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Background Normothermic machine perfusion (NMP) bears the potential for significant prolongation of liver preservation before transplantation. Although safety and feasibility have been recently published, no data are available describing the significant challenges of establishing NMP programs outside clinical studies. We herein present our experience and propose a multidisciplinary approach for liver NMP in the clinical routine. Methods In February 2018, liver NMP was introduced for routine use in marginal organs, logistic challenges, and complex recipients at our institution. In a multidisciplinary effort among transplant coordinators, perfusionists, transplant surgeons, anesthesia, nurses, blood bank as well as laboratory staff, a clinical routine was established and 34 NMP cases were performed without critical incidents or organ loss. Results Nine livers were discarded due to poor organ quality and function observed during NMP. Twenty-five livers were successfully transplanted after preservation of up to 38 h. The extended criteria donors rate was 100% and 92% in discarded and transplanted livers, respectively. Nighttime procedures and parallel transplantations were eventually omitted. Graft and patient survival was 88% at 20 mo. No cholangiopathy was observed despite the use of extended criteria donor organs in 92% of cases. Conclusions NMP in a multidisciplinary approach enables a safe prolongation of liver preservation and overnight organ care. A first field test of NMP indicates safety and benefit of this approach.

As is known, hypoxia leads to an increase in microcirculatory blood flow of the skin in healthy volunteers. In this pilot study, we investigated microcirculatory blood flow and reactive hyperemia of the skin in healthy subjects in normobaric hypoxia. Furthermore, we examined differences in microcirculation between hypoxic subjects with and without short-term acclimatization, whether or not skin microvasculature can acclimatize. Fourty-six healthy persons were randomly allocated to either short-term acclimatization using intermittent hypoxia for one hour over seven days at an FiO2 0.126 (treatment, n = 23) or sham short-term acclimatization for one hour over seven days at an FiO2 0.209 (control, n = 23). Measurements were taken in normoxia and at 360 and 720 minutes during hypoxia (FiO2 0.126). Microcirculatory cutaneous blood flow was assessed with a laser Doppler flowmeter on the forearm. Reactive hyperemia was induced by an ischemic stimulus. Measurements included furthermore hemodynamics, blood gas analyses and blood lactate. Microcirculatory blood flow increased progressively during hypoxia (12.3 ± 7.1 to 19.0 ± 8.1 perfusion units; p = 0.0002) in all subjects. The magnitude of the reactive hyperemia was diminished during hypoxia (58.2 ± 14.5 to 40.3 ± 27.4 perfusion units; p = 0.0003). Short-term acclimatization had no effect on microcirculatory blood flow. When testing for a hyperemic response of the skin’s microcirculation we found a diminished signal in hypoxia, indicative for a compromised auto-regulative circulatory capacity. Furthermore, hypoxic short-term acclimatization did not affect cutaneous microcirculatory blood flow. Seemingly, circulation of the skin was unable to acclimatize using a week-long short-term acclimatization protocol. A potential limitation of our study may be the seven days between acclimatization and the experimental test run. However, there is evidence that the hypoxic ventilatory response, an indicator of acclimatization, is increased for one week after short-term acclimatization. Then again, one week is what one needs to get from home to a location at significant altitude.

Objective We examined the effects of systemic endotoxin on jejunal mucoal microcirculatory parameters in anesthetized pigs. Materials and methods Jejunal mucosal tissue PO2 was measured employing Clark-type surface oxygen electrodes. Oxygen saturation of jejunal microvascular hemoglobin was determined by tissue reflectance spectrophotometry. Jejunal microcirculatory blood flow was assessed by laser Doppler flowmetry. Microvascular conductance and rhythmical oscillation of the tissue PO2 were calculated. Systemic hemodynamic variables, mesenteric-venous and systemic acid base and blood gas variables, and lactate measurements were recorded. Measurements were taken at baseline and after E. coli lipopolysaccharide administration in 20 minutes intervals for 110 min. Results Endotoxin infusion led to a significant (p

Albumin is often cited in textbooks as the gold standard for fluid replacement in paediatrics, but in practice artificial colloids are more frequently used. Although one concern with the use of artificial colloids is their intrinsic action on haemostasis, the available data in children are inconclusive for 6% hydroxyethyl starch 130/0.4 (HES) and no data exist for gelatine solution with respect to coagulation. A total of 42 children (3-15 kg) undergoing surgery and needing colloid replacement were randomly assigned to receive 15 mlxkg(-1) of either albumin 5%, 4% modified gelatine solution or 6% hydroxyethyl starch 130/0.4 solution. Standard coagulation tests and modified thrombelastography (ROTEM) were performed. After colloid administration, routine coagulation test results changed significantly and comparably in all groups, although activated partial thromboplastin time values increased more with gelatine and HES. Coagulation time was unchanged in the children who received albumin or gelatine but other activated modified thrombelastography values were significantly impaired in all groups. After gelatine and after albumin the median clot firmness decreased significantly but remained within the normal range. Following HES, coagulation time increased significantly, and clot formation time, alpha angle, clot firmness, and fibrinogen/fibrin polymerisation were significantly more impaired than for albumin or gelatine, reaching median values below the normal range. From a haemostatic point of view it might be preferable to use gelatine solution as an alternative to albumin; HES showed the greatest effects on the overall coagulation process.

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.

Acute pulmonary arterial hypertension in acute lung injury aggravates the clinical course and complicates treatment. Increased release and turnover of endogenous endothelin-1 is known to be a major determinant in the pathophysiology of pulmonary arterial hypertension of various etiologies. We tested whether intravenous tezosentan, a dual endothelin receptor antagonist, reduced pulmonary artery pressure in a pig model of acute lung injury induced by meconium aspiration. Acute pulmonary arterial hypertension was induced in 12 anesthetized and instrumented pigs by instillation of human pooled meconium in a 20% solution. Hemodynamic and gas exchange parameters were recorded every 30 min. Six animals received tezosentan 5 mg/kg after 0 and 90 min; six animals served as controls. Tezosentan led to a decrease of mean pulmonary artery pressure (PAP) from 33.4 +/- 4.0 mm Hg to 24.7 +/- 2.1 mm Hg and pulmonary vascular resistance (PVR) from 7.8 +/- 1.4 mm Hg.L(-1).min.m2 to 5.2 +/- 0.7 mm Hg.L(-1).min.m2. All animals treated with tezosentan survived, whereas in the control group four out of six animals died. Tezosentan improved survival and decreased pulmonary artery pressure in a porcine model of acute pulmonary arterial hypertension after meconium aspiration. Tezosentan has the potential for effective pharmacological treatment of pulmonary arterial hypertension following acute lung injury.

Background: Tachyarrhythmias (TA) represent a frequent and serious problem after cardiac surgery. We retrospectively analyzed 987 cardiac surgery patients admitted to a surgical intensive care unit between 1996 and 1999 to assess incidence and risk factors associated with development of postoperative TA in the intensive care unit. Methods: TA (n=149) were defined as non-sinus rhythm with a heart rate (HR) ≥100 bpm in patients with preoperative sinus rhythm or as heart rate ≥130 bpm in patients with preoperative atrial fibrillation. A total of 787 patients served as controls (C). Demographic, premorbidity and perioperative data, admission SAPS and MODS-score, presence of clinical syndromes systemic inflammatory response syndrome (SIRS) and sepsis were univariately compared between groups. For prediction of independent risk factors for TA-development two multiple logistic regression models were finally established. Results: Concerning TA, atrial fibrillation and flutter (76%) were observed most frequently, followed by paroxysmal supraventricular tachycardia (15%) and ventricular tachycardia/fibrillation (11%). Age, a history or presence of congestive heart failure, development of SIRS and sepsis, severity of multiple organ dysfunction syndrome and in particular severity of cardiovascular failure proved to be independent risk factors for development of TA. Conclusion: In cardiac surgery patients, age, a history or presence of congestive heart failure, postoperative development of a systemic inflammatory response syndrome or sepsis and the severity of multiple organ function syndrome were independent predictors for development of TA in the intensive care unit. The association of severity of cardiovascular dysfunction with TA strongly suggests a causal relationship between catecholamine therapy and TA-development.

Objectives: To investigate effects of intravenous norepinephrine (NE) and phenylephrine (PE) on intestinal oxygen supply in an autoperfused, innervated jejunal segment. Design and setting: Prospective, randomized animal study in an animal research laboratory. Materials and methods: In 24 anesthetized and normoventilated pigs a segment of the jejunal mucosa was exposed by midline laparotomy and antimesenteric incision. Mucosal oxygen tension (PO2muc; Clark-type surface oxygen electrodes), microvascular hemoglobin oxygen saturation (HbO2, tissue reflectance spectrophotometry), and microvascular blood flow (perfusion units, PU; laser Doppler velocimetry), systemic hemodynamics, mesenteric-venous acid base and blood gas variables, and systemic acid base and blood gas variables were recorded after a resting period and at 20-min intervals during infusion of NE (0.01, 0.05, 0.1, 0.5, 1, 2 µg×kg–1×min–1; n=8) or PE (0.1, 0.5, 1, 2, 5, 10 µg×kg–1×min–1; n=8) and in controls (n=8) without treatment. Results: NE infusion led to significant tachycardia, an increase in cardiac output, and systemic oxygen delivery and consumption while PE progressively increased mean arterial pressure with only small effects on systemic blood flow. NE or PE infusion did not affect mesenteric venous oxygen tension (baseline: PE 53±5, NE, 52±4.2 mmHg), mesenteric oxygen extraction ratio (baseline: PE 0.29±0.08, NE 0.3±0.06), jejunal microvascular blood flow (baseline: PE 254±127, NE 282±72 PU), PO2muc (baseline: PE 31±9.1, NE 33±11 mmHg), and HbO2 (baseline: PE 52±9.6%, NE 58±11.6%). Conclusion: Despite major differences in systemic hemodynamics jejunal tissue oxygen supply is not affected by progressively increasing intravenous infusion of norepinephrine and phenylephrine.

OBJECTIVE To study the effects of increasing dosages of epinephrine given intravenously on intestinal oxygen supply and, in particular, mucosal tissue oxygen tension in an autoperfused, innervated jejunal segment. DESIGN Prospective, randomized experimental study. SETTING Animal research laboratory. SUBJECTS Domestic pigs. INTERVENTIONS Sixteen pigs were anesthetized, paralyzed, and normoventilated. A small segment of the jejunal mucosa was exposed by midline laparotomy and antimesenteric incision. Mucosal oxygen tension was measured by using Clark-type surface oxygen electrodes. Microvascular hemoglobin oxygen saturation and microvascular blood flow (perfusion units) were determined by tissue reflectance spectrophotometry and laser-Doppler velocimetry. Systemic hemodynamics, mesenteric-venous acid-base and blood gas variables, and systemic acid-base and blood gas variables were recorded. Measurements were performed after a resting period and at 20-min intervals during infusion of increasing dosages of epinephrine (n = 8; 0.01, 0.05, 0.1, 0.5, 1, and 2 microg x kg(-1) x min(-1)) or without treatment (n = 8). In addition, arterial and mesenteric-venous lactate concentrations were measured at baseline and at 60 and 120 mins. MEASUREMENTS AND MAIN RESULTS Epinephrine infusion led to significant tachycardia; an increase in cardiac output, systemic oxygen delivery, and oxygen consumption; and development of lactic acidosis. Epinephrine significantly increased jejunal microvascular blood flow (baseline, 267 +/- 39 perfusion units; maximum value, 443 +/- 35 perfusion units) and mucosal oxygen tension (baseline, 36 +/- 2.0 torr [4.79 +/- 0.27 kPa]; maximum value, 48 +/- 2.8 torr [6.39 +/- 0.37 kPa]) and increased hemoglobin oxygen saturation above baseline. Epinephrine increased mesenteric venous lactate concentration (baseline, 2.9 +/- 0.6 mmol x L(-1); maximum value, 5.5 +/- 0.2 mmol x L(-1)) without development of an arterial-mesenteric venous lactate concentration gradient. CONCLUSIONS Epinephrine increased jejunal microvascular blood flow and mucosal tissue oxygen supply at moderate to high dosages. Lactic acidosis that develops during infusion of increasing dosages of epinephrine is not related to development of gastrointestinal hypoxia.

The objective of the present study was to investigate sublingual microvascular blood flow and microcirculatory haemoglobin oxygen saturation (Smc(O(2))) during cardiopulmonary bypass (CPB) using constant systemic blood flow but different perfusion pressures achieved by phenylephrine administration.Fifteen patients undergoing coronary artery bypass grafting were enrolled in this pilot study. Systemic haemodynamics, oxygen transport variables, arterial and mixed venous blood gas analysis, and microcirculatory variables were determined after initiation of general anaesthesia, during CPB (systemic blood flow=2.4 litre m(-2)), after increasing perfusion pressure by 20 mm Hg with a continuous infusion of phenylephrine, and after termination of phenylephrine infusion.CPB immediately resulted in a significant (P0.05) decrease in systemic oxygen transport without alterations in sublingual microcirculatory blood flow and Smc(O(2)). Increasing perfusion pressure from 47 (SD 9) to 68 (7) mm Hg using phenylephrine=1.4 (1.0) microg kg(-1) min(-1) resulted in a significant decrease in sublingual small vessel blood flow (from median 2.5 to 1.8 arbitrary units) representing mostly capillary blood flow, but not in medium-sized vessels (median 3 to 2.8 arbitrary units). Concurrently, global tissue blood flow from 110 (54) to 197 (100) perfusion units and Smc(O(2)) increased from 72 (11)% to 84 (7)%, suggesting significant microcirculatory blood flow shunting in vessels with diameters25 microm.Our data demonstrate that an increased perfusion pressure produced by phenylephrine at constant CPB flow may decrease microcirculatory blood flow in the sublingual mucosal microcirculation due to microvascular blood flow shunting.

The objective of the present study was to determine the effects of increasing dosages of continuously infused epoprostenol (PGI), a prostacyclin analog, on intestinal oxygen supply and jejunal mucosal tissue oxygen tension in an acute endotoxic pig model. Jejunal mucosal tissue PO2, oxygen saturation of jejunal microvascular hemoglobin, and gut microvascular blood flow were investigated. Systemic hemodynamic variables, mesenteric-venous and systemic acid base and blood gas variables, and lactate measurements were recorded. Measurements were performed at baseline, after Escherichia coli LPS administration, and at 20-min intervals during incremental PGI infusion (n = 8; 25, 50, 100, and 200μg·kg−1·h−1, respectively); or infusion of an equal amount of isotonic sodium chloride solution (n = 7). LPS infusion led to a significant decrease in mucosal tissue oxygen tension and microvascular hemoglobin oxygen saturation. Epoprostenol infusion led to a significant, dose-dependent increase in cardiac index and systemic oxygen delivery. Mucosal tissue oxygen tension and microvascular hemoglobin oxygen saturation increased after PGI administration and even returned to more-than-baseline values. Continuously infused PGI increased intestinal hemoglobin oxygen saturation and mucosal tissue oxygen tension in a dose-dependent manner mainly due to an increase in villus blood flow in this acute endotoxic pig model.

Background: Microcirculatory dysfunction has been hypothesized to play a key role in the pathophysiology of multiple organ failure and, consequently, patient outcome. The objective of this study was to investigate the differences in reactive hyperemia response and oscillation frequency in surviving and non-surviving patients with multiple organ dysfunction syndrome. Methods: Twenty-nine patients (15 survivors; 14 non-survivors) with two or more organ failures were eligible for study entry. All patients were hemodynamically stabilized, and demographic and clinical data were recorded. A laser Doppler flowmeter was used to measure the cutaneous microcirculatory response. Reactive hyperemia and oscillatory changes in the Doppler signal were measured during 3 min before and after a 5-min period of forearm ischemia. Results: Non-survivors demonstrated a significantly higher multiple organ dysfunction score when compared with survivors (P= 0.004). Norepinephrine administration was higher in non-survivors (P= 0.018). Non-survivors had higher arterial lactate levels (P= 0.046), decreased arterial pH levels (P= 0.001) and decreased arterial Po2 values (P= 0.013) when compared with survivors. A higher oscillation frequency of the skin microvasculature at rest (P= 0.033) and after an ischemic stimulus (P= 0.009) was observed in non-survivors. The flow motion frequency observed in reactive hyperemia was associated with the severity of multiple organ dysfunction (P= 0.009) and, although not statistically significant, with the arterial lactate concentration (P= 0.052). Conclusion: Increased skin microvascular oscillation frequency at rest and in the hyperemic state after an ischemic stimulus is associated with increased mortality in patients suffering from multiple organ dysfunction. The underlying mechanism could be a response of the skin microvasculature to an impaired oxygen utilization of the skin tissue.

Meconium aspiration induces acute lung injury (ALI) and subsequent pulmonary arterial hypertension (PAH) which may lead to right ventricular failure. Increase of endothelin-1, thromboxane-A, and phosphodiesterases are discussed molecular mechanisms. We investigated the intrapulmonary and hemodynamic effects of the intravenous dual endothelin A and B receptor blocker tezosentan and inhalational iloprost in a model of ALI due to meconium aspiration.Animal study.University-affiliated research laboratory.White farm pigs.Acute lung injury was induced in 24 pigs by instillation of meconium. Animals were randomly assigned to four groups to receive either intravenous tezosentan, inhalational iloprost, or combined tezosentan and iloprost, or to serve as controls.After meconium aspiration-induced lung injury each treatment increased oxyhemoglobin saturations (TEZO: 88 +/- 6% (p = 0.02), ILO: 85 +/- 13% (p = 0.05), TEZO-ILO: 89 +/- 6% (p = 0.02), control: 70 +/- 18%). TEZO but not ILO significantly decreased pulmonary arterial pressure and pulmonary vascular resistance (both p0.01). ILO alone decreased intrapulmonary shunt blood flow (p0.01). Compared with control, TEZO-ILO yielded the highest arterial partial pressure of oxygen (70 +/- 6 torr vs.49 +/- 9 torr, p = 0.04), although it decreased arterial blood pressure (change from 71 +/- 13 mmHg to 62 +/- 12 mmHg vs.85 +/- 14 mmHg to 80 +/- 11 mmHg (p = 0.01).Intravenous TEZO improves pulmonary gas exchange and hemodynamics in experimental acute lung injury secondary to meconium aspiration. Inhaled ILO improves gas exchange only, thereby reducing intrapulmonary shunt blood flow. Combination of TEZO and ILO marginally improves pulmonary gas exchange at the disadvantage of pulmonary selectivity.

Arginine vasopressin (AVP) has been employed successfully during cardiopulmonary resuscitation, but there exist only few data about the effects of AVP infusion for cardiovascular failure during the post-cardiac arrest period. Cardiovascular failure is one of the main causes of death after successful resuscitation from cardiac arrest. Although the "post-resuscitation syndrome" has been described as a "sepsis-like" syndrome, there is little information about the haemodynamic response to AVP in advanced cardiovascular failure after cardiac arrest. In this retrospective study, haemodynamic and laboratory variables in 23 patients with cardiovascular failure unresponsive to standard haemodynamic therapy during the post-cardiac arrest period were obtained before, and 30 min, 1, 4, 12, 24, 48, and 72 h after initiation of a supplementary AVP infusion (4 IU/h). During the observation period, AVP significantly increased mean arterial blood pressure (58+/-14 to 75+/-19 mmHg, p0.001), and decreased noradrenaline (norepinephrine) (1.31+/-2.14 to 0.23+/-0.3 microg/kg/min, p = 0.03), adrenaline (epinephrine) (0.58+/-0.23 to 0.04+/-0.03 microg/kg/min, p = 0.001), and milrinone requirements (0.46+/-0.15 to 0.33+/-0.22 microg/kg/min, p0.001). Pulmonary capillary wedge pressure changed significantly (p0.001); an initial increase being followed by a decrease below baseline values. While arterial lactate concentrations (95+/-64 to 21+/-18 mg/dL, p0.001) and pH (7.27+/-0.14 to 7.4+/-0.14, p0.001) improved significantly, total bilirubin concentrations (1.12+/-0.95 to 3.04+/-3.79 mg/dL, p = 0.001) increased after AVP. There were no differences in the haemodynamic or laboratory response to AVP between survivors and non-survivors. In this study, advanced cardiovascular failure that was unresponsive to standard therapy could be reversed successfully with supplementary AVP infusion in90% of patients surviving cardiac arrest.

The pathophysiology of multiple organ dysfunction syndrome (MODS) is believed to be related to that of microcirculatory dysfunction. We hypothesized that the severity of MODS is determined by measuring regional variables of microvascular function and vascular reactivity in critically ill patients. Therefore, we compared (a) reactive hyperemia response in the forearm using transcutaneous Po2/Pco2 electrodes and laser Doppler velocimetry, (b) microvascular permeability assessed by strain-gauge plethysmography in legs, and (c) variables derived from gastric tonometry in hemodynamically stable patients with moderate (n = 15) and severe (n = 15) MODS. There were no differences in systemic oxygen delivery, consumption, and oxygen extraction ratio between the groups. Mortality was 20% in patients with moderate MODS and 60% in patients with severe MODS (P = 0.025). Patients with a high MODS score had significantly larger arterial lactate concentrations (3.81 +/- 2.7 mmol/L) than patients with moderate MODS (1.66 +/- 0.82 mmol/L; P = 0.006). No significant differences in gastric pHi, gastric regional-to-arterial Pco2 difference, capillary filtration coefficient, isovolumetric venous pressure, and skin reactive hyperemia response were observed between patients with moderate and severe MODS. Once MODS is established, regional variables of microvascular function and vascular reactivity measured in this study do not reflect severity of organ dysfunction.

OBJECTIVE To measure arginine vasopressin (AVP) serum concentrations in critically ill patients. DESIGN Prospective study. SETTING Twelve-bed general and surgical intensive care unit in a tertiary, university teaching hospital. PATIENTS Two-hundred-thirty-nine mixed critically ill patients and 70 healthy volunteers. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Demographic data, hemodynamic variables, vasopressor drug requirements, blood gases, AVP serum concentrations within 24 hrs after admission, multiple organ dysfunction score, and outcome were recorded. Twenty-four hours after admission, study patients had significantly higher AVP concentrations (11.9 +/- 20.6 pg/mL) than healthy controls (0.92 +/- 0.38 pg/mL; p < .001). Males had lower AVP concentrations than females (9.7 +/- 19.5 vs. 15.1 +/- 20.6 pg/mL; p = .014). Patients with hemodynamic dysfunction had higher AVP concentrations than patients without hemodynamic dysfunction (14.1 +/- 27.1 vs. 8.7 +/- 10.8 pg/mL; p = .042). Patients after cardiac surgery (n = 96) had significantly higher AVP concentrations when compared to patients admitted for other diagnoses (n = 143; p < .001). AVP concentrations were inversely correlated with length of stay in the intensive care unit (correlation coefficient, -0.222; p = .002). There was no correlation between serum AVP concentrations and the incidence of shock or specific hemodynamic parameters. Four (1.7%) of the 239 study patients met criteria for an absolute AVP deficiency (AVP

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.Retrospective study.A total of 316 patients.AVP infusion (4 units/hr).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 of0.5 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.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.

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.Prospective, randomized, experimental study.University hospital animal research laboratory.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).LPS infusion leads to a significant (P0.05) 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.AVP administration did not further compromise mucosal tissue oxygen tension and oxygen supply in the acute phase of endotoxic pigs.

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).Retrospective analysis.Twelve-bed general and surgical intensive care unit in a university hospital.A total of 63 critically ill patients with catecholamine-resistant vasodilatory shock.Continuous AVP infusion.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.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.

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.

The relationship between flow motion and tissue oxygenation was investigated during hemorrhage/retransfusion with and without dopamine in 14 pigs. During 45% bleed, jejunal microvascular hemoglobin O2saturation (HBjO2) and mucosal tissue Po2(Po2muc) were recorded in seven control and seven dopamine-treated animals. Mean arterial pressure and systemic O2delivery decreased during hemorrhage and returned to baseline after retransfusion. Hemorrhage decreased Po2mucfrom 33 ± 2.8 to 13 ± 1.6 mmHg and HBjO2from 53 ± 4.9% to 32 ± 3.9%, respectively, in control animals. During reperfusion, Po2mucand HBjO2remained low. Dopamine increased Po2mucfrom 28 ± 4.3 to 45 ± 4.6 mmHg and HBjO2from 54 ± 5.7% to 69 ± 1.5% and attenuated the decrease in Po2mucand HBjO2during hemorrhage. After retransfusion, dopamine restored Po2mucand HBjO2to baseline. Control animals developed rhythmic HBjO2oscillations with increasing amplitude (frequency, 4.5 to 7.6 cycles/min) and showed an inverse relationship between Po2mucand HBjO2oscillation amplitude. Dopamine prevented regular flow motion. The association between decreased Po2mucand increased oscillations in HBjO2after normalization of systemic hemodynamics and O2transport in control animals suggests a cause-and-effect relationship between low tissue Po2and flow motion activity within the jejunal microcirculation.

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.Retrospective study.Twenty-one-bed general and surgical intensive care unit.Forty-one patients with catecholamine-resistant postcardiotomy shock.Continuous infusion of AVP.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.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.

Cardiopulmonary bypass (CPB) has been associated with intestinal tissue hypoxia, but direct measurements of mucosal oxygenation have not been performed. In anaesthetized pigs, jejunal mucosal oxygen tension and microvascular haemoglobin oxygen saturation were measured by a Clark-type electrode and tissue reflectance spectrophotometry. In pigs, normothermic CPB with systemic oxygen transport equivalent to baseline values was performed. In control animals, mucosal oxygen tension and mucosal haemoglobin oxygen saturation were mean 5.01 (SD 1.08) kPa and 38.0 (2.3)%, respectively. CPB was associated with a decrease in mucosal oxygen tension to 2.26 (1.21) kPa, decrease in mucosal microvascular haemoglobin oxygen saturation to 26.0 (3.9)% and appearance of oscillations in mucosal microvascular haemoglobin oxygen saturation. With CPB, arterial lactate concentrations increased from 1.77 (1.37) to 3.52 (1.58) mmol litre-1, but transvisceral lactate and splanchnic venous-arterial carbon dioxide tension gradients remained unchanged. Our results support the concept that CPB is associated with diminished oxygenation of intestinal mucosa that is probably caused by regional redistribution.

Haemorrhage is associated with intestinal mucosal hypoxia and impaired gut barrier function. Dopamine increases oxygen delivery to the intestinal mucosa and may thus counteract haemorrhage-induced mucosal hypoxia. Jejunal mucosal tissue oxygen tension (mucosal PO2) and jejunal oxygen saturation of mucosal microvascular haemoglobin (mucosal HbO2) were measured in 14 anaesthetized pigs. Seven animals served as controls (group C) and seven received continuous infusion of dopamine 16 micrograms kg-1 min-1 (group D) while 45% of blood volume was removed in three equal increments. Resuscitation was performed using shed blood and fluid. Mean arterial pressure and systemic oxygen delivery decreasing significantly during haemorrhage and returned to baseline after resuscitation in both groups. Mucosal PO2 decreased from 4.4 to 1.7 kPa after haemorrhage (P < 0.01) and further to 1.5 kPa after resuscitation (P < 0.01) in group C whereas group D showed an increase from 3.9 to 5.9 kPa after the start of the dopamine infusion (P < 0.05), but no significant difference from baseline after haemorrhage (2.3 kPa) (ns) or resuscitation (3.1 kPa) (ns). Mucosal HbO2 decreased from 52 to 32% after haemorrhage (P < 0.05) and increased to near baseline (37%) (ns) after resuscitation in group C whereas group D showed no significant changes from baseline (54%) throughout the experiment. Comparison between groups showed higher mucosal PO2 and HbO2 values for group D animals after the start of the dopamine infusion (P < 0.05 each), after the first two steps of haemorrhage (P < 0.01 each) and after resuscitation (P < 0.05 each). We conclude that i.v. dopamine 16 micrograms kg-1 min-1 improved tissue oxygenation of the small intestinal mucosa during moderate haemorrhage and subsequent resuscitation.

Microcirculatory dysfunction has been hypothesized to play a key role in the pathophysiology of multiple organ failure, and consequently to patient outcome. The objective of the present study was to investigate differences in reactive hyperemia response and oscillation frequencies in survivors and nonsurvivors of patients with multiple organ dysfunction syndrome (MODS).

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. 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 μg/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. 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. 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.

Arginine–vasopressin (AVP) may promote intestinal ischemia. We studied the effects of increasing doses of AVP on mucosal tissue oxygen tension (PO2muc), microvascular haemoglobin oxygen saturation (HbO2), and microvascular blood flow (PU) in a jejunal segment.

In this study we evaluated effects of blood (B; n = 7), gelatine (G; n = 8) and Ringer's lactate (R; n = 8) resuscitation on jejunal microvascular blood flow (PU), tissue microvascular hemoglobin oxygen saturation (HbO2t) and jejunal mucosal tissue oxygen tension (PO2muc) after severe haemorrhage (50% of estimated blood volume) in pigs.

Multiple organ dysfunction syndrome (MODS) is believed to result from microcirculatory failure in surgical intensive care patients. We hypothesised that degree of MODS is mirrored by severity of capillary leakage assessed by venous congestion plethysmography.

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

We retrospectively investigated the effects of continuous arginine vasopressin (AVP) infusion on systemic hemodynamics, acid/base status, and laboratory variables in patients (mean age [mean +/- SD]= 66.3 +/- 10.1 yr) with catecholamine-resistant septic (n = 35) or postcardiotomy shock (n = 25). Hemodynamic and acid/base data were obtained before; 30 min after; and 1, 4, 12, 24, 48, and 72 h after the start of AVP infusion. Laboratory examinations were recorded before and 24, 48, and 72 h after the start of AVP infusion. For statistical analysis, a mixed-effects model was used. The overall intensive care unit mortality was 66.7%. AVP administration caused a significant increase in mean arterial pressure (+29%) and systemic vascular resistance (+56%), accompanied by a significant decrease in heart rate (-24%) and mean pulmonary arterial pressure (-11%) without any change in stroke volume index. Norepinephrine requirements could be reduced by 72% within 72 h. During AVP infusion, a significant increase in liver enzymes and total bilirubin concentration and a significant decrease in platelet count occurred. Arginine vasopressin was effective in reversing systemic hypotension. However, adverse effects on gastrointestinal perfusion and coagulation cannot be excluded.In this retrospective analysis, the influence of a continuous infusion of an endogenous hormone (arginine vasopressin) on systemic hemodynamics and laboratory variables was assessed in patients with vasodilatory shock unresponsive to conventional therapy. Arginine vasopressin was effective in reversing systemic hypotension. However, adverse effects on gastrointestinal perfusion and coagulation cannot be excluded.