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Background: Inflammatory reactions arise in reaction to a variety of pathogenic insults. The combination of inhaled nitric oxide (iNO) and glucocorticoids (GC) may attenuate endotoxin-induced inflammatory responses. It has been shown that the combination of iNO (30 p.p.m.) and steroids blunted the inflammatory response in a porcine endotoxin model, but not in humans. Therefore, we investigated whether a clinically ‘maximal’ dose of iNO in combination with GC could modulate the systemic inflammatory response in a human endotoxin model. Methods: A double-blind, cross-over, placebo-controlled randomized study including 15 healthy Caucasian volunteers (five females, 10 males). Performed at the Intensive Care Unit in a university hospital. iNO 80 p.p.m. or placebo (nitrogen) was started 2 h before administration of endotoxin (2 ng/kg). Thirty minutes later, GC (2 mg/kg, hydrocortisone) was administered intravenously. Blood samples and clinical signs were collected before and up to 24 h after the endotoxin injection. Results: Body temperature and heart rate increased significantly subsequent to endotoxin challenge. The plasma levels of IFN–γ, IL-1β, IL-2, 4 5, 6, 8, 10, 12, 13 and TNFα were markedly elevated. However, HMGB-1 and sRAGE were unaffected. No difference between placebo/GC and iNO/GC treatment was observed in the clinical or cytokine response, neither was there any difference between the first and the second exposure to endotoxin. Conclusions: Pre-treatment with iNO 80 p.p.m. along with GC (2 mg/kg) administrated after the endotoxin challenge could not modulate the systemic inflammatory response in this model of human experimental inflammation.

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 μg/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.

Background: Endotoxin is a major stimulus for triggering the host response in septicaemia. The pathophysiology of sepsis involves activation of the vascular endothelium and leukocytes, resulting in the release of various mediators, e.g. cytokines, nitric oxide (NO), endothelin (ET-1) and complement factors. We evaluated the blood levels of complement activation, ET-1 and neuropeptide Y (NPY) in parallel with the haemodynamic and oxygen transport response during human experimental endotoxemia. Methods: Eleven healthy men had venous, arterial and pulmonary arterial catheters placed for continuous haemodynamic measuring. After 30 min rest endotoxin (E. Coli 4 ng kg−1, Lot G1) was intravenously administered. Blood samples from pulmonary and arterial catheters were collected hourly over 4 h. Results: Body temperature augmented significantly from baseline values (36.7 ± 0.7 °C, mean ± SEM) with a maximum after 3.5 h (39.1 ± 0.3 °C, P

Background: Muscle pain is a major clinical problem but the underlying mechanisms and its pharmacological modulation need further investigation. This study on 15 volunteers evaluates if two experimental muscle pain models are sensitive to µ-receptor agonists and to an N-methyl-D-aspartate (NMDA)-receptor antagonist. Methods: In the left tibialis anterior, intramuscular electrical (IMES) pain thresholds were determined for single (SPTmuscle) and five (RPTmuscle) repeated stimuli. Also pain to suprathreshold stimulation at 150% of RPTmuscle, 10 s, was assessed on a visual analog scale (VAS) as AUCimes (area under the VAS curve). In the right TA muscle, pain intensity on infusion of 0.5 ml of hypertonic saline, 5% (AUCsaline) and pain distribution indicated as local and referred were evaluated. Pain variables were assessed before, during and after intravenous infusions of morphine (10 µg kg−1 min−1, 10 min), alfentanil (target-controlled infusion, plasma concentration; 60 ng ml−1, 60 min) and ketamine (10 µg kg−1 min−1, 60 min). All data were normalized to baseline pain values (before drug infusions were initiated) and compared with placebo (midazolam, 2 µg kg−1 min−1, 10 min). Results: SPTmuscle increased (log mean values ± SD, mA) with morphine (0.11 ± 0.17, P

Background: Roughly 400 000 cases of sepsis occur every year in the United States only and this is associated with a very high mortality. Bacterial lipopolysaccharide (LPS) triggers systemic inflammatory reactions in sepsis. However, down-stream cellular cascade initiated by LPS is still being elucidated. Nitric oxide (NO) and matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) are known to be induced by LPS. We have investigated the release of NO, MMP-2 and MMP-9 following infusion of LPS to volunteers. Methods: IPS (2 ng kg−1) was infused to 10 healthy volunteers. Before the experiments were started the subjects had an intravenous catheters placed. An electrocardiogram was also placed and monitored constantly. Body temperature was measured by ear thermometer every 10 min Venous blood was collected and cell-free plasma assayed for the presence of MMP-2 and MMP-9 using zymography and NO using HPLC assay for NO metabolites, nitrite and nitrate. Results: The administration of LPS resulted in increased body temperature and tachycardia. Time-dependent release of MMP-9(30 fold increase from the baseline) peaking at 2 h following infusion of LPS was observed. LPS did not significantly modify the activity of MMP-2 (P > 0.05). Infusion of LPS did not significantly change the levels of nitrite and nitrate (from 60 ± 11 to 67 ± 10 µm, P > 0.05). Conclusion: The release of MMP-9, but not MMP-2 or NO, is a sensitive index of endotoxaemia in humans. MMP-9 release may contribute to the pathogenesis of sepsis via its pro-inflammatory effects on the vasculature.

Background: Previous studies have shown that pneumoperitoneum transiently reduces venous admixture as assessed by a calculation based on the shunt formula, and increases arterial oxygen tension (PaO2) in patients without heart or lung disease. The aim of the present study was to further explore the relationship between ventilation-perfusion (V˙A/Q˙) before and during pneumoperitoneum by using the multiple inert gas technique. Methods: Nine patients without heart or lung disease (ASA I), with a mean age of 42 years, scheduled for laparoscopic cholecystectomy were included. After premedication and induction of anaesthesia, radial artery and pulmonary artery catheters were introduced percutaneously. The V˙A/Q˙ relationships were evaluated by the multiple inert gas elimination technique before and during pneumoperitoneum to obtain a direct measure of the pulmonary shunt. Results: Induction of pneumoperitoneum decreased the pulmonary shunt from 5.8 (4.5) to 4.1 (3.2)% (P

Background: Adenosine (Ado) is known, from studies in both animals and humans, to produce antinociception when administered systemically or intrathecally (IT). The current aim was to evaluate, in a placebo-controlled, randomised, double-blind study, whether IT adenosine given before surgery could reduce anaesthetic requirement and the need of opioids during 48 h after visceral surgery. Method: Forty women (37–66 years, ASA I and II) scheduled for elective hysterectomy were included. Before inducing the standardised O2/N2O/isoflurane/fentanyl anaesthesia, the patients received an IT injection of either adenosine (500 μg in 1 ml volume) or placebo 1 ml (saline). Intraoperative anaesthetic drug doses and haemodynamics were recorded. Postoperative pain was assessed by visual analogue scale. For postoperative analgesia, cetobemidone was provided via intravenous patient-controlled analgesia (PCA). Results: During surgery, there were no differences between groups in anaesthetic requirement or haemodynamic parameters. Postoperative cetobemidone requirements were similar in both groups (median 48 mg for adenosine/50 mg for saline) during the first 48 postoperative hours. Conclusion: IT adenosine did not influence the requirement of anaesthetic drug or postoperative analgesics after hysterectomy.

Background: There is often no satisfactory treatment for chronic pain after spinal cord injury. We have previously reported that intrathecal (i.t.) administration of the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) or the opioid morphine has anti-allodynic effects in a model of presumed chronic central pain after photochemically induced spinal cord injury in rats. In the present study, we set out to investigate the possible interaction between i.t. R-PIA and morphine in spinally injured rats. Methods: Sprague-Dawley rats displaying allodynia-like behaviors to mechanical and cold stimuli after photochemically induced spinal cord injury with minor motor deficits were used. R-PIA and morphine, either alone or in combination, were administered i.t. through an implanted catheter to lumbar spinal cord. Results: Cumulative doses of R-PIA or morphine dose-dependently reduced the mechanical allodynia-like behavior, with a threshold of 1 nmol and 1.5 nmol, respectively. When co-administrated, R-PIA and morphine produced marked suppression of mechanical allodynia at doses of 5 pmol and 7.5 pmol, respectively. The effect of i.t. co-administration of R-PIA and morphine on cold allodynia was comparable to i.t. R-PIA alone. The combination of R-PIA and morphine did not increase adverse effects such as motor deficits in comparison to either drug alone. Conclusion: These results demonstrate a supra-additive interaction between the adenosine A1-receptor agonist R-PIA and morphine to reduce mechanical allodynia-like behavior in rats with chronic spinal cord injury. The combination of R-PIA and morphine administered spinally may be superior to R-PIA or morphine alone for treating such pain.

Background: A low dose of systemic adenosine infusion has been shown to induce antinociception in clinical experimental studies as well as in patients. There is no clinical information about the effect of adenosine on the motility of the gastrointestinal tract. The aim of this study was therefore to evaluate the effect of exogenous adenosine administration on gastric emptying in man. Method: Ten healthy male volunteers (22–45 yrs) were included in a placebo-controlled, double-blind, randomised, cross-over study, where the experiments were separated by at least one week. During one session the volunteers received a continuous intravenous infusion of adenosine (50 μg · kg−1 · min−1) initiated 15 min prior to the test of gastric emptying (a standard test meal, followed by oral acetaminophen, 2 g) and lasting throughout the experiment (2 h). During the other experimental session an infusion of saline was given. Acetaminophen absorption test was used as an indirect measure of the rate of gastric emptying. Venous acetaminophen concentration curves were produced and the maximum acetaminophen concentration (Cmax), the time to reach the maximum concentration (Tmax), and the area under the serum acetaminophen concentration time curve from 0 to 60 min (AUC60) were calculated. Results: There was no difference between placebo and adenosine in Cmax (197 vs. 199 μmol · L−1, P=0.80), Tmax (23 vs. 45 min, P=0.14), AUC60 (9633 vs. 9111 min · μmol · L−1, P=0.28). Conclusion: The results demonstrate that adenosine in a clinically antinociceptive dose of 50 μg · kg−1 · min−1 does not affect the rate of gastric emptying in healthy volunteers.

Background: Adenosine (ADO), and stable analogs thereof, have been shown to exert antinociceptive action under experimental conditions in animals and in humans. The aim of this randomized double-blind placebo-controlled study was to evaluate if a low dose of intravenous (i.v.) ADO could reduce isoflurane requirements during joint-associated surgery, as an indication of antinociception in deep somatic pain. Methods: Thirty-two patients, age 19–62 years, ASA I and II, scheduled for shoulder joint surgery, were assigned to receive an i.v. infusion of either adenosine, 80 μg kg-1 min-1, or placebo, during the surgical procedure. Anesthesia was maintained with isoflurane/N2O/O2 inhalation. Results: The peroperative isoflurane concentration was significantly reduced at 50 minutes of surgery in the group receiving adenosine infusion. Also, the systolic blood pressure level was peroperatively more stable during adenosine infusion than during placebo. Other clinical parameters, such as pain, postoperative analgesic requirements and nausea, were not different between groups. Conclusion: A peroperative infusion of a low dose of adenosine during shoulder joint surgery may reduce the peroperative isoflurane requirement.

Adenosine is an endogenously produced substance which in animal experiments exerts anti-nociceptive effects. In humans, algcsic effects have been presented following exogenous adenosine administration. A recent study on anaesthetized patients, however, suggested an anti-nociceptive effect during i.v. adenosine. We have studied the pain-reducing effect in healthy volunteers using adenosine 50–80 μg · kg-1 · min-1 (n = 10), morphine 0.1 mg · kg-1 (n = 5), adenosine 50 μg · kg -1 · min-1 + morphine 0.1 mg · kg-1 (n=6), and ketamine 0.1 mg · kg-1 (n=5); all drugs given i.v., single-blind. Quantitative sensory tests (QST) revealed a significantly increased cutaneous heat pain threshold following adenosine. No effect was seen following ketamine or morphine. Suprathreshold heat pain perception was unchanged in all subjects. Furthermore, warm and cold perception thresholds were not influenced significantly by any drug. Adenosine, morphine and kctamine produced well-known side-effects but of a mild intensity not necessitating any treatment. The present results show that i.v. adenosine can provide a modest but selective increase of cutaneous heat pain thresholds, suggesting a pain-reducing capacity of adenosine in humans.

BACKGROUND Intrathecal injection of sufentanil offers labour pain relief of short duration. This double-blind randomised study evaluates if the combination of adenosine to sufentanil could give relevant prolongation (40%) of the duration of sufentanil spinal analgesia. METHODS Twenty-five healthy parturients requesting labour analgesia were included. Patients received 10 micro g of sufentanil + 500 micro g of adenosine or 10 micro g of sufentanil intrathecally. Pain intensity and duration of pain relief were assessed. RESULTS Pain relief was equal between groups. Duration of analgesia was not increased by adenosine + sufentanil, 99 +/- 54 min, vs. sufentanil, 89 +/- 56 min. CONCLUSION Adding 500 micro g of adenosine to 10 micro g of sufentanil could not provide any prolongation of labour pain relief.

The laparoscopic operating technique is being applied increasingly to a variety of intra-abdominal operations. Intra-abdominal gas insufflation, i.e. pneumoperitoneum (PP), is then used to allow surgical access. The haemodynamic effects of PP in combination with different body positions have not been fully examined. Eleven patients without signs of cardiopulmonary disease were studied before and during laparoscopic cholecystectomy under propofol-fentanyl anaesthesia with controlled ventilation. Swan-Ganz and radial arterial catheterization were used to determine haemodynamic data in the horizontal position, with a 15-20 degree head-down tilt and a 15-20 degree head-up tilt. The measurements were repeated after insufflation of carbon dioxide to an intraabdominal pressure of 11-13 mmHg, as well as during surgery. The ventricular filling pressures of the heart were strictly dependent on body position. PP in the horizontal position increased pulmonary capillary wedge pressure by 32% (P < 0.01), central venous pressure by 58% (P < 0.01), and mean arterial pressure by 39% (P < 0.01). When PP was combined with a head-down tilt, there was a further increase in filling pressures by approximately 40% (P < 0.01), while the reduction in filling pressures during the head-up tilt was counteracted by PP. During PP with a head-up tilt, the filling pressures did not differ from those in the horizontal position without PP. CI showed a certain dependency on filling pressures. It is concluded that PP causes signs of elevated preload and afterload. The combination of PP and a head-up tilt is associated only with signs of an elevated afterload.(ABSTRACT TRUNCATED AT 250 WORDS)

Ventilatory responses to hypoxia (HVR) were investigated using poikilocapnic conditions (i.e. end-tidal CO2's allowed to seek it's own level) in 15 cardio-pulmonary healthy patients who were first studied awake and then at 0.85 MAC isoflurane. The influence of hypercapnia (HyperCapnic Ventilatory Response, HCVR) was also elucidated. Pneumotachography, capnography and airway occlusion pressures at 0.1 s (P degree 0.1) were used before and during both mild hypoxia (end-tidal O2 tension 8.7 kPa) and hypercapnia achieved by an inspired CO2 concentration of 5%. HCVR was attenuated by 60% during anesthesia (P < 0.01). In the awake state, five of the 15 patients decreased HVR during hypoxia as compared with during normoxia. This resulted in a VE that on average increased by 0.6 l.min-1 (P < 0.05) whereas P degree 0.1 was unchanged. In the anesthetized state, no case of decreased HVR was seen and hypoxia induced a mean VE increase (+/- s.d.) by 1.0 +/- 0.2 l.min-1 (P < 0.001) and a P degree 0.1 that on average was improved by 0.63 +/- 0.27 cm H2O (P < 0.01). It is suggested that when the aim is to evaluate the influence of volatile anesthetic agents on HVR and to quantitate its clinical relevance during and immediately after anesthesia, a poikilocapnic technique should be used. It is concluded that the poikilocapnic HVR to PEO2's of 8.7 kPa was maintained during 0.85 MAC isoflurane.

The effect of a non-hypotensive dose of adenosine infusion on myocardial performance after coronary artery bypass surgery was examined. Upon arrival at the intensive care unit, 16 patients (14 males, 2 females; mean age 64.5, range 46–71) were randomized to a blinded infusion of either low-dose adenosine (n = 8) or placebo (n = 8). The infusion continued at a rate corresponding to 30 μg. kg-1. min-1 of adenosine into the right ventricle over 4 h. Data were collected from the arterial line, thermodilution pulmonary artery catheter, transoesophageal echocardiogram (TEE), and 12-lead ECG on six occasions: before infusion, hourly during the infusion, and 1 h after terminating the infusion. Mean arterial blood pressure did not differ between the adenosine and placebo groups at any measurement point. Heart rate increased by approximately 15% during the first hour of adenosine infusion. Cardiac index increased by approximately 50% during infusion of adenosine and cardiac index remained higher while systemic vascular resistance remained lower in the adenosine-treated group during infusion. The E/A ratio (ratio between peak left ventricular inflow blood velocities during early filling and atrial contraction) was significantly higher in the adenosine-treated group after treatment for 1 h while the area injection fraction did not differ between groups at any time. The number of patients with ischaemic events as judged from ECG and from left ventricular regional wall motion abnormalities (RWMA) as visualized by TEE did not differ between groups (ECG: one patient in the adenosine group and one patient in the placebo group - RWMA: four patients in the adenosine group versus three in the placebo group). According to enzyme determinations, three patients (two in the adenosine group and one in the placebo group) developed a perioperative myocardial infarction. In conclusion, adenosine could be infused at a rate that induced peripheral vasodilation and improved cardiac output, without affecting arterial blood pressure. The echo Doppler indices area ejection fraction and E/A ratio revealed no signs of impaired ventricular function during the infusion of adenosine.

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 µg/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.

Background: The prompt haemodynamic response to carbon dioxide insufflation during laparoscopic cholecystectomy suggests involvement of the sympathetic system. The aim of the present study was to examine if a change in vascular resistance in leg skeletal muscle could be an important mechanism behind the increased afterload. Furthermore, the arterio-venous differences of the catecholamines were measured in the leg before and during insufflation of carbon dioxide into the peritoneal cavity. Methods: Ten patients (ASA I) scheduled for laparoscopic cholecystectomy were included. After induction of anaesthesia, catheters were introduced percutaneously into the radial artery, the femoral vein and the cubital vein for pressure monitoring and blood sampling. The arterial blood flow in the legs was measured by mercury-in-Silastic strain gauge venous occlusion plethysmography. Vascular resistance in the right leg (LVR) was calculated from the formula: (MAP–FVP)/calf blood flow. Measurements were made before and 5 min after insufflation of pneumoperitoneum. Results: Induction of pneumoperitoneum increased the heart rate (P

Background: Laparoscopic surgery involves the use of intra-ab-dominal carbon dioxide insufflation (pneumoperitoneum). The increased intra-abdominal pressure causes marked haemodyn-amic changes, which may influence electrocardiographic monitoring. The aim of the present study was to elucidate the influence of pneumoperitoneum on vectorcardiographic recordings. Methods: Vectorcardiographic changes (QRS vector difference= QRSVD, QRS loop area, QRS magnitude, ST vector magnitude, spatial ST vector change) were recorded continuously applying computerized vectorcardiography in 12 anaesthetised cardio-vascularly healthy patients, scheduled for laparoscopic cholecystectomy. Measurements were made before and during pneumoperitoneum in three different body positions (supine, Trendelenburg and reversed Trendelenburg), also employing transesophageal echo-cardiography and invasive blood pressure monitoring. Results: Pneumoperitoneum significantly increased QRSVD, in parallel with an enlargement in loop area and magnitude. The magnitude was significantly increased in the transversal and frontal planes and there was a tendency to increase the magnitude in the sagittal plane. The increase in QRS-VD reached levels previously associated with the development of myocardial ischaemia in patients with coronary artery disease. The ST-variables were not changed by the pneumoperitoneum. The positional changes also influenced QRSVD significantly. Conclusions: When computerized vectorcardiography is used for ischaemia monitoring during pneumoperitoneum, the ST-variables seem reliable. However, vectorcardiographic QRS changes should be interpreted with caution, as the QRS alterations found during pneumoperitoneum mimic the changes seen during myocardial ischaemia.

Background: Adenosine (ADO), and stable analogs thereof, have been shown to exert antinociceptive action in cutaneous and deep somatic pain under experimental and clinical conditions in animals and in humans. The aims of this randomized double-blind placebo-controlled study were to evaluate if a low dose of intravenous (i.v.) ADO could reduce the requirements of volatile anesthetic and postoperative opioid in connection to hysterectomy, where visceral nociception significantly contributes to pain. Methods: Forty-three women, age 32–65 years, ASA I and 11, scheduled for abdominal hysterectomy, were assigned to receive an i.v. infusion of either adenosine, 80 μg. kg-1 min-1, or placebo during surgery. Anesthesia was maintained with isoflurane (ISO)/N2O/ O2 inhalation. Postoperatively, a reduced dose of 40 μg. kg-1. min-1 was continued for 3 h. Results: The end-tidal (ET-) IS0 was equal between groups before surgery. During surgery, the IS0 requirement was increased, compared to the preoperative level, in the placebo group, while the requirement declined in the ADO group. The overall IS0 requirement in the ADO group was reduced by 36% (P

This study primarily examined the effect of three endtidal isoflurane concentrations (0.2, 1.0 and 1.4%) on the isocapnic hypoxic ventilatory response (HVR), as well as the hypercapnic ventilatory response (HCVR), in 18 women (ASA I) who were all in the follicular phase of their menstrual cycle. Capnography was used, together with pulseoximetry to indicate desired levels of hypoxia (SpO2 75-80%). This hypoxic challenge resulted, after 3-4 min, in a stable ventilation, and ventilation measurements were then taken during a 90 s period. The HCVR provocation (inhalation of 4.5% CO2 in air) and measurements were conducted using a similar time frame as for HVR. Isoflurane 0.2% did not affect any ventilatory parameter. Isoflurane 1.0 and 1.4% dose-dependently increased endtidal CO2 and respiratory rate, while tidal volumes decreased. Minute ventilation was not reduced. HVR, as well as HCVR, were both uninfluenced by isoflurane 0.2%. HVR was reduced by 60-70% at isoflurane 1.4% (P < 0.01), and was parallelled by a similar depression of HCVR (P < 0.01). The HVR during anaesthesia was accomplished by a respiratory rate response, while the increase in tidal volume, seen in the awake state, was abolished. The HCVR during anaesthesia was, on the other hand, the result of a dose-dependently depressed tidal volume response, without any increase in respiratory rate. In conclusion, isoflurane 0.2% did not affect the ventilatory response to mild isocapnic hypoxia, nor to mild hypercapnic challenge. During anaesthesia with isoflurane (1.0 and 1.4%), there was a parallel reduction of HVR and HCVR.

In order to evaluate the difference between poikilo-capnic (no CO2 added to inspired gas) and iso-capnic (CO2 added to keep end-tidal CO2 constant) hypoxic ventilatory responses (HVR) awake and during 0.6 MAC isoflurane anaesthesia, seven cardio-pulmonary healthy patients were investigated. Pneumotachography and capnography were used before and during hypoxia (end-tidal O2 tension approx. 7 kPa). In the awake stale, poikilo-capnic hypoxic challenges resulted in an increased HVR as indicated by a VE that on average increased by 1.4 ± 1.0 (mean ± s.d.) 1 · min−1, whereas the iso-capnic hypoxic challenges resulted in a VE increase that was 4.7 ± 2.3 1 · min−1 on average. In the anaesthetized state, the corresponding value during poikilocapnia was 1.3 ± 0.8 1 · min−1 (88% of the awake responses, n.s.) and during iso-capnia 2.3 ± 1.4 1 · min−1 (49% of the awake, P < 0.02). Awake HVR was achieved by greater tidal volumes during poikilocapnia as well as during isocapnic challenges, while respiratory rates were unchanged. In the anaesthetized state, during poikilocapnia, however, HVR was mediated by an increased respiratory rate, (from 17.5 ± 1.7 breath · min−1 to 20.2 ± 2.2) and during isocapnia by a combination of increased rate (from 17.1 ± 1.9 breath · min−1 to 19.1 ± 1.8) and tidal volume (from 496 ± 80 to 560 ± 83 ml). It is concluded that poikilocapnic HVR is maintained at 0.6 MAC isoflurane whereas iso-capnic HVR is depressed by 50%. In addition, both poikilo- and iso-capnic HVR were accomplished by greater tidal volumes at unchanged respiratory rates in the awake state while the opposite occurred during isoflurane anaesthesia. The more dominating chronotropic HVR during hypoxic challenge under anaesthesia will have to be further clarified in experimental studies.

The effects of adenosine and prostacyclin (PGI2) infusions on hypoxia-induced pulmonary hypertension in the pulmonary and systemic circulatory systems of nine pigs were compared. The animals received the drugs in random order, and they were allowed to recover between each experimental sequence. Hypoxia was induced by reducing FiO2 to 0.12-0.13 so as to result in an arterial PO2 of approximately 6 kPa. Dose rates of adenosine or PGI2 during hypoxia were individualized in order to achieve a maximal reduction of 15% in the mean arterial blood pressure. Adenosine and PGI2 produced a fall in pulmonary vascular resistance of 36 +/- 4% (s.e.mean P less than 0.01) and 37 +/- 6% (P less than 0.01), respectively. The mean pulmonary artery pressure was reduced by 19 +/- 3% (P less than 0.01) during adenosine infusion and by 36 +/- 4% (P less than 0.01) during PGI2 infusion. The systemic haemodynamic responses to the two drugs were similar but adenosine produced a 7 +/- 2% (P less than 0.01) increase in cardiac output. Arterial PO2 during hypoxia and vasodilator treatment did not differ from the hypoxic situation without drug infusion. It is concluded that adenosine and PGI2 counteract hypoxia-induced increases in pulmonary vascular resistance similarly, but the reduction in pulmonary artery pressure was greater with PGI2 at infusion rates, causing minor systemic haemodynamic changes.

The effects of graded elevations of intracranial pressure (ICP) on cardiac metabolism, blood flow and electrophysiology, and plasma catecholamines were studied in eight open-chest pigs. ICP was consecutively elevated from 15 +/- 3 mmHg in the control state to 40 +/- 4, 84 +/- 4 and 152 +/- 11 mmHg. Mean arterial blood pressure and heart rate were significantly increased at the two highest ICP levels. Cardiac oxygen uptake was also increased from 2.9 +/- 0.4 ml X min-1 to a maximum of 7.1 +/- 2.0 ml X min-1, and coronary sinus blood flow increased from 49 +/- 7 to 131 +/- 35 ml X min-1 at the highest ICP level. The transmyocardial blood flow distribution was unchanged, as determined by the microspheres technique. Arterial plasma catecholamine concentrations were significantly elevated at the two highest ICP levels, but noradrenaline overflow from the heart did not increase. The high arterial adrenaline concentrations (51 +/- 25 nmol X 1(-1) at the highest ICP level) may be responsible for the cardiac stimulation seen in these experiments. No signs of ischaemia, as judged by myocardial lactate production or the relative flow distribution to the endocardium were observed. Changes in the T-wave morphology appeared in the subendocardial ECG at all ICP levels, the changes being more prominent with increasing ICP levels. It is concluded that the increase in circulating catecholamine levels, adrenaline in particular, together with an elevation of afterload cause an increase of myocardial work, which may explain the T-wave changes in the ECG which are observed upon rapid elevation of intracranial pressure.

The effect of adenosine-induced controlled hypotension (CH) on myocardial performance, blood flow, and metabolism was studied in nine pentobarbital-anaesthetized, open-chest dogs. Adenosine was continuously infused i.v. (0.69 +/- 0.06 and 1.36 +/- 0.11 mg/kg/min) at two stepwise increased rates (12-14 min-periods) in order to induce approximately 20 and 40% reduction of the mean arterial pressure (MAP 62 +/- 4 and 43 +/- 1 mmHg, respectively). The reduction of MAP was associated with decreases in heart rate (6 +/- 2%, P less than 0.05 and 21 +/- 4%, P less than 0.01), left intraventricular systolic pressure (14 +/- 3%, P less than 0.01 and 32 +/- 3%, P less than 0.01), left ventricular end-diastolic pressure (23 +/- 9%, P less than 0.05 and 42 +/- 9%, P less than 0.01) and ventricular intramyocardial systolic pressure (15 +/- 6% n.s. and 27 +/- 6%, P less than 0.01). The rate pressure product was markedly reduced by 49 +/- 3% (P less than 0.01) at the highest infusion rate. The mean coronary vein pressure (20.3 +/- 2.8 mmHg) was unaffected by the adenosine infusion. The systolic pressure time index (SPTI) was decreased by 33 +/- 3% (P less than 0.01) during the highest infusion rate of adenosine, while the diastolic perfusion time index (DPTI) was 15.4 +/- 2.2 mmHg X s and remained unchanged. The DPTI:SPTI ratio increased by 40 +/- 13% (P less than 0.05), suggesting a sufficient endocardial oxygen supply.(ABSTRACT TRUNCATED AT 250 WORDS)

An open–chest preparation was carried out in 14 pentobarbitone anaesthetized dogs in order to evaluate the myocardial effects of controlled hypotension induced by adenosine in the presence of a severe coronary stenosis that caused ischaemia of the left anterior ventricular wall. Myocardial performance, blood flow and metabolism were studied before and during a 78 ± 3% reduction of flow in the left anterior descending coronary artery (LAD) and during adenosine–induced hypotension (approximately 40% reduction of the mean arterial pressure) in the presence of the LAD stenosis. The LAD stenosis decreased the myocardial lactate uptake (P

The cerebral and systemic effects of hypotension induced by adenosine (0.61 +/- 0.07 mg.kg-1.min-1) were studied in eight pigs anesthetized with droperidol, phenoperidine and nitrous oxide. Mean arterial blood pressure (MABP) was reduced by 58%, from 17.2 kPa (128 mmHg) to 6.9 kPa (53 mmHg) during a 30-min period. The hypotension was caused by a decrease in systemic vascular resistance (58%) while the cardiac output was unaffected. Cerebral blood flow (CBF), as determined by microsphere distribution, and the cerebral metabolic rate for oxygen (CMRO2) remained unchanged. Cerebral vascular resistance decreased by 61%. There were no signs of cerebral lactate release. After discontinuation of adenosine infusion, the MABP returned to control levels within 5 min. Thirty minutes later the CBF was increased by approximately 60% in comparison to the control, while the CMRO2 was unchanged. It is concluded that adenosine-induced hypotension in pigs is associated with preserved CBF and CMRO2, whereas cerebral hyperperfusion is present in the early post-hypotensive period.

Graded increases of intracranial pressure (ICP) in anaesthetized pigs induced elevations of plasma levels of neuropeptide Y (NPY)-like immunoreactivity (LI) and catecholamines, simultaneously with hypertension and tachycardia. Plasma adrenaline (ADR) increased at a lower ICP-level than did the plasma levels of noradrenaline (NA) and NPY-LI. At the maximal ICP elevation, 22.9 kPa (172 mmHg), plasma NPY-LI was increased about 10-fold, from 48 +/- 8 pmol/l in the basal state, while NA and ADR concentrations increased more than 100-fold. At this maximal ICP-level the plasma levels of NPY-LI were correlated to the concentrations of both NA (r = 0.87, P less than 0.01) and ADR (r = 0.92, P less than 0.001). Plasma NPY-LI continued to increase to about 1000 pmol/l, 10 min after the maximal elevation of ICP was discontinued, while the catecholamines then had declined considerably. A slight cardiac release of NPY-LI was observed at the maximal elevation of ICP. The half-life of NPY-LI in plasma was about 6 min upon systemic infusion. At plasma levels similar to those obtained upon maximal ICP elevation, exogenous NPY caused slight vasoconstriction in the spleen and skeletal muscle, but had no effects on coronary blood flow or systemic blood pressure. This suggests that NPY mainly exerts local actions after release from nerve endings, while levels of circulating NPY in plasma must be very high to influence blood flow in some organs. It is concluded that elevation of ICP results in hypertension and tachycardia related to elevated plasma levels of NPY-LI and catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)