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CRITICAL CARE AND TRAUMA

The Role of Thoracic Epidural Analgesia in Receptor-Dependent and Receptor-Independent Pulmonary Vasoconstriction in Experimental Pancreatitis

Stefan Lauer, MD^*, Hendrik Freise, MD^*, Lars G. Fischer, MD^*, Kai Singbartl, MD^*, Hugo V. Aken, MD, FRCA, FANZCA^*, Markus M. Lerch, MD, and Andreas W. Sielenkämper, MD, MSc^*

From the *Department of Anesthesiology and Intensive Care Medicine, University Hospital Muenster, Germany; and Department of Gastroenterology, Endocrinology and Nutrition, Ernst-Moritz-Arndt Universität, Greifswald, Germany.

	Abstract

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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.

	Introduction

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Thoracic epidural analgesia (TEA) is routinely used after major thoracic or abdominal surgery and in trauma patients (1,2). In comparison with general anesthesia alone, the use of TEA reduces cardiopulmonary mortality (3). In experimental settings, TEA has been reported to exert beneficial effects on gut mucosal blood flow (4) and to augment intestinal perfusion in systemic hypotension (5). There is also evidence suggesting protective effects of epidural analgesia on gastrointestinal mucosal perfusion in acute pancreatitis (6). Clinical investigations have demonstrated a beneficial influence of TEA on intestinal motility and mucosal perfusion in critically ill patients with peritonitis (7). In pancreatitis, TEA is a therapeutic option for pain relief in selected cases, assuming the potential risks of its use in critically ill patients are thoroughly considered. However, the effects of TEA on pulmonary vasoregulation and pulmonary endothelial function in acute pancreatitis are unknown.

In this setting, we studied pulmonary vasoregulation, oxygenation and the systemic response in experimental necrotizing pancreatitis and the effects of TEA, in vivo and in vitro, as a potential therapeutic target.

	METHODS

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Animal Preparation
The study was approved by the animal ethics committee of the district government of Muenster. Male Sprague-Dawley rats (250–300 mg, Harlan Winkelmann, Borchen, Germany) were allowed food and water ad libitum and were kept in a 12-h light–dark cycle. The animals were used after 1 wk of acclimatization.

For instrumentation, anesthesia was induced and maintained by isoflurane inhalation (MAC 1.4 Vol. %) in 50% oxygen while the rats were spontaneously breathing. Central venous and arterial lines (0.96 mm OD) (Liquiscan, Ueberlingen, Germany) were introduced via the right external jugular vein and the left carotid artery. Epidural catheters (0.61 mm OD) were inserted at L3/L4 and advanced to Th6. A repeated negative liquor aspiration test excluded subdural position of the catheter. All catheters were protected by a swivel device. In animals treated with bupivacaine, weak to moderate motor deficits of the hindlimbs were observed, which were not significant compared to baseline and sham animals. The front paws were not affected. After completion of the experimental protocol, the position of the catheter was verified by autopsy. This model of continuous TEA was established by Freise et al. in our laboratory (8).

After median laparotomy, the pancreas was exposed and the proximal bile duct temporarily clamped. Acute pancreatitis was induced by retrograde intraductal injection of 2 mL/kg taurocholate 5%. The rats were then allowed to wake up. Fluid resuscitation with NaCl 0.9% (6 mL/kg bw) was started postoperatively.

All rats survived 15 h of acute pancreatitis due to taurocholate and underwent successful lung isolation. Independent of treatment with TEA, all animals assigned to acute pancreatitis developed necrotizing pancreatitis, with general signs of illness, tissue and fat necrosis of the pancreas and the interstitial tissue as well as ascites. According to previous studies, taurocholate-induced necrotizing pancreatitis results in significant mechanical and morphological lung alterations similar to those seen in patients with pancreatitis-associated acute respiratory distress syndrome (9).

Study Protocol
Rats were randomly divided into three groups (n = seven per group). Group I received an injection of taurocholate to induce acute pancreatitis, directly followed by a continuous epidural infusion of normal saline (PANC, 15 µL/h for 15 h). Group II received epidural bupivacaine 0.5% after induction of acute pancreatitis (PANC + TEA, 15 µL/h for 15 h), while Group III received a sham laparotomy and epidural saline (SHAM + TEA, 15 µL/h for 15 h). Fifteen hours after induction of acute pancreatitis, mean arterial blood pressure was measured and blood was withdrawn from the arterial catheter in awake, spontaneously breathing rats. Arterial hemoglobin, hematocrit, pH, Pao₂, Paco₂, HCO₃^–, ABE, leukocytes and serum lactate were determined by blood gas analysis (ABL, 620 Radiometer, Copenhagen, Denmark) (Fig. 1).

View larger version (11K): [in this window] [in a new window]   Figure 1. Flowchart of the experimental design. Every protocol started with instrumentation of the catheters and induction of acute pancreatitis (AP)/sham procedure, followed by epidural treatment with saline (sham) or saline/bupivacaine 0.5% (PANC/PANC + TEA) in awake rats for 15 h. Then blood samples were taken and hemodynamic measurements were performed before the rats were anesthetized and tracheostomized. Exhaled nitric oxide (exNO) was measured, followed by induction of isolated perfused lungs.

Isolated Perfused Lungs
Rats were then reanesthetized with intraperitoneal -chloralose (50 mg/kg, Sigma Chemicals, Deisenhofen, Germany) and urethane (650 mg/kg, Sigma Chemicals, Deisenhofen, Germany) and were then tracheostomized with a 17-gauge cannula. The lungs were ventilated with warmed (35°C) and humidified 21% O₂, 5% CO₂ and balanced N₂ using a rodent ventilator (tidal volume 1 mL/100 g, frequency 60 breaths/min, Harvard Apparatus GmbH, Germany). End-expiratory pressure was set at 1 mm/Hg. The exhaled air was collected in a bag for 10 min. The exhaled nitrous oxide (exNO) concentration was analyzed by a TE 42S NO_x analyzer (Thermo Environment, Franklin, MA).

For induction of the isolated perfused lungs, sternotomy was conducted, followed by excision of sections of the right and left anterior chest wall to expose the heart and lungs. After heparinization (100 U) rats were partly exsanguinated by needle aspiration (5–6 mL). A steel cannula (13-gauge) connected to the perfusion system was inserted through the pulmonic valve into the main pulmonary artery via an incision in the right ventricle. A suture tied around the pulmonary artery and aorta secured the cannula. The latter prevented systemic blood flow. The circle was closed by a cannula (3.5 mm outside diameter) that was inserted through the apex of the left ventricle and secured with umbilical tape. The isolation and perfusion procedure followed a technique standardized in our laboratory (10,11).

Perfusate consisted of the rat’s own blood (added to the perfusate after lung isolation) diluted with physiological salt solution (containing in mM: 119.0 NaCl, 4.7 KCl, 1.17 MgSO₄ x 7 H₂O, 22.6 NaHCO₃, 1.18 KH₂PO₄, 3.2 x 2 H₂O, 5.6 dextrose) to a hematocrit of 9%–12%. Indomethacine (30 µg/mL) was added to block prostaglandin synthesis. Perfusate drained from the left ventricle to a glass reservoir and was heated to 38°C by a circumferential water jacket. Perfusate was returned to the pulmonary artery at constant flow (16 mL/min) using a peristaltic pump (Harvard Apparatus, Germany). The isolated lung preparation remained in the thoracic cavity and was warmed with a heating lamp. A warmed and humidified chamber was placed over the thoracic cavity to maintain thoracic temperature at 37°C. Reservoir pH was continuously monitored (Hanna Instruments, Germany) and maintained at 7.35–7.45 by addition of HCl or NaOH as required. Pulmonary artery pressure (P_a) was continuously monitored using a pressure transducer (Becton Dickinson, Singapore). Mean pulmonary venous pressure was set at 2 mm Hg by adjusting the height of the reservoir and held constant. Normoxic (21% O₂) and hypoxic (3% O₂) gas mixtures were administered through individual flowmeters. The inspired O₂ concentration was monitored (Oxydig, Draeger, Germany) near the tracheal tube.

Following stabilization after thoracotomy and isolation of the rat’s lungs, receptor-mediated vasoconstriction was studied.

Receptor-Dependent Pulmonary Vasoconstriction
Functional integrity of vascular smooth muscle cell (VSMC) is important for the regulation of the vascular tone. To test possible functional impairment of pulmonary VSMC during pancreatic injury, the potent receptor-mediated vasoconstrictor angiotensin II (AngII, 0.1 µg, Sigma Chemicals, Germany) was injected into the inflow tract of the isolated perfused lung circuit. Changes in perfusion pressure were measured in mm Hg and expressed as p from baseline pressure.

Several studies have demonstrated that the application of bradykinin (BK) leads to a paradoxical vasoconstriction when the endothelium layer is injured under septic conditions, thus directly provoking VSMC. In healthy controls with an intact endothelial layer, paradox vasoconstriction was not observed (11,12).

To test pulmonary endothelial dysfunction in pancreatitis, BK-induced vasoconstriction was evaluated by injecting increasing concentrations of BK (1, 3, 6 µg; Sigma Chemicals, Germany) into the inflow circuit. Each dose was administered 5 min after the perfusion pressure returned to baseline levels. Changes in perfusion pressure were measured in mm Hg and expressed as p from baseline pressure.

Receptor-Independent Pulmonary Vasoconstriction
Hypoxic pulmonary vasoconstriction (HPV) is an important regulatory mechanism to divert blood away from hypoxic to normoxic regions, thus optimizing matching of ventilation and perfusion and preserving gas exchange. HPV is dependent on VSMC function. To evaluate possible deterioration of pulmonary vasoregulation under hypoxic conditions, HPV was induced 5 min after AngII application. Lungs were ventilated with a hypoxic mixture (3% O₂, 5% CO₂, 92% N₂) for 10 min and then again with the normoxic mixture (21% O₂, 5% CO₂, 74% N₂) for an equal period. Changes in perfusion pressure were measured in mm Hg and expressed as p from baseline pressure.

Myeloperoxidase (MPO) Activity
To avoid interactions with the isolated perfused lung model, MPO activity and wet/dry weight ratio were measured in a second series of experiments. Rats were treated in the same groups according to the previous protocol and were killed 15 h after injury. After the experiment, right lungs were immediately frozen and stored at –70°C until use. MPO, indicating neutrophil infiltration into lung tissue, was measured in equal-sized samples of the right lungs according to published protocols (13). Results were expressed as units of MPO/g of protein of supernatant as determined by bicinchoninic acid assay (Pierce Chemical, Rockford, IL).

Wet and Dry Ratio
For determination of lung edema, the left bronchus was carefully separated from the right bronchus and tied, and the left lung was severed. The lung was weighed immediately and dried at 60 ° in an oven for 4 days to determine the ratio of wet lung weight to dry lung weight. The dry lung weight became stable after 48 h of desiccation in our study.

Statistics
Vasoconstriction from AngII, HPV, and BK was expressed as the peak P_a minus baseline P_a. Data are presented as means ± sd. Sigma Stat 3.1 software was used for statistical analysis. The various treatments were compared with one-way analysis of variance (ANOVA) and t-test (Student-Newman-Keuls method). When data were not normally distributed they were tested with Kruskal-Wallis analysis of variance. Differences at the level of P < 0.05 were considered significant.

	RESULTS

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Systemic and Pulmonary Effects
In the blood gas analysis 15 h after injury, Pao₂ was reduced in PANC compared to SHAM animals (P < 0.05; Table 1). In PANC + TEA rats, Pao₂ was increased compared to PANC (P < 0.05) and showed no differences to sham animals. Paco₂ was comparable among groups (Table 1). Base Excess was increased in the PANC group but was normalized to sham levels with epidurally administered bupivacaine (PANC + TEA; P < 0.05; Table 1). Arterial bicarbonate levels were reduced in PANC compared to SHAM animals (P < 0.05). In PANC + TEA rats, bicarbonate levels were normalized compared to PANC (P < 0.05; Table 1).

Mean arterial blood pressure was reduced in PANC compared to SHAM animals (P < 0.05). In animals treated with epidural bupivacaine, mean arterial blood pressure was higher in relation to PANC and reached levels of SHAM animals (Table 2). Hemoglobin and hematocrit, however, did not differ among groups (Table 2).

In PANC animals, serum lactate was increased compared to SHAM 15 h after injury (P < 0.05; Table 2). In animals treated with TEA, serum lactate levels were reduced in relation to PANC (P < 0.05, Table 2).

Leukocyte count declined in PANC compared to SHAM animals. In PANC + TEA rats, leukocytes were significantly lower compared to SHAM (P < 0.05; Table 2).

At 15 h after injury, exNO was increased in PANC compared to SHAM animals (P < 0.05). Rats treated with epidural bupivacaine demonstrated a reduced exNO in contrast to untreated animals (Fig. 2).

View larger version (15K): [in this window] [in a new window]   Figure 2. Exhaled nitric oxide (parts per billion) in sham animals, pancreatitis and epidural-treated pancreatitis 15 h after injury (mean ± sd). #P < 0.05 versus SHAM; *P < 0.05 versus PANC.

The wet/dry ratio detected 15 h after injury was increased in PANC and PANC + TEA compared to SHAM animals (P < 0.05, Table 2).

Pulmonary leukocyte sequestration was measured 15 h after injury as evidenced by pulmonary MPO activity. In PANC and PANC + TEA rats, MPO activity was increased compared to SHAM (P < 0.05, Table 2).

Receptor-Dependent Pulmonary Vasoconstriction
Baseline P_a after lung isolation did not differ between PANC, PANC + TEA, and SHAM animals (data not shown). In PANC rats, vasoreactivity due to AngII was nearly abolished compared to SHAM (P < 0.05). In PANC + TEA rats, AngII-induced pulmonary vasoconstriction was partly restored in relation to PANC (P < 0.05 each; Fig. 3).

View larger version (13K): [in this window] [in a new window]   Figure 3. Vasoconstriction due to angiotensin II in sham animals, pancreatitis and epidural-treated pancreatitis 15 h after injury indicating vascular smooth muscle cell function (mean ± sd). #P < 0.05 versus SHAM; *P < 0.05 versus PANC.

In PANC animals, BK-induced vasoconstriction in the pulmonary circulation was concentration-dependent. In comparison to SHAM animals, BK-induced vasoconstriction was significantly enhanced after application of BK only at a dose of 6 µg (P < 0.05; Fig. 5). In SHAM animals vasoconstriction due to BK was negligible.

View larger version (16K): [in this window] [in a new window]   Figure 5. Hypoxic pulmonary vasoconstriction. Pulmonary vascular responses were evaluated with hypoxic mixture (HPV 3%) for 10 min (mean ± sd) 15 h after injury. #P < 0.05 versus SHAM; *P < 0.05 versus PANC.

In TEA-treated rats, pulmonary vasoconstriction after BK injection was concentration-dependent. Compared to PANC rats, BK-induced vasoconstriction was significantly enhanced at a concentration of 1 and 3 µg (P < 0.05). In PANC + TEA animals, vasoreactivity was strongly increased at all concentrations compared to SHAM (P < 0.05 each; Fig. 4).

View larger version (15K): [in this window] [in a new window]   Figure 4. Comparison of bradykinin (BK)-induced vasoconstriction in isolated perfused rat lungs for evaluation of endothelial dysfunction. The difference in perfusion pressure in SHAM, PANC and TEA due to different concentrations of BK (1, 3 and 6 µg) is demonstrated (mean ± sd). #P < 0.05 versus SHAM; *P < 0.05 versus PANC, P < 0.05 versus BK 6 µg within group.

Receptor-Independent Pulmonary Vasoconstriction
The first and second response to HPV did not differ (data not shown), therefore we continued with the first response only. PANC animals showed only a small HPV in relation to SHAM animals (P < 0.05). In PANC + TEA rats, HPV was partly restored, but vasoconstriction was smaller compared to SHAM animals (P < 0.05; Fig. 5).

	DISCUSSION

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In this study, continuous administration of bupivacaine in the thoracic epidural space attenuated pancreatitis-induced circulatory shock and pulmonary dysfunction. TEA reduced pulmonary shunting, improved gas exchange, and decreased exNO concentration, possibly by the inhibition of lung NO synthesis. Moreover, TEA partially restored receptor-dependent pulmonary vasoconstriction (AngII) and HPV, suggesting restoration of receptor-dependent vasoconstriction.

Severe attacks of acute pancreatitis are often associated with acute lung injury (ALI). Arterial hypoxemia, pulmonary infiltrates, and pleural effusions may develop as complications of acute pancreatitis. In addition to alterations in the pulmonary vascular barrier and progressive pulmonary edema, ALI in acute pancreatitis is characterized by distal airway contractions, intra-alveolar edema, endothelial cell damage, leukocyte sequestration, and increased pulmonary MPO activity (14). In this context, increased NO production in inflammatory diseases has detrimental effects on vascular responsiveness and causes disruption of endothelial permeability and integrity, thus leading to reduced responsiveness to hypoxia and increased shunt phenomena.

One established method to test pulmonary endothelial dysfunction in isolated perfused lungs is the application of BK into the pulmonary artery. In contrast to an intact endothelial layer, BK provokes paradoxical pulmonary vasoconstriction in sepsis-induced endothelial injury by direct stimulation of the underlying VSMC. The dose-dependent effects of BK to induce receptor-dependent pulmonary vasoconstriction have been studied in lipopolysaccharide and peritonitis-induced sepsis (11,12).

In this model, exNO, a marker of increased NO synthase activity, was distinctly increased in acute pancreatitis. Furthermore, neutrophil influx into the lungs and the development of pulmonary edema, arterial hypoxia, lactate acidosis, and arterial hypotension reflected the development of pulmonary injury and circulatory shock in this experimental setting. Together with the 2.5-fold increase of exNO, HPV was blunted in pancreatitis, underscoring the inability of the pulmonary vessels to vasoconstrict under hypoxic conditions and causing pulmonary shunting. Besides the pulmonary vasodilatative effects of NO, one possible explanation for this reduced vasoreactivity may be the reduced receptor-dependent vasoconstriction to AngII at the level of VSMC. The integrity of VSMC is indispensable for intact HPV.

In addition to impairment of receptor-dependent pulmonary vasoconstriction (AngII) and HPV, we demonstrated pancreatitis-associated pulmonary endothelial injury by BK-induced pulmonary vasoconstriction. This microvascular injury was described in septic animals and was partly explained by increased pulmonary NO production (11).

The effects of TEA on pulmonary injury and vasoregulation, and especially on HPV, are poorly defined. In experimental studies, epidural analgesia failed to influence HPV, and only minimally influenced pulmonary and systemic hemodynamics (15,16). One study demonstrated that TEA analgesia did not affect vascular tone during one-lung ventilation in dogs, but enhanced the diversion of blood flow and arterial blood oxygenation during lobar hypoxia (16). In another experimental setting, HPV was enhanced by ß blockade, + ß blockade, and epidural blockade in anesthetized dogs and attenuated after blockade. HPV was not affected by epidural blockade after + ß blockade. The authors concluded that epidural blockade had no significant adrenergic-related effect on the pulmonary vasculature (15). Studies providing information about effects of TEA on pulmonary dysfunction and gas exchange in inflammatory diseases are completely lacking.

Our study provides new information on pulmonary injury, especially on receptor-dependent and receptor-independent pulmonary vasoregulation in pancreatitis after continuous TEA. TEA partly restored receptor-dependent vasoconstriction to AngII as well as HPV. As a possible direct result, pulmonary shunting was accompanied by markedly improved arterial oxygenation. Furthermore, circulatory shock seemed to be attenuated, as indicated by increased arterial blood pressure and a steep decline in lactic acidosis. The possible suppression of lung NO synthases and decreased exNO by TEA may be a logical explanation for the observed improvements in pulmonary vasoregulation. In this context, several investigators have already demonstrated a restoration of perturbed HPV and pulmonary vasoreactivity using NO synthase inhibitors in septic animals (10,17,18). However, the restoration of pulmonary vasoconstriction due to AngII and HPV in our setting remained incomplete, suggesting the presence of further pathways in the regulation of pulmonary vascular tone in addition to the NO pathway (17).

BK-induced vasoconstriction to evaluate pulmonary endothelial dysfunction was not influenced by TEA. Moreover, endothelial dysfunction seemed to be more profound when treated with TEA. The different degree of BK-induced vasoconstriction in TEA-treated and TEA-untreated animals may not reflect divergent endothelial damage but, rather, may express improved receptor-dependent vasoconstriction per se, as demonstrated with the application of AngII.

Furthermore, in previous studies, BK administration as well as hypoxia failed to induce pulmonary vasoconstriction in late cecal ligation and puncture sepsis, leading to the conclusion that impaired receptor-dependent and receptor-independent vasoconstriction could be interpreted as complete vasoplegia in late septic shock (10,11,18).

According to recent studies, the mechanisms by which TEA influences pulmonary function may derive from segmental sympathetic block, with redistribution of blood flow from the segments with maintained or increased sympathetic activity towards the intestinal tract. In a recently published study, TEA improved arteriolar blood flow and capillary perfusion in necrotizing pancreatitis, thus leading to reduced serum lactate levels and systemic inflammatory response, as measured by decreased levels of interleukin-6. Mortality from acute experimental pancreatitis was reduced by 66% when TEA was administered (6). In other studies, epidural blockade was shown to increase mucosal blood flow in healthy animals (4), but TEA also improved mucosal oxygenation and reduced portal endotoxin concentrations in conditions of deprived mucosal oxygenation (19).

Although the present study provides possible explanations for the observed beneficial effects on pancreatitis-induced circulatory shock and pulmonary dysfunction, such as improved receptor-dependent pulmonary vasoconstriction and HPV, improved gas exchange, and reduced lactic acidosis, we do not know the exact reasons for these TEA-related effects. In this context, systemic absorption of bupivacaine could play a role. Several investigators have described a protective role of IV administered local anesthetics in various animal models of acute respiratory distress syndrome. The underlying mechanism appears to be an antiinflammatory action. It was reported that IV administered lidocaine reduced lung injury in a rabbit model of ALI (20). In two different animal models of lung injury, continuous IV administration of lidocaine also exhibited protective effects (21,22). With respect to these findings, lidocaine improved lung function, probably as a result of inhibition of sequestration and activation of leukocytes (22). One study demonstrated dose-related beneficial effects of systemically administered bupivacaine on inflammatory response, organ function, and mortality in murine septic peritonitis (23). Seen in context with these results, the systemic absorption of epidurally administered bupivacaine could have played an important role in our study, but further studies are needed to clarify the specific effects of local anesthetics under conditions of systemic inflammation.

The use of TEA in critically ill patients remains controversial despite increasing interest in the recent years (7,24,25). This experiment was not performed to investigate the safety of TEA in critical illness, but to describe the (patho-) physiological actions of TEA on the lung. Further studies are warranted for safety assessment.

	ACKNOWLEDGMENTS

 
The authors thank Christina Großerichter, laboratory technician, for expert technical assistance.

	Footnotes

 
Accepted for publication April 17, 2007.

Supported by the Deutsche Forschungsgemeinschaft (DFG Grant Si 629-1/629-2 and Le 625/8-1 and Le 625/9-1).

Part of this work was presented at the Society of Critical Care Medicine meeting, Phoenix, AZ, USA. 2005.

Address correspondence and reprint request to Andreas Sielenkämper, MD, MSc, Department of Anesthesiology and Intensive Care Medicine, University Hospital Muenster, Albert-Schweitzer-St. 33, 48149 Muenster, Germany. Address e-mail to sieland{at}uni-muenster.de.

	REFERENCES

Top Abstract Introduction METHODS RESULTS DISCUSSION REFERENCES

 

1. Brodner G, Mertes N, Buerkle H, Marcus MA, Van Aken H. Acute pain management: analysis, implications and consequences after prospective experience with 6349 surgical patients. Eur J Anaesthesiol 2000;17:566–75[Web of Science][Medline]
2. Wu CL, Jani ND, Perkins FM, Barquist E. Thoracic epidural analgesia versus intravenous patient-controlled analgesia for the treatment of rib fracture pain after motor vehicle crash. J Trauma 1999;47:564–7[Web of Science][Medline]
3. Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S. Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ 2000;321:1493[Abstract/Free Full Text]
4. Sielenkamper AW, Eicker K, Van Aken H. Thoracic epidural anesthesia increases mucosal perfusion in ileum of rats. Anesthesiology 2000;93:844–51[Web of Science][Medline]
5. Bone HG, Sielenkamper A, Booke M. [Oxygen delivery in sepsis. After 10 years more questions than answers]. Anaesthesist 1999;48:63–79[Web of Science][Medline]
6. Freise H, Lauer S, Anthonsen S, Hlouschek V, Minin E, Fischer LG, Lerch MM, Van Aken HK, Sielenkamper AW. Thoracic epidural analgesia augments ileal mucosal capillary perfusion and improves survival in severe acute pancreatitis in rats. Anesthesiology 2006;105:354–9[Web of Science][Medline]
7. Spackman DR, McLeod AD, Prineas SN, Leach RM, Reynolds F. Effect of epidural blockade on indicators of splanchnic perfusion and gut function in critically ill patients with peritonitis: a randomised comparison of epidural bupivacaine with systemic morphine. Intensive Care Med 2000;26:1638–45[Web of Science][Medline]
8. Freise H, Anthonsen S, Fischer LG, Van Aken HK, Sielenkamper AW. Continuous thoracic epidural anesthesia induces segmental sympathetic block in the awake rat. Anesth Analg 2005;100:255–62[Abstract/Free Full Text]
9. Milani Junior R, Pereira PM, Dolhnikoff M, Saldiva PH, Martins MA. Respiratory mechanics and lung morphometry in severe pancreatitis-associated acute lung injury in rats. Crit Care Med 1995;23:1882–9[Web of Science][Medline]
10. Fischer LG, Freise H, Hilpert JH, Wendholt D, Lauer S, Van Aken H, Sielenkamper AW. Modulation of hypoxic pulmonary vasoconstriction is time and nitric oxide dependent in a peritonitis model of sepsis. Intensive Care Med 2004;30:1821–8[Web of Science][Medline]
11. Fischer LG, Hilpert JH, Freise H, Wendholt D, Van Aken H, Sielenkamper AW. Bradykinin-induced pulmonary vasoconstriction is time and inducible nitric oxide synthase dependent in a peritonitis sepsis model. Anesth Analg 2004;99:864–71[Abstract/Free Full Text]
12. Fischer LG, Horstman DJ, Hahnenkamp K, Kechner NE, Rich GF. Selective iNOS inhibition attenuates acetylcholine-and bradykinin-induced vasoconstriction in lipopolysaccharide-exposed rat lungs. Anesthesiology 1999;91:1724–32[Web of Science][Medline]
13. Singbartl K, Green SA, Ley K. Blocking P-selectin protects from ischemia/reperfusion-induced acute renal failure. FASEB J 2000;14:48–54[Abstract/Free Full Text]
14. Pastor CM, Matthay MA, Frossard JL. Pancreatitis-associated acute lung injury: new insights. Chest 2003;124:2341–51[Web of Science][Medline]
15. Ishibe Y, Shiokawa Y, Umeda T, Uno H, Nakamura M, Izumi T. The effect of thoracic epidural anesthesia on hypoxic pulmonary vasoconstriction in dogs: an analysis of the pressure-flow curve. Anesth Analg 1996;82:1049–55[Abstract]
16. Brimioulle S, Vachiery JL, Brichant JF, Delcroix M, Lejeune P, Naeije R. Sympathetic modulation of hypoxic pulmonary vasoconstriction in intact dogs. Cardiovasc Res 1997;34:384–92[Abstract/Free Full Text]
17. Fischer SR, Deyo DJ, Bone HG, McGuire R, Traber LD, Traber DL. Nitric oxide synthase inhibition restores hypoxic pulmonary vasoconstriction in sepsis. Am J Respir Crit Care Med 1997;156:833–9[Abstract/Free Full Text]
18. Li S, Fan SX, McKenna TM. Role of nitric oxide in sepsis-induced hyporeactivity in isolated rat lungs. Shock 1996;5:122–9[Web of Science][Medline]
19. Ai K, Kotake Y, Satoh T, Serita R, Takeda J, Morisaki H. Epidural anesthesia retards intestinal acidosis and reduces portal vein endotoxin concentrations during progressive hypoxia in rabbits. Anesthesiology 2001;94:263–9[Web of Science][Medline]
20. Kiyonari Y, Nishina K, Mikawa K, Maekawa N, Obara H. Lidocaine attenuates acute lung injury induced by a combination of phospholipase A2 and trypsin. Crit Care Med 2000;28:484–9[Web of Science][Medline]
21. Mikawa K, Maekawa N, Nishina K, Takao Y, Yaku H, Obara H. Effect of lidocaine pretreatment on endotoxin-induced lung injury in rabbits. Anesthesiology 1994;81:689–99[Web of Science][Medline]
22. Nishina K, Mikawa K, Takao Y, Shiga M, Maekawa N, Obara H. Intravenous lidocaine attenuates acute lung injury induced by hydrochloric acid aspiration in rabbits. Anesthesiology 1998;88:1300–9[Web of Science][Medline]
23. Gallos G, Jones DR, Nasr SH, Emala CW, Lee HT. Local anesthetics reduce mortality and protect against renal and hepatic dysfunction in murine septic peritonitis. Anesthesiology 2004;101:902–11[Web of Science][Medline]
24. Sielenkamper AW, Van Aken H. Thoracic epidural anesthesia: more than just anesthesia/analgesia. Anesthesiology 2003;99:523–5[Web of Science][Medline]
25. Low JH. Survey of epidural analgesia management in general intensive care units in England. Acta Anaesthesiol Scand 2002;46:799–805[Web of Science][Medline]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lauer, S. Articles by Sielenkämper, A. W. Search for Related Content PubMed PubMed Citation Articles by Lauer, S. Articles by Sielenkämper, A. W. Related Collections Critical Care Physiology Regional Anesthesia