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Adherence to low tidal volume (V T ) ventilation and selected positive end-expiratory pressures are low during mechanical ventilation for treatment of the acute respiratory distress syndrome. Using a pig model of severe lung injury, we tested the feasibility and physiological responses to a novel fully closed-loop mechanical ventilation algorithm based on the "open lung" concept. Lung injury was induced by surfactant washout in pigs (n = 8). Animals were ventilated following the principles of the "open lung approach" (OLA) using a fully closed-loop physiological feedback algorithm for mechanical ventilation. Standard gas exchange, respiratory- and hemodynamic parameters were measured. Electrical impedance tomography was used to quantify regional ventilation distribution during mechanical ventilation. Automatized mechanical ventilation provided strict adherence to low V T -ventilation for 6 h in severely lung injured pigs. Using the "open lung" approach, tidal volume delivery required low lung distending pressures, increased recruitment and ventilation of dorsal lung regions and improved arterial blood oxygenation. Physiological feedback closed-loop mechanical ventilation according to the principles of the open lung concept is feasible and provides low tidal volume ventilation without human intervention. Of importance, the "open lung approach"-ventilation improved gas exchange and reduced lung driving pressures by opening atelectasis and shifting of ventilation to dorsal lung regions.

Various animal models of lung injury exist to study the complex pathomechanisms of human acute respiratory distress syndrome (ARDS) and evaluate future therapies. Severe lung injury with a reproducible deterioration of pulmonary gas exchange and hemodynamics can be induced in anesthetized pigs using repeated lung lavages with warmed 0.9% saline (50 ml/kg body weight). Including standard respiratory and hemodynamic monitoring with clinically applied devices in this model allows the evaluation of novel therapeutic strategies (drugs, modern ventilators, extracorporeal membrane oxygenators, ECMO), and bridges the gap between bench and bedside. Furthermore, induction of lung injury with lung lavages does not require the injection of pathogens/endotoxins that impact on measurements of pro- and anti-inflammatory cytokines. A disadvantage of the model is the high recruitability of atelectatic lung tissue. Standardization of the model helps to avoid pitfalls, to ensure comparability between experiments, and to reduce the number of animals needed.

Acetazolamide (ACZ) prevents hypoxic pulmonary vasoconstriction (HPV) in isolated lungs, animals, and humans, but not by carbonic anhydrase (CA) inhibition. We studied administration routes in, and certain structural aspects of, ACZ critical to HPV inhibition. Analogs of ACZ during acute hypoxia were tested in unanesthetized dogs. Dogs breathed normoxic gas for 1 h (inspired O2 fraction = 0.21), followed by 10% O2 for 2 h (hypoxia) in these protocols: 1) controls; 2) ACZ intravenously (2 mg · kg(-1) · h(-1)); 3) ACZ orally (5 mg/kg, 12 and 1 h before the experiment); 4) inhaled ACZ (750 mg); 5) methazolamide (MTZ) intravenously (3 mg · kg(-1) · h(-1)); and 6) N-methyl-acetazolamide (NMA) intravenously (10 mg · kg(-1) · h(-1)). In controls, mean pulmonary arterial pressure (MPAP) increased 7 mmHg, and pulmonary vascular resistance (PVR) 224 dyn · s · cm(-5) with hypoxia (P < 0.05). With intravenous and inhaled ACZ, MPAP and PVR did not change during hypoxia. With oral ACZ, HPV was only slightly suppressed; MPAP increased 5 mmHg and PVR by 178 dyn · s · cm(-5) during hypoxia. With MTZ and NMA, the MPAP rise (4 ± 2 mmHg) was reduced, and PVR did not increase during hypoxia compared with normoxia (MTZ intravenous: 81 ± 77 and 68 ± 82 dyn · s · cm(-5) with NMA intravenous). Inhaled ACZ prevents HPV, but not without causing systemic CA inhibition. NMA, a compound lacking CA inhibiting effects by methylation at the sulfonamide moiety, and MTZ, a CA-inhibiting analog methylated at the thiadiazole ring, are only slightly less effective than ACZ in reducing HPV.

Objective: To investigate changes in standard base excess (SBE) when administering two different infusion regimens for elective hip replacement within a goal-directed haemodynamic algorithm., Methods: This prospective, double-blind, randomized, controlled study enrolled patients scheduled for primary hip replacement surgery, who were randomized to receive either an unbalanced crystalloid (chloride: 155.5 mmol/l) or a 1 : 1 mixture of a balanced crystalloid and a balanced colloid (6% w/v hydroxyethyl starch 130/0.42; chloride: 98 and 112 mmol/l, respectively). Fluid management was goal-directed to optimize stroke volume using oesophageal Doppler., Results: A total of 40 patients (19 female/21 male) participated in the study. After surgery, median (25-75% percentiles) SBE was significantly lower in the unbalanced group compared with the balanced group: -2.0 mmol/l (-3.1 to -1.1) versus -0.4 mmol/l (-1.2 to 0.7), respectively. This difference was mainly due to greater plasma chloride concentrations in the unbalanced group. The amount of study medication required to reach haemodynamic stability (median 1200 ml) did not differ between the two groups., Conclusion: SBE decreased in the unbalanced group without influence on fluid requirements and haemodynamic stability.

Purpose: Combination of prone positioning (PrP) and extracorporeal membrane oxygenation (ECMO) might be beneficial in severe acute respiratory distress syndrome (ARDS), because both approaches are recommended. However, PrP during ECMO might be associated with complications such as dislocation of ECMO cannulae. We investigated complications and change of oxygenation effects of PrP during ECMO to identify "responders" and discuss our results considering different definitions of response in the literature.
, Methods: Retrospective analysis of complications, gas exchange, and invasiveness of mechanical ventilation during first and second PrP on ECMO at specified time points (before, during, and after PrP). We used multivariate nonparametric analysis of longitudinal data (MANOVA) to compare changes of mechanical ventilation and hemodynamics associated with the first and second procedures.
, Results: In 12 ECMO patients, 74 PrPs were performed (median ECMO duration: 10 days (IQR: 6.3-
15.5 days)). No dislocations of intravascular catheters/cannulae, endotracheal tubes or chest tubes were observed. Two PrPs had to be interrupted (endotracheal tube obstruction, acute pulmonary embolism). PaO2/FiO2-ratio increased associated with the first and second PrP (p = 0.002) and lasted after PrP in 58% of these turning procedures ("responders") without changes in ECMO blood flow, respiratory pressures, minute ventilation, portion of spontaneously triggered breathing, and compliance. Hemodynamics did not change with exception of increased mean pulmonary arterial pressure during PrP and decrease after PrP (p<0.001), while norepinephrine dosage decreased (p = 0.03) (MANOVA).
, Conclusions: Prone position during ECMO is safe and improves oxygenation even after repositioning. This might ameliorate hypoxemia and reduce the harm from mechanical ventilation.

Objective: This institutional anaesthetic practice evaluation compared patient safety with respect to residual neuromuscular blockade (NMB) at the time of tracheal extubation in patients undergoing high-risk eye surgery., Methods: Two muscle relaxation regimens were compared: rocuronium administered via intravenous (i.v.) bolus dosing combined with reversal through sugammadex at end of surgery (group R/S; 17 patients); mivacurium administered via continuous i.v. infusion without antagonization (group M; 22 patients). Train-of-four (TOF) monitoring determined the depth of NMB., Results: The TOF ratio at the time of tracheal extubation was greater in group R/S (median 1.03) than in group M (median 0.62). Time from end of surgery to tracheal extubation was not significantly different. The surgeons were 100% satisfied with the working conditions provided under both relaxation regimens., Conclusions: Residual postoperative curarization at the time of extubation was frequently observed in group M, whereas there was complete recovery in group R/S. Reversal of NMB by sugammadex provides an additional safety dimension to patient care and should thus be considered especially for those at risk of airway complications or aspiration, in addition to frail patients.

Context: Standardised drug syringe labelling may reduce drug errors, but data on drug syringe labelling use in European anaesthesiology departments are lacking., Objectives: Survey investigating if standardised drug syringe labelling is used, and if there are geographical, demographic and professional differences in hospitals with and without use of drug syringe labelling., Design: Structured, web-based anonymised questionnaire., Setting: European anaesthesia departments., Participants: Members of the European Society of Anaesthesiology., Intervention: Online survey from 2 February to 12 April 2011., Main Outcome Measure: Standardised drug syringe labelling use and, if yes, drug syringe labelling for insulin and norepinephrine., Methods: Descriptive and comparative analyses of users and nonusers of standardised drug syringe labelling., Results: One thousand and sixty-four of 4163 members (25.6%) from 72 countries participated, among whom 660 (62.0%) used standardised drug syringe labelling; in Northern and Western Europe, there were 428 users of drug syringe labelling and 112 nonusers, and in Southern and Eastern Europe, there were 184 users and 255 nonusers (P < 0.001). Three hundred and ninety-four (37%) respondents used standardised drug syringe labelling hospital-wide; 202 (30.1%) used International Organisation of Standardisation-based standardised drug syringe labelling, 101 (15.1%) used similar systems, 278 (41.5%) used other systems and 89 (13.3%) used labels supplied by drug manufacturers. The label colour for insulin was reported as white or 'none' in 519 (76.7%) answers and another colour in 158 (23.3%). The label colour for norepinephrine was reported as violet in 206 (30.4%) answers, white or 'none' in 226 (33.3%), red in 114 (16.8%) and another colour in 132 (19.5%). A standardised drug syringe labelling system supplied by the pharmaceutical industry was supported by 819 (76.9%) respondents, and not supported by 227 (21.3%)., Conclusion: A majority of European anaesthesiology departments used standardised drug syringe labelling, with regional differences and mostly without following an international standard. Thus, there are options for quality improvement in drug syringe labelling.

Purpose: Standardised coloured drug labels may increase patient safety in the intensive care unit (ICU). The rates of adherence to standardised drug syringe labelling (DSL) in European and non-European ICUs, and the standards applied are not known. The aim of this survey among ESICM members was to assess if and what standardised drug syringe labelling is used, if the standards for drug syringe labelling are similar internationally and if intensivists expect that standardised DSL should be delivered by the pharmaceutical industry., Methods: A structured, web-based, anonymised survey on standardised DSL, performed among ESICM members (March-May 2011; Clinicaltrials.gov NCT01232088). Descriptive data analysis was performed and Fisher's exact test was applied where applicable., Results: Four hundred eighty-two submissions were analysed (20 % non-European). Thirty-five percent of the respondents reported that standardised drug labelling was used hospital-wide, and 39 % reported that standardised DSL was used in their ICU (Europe: Northern 53 %, Western 52 %, Eastern 17 %, Southern 22 %). The International Organization of Standardization (ISO) 26825 norm in its original form was used by 30 %, an adapted version by 19 % and local versions by 45 %; 6 % used labels that were included in the drug's packaging. Eighty percent wished that the pharmaceutical industry supplied ISO 26825 norm labelling together with the drugs., Conclusions: Standardised DSL is not widely applied in European and non-European ICUs and mostly does not adhere strictly to the ISO norm. The frequency and quality of DSL differs to a great extent among European regions. This leaves much room for improvement.

The authors aimed to test the hypothesis that xenon anesthesia limits adverse hypotensive effects of losartan during acute hemorrhage. In six conscious unsedated Beagle dogs, the systemic and pulmonary circulation were monitored invasively, and two subsequent 60-min hypotensive challenges were performed by (a) induction (propofol) and maintenance of anesthesia with isoflurane/remifentanil or xenon/remifentanil and by (b) subsequent hemorrhage (20 mL kg⁻¹ within 5 min) from a central vein. The same amount of blood was retransfused 1 h after hemorrhage. Experiments were performed with or without acute angiotensin II receptor subtype 1 blockade by i.v. losartan (100 μg·kg⁻¹·min⁻¹) starting 45 min before induction of anesthesia. Four experiments were performed in each individual dog. Xenon/remifentanil anesthesia provided higher baseline mean arterial blood pressure (85 ± 6 mmHg) than isoflurane/remifentanil anesthesia (67 ± 3 mmHg). In losartan-treated animals, isoflurane/remifentanil caused significant hypotension (42 ± 4 mmHg for isoflurane/remifentanil vs. 71 ± 6 mmHg for xenon/remifentanil). Independent of losartan, hemorrhage did not induce any further reduction of mean arterial blood pressure or cardiac output in either group. Spontaneous hemodynamic recovery was observed in all groups before retransfusion was started. Losartan did not alter the adrenaline, noradrenaline, and vasopressin response to acute hemorrhage. Losartan potentiates hypotension induced by isoflurane/remifentanil anesthesia but does not affect the hemodynamic stability during xenon/remifentanil anesthesia. Losartan does not deteriorate the hemodynamic adaptation to hemorrhage of 20 mL kg⁻¹ during xenon/remifentanil and isoflurane/remifentanil anesthesia. Therefore, xenon/remifentanil anesthesia protects against circulatory side effects of losartan pretreatment and thus may afford safer therapeutic use of losartan during acute hemorrhage.

Objective: To test the compensatory role of endothelin-1 when acute blood loss is superimposed on anaesthesia, by characterizing the effect of systemic endothelin receptor subtype A (ET(A)) blockade on the haemodynamic and hormonal responses to haemorrhage in dogs anaesthetized with xenon/remifentanil (X/R) or isoflurane/remifentanil (I/R)., Study Design: Prospective experimental randomized controlled study., Animals: Six female Beagle dogs, 13.4 +/- 1.3 kg., Methods: Animals were anaesthetized with remifentanil 0.5 microg kg(-1) minute(-1) plus either 0.8% isoflurane (I/R) or 63% xenon (X/R), with and without (Control) the systemic intravenous endothelin receptor subtype A antagonist atrasentan (four groups, n = 6 each). After 60 minutes of baseline anaesthesia, the dogs were bled (20 mL kg(-1)) over 5 minutes and hypovolemia was maintained for 1 hour. Continuous haemodynamic monitoring was performed via femoral and pulmonary artery catheters; vasoactive hormones were measured before and after haemorrhage., Results: In Controls, systemic vascular resistance (SVR), vasopressin and catecholamine plasma concentrations were higher with X/R than with I/R anaesthesia at pre-haemorrhage baseline. The peak increase after haemorrhage was higher during X/R than during I/R anaesthesia (SVR 7420 +/- 867 versus 5423 +/- 547 dyne seconds cm(-5); vasopressin 104 +/- 23 versus 44 +/- 6 pg mL(-1); epinephrine 2956 +/- 310 versus 177 +/- 99 pg mL(-1); norepinephrine 862 +/- 117 versus 195 +/- 33 pg mL(-1), p < 0.05). Haemorrhage reduced central venous pressure from 3 +/- 1 to 1 +/- 1 cm H(2)O (I/R, ns) and from 8 +/- 1 to 5 +/- 1 cm H(2)O (X/R, p < 0.05), but did not reduce mean arterial pressure, nor cardiac output. Atrasentan did not alter the haemodynamic and hormonal response to haemorrhage during either anaesthetic protocol., Conclusions and Clinical Relevance: Selective ET(A) receptor blockade with atrasentan did not impair the haemodynamic and hormonal compensation of acute haemorrhage during X/R or I/R anaesthesia in dogs.

This paper presents the results of a prospective observational cohort study investigating referral practices to six specialized pain centres (SPCs) in 303 patients with headache (HD), low back pain (LBP), and neuropathic pain (NP). The study was divided into three parts. Part 1: The pain health care history (contacts with general practitioners and specialists, further referrals, time spans, therapies) before first contact with the SPC. Part 2: Reality of pain therapy and management in the SPC (patients' attrition, interdisciplinarity of therapy and novel therapeutic strategies instigated). Part 3: Follow-up and assessment of pain levels (NRS, SES), disability scores (PDI), QoL scores (SF 12), and anxiety and depression scores (HADS) at 0, 6 and 12 months. Using an ordinal linear regression model, factors predicting a good treatment outcome were identified. On average it took 3 years of pain symptoms before first consultation with GP. The median time period from the first pain sensations until the appointment in the SPC was 12 years. Nearly half of the referrals to specialists or SPCs were initiated by a non-professional. In the SPC the medication was changed in 71% of cases. Care was interdisciplinary in only 32%. At 6 and 12 months after the first contact with the SPC, only 20% of the patients had improved with respect to levels of pain and psychometric data. A high degree of chronicity, a history of pain-associated surgeries and low social support were negative predictors for treatment outcome., (Copyright 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

This study investigated the applicability of two human radio-immunoassays (RIA) to detect epinephrine (EPI), norepinephrine (NE), and their O-methylated metabolites metanephrine (MN) and normetanephrine (NMN) in canine plasma. The analysis yielded a positive correlation between metabolites and their respective parent compounds: EPI and MN (r=0.63), NE and NMN (r=0.47), as well as between parent compounds, EPI and NE (r=0.48), and between metabolites MN and NMN (r=0.71). Moreover, EPI (r=0.99) and NE (r=0.77) concentrations determined by RIA did correlate positively with high pressure liquid chromatography (HPLC). However, there was limited agreement between both methods. It was concluded that complete validation tests for accuracy, precision and agreement are needed before this RIA can be applied to quantify catecholamines, metanephrine, and normetanephrine in canine plasma. The assay may prove to be a potential alternative to HPLC or tandem mass spectrometry in the work-up of pheochromocytoma and the detection of overall sympathetic activity in dogs., (Copyright (c) 2008 Elsevier Ltd. All rights reserved.)

Background: Combination of epidural and general anesthesia (combined anesthesia) avoids the intraoperative use of intravenous analgesics and may reduce the surgical stress response during major abdominal surgery. This study examines the differences in intraoperative hemodynamic stability, cortisol levels and activity of cardiovascular hormones between combined anesthesia and isoflurane/fentanyl anesthesia., Material/methods: Sixty ASA I-II patients were prospectively randomized to receive either combined anesthesia, i.e, isoflurane anesthesia combined with thoracic epidural analgesia (bolus of 12 ml 0.2% ropivacaine containing 1 microg/ml sufentanil 30 min before incision, followed by continuous infusion at 6 ml/h) or isoflurane/fentanyl anesthesia (IV fentanyl as required) for major abdominal surgery. Depth of anesthesia was monitored using Bispectral Index. Administration of fluids and of vasopressors was directed by a standardized protocol. Blood samples for angiotensin II, vasopressin, catecholamines, and cortisol were drawn before anesthesia, after induction (but before using the epidural catheter), and 40 min after skin incision., Results: After induction of anesthesia, mean arterial pressure decreased by 12-20 mmHg in both groups and angiotensin-II concentrations increased. Vasopressin increased predominantly after opening the abdomen in both groups. Under combined anesthesia, intraoperative epinephrine and cortisol concentrations were considerably lower. Intraoperative crystalloid fluid substitution, blood loss and urine output did not differ between groups. There were more hypotensive periods and the demand for colloids and low-dose continuous norepinephrine was greater under combined anesthesia., Conclusions: Combined anesthesia reduces the intraoperative stress response, but moderate hemodynamic instability is relatively common and has to be compensated for by adequate volume replacement and vasopressor support.

We recently demonstrated that inhalation of the endothelin receptor A (ETA) antagonist LU 135252 improved arterial oxygenation and reduced pulmonary artery pressure in experimental acute lung injury (ALI). In this study we analyzed potential immune modulatory effects of inhaled LU 135252 in experimental ALI. ALI was induced by repeated lung lavage in intubated (100% O2) and anesthetized piglets. Animals were randomly assigned to inhale either nebulized LU 135252 (0.3 mg.kg(-1), ALI + LU group, n = 8) or saline buffer (ALI control group, n = 16), both for 30 min. Surviving animals were sacrificed 6 h after induction of ALI, and lung tissue specimens were obtained from all animals for histology and immunhistochemistry. Induction of ALI significantly decreased arterial oxygenation in all animals. Inhalation of LU 135252 significantly reduced mortality and induced significant and sustained increase in PaO2 (316 +/- 47 mm Hg vs. control 53 +/- 3 mm Hg, p < 0.001). We measured a significant reduction in the number of pulmonary leukocyte L1 antigen-positive cells in ALI + LU animals (8% +/- 1% positive cells vs. control 12% +/- 2% positive cells, p < 0.05). The number of CD3-positive cells was not altered by treatment with LU 135252. Pulmonary tissue concentration of IL-6 was significantly suppressed by LU 135252 inhalation (4 +/- 1 pg.100 mg-1 wet weight vs. control 7 +/- 1 pg.100 mg(-1) wet weight, p < 0.05). Concentrations of TNF-alpha, IL-1beta, and ET-1 in pulmonary tissue were not influenced by inhalation of LU 135252. In conclusion, we demonstrated that inhalation of LU 135252 not only improves mortality and gas exchange, but also blunts the local immune response in experimental ALI.

The noble gas xenon seems to have minimal cardiovascular side-effects and so may be an ideal anaesthetic agent when investigating cardiovascular physiology. In comparison with standard modern anaesthetics, we investigated the haemodynamic and hormonal effects of xenon in Beagle dogs. After a 30 min baseline period, anaesthesia was induced with propofol and maintained with either (1) 1.2% isoflurane/70% nitrous oxide (N(2)O), (2) 0.8% isoflurane/0.5 microg/kg/min remifentanil or (3) 63% xenon/0.5 microg/kg/min remifentanil (n = 6 per group). Haemodynamics were recorded and blood samples taken before and 60 min after induction. Mean arterial blood pressure (MAP) was higher in conscious dogs than during isoflurane/N(2)O (86 +/- 2 vs. 65 +/- 2 mmHg, mean +/- SEM) and isoflurane/remifentanil anaesthesia (95 +/- 2 vs. 67 +/- 3 mmHg), whereas MAP did not decrease significantly in response to xenon/remifentanil anaesthesia (96 +/- 4 vs. 85 +/- 6 mmHg). Bradycardia was present during isoflurane/remifentanil (54 +/- 2/min) and xenon/remifentanil (40 +/- 3/min), but not during isoflurane/N(2)O anaesthesia (98 +/- 3/min, P < 0.05). Xenon/remifentanil anaesthesia induced the highest reduction in cardiac output (CO) (-61%), and the highest increase in systemic vascular resistance (+120%) among all treatment groups (P < 0.05). A simultaneous increase in endogenous adrenaline and noradrenaline concentrations could only be observed in the xenon/remifentanil group, whereas angiotensin II and vasopressin concentrations increased in all groups. In conclusion, xenon/remifentanil anaesthesia maintains MAP but reduces heart rate and CO and is associated with a considerable stimulation of vasopressor hormones in Beagle dogs. Therefore, xenon/remifentanil exerts a new quality of adverse haemodynamic effects different from volatile anaesthetics and may not perform better during studies of cardiovascular physiology.

Unlabelled: The effects of endothelin receptor subtype A (ETA) blockade on hemodynamics and hormonal adaptation during hemorrhage were studied in xenon/remifentanil-anesthetized dogs (n=6) pretreated with an angiotensin II type 1 (AT1)-receptor blocker., Controls: after a baseline awake period, anesthesia was induced in the dogs with propofol and maintained with xenon/remifentanil (baseline anesthesia). Sixty minutes later, 20 mL x kg(-1) of blood was withdrawn within 5 min and the dogs observed for another hour (hemorrhage). AT1 group followed the same protocol as controls except the AT1-receptor blocker losartan (i.v. 100 microg x kg(-1) x min(-1)) was started at the beginning of the experiment. AT1+ETA group was the same as AT1 group but with the addition of the ETA-receptor blocker atrasentan (i.v. 1 mg x kg(-1), then 0.01 mg x kg(-1) x min(-1)). In controls, mean arterial pressure (MAP) remained unchanged during baseline anesthesia, whereas systemic vascular resistance (SVR) increased from 3282+/-281 to 7321+/-803 dyn.s.cm-5, heart rate (HR) decreased from 86+/-4 to 40+/-3 beats x min(-1), and cardiac output (CO) decreased from 2.3+/-0.2 to 0.9+/-0.1 L x min(-1) (p<0.05), with no further changes after hemorrhage. In AT1-inhibited dogs, MAP (71+/-6 mm Hg) and SVR (5939+/-611 dyn x s x cm(-5)) were lower during baseline anesthesia and after hemorrhage, but greater than those in AT1+ETA (66+/-7 mm Hg, 5034+/-658 dyn x s x cm(-5)) (p<0.05). HR and CO were not different between groups. Plasma concentration of vasopressin was highest with AT1+ETA inhibition after hemorrhage. Combined AT1+ETA-receptor blockade impaired vasoconstriction more than did AT1-receptor blockade alone, both during baseline xenon anesthesia and after hemorrhage. Even a large increase in vasoconstrictor hormones could not prevent the decrease in blood pressure and the smaller increase in SVR. Thus, endothelin is an important vasoconstrictor during hemorrhage, and both endothelin and angiotensin II are essential hormones for cardiovascular stabilization after hemorrhage.

Endogenous endothelin (ET)-1 modulates hypoxic pulmonary vasoconstriction (HPV). Accordingly, intravenously applied ET(A) receptor antagonists reduce HPV, but this is accompanied by systemic vasodilation. We hypothesized that inhalation of an ET(A) receptor antagonist might act selectively on the pulmonary vasculature and investigated the effects of aerosolized LU-135252 in an experimental model of HPV. Sixteen piglets (weight: 25 +/- 1 kg) were anesthetized and mechanically ventilated at an inspiratory oxygen fraction (Fi(O(2))) of 0.3. After 1 h of hypoxia at Fi(O(2)) 0.15, animals were randomly assigned either to receive aerosolized LU-135252 as bolus (0.3 mg/kg for 20 min; n = 8, LU group), or to receive aerosolized saline (n = 8, controls). In all animals, hypoxia significantly increased mean pulmonary arterial pressure (32 +/- 1 vs. 23 +/- 1 mmHg; P < 0.01; means +/- SE) and increased arterial plasma ET-1 (0.52 +/- 0.04 vs. 0.37 +/- 0.05 fmol/ml; P < 0.01) compared with mild hyperoxia at Fi(O(2)) 0.3. Inhalation of LU-135252 induced a significant and sustained decrease in mean pulmonary arterial pressure compared with controls (LU group: 27 +/- 1 mmHg; controls: 32 +/- 1 mmHg; values at 4 h of hypoxia; P < 0.01). In parallel, mean systemic arterial pressure and cardiac output remained stable and were not significantly different from control values. Consequently, in our experimental model of HPV, the inhaled ET(A) receptor antagonist LU-135252 induced selective pulmonary vasodilation without adverse systemic hemodynamic effects.

Background: Deep brain stimulation (DBS) has emerged as a promising therapy for movement disorders. During the implantation procedure for the electrodes, the patient emerges from anesthesia repeatedly to facilitate neurological testing. We investigated whether Bispectral Index (BIS) monitoring would be beneficial in patients receiving "sleep-awake-sleep" anesthesia with respect to time of arousal, consumption of propofol, and cardiopulmonary stability (i.e., heart rate, arterial blood pressure, and end-tidal carbon dioxide)., Methods: We investigated 21 patients scheduled for implantation of DBS electrodes. Depth of propofol anesthesia was controlled either with BIS guidance in 10 patients (BIS group) or without in 11 patients (non-BIS group). In the BIS group, a BIS score of 40-60 was targeted during sleep periods, whereas in the non-BIS group, a value of 1 (= no response to tactile stimulation [unconsciousness]) on the Observers' Assessment of Alertness/Sedation Scale was targeted. For analgesia, the sites for the burr holes and for the pins of the stereotactic ring were infiltrated with 2% lidocaine; no opioids were used. For periods during which an awake patient required neurological testing, propofol was discontinued., Results: We found no difference between groups with respect to times of arousal, total amount of propofol consumption, and cardiopulmonary stability. However, significantly more propofol boluses had to be administered in the BIS group (30 +/- 11.6 vs 17 +/- 4.6) to maintain the BIS score within the target range (P < 0.05)., Conclusion: BIS monitoring does not improve anesthesia management for DBS electrode implantation in patients with movement disorders.

Acute hypoxic pulmonary vasoconstriction can be inhibited by high doses of the carbonic anhydrase inhibitor acetazolamide. This study aimed to determine whether acetazolamide is effective at dosing relevant to human use at high altitude and to investigate whether its efficacy against hypoxic pulmonary vasoconstriction is dependent on carbonic anhydrase inhibition by testing other potent heterocyclic sulfonamide carbonic anhydrase inhibitors. Six conscious dogs were studied in five protocols: 1) controls, 2) low-dose intravenous acetazolamide (2 mg.kg(-1).h(-1)), 3) oral acetazolamide (5 mg/kg), 4) benzolamide, a membrane-impermeant inhibitor, and 5) ethoxzolamide, a membrane-permeant inhibitor. In all protocols, unanesthetized dogs breathed spontaneously during the first hour (normoxia) and then breathed 9-10% O(2) for the next 2 h. Arterial oxygen tension ranged between 35 and 39 mmHg during hypoxia in all protocols. In controls, mean pulmonary artery pressure increased by 8 mmHg and pulmonary vascular resistance by 200 dyn.s.cm(-5) (P <0.05). With intravenous acetazolamide, mean pulmonary artery pressure and pulmonary vascular resistance remained unchanged during hypoxia. With oral acetazolamide, mean pulmonary artery pressure increased by 5 mmHg (P < 0.05), but pulmonary vascular resistance did not change during hypoxia. With benzolamide and ethoxzolamide, mean pulmonary artery pressure increased by 6-7 mmHg and pulmonary vascular resistance by 150-200 dyn.s.cm(-5) during hypoxia (P < 0.05). Low-dose acetazolamide is effective against acute hypoxic pulmonary vasoconstriction in vivo. The lack of effect with two other potent carbonic anhydrase inhibitors suggests that carbonic anhydrase is not involved in the mediation of hypoxic pulmonary vasoconstriction and that acetazolamide acts on a different receptor or channel.

The objective of this study was to investigate whether circulatory and hormonal changes during xenon plus remifentanil or isoflurane plus remifentanil anesthesia are altered by endothelin-A (ET(A)) receptor blockade. Eight beagle dogs were studied in four protocols (n = 7 each). After a 30-min awake period, anesthesia was induced with 8 mg/kg propofol, administered intravenously (iv), and maintained with either 0.8% +/- 0.01% (vol/vol) isoflurane plus 0.5 microg/kg/min remifentanil (Protocol 1) or 63% +/- 1% (vol/vol) xenon plus 0.5 microg/kg/min remifentanil (Protocol 2) for 1 hr. Protocols 3 and 4 were preceded by ET(A) blockade with ABT-627 (Atrasentan; iv bolus of 1 mg/kg, then 100 microg/kg/h continuously). Irrespective of Atrasentan administration, the mean arterial blood pressure (MAP) ranged between 92 and 96 mm Hg in the awake state and fell to 67 +/- 3 mm Hg in controls (mean +/- SEM) and to 64 +/- 2 mm Hg in the Atrasentan group during isoflurane plus remifentanil anesthesia, whereas MAP remained constant during xenon plus remifentanil anesthesia. A decrease in heart rate was observed during either kind of anesthesia, but bradycardia was most prominent during xenon plus remifentanil anesthesia. In the control groups, and in the Atrasentan-treated dogs, a decrease in cardiac output and an increase in systemic vascular resistance were more prominent during xenon plus remifentanil than during isoflurane plus remifentanil anesthesia. Hormonal alterations during anesthesia remained unaffected by ET(A) receptor blockade. Angiotensin II and vasopressin increased in all protocols, and adrenaline and noradrenaline concentrations rose only during xenon plus remifentanil anesthesia. We conclude that the hemodynamic and hormonal adaptation after xenon plus remifentanil and isoflurane plus remifentanil anesthesia does not depend on the endothelin system, because it is unaffected by ET(A) receptor inhibition. Therefore, the use of Atrasentan does not impair cardiovascular stability during xenon- or isoflurane-based anesthesia in our dog model. However, the way anesthesia is performed is of crucial importance for hemodynamic and hormonal reactions observed during research in animals because the release of vasopressin and catecholamines may be intensified by xenon plus remifentanil anesthesia.

Beneficial effects of inhaled nitric oxide (iNO) on arterial oxygenation in acute lung injury (ALI) suggest the presence of vasoconstriction in ventilated lung regions and this may be influenced by endothelin-1 (ET-1). We studied a possible interaction between ET-1 and iNO in experimental ALI. Sixteen piglets were anesthetized and mechanically ventilated (inspired O2 fraction, 1.0). After induction of ALI by surfactant depletion, animals were randomly assigned to either inhale 30 ppm NO (iNO group, n = 8), or to receive no further intervention (controls, n = 8). Measurements were performed during the following 4 hrs. In all animals, induction of ALI significantly decreased arterial oxygen tension (PaO2) from 569 +/- 15 (prelavage) to 58 +/- 3 mm Hg. Inhaled NO significantly increased PaO2 when compared with controls (iNO group: 265 +/- 51 mm Hg; controls: 50 +/- 4 mm Hg, values at 4 hrs, P < 0.01). Prelavage ET-1 plasma levels were comparable between groups (iNO: 0.74 +/- 0.03, controls: 0.71 +/- 0.03 fmol/ml, NS). During the protocol, the ET-1 levels increased and were different at 3 hrs (iNO: 0.93 +/- 0.06, controls: 1.25 +/- 0.09 fmol/ml; P < 0.05). PaO2 changes induced by iNO revealed a moderate and significant correlation with ET-1 plasma levels (R = 0.548, P = 0.001). Our data suggest that endogenous ET-1 production influences the efficacy of iNO in ALI. Furthermore, iNO reduced ET-1 plasma levels, possibly indicating anti-inflammatory properties of iNO in the early phase of ALI.

Inhalation of endothelin (ET)-A receptor antagonists has been shown to improve gas exchange in experimental acute lung injury (ALI) but may induce side effects by increasing circulating ET-1 levels. We investigated whether the inhaled ET(A) receptor antagonist, LU-135252, at low doses, improves gas exchange without affecting ET-1 plasma concentrations and lung injury in an animal model of ALI. Twenty-two piglets were examined in a prospective, randomized, controlled study. In anesthetized animals, ALI was induced by surfactant depletion. Animals received either LU-135252 at a dose of 0.3 mg/kg during 20 mins (LU group; n = 11), or nebulization of saline buffer (control group; n = 11). The Mann-Whitney U test was used to compare groups (P < 0.05). In the LU group, arterial partial pressure of oxygen (PaO2) and mean pulmonary artery pressure (MPAP) improved compared with the control group (PaO2, 319 +/- 44 mm Hg vs. 57 +/- 3 mm Hg; MPAP, 32 +/- 2 mm Hg vs. 41 +/- 2 mm Hg; values at 6 hrs after induction of ALI; P < 0.05). Mean arterial pressure and cardiac output were not different between groups. ET-1 plasma concentrations increased from 0.96 +/- 0.06 fmol/ml after induction of ALI to a maximum of 1.17 +/- 0.09 fmol/ml at 3 hrs after ALI onset in the LU group and did not differ significantly from the control group (1.21 +/- 0.08 fmol/ml, not significant). On histologic examination, we found no differences in total lung injury score between groups. However, the LU group revealed significantly reduced interstitial inflammation and hemorrhage (P < 0.05 vs. control group). In this animal model of ALI, inhalation of LU-135252 at a dose of 0.3 mg/kg induced a significant and sustained improvement in gas exchange, whereas there were no changes in ET-1 plasma concentrations. Furthermore, our data indicate a trend toward decreased pulmonary inflammation in the group receiving the inhaled ET(A) receptor antagonist.

Awake craniotomy in tumor and epilepsy surgery or for the implantation of electrodes for deep brain stimulation requires specific anesthesiological strategies. Propofol allows for quick emergence and has little effect on the respiratory function of the usually spontaneously breathing patient. Pain control may be instituted by hemiscalp block for trepanation or local infiltration for deep brain electrode implantation. In addition, low dose remifentanil is recommended for trepanation (i.e. tumor or epilepsy surgery). The airway may be secured by an ordinary Magill tube placed transnasally with its tip underneath the epiglottis. To protect the patient against vomiting an adequate antiemetic prophylaxis is required.

We studied the effects of the inhaled endothelin-A receptor antagonist LU-135252 at different doses on hemodynamics and gas exchange in an animal model of acute lung injury. Thirtysix piglets (27 +/- 1 kg) were anesthetized, mechanically ventilated (FiO2 1.0), and surfactant-depleted by repeated lung lavage. The animals were randomly assigned to receive either nebulized LU- 135252 for 30 minutes at a dose of 0.3 mg/kg (n = 12), or at a dose of 3.0 mg/kg (n = 12); n = 12 animals received no further treatment (Controls). Induction of acute lung injury decreased PaO2 from 566 +/- 8 mmHg to 53 +/- 2 mmHg (mean +/- SEM) and increased intrapulmonary shunt (QS/QT) from 13 +/- 1% to 57 +/- 2%. Inhalation of LU-135252 at either dose induced a significant and sustained increase in PaO2 (0.3 mg/kg: 349 +/- 39 mmHg; 3.0 mg/kg: 219 +/- 40 mmHg), and a significant decrease in QS/QT (0.3 mg/kg: 19 +/- 2%; 3.0 mg/kg: 27 +/- 3%) when compared with Controls (PaO2: 50 +/- 3 mmHg, QS/QT: 50 +/- 5%) (P < 0.05; values at 4 hours). Mean pulmonary artery pressure in LU-135252-treated animals (0.3 mg/kg: 31 +/- 2 mmHg; 3.0 mg/kg: 30 +/- 1 mmHg) was significantly lower than in Controls (40 +/- 2 mmHg), while there were no differences in mean arterial pressure and cardiac output. We conclude that inhalation of LU-135252 at either dose improved gas exchange and hemodynamics comparably, indicating that the lower dose was already sufficient to block the majority of endothelin-A receptors in ventilated regions of the injured lung.

Acute hypoxia increases pulmonary arterial pressure and vascular resistance. Previous studies in isolated smooth muscle and perfused lungs have shown that carbonic anhydrase (CA) inhibition reduces the speed and magnitude of hypoxic pulmonary vasoconstriction (HPV). We studied whether CA inhibition by acetazolamide (Acz) is able to prevent HPV in the unanesthetized animal. Ten chronically tracheotomized, conscious dogs were investigated in three protocols. In all protocols, the dogs breathed 21% O(2) for the first hour and then 8 or 10% O(2) for the next 4 h spontaneously via a ventilator circuit. The protocols were as follows: protocol 1: controls given no Acz, inspired O(2) fraction (Fi(O(2))) = 0.10; protocol 2: Acz infused intravenously (250-mg bolus, followed by 167 microg.kg(-1).min(-1) continuously), Fi(O(2)) = 0.10; protocol 3: Acz given as above, but with Fi(O(2)) reduced to 0.08 to match the arterial Po(2) (Pa(O(2))) observed during hypoxia in controls. Pa(O(2)) was 37 Torr during hypoxia in controls, mean pulmonary arterial pressure increased from 17 +/- 1 to 23 +/- 1 mmHg, and pulmonary vascular resistance increased from 464 +/- 26 to 679 +/- 40 dyn.s(-1).cm(-5) (P < 0.05). In both Acz groups, mean pulmonary arterial pressure was 15 +/- 1 mmHg, and pulmonary vascular resistance ranged between 420 and 440 dyn.s(-1).cm(-5). These values did not change during hypoxia. In dogs given Acz at 10% O(2), the arterial Pa(O(2)) was 50 Torr owing to hyperventilation, whereas in those breathing 8% O(2) the Pa(O(2)) was 37 Torr, equivalent to controls. In conclusion, Acz prevents HPV in conscious spontaneously breathing dogs. The effect is not due to Acz-induced hyperventilation and higher alveolar Po(2), nor to changes in plasma endothelin-1, angiotensin-II, or potassium, and HPV suppression occurs despite the systemic acidosis with CA inhibition.

Background: The objective of this study was to determine whether endothelin-A receptor blockade (ETAB) impairs hemodynamic and hormonal regulation compared with controls and angiotensin II receptor blockade (AT1B) during hypotensive hemorrhage in dogs under isoflurane-nitrous oxide anesthesia., Methods: Six dogs were studied in four protocols: (1) control experiments (controls); (2) ETA blockade using ABT-627 (ETAB); (3) AT1 blockade using losartan (AT1B); and (4) combined AT1B and ETAB (AT1B + ETAB). After a 30-min awake period, isoflurane-nitrous oxide anesthesia was established (1.3 minimum anesthetic concentration). After 60 min of anesthesia, 20 ml blood/kg body weight was withdrawn within 5 min, and the dogs were observed for another hour. Thereafter, the blood was retransfused, and the dogs were observed for a final hour., Results: Anesthesia: Cardiac output decreased in all protocols, whereas mean arterial pressure decreased more in AT1B and AT1B + ETAB than in controls and ETAB. Hemorrhage: After 60 min, cardiac output had decreased less in controls than in all other protocols. Mean arterial pressure decreased more during ETAB than in controls, but most severely during AT1B and AT1B + ETAB. Angiotensin II increased further only in controls and ETAB, whereas vasopressin and catecholamines increased similarly in all protocols. Retransfusion: Mean arterial pressure remained below controls in all protocols but was lowest when the AT1 receptor was blocked. Cardiac output fully recovered in all but the ETAB protocol., Conclusions: ETAB impairs long-term hemodynamic regulation after hemorrhage and retransfusion during anesthesia despite an activation of vasoconstrictive hormones. This suggests that endothelins have a role in long-term cardiovascular regulation. AT1B impairs both short- and long-term blood pressure regulation during anesthesia and after hemorrhage.

Evidence indicates that nitric oxide (NO) suppresses myocardial oxygen consumption (MVO(2)) and regulates myocardial substrate oxidation, however data from in vivo and isolated heart preparations are conflicting. In addition, cardiac endothelin (ET-1) release has been shown to increase with inhibition of NO synthase (NOS), however the effects of ET-1 on myocardial energetics is not clear. We employed the isolated rat heart model to assess the role of NO and ET-1 on myocardial function and metabolism. Oxidation of glucose and FFA was measured using [U-(14)C]glucose and [9,10-(3)H]palmitate. NOS inhibition with N(G)-methyl-L-arginine acetate salt (L-NMMA, 50 microM), resulted in an increase in MVO(2) at a given rate of myocardial external workload, and no change in myocardial glucose or FFA oxidation. ET-1 (25 pM), which caused coronary vasoconstriction similar to that produced by L-NMMA, also increased MVO(2) without an effect on cardiac workload, or substrate oxidation, suggesting a role for ET-I in the regulation of myocardial energetics. We assessed also the effect of ET(A)/ET(B) receptor blockade (tezosentan; 5 nM) on MVO(2) and glucose and FFA oxidation and observed no effect, suggesting that basal ET-1 production does not play a role in regulating MVO2 or substrate selection. In conclusion, inhibition of NOS or the addition of ET-1 resulted in an increase in MVO2, but did not affect glucose or FFA oxidation.

Unlabelled: Hypoxic pulmonary vasoconstriction (HPV) is encountered during ascent to high altitude. Atrial natriuretic peptide (ANP) could be an option to treat HPV because of its natriuretic, diuretic, and vasodilatory properties. Data on effects of ANP on pulmonary and systemic circulation during HVP are conflicting, partly owing to anesthesia, surgical stress or uncontrolled dietary conditions. Therefore, ten conscious, chronically tracheotomized dogs were studied under standardized dietary conditions. The dogs were trained to breathe spontaneously at a ventilator circuit., Protocol: 30min of normoxia [inspiratory oxygen fraction (F(i)O(2))=0.21] were followed by 30min of hypoxia without ANP infusion (Hypoxia I, F(i)O(2)=0.1). While maintaining hypoxia an intravenous infusion of atrial natriuretic peptide was started with 50ng x kg body wt(-1) x min(-1) for 30min (Hypoxia+ANP1=low dose), followed by 1000ng x kg body wt(-1) x min(-1) for 30min (Hypoxia+ANP2=high dose). Thereafter, ANP infusion was stopped and hypoxia maintained for a final 30min (Hypoxia II). Compared to normoxia, mean pulmonary arterial pressure (MPAP) (16+/-0.7 vs. 26+/-1.3mmHg) and pulmonary vascular resistance (PVR) (448+/-28 vs. 764+/-89dyn x s(-1) x cm(-5)) increased during Hypoxia I and decreased during Hypoxia+ANP 1 (MPAP 20+/-1mmHg, PVR 542+/-55dyn x s(-1) x cm(-5)) (P<0.05). The higher dose of ANP did not further decrease MPAP or PVR, but started to have a tendency to decrease mean arterial pressure and cardiac output. We conclude that low dose ANP is able to reduce HPV without affecting systemic circulation during acute hypoxia.

Acute hypoxia induces a decrease in plasma renin activity (PRA), mediated, e.g., by an increase in adenosine concentration, calcium channel activity, or inhibition of ATP-sensitive potassium channels. The decrease in PRA results in a decrease in angiotensin II (AngII) and plasma aldosterone concentration (PAC). This study investigates whether these hypoxia-induced mechanisms can be inhibited by the L-type voltage-dependent calcium channel antagonist nifedipine. Eight conscious, chronically tracheotomized dogs received a low sodium diet (0.5 mmol Na x kg body wt(-1) x day(-1)). The dogs were studied twice in randomized order, either with nifedipine infusion (1.5 microg x kg body wt(-1) x min(-1), Nifedipine) or without (Control). The dogs were breathing spontaneously: first hour, normoxia [inspiratory oxygen fraction (FiO2)=0.21]; second and third hour hypoxia (FiO2=0.1). In Controls, PRA (6.8+/-0.8 vs. 3.0+/-0.5 ngAngI x ml(-1) x min(-1)), AngII (13.3+/-1.9 vs. 7.3+/-1.9 pg/ml), and PAC (316+/-50 vs. 69+/-12 pg/ml) decreased during hypoxia (P<0.05). In Nifedipine experiments, PRA (6.5+/-0.9 vs. 10.5+/-2.4 ngAngI x ml(-1) x min(-1)) and AngII (14+/-1.1 vs. 18+/-3.9 pg/ml) increased during hypoxia, whereas the decrease in PAC (292+/-81 vs. 153+/-41 pg/ml) was blunted (P<0.05). These results foster the idea that the hypoxia-induced decrease in PRA involves L-type calcium channel activity.

This study compares the haemodynamic and hormonal responses during haemorrhage of conscious dogs pre-treated with an endothelin-A (ET-A) receptor inhibitor. The dogs were studied in two different randomized groups: the control group and a group that was given the ET-A receptor antagonist ABT-627 (as a bolus of 1 mg x kg of body weight(-1) followed by 0.01 mg x kg body weight(-1) x min(-1) intravenously). The time-course was the same for both groups: after a 1 h baseline period (pre-haemorrhage), blood (25 ml x kg of body weight(-1)) was withdrawn within 5 min. Haemodynamics were continuously recorded and hormone levels measured after 1 h (post-haemorrhage). Thereafter, the blood withdrawn was retransfused within 5 min and haemodynamics again observed for 1 h (post-retransfusion). In ABT-627-treated dogs, the decrease in mean arterial pressure from 87+/-3 to 64+/-3 mmHg (P<0.05 versus pre-haemorrhage), and cardiac output from 2.1+/-0.1 to 1.3+/-0.1 l x min(-1) (P<0.05 versus pre-haemorrhage) and the increase in systemic vascular resistance from 3286+/-174 to 4211+/-230 dyn.s.cm(-5) (P<0.05 versus pre-haemorrhage) during acute haemorrhage are comparable with controls. During haemorrhage in controls, vasopressin levels increased from 0+/-0 to 13+/-2 pg x ml(-1) (P<0.05 versus pre-haemorrhage), angiotensin II levels increased from 9+/-1 to 28+/-9 pg x ml(-1) (P<0.05 versus pre-haemorrhage) and adrenaline levels increased from 134+/-22 to 426+/-74 pg x ml(-1) (P<0.05 versus pre-haemorrhage) whereas noradrenaline levels did not change (approx. 200 pg x ml(-1)). In ABT-627-treated dogs, vasopressin levels increased from 0.2+/-0.0 to 22.2+/-6.1 pg x ml(-1) (P<0.05 versus pre-haemorrhage and P<0.05 versus control), angiotensin II levels increased from 8+/-1 to 37+/-8 pg x ml(-1) (P<0.05 versus pre-haemorrhage), noradrenaline levels increased from 147+/-16 to 405+/-116 pg x ml(-1) (P<0.05 versus pre-haemorrhage) and adrenaline levels did not change (200 pg x ml(-1)) during haemorrhage. We conclude from our results that dogs receiving the selective ET-A inhibitor ABT-627 seem to show a different hormonal response after haemorrhage compared with controls, displaying considerably higher noradrenaline concentrations. Independent of ET-A receptor inhibition, cardiac output during haemorrhage was maintained within the control range. This may indicate that the organism is defending blood flow (cardiac output) over blood pressure during haemorrhage, and that this defence strategy is not compromised by ET-A receptor inhibition.

To investigate the hypothesis that the inhaled ET(A) receptor antagonist LU-135252 acts as selective pulmonary vasodilator, we compared inhaled LU-135252 and inhaled nitric oxide (iNO) in an experimental model of acute lung injury (ALI), in a prospective, randomized, controlled animal study. A total of 30 anaesthetized, tracheotomized and mechanically ventilated pigs underwent induction of ALI by repeated saline washout of surfactant. The animals were then randomly assigned to receive the nebulized ET(A) receptor antagonist LU-135252 (0.3 mg x kg(-1), inhaled over 20 min; ET(A)-A group; n=10), inhaled NO (30 p.p.m. continuously; iNO group; n=10) or nebulized saline buffer (5 ml inhaled over 20 min; control group; n=10). Measurements of pulmonary gas exchange and haemodynamics were performed hourly over a 4 h period after induction of ALI. In the ET(A)-A group, the arterial oxygen tension (Pa(2)) increased from 58+/-3 to 377+/-39 mmHg at 4 h after intervention, while the intrapulmonary shunt (Q(S)/Q(T)) decreased from 53+/-4% to 18+/-2% (P<0.01 compared with controls). In the iNO group, Pa(2) increased from 62+/-4 to 224+/-48 mmHg, and Q(S)/Q(T) decreased from 47+/-2% to 27+/-5%, at 4 h after induction of ALI (P<0.05 compared with controls). In the ET(A)-A and iNO groups, the increase in mean pulmonary artery pressure was significantly attenuated compared with controls (ETA-A group, 14+/-4%; iNO group, 6+/-4%; values at 4 h; P<0.01 compared with controls). In contrast, there were no significant differences in changes of mean arterial pressure and cardiac output between groups. Thus, in this experimental model of ALI, both inhaled LU-135252 and iNO significantly improved gas exchange and prevented an increase in mean pulmonary artery pressure, without significant systemic effects, when compared with controls. Our results indicate the occurrence of selective pulmonary vasodilation in both treatment groups.

Acute hypoxia causes hyperventilation and respiratory alkalosis, often combined with increased diuresis and sodium, potassium, and bicarbonate excretion. With a low sodium intake, the excretion of the anion bicarbonate may be limited by the lower excretion rate of the cation sodium through activated sodium-retaining mechanisms. This study investigates whether the short-term renal compensation of hypoxia-induced respiratory alkalosis is impaired by a low sodium intake. Nine conscious, tracheotomized dogs were studied twice either on a low-sodium (LS = 0.5 mmol sodium x kg body wt-1 x day-1) or high-sodium (HS = 7.5 mmol sodium x kg body wt-1 x day-1) diet. The dogs breathed spontaneously via a ventilator circuit during the experiments: first hour, normoxia (inspiratory oxygen fraction = 0.21); second to fourth hour, hypoxia (inspiratory oxygen fraction = 0.1). During hypoxia (arterial PO2 34.4 +/- 2.1 Torr), plasma pH increased from 7.37 +/- 0.01 to 7.48 +/- 0.01 (P < 0.05) because of hyperventilation (arterial PCO2 25.6 +/- 2.4 Torr). Urinary pH and urinary bicarbonate excretion increased irrespective of the sodium intake. Sodium excretion increased more during HS than during LS, whereas the increase in potassium excretion was comparable in both groups. Thus the quick onset of bicarbonate excretion within the first hour of hypoxia-induced respiratory alkalosis was not impaired by a low sodium intake. The increased sodium excretion during hypoxia seems to be combined with a decrease in plasma aldosterone and angiotensin II in LS as well as in HS dogs. Other factors, e.g., increased mean arterial blood pressure, minute ventilation, and renal blood flow, may have contributed.

Nitric oxide modulates renal hemodynamics and salt and water handling. Studies on the latter have provided conflicting results, however. Electrolyte and water balances were therefore studied in 28 beagles for 4 d, to determine the various effects of nitric oxide synthase (NOS) inhibition on renal function. The dogs were chronically equipped with aortic occluders to reduce renal perfusion pressure (RPP), bladder catheters, and catheters for measurements of RPP and mean arterial BP. A swivel system allowed free movement within the kennels. In a first set of experiments, a nonpressor dose of L-Nomega-nitroarginine (LN) (3 microg/min per kg body wt) was administered, to prevent increases in mean arterial BP and thus pressure effects on renin release and natriuresis. Remarkably, the nonpressor dose of LN caused a negative sodium balance. The natriuretic effect may involve reduced plasma renin activity, reduced aldosterone concentrations, and increased atrial natriuretic peptide concentrations. Changes in aldosterone levels, however, were the only parameters to parallel the time course of sodium excretion. In a second set of experiments, a sodium-retaining challenge was elicited by reduction of RPP. Dogs without NOS inhibition escaped sodium retention during RPP reduction after 2 d ("pressure escape"). LN neither ameliorated nor aggravated the sodium-retaining effect of reduced RPP, nor did it compromise the accomplishment of pressure escape. In conclusion, inhibition of NOS with a low dose of LN results in a reduction of total-body sodium. This effect mainly relies on reduced aldosterone concentrations. Furthermore, LN does not change the regulatory response to long-term RPP reduction.

Angiotensin (ANG) II effects may be partly mediated by endothelin (ET)-1. This study analyses the hemodynamic, renal, and hormonal responses of acute ET(A) receptor antagonism (LU-135252) at two ANG II plasma levels in eight conscious dogs. Protocol 1 involved a 60-min baseline, followed by two doses of ANG II for 60 min each (4 and 20 ng. kg(-1). min(-1)), termed ANG II 4 (slightly increased) and ANG II 20 (pathophysiologically increased ANG II plasma concentration). Protocol 2 was the same as protocol 1 but included 15 mg/kg iv LU-135252 after the baseline period. Protocol 3 was a 3-h time control. ANG II without LU-135252 did not increase plasma big ET-1 and ET-1, whereas LU-135252 increased ET-1 transiently after injection. This transient ET-1 increase was not reflected in urinary ET-1 excretion. The ANG II induced decreases in sodium, water, and potassium excretion, glomerular filtration rate, and fractional sodium excretion were not different with and without LU-135252. Mean arterial pressure increased during ANG II and was not lower with LU-135252 (-6 mmHg, not significant). Most importantly, during ANG II 20 LU-135252 prevented the decrease in cardiac output. Simultaneously, systemic vascular resistance increased 40% less, pulmonary vascular resistance was maintained at baseline levels, and central venous and wedge pressure were lower. Because ANG II stimulated endothelin de novo synthesis should just have started after 2 h of ANG II infusion, there must be mechanisms other than blocking the coupling of de novo synthesized endothelins to the ET(A) receptors to explain the effects of acute ET(A) receptor inhibition in our setting.

This study investigated whether adenosine mediates the decrease in plasma renin activity (PRA) during acute hypoxia. Eight chronically tracheotomized, conscious beagle dogs were kept under standardized environmental conditions and received a low-sodium diet (0.5 mmol.kg body wt(-1).day(-1)). During the experiments, the dogs were breathing spontaneously via a ventilator circuit: first hour, normoxia (21% inspiratory concentration of O(2)); second and third hours, hypoxia (10% inspiratory concentration of O(2)). Each of the eight dogs was studied twice in randomized order in control and theophylline experiments. In theophylline experiments, theophylline, an A(1)-receptor antagonist, was infused intravenously during hypoxia (loading dose: 3 mg/kg within 30 min, maintenance: 0.5 mg. kg(-1). h(-1)). In theophylline experiments, PRA (5.9 +/- 0.8 ng ANG I. ml(-1). h(-1)) and ANG II plasma concentration (15.9 +/- 2.3 pg/ml) did not decrease during hypoxia, whereas plasma aldosterone concentration decreased from 277 +/- 63 to 132 +/- 23 pg/ml (P < 0.05). In control experiments, PRA decreased from 6.8 +/- 0.8 during normoxia to 3.0 +/- 0.5 ng ANG I. ml(-1). h(-1) during hypoxia, ANG II decreased from 13.3 +/- 1.9 to 7.3 +/- 1.9 pg/ml, and plasma aldosterone concentration decreased from 316 +/- 50 to 70 +/- 13 pg/ml (P < 0.05). Thus infusion of the adenosine receptor antagonist theophylline inhibited the suppression of the renin-angiotensin system during acute hypoxia. The decrease in aldosterone occurred independently and is apparently directly related to hypoxia. In conclusion, it is likely that adenosine mediates the decrease in PRA during acute hypoxia in conscious dogs.

Acute hypoxic pulmonary vasoconstriction (HPV) may be mediated by vasoactive peptides. We studied eight conscious, chronically tracheostomized dogs kept on a standardized dietary sodium intake. Normoxia (40 min) was followed by hypoxia (40 min, breathing 10% oxygen, arterial oxygen pressures 36 +/- 1 Torr) during both control (Con) and losartan experiments (Los; iv infusion of 100 microg. min-1. kg-1 losartan). During hypoxia, minute ventilation (by 0.9 l/min in Con, by 1.3 l/min in Los), cardiac output (by 0.36 l/min in Con, by 0.30 l/min in Los), heart rate (by 11 beats/min in Con, by 30 beats/min in Los), pulmonary artery pressure (by 9 mmHg in both protocols), and pulmonary vascular resistance (by 280 and 254 dyn. s. cm-5 in Con and Los, respectively) increased. Mean arterial pressure and systemic vascular resistance did not change. In Con, PRA decreased from 4.2 +/- 0.7 to 2.5 +/- 0.5 ng ANG I. ml-1. h-1, and plasma ANG II decreased from 11.9 +/- 3.0 to 8.2 +/- 2.1 pg/ml. The renin-angiotensin system is inhibited during acute hypoxia despite sympathetic activation. Under these conditions, ANG II AT1-receptor antagonism does not attenuate HPV.

In 12 conscious dogs, we investigated whether the angiotensin II-receptor antagonist losartan increases renal sodium excretion and urine volume during controlled mechanical ventilation (CMV) with positive end-expiratory pressure. In four experimental protocols, the dogs were extracellular volume (ECV) expanded (electrolyte solution, 0.5 ml. kg-1. min-1 iv) or not and received losartan (100 micrograms. kg-1. min-1 iv) or not. They breathed spontaneously during the 1st and 4th hour and received CMV with positive end-expiratory pressure (mean airway pressure 20 cmH2O) during the 2nd and 3rd hours. In the expansion group, dogs with losartan excreted approximately 18% more sodium (69 +/- 7 vs. 38 +/- 5 micromol. min-1. kg-1) and 15% more urine during the 2 h of CMV because of a higher glomerular filtration rate (5.3 +/- 0.3 vs. 4.5 +/- 0.2 ml. min-1. kg-1) and the tubular effects of losartan. In the group without expansion, sodium excretion (2.0 +/- 0.6 vs. 2.6 +/- 1.0 micromol. min-1. kg-1) and glomerular filtration rate (3.8 +/- 0.3 vs. 3.8 +/- 0.4 ml. min-1. kg-1) did not change, and urine volume decreased similarly in both groups during CMV. Plasma vasopressin and aldosterone increased in both groups, and plasma renin activity increased from 4.9 +/- 0.7 to 7.8 +/- 1.3 ng ANG I. ml-1. h-1 during CMV in nonexpanded dogs without losartan. Mean arterial pressure decreased by 10 mmHg in nonexpanded dogs with losartan. In conclusion, losartan increases sodium excretion and urine volume during CMV if the ECV is expanded. If the ECV is not expanded, a decrease in mean arterial blood pressure and/or an increase in aldosterone and vasopressin during CMV attenuates the renal effects of losartan.

Background: The role of renal nerves during positive end-expiratory pressure ventilation (PEEP) has only been investigated in surgically stressed, anesthetized, unilaterally denervated dogs. Anesthesia, sedation, and surgical stress, however, decrease urine volume and sodium excretion and increase renal sympathetic nerve activity independent of PEEP. This study investigated in awake dogs the participation of renal nerves in mediating volume and water retention during PEEP., Methods: Eight tracheotomized, trained, awake dogs were used. The protocol consisted of 60 min of spontaneous breathing at a continuous positive airway pressure of 4 cm H2O, followed by 120 min of controlled mechanical ventilation with a mean PEEP of 15-17 cm H2O (PEEP), and 60 min of continuous positive airway pressure. Two protocols were performed on intact dogs, in which volume expansion had (hypervolemic; electrolyte solution, 0.5 ml x kg(-1) x min(-1)) and had not (normovolemic) been instituted. This was repeated on the same dogs 2 or 3 weeks after bilateral renal denervation., Results: Hypervolemic dogs excreted more sodium and water than did normovolemic dogs. There was no difference between intact and renal-denervated dogs. Arterial pressure did not decrease when continuous positive airway pressure was switched to PEEP. Plasma renin activity, aldosterone, and antidiuretic hormone concentrations were greater in normovolemic dogs. The PEEP increased aldosterone and antidiuretic hormone concentrations only in normovolemic dogs., Conclusions: In conscious dogs, renal nerves have no appreciable contribution to sodium and water retention during PEEP. Retention in normovolemic dogs seems to be primarily caused by an activation of the renin-angiotensin system and an increase in the antidiuretic hormone. Excretion rates depended on the volume status of the dogs.

Unlabelled: Studies were performed in partly free moving Beagle dogs, kept under standardized environmental and dietetic conditions (food intake: once daily at 8:30 a.m., 5.5 mmol Na/kg body weight per 24 h). The dogs were chronically instrumented with an inflatable cuff around the aorta above the renal arteries, two aortic catheters above and below the cuff, and a bladder catheter. Three protocols were performed in 7 dogs each: (i), Control: urine collection in 20-min intervals and measurement of Na excretion, continuous registration of mean arterial blood pressure (MABP) and heart rate for 4 consecutive days. (ii) As (i), but additional servocontrolled reduction of the renal perfusion pressure (rRPP) to stimulate renin secretion and the formation of angiotensin II and aldosterone. (iii) As (ii), but additional constant infusion of the angiotensin converting enzyme inhibitor Captopril. Despite rRPP Na is only transiently retained (pressure escape). MABP level is elevated, as long as total-body Na is augmented. In protocol iii no Na retention occurs, indicating that rRPP per se causes no Na retention. MABP level remained unchanged. Independent of the preset MABP level similar diurnal variation in MABP are present in all protocols. During control days major amounts of Na are excreted postprandially. Up to 5:00 p.m. 65% of the daily Na intake is excreted. After disturbance of Na control (protocols ii and iii) the Na excretion is shifted to the evening and night. Probably due to this shift Na retention can be prevented. Furthermore, these results demonstrate that rRPP-induced increases of total body Na and MABP are solely mediated by the activation of the renin-angiotensin-aldosterone system.

In 5 conscious dogs the diurnal patterns of urinary sodium excretion (UNaV) were investigated, initially during 1 control day and, thereafter, during 4 days of servo-controlled reduction of renal perfusion pressure (rRPP). The individual dog's mean arterial blood pressure was reduced to 80% of the blood pressure on the control day. This value was always found to be below the threshold for the pressure-dependent renin release. During the entire study period urine was collected in 4-hour intervals and blood samples were taken every 4 h. The dogs were kept on a standardized high sodium and high water intake and were fed once daily at 8.30 h. On the control day, UNaV, urinary flow rate (UV), fractional lithium excretion (FELi) and fractional sodium excretion (FENa) had similar diurnal patterns. They peaked 4-8 h after food intake and decreased to low values during the night. On day 1 of rRPP, UNaV and FENa were maintained at very low levels in all collection periods, whereas the patterns of UV and FELi were unaltered compared with the patterns on the control day. On days 2-4 of rRPP, a clear-cut maximum in the patterns of UNaV and FENa recurred, comparable with the patterns on the control day. However, compared with the control day this maximum was shifted by 4 h towards the night. In contrast, the patterns of UV and FELi remained unchanged compared with the control day. The results indicate that UNaV has a typical time course in conscious, sodium- and water-replete dogs fed once daily. Endogenous stimulation of sodium reabsorption by means of rRPP results in a characteristic 4-hour shift of UNaV and FENa towards the night during rRPP days 2-4. This delay in UNaV seems to be evoked by processes in the distal tubule.

1. We studied post-prandial changes in renal function in dogs adapted to either low or high sodium intake with and without concomitant post-prandial infusion of angiotensin II. Six trained dogs were exposed to diets containing either 0.5 or 14.5 mmol Na+ day-1 kg-1 body weight (low or high sodium respectively). They were studied from 20 min before to 4 h after food intake. In half of the experiments a physiological dose of angiotensin II (4 ng min-1 kg-1 body weight) was administered after food intake for four post-prandial hours. The water intake was high and equal on both diets (91 ml day-1 kg-1 body weight). 2. On a high-salt diet post-prandial sodium excretion and urine volume increased considerably above fasting values. This post-prandial increase was attenuated when angiotensin II was infused (post-prandial sodium excretion was 31% +/- 3% of intake without versus 10% +/- 1% with angiotensin II, post-prandial urine volume was 22% +/- 2% without versus 8% +/- 1% with angiotensin II, P < 0.05). Post-prandial increases in glomerular filtration rate and fractional sodium excretion were attenuated during angiotensin II infusion in dogs on a high-salt diet. 3. On a low-salt diet post-prandial sodium excretion remained low with or without angiotensin II infusion, whereas urine volume increased post-prandially, and this increase was greater when angiotensin II was administered (40% +/- 3% versus 34% +/- 2% of intake, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The diurnal time course of urinary flow rate (UV), urinary sodium (UNaV), and potassium (UKV) excretion, and of hormones such as atrial natriuretic peptide (ANP) and aldosterone, was investigated during 5 days of continuous captopril infusion (15 micrograms.kg body weight-1.min-1) in 4 conscious dogs on a high sodium diet (14.5 mmol Na.kg body weight-1.24 h-1). All food and water was given once daily at 8.30 a.m. On the control day and on days 1, 3, and 5 of captopril infusion, urine was collected by an automated system at 20-min intervals over 24 h, blood was taken every 4 h. Mean arterial blood pressure (MABP) and heart rate were evaluated as 5-min averages. Time courses of UNaV, UV, and UKV were compared with the individual control day without captopril. With captopril, 24-hour balances for Na and H2O were slightly negative, while the K balance was slightly positive for 2-3 days. Thereafter, all 24-hour balances were restored. MABP continued to decrease even after Na and water intake and output had come into balance again. Captopril treatment changed the diurnal excretion pattern for UNaV and UV characteristically. In the postprandial period until 5 p.m., less Na and urine were excreted than on the control day, whereas during the evening and night more Na and urine were excreted. The changes in the excretion pattern persisted for the entire observation period. The results indicate that disturbances in the regulating systems, induced by converting-enzyme blockade, bring about complex reactions of, e.g., MABP, ANP and aldosterone that finally restore Na and water 24-hour input/output balances.

A new method of skin surface electromyography (EMG) was evaluated. Twelve electrodes were placed symmetrically in the cricothyroid and thyroid lamina region. Raw EMG signals were continuously recorded, filtered, and rectified. Phonation of the vowel /a/ triggered a computer, which thereafter stored a 625-ms EMG recording, starting 375 ms before and ending 250 ms after onset of the audible phonation. Sixteen to 64 of these recordings were averaged to eliminate random noise. Twenty-six healthy subjects and 9 patients with unilateral laryngeal paralysis were studied. EMG activity exhibited great intra- and interindividual variation. Often, even in healthy subjects, EMG levels were different between the left and right side of the larynx. Thus, this method is not suitable for diagnosis or follow-up of laryngeal paralysis. Sources of variation in EMG activity are discussed.