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Introduction: Lung protective ventilation (LPV) comprising low tidal volume (VT) and high positive end-expiratory pressure (PEEP) may compromise cerebral perfusion in acute brain injury (ABI). In patients with ABI, we investigated whether LPV is associated with increased intracranial pressure (ICP) and/or deranged cerebral autoregulation (CA), brain compensatory reserve and oxygenation., Methods: In a prospective, crossover study, 30 intubated ABI patients with normal ICP and no lung injury were randomly assigned to receive low VT [6 ml/kg/predicted (pbw)]/at either low (5 cmH 2 O) or high PEEP (12 cmH 2 O). Between each intervention, baseline ventilation (VT 9 ml/kg/pbw and PEEP 5 cmH 2 O) were resumed. The safety limit for interruption of the intervention was ICP above 22 mmHg for more than 5 min. Airway and transpulmonary pressures were continuously monitored to assess respiratory mechanics. We recorded ICP by using external ventricular drainage or a parenchymal probe. CA and brain compensatory reserve were derived from ICP waveform analysis., Results: We included 27 patients (intracerebral haemorrhage, traumatic brain injury, subarachnoid haemorrhage), of whom 6 reached the safety limit, which required interruption of at least one intervention. For those without intervention interruption, the ICP change from baseline to "low VT/low PEEP" and "low VT/high PEEP" were 2.2 mmHg and 2.3 mmHg, respectively, and considered clinically non-relevant. None of the interventions affected CA or oxygenation significantly. Interrupted events were associated with high baseline ICP (p < 0.001), low brain compensatory reserve (p < 0.01) and mechanical power (p < 0.05). The transpulmonary driving pressure was 5 ± 2 cmH 2 O in both interventions. Partial arterial pressure of carbon dioxide was kept in the range 34-36 mmHg by adjusting the respiratory rate, hence, changes in carbon dioxide were not associated with the increase in ICP., Conclusions: The present study found that most patients did not experience any adverse effects of LPV, neither on ICP nor CA. However, in almost a quarter of patients, the ICP rose above the safety limit for interrupting the interventions. Baseline ICP, brain compensatory reserve, and mechanical power can predict a potentially deleterious effect of LPV and can be used to personalize ventilator settings. Trial registration NCT03278769 . Registered September 12, 2017., (© 2023. The Author(s).)

Background: We recently introduced the efficacy safety score (ESS) as a new "call-out algorithm" for management of postoperative pain and side effects. In this study, we report the influence of ESS recorded hourly during the first 8 hours after surgery on the mobility degree, postoperative nonsurgical complications, and length of hospital stay (LOS)., Methods: We randomized 1152 surgical patients into three groups for postoperative observation: (1) ESS group ( n = 409), (2) Verbal Numeric Rate Scale (VNRS) for pain group ( n = 417), and (3) an ordinary qualitative observation (Control) group ( n = 326). An ESS > 10 or VNRS > 4 at rest or a nurse's observation of pain or adverse reaction to analgesic treatment in the Control group served as a "call-out alarm" for an anaesthesiologist., Results: We found no significant differences in the mobility degree and number of postoperative nonsurgical complications between the groups. LOS was significantly shorter with 12.7 ± 6.3 days (mean ± SD) in the ESS group versus 14.2 ± 6.2 days in the Control group ( P < 0.001)., Conclusion: Postoperative ESS recording in combination with the possibility to call upon an anaesthesiologist when exceeding the threshold score might have contributed to the reductions of LOS in this two-centre study. This trial is registered with NCT02143128.

Introduction: Studies in vitro reveal that endothelin-1 (ET-1) activates the alpha isoform of protein kinase C (PKC-alpha) in cultures of endothelial cells, thereby deranging cellular integrity. Sepsis and endotoxemia are associated with increased plasma concentrations of ET-1 that induce acute lung injury (ALI). We recently reported that non-selective ET-1 receptor blockade attenuates ALI in sheep by reducing the endotoxin-induced increase in extravascular lung water index (EVLWI). The aim of this study was to find out whether this attenuation is associated with reduced translocation of PKC-alpha from the cytosolic to the membrane fraction of lung tissue homogenate., Methods: Seventeen awake, instrumented sheep were randomly assigned to a sham-operated group (n = 3), a lipopolysaccharide (LPS) group (n = 7) receiving an intravenous infusion of Escherichia coli 15 ng/kg per min for 24 hours, and a tezosentan group (n = 7) subjected to LPS and, from 4 hours, an intravenous injection of tezosentan 3 mg/kg followed by infusion at 1 mg/kg per hour for the reminder of the experiment. Pulmonary micro-occlusion pressure (Pmo), EVLWI, plasma concentrations of ET-1, tumor necrosis factor-a (TNF-a), and interleukin-8 (IL-8) were determined every 4 hours. Western blotting was used to assess PKC-alpha., Results: In non-treated sheep a positive correlation was found between the plasma concentration of ET-1 and Pmo in the late phase of endotoxemia (12 to 24 hours). A positive correlation was also noticed between Pmo and EVLWI in the LPS and the LPS plus tezosentan groups, although the latter was significantly reduced in comparison with LPS alone. In both endotoxemic groups, plasma concentrations of ET-1, TNF-alpha, and IL-8 increased. In the LPS group, the cytosolic fraction of PKC-alpha decreased by 75% whereas the membrane fraction increased by 40% in comparison with the sham-operated animals. Tezosentan completely prevented the changes in PKC-alpha in both the cytosolic and the membrane fractions, concomitantly causing a further increase in the plasma concentrations of ET-1, TNF-alpha, and IL-8., Conclusion: In endotoxemic sheep, ET-1 receptor blockade alleviates lung injury as assessed by a decrease in EVLWI paralleled by a reduction in Pmo and the prevention of activation of PKC-alpha.

Introduction: We recently demonstrated that the non-selective endothelin-1 (ET-1) receptor blocker tezosentan antagonizes ovine acute lung injury (ALI) following infusion of endotoxin or ET-1 by reducing the enhanced lung microvascular pressure, although we could not exclude the possibility of a simultaneous decline in microvascular permeability. In the present study, our aim was to find out if tezosentan reverses the rise in microvascular filtration coefficient (Kfc) in rat lungs that have been isolated and perfused 12 h after cecum ligation and puncture (CLP) or infusion of ET-1., Methods: Wistar rats (n = 42) were subjected to CLP. Postoperatively, rats were randomized to a CLP group (n = 7) and a CLP + tezosentan group (n = 7); the latter received tezosentan 30 mg/kg. A sham-operated group (n = 5) underwent laparotomy without CLP. Twelve hours postoperatively, the lungs were isolated and perfused with blood from similarly treated rats that also were used to assess plasma concentration of ET-1 and protein kinase Calpha (PKCalpha) in lung tissue. Additionally, isolated blood perfused lungs from healthy rats were randomized to a control group (n = 8), an ET-1 group (n = 7) subjected to pulmonary arterial injection of ET-1 10 nM, and an ET-1 + tezosentan group (n = 7) that received tezosentan 30 mg/kg. All lung preparations received papaverine 0.1 microg/kg added to the perfusate for vasoplegia. Pulmonary hemodynamic variables, Kfc and lung compliance (CL) were assessed., Results: After CLP, the plasma concentration of ET-1 increased. Papaverine abolished the vasoconstrictor response to ET-1 and the pulmonary vascular pressures remained close to baseline throughout the experiments. Both CLP and injection of ET-1 caused significant changes in Kfc and CL that were prevented in tezosentan-treated rats. Compared to sham-operated animals, CLP increased the content of PKCalpha by 50% and 70% in the cytosolic and the membrane fractions of lung tissue homogenates, respectively. Tezosentan prevented the upregulation of PKCalpha in the membrane fraction., Conclusion: In rat lungs isolated and perfused after CLP, tezosentan precludes both the increase in Kfc and the upregulation of PKCalpha in the membrane fraction of lung tissue.

Background: Severe sepsis is a common cause of mortality in critically ill patients. Drotrecogin alfa (activated), synonymous with recombinant human activated protein C (rhAPC), is a new therapeutic tool with anticoagulant, anti-inflammatory and profibrinolytic properties with proven effect in reducing mortality in severe sepsis., Material and Methods: As part of a multi-centre study, the patients received an infusion of rhAPC, 24 microg/kg/h for 96 hours according to an open-labeled phase IIIb study protocol., Results: Out of a total of 28 patients, 6 (21%) died before day 28. One of the deaths was classified as possibly related to rhAPC. In three patients rhAPC was transiently stopped because of surgery or postoperative bleeding. Use of the compound rarely interfered with commonly used diagnostic and therapeutic procedures., Interpretation: Treatment with rhAPC is easily carried out in an intensive care unit. Patients with severe sepsis and two or more failing vital organs should be considered for treatment with rhAPC.

The effects of methylprednisolone (MP) on the acute airway and pulmonary vascular responses induced by reactive oxygen species (ROS) were investigated in isolated, plasma-perfused rat lungs. ROS were generated by adding xanthine oxidase and hypoxanthine to the perfusate. MP was administered in 3 different ways: 1. Added to the perfusate (1 mg*ml-1) 5 min prior to xanthine oxidase and hypoxanthine, 2. Given as intraperitoneal injections (40 mg*kg-1) to lung donor rats 12 and 2 hours prior to the experiments, or 3. Combining 1 and 2. The lungs were perfused at constant volume inflow (15 ml*min-1). Pulmonary arterial pressure and transpulmonary pressure were followed for 30 min after addition of xanthine oxidase and hypoxanthine. ROS induced a powerful, acute broncho- and vasoconstriction, which was inhibited by addition of MP to the perfusate. Pretreatment with MP also inhibited the vascular and airway responses. Adding MP to the perfusate of pretreated lungs further reduced the ROS-induced smooth muscle constriction. In conclusion, MP inhibits vasoconstriction and bronchoconstriction induced by ROS in isolated rat lungs.

Extracorporeal membrane oxygenation (ECMO) may serve as extracorporeal lung assist (ECLA) in patients with acute respiratory failure (ARF) or as extracorporeal heart assist (ECHA) in patients with low output syndrome (LOS) after open heart surgery. From 1988 to 1992 seven patients underwent ECMO in our hospital; four suffered from ARF and three from LOS. Various bypass techniques were employed. Two ARF patients, aged 58 and 18 years, had veno-venous bypass; in the latter, ECMO was reinstituted as a veno-arterial bypass one week after weaning. In a three-year-old boy, the ECMO outflow tubing was primarily connected to the pulmonary artery, and shortly afterwards relocated to the common carotid artery. In a 31-year-old man with ARF, and three LOS patients, a 56-year-old woman, and two men aged 68 and 70 years, ECMO was veno-arterial with direct access to the ascending aorta. A heparin-coated system was used, and all but one patient, who was treated with warfarin, received a daily low dose of heparin, which was withdrawn after from one to nine days. Six patients were weaned off ECMO after 4.5 to 21 days. Three ARF patients recovered completely; the child died. In one LOS patient, ECMO was withdrawn due to a poor general condition. Two others were weaned off ECMO and the intra-aortic balloon pump, and the inotropic support was significantly reduced, but both died of multiple system organ failure. Although no firm conclusions can be drawn from these few case reports, the heparin-coated system used as ECLA appears promising, whereas ECHA seems to imply a poor prognosis in patients who are not candidates for cardiac transplantation.

The release and vascular effects of calcitonin gene-related peptide (CGRP) and endothelin-1 (ET-1) during acute alveolar hypoxia (O2 2%) were examined in isolated blood-perfused rat lungs. In 10 lungs, repeatedly ventilated with hypoxic gas for 5 min, samples from effluent blood were taken during hypoxia and analysed for plasma levels of CGRP-like immunoreactivity (-LI) and ET-1-LI. The plasma levels of ET-1-LI were significantly (p < 0.05) increased in hypoxic lungs (5.5 +/- 0.5 pmol l-1) compared with normoxic controls (3.7 +/- 0.56 pmol l-1). Plasma levels of CGRP-LI were significantly (p < 0.01) lower in hypoxic lungs (43.9 +/- 2.9 pmol l-1) than in normoxic controls (55.5 +/- 4.0 pmol l-1). No significant correlation was seen between perfusate peptide levels and pulmonary artery pressure (Ppa) during ventilation with normoxic or hypoxic gas. Infusion of the CGRP receptor blocker, CGRP, did not influence either the baseline Ppa or the development of the hypoxic pulmonary vasoconstriction response (HPV). In lungs undergoing HPV, 2 nmol l-1 ET-1 added to the perfusate, significantly reduced the hypoxic pressor response by 14 +/- 3% (p < 0.05), while addition of 200 nmol l-1 ET-1 caused no significant changes in HPV. CGRP 2 nmol l-1 caused no significant attenuation of HPV (8.9%), while 200 nmol l-1 CGRP significantly reduced HPV by 16 +/- 5% (p < 0.05). To conclude: acute alveolar hypoxia changes release of CGRP and ET-1 to the perfusate in isolated rat lungs. The results further suggest that CGRP and ET-1 are not involved in the development and regulation of the hypoxic pulmonary vasoconstriction response.

Unlike other vascular beds, lung vessels constrict when exposed to hypoxia. However, a marked difference has been noticed as regards the elicitability of hypoxic pulmonary vasoconstriction (HPV) in vivo as compared to in vitro models, like a preparation of isolated rat lungs; in the latter, HPV cannot be evoked from the onset of perfusion, but might be triggered gradually by repeated hypoxic challenges. The formation of adenosine, a potent dilator of most vascular beds, is enhanced during conditions of hypoxia or ischemia. Our hypothesis therefore was that pulmonary vasoconstriction was initially antagonized by tissue-adenosine accumulating during the circulatory arrest necessary for lung isolation, and then, gradually invigorated along with the elimination of adenosine during periods of perfusion with normally oxygenated blood. In a first series of isolated rat lungs, we studied release of adenosine in connection with the third and the sixth hypoxic challenges. Although the vascular responses were of significantly different size, there was no sign of increased adenosine formation during any of the two provocations, as assessed by release of its more stable metabolites hypoxanthine, xanthine and uric acid. In a series of tissue preparations taken at the height of a fully developed hypoxic pressor response and immediately frozen, we could not find significant changes in tissue level of adenosine, hypoxanthine and inosine as compared to controls that had never been exposed to hypoxic challenges. Further, we found no correlation between the size of pressor responses and concentrations of adenosine and its metabolites, in either blood or in lung tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

The metabolic function of the lungs may be impaired in acute lung injuries. The present work examined the effect of toxic oxygen metabolites (TOM) on the pulmonary clearance of prostaglandin E2 (PGE2). Isolated rat lungs perfused with plasma were exposed to TOM, generated by xanthine oxidase (XO) and hypoxanthine (HX) in the perfusate. Inactivation of PGE2 was determined by superfusion bioassay technique. XO and HX (n = 6) reduced the inactivation of PGE2 from 78 +/- 4% (mean +/- SE) to 61 +/- 3%. This reduction was inhibited by the free radical scavengers superoxide dismutase and catalase, as well as by allopurinol, an inhibitor of XO. Neither hydrostatic lung edema nor perfusion per se decreased the inactivation of PGE2. Lungs pretreated with indomethacin still showed impaired PGE2 inactivation after exposure to XO and HX, indicating that a possible release of PGE2-like substances did not influence our findings. This study indicates that TOM may impair pulmonary metabolic function as shown by reduced inactivation of PGE2.

Toxic oxygen metabolites (TOM) have been suggested to be mediators of permeability edema associated with the adult respiratory distress syndrome (ARDS). Because corticosteroids have possible beneficial effects in ARDS, we have examined the effect of methylprednisolone (MP) on TOM-induced lung edema in isolated, plasma-perfused rat lungs. TOM were generated by adding xanthine oxidase (XO) and hypoxanthine (HX) to the perfusate. Microvascular permeability was assessed by fluid filtration rate (FFR). FFR was determined before and 30 min after administration of XO and HX by measuring the weight increase of the lungs for the last 3 min during a standard 5 min elevation of the outlet pressure. MP was administered in two different ways: 1) Added to the perfusate 5 or 60 min before XO and HX (0.1 and 1 mg ml-1), and 2) given as pretreatment to the rats 12 and 2 hr before preparation of the lungs (40 mg kg -1). XO and HX significantly increased FFR compared to lungs perfused with untreated plasma. Pretreatment with MP significantly attenuated the increase in FFR caused by XO and HX. Addition of MP to the perfusate also inhibited the effect of TOM. This latter protection occurred irrespective of when MP was added before XO and HX. However, when the highest dose of MP was added 5 min before XO and HX, there was a loss of the protective effect. In summary, this study provides evidence that MP may directly prevent microvascular injury induced by TOM in isolated perfused rat lungs. The effect was dependent on the dose of MP applied, but not on when MP was administered prior to exposure to TOM.

Effects of toxic oxygen metabolites (TOM) on the pulmonary vascular bed and airways were studied in isolated, plasma-perfused rat lungs. TOM were generated by xanthine oxidase (XO) (0.1 or 0.25 unit.ml-1) and hypoxanthine (HX) (1 mol.l-1). In vitro measurements by chemiluminescence indicated that the major oxygen metabolite generated by XO and HX was H2O2. Measurements of PO2 in the perfusate as an indicator of O2-consumption suggested that production of TOM by XO and HX was finished within 30 min. XO and HX induced an early dose-dependent bronchoconstriction and a late increase in transpulmonary pressure (Ptp). Pulmonary arterial pressure (Ppa) increased gradually and levelled off within 30 min with low-dose XO, but not with high-dose XO. As judged by weight increase of the lungs, interstitial edema occurred regularly. Allopurinol, an inhibitor of XO, blocked the lung responses caused by XO and HX. Catalase attenuated all lung responses induced by XO and HX, while superoxide dismutase had no effect. The hydroxyl radical scavenger dimethylsulfoxide abolished the increase in Ptp and attenuated the increase in Ppa, but did not consistently protect the lungs from edema development. This study shows that TOM induce vasoconstriction, bronchoconstriction and lung edema in plasma-perfused rat lungs, mainly due to generation of H2O2 and the hydroxyl radical.

Increased pulmonary vascular resistance (PVR) and microvascular hyperpermeability resulting in lung edema and arterial hypoxemia are mainstays in the development of adult respiratory distress syndrome (ARDS). The proposed pathophysiologic mechanisms include activation of complement and polymorphonuclear leukocytes secreting lysosomal enzymes, toxic oxygen metabolites (TOM) and eicosanoids. Platelets and coagulation factors are also involved, and in the most severe cases even monocytes are activated as reflected in release of thromboplastin. The latter may elicit disseminated intravascular coagulation (DIC). Under physiologic conditions lung blood flow is diverted from poorly to better oxygenated areas by way of hypoxic pulmonary vasoconstriction (HPV), thereby counteracting a decrease in arterial oxygenation. Many vasoactive substances have been proposed and again refuted as possible mediators of HPV. In this study we have focused on the following: histamine, catecholamines, arachidonates, calcium, phosphoinositides and TOM as well as endothelium-derived relaxing and constricting factors. Whether HPV is present in ARDS and whether it is advantageous or not seems to depend on the stage and extent of disease. We discuss possible interactions between HPV and ARDS mediators and between HPV and various vasoactive agents tested for therapeutic effects. Out of the abundance of mediators released, prostacyclin, prostaglandin E1, activated complement and platelet activating factor have been shown explicitly to inhibit HPV whereas others are suspected of doing so. In therapeutical use, prostacyclin has proved to reduce PVR and at the same time enhance cardiac output and oxygen delivery. In mild to moderate ARDS, improvement of arterial oxygenation has also been obtained employing almitrine bismesylate, a potentiator of HPV. Experimentally, adenosine effectively reduces increments in PVR and microvascular permeability with modest effects on systemic circulation. However, further investigations are warranted to decide whether adenosine or more specific blockers as, for instance, monoclonal antibodies against tumor necrosis factor should be integrated in ARDS therapy in the future.

It is a generally held opinion that steroids attenuate the activation of phagocytes. However, this statement has its limitations; in rabbit endotoxemia, for instance, steroids enhance the procoagulant activity of monocytes. The present study aimed to investigate the release of toxic oxygen metabolites (TOM) from granulocytes and alveolar macrophages 24 h after endotoxin injection in rabbits, and the effect of concomitant injection of methylprednisolone (MP). Release of TOM was assessed by peak chemiluminescence (CLP). Expression of thromboplastin activity by alveolar macrophages was determined as well, employing a recognized method for assessment of activity. In terms of mean +/- s.e.mean, endotoxin increased granulocyte count from a baseline value of 1.8 +/- 0.2 X 10(6) cells/ml to 3.7 +/- 1 X 10(6) cells/ml, which increased further to 9.8 +/- 2.5 X 10(6) cells/ml following administration of MP. Whereas endotoxin given alone caused no significant change in granulocyte CLP, additional administration of MP increased CLP from 1723 +/- 389 to 16610 +/- 8428 counts. On the other hand, MP attenuated an endotoxin-induced increase in both CLP and thromboplastin activity of alveolar macrophages. Thus, MP appears to have a proinflammatory effect on circulating granulocytes in rabbit endotoxemia, simultaneously depressing the function of stationary macrophages. This may suggest an injurious effect of MP in rabbit endotoxemia.

The exact mechanism whereby hypoxic pulmonary vasoconstriction (HPV) is elicited is still unsettled. We have evaluated a possible role for toxic oxygen metabolites (TOM), employing a set-up of blood-perfused isolated rat lungs. HPV reflected as pulmonary arterial pressor responses, was evoked by alternately challenging the airways with a hypoxic- and a normoxic gas mixture, resulting in gradually increasing responses until a maximum was obtained. In a sequence of responses (mean +/- s.e. mean) increasing from 2.5 +/- 0.2 kPa to 3.2 +/- 0.1 kPa, administration to the perfusate of the inhibitor of xanthine oxidase (XO), allopurinol (AP) reduced the subsequent response to 2.5 +/- 0.2 kPa (P less than 0.001). By contrast, AP did not affect vasoconstriction induced by serotonin or bradykinin. In control experiments responses continued to increase after administration of hypoxanthine (substrate of XO). Neither pretreatment with daily injections of the antioxidant vitamin E for 3 days in advance, nor addition to the perfusate of the scavenger enzymes superoxide dismutase and catalase, or dimethylsulfoxide had any impact on HPV; the subsequent responses rose at the same rate and in the same way as before. Thus, the present study has shown that AP inhibition of XO depresses HPV. This could be due either to reduced production of TOM or to accumulation of purine metabolites. The absence of inhibitory effects of quenchers of TOM refutes a role for these metabolites in the elicitation of HPV. More likely, AP inhibits HPV by interfering with the purine metabolism.

The aim of the present work was to investigate whether prostaglandins (PGs) are synthetized and released from isolated blood-perfused rat and cat lungs secondary to vasoconstriction induced by alveolar hypoxia. The lungs were perfused with autologous blood with constant volume inflow via the pulmonary artery in a recirculating system. They were ventilated with constant volume positive pressure, and acute alveolar hypoxia was induced by ventilation with a gas containing 2% O2. A superfusion bioassay technique was used to measure PG-like activity in the perfusate from the lungs, the blood being re-oxygenated before reaching the assay tissues. The oxygenator prevented the perfusate hypoxia induced by ventilation hypoxia to affect the bioassay tissues. The assay tissues were rat stomach strip, rat colon and chick rectum. They were sensitive to calibrating doses of 0.5--1 ng/ml PGE2 and 1--2 ng/ml PGF2alpha. In another series of experiments PGs of the F-series were measured in lung tissue from normoxic and hypoxic lungs with radioimmunoassay technique. No increase in PG-like activity could be detected in the venous effluent by means of bioassay during hypoxia, nor was the lung tissue content of immunoactive PGF increased by hypoxia. The present findings indicate that alveolar hypoxia does not stimulate PG-synthesis in lungs, refuting that PGs are important mediators of the pulmonary vasoconstrictor response to alveolar hypoxia. It is concluded that PGs play no significant role in producing the pressor response to alveolar hypoxia.

Mortality among patients suffering from meningococcal septicaemia has reached nearly 50% in parts of northern Norway despite intensive care. The activation of complement and blood cells by endotoxin is assumed to be the cause of most of the associated pathophysiological changes. Consequently, it would seem logical to remove such constituents either by combined plasmapheresis and leucapheresis or by blood exchange in patients with a fatal prognosis. Three patients were treated with plasmapheresis and leucapheresis and one with blood exchange. All recovered without sequelae, and no complications or serious problems caused by these procedures were observed. It is concluded that either combined leucapheresis and plasmapheresis or blood exchange is well tolerated and a valuable supplement to conventional intensive care in fulminant meningococcal septicaemia.

Recent investigations have revealed that intravenous anesthetics, including fentanyl, do not reduce the pulmonary vasoconstrictor response to alveolar hypoxia. In contrast, the response is markedly reduced or abolished by inhalation anesthetics. Recent investigations have demonstrated that the route of administration is of importance. Halothane, which inhibits the response when administered via the airways, behaves more like an intravenous anesthetic following administration via the blood stream, provided the alveolar concentration has been kept low (Bjertnaes et al. 1977). It was therefore a distinct possibility that the lack of any damping effect of fentanyl on the response could be due to the route of administration rather than to a different pharmacological property. We have tested this hypothesis by introducing fentanyl in nebulized form via the airways in one group of isolated rat lungs, and via the blood stream in another group. We found, however, no effect of fentanyl on the pulmonary vasoconstrictor response to hypoxia, regardless of the route of administration. Plasma concentrations of fentanyl were determined by radioimmunoassay and compared with those encountered in anesthetic practice.

The cardiovascular adjustments to face immersion and apnea (FIA) in human beings during steady-state muscle exercise (163 and 98 watt) have been investigated. Using a triple lumen flow directed catheter inserted into the pulmonary artery we were able to measure cardiac output (CO) by thermodilution technique, pulmonary arterial pressure (PPA) right atrial pressure (PRA) and left ventricular filling pressure (PAD). Phasic arterial blood pressure (BP) was measured via a cannula in the radial artery. A 12 lead ECG was recorded continuously. FIA caused an immediate rise in BP (median 61%), the highest level being 25.33 kPa. CO during the last half of FIA was reduced by 49% (range 46-59, n = 7) systemic vascular resistance increased by median 200% (range 111-280). Myocardial oxygen demand determined by the heart rate pressure double product fell from median 33.6 to 16.8 (163 W) and 28.5 to 19.1 (98 W) given as beats/min X kPa X 10(2). Mean reduction was by 42%. PPA and PRA immediately increased and remained constant until a further pronounced increase was seen towards the end of FIA when pulmonary vascular resistance (PVR) went up. PACO2 and PAO2 at the end of 30 sec FIA (163 W) was 10.0 and 5.6 kPa, respectively, values which expectedly would cause pulmonary vasoconstriction. Our findings demonstrate that humans are able to make principally the same cardiovascular adjustments to diving as aquatic mammals, although the response patterns are slower and less efficient.(ABSTRACT TRUNCATED AT 250 WORDS)

The main purpose of the present work was to determine whether prostaglandins (PGs) synthetised in the lungs mediate the vasoconstrictor response to acute alveolar hypoxia. Isolated and ventilated lungs of rats were perfused at 37 degrees C with homologous blood at constant-volume, pulsatile inflow, and pressor responses to 3 min periods of standardized ventilation hypoxia recorded. Indomethacin, sodium meclofenamate and acetylsalicylic acid (all 100 mug/ml), which are potent inhibitors of PG biosynthesis, did not reduce the hypoxic vasoconstrictor response. Sometimes they even enhanced this response. We conclude that PGs do not mediate the hypoxia-induced vasoconstriction. We suggest that vasodilatory PGs might act to reduce and modify pulmonary arterial hypertension due to hypoxia.

Isolated rat lungs were perfused with homologous blood at constant volume inflow. The effect of ventilation hypoxia on pulmonary vascular resistance, preparation weight and reservoir volume (vascular capacitance) were studied. In some experiments also wet/dry weight ratio of the preparation was estimated (extravascular water content). There was no difference in this last parameter between hypoxic and normoxic lungs, thus alveolar hypoxia had no effect on tissue water content as previously described in intact rats. With forward perfusion small and transient changes in either direction were seen in preparation weight and reservoir volume, even though inflow pressure exceeded 5 kPa during alveolar hypoxia. With backward perfusion marked weight increases were seen, and if inflow pressure in this situation was above 3.5 kPa, the weight change was irreversible, thus indicating outward fluid filtration. It is concluded that the vessels responding to alveolar hypoxia are located on the arterial side of the pulmonary vasculature.

The pure and selective serotonin blocking agent ketanserin (5-HT2 receptor blocker) was used to evaluate a possible role for serotonin as a mediator of the pulmonary vasoconstrictor response to alveolar hypoxia. Isolated and ventilated lungs (FiO2 = 0.21) from rats were perfused at 310 degrees (K) with homologous blood at constant volume inflow, and pressor responses to standardized periods of ventilation hypoxia (FIO2 = 0.02) were recorded. Pressor responses to pulmonary arterial bolus-injections of serotonin were tested both before and after administration of ketanserin for comparison with the responses to hypoxia. We found that ketanserin in doses adequate to block the response to serotonin, had no effect on the pulmonary vasoconstrictor response to hypoxia.

Reactive oxygen intermediates such as free radicals have been proposed to mediate lung injury. The present work examined whether or not enzymatically generated oxygen metabolites altered serotonin clearance. Isolated, plasma-perfused rat lungs were exposed to xanthine oxidase (XO) and hypoxanthine (HX). Pulmonary arterial pressure (Ppa) and lung weight were recorded. Fulminant edema was defined as a spontaneous weight increase exceeding 500 mg. Inactivation of serotonin was determined by superfusion bioassay. XO and HX reduced serotonin inactivation from 74 +/- 3% (mean +/- SEM) to 62 +/- 2%. This reduction was inhibited by the scavenger enzymes superoxide dismutase (SOD) and catalase and by allopurinol, an inhibitor of XO. Hydrostatic edema and perfusion per se did not decrease the pulmonary clearance of serotonin. XO and HX did not significantly alter Ppa. Fulminant edema developed in four of six lungs after exposure to XO and HX compared with none in the other groups. It was concluded that reactive oxygen intermediates inhibited serotonin inactivation in isolated rat lungs.

We have compared the pulmonary vascular responses to a standardized hypoxic vasoconstrictor stimulus (FIO2 = 0.02) obtained during 1) constant volume inflow, with pulmonary arterial pressure as the dependent variable, and 2) constant inflow pressure, with flow as the dependent variable. Isolated rat lungs were perfused at different baseline transvascular pressures. The experimental arrangement allowed changes between the two types of perfusion. Hypoxia at constant pressure perfusion gave a higher percentage rise in pulmonary vascular resistance (PVR) at all pressure levels. This advantage was however, more than offset by the finding that a) vascular closure (total or partial) often occurred, particularly below arterial pressure of 3 kPa, making detection of graded responses impossible, and b) the control situation was rarely regained. Responses obtained during constant flow were less reduced by elevations in baseline transvascular pressure, and the control situtaion was rapidly and completely regained. The observation that hypoxic vascular closure may occur in the pulmonary vascular bed supports the hypothesis that high altitude edema is caused by precapillary occlusion of a major part of the vascular bed, thereby subjecting still perfused regions to very high pressure and flow.

We have investigated the relative contribution of mechanical obstruction and hypoxia-induced vasoconstriction to the increased pulmonary vascular resistance (PVR) in atelectatic lungs. For this purpose we have utilized the previous observation that inhalation anesthetics inhibit the vasoconstrictor response to pulmonary hypoxia. The effects of halothane, enflurane and ether on PVR in atelectatic lungs have been explored. Two pairs of isolated rat lungs were perfused in series at constant flow. One of the preparations was made atelectatic by airway occlusion subsequent to ventilation with a high PO2 gas (95% O2). Ventilation of the other preparation continued with hypoxic gas (2% O2), resulting in a gradual increase in PVR in both preparations. When maximum PVR was reached, one of the above inhalation anesthetics was administered to the atelectatic lungs via the ventilated lung preparation. This caused a dose-dependent, reversible reduction of PVR. The same effect was observed when pulmonary arterial PO2 was increased (greater than 66.5 kPa). Histological examination revealed that two out of four preparations were completely atelectatic 1 h after airway occlusion, whereas atelectasis was nearly complete in the other two. In two groups, airways were occluded for 1 h. In the first group PVR increased to 163% (median) above baseline level, as found during ventilation with high PO2. High arterial PO2 reduced PVR in the atelectatic lungs to 50% (median) above baseline, whereas papaverine induced a further PVR reduction, to 7% (median) above baseline. In the other group, papaverine was given before airway occlusion, and PVR increased to 10% (median) above baseline. Comparison of the two groups shows that mechanical obstruction accounts for about 6% (10/163) of the overall rise in PVR during atelectasis.

Toxic oxygen metabolites (TOM) released from stimulated phagocytes and lung tissue have been shown to injure the pulmonary microcirculation. In the present study we evaluated microvascular injury caused by TOM in rat lungs perfused with plasma. The injury, as indicated by an increase in vascular permeability, was assessed by determining the fluid filtration rate (FFR) after paralysing the pulmonary vascular bed with papaverine (0.1 mg/ml). TOM were generated by adding xanthine oxidase (XO) (0.05-0.125 U/ml) and hypoxanthine (HX) (1 mmol/l) to the perfusate. FFR was measured before, 30 and 60 min after addition of XO and HX. The following interventions were done: 1. the H2O2-scavenger catalase, 2. substitution of the perfusate after 30 min, 3. BW 755 C, a combined lipoxygenase and cyclooxygenase inhibitor, and 4. indomethacin, a cyclooxygenase inhibitor. Addition of XO and HX caused FFR to increase from 14 +/- 4 mg/min (mean +/- s.e. mean) at the onset to 56 +/- 7 mg/min and 86 +/- 10 mg/min after 30 and 60 min, respectively. Replacing the perfusate with fresh plasma after 30 min caused a significant reduction in FFR at 60 min, from 86 +/- 11 mg/min to 58 +/- 10 mg/min. Catalase prevented the increase in FFR. Indomethacin and BW 755 C had no effect on the increase in FFR. We conclude that TOM induced a partly reversible increase in microvascular permeability of isolated rat lungs. From previous studies, the activity of XO was expected to cease after 30 min. Therefore it is suggested that secondary products of TOM propagate the lung injury. The increase in permeability was not mediated by arachidonic acid metabolites.

Effects of PEEP on cardiac function, myocardial blood flow (MBF) and myocardial oxygen consumption (mVO2) were studied in eight mongrel dogs anesthetized with pentobarbital. Myocardial oxygen demand was increased by isoproterenol infusion or atrial pacing, or decreased by beta-receptor blockade. PEEP was set to 15 cm H2O in all groups. The greatest reduction in cardiac output due to PEEP was seen during isoproterenol infusion (44%), and the smallest during beta-receptor blockade (18%). This is attributed to increased sensitivity to the reduced left ventricular (LV) preload induced by PEEP, when cardiac inotropy is augmented by isoproterenol, compared to normal and reduced cardiac inotropy. PEEP decreased MBF similarly and significantly in all groups. However, myocardial oxygen extraction did not increase, and reduction in MBF caused by PEEP was closely related to concomitant reduction in mVO2. A significant correlation was also observed between reductions in LV work and reduction in mVO2 when PEEP was applied in all groups. We conclude that the reduced MBF observed with use of PEEP was probably due to reduced myocardial oxygen demand.