Effects of hydroxyethyl starch and cell-free hemoglobin on microcirculation, tissue oxygenation, and survival in severe acute porcine pancreatitis: results of a randomized experimental trial.

OBJECTIVE: Severe acute pancreatitis is a life-threatening disease with a high mortality; so far, no causal treatment is known. The aim of this study was to evaluate the therapeutic potential of hydroxyethyl starch (HES) and cell-free hemoglobin in an experimental model. METHODS: Thirty-nine pigs were randomly assigned into 3 groups. Severe acute pancreatitis was induced by intraductal injection of glycodeoxycholic acid in combination with intravenous administration of cerulein. All animals were kept in isovolemic conditions by application of Ringer solution, 10% HES, or cell-free hemoglobin. The pancreatic microcirculation was evaluated over 8 hours. Thereafter, the animals were observed for 6 days followed by killing of the animals and histopathologic examination. RESULTS: The administration of HES and cell-free hemoglobin led to improved microcirculation and tissue oxygenation compared with the Ringer's group. Consequently, the histopathologic damage was reduced (5.5 [3-8.5] vs 9.5 [7.5-11]; P < 0.001). In addition, the mean survival was significantly longer at 121 hours (95% confidence interval, 102-139) versus the Ringer group's 57 hours (95% confidence interval, 32-82; P < 0.001). CONCLUSIONS: The administration of HES and cell-free hemoglobin can improve microcirculation in severe acute porcine pancreatitis, with consequent reduction in histopathologic damage and mortality. Therefore, this might represent an interesting therapeutic option in the treatment of severe acute pancreatitis.

Effects of systemic administration of a local anesthetic on pain in acute pancreatitis: a randomized clinical trial.

OBJECTIVES: Intravenous local anesthetics may ameliorate pain and clinical course in patients with major abdominal surgery. AIM: To investigate their effects in acute pancreatitis. METHODS: Forty-six consecutive patients with acute pancreatitis randomly received intravenous procaine (2 g/24 h) or placebo for 72 hours in a double-blind fashion. Pain severity (visual analog scale, 0-100), on-demand pain medication (metamizole and/or buprenorphine), and the clinical course were monitored every 24 hours. RESULTS: Data of 44 patients were subjected to intention-to-treat analysis. Although there were no differences between groups before treatment, procaine treatment was associated with a stronger decrease in pain compared with placebo (median visual analog scale decrement, -62 vs -39, P = 0.025). Moreover, there was a greater proportion of patients with adequate (≥ 67%) pain reduction (75% vs 43%, P = 0.018), less use of additional analgesics (P = 0.042), and overall analgesic superiority (P = 0.015). Compared with placebo, the proportion of patients hospitalized after 2 weeks was reduced by 80% after procaine treatment (P = 0.012). CONCLUSIONS: These findings support the hypothesis that systemic administration of local anesthetics might improve pain and accelerate clinical recovery in acute pancreatitis.

The role of vascular adhesion molecules PECAM-1 (CD 31), VCAM-1 (CD 106), E-selectin (CD62E) and P-selectin (CD62P) in severe porcine pancreatitis.

Inflammatory cytokines have been shown to mediate organ damage by their action on vascular endothelia and leukocytes, in part by upregulating the expression of adhesion molecules, which in turn convey transmigration of leukocytes into tissue. The upregulation and activation of vascular cell adhesion molecules on the endothelial cells avail firm leukocyte adhesion to the vascular endothelium and enhance their transmigration and consecutive tissue injury. The aim of this study was to evaluate the expression of vascular adhesion molecules CD 31 (PECAM-1), CD 106 (VCAM-1), CD 62E (E-Selectin) and CD 62P (P-Selectin) in the pancreas and distant organs of pigs suffering from acute necrotizing pancreatitis (AP). AP was induced in 13 pigs by a combination of intravenous cerulein and intraductal glycodeoxycholic acid. For immunostaining of vascular adhesion molecules slides of porcine pancreas, lung, kidney and liver tissue were stained with monoclonal antibodies (Ab) against PECAM-1-1, VCAM-1 E- and P- SELECTIN. The endothelial cell expression of CD 31 (PECAM-1), CD 106 (VCAM), CD 62E (E-Selectin) and CD 62P (P-SELECTIN) in severe porcine pancreatitis is detectable and upregulation is partly significantly.

Failed induction of heme oxygenase 1 in endothelial cells exposed to the hemoglobin based oxygen carrier Oxyglobin.

We investigated the effect of the bovine hemoglobin based oxygen carrier HBOC-200 (Oxyglobin) in rat aortic endothelial cells (RAEC) on the activation of heme oxygenase 1 (HO-1). RAEC were incubated in the presence of 75 microM (G1) or 225 microM (G2) HBOC-200. The positive control (G3) was performed by incubation with 50 microM Hemin. For negative control (G4) cells were incubated with medium alone. G2 and G3 reached a significant increase of bilirubin concentration compared to G4. A positive HO-1 signal in the Western Blot was seen in G3 12 and 24 h after incubation. The Western Blot of G1, G2 and G4 showed no HO-1 signal. These data suggest that HBOC-200 in the applied dosage cannot induce HO-1 expression in RAEC, and may be degraded by isoenzymes at a lower level.

Improvement of impaired microcirculation and tissue oxygenation by hemodilution with hydroxyethyl starch plus cell-free hemoglobin in acute porcine pancreatitis.

AIMS: To avoid the progression from mild edematous acute pancreatitis (AP) to the severe necrotizing form, one therapeutic option is to improve pancreatic microcirculation and tissue oxygenation. The aim of the study was to evaluate the influence of improved rheology (isovolemic hemodilution) plus enhanced oxygen supply (bovine hemoglobin HBOC-301) on pancreatic microcirculation, tissue oxygenation and survival in severe acute experimental pancreatitis. METHODS: Severe AP was induced in 39 pigs (25-30 kg BW) by stimulation with intravenous administration of cerulein plus a pressure- and volume-controlled 10-min intraductal infusion of glycodeoxycholic acid. Seventy-five minutes after induction of AP, animals were randomized and hemodiluted isovolemically (PAOP constant) with either 10% hydroxyethyl starch (HES) 200,000/0.5 plus HBOC-301 (+0.6 g/dl plasmatic hemoglobin; Oxyglobin, Biopure, Cambridge, Mass., USA), or 10% HES 200,000/0.5, or Ringer's solution to a hematocrit of 15%. Hemodynamics, oxygen transport parameters, pancreatic microcirculation and tissue oxygen tension were evaluated over 6 h. Then the abdomen was closed, animals were extubated and observed for 6 days. After that, the surviving animals were sacrificed and specimens were taken from the pancreas. The histopathologic findings were scored by two blinded pathologists who quantified acinar necrosis, fat necrosis, inflammation and edema. RESULTS: Isovolemic hemodilution with HES plus HBOC-301 reduced mortality and preserved pancreatic microcirculation compared with Ringer's solution, but was not significantly different from hemodilution with HES alone. Only treatment with HES plus HBOC-301 normalized pancreatic tissue oxygen tension compared with IHD with HES or Ringer's solution alone. CONCLUSIONS: IHD with HES plus HBOC-301 as a combination of rheologic and O(2)-delivering therapy may represent a novel therapeutic option for treatment of AP.

Influence of the hemoglobin solution HBOC-201 on tissue oxygenation in the rat R1H-tumor.

BACKGROUND: HBOC-201 is an ultra purified bovine hemoglobin solution. It has already been used in clinical phase II/III trials for emergency treatments. Animal experiments have shown that HBOC-201 is highly effective in tissue oxygenation. The study was performed in order to assess the potential of low dose HBOC-201 to improve tumor oxygenation. METHODS: 30 rats with a subcutaneously growing rhabdomyosarcoma R1H tumor were randomly assigned either to be ventilated with carbogen (n = 10), or to receive an IV injection of 0.3 g/kg HBOC-201 (n = 10) or a combination of 0.3 g/kg HBOC-201 and carbogen breathing (n = 10). Under general anesthesia the effects of the respective treatment on the tissue oxygen tension (tpO2) of the tumor were determined using a flexible stationary probe at baseline (b) and 15 and 60 min after application of the respective medication. RESULTS: HBOC-201 alone failed to improve tumor tpO2 (b: 1.3 +/- 1.2mmHg; 15min: 1.4 +/- 1 mmHg; 60min: 1 +/- 1 mmHg). In combination with carbogen the mean tpO2 of the tumor raised in comparison to baseline values (b: 3.1 +/- 4.6 mmHg; mmHg; 15min: 8.5 +/- 11*mmHg; 60min: 4.8 +/- 5mmHg; *p < 0.05 vs. b), but this effect was less pronounced than the increase in tpO2 by carbogen alone (b: 3.4 +/- 3.4mmHg; 15min: 9 +/- 10* mmHg; 60 min: 13 +/- 19* mmHg; *p < 0.05 vs. b). CONCLUSION: The application of low dose hemoglobin solution HBOC-201 does not result in improvement of tissue oxygenation in the rat rhabdomyosarcoma R1H.

Enhanced central organ oxygenation after application of bovine cell-free hemoglobin HBOC-201.

PURPOSE: While the effects of dilutional anemia or isovolemic hemodilution (IHD) on the oxygen extraction and tissue oxygenation in peripheral organs after application of hemoglobin-based oxygen carriers like HBOC-201 have been studied intensively, little is known about tissue oxygenation properties of hemoglobin solutions in central organs like the liver. METHODS: Twelve Foxhounds were anesthetized and then randomized to either a control group without hemodilution (Group 1) or underwent first step isovolemic hemodilution (pulmonary artery occlusion pressure constant) with Ringer's solution (Group 2) to a hematocrit of 25% with second step infusion of HBOC-201 until a hemoglobin concentration of +0.6 g.dL(-1) was reached. Tissue oxygen tensions (tpO2) were measured in the gastrocnemius muscle using a polarographic needle probe, and in the liver using a flexible polarographic electrode. RESULTS: While arterial oxygen content and oxygen delivery decreased with hemodilution in Group 2, global liver and muscle oxygen extraction ratio increased after hemodilution and additional application of HBOC-201. Hemodilution and application of HBOC-201 provided augmentation of the mean liver tpO2 (baseline: 48 +/- 9, 20 min: 53 +/- 10, 60 min: 67 +/- 11*, 100 min: 68 +/- 7*; *P < 0.05 vs baseline and Group 1), while oxygen tensions in Group 1 remained unchanged. Oxygen tension in the skeletal muscle increased after hemodilution and additionally after application of HBOC-201 in comparison to baseline and to the control group (P < 0.05). CONCLUSION: In the present animal model, IHD with Ringer's solution and additional application of HBOC-201 increased oxygen extraction and tpO(2) in the liver and skeletal muscle, in parallel and in comparison with baseline values and a control group.

Microcirculatory function and tissue damage is improved after therapeutic injection of bovine hemoglobin in severe acute rodent pancreatitis.

OBJECTIVES: Stasis of the pancreatic microcirculation initiates and aggravates acute pancreatitis. Bovine hemoglobin has been shown to improve microcirculation in acute pancreatitis if prophylactically infused 15 minutes after initiation of acute pancreatitis. The purpose of this study was to evaluate the therapeutic effectiveness of bovine hemoglobin on pancreatic microcirculation and tissue damage later in the course of experimental acute rodent pancreatitis. METHODS: In Wistar rats, severe acute pancreatitis was induced by administration of glyco-deoxycholic-acid intraductally and cerulein intravenously. Pancreatic microcirculation was continuously monitored by intravital microscopy. Three hours after the initiation of acute pancreatitis, animals received either 0.8 mL bovine hemoglobin (Oxyglobin), hydroxyethyl starch (HES), or 2.4 mL 0.9% NaCl intravenously at random. After 6 hours, animals were killed, and histopathological damage of the pancreas was assessed using a validated histology score. RESULTS: Pancreatic microcirculation assessed by leukocyte adherence was significantly improved by the administration of bovine hemoglobin in comparison with normal saline over time (mean difference, 51.6 +/- 9.2; P < 0.001) and HES (mean difference, 24.1 +/- 9.2; P = 0.037). This result was paralleled by decreased tissue damage in the bovine hemoglobin group as opposed to NaCl (6.75 vs. 12; range, 5.25-7.75 vs. 8.25-14; P < 0.001) and HES (6.75 vs. 9; range, 5.25-7.75 vs. 7.5-10.75; P < 0.001). CONCLUSION: Therapeutic intravenous infusion of bovine hemoglobin improves pancreatic microcirculation and reduces pancreatic tissue damage in severe acute rodent pancreatitis but is not as effective as early (prophylactic) administration.

Quality of postoperative pain using an intraoperatively placed epidural catheter after major lumbar spinal surgery.

BACKGROUND: Major spinal surgery is associated with high postoperative pain scores and opioid requirement. The aim of the current prospective, randomized, placebo-controlled, double-blind study was to assess the reduction of opioid requirement and pain scores using an intraoperatively placed epidural catheter with infusion of 0.1% ropivacaine during the postoperative period. METHODS: Thirty patients undergoing major lumbar spinal surgery from a dorsal approach were included in this study. Before wound closure, the orthopedic surgeon inserted an epidural catheter. Postoperatively, patients were randomly assigned to receive an infusion of 12 ml/h ropivacaine, 0.1% (group R), or 12 ml/h saline (group N) after an initial bolus of 10 ml of the respective study solution. Additional pain relief was provided using an intravenous patient-controlled analgesia pump with the opioid piritramide. Patients were assessed with respect to pain scores (visual analog scale of 0-100), cumulative opioid requirement, side effects, and satisfaction with pain management. RESULTS: : Demographic data, duration of surgery, and type of surgery were comparable between groups. Pain scores were assessed as follows (group R vs. group N: 6 h: 24 +/-20 vs. 51 +/- 20, P = 0.002; 24 h: 33 +/- 19 vs. 53 +/- 27, P = 0.04; 48 h: 21 +/-17 vs. 40 +/- 26, P = 0.04; 72 h: 14 +/- 13 vs. 38 +/- 25, P = 0.02). The cumulative piritramide requirement after 72 h was 97 +/- 23 mg in group R and 157 +/-72 mg in group N (P = 0.03). The incidence of side effects was comparable between groups, and patient satisfaction was always higher in group R (P < 0.05). CONCLUSION: Continuous epidural infusion of 0.1% ropivacaine results in lower pain scores and opioid consumption and higher patient satisfaction when compared with placebo. Application of ropivacaine using an epidural catheter seems to be a highly effective treatment for postoperative pain after major lumbar spinal surgery.

Cost drivers in patient-controlled epidural analgesia for postoperative pain management after major surgery.

UNLABELLED: In this retrospective study, we determined efficiency, treatment length, and resource use for postoperative pain management with patient-controlled epidural analgesia (PCEA) in 350 consecutive patients undergoing major abdominal, thoracic, gynecological, or orthopedic surgery. Average pain scores on a visual analog scale were 16 +/- 23 and 9 +/- 16 (visual analog scale range, 0 to 100) on postoperative Days 1 and 3, respectively, and were similar among groups. The treatment length was 4.9 +/- 2.2 days in general surgical, 5.2 +/- 3.1 days in gynecological, and 4.5 +/- 2.8 days in orthopedic patients. The total volumes of the mixture of local anesthetic and opioid received epidurally were 707 +/- 507 mL, 770 +/- 576 mL, and 593 +/- 456 mL in the general surgical, gynecological, and orthopedic groups, respectively. The average total costs for all groups for the full treatment course with PCEA were 447 +/- 218 per case (1 equals approximately US dollar 1). Fifty-one percent of these costs were staff costs, 20% were costs for the applied drugs, 15% were costs for PCEA pumps and pump material, and 13% were costs for the initial catheter insertion. In the light of these costs and the availability of less costly alternatives, measurements for cost containment by using PCEA are recommended. Because treatment length is the main cost driver both for drug and staff costs, close monitoring of treatment length and a predefined migration path to alternative techniques after PCEA should be considered. IMPLICATIONS: Patient-controlled epidural analgesia is increasingly used as first-line treatment for postoperative pain management. In this study, costs and cost drivers are analyzed for the first time for this new technique, based on 350 cases of pain therapy after major surgery in a university hospital.

Pre- and intraoperative epidural ropivacaine have no early preemptive analgesic effect in major gynecological tumour surgery.

PURPOSE: Thoracic epidural analgesia (TEA) is an established technique for postoperative pain relief after major abdominal surgery. However it is still under discussion whether pre-incisional TEA can reduce postoperative pain perception or postoperative analgesic consumption. METHODS: The present prospective, randomized, double-blind study was performed to investigate the effects of intra- and postoperative TEA vs only postoperative TEA using ropivacaine 0.375% in 30 women scheduled for major abdominal tumour surgery. Prior to induction of general anesthesia patients received an epidural bolus of 10 mL saline in Group I (GI) and 10 mL ropivacaine 0.375% in Group II (GII) followed by an infusion of 6 mL x hr(-1) of the respective solution during surgery. Postoperatively all patients received an epidural infusion of 6 mL x hr(-1) ropivacaine 0.375% during 24 hr followed by patient controlled epidural analgesia for the next 72 hr. Operative data, dynamic pain scores, consumption of local anesthetics and standardized supplemental analgesics were analyzed. RESULTS: No difference was seen between groups with respect to the amount of required postoperative local anesthetics and supplemental analgesics, pain scores and side effects during the first 96 hr following surgery except a reduction of intraoperative sufentanil consumption (GI: 143.2 +/- 52.6 vs GII: 73.3 +/- 32.6 microg, P < 0.001). CONCLUSION: Intraoperative TEA with ropivacaine 0.375% did not significantly reduce the amount of analgesics required after major abdominal gynecological tumour surgery.

Hydroxyethyl starch (HES) 130/0.4 provides larger and faster increases in tissue oxygen tension in comparison with prehemodilution values than HES 70/0.5 or HES 200/0.5 in volunteers undergoing acute normovolemic hemodilution.

UNLABELLED: Stable hemodynamics and improved rheology are important effects of hemodilution with hydroxyethyl starch (HES) infusions. One clinical indicator of improved rheology is increased tissue oxygen tension (tpO(2)). In this prospective, randomized, double-blinded, crossover study, we examined the effects of acute normovolemic hemodilution with HES 130/0.4 on hemodynamics and skeletal muscle tpO(2) in comparison with conventional HES solutions. Twelve healthy volunteers were randomly enrolled in each group. At an interval of >8 days, volunteers donated 18% of their calculated blood volume within 30 min and randomly received 6% HES 130/0.4, 6% HES 70/0.5, or 6% HES 200/0.5 (crossover design) in a 1:1.2 ratio to their blood loss. Hemodynamic variables, tpO(2) in the quadriceps muscle, hematocrit, plasmatic HES concentrations, plasma viscosity, colloid osmotic pressures, and platelet aggregation were measured until 6 h after the infusion of HES. No differences were found among groups with respect to changes of hemodynamics, hematocrit, or platelet aggregation. With HES 200, colloid osmotic pressures and plasma viscosities were larger than after HES 70 (P < 0.05). HES 130 in comparison with HES 70 and 200 caused the fastest (30 min versus 90 min and 150 min after hemodilution; P < 0.05) and largest increase of tpO(2) in comparison to baseline (+93% versus +33% and 40%; P < 0.05). In healthy volunteers undergoing acute normovolemic hemodilution, the newly designed HES 130/0.4 showed a more pronounced and earlier increase of skeletal muscle tpO(2) in comparison with prehemodilution values than HES 70/0.5 or 200/0.5. IMPLICATIONS: The effects of three different hydroxyethyl starch (HES) solutions on hemodynamics, rheology, and skeletal muscle tissue tension after acute normovolemic hemodilution were examined in awake volunteers. With HES 130/0.4, increases of tissue oxygen tension in comparison to baseline were larger and more rapid than with HES 70/0.5 or HES 200/0.5.

Patient-controlled thoracic epidural infusion with ropivacaine 0.375% provides comparable pain relief as bupivacaine 0.125% plus sufentanil after major abdominal gynecologic tumor surgery.

BACKGROUND AND OBJECTIVES: We tested the hypothesis that an opioid-free local anesthetic alone is able to provide comparable analgesia to the opioid supplemented epidural application of local anesthetics using thoracic epidural catheters after major abdominal surgery. METHODS: In a prospective, randomized, and double-blind study, we have compared the analgesic efficacy and side effects of ropivacaine 0.375% (group R) versus bupivacaine 0.125% in combination with sufentanil 0.5 microg/mL(-1) (group B/S) via a thoracic epidural catheter for a duration of 96 hours after major abdominal surgery in 30 gynecologic tumor patients. Piritramide was given for breakthrough pain. Assessments were performed every 12 hours after start of the epidural infusion using continuous (first 24 hours) and patient-controlled epidural analgesia (PCEA) (24 to 96 hours). RESULTS: No differences were seen in demographic and perioperative data. Dynamic pain scores (visual analog scale [VAS] values) were comparable between groups during mobilization (group R v group B/S: 24 hours: 40 +/- 30 v 36 +/- 14, P =.9; 48 hours: 46 +/- 33 v 42 +/- 25, P =.93; 72 hours: 42 +/- 24 v 48 +/- 26, P =.78; 96 hours: 42 +/- 25 v 29 +/- 28, P =.49) and on coughing during the whole study period. Hemodynamics, intensity of motor block (Bromage scale), and side effects like nausea, vomiting, pruritus, and bladder disfunction also did not differ between groups. CONCLUSION: The present study shows that thoracic epidural infusion of ropivacaine 0.375% provides comparable pain relief and incidence of side effects after major abdominal gynecologic surgery as bupivacaine 0.125% in combination with 0.5 microg/mL(-1) sufentanil and may therefore represent an alternative in epidural pain management.

Influence of early defibrillation on the survival rate and quality of life after CPR in prehospital emergency medical service in a German metropolitan area.

Early defibrillation by emergency medical personnel has been shown to improve survival in patients suffering from out-of-hospital cardiac arrest with ventricular fibrillation. Due to organisational differences it is difficult to compare results in various studies. Comparison of studies has been simplified by introduction of the Utstein template. After introduction of an early defibrillation program in Hamburg, we compared the patients being treated with early defibrillation by emergency medical technicians (EMTs) with patients being defibrillated by physicians in an out-of-hospital emergency service in a prospective study. All patients suffered from non EMT-witnessed ventricular fibrillation of cardiac origin. During 1 year, 103 patients were analyzed with respect to survival rate and quality of life. Of the 53 patients in the early defibrillation group (G1) 11 regained a palpable pulse at physicians' arrival, whereas all patients of the control group (G2) showed ventricular fibrillation. More patients treated with early defibrillation regained sinus rhythm without antiarrhythmics in the prehospital phase (G1: n=43 (86%); G2: n=32 (60%); P<0.05) and had a shorter in-hospital stay (G1: median, 23 days; range 5-51 days; G2: median 39, range 15-88 days; P<0.05). Twelve patients in G1 and 16 in G2 were discharged from hospital. The survival rate was similar in both groups (after 6 months G1: n=12; G2: n=14, after 12 months G1: n=10; G2: n=13 and after 24 months G1: n=9; G2: n=10), and the quality of life according to Glasgow-Pittsburgh Cerebral Performance Category (CPC) and Overall Performance Category (OPC) scores also was comparable between groups. We conclude that early defibrillation provides a higher incidence of return of a spontaneous circulation, a reduced need for antiarrhythmics and shorter in-hospital treatment times in patients with out-of-hospital ventricular fibrillation.