Stefan Lauer

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.

Thoracic epidural anesthesia reverses sepsis-induced hepatic hyperperfusion and reduces leukocyte adhesion in septic rats

IntroductionLiver dysfunction is a common feature of severe sepsis and is associated with a poor outcome. Both liver perfusion and hepatic inflammatory response in sepsis might be affected by sympathetic nerve activity. However, the effects of thoracic epidural anesthesia (TEA), which is associated with regional sympathetic block, on septic liver injury are unknown. Therefore, we investigated hepatic microcirculation and inflammatory response during TEA in septic rats.MethodsForty-five male Sprague-Dawley-rats were instrumented with thoracic epidural catheters and randomized to receive a sham procedure (Sham), cecal ligation and puncture (CLP) without epidural anesthesia (Sepsis) and CLP with epidural infusion of 15 ul/h bupivacaine 0.5% (Sepsis + TEA). All animals received 2 ml/100 g/h NaCl 0.9%. In 24 (n = 8 in each group) rats, sinusoidal diameter, loss of sinusoidal perfusion and sinusoidal blood flow as well as temporary and permanent leukocyte adhesion to sinusoidal and venolar endothelium were recorded by intravital microscopy after 24 hours. In 21 (n = 7 in each group) separate rats, cardiac output was measured by thermodilution. Blood pressure, heart rate, serum transaminase activity, serum TNF-alpha concentration and histologic signs of tissue injury were recorded.ResultsWhereas cardiac output remained constant in all groups, sinusoidal blood flow increased in the Sepsis group and was normalized in rats subjected to sepsis and TEA. Sepsis-induced sinusoidal vasoconstriction was not ameliorated by TEA. In the Sepsis + TEA group, the increase in temporary venolar leukocyte adherence was blunted. In contrast to this, sinusoidal leukocyte adherence was not ameliorated in the Sepsis + TEA group. Sepsis-related release of TNF-alpha and liver tissue injury were not affected by Sepsis + TEA.ConclusionsThis study demonstrates that TEA reverses sepsis-induced alterations in hepatic perfusion and ameliorates hepatic leukocyte recruitment in sepsis.

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.

Hepatic effects of thoracic epidural analgesia in experimental severe acute pancreatitis.

Background:Thoracic epidural anesthesia (TEA) protects the intestinal microcirculation and improves perioperative outcomes. TEA also reduces mortality in acute experimental pancreatitis. Its impact on hepatic microcirculation, however, in health and critical illness is unknown. Therefore, the authors studied the effect of TEA on the liver in healthy rats and in experimental severe acute pancreatitis. Methods:TEA was induced by 15 &mgr;l/h bupivacaine, 0.5%. Necrotizing pancreatitis was induced by intraductal infusion of 2 ml/kg taurocholic acid, 5%. Twenty-eight rats were assigned to either Sham operation, Sham + TEA, Pancreatitis, or Pancreatitis + TEA. After 15 h, mean arterial pressure, heart rate, and respiratory function were recorded. Sinusoidal width and perfusion rate and the intrahepatic leukocyte adhesion were assessed by intravital microscopy. In an additional 22 rats randomly assigned to Sham, Pancreatitis, and Pancreatitis + TEA, hepatic apoptosis was evaluated by staining for single-stranded DNA and Fas ligand–positive cells. Results:TEA did not affect hepatic microcirculation and leukocyte adhesion in healthy rats. Blood pressure remained unchanged in the Sham + TEA group. In Pancreatitis, mean arterial pressure decreased from 141 ± 6 mmHg to 127 ± 13 mmHg but remained stable in Pancreatitis + TEA. The sinusoidal diameter decreased from 5.4 ± 0.1 &mgr;m to 5.0 ± 0.2 &mgr;m in Pancreatitis. This was restored in Pancreatitis + TEA. Intrahepatic leukocyte adhesion was not affected by TEA. The increased hepatocyte apoptosis in Pancreatitis was abolished in Pancreatitis + TEA. This might be mediated by inhibition of the Fas ligand pathway. Conclusion:TEA reduces liver injury in necrotizing acute pancreatitis. This could be related to a regional sympathetic block. TEA could thus preserve liver function in systemic inflammatory disorders such as acute pancreatitis.

Apneic Oxygenation During Prolonged Laryngoscopy in Obese Patients: A Randomized, Controlled Trial of Buccal RAE Tube Oxygen Administration.

BACKGROUND: Despite optimal preoxygenation, obese patients undergoing induction of general anesthesia exhibit significant hypoxemia after 2 to 4 minutes of apnea. Apneic oxygenation techniques can assist airway management by extending the safe apnea time. We hypothesized that a novel method of apneic oxygenation via the oral route would effectively prolong safe apnea in an obese surgical population. METHODS: In this open-label, parallel-arm, randomized-controlled efficacy trial, 40 ASA physical status I–II obese patients with body mass index (BMI) 30–40 were randomly assigned to standard care (n = 20) or buccal oxygenation (n = 20) during induction of total IV anesthesia. Buccal oxygen was administered via a modified 3.5-mm Ring-Adair-Elwyn (RAE) tube apposed to the left internal cheek. Prolonged laryngoscopy maintained apnea with a patent airway until SpO2 dropped below 95% or 750 seconds elapsed. The primary outcome was time to reach SpO2 < 95%. RESULTS: Patient characteristics were similar in both study arms. Recipients of buccal oxygenation were less likely to exhibit SpO2 < 95% during 750 seconds of apnea; hazard ratio 0.159 (95% confidence interval 0.044–0.226, P < .0001). Median (interquartile range [IQR]) apnea times with SpO2 ≥ 95% were prolonged in this group; 750 (389–750) versus 296 (244–314) seconds, P < .0001. CONCLUSIONS: Clinically important prolongation of safe apnea times can be achieved delivering buccal oxygen to obese patients on induction of anesthesia. This novel use of apneic oxygenation via the oral route may improve management of the difficult airway and overcome some of the limitations of alternative techniques.

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

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

Recombinant factor VIIa and factor VIII treatment for acquired factor VIII deficiency: a case of repeated thrombotic endotracheal occlusion in a mechanically ventilated patient

Acquired hemophilia A is caused by autoantibodies to coagulation factor VIII (FVIII). Preoperative diagnosis is impaired by the lack of a personal or family history of bleeding episodes. Therefore, surgical procedures can lead to life-threatening hemorrhage [1]. We present a case of a 72-year-old woman who had no history of coagulopathy and who was undergoing hysteroscopy and abrasion in a district hospital. Persistent vaginal bleeding began immediately after surgery, resulting in vaginal hysterectomy on postoperative day (POD) 7 and multiple re-laparotomies with intermittent abdominal packing between PODs 8 and 37. Acquired FVIII deficiency was suspected on POD 30, but a disseminated intravascular coagulation and treatment with various pro-coagulants made the definitive diagnosis difficult. Bolus applications of recombinant factor VIIa (rFVIIa) and von Willebrandt factor-FVIII complex between PODs 33 and 38 plus prednisolone pulse therapy remained ineffective. Acquired FVIII deficiency was finally diagnosed upon admission of the intubated and ventilated patient to the intensive care unit of a university hospital on POD 40. Further FVIII was administered because of persistent surgical bleeding. Following massive abdominal bleeding on POD 44, the patient received FVIII for the next 24 hours and rFVIIa until POD 49. On POD 47, the abdominal bleeding ceased. Three life-threatening airway complications occurred under rFVIIa and FVIII therapy. On POD 40, the endotracheal tube (ETT) was completely obstructed by blood clots. On POD 46, pulmonary gas exchange rapidly deteriorated because of a huge thrombus in the left main bronchus (2 × 5 cm). On POD 49, a large endobronchial thrombus (2 × 7 cm), which was attached to the tip of the ETT, was fortunately extracted during the emergency removal of the ETT (Figure ​(Figure1a1a). Figure 1 A bronchial thrombus critically obstructed the airways in a long-term ventilated patient under recombinant factor VIIa and factor VIII therapy. (a) The thrombus (arrow) was still attached to the tip of the removed endotracheal tube. (b) The detached thrombus ... Each time, bronchoscopy showed only moderate diffuse bleeding from minor mucosal erosions. After the critical incident on POD 49, the patient was weaned from the respirator and eventually fully recovered. Intravascular thromboembolic events under treatment with rFVIIa and FVIII present a well-known complication [2,3]. Life-threatening thrombotic airway obstructions in a mechanically ventilated patient, however, are a rare complication. The fact that activated partial thromboplastin times (aPTTs) were spontaneously prolonged (53 to 66 seconds) and active bleeding was present during these events highlights the unpredictable local imbalance of pro- and anticoagulant effects during such a treatment. In conclusion, intensive care clinicians should be aware that minor lacerations of the bronchial mucosa in mechanically ventilated patients could lead to blood clots and critical airway obstruction under the treatment with rFVIIa and FVIII.

Somatostatin infusion increases intestinal ischemia and does not improve vasoconstrictor response to norepinephrine in ovine endotoxemia.

Hemodynamic support of patients with septic shock is often complicated by a tachyphylaxis against exogenous catecholamines. Because an increase in somatotropic hormones may play a pivotal role in the regulation of the inflammatory response to endotoxin, intravenous supplementation of the neuroendocrine hormone somatostatin (SOMA) may attenuate hemodynamic dysfunction resulting from endotoxemia. The objective of the present study was to assess the short-term effects of SOMA alone and in combination with norepinephrine (NE) on cardiopulmonary hemodynamics, global oxygen transport, plasma nitrate/nitrite levels, and intestinal integrity compared with single NE therapy in ovine endotoxemia. After a baseline measurement in healthy sheep (n = 16) had been performed, Salmonella typhosa endotoxin was centrally infused (10 ng·kg−1·min−1) to induce a hypotensive-hyperdynamic circulation using an established protocol. Animals surviving 16 h of endotoxemia were randomly assigned to one of the two groups (each n = 6). Sheep allocated to the SOMA + NE group received SOMA as a loading dose of 10.5 &mgr;g·kg−1·min−1 for 1 h, followed by a continuous infusion of 3.5 &mgr;g·kg−1·min−1 for the next 2 h. After the SOMA loading dose had been given, NE was concurrently infused (0.3&mgr;g·kg−1·min−1) for 2 h. In the NE group (control), NE (0.3 &mgr;g·kg−1·min−1) was continuously infused for 3 h. Endotoxemia caused a decrease in MAP and systemic vascular resistance index in both groups, but to a greater extent in the NE group. Arterial hypotension persisted despite administration of the study drugs. Infusion of SOMA alone and in combination with NE did not significantly increase systemic vascular resistance index. Neither SOMA nor NE infusion alone affected pulmonary vasoregulation. Plasma nitrate/nitrite levels did not differ between groups. However, combined infusion of SOMA and NE significantly increased arterial lactate concentrations, oxygen consumption index, and oxygen extraction rate (P < 0.05) and aggravated ileal mucosal injury. In conclusion, short-term treatment with SOMA failed to attenuate cardiocirculatory shock resulting from endotoxemia and did not improve vasopressor response to NE. In addition, combined SOMA and NE therapy resulted in intestinal injury. Therefore, SOMA does not seem to represent a therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome.