Intravenous anti-P. aeruginosa IgY-antibodies do not decrease pulmonary bacterial concentrations in a porcine model of ventilator-associated pneumonia.

Ventilator associated pneumonia (VAP) caused by P. aeruginosa is a cause of morbidity and mortality in critically ill patients. The spread of pathogens with anti-microbial resistance mandates the investigation of novel therapies. Specific polyclonal anti-P. aeruginosa IgY-antibodies (Pa-IgY) might be effective for VAP caused by P. aeruginosa. The objective of this study was to investigate if intravenous Pa-IgY decreases the lower airway concentration of P. aeruginosa in VAP. We used a double blind randomized placebo controlled porcine model of VAP caused by P. aeruginosa. Eighteen pigs were randomized to either receive intravenous Pa-IgY or placebo. Repeated registration of physiological parameters and sampling was performed for 27 h. Concentration of P. aeruginosa in BAL-cultures was similar in both groups with 104.97 ± 102.09 CFU/mL in the intervention group vs 104.37 ± 102.62 CFU/mL in the control group at the end of the experiment. The intervention group had higher heart rate, cardiac index, oxygen delivery and arterial oxygen tension/fraction of inspired oxygen-ratio, but lower plasma lactate and blood hemoglobin levels than the control group. In summary, in an anesthetized and mechanically ventilated porcine model of VAP, Pa-IgY at the dose used did not decrease concentrations of P. aeruginosa in the lower airways.

The effects of isoflurane anesthesia and mechanical ventilation on renal function during endotoxemia.

BACKGROUND: Isoflurane is a common anesthetic agent used in human surgery and in animal models of sepsis. It has been suggested to have beneficial anti-inflammatory properties and to protect kidney function. Here, we investigated the effect of isoflurane on the development of kidney injury and dysfunction during 48-h endotoxemia in sheep. METHODS: Before the experiments, the sheep (n=16) were surgically equipped with transit-time flowprobes around the renal, femoral and superior mesenteric artery. The animals were randomized to either be anesthetized with isoflurane and mechanically ventilated or to remain conscious while they received intravenous Escherichia coli lipopolysaccharide (LPS) for 48 h (25 ng/kg/min). In two animals in each group, the LPS was excluded to investigate any effect of isoflurane per se over time. RESULTS: Endotoxemia caused cardiovascular changes typical for hyperdynamic sepsis and, although renal hyperemia occurred, impaired renal function in both groups. Compared with conscious animals, isoflurane significantly (P<0.05) reduced urine output, renal creatinine clearance, fractional sodium excretion and renal blood flow during endotoxemia. Furthermore, the plasma concentrations of urea and creatinine increased more in the anesthetized animals. Isoflurane anesthesia also enhanced neutrophil activity and accumulation in the kidney during endotoxemia. N-acetyl-ß-D-glucosaminidase was significantly increased, with no inter-group difference as an indication of tubular injury. CONCLUSIONS: The results of the current study suggest that isoflurane anesthesia (minimum alveolar concentration 1.0) with mechanical ventilation aggravates renal dysfunction during 48 h of endotoxemia and does not significantly reduce the inflammatory response or signs of tubular damage.

Endothelin-mediated gut microcirculatory dysfunction during porcine endotoxaemia.

BACKGROUND: The potent vasoconstrictor endothelin-1 has been implicated in the pathogenesis of the microcirculatory dysfunction seen in sepsis. The mixed endothelin receptor antagonist tezosentan and the selective endothelin A-receptor antagonist TBC3711 were used to investigate the importance of the different endothelin receptors in modulating splanchnic regional blood flow and microvascular blood flow in endotoxaemia. METHODS: Eighteen anaesthetized pigs were i.v. infused with endotoxin (Escherichia coli lipopolysaccharide, serotype 0111:b4) for 300 min. After 120 min, six animals received tezosentan and six animals received TBC3711. Six animals served as endotoxin-treated controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and ileum. Superior mesenteric artery flow (SMA(FI)) and portal vein flow (PV(FI)) were measured with ultrasonic flow probes, and air tonometry was used to measure Pco2 in the ileal mucosa. RESULTS: TBC3711 did not improve splanchnic regional blood flow or splanchnic microvascular blood flow compared with endotoxin-treated controls. Tezosentan increased PV(FI) (P<0.05), but SMA(FI) was not improved compared with the other groups. In the tezosentan group, microvascular blood flow in the ileal mucosa (MCQ(muc)) improved and mucosal-arterial Pco2 gap decreased (P<0.05 for both) compared with endotoxin-treated controls and the TBC3711 group. CONCLUSIONS: Tezosentan improved MCQ(muc) without any concomitant increase in SMA(FI), implying a direct positive effect on the microcirculation. TBC3711 was not effective in improving regional splanchnic blood flow or splanchnic microvascular blood flow. Dual endothelin receptor antagonism was necessary to improve MCQ(muc), indicating a role for the endothelin B-receptor in mediating the microcirculatory failure in the ileal mucosa.

Sequential Organ Failure Assessment predicts the outcome of SCT recipients admitted to intensive care unit.

We analyzed all patients undergoing allogeneic stem cell transplantation (ASCT) and transferred to the intensive care unit (ICU) from January 1995 to December 2005. During this period, 661 patients underwent ASCT at our center. A total of 91 patients were admitted to the ICU. Median time from ASCT to ICU admission was 69 days (-24 to 1572) and median stay at the ICU was 4 (1-60) days. The survival after transfer to the ICU at day 100 and at 1 year was 22 and 16%, respectively. Median Sequential Organ Failure Assessment (SOFA) score was 10 (1-17). Patients with SOFA score <8 (n=18) had a 44% survival compared with 17% with SOFA score 8-11 (n=30) and no survival with SOFA score >11 (n=20) (P=0.0002). None of the 14 retransplanted patients survived compared with 31% among patients after first ASCT (P=0.006). Patients receiving TBI had a lower survival compared with patients treated with chemotherapy only (14 vs 45%, P=0.02). Patients needing vasopressor support had a worse survival, 15 vs 41%, compared with patients without vasopressor treatment (P=0.01). In multivariate analysis of death, SOFA score was the only significant factor (P<0.001). In conclusion, SOFA score predicted prognosis in ASCT patients treated at the ICU.

The endothelin receptor antagonist tezosentan improves renal microcirculation in a porcine model of endotoxemic shock.

BACKGROUND: Impaired renal microcirculation has been suggested as a factor contributing to the development of renal dysfunction in sepsis. This study was conducted to elucidate the role of endothelin-1 (ET-1)in mediating reductions in renal microcirculatory blood flow during endotoxemic shock. METHODS: A prospective, randomized, and experimental study was performed with 16 anesthetized and mechanically ventilated pigs. After 2 h of lipopolysaccaride-induced endotoxemia, eight animals received a bolus dose of the dual endothelin receptor antagonist tezosentan (1 mg/kg), followed by a continuous infusion of 1 mg/kg/h throughout the experiment. Eight animals served as the control group. Renal microcirculation, total renal blood flow, plasma creatinine levels, cardiac index, and mean arterial pressure were measured. Plasma samples were collected for the measurement of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), ET-1, angiotensin II, and aldosterone. RESULTS: Endotoxin infusion resulted in a state of circulatory shock with impairment of renal microcirculation. An increase in the plasma levels of TNF-alpha, IL-6, IL-10, ET-1, angiotensin II, and aldosterone was also observed. Tezosentan attenuated the decrease in renal microcirculation and renal blood flow, and attenuated the increase in plasma creatinine. Treatment with tezosentan did not significantly affect the plasma cytokine, angiotensin II, or aldosterone response to endotoxemia. CONCLUSION: These results indicate that treatment with the dual endothelin receptor tezosentan in endotoxemic shock attenuates the reduction of renal microcirculation and total renal blood flow independently of plasma changes in the renin-angiotensin-aldosterone system or early plasma cytokine response.

Monitoring of fluid absorption with nitrous oxide during transurethral resection of the prostate.

BACKGROUND: The fluid absorption that occurs during transurethral resection of the prostate (TURP) can be indicated and quantified by the ethanol method. Recently, nitrous oxide (N(2)O) was tested in animals and volunteers and seemed to be more accurate and safe. The present study compared these two methods in surgical patients. METHODS: Eighty-six TURPs were performed at two hospitals using an irrigating fluid that contained 3% mannitol, 1% ethanol and 0.004% N(2)O (40 ml/l). The ethanol concentration was measured by end-expiratory tests every 10 min. The N(2)O concentration was measured by a flared nasal cannula every second. Fluid absorption was calculated based on a regression equation (ethanol method) from the area under the curve based on the samples where CO(2) >median (N(2)O method). RESULTS: Thirteen patients (15%) absorbed >300 ml of fluid as indicated by the ethanol method. The median volume was 707 ml (range 367-1422). Ethanol yielded higher figures for fluid absorption up to 700-800 ml, whereafter the N(2)O method indicated that the absorption was larger. Over the entire range, the mean difference between the two methods at the end of any 10-min period of TURP was only +45 ml, although the 95% limits of agreement were quite separated (-479 to +569 ml). CONCLUSIONS: The N(2)O method does not require forced breath sampling and was successfully apply clinically. However, there was a dose-dependent difference in result between the ethanol and N(2)O methods, which markedly separated the limits of agreement for a wider range of fluid absorption events.

Effects of the dual endothelin receptor antagonist tezosentan and hypertonic saline/dextran on porcine endotoxin shock.

AIM: To evaluate the haemodynamic effects of the dual endothelin receptor antagonist tezosentan, both alone and combined with hypertonic saline/dextran (HSD), on porcine endotoxin shock, with focus on cardiopulmonary circulation. The effects on gas exchange and short-term survival were also studied. METHODS: A prospective, randomized experimental study was carried out. Thirty-two anaesthetized pigs underwent pulmonary and carotid artery catheterization. Following haemodynamic stabilization and baseline measurements, endotoxaemia was induced by an Escherichia coli-endotoxin infusion over 180 min and the animals observed another 120 min. After 60 min of endotoxaemia, directly before intervention, animals were randomized into four groups: a tezosentan group, an HSD group, a combined tezosentan/HSD group and a control group. The consequent haemodynamic effects and blood gas results were recorded. RESULTS: The endotoxin infusion reduced mean arterial blood pressure from 111 +/- 14 (mean +/- standard deviation) to 77 +/- 27 mmHg and cardiac index from 126.9 +/- 27.2 to 109.3 +/- 22.6 mL min(-1) kg(-1) within 90 min in the control group. In addition, endotoxin simultaneously increased mean pulmonary artery pressure from 24 +/- 17 to 38 +/- 19 mmHg and reduced arterial oxygenation from 18.9 +/- 2.0 to 12.2 +/- 5.3 kPa. Tezosentan, alone and combined with HSD, reversed the pulmonary hypertension and prevented the reduction in cardiac index and arterial oxygenation, resulting in reduced metabolic acidosis. Additionally, in the tezosentan group, the mean arterial blood pressure was reduced to the same level as in controls, an effect not prevented by the addition of HSD. It was found that all three interventions improved survival rates. CONCLUSION: Tezosentan, alone and in combination with HSD, improved cardiac index and arterial oxygenation. The addition of HSD to tezosentan treatment did not improve the endotoxin-induced hypotension, but beneficial effects on microcirculation and systemic oxygenation were seen despite low perfusion pressure, as indicated by increased SvO(2) and reduced metabolic acidosis.

Haemodynamic and metabolic effects of resuscitation with Ringer's ethyl pyruvate in the acute phase of porcine endotoxaemic shock.

BACKGROUND: Ethyl pyruvate has been shown to possess anti-inflammatory and free radical scavenging properties. However, the haemodynamic effects of ethyl pyruvate have not been studied in detail. We investigated the systemic, regional and microcirculatory haemodynamic and metabolic effects of resuscitation with Ringer's ethyl pyruvate solution (REPS) vs. Ringer's acetate (RA) in an acute model of porcine endotoxaemic shock. METHODS: Fourteen anaesthetized pigs received an infusion of endotoxin that was increased stepwise over 30 min to a rate of 2.5 microg/kg/h. After 60 min of endotoxaemia, the animals were resuscitated with either ethyl pyruvate 40 mg/kg, given as REPS, or the equivalent volume of RA, administered over 10 min. Thereafter, an infusion of either ethyl pyruvate 40 mg/kg/h, given as REPS, or the equivalent volume of RA, was started, and the maintenance fluid was reduced so that the total amount of fluid given was kept constant. The experiment was terminated after 300 min of endotoxaemia. RESULTS: Endotoxin infusion led to a hypodynamic state that was reversed by fluid resuscitation after 60 min. Progressive deterioration ensued and, after 300 min, all animals were again hypodynamic. No differences in response to treatment were found between the groups with regard to systemic haemodynamics, renal artery or portal vein flow or microcirculatory flow in the liver, kidney, ileal serosa or mucosa. Metabolic acidosis and increased arterial blood lactate developed in both groups, but, in the REPS group, the base excess was significantly lower from 150 min and the anion gap was significantly higher at 150 and 210 min. CONCLUSION: We could not demonstrate any difference between REPS and RA for resuscitation in this model of acute porcine endotoxaemic shock.

Beneficial effects of hypertonic saline/dextran on early survival in porcine endotoxin shock.

BACKGROUND: Hypertonic saline/dextran (HSD) has been shown to have beneficial effects in haemorrhagic shock. These effects, with improved haemodynamics and organ perfusion, would in theory also be of benefit in septic shock. However, this is less studied. We have therefore further evaluated the effect of additional treatment with HSD in a porcine endotoxin shock model. METHODS: Sixteen anaesthetized pigs were used. A continuous infusion of endotoxin (LPS EC) was increased stepwise during 30 min to a rate of 5 microg/kg/h. The infusion was discontinued after 3 h and the animals were observed for another 2 h. The animals received continuous basal fluid resuscitation with isotonic Ringer's glucose 2.5% at a rate of 20 ml/kg/h throughout the experiment. After 1 h of endotoxin infusion, the animals were randomized to additional treatment with HSD, 4 ml/kg over 5 min, or the same volume of isotonic saline. Every 30 min, haemodynamics and mixed venous saturation (SvO2) were measured via a pulmonary artery catheter. Regional blood flow rates were measured continuously by perivascular ultrasonic flow probes. The metabolic response was measured by arterial blood gas analysis. RESULTS: The endotoxin put all animals into a progressive hypodynamic circulatory shock during the experiment. Treatment with HSD improved survival rate to 8/8 compared with controls 3/8. There was a transient circulatory recovery with improved central and regional haemodynamics, accompanied by stabilized metabolic response. CONCLUSION: Treatment with additional HSD improves survival in an early phase of endotoxin shock. Generally improved haemodynamics and oxygenation of peripheral tissues are suggested as possible mechanisms.

Early resuscitation with hypertonic saline/dextran in uncontrolled intra-abdominal bleeding in swine combined with a soft tissue gunshot wound.

The effects of hypertonic saline/dextran (HSD) on hemodynamics and on rebleeding were studied during an uncontrolled intra-abdominal hemorrhage combined with a high-energy gunshot wound (GSW) in the hind limb of anesthetized swine. The GSW had instant effects on the central hemodynamics, which were aggravated when the internal hemorrhage was induced. Compared with baseline, cardiac output decreased to about 42%, mean arterial pressure decreased to 52 +/- 4%, and mean flow rates in the splanchnic region, in the upper aorta, and in the kidney decreased to 51 to 15%. The injection of HSD at 10 minutes was followed by a prompt increase in blood flow rates, but rebleeding occurred in five of eight animals, although only two died. In conclusion, GSW induced instant changes in hemodynamics at distance from the injury. When HSD treatment was given in a bolus injection, rebleeding occurred in five of eight animals, although the second hemorrhage became fatal in only one animal.

Acute hemodynamic effects of induced hypothermia in hemorrhagic shock: an experimental study in the pig.

Hypothermia (HT) is used in certain surgical procedures to reduce metabolism and protect the brain, but in trauma victims accidental HT is considered harmful. Recent animal studies indicate that HT has protective effects in hemorrhagic shock. The aim of the present study was to examine how induced HT modifies the hemodynamic pattern in hemorrhagic shock. Twenty pigs with a body weight of between 17 and 24 kg (mean 20.8) were anesthetized, 50% of their blood volume was withdrawn, and hypothermia (30 degrees C) was induced in half of them (HT group) while the others served as controls. Central hemodynamics was monitored during 4 h via an arterial line and a pulmonary artery catheter. Blood samples were obtained for measurement of leukocyte and platelet counts. Three of the control pigs died while all the animals in the HT group survived the experiment. The hemorrhage resulted in a marked increase in heart rate and a drop in cardiac output and mean arterial pressure. HT slowed the heart rate and induced a further reduction of cardiac output, which parallelled the depression of the core temperature, while the stroke volume did not change in any of the groups. A significant decrease in mean arterial pressure and the leukocyte count became apparent 2 h after the induction of HT. HT aggravated the hypokinetic situation resulting from hemorrhagic shock but without increasing the mortality.

Physiological changes in pigs exposed to a blast wave from a detonating high-explosive charge.

The aim of this project was to study respiration, circulation, and brain activity in pigs during and after a blast wave exposure. Ten anesthetized pigs were used. Seven were exposed to blast and three were controls. Physiological parameters of respiration and circulation as well as cortical activity were followed from 30 minutes before until 120 minutes after the real or simulated blast. There were no significant changes in heart rhythm, cardiac output, arterial oxygen or carbon dioxide tension, blood pH, or mixed venous saturation during the experiment. The blast exposure caused intestinal injuries but no lung damage. A transient flattening of the electroencephalogram was seen immediately after the blast in four experimental animals, in contrast to the unchanged baseline electroencephalogram of the control animals. This momentary depression of cortical activity accompanied by short-lasting apnea indicates a blast wave-induced effect on the brainstem or higher controlling center.

Short-term crystalloid fluid resuscitation in uncontrolled intra-abdominal bleeding in swine.

INTRODUCTION: Fluid therapy in uncontrolled bleeding is controversial. In a previously used experimental animal model of aortic injury, the outcome often was impaired by re-bleeding that began at least 20 minutes after crystalloid fluid resuscitation was initiated. Therefore, it was hypothesized that re-bleeding might be avoided if volume loading is carried out for 20 minutes and then discontinued. METHODS: Ten minutes after a 5 mm laceration was produced in the infra-renal aorta on eight anesthetized pigs, they received a 20-minute intravenous infusion of Ringer's solution in the ratio of 1:1 to the expected blood loss. Hemodynamics were studied for 120 minutes using arterial and pulmonary artery catheters and blood flow probes placed proximal and distal to the aortic lesion and around the left renal artery and portal vein. RESULTS: The bleeding stopped between three and four minutes after the onset of bleeding. The blood flow rate dropped to 38% (mean) of baseline in the splanchnic region, to 31% in the upper aorta, and to 13% in the kidney. The flow rates and the oxygen consumption increased transiently during fluid resuscitation, but never reached baseline levels. Re-bleeding amounted to about 15% of the initial bleeding and occurred in only three of the animals. Four of the pigs died of shock within 90 minutes (range 47-85 minutes) after the aortic injury. CONCLUSION: Short-term crystalloid fluid therapy in uncontrolled aortic hemorrhage transiently improved the hemodynamic status and the oxygen consumption following the initial bleeding. Furthermore, the infusion did not cause re-bleeding of more than 100 ml, which occurred in previously conducted experiments when the infusion was continued for more than 20 minutes.

Central and regional hemodynamics during uncontrolled bleeding using hypertonic saline dextran for resuscitation.

The effects of hypertonic (7.5%) saline/6% dextran 70 (HSD) on central and regional hemodynamics were studied during uncontrolled intra-abdominal bleeding in 16 anesthetized pigs. Ultrasonic flow probes were placed proximally and distally to an aortic injury to indicate the incidence and extent of rebleeding after injecting 4 mL kg(-1) (N = 8) and 2.65 mL kg(-1) (N = 8) of HSD 10 min after the vascular injury was induced. The initial aortic bleeding reduced the blood flow rates to 71% of baseline in the skin, 53% in the splanchnic region, 42% in the upper aorta, and 15% in the kidney. Cardiac output dropped to 46% and the mean arterial pressure to 57% of baseline. The injection of HSD was followed by a prompt increase in all blood flow rates, but rebleeding started within 2 min in 13 of the pigs (81%). A second period of rebleeding occurred in six of them. The rebleeding averaged 300 mL, which is 62% of the blood lost when the aortic injury was induced. There was no significant difference between the treatment groups with respect to these blood losses or to the oxygen consumption, which was not restored by HSD. Five animals in each treatment group died after about 70 min, while the remaining six pigs (38%) survived the 120 min study period. These results suggest that HSD in the recommended dose, and even two-thirds thereof, promotes rebleeding when given shortly after a low energy intra-abdominal aortic injury. The fluid seems to have no beneficial effect on this type of uncontrolled hemorrhage.

Acute metabolic and endocrine effects of induced hypothermia in hemorrhagic shock: an experimental study in the pig.

BACKGROUND: Hypothermia is considered harmful in trauma patients. In surgery, hypothermia is occasionally used to reduce metabolism and protect the brain. Recent studies in animals have also shown protective effects of hypothermia in hemorrhagic shock. The aim of this study was to evaluate the metabolic and endocrine effects of induced hypothermia in hemorrhagic shock. METHODS: Half of the individually calculated blood volume was removed from 17 anesthetized piglets. They were then randomized to normothermia or hypothermia and followed for 4 hours after hemorrhage. RESULTS: In the hypothermic pigs, arterial PO2 increased from 10.3 +/- 0.7 to 16.4 +/- 0.9 kPa, but it remained unchanged in the normothermic group. The serum levels of potassium increased from 3.9 +/- 0.2 to 5.0 +/- 0.2 mmol/L in the normothermic group. In the hypothermic pigs, the potassium levels temporarily decreased from 3.8 +/- 0.1 to 3.0 +/- 0.1 mmol/L but then returned to baseline levels. The levels of serum catecholamines surged in both groups during hemorrhage. They remained elevated in normothermic pigs but declined in the hypothermic group. CONCLUSION: In porcine hemorrhagic shock, induced hypothermia increases arterial oxygen tension and stabilizes serum levels of potassium and catecholamines.

Vasodilation and glomerular binding of adrenomedullin in rabbit kidney are not CGRP receptor mediated.

The polypeptide adrenomedullin (ADM) was infused systemically to conscious rabbits to elucidate its actions on overall circulation and especially the renovascular bed and the formation and/or release of hormones important for body fluid homeostasis, including adrenocortical steroids. ADM lowered mean arterial pressure from 71.5 +/- 3.2 to 64.7 +/- 3.2 mmHg only at the highest dose of 25 pmol.min-1.kg-1 infused intravenously for 20 min and concomitantly induced tachycardia, possibly due to both baroreflex activation and direct cardiostimulatory effects. Renal blood flow (RBF) determined in rabbits chronically equipped with a perivascular ultrasonic flow probe increased from 55.4 +/- 2.1 to 67.4 +/- 2.7 and from 58.2 +/- 3.5 to 75.2 +/- 6.0 ml/min at ADM infusions of 5 and 25 pmol.min-1.kg-1, respectively. The elevation in RBF persisted even in the presence of the calcitonin gene-related peptide (CGRP1 receptor antagonist CGRP-(8-37). Of all osmoregulatory hormones tested, only corticosterone (Cort) plasma concentration increased in response to the highest ADM dose from 17.6 +/- 3.1 to 38.9 +/- 6.2 ng/ml, probably due to haroreflex activation. Subdepressor doses of ADM, however, caused a mild reduction in circulating Cort. Expression of functional high-affinity binding sites specific for ADM in vitro could be demonstrated for the renal artery and outer cortical glomeruli using 125I-labeled rat ADM as radioligand and determination of cellular adenosine 3',5'-cyclic monophosphate (cAMP) formation within the glomeruli. The ineffectiveness of CGRP-(8-37) to displace radiolabeled ADM from its binding sites, to inhibit ADM-induced glomerular cAMP formation, and to prevent ADM-induced renal vasodilation supports the hypothesis of ADM altering renal hemodynamics by interacting with ADM- and not CGRP-specific membrane receptors.

Effects of rapid colloid volume expansion on pulmonary microvascular pressure and lung water in the conscious sheep.

Increased pulmonary microvascular pressure (Pmv), in combination with other factors, may cause pulmonary interstitial oedema. Whether increased Pmv alone induces alveolar oedema is questionable. In the present study we used the heavy water-indocyanine green dilution method to measure lung water during a rapid intravascular volume expansion in the sheep. Eight conscious sheep were given two 10-min intravenous infusions of either 50 ml/kg (N = 2) or 35 ml/kg (N = 6) of dextran 60 with an interval of 10 min between them. At a Pmv of 40 mmHg, respiratory distress was observed in sheep no. 2 which had been given a total amount of 100 ml/kg of dextran; this was immediately followed by a lethal pulmonary haemorrhage. Mean Pmv in the remaining seven sheep increased to 31 (7) mmHg in response to the volume expansion without causing any respiratory distress or increase in lung water. These results show that in conscious sheep the lungs have strong protective mechanisms against hydrostatic oedema. They do not support the hypothesis that increased Pmv alone induces alveolar oedema, but suggest that an increase in Pmv to 40 mmHg may cause stress failure of the pulmonary vasculature.

Nitric oxide increases cutaneous and respiratory heat dissipation in conscious rabbits.

The influence of systemic nitric oxide (NO) donor infusion and NO synthase inhibition on major thermoregulatory mechanisms was investigated under thermoneutral conditions (24 degrees C) in the conscious rabbit. Both low (25 nmol.min-1.kg-1) and high-dose (75 nmol.min-1.kg-1) infusion of the NO donors 3-morpholinosydnonimine-hydrochloride and S-nitroso-N-acetylpenicillamine augmented respiratory heat dissipation due to raised respiratory frequency (RF) and evaporative water loss (REWL). At the higher dose of NO donor, RF and REWL increased (from 107 +/- 16 to 156 +/- 19 breaths/min and from 7.12 +/- 0.97 to 11.29 +/- 1.29 mg.min-1.kg-1; P < 0.05), and, combined with a moderate rise in cutaneous heat dissipation (ear skin temperature increased from 29.03 +/- 1.76 to 33.29 +/- 2.71 degrees C; P < 0.05), deep body temperature was slightly reduced (-0.1 degrees C, P > 0.05) without a change in metabolic heat production. In contrast, blockade of endogenous NO synthesis induced a sustained rise in body temperature (0.2 degrees C, P < 0.05), concomitant with a reduction in both RF and REWL (from 131 +/- 11 to 94 +/- 12 breaths/min and from 10.86 +/- 1.14 to 8.70 +/- 0.88 mg.min-1.kg-1, P < 0.05), whereas metabolic heat production decreased slightly and cutaneous heat dissipation was minimally altered. The data indicate that, under thermoneutral conditions, systemically applied NO primarily influences body temperature in the conscious rabbit by modulating the rate of respiratory heat dissipation, whereas the roles of cutaneous heat dissipation and metabolic heat production are relatively minor.

Central application of a nitric oxide donor activates heat defense in the rabbit.

In chronically instrumented, conscious rabbits at moderately warm ambient thermal conditions, infusion of the NO-donor SIN-1 into the anterio-ventral 3rd cerebral ventricle (1-2 microg/min per kg BW, 2-4 microl/min, 30 min) initiated a co-ordinated activation of autonomic heat loss mechanisms, as indicated by the rise in ear skin temperature and by increases in panting frequency and respiratory evaporative water loss, while oxygen consumption decreased slightly. The heat loss responses were similar to those attributed to NO in studies employing systemic application of NO-donors. Different from NO acting peripherally, which causes arterial hypotension and tachycardia, centrally acting NO induced arterial hypertension and bradycardia. The observation of the same heat loss responses despite opposing circulatory actions suggests that NO is specifically involved in thermoregulation as a central activator of heat defense mechanisms.