Andreas W. Sielenkämper

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

ObjectiveTo 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. DesignProspective controlled trial. SettingUniversity research laboratory. SubjectsSix adult ewes. InterventionsHealthy 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 &mgr;g·kg−1·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·kg−1·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 ResultsHemodynamics 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). ConclusionsDuring 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.

Endotoxin promotes adhesion of human erythrocytes to human vascular endothelial cells under conditions of flow.

Objective To investigate the effects of endotoxin on adhesion of human red blood cells to human vascular endothelial cells under conditions of flow. Design Prospective, randomized, controlled in vitro study. Settings University-affiliated cell biology laboratory. Subjects Human erythrocytes and human vascular endothelial cells. Interventions Fresh human erythrocytes and human vascular endothelial cells grown as monolayers were incubated with either saline or endotoxin. After incubation, endothelial monolayers were superfused with erythrocytes, and the number of erythrocytes adhering to the endothelial monolayer was quantified. Measurements and Main Results Adhesion of erythrocytes to vascular endothelium was measured under conditions of continuous flow in different settings: a) exposure of both endothelial cells and erythrocytes to saline; b) incubation of both erythrocytes and endothelial cells with endotoxin; c) exposure of erythrocytes only to endotoxin; d) incubation of endothelial cells only to endotoxin; and e) both the endothelial cells and erythrocytes incubated with different concentrations of endotoxin. Erythrocyte adhesion in the saline control group was 71 ± 8 cells/mm2. Incubation of both components with endotoxin increased the number of adhesive erythrocytes to 172 ± 9 cells/mm2 (p < .05). When only the endothelial cells were treated with endotoxin, 142 ± 8 cells/mm2 adhered to the endothelial monolayer, whereas the incubation of the erythrocytes only to endotoxin resulted in adhesion of 102 ± 3 cells/mm2. Decreasing concentrations of endotoxin reduced adhesion from 172 ± 9 cells/mm2 (endotoxin, 75 &mgr;g/mL) to 165 ± 9 cells/mm2 (endotoxin, 25 &mgr;g/mL), 153 ± 4 cells/mm2 (endotoxin, 1 &mgr;g/mL), and 146 ± 6.1 cells/mm2 (endotoxin, 5 ng/mL). Conclusions Exposure of human erythrocytes and human venous vascular endothelial cells to an inflammatory stimulus such as endotoxin promotes a dose-dependent adhesion of erythrocytes to endothelium in a dynamic environment. These adhesive erythrocyte-endothelium interactions can be produced by exposure of either red blood cells or endothelial cells to endotoxin, with a higher degree of adhesion after activation of the endothelial cell component.

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.

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.

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° ± 0.3°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.

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 μm2) and continuously perfused intercapillary areas (1,937 ± 512 vs. 1,311 ± 678 μm2, 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.

Dopexamine reverses the vasopressin-associated impairment in tissue oxygen supply but decreases systemic blood pressure in ovine endotoxemia

Since arginine vasopressin (AVP)may reduce cardiacout-put and, in proportion, oxygen delivery, we studied the efficacy of dopexamine (DPX) as an adjunct to AVP infusion. After1 h of continuous AVP infusion (0.04U/min)in healthy sheep(n = 7),DPX was additionally administered in incremental doses (1, 5, and 10 μg · kg−1 · min−1; each dose for 30 min). After a 24-h period of recovery, endotoxin was continuously infused in the same sheep to induce and maintain a hypotensive/hyperdynamic circulation. After 16 h of endotoxemia, AVP and DPX were given as described previously. AVP infusion increase dsystemic vascular resistance index and decreased cardiac index in both healthy and endotoxemic conditions (P < 0.001 each). This was accompanied by an augmented pulmonary vascular resistance index in endotoxemia (159 ± 13 dynes · cm−5 · m−2 versus 202 ± 16 dynes · cm−5 · m−2) and a decrease in oxygen delivery index (health: 842 ± 66 mL · min−2 · m−2 versus 475 ± 38 mL · min−2 · m−2; endotoxemia: 1073 ± 49 mL · min−2 · m−2 versus 613 ± 44 mL · min−2 · m−2) and mixed venous oxygen content (health: 63% ±2% versus 47% ± 2%; endotoxemia: 68% ± 2% versus 51% ± 3%; P < 0.001 each). Small doses of DPX (1 and 5 μg · kg−1 · min−1) improved not only the AVP-associated depressions in cardiac index, oxygen delivery index, and mixed venous oxygen content, but also the pulmonary vasopressive effect in both groups. While large-dose DPX (10 μg · kg−1 · min−1) also reduced mean pulmonary arterial pressure in endotoxemia (27 ± 1 mm Hg versus 23 ± 1 mm Hg; P < 0.05 versus baseline), mean arterial blood pressure decreased (105 ± 4 mm Hg versus 80 ± 3 mm Hg) and heart rate increased (84 ± 4 bpm versus 136 ± 9 bpm; P < 0.001 versus AVP alone), thereby limiting its therapeutic use.

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

IntroductionIncreasing 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.MethodsThirty-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 μl/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 μl/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.ResultsIn 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.ConclusionsThe 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.

Diaspirin cross-linked hemoglobin improves mucosal perfusion in the ileum of septic rats.

Objective: To determine the effect of a bolus infusion of diaspirin cross‐linked hemoglobin (DCLHb or hemoglobin crosfumaril) on the ileal mucosal microcirculation in septic rats. Design: Prospective, randomized, single‐blinded study. Setting: University‐affiliated animal research laboratory. Subjects: Twenty‐four male Sprague‐Dawley rats, weighing 320‐380 g. Interventions: Under inhalational anesthesia, arterial and venous catheters were inserted and sepsis was created by cecal ligation and perforation (CLP). Twenty‐four hours later, animals were reanesthetized and ventilated. Via midline abdominal incision, the ileum was mobilized and prepared for intravital microscopy. Post‐CLP hemodynamic values were obtained, and videomicroscopy was performed on four to ten villi. Animals were then randomized to receive 2 mL of DCLHb solution (100 mg/mL; n = 12) or pentastarch (n = 12) intravenously, and measurements were repeated after 20 mins. Rats treated with DCLHb then received nitroprusside to restore mean arterial pressure to post‐CLP levels, and final measurements were obtained 15 mins later. Measurements and Main Results: Cardiac index increased with both treatments (p < .001), whereas systemic vascular resistance index and mean arterial blood pressure were augmented only with DCLHb (p < .0001 compared with pentastarch). Intercapillary areas (ICA; inversely related to capillary density) were determined using computerized image analysis. ICA size decreased after treatment, from 974 ± 79 to 791 ± 106 μm2 with DCLHb and from 1044 ± 90 to 840 ± 82 μm2 with pentastarch (both p < .05). Red blood cell velocity in terminal arterioles, as assessed by velocimetry from the recorded images, increased by 15% with both treatments (p < .05). Restoration of mean arterial pressure to post‐CLP levels in DCLHb animals by nitroprusside infusion abolished the effects of the hemoglobin solution on ICA size and red blood cell velocity. Conclusion: Both DCLHb and pentastarch infusion improved microcirculatory perfusion in the ileum of septic rats. In addition, DCLHb also exhibited vasopressor properties, which in combination with improved perfusion may be particularly useful in the treatment of sepsis.

Effects of F I O 2 on hemodynamic responses and O2 transport during RSR13-induced reduction in P50

Reduced Hb-O(2) affinity facilitates O(2) release to tissue but may impair pulmonary O(2) uptake, affecting cardiac output and systemic vascular resistance (SVR). We studied the effects of shifting the O(2)-dissociation curve (ODC) to the right with a continuous infusion of RSR13, an allosteric modifier of Hb, and of different inspired O(2) fractions (FI(O(2))) on arterial O(2) saturations (Sa(O(2))) in Hb and on hemodynamics in nonanesthetized rats. At an FI(O(2)) of 0.21, Sa(O(2)) fell during RSR13 from 95 to 81%. Elevation of FI(O(2)) to 0.30 returned Sa(O(2)) to baseline in the RSR13 group. The decrease in mean arterial pressure (MAP) was significantly greater in the control than in the RSR13 group at 30% O(2). Cardiac index (CI) increased only during RSR13 at 21% O(2) and returned to baseline at 30% O(2). In contrast, SVR decreased after RSR13 was infused at 21% O(2) but returned to baseline at 30%O(2), whereas controls showed the opposite, a sustained SVR. In the follow-up period, when 21 O(2)% was reestablished and mild anemia was present, MAP and SVR fell significantly more in controls, whereas CI only increased in controls. Lactate was significantly lower in the RSR13 than in the control group during RSR13 and the follow-up period. These results demonstrate that 1) continuous infusion of RSR13 produces a constant shift in the O(2) tension at which Hb is 50% saturated (P(50)), 2) FI(O(2)) of 0.30 compensates for the effects of increased P(50) on pulmonary O(2) loading, and 3) right-shifted ODC combined with supplemental O(2) may improve tissue O(2) availability.Reduced Hb-O2 affinity facilitates O2 release to tissue but may impair pulmonary O2 uptake, affecting cardiac output and systemic vascular resistance (SVR). We studied the effects of shifting the O2-dissociation curve (ODC) to the right with a continuous infusion of RSR13, an allosteric modifier of Hb, and of different inspired O2fractions ([Formula: see text]) on arterial O2 saturations ([Formula: see text]) in Hb and on hemodynamics in nonanesthetized rats. At an[Formula: see text] of 0.21,[Formula: see text] fell during RSR13 from 95 to 81%. Elevation of [Formula: see text] to 0.30 returned [Formula: see text] to baseline in the RSR13 group. The decrease in mean arterial pressure (MAP) was significantly greater in the control than in the RSR13 group at 30% O2. Cardiac index (CI) increased only during RSR13 at 21% O2 and returned to baseline at 30% O2. In contrast, SVR decreased after RSR13 was infused at 21% O2 but returned to baseline at 30%O2, whereas controls showed the opposite, a sustained SVR. In the follow-up period, when 21 O2% was reestablished and mild anemia was present, MAP and SVR fell significantly more in controls, whereas CI only increased in controls. Lactate was significantly lower in the RSR13 than in the control group during RSR13 and the follow-up period. These results demonstrate that 1) continuous infusion of RSR13 produces a constant shift in the O2 tension at which Hb is 50% saturated (P50), 2)[Formula: see text] of 0.30 compensates for the effects of increased P50 on pulmonary O2 loading, and 3) right-shifted ODC combined with supplemental O2 may improve tissue O2 availability.