[Single center analysis of the dermatosurgical patient cohort of a tumor center in Germany]. / Betrachtung des dermatochirurgischen Patientenkollektivs an einem Hauttumorzentrum in Deutschland.

BACKGROUND: The incidence of skin cancer continues to increase. However, little is known about the dermatosurgical characteristics of the patients. PATIENTS AND METHODS: In this single center, retrospective study, dermatosurgical reports of all patients treated because of basal cell carcinomas (BCC), squamous cell carcinomas (SCC), and malignant melanoma (MM) between 2004 and 2013 were analyzed. RESULTS: During the observed period, the number of operated BCC rose by a factor of 1.86 and the number of MM by a factor of 2.3. In comparison to BCC/MM, there was a disproportionately high increase of SCC by a factor of 4.02. The average age was 71.5 ± 13.4 years (minimum: 14 years; maximum: 104 years), whereupon a significant increase of male age and a significant decrease of female age occurred. Almost 70% of all tumors were located in the head and neck area. The nose was most commonly treated. CONCLUSIONS: During the last 10 years, the cohort of dermatosurgical patients changed in the tumor center. This should be verified in multicenter studies.

Prospective multicentre cohort study on 9154 surgical procedures to assess the risk of postoperative bleeding - a DESSI study.

BACKGROUND: To date, there is still a debate how to deal with patients receiving antithrombotic agents prior to surgical procedures on the skin. OBJECTIVE: To prospectively assess complications after dermatosurgical interventions, especially bleeding, depending on anticoagulation therapy. METHODS: Patients underwent surgery consecutively as scheduled, without randomization, whether or not they were currently taking anticoagulants. Nine institutions of the DESSI (DErmatoSurgical Study Initiative) working group documented patient data prospectively on a standardized study sheet prior to and after 9154 dermatosurgical interventions. RESULTS: Bleeding complications were observed in 7.14% of cases (654/9154 surgeries). A severe bleed requiring intervention by a physician occurred in 83 surgeries (0.91%). In multivariate analysis, INR, length of the defect, perioperative antibiotic treatment, current treatment with anticoagulation therapy, age and surgery on hidradenitis suppurativa/acne inversa (HS/AI) were significant parameters independently influencing the risk of bleeding. Discontinuation of phenprocoumon therapy and subsequent switching to low molecular weight heparin was associated with the highest risk of bleeding (9.26%). CONCLUSION: Bleeding complications in skin surgery are generally rare. Even if slightly increased complication rates are found in patients taking anticoagulants during skin surgery, platelet inhibitors should not be stopped prior to surgery. If a surgical procedure in patients on a combination therapy of 2 or more antiplatelet cannot be postponed, it should be conducted with the patient remaining on combination therapy. Discontinuation of DOACs is recommended 24 h prior to surgery. Bridging of phenprocoumon should be terminated. In patients with a bleeding history, the INR value should be within the therapeutic range.

A new subtype of pachydermodactyly: unilateral pachydermodactyly transgrediens.

Pachydermodactyly describes a rare condition of localized fibromatosis, usually symmetrically affecting the interphalangeal joints of both hands. We describe a case of a new subtype of pachydermodactyly in a 14-year-old boy, which we term 'unilateral pachydermodactyly transgrediens'. This atypical pattern is caused by specific localized mechanical manipulation of the hands. This condition contributes to the completely indolent spectrum of pachydermodactyly, and usually does not need therapy. Therefore it is essential not to misinterpret it as an inflammatory state such as juvenile idiopathic arthritis. The correct diagnosis of pachydermodactyly and its rare subtypes, as we describe in this case, often spares the affected patients unnecessary invasive diagnostic procedures and immunosuppressive therapy.

[Foam sclerotherapy. Uses and indications in dermatology and phlebology]. / Schaumsklerosierung. Anwendung und Indikation in der Dermatologie und Phlebologie.

Foam sclerotherapy is a minimally invasive, effective technique for the treatment of varicoses up though venous malformations. This efficient therapy can be easily integrated in daily clinical practice and shows only minor side effects. It provides an alternative to invasive therapies like vein stripping, endovenous laser therapy or endovenous radiofrequency ablation, but without the need for anesthesia. The treatment can be performed in an outpatient setting and the patient is able to return quickly to everyday life.

[Structures of lip reconstruction]. / Strukturierte Versorgung von Lippendefekten.

Although the incidence of tumors of the lips is low, they are the most common oral tumors and their therapy is often challenging for the surgeon. Depending on the extent of resected lip tissue, various surgical procedures are performed for reconstruction. They all follow the goal to combine complete tumor resection with maximal functional and aesthetic restoration. Surgical procedures are classified regarding the direction of tissue mobilization into one-, two- and three-dimensional techniques. Even though more than two hundred different techniques have been described, only a small number are used on a regular basis. To select the appropriate procedure for the individual patient the exact anatomic location and size of the defect have to be taken into consideration. Treatment algorithms may guide the surgeon to a suitable reconstructive procedure for each case. Complications may occur more often due to the size and the site of the procedure. Final functional and aesthetic results are usually satisfying.

[Asymptomatic nodule on an elderly lady's thumb tip]. / Asymptomatischer Nodus am Daumen einer älteren Frau.

A 71-year-old woman presented with an asymptomatic growing dermal tumor on her thumb. Clinical picture, ultrasound, laboratory investigations and histology were consistent with the diagnosis of gouty tophus. Pathogenesis, risk factors and therapy of tophaceous gout are discussed.

One-stage reconstruction of deep facial defects with a single layer dermal regeneration template.

BACKGROUND: The reconstruction of deep facial wounds in oncological surgery is challenging. Especially for elderly multimorbid patients, a rapid procedure with acceptable aesthetic and reliable functional outcome is required. Recently, a new single layer skin substitute was developed. Integra® dermal regeneration template single layer (IDRT-SL) allows one-stage surgery in combination with split thickness skin grafting. However, no study has yet analysed the efficiency of IDRT-SL treatment. OBJECTIVES: To evaluate applicability and efficiency of the IDRT-SL treatment in combination with split thickness skin grafting for a one-step closure of deep facial surgical wounds in elderly multimorbid patients. PATIENTS/METHODS: This prospective study analysed the functional and aesthetic outcome after reconstruction with an IDRT-SL template and an immediate split thickness skin graft in the face (80±3 years; >3 concomitant diseases). RESULTS: Nine tumours, four basal cell carcinoma, two lentigo maligna, one spinal cell carcinoma, one lentigo maligna melanoma and one Bowen carcinoma were resected. Five defects were located on the nose and four on the cheek. The mean defect size was 11±3 cm2. All but one graft were taken completely without any complication. One patient suffered from a partial graft loss (30%). All defects showed significant shrinkage of 61±4%. CONCLUSIONS: One-stage reconstruction with a combination of IDRT-SL and split thickness skin grafting is an elegant, easy and rapid method to treat deep skin defects. The take rates, functional and early cosmetic outcome are promising. This new method should be considered for selected cases of elderly multimorbid patients with deep facial wounds.

Skin substitutes in dermatosurgery.

Skin substitutes are a growing market since technical advancements have allowed a substantial progress in treating extensive defects of the skin. A variety of skin substitutes with different properties and thus resulting different indications is offered on the market. Important benefits of skin substitutes are their ready availability in almost any quantity and the predictable product properties concerning implantation, incorporation, resorption and long-term outcome. Although, most skin substitutes still need skin grafts at a later date which is disadvantageous. Nevertheless dermal substitutes have reduced the need for thick skin grafts allowing the donor site and the patient to heal faster with fewer surgeries. The use of skin substitutes in dermatologic surgery is widespread and new fields of application are emerging. The variety of artificial skin has definitely changed the reconstructive ladder helping to cover larger defects with less time and effort which is an important issue especially in elderly and multimorbid patients. In the last years a growing number of studies in the literature report the use of artificial skin substitutes to secure a rapid reconstruction with reliable cosmetic and functional results after oncological resections. Furthermore, skin substitutes are used to cover chronic wounds like diabetic foot ulcers or venous leg ulcers to promote healing. Congenital diseases like giant hairy nevi, aplasia cutis congenital or epidermolysis bullosa are conditions in children where skin substitutes play a role. But even in tissue augmentation or in cosmetic surgery skin substitutes come into vogue. The latest advance are cultured autologous or allogenic substitutes some even in combination with alloplastic material. Besides of medical questions that arise from the use of these materials in reconstructive surgery legal and economic aspects have to be taken into account. This article is giving an overview over the most common skin substitutes and their use in dermatosurgery.

Influence of high dose tumescent local anaesthesia with prilocaine on systemic interleukin (IL)-6, IL-8 and tumour necrosis factor-α.

BACKGROUND AND OBJECTIVE: Tumescent local anaesthesia (TLA) with high prilocaine doses leads to formation of methemoglobin (MHb) which is known to be a potent activator of pro-inflammatory endothelial cell response in vitro. As TLA is widely used for large dermatological resections, the aim of this study was to investigate the effects of high prilocaine doses on the systemic inflammatory response in vivo and its clinical relevance. METHODS: This prospective study examines the influence of MHb on serum interleukin (IL)-6, IL-8 and tumour necrosis tumour necrosis (TNF)-α levels up to 72 h after application of TLA with prilocaine in doses higher than 600 mg. RESULTS: A total of 30 patients received prilocaine in a median dose of 1500 mg (range: 880-4160 mg) for large resections. Peak prilocaine serum concentration was reached 4 h (0.72 ± 0.07 µg/mL), the maximum concentration of MHb (7.43 ± 0.87%) and IL-6 (28.4 ± 4.1 U/L) 12 h after TLA application. TNF-α and IL-8 release were not found significantly increased. Three patients developed MHb concentrations >15%. CONCLUSIONS: This clinical study shows for the first time that a high prilocaine serum concentration leads in vivo to elevated systemic levels of IL-6 but not of IL-8 and TNF-α because of initial high MHb levels. Because of possible and unpredictable high MHb concentrations, TLA should only be performed with prilocaine in doses of 2.5 mg/kg. In general, new solutions of TLA are necessary to achieve adequate anaesthesia for large dermatological resections to decrease the risk of methemoglobinaemia.

Long-term results after reconstruction of full thickness scalp defects with a dermal regeneration template.

OBJECTIVE: Large scalp defects in which the pericranium has to be resected can be reliably reconstructed using Integra. In the present study, we retrospectively analysed the long-term outcome of our patients. METHODS: Nineteen patients were included who had received Integra dermal regeneration template for treatment of full thickness scalp defects after resection of various malignant tumours. All patients were followed up with a mean follow-up time of 31 months (14-72). RESULTS: All transplants were on almost equal levels with the surrounding skin. Cosmetic results were acceptable and scars were stable. Nodal ultrasound status was negative in all patients. During the follow-up period of up to 72 months, no local recurrences were observed. One patient with a leiomyosarcoma received radiotherapy after transplantation. In the irradiated area, multiple small regular-shaped round ulcerations and later on partial necrosis of the transplant occurred when the patient developed renal failure 29 months after the initial operation. Five patients died of disease not related to the primary skin tumour. All other patients are alive and free of disease without any complications. CONCLUSION: After reconstruction of full thickness scalp defects with Integra, the cosmetic results are appealing and we observed no local recurrences during the follow-up period.

Expanding the horizons of histoplasmosis: disseminated histoplasmosis in a renal transplant patient after a trip to Bangladesh.

Histoplasmosis is recognized to occur in the Ohio and Mississippi River Valleys of the United States, but less widely appreciated is its worldwide distribution. We report a case of disseminated histoplasmosis with disease involving skin, lungs, and epiglottis in a renal transplant patient 6 months after a trip to Bangladesh, to highlight the potential risk of acquisition of this infection in the Indian subcontinent.

Effectiveness of highly active antiretroviral therapy using non-brand name drugs in Brazil.

In Brazil, HIV-infected individuals receive drugs (including non-brand name drugs which comprise locally produced generics and drugs that have not been tested in bioequivalence trials) free of charge from the government. The objective of the present study was to evaluate the effectiveness of highly active antiretroviral therapy (HAART) in Rio de Janeiro, Brazil, where non-brand drugs are widely used. For this purpose, we estimated the proportion of subjects with virologic failure (plasma HIV viral load greater than 400 copies/mL at 6 months after initiation of treatment). This was a retrospective cohort study of drug-naive HIV-infected subjects who initiated HAART. Subjects were included in the analysis if they were 18 years of age or older, were treatment naive, started HAART with a minimum of 3 drugs, and had available information on blood plasma HIV-1 viral load after 6 months on therapy. All subjects used antiretrovirals in dosing regimens recommended by the Brazilian National Advisory Committee for Antiretroviral Therapy. Chart reviews were conducted in three settings: at two public health outpatient units, at one clinical trial unit and at one private office. No comparisons of the effectiveness of non-brand name with the effectiveness of brand name drugs were made. We present results for 485 patients; of these, 354 (73%), 55 (11%), and 76 (16%) were seen at the public health outpatient units, private office, and clinical trial unit, respectively. Virologic failure was observed in 119 (25%) of the subjects. This study demonstrates the effectiveness of HAART in a setting where non-brand name drugs are widely used.

Effectiveness of highly active antiretroviral therapy using non-brand name drugs in Brazil

In Brazil, HIV-infected individuals receive drugs (including non-brand name drugs which comprise locally produced generics and drugs that have not been tested in bioequivalence trials) free of charge from the government. The objective of the present study was to evaluate the effectiveness of highly active antiretroviral therapy (HAART) in Rio de Janeiro, Brazil, where non-brand drugs are widely used. For this purpose, we estimated the proportion of subjects with virologic failure (plasma HIV viral load greater than 400 copies/mL at 6 months after initiation of treatment). This was a retrospective cohort study of drug-naive HIV-infected subjects who initiated HAART. Subjects were included in the analysis if they were 18 years of age or older, were treatment naive, started HAART with a minimum of 3 drugs, and had available information on blood plasma HIV-1 viral load after 6 months on therapy. All subjects used antiretrovirals in dosing regimens recommended by the Brazilian National Advisory Committee for Antiretroviral Therapy. Chart reviews were conducted in three settings: at two public health outpatient units, at one clinical trial unit and at one private office. No comparisons of the effectiveness of non-brand name with the effectiveness of brand name drugs were made. We present results for 485 patients; of these, 354 (73 percent), 55 (11 percent), and 76 (16 percent) were seen at the public health outpatient units, private office, and clinical trial unit, respectively. Virologic failure was observed in 119 (25 percent) of the subjects. This study demonstrates the effectiveness of HAART in a setting where non-brand name drugs are widely used.

RES function and liver microcirculation in the early stage of acute experimental pancreatitis.

BACKGROUND/AIMS: The reticuloendothelial system and in particular the Kupffer cells in the liver are important for eliminating antigens and toxic substances in many diseases including acute pancreatitis. Optimal Kupffer cell function is believed to depend on numerous factors including intact hepatic blood supply and microcirculation. The aim of the study was to evaluate whether hepatic microcirculation and Kupffer cell function are impaired in acute pancreatitis and whether enhancement of hepatic capillary blood flow leads to improved reticuloendothelial system function. METHODOLOGY: Acute pancreatitis was induced in rats by intraductal infusion of bile salt followed by i.v. cerulein hyperstimulation. Animals were randomized to receive either a selective endothelin-A receptor antagonist (ET-RA; LU-135252; 50 mg/kg) or saline. Sham-operated animals (intraductal and i.v. saline infusion) treated according to the same protocol served as controls. Liver phagocytic function was evaluated in 6 animals per group 6 and 24 hrs after acute pancreatitis induction and treatment using 99mTc-labeled Nanocoll and a scintillation camera technique. Another 6 animals of each group were used for intravital microscopic determination of hepatic capillary blood flow using fluorescein-labeled erythrocytes. RESULTS: Six hours after acute pancreatitis induction, hepatic capillary blood flow and nanocoll clearance were significantly decreased in saline-treated animals (compared to saline-treated healthy controls). Endothelin-A receptor antagonist significantly improved hepatic capillary blood flow and nanocoll clearance. This beneficial effect was no longer seen after 24 hrs when these parameters had spontaneously returned to values not significantly different from normal. CONCLUSIONS: Reticuloendothelial system function and hepatic capillary blood flow are impaired (only) in the early stage of this acute pancreatitis model. Endothelin-A receptor antagonist improves hepatic capillary blood flow at this stage. Enhancement of hepatic capillary blood flow is accompanied by normalization of nanocoll clearance, suggesting that hepatic microcirculation influences phagocytic Kupffer cell function early in acute pancreatitis.

Lack of neurotrophin-4 causes selective structural and chemical deficits in sympathetic ganglia and their preganglionic innervation.

Neurotrophin-4 (NT-4) is perhaps the still most enigmatic member of the neurotrophin family. We show here that NT-4 is expressed in neurons of paravertebral and prevertebral sympathetic ganglia, i.e., the superior cervical (SCG), stellate (SG), and celiac (CG) ganglion. Mice deficient for NT-4 showed a significant reduction (20-30%) of preganglionic sympathetic neurons in the intermediolateral column (IML) of the thoracic spinal cord. In contrast, neuron numbers in the SCG, SG, and CG were unchanged. Numbers of axons in the thoracic sympathetic trunk (TST) connecting the SG with lower paravertebral ganglia were also reduced, whereas axon numbers in the cervical sympathetic trunk (CST) were unaltered. Axon losses in the TST were paralleled by losses of synaptic terminals on SG neurons visualized by electron microscopy. Furthermore, immunoreactivity for the synaptic vesicle antigen SV2 was clearly reduced in the SG and CG. Levels of catecholamines and tyrosine hydroxylase immunoreactivity were dramatically reduced in the SG and the CG but not in the SCG. Despite this severe phenotype in the sympathetic system, blood pressure levels were not reduced and displayed a pattern more typical of deficits in baroreceptor afferents. Numbers of IML neurons were unaltered at postnatal day 4, suggesting a postnatal requirement for their maintenance. In light of these and previous data, we hypothesize that NT-4 provided by postganglionic sympathetic neurons is required for establishing and/or maintaining synapses of IML neurons on postganglionic cells. Impairment of synaptic connectivity may consequently reduce impulse flow, causing a reduction in transmitter synthesis in postganglionic neurons.

Endothelin mediates local and systemic disease sequelae in severe experimental pancreatitis.

Endothelin-1 has been shown to reduce pancreatic blood flow and cause focal acinar cell necrosis similar to those seen in acute pancreatitis (AP), whereas therapy with endothelin receptor antagonists enhanced pancreatic capillary blood flow (PCBF) and decreased mortality rates. The current study evaluated the role of endothelin in the development of severe AP. Trypsinogen activation peptides, acinar cell necrosis, and PCBF were used as local indicators of disease severity, fluid sequestration, cardiorespiratory and renal parameters, and colonic capillary blood flow as systemic disease indicators. The following groups of animals were examined: 1) rats with mild edematous AP and 2) severe necrotizing AP treated with and without endothelin, 3) transgenic rats overexpressing endothelin with severe AP, and 4) rats with severe AP prophylactically treated with endothelin receptor antagonists. The following observations were made: endothelin superimposed on mild AP caused hemoconcentration, a decrease in PCBF, and necrosis and ascites not seen in this model without endothelin exposure. Endothelin superimposed on severe AP had no significant effects. After induction of severe AP, less PCBF and more acinar cell necrosis were observed in transgenic rats than in their normal littermates. Prophylactic endothelin receptor antagonists improved local (acinar necrosis, PCBF) and systemic parameters (ascites, urine production, colonic capillary blood flow) of disease severity in animals with severe AP. These observations underscore the role of endothelin as a mediator of disease severity in AP and suggest that endothelin receptor blockade may become a promising therapeutic tool in this disease.

Regional alterations of repolarizing K+ currents among the left ventricular free wall of rats with ascending aortic stenosis.

The effect of cardiac hypertrophy on electrocardiogram (ECG), action potential duration (APD) and repolarizing K+ currents was investigated in epicardial, midmyocardial and endocardial myocytes isolated from the rat left ventricular free wall. Cardiac hypertrophy was induced by stenosis of the ascending aorta (AS), which led to an increased pressure load (+85 +/- 10 u1v1vZ mm11Z Hg) of the left ventricle; sham-operated animals served as controls. In ECG recordings from AS rats, the QTc interval was prolonged and the main vectors of the QRS complex and the T-wave pointed in opposite directions, indicating an abnormal sequence of repolarization. APD and K+ currents were recorded using the whole-cell patch-clamp technique. In the AS group, APD90 (90 % repolarization) was significantly prolonged in epicardial and midmyocardial, but not endocardial myocytes. Corresponding to the increase in APD, the magnitude of the transient outward K+ current (Ito1) was significantly smaller (-30 %) in epicardial and midmyocardial, but not endocardial myocytes. Inactivation and steady-state inactivation of Ito1 were not affected by hypertrophy. Recovery from inactivation was slightly prolonged in endocardial myocytes from AS rats. No differences in delayed rectifier currents (IK) or inwardly rectifying K+ currents (IK1) were detected between myocytes of the three regions of sham-operated or AS animals. However, both currents were reduced by AS. The present data show that cardiac hypertrophy caused by pressure overload leads to an increase in APD and a decrease in Ito1 primarily in epicardial and midmyocardial myocytes, which implies a major role of alterations in Ito1 for the reduced gradient in APD. The effects of AS on IK1 and IK may slightly counteract the decrease in APD gradient. The observed changes in APD and underlying ionic currents could well explain the alterations in repolarization observed in the ECG induced by cardiac hypertrophy.

Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure.

Large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) sense both changes in membrane potential and in intracellular Ca(2+) concentration. BK channels may serve as negative feedback regulators of vascular tone by linking membrane depolarization and local increases in intracellular Ca(2+) concentration (Ca(2+) sparks) to repolarizing spontaneous transient outward K(+) currents (STOCs). BK channels are composed of channel-forming BKalpha and auxiliary BKbeta1 subunits, which confer to BK channels an increased sensitivity for changes in membrane potential and Ca(2+). To assess the in vivo functions of this ss subunit, mice with a disrupted BKbeta1 gene were generated. Cerebral artery VSMCs from BKbeta1 -/- mice generated Ca(2+) sparks of normal amplitude and frequency, but STOC frequencies were largely reduced at physiological membrane potentials. Our results indicate that BKbeta1 -/- mice have an abnormal Ca(2+) spark/STOC coupling that is shifted to more depolarized potentials. Thoracic aortic rings from BKbeta1 -/- mice responded to agonist and elevated KCl with a increased contractility. BKbeta1 -/- mice had higher systemic blood pressure than BKbeta1 +/+ mice but responded normally to alpha(1)-adrenergic vasoconstriction and nitric oxide-mediated vasodilation. We propose that the elevated blood pressure in BKbeta1 -/- mice serves to normalize Ca(2+) spark/STOC coupling for regulating myogenic tone. The full text of this article is available at http://www.circresaha.org.

Autonomic cardiovascular control in conscious mice.

Autonomic cardiovascular control was characterized in conscious, chronically catheterized mice by spectral analysis of arterial pressure (AP) and heart rate (HR) during autonomic blockade or baroreflex modulation of autonomic tone. Both spectra were similar to those obtained in humans, but at approximately 10x higher frequencies. The 1/f relation of the AP spectrum changed to a more shallow slope below 0.1-0.2 Hz. Coherence between AP and HR reached 0.5 or higher below 0.3-0.4 Hz and also above 2.5 Hz. Muscarinic blockade (atropine) or beta-adrenergic blockade (atenolol) did not significantly affect the AP spectrum. Atropine reduced HR variability at all frequencies, but this effect waned above 1 Hz. beta-Adrenergic blockade (atenolol) slightly enhanced the HR variability only above 1 Hz. alpha-Adrenergic blockade (prazosin) reduced AP variability between 0.05 and 3 Hz, most prominently at 0. 15-0.7 Hz. A shift of the autonomic nervous tone by a hypertensive stimulus (phenylephrine) enhanced, whereas a hypotensive stimulus (nitroprusside) depressed AP variability at 1-3 Hz; other frequency ranges of the AP spectrum were not affected except for a reduction below 0.4 Hz after nitroprusside. Variability of HR was enhanced after phenylephrine at all frequencies and reduced after nitroprusside. As with atropine, the reduction with nitroprusside waned above 1 Hz. In conclusion, in mice HR variability is dominated by parasympathetic tone at all frequencies, during both blockade and physiological modulation of autonomic tone. There is a limitation for further reduction but not for augmentation of HR variability from the resting state above 1 Hz. The impact of HR on AP variability in mice is confined to frequencies higher than 1 Hz. Limits between frequency ranges are proposed as 0.15 Hz between VLF (very low frequency range) and LF (low frequency range) and 1.5 Hz between LF and HF (high frequency range).

Endothelin receptor blockade in severe acute pancreatitis leads to systemic enhancement of microcirculation, stabilization of capillary permeability, and improved survival rates.

BACKGROUND: We previously demonstrated that therapy with a new endothelin A receptor antagonist (ET-RA) significantly reduced mortality rates in severe acute pancreatitis (AP) in the rat without attenuating local signs of disease severity (intrapancreatic protease activation, acinar cell necrosis). This raised the question as to why ET-RA was so effective. The purpose of this study was to assess the effect of ET-RA on microcirculation (particularly capillary permeability) within and outside of the pancreas on intravascular fluid loss and extravascular fluid sequestration and on distant organ function. METHODS: Severe AP was induced in rats by standardized intraductal bile acid infusion and cerulein hyper-stimulation. Starting 6 hours (n = 24 rats) and 12 hours (n = 30 rats) after the onset of AP, animals randomly received either the ET-RA (LU-135252) or saline solution with fluid resuscitation (6 mL/kg/h Ringer's lactate). At 24 hours, animals were relaparotomized for intravital microscopic determination of capillary blood flow, leukocyte rolling, and capillary permeability in the pancreas and colon. Further monitoring included cardiorespiratory and renal parameters, hematocrit levels and quantification of ascites and pleural effusions, and acinar cell necrosis at autopsy. Groups of sham-operated healthy animals (n = 6 animals each) that had been treated according to the same protocol served as control animals. RESULTS: ET-RA treatment that was started 6 hours after AP-induction significantly decreased hematocrit levels (38% +/- 1% vs 45% +/- 2% with saline solution treatment), reduced ascites and pleural effusions (6.7 +/- 1.3 mL vs 11.9 +/- 1.3 mL), and improved urine production (4.8 +/- 0.5 mL vs 2.9 +/- 0.6 mL) and respiratory parameters. Moreover, all microcirculatory parameters were improved; in particular, capillary permeability was stabilized (158% +/- 9% vs 248% +/- 8% in the colon). These beneficial effects were also seen when therapy was delayed until 12 hours after AP induction. Pancreatic necrosis was not significantly reduced. The overall mortality rate was 12% in ET-RA-treated animals and 42% in saline solution-treated control animals (P <.05). In healthy animals ET-RA did not significantly alter the target parameters, except for a reduction of capillary permeability in the pancreas. CONCLUSIONS: Improved microcirculation and stabilized capillary permeability in ET-RA-treated animals together with reduced intravascular fluid loss and extravascular fluid sequestration and improved renal and pulmonary function (1) may explain improved survival in this model, (2) support the hypothesis that systemic disease sequelae significantly contribute to outcome in AP, and (3) suggest that ET-RA may be a promising therapeutic tool in AP because it counteracts microcirculatory disorders that contribute to pancreatitis-associated organ dysfunction even when therapy is delayed to a point at which pancreatic injury may no longer be influenced.