with vasodilatory shock cannot be excluded but seems less important than in septic or postcardiotomy shock.

Objective: To compare the course of arginine vasopressin (AVP) and copeptin plasma concentrations between patients with infection, severe sepsis, and septic shock., Design: Prospective, closed-cohort study., Setting: Twelve-bed general and surgical intensive care unit and 33-bed internal medicine ward in a university hospital., Patients: Ten patients with infection, 22 with severe sepsis, and 28 with septic shock., Interventions: None., Measurements and Main Results: Hemodynamic, laboratory and clinical data were recorded daily during the first 7 days after intensive care unit or hospital admission. Parallel thereto, blood was withdrawn to determine plasma AVP (radioimmunoassay) and copeptin (immunoluminometric assay) concentrations. Standard tests, a mixed effects model, and a linear regression analysis were used for statistical analysis. The AVP response was different between the three study groups (p < 0.001) but did not change over time (p = 0.12). Although patients with severe sepsis and septic shock had higher AVP levels than did patients with infection (both p < 0.001), no difference in AVP concentrations was seen between severe sepsis and septic shock patients (p = 0.98). No difference in AVP was observed between survivors and nonsurvivors at day 28 (p = 0.87). In patients with severe sepsis, serum osmolarity (p < 0.001), arterial pH (p = 0.001), lactate (p < 0.001), and Pao2 (p = 0.04) were associated with the course of AVP plasma levels, whereas it was serum osmolarity alone in patients with septic shock (p = 0.03). Plasma AVP concentrations correlated with copeptin (r = .614, p < 0.001), but this correlation was influenced by continuous veno-venous hemofiltration (p = 0.002)., Conclusions: Severe sepsis induced a stronger AVP response than infection without systemic inflammation. However, the lack of a difference in AVP plasma concentrations between patients with and without shock indicates that the AVP system does not function normally in severe sepsis. Our data support the hypothesis that impaired AVP response is at least partially responsible for the failure to restore vascular tone in septic shock.

Background: Arginine vasopressin (AVP) is increasingly being used to treat advanced vasodilatory shock states due to sepsis, systemic inflammatory response syndrome (SIRS) or after cardiac surgery. There are currently no data available on long-term survival., Patients and Methods: Demographic and clinical data, length of intensive care unit (ICU) stay, 1-year survival and causes of death after ICU discharge of 201 patients who received AVP because of advanced vasodilatory shock were collected retrospectively., Results: The intensive care unit (ICU) survival rate was 39.8% (80 out of 201 patients). After ICU discharge 13 out of the 80 patients died within 1 year resulting in a 1-year survival rate of 33.3% (67 out of 201 patients). In nine patients, the cause of death was attributed to the same disease that led to ICU admission. One-year survival of patients with shock following cardiac surgery (42.1%) was higher than in patients suffering from SIRS (22.6%, p=0.005) or sepsis (28.3%, p=0.06)., Conclusions: If advanced vasodilatory shock can be reversed with AVP and patients can be discharged alive from the ICU, 1-year survival rates appear to be reasonable despite severe multi-organ dysfunction syndrome (MODS).

Arginine vasopressin (AVP) constitutes an integral part of the neuroendocrine stress response during cardiac arrest. A strong correlation between endogenous AVP secretion and outcome from cardiac arrest has led to a number of experimental studies indicating a survival benefit of AVP compared to epinephrine. In the clinical setting, however, things are less clear. Although current data suggest that both epinephrine and AVP are equally effective to restore spontaneous circulation in out-of-hospital cardiac arrest, benefits of AVP in specific patient groups, e.g. those with asystolic cardiac arrest, have been shown. The latest international guidelines recommend AVP as an alternative vasopressor drug which may replace the first or second dosage of epinephrine in the treatment of pulseless arrest If the combined use of AVP and epinephrine is superior to epinephrine alone in terms of improved hospital admission and discharge rates this needs to be re-confirmed by the results of an ongoing multicenter trial.

Haemorrhagic shock is one of the most frequent types of shock. If haemorrhage cannot be controlled and fluid resuscitation as well as catecholamines are insufficient to stabilize cardiovascular function, uncontrolled haemorrhagic shock occurs. Several approaches have been suggested as promising alternatives to volume resuscitation. The rationale for the use of arginine vasopressin (AVP) is the pharmacologic amplification of the neuroendocrine stress response. AVP-mediated vasoconstriction is the first physiologic step to haemostasis and shifts blood away from the bleeding site towards the heart, lungs and brain. Particularly, when uncontrolled haemorrhage is accompanied by traumatic brain injury this may help to reduce secondary neurological damage. Since AVP can prevent acute death only transiently, it must comprehensively be combined with rapid hospital admission, immediate control of haemorrhage followed by aggressive fluid resuscitation and blood transfusion. This review article summarizes current experimental and clinical evidence on the use of AVP in uncontrolled haemorrhagic shock.

Epidural anaesthesia is a well-established and recognized technique in anaesthetic practice. Its benefits are multiple and range from positive effects on the respiratory and cardiocirculatory system, a reduced need for analgesics and decreased costs to earlier hospital discharge. Disadvantages like sympathetic blockade followed by hypotension, bradycardia, and cardiac arrest, however, must be taken into consideration. Treatment of these side effects consists of fluid infusion and vasopressor drugs. During epidural anaesthesia, plasma arginine vasopressin (AVP) concentrations are increased. In case reports and a small clinical study, administration of AVP or one of its analogues could rapidly reverse hypotension and restore cardiovascular stability. Because no major controlled clinical trial has yet evaluated the effects of AVP on morbidity, AVP can so far not be recommended as a first-line drug to treat cardiovascular instability during epidural anaesthesia. In refractory cases, however, the use of AVP as a rescue vasopressor may be beneficial.

Purpose of Review: To describe the effects of arginine vasopressin other than its vasoconstrictive and antidiuretic potential in vasodilatory shock., Recent Findings: Arginine vasopressin influences substrate metabolism by stimulation of hepatic glucose release, gluconeogenesis, ureogenesis and fatty acid esterification. Although arginine vasopressin is a secretagogue of different hormones, only prolactin increases during arginine vasopressin therapy. Plasmatic and cellular coagulation are affected by arginine vasopressin, resulting in thrombocyte aggregation. Therefore, platelet count typically decreases following arginine vasopressin infusion in critically ill patients. In addition, arginine vasopressin reduces bile flow and may increase bilirubin concentrations. Despite its potential to decrease serum sodium, no change in electrolytes was observed in critically ill patients receiving arginine vasopressin. Although arginine vasopressin is an endogenous antipyretic, body temperature is not decreased by central venous arginine vasopressin infusion. In addition, arginine vasopressin modulates immune function through V1 receptors. Compared with norepinephrine, arginine vasopressin may have protective effects on endothelial function. Net arginine vasopressin effects on gastrointestinal motility seem to be inhibitory and are dose dependent., Summary: Except for its antidiuretic and vasoconstrictive actions, the effects of arginine vasopressin in patients with vasodilatory shock have so far only been partially examined. Potential influences of arginine vasopressin on metabolism and immune, liver and mitochondrial function remain to be assessed in future studies.

Endogenous arginine vasopressin (AVP) levels in multiple trauma patients are unknown. Arginine vasopressin is considered to play an important role in severe hemorrhage. In this prospective study, 87 multiple trauma patients (Injury Severity Score >15) and 50 healthy volunteers were enrolled. On admission to the emergency department (ED), demographic, clinical, and laboratory data were documented, and blood was sampled for determination of AVP (radioimmunosassay) and copeptin, a stable fragment of the AVP precursor (immunoluminometric assay). In patients requiring intensive care unit (ICU) therapy, blood and data sampling were repeated at 4, 6, and 24 h after ED admission. Linear logistic and mixed-effects regression analyses were used for statistical analysis. On ED admission, AVP plasma concentrations (43.2 +/- 84.9 pM) were significantly increased when compared with controls (0.92 +/- 0.44 pM, P < 0.001). Plethysmographic oxygen saturation was the only parameter independently associated with AVP (regression coefficient, -0.126; 95% confidence interval, -0.237 to -0.014; P = 0.03). No correlation was observed between AVP and survival (P = 0.62), hemodynamic variables (systolic arterial pressure, P = 0.24; MAP, P = 0.59; diastolic arterial pressure, P = 0.74; central venous pressure, P = 0.36), or brain trauma (P = 0.46). In ICU patients, AVP decreased during the first 24 h (P < 0.001) and was independently associated with heart rate (P = 0.02) and blood glucose (P = 0.009). Copeptin concentrations were correlated with AVP (r2 = 0.718, P < 0.001). In conclusion, AVP was significantly increased in multiple trauma patients and seems to be an integral part of the neuroendocrine response to severe injury. In ICU patients, AVP decreased to moderately elevated levels within 24 h after ED admission.

Vasodilatory shock is the most common form of shock in the critically ill patient. As a consequence of overwhelming and prolonged mediator production, vasodilatory shock can be the common final pathway of primary non-vasodilatory shock (e.g. cardiogenic or hypovolemic shock). A supplementary infusion of arginine vasopressin (AVP) showed beneficial effects on hemodynamics and potentially on the outcome in patients with vasodilatory shock due to sepsis or after major surgery. In this case series, successful administration of AVP in three surgical patients with primary cardiogenic shock forms is reported. The hemodynamic effects of AVP were comparable to those AVP-induced alterations described in septic shock and seem to be predominantly mediated by potent vasoconstriction and the facilitated reduction of higher, potentially toxic catecholamine doses. Thus, an AVP-induced decrease in heart rate and pulmonary arterial pressures may be particularly beneficial in patients with impaired cardiac function.

Objective: To evaluate the effects of two arginine vasopressin (AVP) dose regimens (0.033 vs. 0.067 IU/min) on treatment efficacy, hemodynamic response, prevalence of adverse events, and changes in laboratory variables., Design: Retrospective, controlled study., Patients: A total of 78 patients with vasodilatory shock (mean norepinephrine dosage, 1.07 microg.kg-1.min-1; 95% confidence interval, 0.82-1.56 microg.kg-1.min-1)., Interventions: Supplementary infusion of AVP at 0.033 (n = 39) and 0.067 IU/min (n = 39)., Measurements and Main Results: Cardiocirculatory, laboratory, and clinical variables were evaluated and compared between groups before and at 0.5, 1, 4, 12, 24, 48, and 72 hrs after initiation of AVP. Treatment efficacy was assessed by the increase in mean arterial blood pressure and the extent of norepinephrine reduction during the first 24 hrs of AVP therapy. Standard tests and a mixed-effects model were used for statistical analysis. Although the relative increase in mean arterial pressure was comparable between groups (0.033 vs. 0.067 IU/min: 16.8 +/- 18.4 vs. 21.4 +/- 14.9 mm Hg, p = .24), norepinephrine could be reduced significantly more often in patients receiving 0.067 IU/min. AVP at 0.067 IU/min resulted in a higher mean arterial pressure (p < .001), lower central venous pressure (p = .001), lower mean pulmonary arterial pressure (p = .04), and lower norepinephrine requirements (p < .001) during the 72-hr observation period. Increases in liver enzymes occurred more often in patients treated with 0.033 IU/min (71.8% vs. 28.2%, p < .001). The prevalence of a decrease in cardiac index (69.2% vs. 53.8%, p = .24), decrease in platelet count (94.8% vs. 84.6%, p = .26), and increase in total bilirubin (48.7% vs. 71.8%, p = .06) was not significantly different between groups. Bilirubin levels (3.1 +/- 3.4 vs. 5.2 +/- 5.5 mg/dL, p = .04) and base deficit (-7.2 +/- 4.3 vs. -3.9 +/- 5.9 mmol/L, p = .005) were lower and arterial lactate concentrations higher (76 +/- 67 vs. 46 +/- 38 mg/dL, p < .001) in patients receiving 0.033 IU/min., Conclusions: AVP dosages of 0.067 IU/min seem to be more effective to reverse cardiovascular failure in vasodilatory shock requiring high norepinephrine dosages than 0.033 IU/min., ((C) 2007 Lippincott Williams & Wilkins, Inc.)

Unlabelled: We have shown previously that arginine vasopressin (AVP) given during sinus rhythm increases mean arterial blood pressure (MAP) and left anterior descending (LAD) coronary artery cross sectional area. AVP was assumed to result in vasodilatation via activation of the endothelial nitric oxide system. The purpose of the present study was to assess the effects of AVP before and after NO-inhibition. Nine domestic pigs were instrumented for measurement of haemodynamic variables using micromanometer-tipped catheters, and measurement of LAD coronary artery cross sectional area employing intravascular ultrasound (IVUS). Haemodynamic variables, LAD coronary artery cross sectional area and cardiac output were measured at baseline, 90 s and 5, 15, and 30 min after AVP (0.4 U kg (-1) IV) before and after blockade of nitric oxide synthase with N(G)-nitro L-arginine methyl ester (L-NAME). Compared with baseline, AVP significantly increased MAP after 90 s (89+/-4 versus 160+/-5 mm Hg), increased LAD coronary artery cross sectional area (11.3+/-1 versus 11.8+/-1 mm(2)) and decreased cardiac index (138+/-6 versus 53+/-6 mL/min kg(-1)). After blockade of nitric oxide synthase, AVP significantly increased MAP after 90 s (135+/-4 versus 151+/-3 mm Hg), increased LAD coronary artery cross sectional area (8.7+/-1 versus 8.9+/-1 mm(2)), and significantly decreased cardiac index (95+/-6 versus 29+/-4 mL/min kg (-1))., Implications: During sinus rhythm, AVP increased MAP and LAD coronary artery cross sectional area, but decreased cardiac index.

Current therapy of septic/vasodilatory cardiovascular failure includes volume resuscitation and infusion of inotropic and vasopressor agents. Norepinephrine is the first-line vasoconstrictor, and can stabilize hemodynamic variables in most patients. Nonetheless, irreversible cardiovascular failure which is resistant to conventional hemodynamic therapies still is the main cause of death in patients with severe sepsis and septic shock. In such advanced, catecholamine-resistant shock states, arginine-vasopressin (AVP) has repeatedly caused an increase in mean arterial blood pressure, a decrease in toxic norepinephrine-dosages, as well as further beneficial hemodynamic, endocrinologic and renal effects. Although AVP exerted negative inotropic effects in previous clinical trials and in selected animal experiments, a continuous low-dose AVP infusion during advanced septic/vasodilatory shock caused a decrease in cardiac index only in patients with a hyperdynamic circulation. Adverse effects on gastrointestinal circulation and the systemic microcirculation can not be excluded, but have not yet been confirmed in clinical prospective trials. Negative side effects of a supplementary AVP therapy are an increase in total bilirubin concentrations, and a decrease in platelet count. A transient increase in hepatic transaminases during AVP infusion is most likely related to preceding hypotensive episodes. Important points which must be considered when using AVP as a "rescue vasopressor" in septic/vasodilatory shock states are: 1) AVP infusion only in advanced shock states that can not be adequately reversed by conventional hemodynamic therapy (e.g. norepinephrine >0,5-0,6 mug/kg/min), 2) presence of normovolemia, 3) AVP infusion only in combination with norepinephrine, 4) strict avoidance of bolus injections and dosages >4 IU/h. Effects of a supplementary AVP infusion in advanced vasodilatory shock on survival are currently examined in a large, prospective multicenter trial in North America and Australia.

Context: Determination of arginine vasopressin (AVP) concentrations may be helpful to guide therapy in critically ill patients. A new assay analyzing copeptin, a stable peptide derived from the AVP precursor, has been introduced., Objective: Our objective was to determine plasma copeptin concentrations., Design: We conducted a post hoc analysis of plasma samples and data from a prospective study., Setting: The setting was a 12-bed general and surgical intensive care unit (ICU) in a tertiary university teaching hospital., Patients: Our subjects were 70 healthy volunteers and 157 ICU patients with sepsis, with systemic inflammatory response syndrome (SIRS), and after cardiac surgery., Interventions: There were no interventions., Main Outcome Measures: Copeptin plasma concentrations, demographic data, AVP plasma concentrations, and a multiple organ dysfunction syndrome score were documented 24 h after ICU admission., Results: AVP (P < 0.001) and copeptin (P < 0.001) concentrations were significantly higher in ICU patients than in controls. Patients after cardiac surgery had higher AVP (P = 0.003) and copeptin (P = 0.003) concentrations than patients with sepsis or SIRS. Independent of critical illness, copeptin and AVP correlated highly significantly with each other. Critically ill patients with sepsis and SIRS exhibited a significantly higher ratio of copeptin/AVP plasma concentrations than patients after cardiac surgery (P = 0.012). The American Society of Anesthesiologists' classification (P = 0.046) and C-reactive protein concentrations (P = 0.006) were significantly correlated with the copeptin/AVP ratio., Conclusions: Plasma concentrations of copeptin and AVP in healthy volunteers and critically ill patients correlate significantly with each other. The ratio of copeptin/AVP plasma concentrations is increased in patients with sepsis and SIRS, suggesting that copeptin may overestimate AVP plasma concentrations in these patients.

In this case report, the course of arginine vasopressin and copeptin, the stable C-terminal part of the arginine vasopressin precursor, is described during the period of critical illness in a septic shock patient. Arginine vasopressin and copeptin concentrations were substantially increased during the initial 36 hours of shock. Subsequently, both hormones continuously decreased, but exhibited another peak in response to stress during extubation. During restoration of cardiovascular stability, endogenous arginine vasopressin levels further decreased and obviously did not contribute to haemodynamic improvement. In contrast, the decrease in arginine vasopressin and copeptin can be at least partly explained by an improvement of cardiovascular function.

We present the case of an 83-year-old patient who underwent cardiac surgery and developed postoperative non-occlusive mesenteric ischemia (NOMI), which was treated with a local intra-arterial papaverine and prostaglandin E1 infusion. After successful mesenteric reperfusion, a multiple organ dysfunction syndrome with severe cardiovascular failure developed. High norepinephrine dosages (1.09 microg/kg body weight/min) and catecholamine-related complications (tachycardiac atrial fibrillation) required initiation of supplementary argininevasopressin (AVP) infusion (4 U/h). AVP stabilized vasodilatory shock, ensured adequate gut perfusion pressure and had no adverse clinical or angiographic effects on restitution of gut integrity. In conclusion, after reperfusion of NOMI in this patient, adjunct AVP therapy combined with local vasodilator infusion was beneficial as a potentially life-saving vasopressor.

Introduction: Disturbances in microcirculatory homeostasis have been hypothesized to play a key role in the pathophysiology of multiple organ dysfunction syndrome and vasopressor-associated ischemic skin lesions. The effects of a supplementary arginine vasopressin (AVP) infusion on microcirculation in vasodilatory shock and postoperative multiple organ dysfunction syndrome are unknown., Method: Included in the study were 18 patients who had undergone cardiac or major surgery and had a mean arterial blood pressure below 65 mmHg, despite infusion of more than 0.5 microg/kg per min norepinephrine. Patients were randomly assigned to receive a combined infusion of AVP/norepinephrine or norepinephrine alone. Demographic and clinical data were recorded at study entry and after 1 hour. A laser Doppler flowmeter was used to measure the cutaneous microcirculatory response at randomization and after 1 hour. Reactive hyperaemia and oscillatory changes in the Doppler signal were measured during the 3 minutes before and after a 5-minute period of forearm ischaemia., Results: Patients receiving AVP/norepinephrine had a significantly higher mean arterial pressure (P = 0.047) and higher milrinone requirements (P = 0.025) than did the patients who received norepinephrine only at baseline. Mean arterial blood pressure significantly increased (P < 0.001) and norepinephrine requirements significantly decreased (P < 0.001) in the AVP/norepinephrine group. Patients in the AVP/norepinephrine group exhibited a significantly higher oscillation frequency of the Doppler signal before ischaemia and during reperfusion at randomization. During the study period, there were no differences in either cutaneous reactive hyperaemia or the oscillatory pattern of vascular tone between groups., Conclusion: Supplementary AVP infusion in patients with advanced vasodilatory shock and severe postoperative multiple organ dysfunction syndrome did not compromise cutaneous reactive hyperaemia and flowmotion when compared with norepinephrine infusion alone.

Supplementary arginine vasopressin infusion in advanced vasodilatory shock may be accompanied by a decrease in cardiac index and systemic oxygen transport capacity in approximately 40% of patients. While a reduction of cardiac output most frequently occurs in patients with hyperdynamic circulation, it is less often observed in patients with low cardiac index. Infusion of inotropes, such as dobutamine, may be an effective strategy to restore systemic blood flow. However, when administering inotropic drugs, systemic blood flow should be increased to adequately meet systemic demands (assessed by central or mixed venous oxygen saturation) without putting an excessive beta-adrenergic stress on the heart. Overcorrection of cardiac index to hyperdynamic values with inotropes places myocardial oxygen supply at significant risk.

Objective: To determine the effects of increasing dosages of continuously infused arginine-vasopressin (AVP) on mucosal tissue oxygen tension and oxygen supply in an auto-perfused, innervated jejunal segment in an acute endotoxic porcine model., Design: Prospective, randomized, experimental study., Setting: University hospital animal research laboratory., Interventions: Jejunal mucosal tissue PO2 was measured employing two Clark-type surface oxygen electrodes. Oxygen saturation of jejunal microvascular hemoglobin was determined by tissue reflectance spectrophotometry. Systemic hemodynamic variables, mesenteric-venous and systemic acid base and blood gas variables and lactate measurements were recorded. Measurements were performed at baseline, after E. coli lipopolysaccharide (LPS) administration and at 20 min intervals during incremental AVP infusion (n=8; 0.014, 0.029, 0.057, 0.114 and 0.229 IU kg(-1) h(-1), respectively) or infusion of saline (n =8)., Measurements and Results: LPS infusion leads to a significant (P<0.05) decrease of mucosal tissue oxygen tension (PO2muc, 24+/-3 to 12+/-2 mmHg) and microvascular hemoglobin oxygen saturation (HbO2, 38+/-4 to 21+/-4%). Mesenteric venous lactate level increased (2.4+/-0.3 to 4.7+/-1.7 mmol l(-1)), while mesenteric venous pH decreased (7.38+/-0.02 to 7.26+/-0.12), indicating tissue hypoxia. AVP significantly increased mean arterial pressure (MAP, 81+/-15 to 97+/-17 at 0.057 IU kg(-1) h(-1)). No differences in jejunal mucosal oxygenation occurred between study groups at any dosage during the experimental protocol., Conclusion: AVP administration did not further compromise mucosal tissue oxygen tension and oxygen supply in the acute phase of endotoxic pigs.

Introduction: This study was designed to examine differences in the arteriolar vasoconstrictive response between arginine vasopressin (AVP) and norepinephrine (NE) on the microcirculatory level in the hamster window chamber model in unanesthetized, normotonic hamsters using intravital microscopy. It is known from patients with advanced vasodilatory shock that AVP exerts strong additional vasoconstriction when incremental dosage increases of NE have no further effect on mean arterial blood pressure (MAP)., Methods: In a prospective controlled experimental study, eleven awake, male golden Syrian hamsters were instrumented with a viewing window inserted into the dorsal skinfold. NE (2 microg/kg/minute) and AVP (0.0001 IU/kg/minute, equivalent to 4 IU/h in a 70 kg patient) were continuously infused to achieve a similar increase in MAP. According to their position within the arteriolar network, arterioles were grouped into five types: A0 (branch off small artery) to A4 (branch off A3 arteriole)., Results: Reduction of arteriolar diameter (NE, -31 +/- 12% versus AVP, -49 +/- 7%; p = 0.002), cross sectional area (NE, -49 +/- 17% versus AVP, -73 +/- 7%; p = 0.002), and arteriolar blood flow (NE, -62 +/- 13% versus AVP, -80 +/- 6%; p = 0.004) in A0 arterioles was significantly more pronounced in AVP animals. There was no difference in red blood cell velocities in A0 arterioles between groups. The reduction of diameter, cross sectional area, red blood cell velocity, and arteriolar blood flow in A1 to A4 arterioles was comparable in AVP and NE animals., Conclusion: Within the microvascular network, AVP exerted significantly stronger vasoconstriction on large A0 arterioles than NE under physiological conditions. This observation may partly explain why AVP is such a potent vasopressor hormone and can increase systemic vascular resistance even in advanced vasodilatory shock unresponsive to increases in standard catecholamine therapy.

Objective: To assess the effects of arginine vasopressin (AVP) on hemodynamic, clinical, and laboratory variables and to determine its adverse side effects in advanced vasodilatory shock., Design: Retrospective study., Patients: A total of 316 patients., Interventions: AVP infusion (4 units/hr)., Measurements and Main Results: Cardiocirculatory, laboratory, and clinical variables were evaluated before, 0.5, 1, 4, 12, 24, 48, and 72 hrs after administration of AVP. AVP increased mean arterial pressure, systemic vascular resistance, and stroke volume index. Heart rate, central venous pressure, mean pulmonary arterial pressure, norepinephrine, milrinone, and epinephrine requirements decreased. There was no difference in the hemodynamic response between patients with septic shock, postcardiotomy shock, or systemic inflammatory response syndrome. Cardiac index decreased in 41.1% of patients during AVP treatment. In patients with hyperdynamic circulation before AVP, cardiac index decreased, whereas it remained uncharged or tended to increase in patients with normodynamic or hypodynamic circulation. During the course of AVP treatment, liver enzymes (28.5% of patients) and total bilirubin concentrations (69.3% of patients) increased, whereas platelet count decreased (73.4% of patients). Simultaneous hemofiltration significantly contributed to the decrease in platelet count (p < .001) and increase in bilirubin (p < .001). Whereas patients with an increase in bilirubin were more likely to die, a decrease in cardiac index or platelet count and an increase in liver enzymes did not affect mortality. Systemic inflammatory response syndrome as admission diagnosis, a high degree of multiple organ dysfunction, and norepinephrine requirements of >0.5 microg x kg x min before AVP treatment were independent risk factors for death from advanced vasodilatory shock treated with AVP. If norepinephrine dosages exceeded 0.6 microg x kg x min before AVP treatment, a substantial increase in mortality occurred., Conclusions: Supplementary AVP infusion improved cardiocirculatory function in advanced vasodilatory shock, but an increase in liver enzymes and bilirubin, and a decrease in platelet count occurred during AVP therapy, particularly during simultaneous hemofiltration. Initiation of AVP infusion before norepinephrine requirements exceeding 0.6 microg x kg x min may improve outcome.

We investigated intestinal oxygen supply and mucosal tissue PO2 during administration of increasing dosages of continuously infused arginine vasopressin (AVP) in an autoperfused, innervated jejunal segments in anesthetized pigs. Mucosal tissue PO2 was measured by employing two Clark-type surface oxygen electrodes. Oxygen saturation of jejunal microvascular hemoglobin was determined by tissue reflectance spectrophotometry. Microvascular blood flow was assessed by laser-Doppler velocimetry. Systemic hemodynamic variables, mesenteric venous and systemic acid-base and blood gas variables, and lactate measurements were recorded. Measurements were performed at baseline and at 20-min intervals during incremental AVP infusion (n = 8; 0.007, 0.014, 0.029, 0.057, 0.114, and 0.229 IU.kg(-1).h(-1), respectively) or infusion of saline (n=8). AVP infusion led to a significant (P < .05), dose-dependent decrease in cardiac index (from 121 +/- 31 to 77 +/- 27 ml.kg(-1).min(-1) at 0.229 IU.kg(-1).h(-1)) and systemic oxygen delivery (from 14 +/- 3 to 9 +/- 3 ml.kg(-1).min(-1) at 0.229 IU.kg(-1).h(-1)) concomitant with an increase in systemic oxygen extraction ratio (from 31 +/- 4 to 48 +/- 10%). AVP decreased microvascular blood flow (from 133 +/- 47 to 82 +/- 35 perfusion units at 0.114 IU.kg(-1).h(-1)), mucosal tissue PO2 (from 26 +/- 7 to 7 +/- 2 mmHg at 0.229 IU.kg(-1).h(-1)), and microvascular hemoglobin oxygen saturation (from 51 +/- 9 to 26 +/- 12% at 0.229 IU.kg(-1).h(-1)) without a significant increase in mesenteric venous lactate concentration (2.3 +/- 0.8 vs. 3.4 +/- 0.7 mmol/l). We conclude that continuously infused AVP decreases intestinal oxygen supply and mucosal tissue PO2 due to a reduction in microvascular blood flow and due to the special vascular supply in the jejunal mucosa in a dose-dependent manner in pigs.

The microvascular distribution of oxygen was studied in the arterioles and venules of the awake hamster window chamber preparation to determine the contribution of vascular smooth muscle contraction to oxygen consumption of the microvascular wall during arginine vasopressin (AVP)-induced vasoconstriction. AVP was infused intravenously at the clinical dosage (0.0001 IU.kg(-1).min(-1)) and caused a significant arteriolar constriction, decreased microvascular flow and functional capillary density, and a substantial rise in arteriolar vessel wall transmural Po(2) difference. AVP caused tissue Po(2) to be significantly lowered from 25.4 +/- 7.4 to 7.2 +/- 5.8 mmHg; however, total oxygen extraction by the microcirculation increased by 25%. The increased extraction, lowered tissue Po(2), and increased wall oxygen concentration gradient are compatible with the hypothesis that vasoconstriction significantly increases vessel wall oxygen consumption, which in this model appears to constitute an important oxygen-consuming compartment. This conclusion was supported by the finding that the small percentage of the vessels that dilated in these experiments had a vessel wall oxygen gradient that was smaller than control and which was not determined by changes in tissue Po(2). These findings show that AVP administration, which reduces oxygen supply by vasoconstriction, may further impair tissue oxygenation by the additional oxygen consumption of the microcirculation.

Background: Arginine-vasopressin (AVP) can successfully stabilize hemodynamics in patients with advanced vasodilatory shock. It has been suggested that inhibition of cytokine-induced nitric oxide production may be an important mechanism underlying AVP-induced vasoconstriction. Therefore, serum concentrations of nitrite/nitrate (NOx), the stable metabolite of nitric oxide, were measured in patients suffering from advanced vasodilatory shock treated with either AVP in combination with norepinephrine (NE) or NE alone., Methods: This trial was a separate study arm of a previously published prospective, randomized, controlled study on the effects of AVP in advanced vasodilatory shock. Thirty-eight patients were prospectively randomized to receive a combined infusion of AVP (4 U h(-1)) and NE, or NE infusion alone. Serum NOx concentrations were measured at baseline, 24, and 48 h after randomization. The increase in mean arterial pressure during the first hour after study enrollment was documented in all patients., Results: No difference in NOx concentrations was found between groups throughout the study period. AVP patients demonstrated a significantly greater increase in mean arterial pressure than NE patients (22 +/- 10 vs. 5 +/- 9 mmHg; P < 0.001). The magnitude of pressure response to AVP was not correlated with NOx concentrations before start of AVP infusion (Pearson's correlation coefficient, -.009; P = 0.971)., Conclusion: Cardiovascular effects of AVP infusion in advanced vasodilatory shock are not mediated by a clinically relevant reduction in serum NOx concentrations. Therefore, hemodynamic improvement of patients in advanced vasodilatory shock during continuous infusion of AVP has to be attributed to other mechanisms than inhibition of nitric oxide synthase. In addition, the magnitude of pressure response to AVP is not correlated with baseline concentrations of NOx.

Arginine vasopressin (AVP) is a potent supplementary vasopressor in advanced vasodilatory shock, but decreases in platelet count have been reported during AVP therapy. In this study we evaluated the effects of AVP infusion on the coagulation system in advanced vasodilatory shock when compared to norepinephrine (NE) infusion alone. Forty-two patients with advanced vasodilatory shock (NE requirements >0.5 microg x kg(-1) x min(-1), mean arterial blood pressure <70 mm Hg) were prospectively randomized to receive an additional AVP infusion (4 U/h) or NE infusion alone. Most patients received coagulation active treatment (fresh-frozen plasma, thrombocyte concentrates, coagulation factors, and continuous veno-venous hemofiltration with heparin). At baseline and 1, 24, and 48 h after randomization, coagulation laboratory variables and a modified thrombelastography were measured. There were no differences between groups in plasmatic coagulation variables. Although there was no significant difference between groups, platelet count significantly decreased in AVP patients (P = 0.036). There were no differences in results of modified thrombelastography analyses between groups. AVP infusion in advanced vasodilatory shock with severe multiorgan dysfunction syndrome does not increase plasma concentrations of Factor VIII, von Willebrand Factor antigen, and ristocetin Co-Factor but may stimulate platelet aggregation and induce thrombocytopenia. Global coagulation, assessed by modified thrombelastography, is not different from patients receiving NE infusion alone.

Objectives: To evaluate the endocrinologic response to a combined arginine vasopressin and norepinephrine (AVP/NE) infusion in advanced vasodilatory shock, and to examine the relationship between baseline plasma AVP concentrations and the hemodynamic response to AVP., Design: Preliminary, prospective, randomized, controlled clinical study., Setting: Twenty-three-bed general and surgical intensive care unit., Patients: Thirty-eight patients with advanced vasodilatory shock. Hemodynamic and laboratory data of 34 patients have already been presented in a recently published prospective, randomized, controlled study., Interventions: Continuous AVP (4 units/hr) and NE infusion in study patients; NE infusion only in control patients., Measurements and Main Results: At baseline, 24 hrs, and 48 hrs after randomization, plasma concentrations of AVP, adrenocorticotropic hormone, cortisol, renin, angiotensin II, aldosterone, prolactin, endothelin I, and atrial natriuretic factor were determined. Hemodynamic variables were recorded at baseline and 1, 12, and 24 hrs after randomization. Linear mixed effects models were used to test for differences between groups. The relationship between AVP plasma concentrations and hemodynamic response to AVP was analyzed using linear regression analyses. AVP/NE patients exhibited significantly higher AVP (p <.001) and prolactin (p <.001) plasma concentrations during the study period; there were no significant differences in plasma concentrations of other hormones. No significant correlation was detected between plasma AVP concentrations and the increase in mean arterial pressure after 1 hr (Pearson's correlation coefficient =.134, p =.584) and after 24 hrs (Pearson's correlation coefficient = -.198, p =.417). There were further no correlations between AVP plasma concentrations and the 24-hr response to AVP therapy in heart rate (Pearson's correlation coefficient = -.065, p =.791), stroke volume index (Pearson's correlation coefficient = -.106, p =.687), and NE requirements (Pearson's correlation coefficient =.04, p =.869)., Conclusions: The preliminary results of this study indicate that a combined AVP and NE infusion increases prolactin plasma concentrations in advanced vasodilatory shock. Hemodynamic effects of AVP infusion are independent of baseline plasma AVP concentrations.

Background: Vasodilatory shock is a potentially lethal complication of severe disease in critically ill patients. Currently, catecholamines are the most widely used vasopressor agents to support blood pressure, but loss of catecholamine pressor effects is a well-known clinical dilemma. Arginine vasopressin (AVP) has recently been shown to be a potent vasopressor agent to stabilize cardiocirculatory function even in patients with catecholamine-resistant vasodilatory shock., Methods and Results: Forty-eight patients with catecholamine-resistant vasodilatory shock were prospectively randomized to receive a combined infusion of AVP and norepinephrine (NE) or NE infusion alone. In AVP patients, AVP was infused at a constant rate of 4 U/h. Hemodynamic, acid/base, single-organ, and tonometrically derived gastric variables were reported before the study and 1, 12, 24, and 48 hours after study entry. For statistical analysis, a mixed-effects model was used. AVP patients had significantly lower heart rate, NE requirements, and incidence of new-onset tachyarrhythmias than NE patients. Mean arterial pressure, cardiac index, stroke volume index, and left ventricular stroke work index were significantly higher in AVP patients. NE patients developed significantly more new-onset tachyarrhythmias than AVP patients (54.3% versus 8.3%). Gastrointestinal perfusion as assessed by gastric tonometry was better preserved in AVP-treated patients. Total bilirubin concentrations were significantly higher in AVP patients., Conclusions: The combined infusion of AVP and NE proved to be superior to infusion of NE alone in the treatment of cardiocirculatory failure in catecholamine-resistant vasodilatory shock.

Objective: To report on the incidence and risk factors associated with the development of ischemic skin lesions (ISL) in critically ill patients with catecholamine-resistant vasodilatory shock treated with a continuous infusion of arginine-vasopressin (AVP)., Design: Retrospective analysis., Setting: Twelve-bed general and surgical intensive care unit in a university hospital., Patients: A total of 63 critically ill patients with catecholamine-resistant vasodilatory shock., Interventions: Continuous AVP infusion., Measurements and Main Results: Demographic, hemodynamic, laboratory data, and skin status were evaluated 24 hrs before and during AVP therapy (24 and 48 hrs). Patients were grouped according to development of new ISL during AVP therapy. A mixed-effects model was used to compare groups. A multiple logistic regression analysis was used to identify independent risk factors for the development of ISL. ISL developed in 19 of 63 patients (30.2%). Thirteen of 19 patients (68%) developed ISL in distal limbs, two patients (10.5%) developed ISL of the trunk, four patients (21%) developed ISL in distal limbs and in the trunk. Five patients (26%) had additional ischemia of the tongue. Body mass index, preexistent peripheral arterial occlusive disease, presence of septic shock, and norepinephrine requirements were significantly higher in patients developing ISL. ISL patients received significantly more units of fresh frozen plasma and thrombocyte concentrates than patients without ISL. Preexistent peripheral arterial occlusive disease and presence of septic shock were independently associated with the development of ISL during AVP therapy., Conclusions: ISLs are a common complication during continuous AVP infusion in patients with catecholamine-resistant vasodilatory shock. The presence of septic shock and a history of peripheral arterial occlusive disease are independent risk factors for the development of ISL.

Objective: Arginine-vasopressin (AVP) might be a potent vasopressor agent in catecholamine-resistant postcardiotomy shock. However, its use remains experimental because of considerations about deleterious effects on the heart. We report on the effects of continuous AVP-infusion on cardiac performance, biomarkers of myocardial ischemia, and systemic hemodynamics in catecholamine-resistant postcardiotomy shock., Design: Retrospective study., Setting: Twenty-one-bed general and surgical intensive care unit., Patients: Forty-one patients with catecholamine-resistant postcardiotomy shock., Interventions: Continuous infusion of AVP., Measurements and Results: Heart rate (HR), heart rhythm, mean arterial pressure (MAP), central venous pressure, mean pulmonary arterial pressure, cardiac index (CI), stroke volume index (SVI), left ventricular stroke work index (LVSWI), systemic vascular resistance (SVR) as well as milrinone and norepinephrine requirements were collected before and 1, 4, 12, 24, and 48 h after start of AVP infusion. Creatine kinase MB and troponin-I serum concentrations were measured daily. During AVP administration we observed a significant decrease in HR (-14.8%), milrinone (-17.5%), and norepinephrine requirements (-54.9%) as well as biomarkers of cardiac ischemia and a significant increase in LVSWI (+46.2%), MAP (+41.8%) and SVR (+60%). CI and SVI remained unchanged. Forty-five percent of postoperative new-onset tachyarrhythmias (TA) converted into sinus rhythm during AVP infusion., Conclusions: AVP was devoid of adverse effects on the heart in these patients with catecholamine-resistant postcardiotomy shock. The significant reduction in HR, vasopressor, and inotropic support suggest a substantial improvement in myocardial performance. These findings are supported by a significant decrease of cardiac enzymes and cardioversion of TA into sinus rhythm in 45.5% of patients with new-onset TA.