Effects of balanced hydroxyethyl starch solutions on gut mucosal microcirculation and exhaled nitric oxide in septic rats: A randomised, animal study.

CONTEXT: Balanced hydroxyethyl starch (HES) solutions with a molecular weight of 130 kDa (tetrastarches) are frequently used in clinical practice. These solutions are derived either from waxy maize or potato starch and they are not bioequivalent. OBJECTIVES: Investigation of the effects of waxy maize-derived and potato-derived starches on intestinal microcirculation and pulmonary inflammation in experimental sepsis. DESIGN: A randomised (three groups), blinded animal study. SETTING: Animal experimental facility in a university hospital. ANIMALS: Twenty-one male Sprague-Dawley rats weighing 275 to 300 g. INTERVENTION: Sepsis was induced by caecal ligation and puncture. Animals received balanced crystalloid infusion (6 ml kg h) for 23 h followed by randomised 1 h bolus infusion (30 ml kg h) of crystalloid: balanced crystalloid solution or waxy maize starch: 6% wt/vol HES 130/0.4 or potato starch: 6% wt/vol HES 130/0.42. Results are presented as median (interquartiles). MAIN OUTCOME MEASURES: Using intravital microscopy, mucosal perfusion was assessed by intercapillary area (ICA) between all perfused capillaries (ICAtotal) and continuously perfused capillaries only (ICAcont). Mucosal blood flow was calculated from arteriolar diameter and red blood cell velocity. Intestinal wall 3-nitrotyrosine (3-NTint) content and exhaled nitric oxide (exNO), to indicate pulmonary inflammation, were measured. RESULTS: Both tetrastarches improved capillary perfusion compared to the crystalloid group, as indicated by reduced ICAtotal [crystalloid 1054 (905 to 1211) µm; waxy maize starch 789 (744 to 940) µm, P <0.05; potato starch 674 (536 to 693) µm, P < 0.05] and reduced ICAcont [crystalloid 1060 (996 to 1340) µm; waxy maize starch 860 (793 to 975) µm, P <0.05; potato starch 701 (558 to 728) µm, P <0.05]. Mucosal blood flow and systemic blood pressure did not differ significantly between groups. 3-NTint was comparable among all groups. exNO was significantly reduced from 11.1 (5.0 to 16.5) ppb to 4.2 (4.0 to 4.8) ppb in the waxy maize group, whereas no significant difference was detected in the potato starch group 6.2 (4.8 to 10.5). CONCLUSION: Bolus infusion of balanced 6% wt/vol tetrastarches augments mucosal capillary perfusion. Pulmonary inflammation in sepsis is differentially influenced by tetrastarches produced from different raw materials.

Thoracic epidural anesthesia time-dependently modulates pulmonary endothelial dysfunction in septic rats.

INTRODUCTION: Increasing evidence indicates that epidural anesthesia improves postoperative pulmonary function. The underlying mechanisms, however, remain to be determined. Because pulmonary nitric oxide has been identified to play a critical role in pulmonary dysfunction in sepsis, we hypothesized that thoracic epidural anesthesia (TEA) modulates endothelial dysfunction via a nitric oxide-dependent pathway. METHODS: Thirty-six Sprague-Dawley rats underwent sham laparotomy or induction of peritoneal sepsis caused by cecal ligation and puncture (CLP). Septic animals were then treated with either bupivacaine 0.5% or normal saline epidurally (15 microl/h-1) for 6 hours or 24 hours after injury. Previous experiments demonstrated that these time points correspond with a hyperdynamic (at 6 hours) and hypodynamic circulation (at 24 hours), respectively. In addition, two sham control groups received either bupivacaine 0.5% or normal saline epidurally (15 microl/h-1). Six and 24 hours after injury, hemodynamic measurements and arterial blood gas analyses were performed in awake, spontaneously breathing rats. Exhaled nitric oxide, bradykinin-induced pulmonary vasoconstriction (a surrogate marker of endothelial dysfunction), pulmonary wet/dry-weight ratio (an estimate of pulmonary edema), and myeloperoxidase activity (MPO, a surrogate marker of neutrophil infiltration into lung tisssue) were investigated at 6 and 24 hours by using an established model of isolated and perfused lungs. RESULTS: In hyperdynamic sepsis, treatment with TEA resulted in reduced bradykinin-induced pulmonary vasoconstriction (P < 0.05) and lower levels of exhaled NO as compared with those in untreated septic rats (P < 0.05). However, the development of pulmonary edema or MPO activity in the lungs was not alleviated by sympathetic blockade in this phase of sepsis. Conversely, TEA led to an increased bradykinin-induced pulmonary vasoconstriction and pulmonary edema despite reduced exNO levels and pulmonary MPO activity in hypodynamic sepsis (each P < 0.05 versus CLP 24 h). Pulmonary gas exchange was only marginally affected under the influence of TEA in hypodynamic sepsis. Mean arterial pressure and heart rate were not affected beyond the changes caused by sepsis itself. CONCLUSIONS: The results of the present study suggest that TEA modulates the NO pathway and exerts positive effects on pulmonary endothelial integrity only in hyperdynamic sepsis. Whether the negative effects on endothelial function in hypodynamic sepsis have an impact on overall morbidity and mortality remains to be determined in future studies.

Thoracic epidural analgesia with low concentration of bupivacaine induces thoracic and lumbar sympathetic block: a randomized, double-blind clinical trial.

BACKGROUND: Clinical benefits of thoracic epidural anesthesia (TEA) are partly ascribed to thoracic sympathetic block. However, data regarding sympathetic activity during TEA are scarce and contradictory. This prospective, randomized, double-blind study evaluated the segmental propagation of sympathetic block after low-concentration, high-volume TEA using digital thermography. METHODS: Twenty-four patients were included in the study. Thoracic epidural catheters were placed at a median insertion level of T8-T9. Patients were accommodated for 20 min to the room temperature of 23 degrees +/- 0.3 degrees C. Skin temperature was recorded by digital thermography. After baseline measurement of heart rate, arterial pressure, and core body and skin temperature, 10 ml saline (control group) or 10 ml bupivacaine, 0.25% (TEA group), respectively, was administered epidurally. Five minutes (t5) and 20 min (t20) after baseline measurements, hemodynamic parameters and core body temperature were again measured, and sensory block was identified by loss of cold-warm discrimination. In the thumb, the toe, and each thoracic dermatome, difference from baseline temperature was calculated at t5 and t20. Data were analyzed by Mann-Whitney U test. RESULTS: Baseline characteristics did not differ among groups. Median spread of sensory block at t20 was T5-L5. At both t5 and t20, skin temperature decreased more in the control group than in the TEA group in all thoracic dermatomes (P < 0.05). Toe temperature increased in the TEA group compared with the control group (P < 0.05), whereas thumb temperature remained unchanged. CONCLUSION: TEA with 10 ml bupivacaine, 0.25%, induced thoracic and lumbar sympathetic block that precedes and exceeds sensory block. Caudal limit of sympathetic block could not be demonstrated in this study.

Reversal of profound, high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dose-finding, safety assessor-blinded, phase II trial.

BACKGROUND: Sugammadex (Org 25969), a novel, selective relaxant binding agent, was specifically designed to rapidly reverse rocuronium-induced neuromuscular blockade. The efficacy and safety of sugammadex for the reversal of profound, high-dose rocuronium-induced neuromuscular blockade was evaluated. METHODS: A total of 176 adult patients were randomly assigned to receive sugammadex (2, 4, 8, 12, or 16 mg/kg) or placebo at 3 or 15 min after high-dose rocuronium (1.0 or 1.2 mg/kg) during propofol anesthesia. The primary endpoint was time to recovery of the train-of-four ratio to 0.9. Neuromuscular monitoring was performed using acceleromyography. RESULTS: Sugammadex administered 3 or 15 min after injection of 1 mg/kg rocuronium decreased the median recovery time of the train-of-four ratio to 0.9 in a dose-dependent manner from 111.1 min and 91.0 min (placebo) to 1.6 min and 0.9 min (16 mg/kg sugammadex), respectively. After 1.2 mg/kg rocuronium, sugammadex decreased time to recovery of train-of-four from 124.3 min (3-min group) and 94.2 min (15-min group) to 1.3 min and 1.9 min with 16 mg/kg sugammadex, respectively. There was no clinical evidence of reoccurrence of neuromuscular blockade or residual neuromuscular blockade. Exploratory analysis revealed that prolongation of the corrected QT interval considered as possibly related to sugammadex occurred in one patient. Another two patients developed markedly abnormal arterial blood pressure after sugammadex that lasted approximately 15 min. CONCLUSION: Sugammadex provides a rapid and dose-dependent reversal of profound neuromuscular blockade induced by high-dose rocuronium (1.0 or 1.2 mg/kg) in adult surgical patients.

Diagnosis and treatment of pancreatic pseudocysts in chronic pancreatitis.

Pancreatic pseudocysts are a well-known complication of acute or chronic pancreatitis, with a higher incidence in the latter. Diagnosis is accomplished most often by computed tomographic scanning, by endoscopic retrograde cholangiopancreatography, or by ultrasound, and a rapid progress in the improvement of diagnostic tools enables detection with high sensitivity and specificity. Different strategies contribute to the treatment of pancreatic pseudocysts: endoscopic transpapillary or transmural drainage, percutaneous catheter drainage, or open surgery. The feasibility of endoscopic drainage is highly dependent on the anatomy and topography of the pseudocyst, but provides high success and low complication rates. Percutaneous drainage is used for infected pseudocysts. However, its usefulness in chronic pancreatitis-associated pseudocysts is questionable. Internal drainage and pseudocyst resection are frequently used as surgical approaches with a good overall outcome, but a somewhat higher morbidity and mortality compared with endoscopic intervention. We therefore conclude that pseudocyst treatment in chronic pancreatitis can be effectively achieved by both endoscopic and surgical means. This review entails publications referring to the classification of pancreatic pseudocysts, epidemiology, diagnostic tools, and therapeutic options for pancreatic pseudocysts. Only full articles were considered for the review. Based on a search in PubMed, the MeSH terms "pancreatic pseudocysts and classification," "diagnosis," and "endoscopic, percutaneous, and surgical treatment" were used either alone or in combination.

Hemodynamic effects of thoracic epidural analgesia in ovine hyperdynamic endotoxemia.

BACKGROUND AND OBJECTIVES: Thoracic epidural analgesia (TEA) is increasingly used for perioperative analgesia. If patients with TEA develop sepsis or systemic inflammatory response subsequent to extended surgery the question arises if it would be safe to continue TEA with its beneficial effects of improving gastrointestinal perfusion and augmenting tissue oxygenation. A major concern in this regard is hemodynamic instability that might ensue from TEA-induced vasodilation. The objective of the present study was to assess the effects of TEA on systemic and pulmonary hemodynamics in a sepsis model of hyperdynamic endotoxemia. METHODS: After a baseline measurement in healthy sheep (n = 14), Salmonella thyphosa endotoxin was continuously infused at a rate of 10 ngxkg(-1)xmin(-1) over 16 hours. The surviving animals (n = 12) were then randomly assigned to 1 of 2 study groups. In the treatment group (n = 6), continuous TEA was initiated with 0.1 mLxkg(-1) bupivacaine 0.125% and maintained with 0.1 mLxkg(-1)xh(-1). In the control group (n = 6) the same amount of isotonic sodium saline solution was injected at the same rate through the epidural catheter. RESULTS: In both experimental groups cardiac index increased and systemic vascular resistance decreased concurrently (each P < .05). Functional epidural blockade in the TEA group was confirmed by sustained suppression of the cutaneous (or panniculus) reflex. During the observational period of 6 hours neither systemic nor pulmonary circulatory variables were impaired by TEA. CONCLUSIONS: From a hemodynamic point of view, TEA presents as a safe treatment option in sepsis or systemic inflammatory response syndrome.

The role of thoracic epidural analgesia in receptor-dependent and receptor-independent pulmonary vasoconstriction in experimental pancreatitis.

BACKGROUND: Acute pancreatitis commonly results in lung injury and deterioration of pulmonary endothelial function and vasoregulation. Despite a variety of potential risks with the use of thoracic epidural analgesia (TEA) in the critically ill, this technique is an important component of pain management in pancreatitis in selected cases. Although there is evidence that epidural analgesia improves lung function through effective pain relief, the influence of continuously applied epidural local anesthetics on pulmonary endothelial dysfunction is still unknown. METHODS: In an in vivo model of TEA in awake rats with acute pancreatitis, we evaluated blood gas analysis, arterial blood pressure, and exhaled nitric oxide. This was followed by in vitro studies of receptor-dependent and receptor-independent pulmonary vasoconstriction using an isolated perfused lung model. Pulmonary myeloperoxidase activity, indicating leukocyte sequestration into the lungs and wet/dry ratio evaluating pulmonary edema, were also measured. RESULTS: Deteriorated oxygenation, metabolic and lactate acidosis, as well as exhaled nitric oxide levels occurring during acute pancreatitis, were reduced by TEA to levels observed in sham-operated animals. TEA also partially ameliorated the hypotension occurring in pancreatitis. In isolated perfused lungs, receptor-dependent vasoconstriction due to angiotensin II was reduced during acute pancreatitis, indicating pulmonary vascular smooth muscle cell dysfunction. Hypoxic pulmonary vasoconstriction was likewise abolished. Treatment with TEA partly restored the vasoreactivity to angiotensin II and hypoxia. Bradykinin-induced vasoconstriction, indicating pulmonary endothelial dysfunction, myeloperoxidase activity and the degree of pulmonary edema, was not influenced by TEA. CONCLUSIONS: Our study demonstrated that TEA improves pancreatitis-associated impairment of pulmonary vasoreactivity and gas exchange.

Continuous thoracic epidural anesthesia improves gut mucosal microcirculation in rats with sepsis.

Microcirculatory dysfunction contributes significantly to tissue hypoxia and multiple organ failure in sepsis. Ischemia of the gut and intestinal hypoxia are especially relevant for the evolution of sepsis because the mucosal barrier function may be impaired, leading to translocation of bacteria and toxins. Because sympathetic blockade enhances intestinal perfusion under physiologic conditions, we hypothesized that thoracic epidural anesthesia (TEA) may attenuate microcirculatory perturbations during sepsis. The present study was designed as a prospective and controlled laboratory experiment to assess the effects of continuous TEA on the mucosal microcirculation in a cecal ligation and perforation model of sepsis in rats. Anesthetized Sprague-Dawley rats underwent laparotomy and cecal ligation and perforation to induce sepsis. Subsequently, either bupivacaine 0.125% (n = 10) or isotonic sodium chloride solution (n = 9) was continuously infused via the thoracic epidural catheter for 24 h. In addition, a sham laparotomy was carried out in eight animals. Intravital videomicroscopy was then performed on six to ten villi of ileum mucosa. The capillary density was measured as areas encircled by perfused capillaries, that is, intercapillary areas. The TEA accomplished recruitment of microcirculatory units in the intestinal mucosa by decreasing total intercapillary areas (1,317 +/- 403 vs. 1,001 +/- 236 microm2) and continuously perfused intercapillary areas (1,937 +/- 512 vs. 1,311 +/- 678 microm2, each P < 0.05). Notably, TEA did not impair systemic hemodynamic variables beyond the changes caused by sepsis itself. Therefore, sympathetic blockade may represent a therapeutic option to treat impaired microcirculation in the gut mucosa resulting from sepsis. Additional studies are warranted to assess the microcirculatory effects of sympathetic blockade on other splanchnic organs in systemic inflammation.

Thoracic epidural analgesia augments ileal mucosal capillary perfusion and improves survival in severe acute pancreatitis in rats.

BACKGROUND: Acute pancreatitis has been linked to intestinal barrier dysfunction and systemic inflammatory response with high mortality. Thoracic epidural analgesia improves intestinal perfusion. The authors hypothesized that thoracic epidural analgesia influences microcirculation injury, inflammatory response, and outcome of acute pancreatitis in rats. METHODS: Control groups underwent a sham procedure or untreated pancreatitis induced by intraductal taurocholate injection. In the treatment groups, epidural analgesia was commenced immediately or after a 7-h delay. Fifteen hours after injury, the ileal mucosal perfusion was assessed by intravital microscopy. Thereby, the intercapillary area between all perfused capillaries and between continuously perfused capillaries only was used to differentially quantify total and continuous capillary mucosal perfusion. Villus blood flow and serum levels of amylase, lactate, and interleukin 6 were determined, and pancreatic injury was scored histologically. Seven-day survival was recorded in an additional 30 rats undergoing untreated pancreatitis or pancreatitis with epidural analgesia. RESULTS: In untreated pancreatitis, decreased total capillary perfusion increased the total intercapillary area by 24%. Furthermore, loss of continuous perfusion increased continuous intercapillary area to 228%. After immediate and delayed epidural analgesia, continuous perfusion was restored (P < 0.05). Blood flow decreased 50% in untreated pancreatitis but was preserved by epidural analgesia (P < 0.05). Biochemical and histologic signs of pancreatitis were not affected by epidural analgesia. Lactate and interleukin-6 levels increased in untreated pancreatitis, which was prevented in the treatment groups (P < 0.05). Epidural analgesia increased 7-day survival from 33% to 73% (P < 0.05). CONCLUSION: Thoracic epidural analgesia attenuated systemic response and improved survival in severe acute pancreatitis. These effects might be explained by improved mucosal perfusion.

Epidural anaesthesia restores pancreatic microcirculation and decreases the severity of acute pancreatitis.

AIM: To investigate the effect of epidural anaesthesia (EA) on pancreatic microcirculation during acute pancreatitis (AP). METHODS: AP was induced by injection of sodium taurocholate into the pancreatic duct of Sprague-Dawley rats. To realize EA, a catheter was introduced into the epidural space between T7 and T9 and bupivacaine was injected. Microcirculatory flow was measured by laser Doppler flowmetry. Arterial blood gas analyses were performed. At the end of the experiment (

Pancreatic pseudocysts--when and how to treat?

Pancreatic pseudocysts are a well-known complication of acute or chronic pancreatitis, with a higher incidence in the latter. Currently several classification systems are in use that are based on the origin of the pseudocyst, their relation to pancreatic duct anatomy and a possible pseudocyst-duct communication. Diagnosis is accomplished most often by CT scanning, by endoscopic retrograde cholangiopancreaticography (ERCP) or by ultrasound, and rapid progress in the improvement of diagnostic tools has enabled detection with high sensitivity and specificity. There are different therapeutic strategies: endoscopic transpapillary or transmural drainage, percutaneous catheter drainage, or open surgery. The feasibility of endoscopic drainage is highly dependent on the anatomy and topography of the pseudocyst, but provides high success and low complication rates. Percutaneous drainage is used for infected pseudocysts. However, its usefulness in chronic pancreatitis-associated pseudocysts is questionable. Internal drainage and pseudocyst resection are frequently used as surgical approaches with a good overall outcome, but a somewhat higher morbidity and mortality compared with endoscopic intervention. We therefore conclude that pseudocyst treatment in chronic pancreatitis can be effectively achieved by both endoscopic and surgical means.

Continuous thoracic epidural anesthesia induces segmental sympathetic block in the awake rat.

Thoracic epidural anesthesia (TEA) is used increasingly in critical care, especially for cardiac and intestinal sympathetic block. In this study we evaluated cardiorespiratory function and sympathetic activity in a new model of continuous TEA in awake rats. Thirteen rats received epidural saline control (CON) or bupivacaine 0.5% epidural infusion (EPI) at 15 microl/h for 2 h on day 1 and day 3. Mean arterial blood pressure, heart rate, respiration rate, arterial PCO2, and motor score were recorded at baseline and after 30, 60, 90, and 120 min. Skin temperature was measured at front paws, high-thoracic, mid-thoracic, and low-thoracic, hind paws, and the proximal and distal tail. Changes in sympathetic activity were assessed by skin temperature changes from baseline (DeltaT). In the EPI group, hemodynamics and respiration remained unchanged and only mild motor deficits occurred. DeltaT in thoracic segments was higher in the EPI than in the CON group (P <0.001 at all times at high-thoracic, mid-thoracic, and low-thoracic segments). Skin temperature decreased in the distal tail in the EPI group, e.g., after 90 min DeltaT=-0.86 +/- 0.25 degrees C (EPI) versus 0.4 +/- 0.12 degrees C (CON) (P <0.05 at 60, 90, and 120 min). DeltaT on day 3 was comparable to day 1. TEA induced stable segmental sympathetic block without cardiorespiratory and motor side effects in awake rats. This new technique may be applied in prolonged models of critical illness.

Bradykinin-induced pulmonary vasoconstriction is time and inducible nitric oxide synthase dependent in a peritonitis sepsis model.

In an isolated perfused lung model, bradykinin induced pulmonary vasoconstriction in rats made septic by the injection of lipopolysaccharide (LPS). To mimic the pathophysiology of sepsis in humans more closely, we investigated pulmonary endothelial injury in a peritonitis model (cecal ligation and perforation; CLP). Male Sprague-Dawley rats were randomly divided into nine groups (n = 6-8). LPS and CLP rats were compared after 6 h with and without treatment with a selective inhibitor of inducible nitric oxide synthase (iNOS), L-N(6)-(1-iminoethyl)-lysine. Time dependency was investigated in CLP-treated rats at 24 h. The pulmonary circulation was isolated and perfused with a constant flow after the rats' tracheas were intubated and ventilated. Bradykinin (1, 3, and 6 microg) was injected, and changes in perfusion pressure were measured. Lungs were harvested for Western blot analysis to determine the role of iNOS in pulmonary endothelial dysfunction. In contrast to CLP 24 h rats, dose-dependent bradykinin-induced pulmonary vasoconstriction was observed in LPS and CLP 6 h rats. Concomitant administration of L-N(6)-(1-iminoethyl)-lysine significantly attenuated this vasoconstriction in both groups. The iNOS protein was expressed in lung homogenates from LPS 6 h and CLP 6 h but not from CLP 24 h rats. Both sepsis models caused bradykinin-induced pulmonary vasoconstriction, with the CLP groups demonstrating a time dependency of this effect. In conjunction with the time-dependent decrease in iNOS protein, the attenuated bradykinin-induced vasoconstriction due to selective iNOS inhibition suggests an important role for iNOS in pulmonary endothelial injury for both sepsis models.

Arginine vasopressin compromises gut mucosal microcirculation in septic rats.

OBJECTIVE: Arginine vasopressin (AVP) is increasingly used in the therapy of septic patients with hypotension. However, its effects on the microvascular networks have not been studied in detail. This study was designed to determine the effects of AVP infusion on the villus microcirculation of the septic rat ileum. DESIGN: Prospective, placebo-controlled, randomized, single-blinded trial. SETTING: University research laboratory. SUBJECTS: Fifteen male Sprague-Dawley rats. INTERVENTIONS: Twenty-four hours after cecal ligation and perforation to create sepsis (M1), rats (n = 8) received a continuous AVP infusion to increase mean arterial pressure by 20 mm Hg (M2) and 40 mm Hg (M3) from M1. In the control group (n = 7), an equivalent volume of normal saline was infused. MEASUREMENTS AND MAIN RESULTS: Videomicroscopy was performed on 6-10 villi of ileum mucosa at M1 and was repeated at M2 and M3. Blood was drawn to determine plasma levels of AVP and interleukin-6. At M1, both study groups were hypotensive compared with preseptic data (mean arterial pressure, -25%). The increase in mean arterial pressure was linked to supraphysiologic AVP plasma levels and was accompanied by a decrease in mean mucosal blood flow by 76% at M2 and 81% at M3 (p <.001 vs. control). Red blood cell velocity fell by 45% and 47%, respectively (p <.05 vs. control). Whereas periods of arrested villus blood flow increased from 8.1 +/- 2.6 secs/min to 43.8 +/- 5.2 and 47 +/- 6.2 secs/min at M2 and M3 (p <.001), the diameter of terminal arterioles remained unchanged. In addition, AVP infusion further augmented the sepsis-associated increase in interleukin-6 levels (AVP, 905 +/- 160 vs. control, 638 +/- 55 pg/mL; p =.022). CONCLUSIONS: This study provides evidence for severe abnormalities in gut mucosal blood flow after AVP infusion in septic rats, accompanied by an augmented inflammatory response to the septic injury. The effects of AVP on microvascular blood flow in this model may be related to AVP activities on larger arterioles (>40 microm), a concomitant reduction in cardiac output, or even both.

Effects of titrated arginine vasopressin on hemodynamic variables and oxygen transport in healthy and endotoxemic sheep.

OBJECTIVE: To determine the effects of titrated arginine vasopressin (AVP) alone or in combination with norepinephrine (NE) on hemodynamics and oxygen transport in healthy and endotoxemic sheep. DESIGN: Prospective controlled trial. SETTING: University research laboratory. SUBJECTS: Six adult ewes. INTERVENTIONS: Healthy sheep received AVP as a titrated infusion, initiated with 0.6 units/hr and increased by 0.6 units/hr every 15 mins, either until mean arterial pressure was increased by 20 mm Hg vs. baseline or a maximum of 3.6 units/hr was administered. After 90 mins, AVP infusion was continued with the investigated dosage, and NE (0.2 microg x kg(-1) x min(-1)) was also infused for 90 mins. After a 24-hr period of recovery, endotoxemia was induced and maintained (Salmonella typhosa endotoxin, 10 ng x kg(-1) x min(-1)) in the same sheep for the next 19 hrs. After 16 hrs of endotoxemia, AVP and NE were administered as described previously. MEASUREMENTS AND MAIN RESULTS: Hemodynamics were obtained at baseline, every 15 mins during the titration period, and 60 and 90 mins after additional NE infusion. Variables of oxygen transport were calculated before and after the titration period. In healthy and endotoxemic sheep, AVP reduced heart rate and cardiac index (p <.001) and compromised oxygen delivery (p <.001) and oxygen consumption (healthy sheep, p =.003; endotoxemic sheep, p <.001). Vasopressin infusion did not alter mean pulmonary arterial pressure but increased pulmonary vascular resistance index in both groups (p <.001). Additional infusion of NE further augmented mean arterial pressure and increased cardiac index during endotoxemia (p <.001). This was accompanied by an increase in oxygen delivery and consumption (p <.05 each). CONCLUSIONS: During ovine endotoxemia, AVP decreased cardiac index, compromised oxygen delivery, and increased pulmonary vascular resistance index. These side effects may limit its use as a sole vasopressor during sepsis. Potentially, a simultaneous infusion of AVP and NE could represent a useful therapeutic option.