RÉSUMÉ
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 2h before administration of endotoxin (2 ng/kg). Thirty minutes later, GC (2mg/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-1ß, 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 (2mg/kg) administrated after the endotoxin challenge could not modulate the systemic inflammatory response in this model of human experimental inflammation.
Sujet(s)
Endotoxémie/anatomopathologie , Endotoxines/toxicité , Glucocorticoïdes/pharmacologie , Immunomodulation/effets des médicaments et des substances chimiques , Monoxyde d'azote/pharmacologie , Administration par inhalation , Adulte , Hémogramme , Température du corps/effets des médicaments et des substances chimiques , Études croisées , Cytokines/sang , Méthode en double aveugle , Endotoxémie/métabolisme , Femelle , Glucocorticoïdes/administration et posologie , Rythme cardiaque/effets des médicaments et des substances chimiques , Humains , Hydrocortisone/administration et posologie , Hydrocortisone/pharmacologie , Inflammation/induit chimiquement , Inflammation/anatomopathologie , Injections veineuses , Mâle , Monoxyde d'azote/administration et posologie , Jeune adulteRÉSUMÉ
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.
Sujet(s)
Endothéline-1/physiologie , Endotoxémie/physiopathologie , Animaux , Antagonistes du récepteur de type A de l'endothéline , Antagonistes du récepteur de type B de l'endothéline , Endotoxémie/complications , Femelle , Hypertension pulmonaire/étiologie , Hypertension pulmonaire/prévention et contrôle , Iléum/vascularisation , Muqueuse intestinale/vascularisation , Isoxazoles/pharmacologie , Microcirculation/effets des médicaments et des substances chimiques , Microcirculation/physiologie , Pyridines/pharmacologie , Récepteur de type A de l'endothéline/physiologie , Récepteur de l'endothéline de type B/physiologie , Circulation splanchnique/effets des médicaments et des substances chimiques , Circulation splanchnique/physiologie , Sulfones/pharmacologie , Sus scrofa , Tétrazoles/pharmacologie , Vasodilatateurs/pharmacologieRÉSUMÉ
AIM: To evaluate possible anti-inflammatory effects of pre-treatment with adenosine in a human experimental inflammatory model. METHODS: The study design was double-blind, crossover, placebo-controlled and randomized. In the Intensive Care Unit of a university hospital, 16 healthy male volunteers were treated for 5.5 h with infusions of adenosine 40 microg kg(-1) min(-1) or placebo. Thirty minutes after the start of adenosine or placebo, 2 ng kg(-1)E-Coli endotoxin was administered. Heart rate, body temperature, blood pressure, plasma cytokines (TNF-alpha, IL-6 and IL-10), soluble RAGE and resistin, exhaled nitric oxide and nitrite/nitrate in urine were determined. RESULTS: Endotoxin elicited the expected clinical signs of an inflammatory reaction (tachycardia, fever) and led to prominent release of the cytokines studied (P < 0.001). Resistin in plasma increased after endotoxin (P < 0.001). After placebo treatment, soluble RAGE (sRAGE) in plasma increased 5 h after the endotoxin challenge (P < 0.001) but not after adenosine. After placebo, orally exhaled NO increased with a peak at 4 h (P < 0.001), although there was no statistically significant difference between the two treatments. Nitrite/nitrate in urine (n = 11) did not differ between adenosine and placebo treatments. CONCLUSION: In conclusion, adenosine infusion starting before endotoxin challenge in humans attenuated sRAGE significantly but otherwise had no clear anti-inflammatory effect. Adenosine as a potential anti-inflammatory treatment in humans needs further study, including use of higher doses. The mechanism underlying the effect of adenosines on sRAGE remains unknown.
Sujet(s)
Adénosine/immunologie , Anti-inflammatoires/immunologie , Cytokines/immunologie , Récepteurs immunologiques/immunologie , Résistine/immunologie , Adénosine/administration et posologie , Anti-inflammatoires/administration et posologie , Température du corps , Études croisées , Cytokines/sang , Cytokines/effets des médicaments et des substances chimiques , Méthode en double aveugle , Endotoxines/immunologie , Rythme cardiaque , Humains , Perfusions veineuses , Mâle , Monoxyde d'azote/métabolisme , Récepteur spécifique des produits finaux de glycosylation avancée , Récepteurs immunologiques/sang , Récepteurs immunologiques/effets des médicaments et des substances chimiques , Valeurs de référence , Résistine/sang , Résultat thérapeutiqueRÉSUMÉ
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.
Sujet(s)
Endotoxémie/traitement médicamenteux , Rein/vascularisation , Microcirculation/effets des médicaments et des substances chimiques , Pyridines/pharmacologie , Tétrazoles/pharmacologie , Vasodilatateurs/pharmacologie , Aldostérone/sang , Angiotensine-II/sang , Animaux , Modèles animaux de maladie humaine , Antagonistes des récepteurs de l'endothéline , Endotoxémie/physiopathologie , Femelle , Hémodynamique/effets des médicaments et des substances chimiques , Interleukines/sang , Microcirculation/physiologie , Concentration osmolaire , Répartition aléatoire , Suidae , Résultat thérapeutique , Facteur de nécrose tumorale alpha/sangRÉSUMÉ
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.
Sujet(s)
Dextrane/usage thérapeutique , Antagonistes des récepteurs de l'endothéline , Pyridines/usage thérapeutique , Solution saline hypertonique/usage thérapeutique , Choc septique/traitement médicamenteux , Tétrazoles/usage thérapeutique , Équilibre acido-basique/effets des médicaments et des substances chimiques , Équilibre acido-basique/physiologie , Acidose/traitement médicamenteux , Acidose/métabolisme , Acidose/physiopathologie , Animaux , Circulation sanguine/effets des médicaments et des substances chimiques , Circulation sanguine/physiologie , Pression sanguine/effets des médicaments et des substances chimiques , Pression sanguine/physiologie , Dextrane/pharmacologie , Association de médicaments , Endotoxines , Escherichia coli , Femelle , Hypotension artérielle/traitement médicamenteux , Hypotension artérielle/métabolisme , Hypotension artérielle/physiopathologie , Mâle , Échanges gazeux pulmonaires/effets des médicaments et des substances chimiques , Échanges gazeux pulmonaires/physiologie , Pyridines/pharmacologie , Répartition aléatoire , Solution saline hypertonique/pharmacologie , Choc septique/induit chimiquement , Choc septique/physiopathologie , Suidae , Tétrazoles/pharmacologie , Vasodilatation/effets des médicaments et des substances chimiques , Vasodilatation/physiologieRÉSUMÉ
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.
Sujet(s)
Solution isotonique/usage thérapeutique , Réanimation/méthodes , Choc septique/physiopathologie , Maladie aigüe , Animaux , Circulation sanguine/effets des médicaments et des substances chimiques , Débit cardiaque/effets des médicaments et des substances chimiques , Modèles animaux de maladie humaine , Endotoxémie , Circulation pulmonaire , Choc septique/thérapie , Suidae , Résistance vasculaire/effets des médicaments et des substances chimiquesRÉSUMÉ
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.
Sujet(s)
Anticoagulants/usage thérapeutique , Dextrane/usage thérapeutique , Solution saline hypertonique/usage thérapeutique , Choc septique/traitement médicamenteux , Analyse de variance , Animaux , Gazométrie sanguine/méthodes , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Femelle , Mâle , Taux de survie , Suidae , Facteurs tempsRÉSUMÉ
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 < 0.05) and also increased mean arterial pressure and femoral vein pressure as well as the calculated leg vascular resistance (P < 0.01). Calf blood flow did not change significantly in either leg. Both arterial and venous noradrenaline concentrations were higher after insufflation (P < 0.01). CONCLUSION: In patients without heart or lung disease, pneumoperitoneum at an intra-abdominal pressure level of 11-13 mmHg increased the peripheral vascular resistance in the leg while the arterial blood flow in the leg was unaffected. Catecholamine levels increased, but were still low. Therefore, we suggest that the increase in peripheral vascular resistance is caused by increased myogenic activity in the resistance vessels secondary to increased arterial and transmural pressure rather than by increased neurogenic sympathetic activity.
Sujet(s)
Dioxyde de carbone/administration et posologie , Cholécystectomie laparoscopique/méthodes , Jambe/vascularisation , Pneumopéritoine artificiel/méthodes , Résistance vasculaire/physiologie , Adolescent , Adulte , Pression sanguine/physiologie , Catécholamines/sang , Femelle , Rythme cardiaque/physiologie , Humains , Mâle , Adulte d'âge moyen , Surveillance peropératoire/méthodes , Muscles squelettiques/vascularisation , Norépinéphrine/sang , Débit sanguin régional/physiologieRÉSUMÉ
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 degrees C, mean +/- SEM) with a maximum after 3.5 h (39.1 +/- 0.3 degrees C, P < 0.001). Cardiac output increased by 100%, systemic vascular resistance decreased by 50%, the oxygen consumption and the tissue oxygen transport increased. Activation of the complement system was indicated by an increase in SC5b-9. Endothelin-1-like immunoreactivity (ET-1-LI) increased over time in arterial blood. NPY-like immunoreactivity (NPY-LI) did not change over time. CONCLUSION: A dose of endotoxin associated with reproducible systemic vasodilation and fever in healthy subjects causes complement activation and increased systemic levels of ET-1-LI, illustrating that the model is a useful tool for inducing moderate systemic inflammation where several mediator systems are activated.
Sujet(s)
Activation du complément/physiologie , Endothéline-1/sang , Endotoxines , Hémodynamique/physiologie , Inflammation/induit chimiquement , Inflammation/physiopathologie , Neuropeptide Y/sang , Adulte , Température du corps/effets des médicaments et des substances chimiques , Endotoxémie/physiopathologie , Humains , Mâle , Consommation d'oxygène/effets des médicaments et des substances chimiques , Alvéoles pulmonaires/métabolisme , Alvéoles pulmonaires/physiologie , Échanges gazeux pulmonaires/effets des médicaments et des substances chimiquesRÉSUMÉ
This study examined the hypothesis that nicotinamide could attenuate endotoxin-induced inflammatory responses in humans as indicated by levels of cytokines and nitric oxide. Ten healthy male volunteers participated in a randomised, double-blind, cross-over design with regard to the effects of nicotinamide. The volunteers received orally 4 g nicotinamide or placebo at 14 h and at 2 h preceding the experiment (total dose of 8 g). Endotoxin (E. coli, 2 ng/kg), was administered intravenously. Blood samples and haemodynamic data were collected prior to and up to 6 h after the endotoxin infusion. Orally exhaled NO was measured hourly. Following endotoxin, body temperature increased from baseline 36.3 +/- 0.09 degrees C to a maximum of 38.0 +/- 0.1 degrees C for all (mean +/- SEM, P < 0.001) and heart rate increased from 59 +/- 1.9 to 87.0 +/- 2.6 beats/min after 3 h (mean +/- SEM, P < 0.001). Endotoxin challenge also markedly elevated the TNF-alpha, IL-6, IL-8 and IL-10 concentrations (P < 0.001 versus baseline for all) during the study period. Orally exhaled NO also increased (P < 0.01) compared to baseline. Nicotinamide treatment did not influence the patterns of cytokine and NO response to endotoxin. In conclusion, there was no effect on the inflammatory parameters by oral nicotinamide at a dose of 8 g, limiting the potential use of this agent for anti-inflammatory purpose in man.
Sujet(s)
Anti-inflammatoires non stéroïdiens/usage thérapeutique , Cytokines/biosynthèse , Endotoxémie/prévention et contrôle , Nicotinamide/usage thérapeutique , Monoxyde d'azote/métabolisme , Adulte , Tests d'analyse de l'haleine/méthodes , Études croisées , Méthode en double aveugle , Endotoxémie/immunologie , Endotoxines , Humains , MâleRÉSUMÉ
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 micro -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 microg x kg-1 min-1, 10 min), alfentanil (target-controlled infusion, plasma concentration; 60 ng ml-1, 60 min) and ketamine (10 microg x 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 microg x kg-1 min-1, 10 min). RESULTS: SPTmuscle increased (log mean values +/- SD, mA) with morphine (0.11 +/- 0.17, P < 0.05), alfentanil (0.28 +/- 0.24, P < 0.001) and ketamine (0.19 +/- 0.18, P < 0.01) as compared with placebo (-0.03 +/- 0.12). Alfentanil and ketamine also increased RPTmuscle (0.25 +/- 0.21, P < 0.01 and 0.21 +/- 0.19, P < 0.05, respectively) as compared with placebo (0.00 +/- 0.17). Pain to IMES (AUCimes) was reduced (median values [25th-75th percentiles], cm x s) by alfentanil and ketamine (-19.7 [-14.6 - -29.6] and-12.8 [-8.3 - -27.8], P < 0.05, respectively) vs. placebo (-0.8 [1.6 - -12.3]). Similar drug effects were seen when pain to infusion of hypertonic saline (AUCsaline) was assessed (alfentanil:-388 [-99 - -677] and ketamine:-326 [-227 - -573], P < 0.05 compared with placebo: 150 [449--240]). Ketamine also reduced the size of the local pain area (-58.4 [-21.2 - -176.1], < 0.05) as compared with placebo (-0.4 [70.6 - -13.4]). The frequency of referred pain was also lower when ketamine was given (3/13, P < 0.05) vs. placebo (9/14). CONCLUSION: The study demonstrates that experimental muscle pain induced in humans by electrical stimulation and infusion of hypertonic saline is sensitive to pharmacological modulation similar to preclinical animal tests and clinical trials. The data suggest that these models can be valuable tools in analgesic drug development.
Sujet(s)
Alfentanil/pharmacologie , Kétamine/pharmacologie , Morphine/pharmacologie , Muscles squelettiques/physiologie , Douleur/traitement médicamenteux , Adulte , Stimulation électrique , Femelle , Humains , Mâle , Douleur/physiopathologie , Seuil nociceptif/effets des médicaments et des substances chimiques , Récepteurs du N-méthyl-D-aspartate/effets des médicaments et des substances chimiques , Récepteurs du N-méthyl-D-aspartate/physiologie , Récepteur mu/effets des médicaments et des substances chimiques , Récepteur mu/physiologie , Solution saline hypertoniqueRÉSUMÉ
Nitric oxide (NO) is believed to be involved in the pathophysiology of sepsis. This study evaluated the activity of the NO pathway in a human endotoxin model. At baseline and after endotoxin, on-line measurements of exhaled NO (eNO) were made using a chemiluminescence technique with a single-breath method. NO-free air was inhaled prior to exhalation against a resistance. NO in orally and nasally exhaled air and in rectal gas was investigated. Plasma nitrite, nitrate, and guanosine 3', 5'-monophosphate (cGMP) and the events after diclophenac administration were also studied. Endotoxin infusion resulted in tachycardia and fever. An early increase in oral eNO concentration was observed and oral eNO decreased after diclophenac administration. NO exhaled nasally, NO in rectum gas and nitrite/nitrate levels remained unchanged over the study period, cGMP increased after 4 h. These findings suggest an early increase in nitric oxide production from the lungs, probably due to increased activity of the constitutive nitric oxide synthase upon endotoxin stimulation. In contrast, nitric oxide production in the upper airways, measured as nasally exhaled nitric oxide and nitric oxide in rectal gas, remained unchanged. Further studies will elucidate if exhaled nitric oxide is a valuable marker of sepsis-induced lung injury and if monitoring of treatment is possible.
Sujet(s)
GMP cyclique/sang , Endotoxines/administration et posologie , Poumon/métabolisme , Monoxyde d'azote/métabolisme , Adulte , Analyse de variance , Humains , Lipopolysaccharides/administration et posologie , Mesures de luminescence , Mâle , Nitrates/sang , Nitrites/sang , Sepsie/métabolisme , Sepsie/physiopathologieRÉSUMÉ
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 micro m, 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.
Sujet(s)
Endotoxines/pharmacologie , Lipopolysaccharides/pharmacologie , Matrix metalloproteinase 9/métabolisme , Monoxyde d'azote/métabolisme , Adulte , Température du corps , Endotoxémie/métabolisme , Rythme cardiaque , Humains , Perfusions veineuses , Mâle , Matrix metalloproteinase 2/métabolismeRÉSUMÉ
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.
Sujet(s)
Adénosine , Adjuvants des anesthésiques , Analgésie obstétricale , Analgésiques morphiniques , Sufentanil , Adulte , Analgésiques morphiniques/administration et posologie , Méthode en double aveugle , Femelle , Humains , Injections rachidiennes , Grossesse , Sufentanil/administration et posologieRÉSUMÉ
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 (PaO(2)) 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<0.05) and increased PaO(2) from 21.7 (5.9) to 24.7 (4.8) kPa (P<0.01). During surgery, the shunt increased from 3.2 (2.8) to 5.2 (3.4)% to the same level as before pneumoperitoneum induction. No area with low V(A)Q was seen. Dead space ventilation amounted to 20.0 (1.2)% in the supine position and did not change during the investigation. CONCLUSIONS: In patients without heart or lung disease, pneumoperitoneum at an intra-abdominal pressure level of 11-13 mmHg causes a transient reduction of the pulmonary shunt. The mechanisms underlying the present finding remain to be elucidated.
Sujet(s)
Dioxyde de carbone , Cholécystectomie laparoscopique/effets indésirables , Pneumopéritoine/physiopathologie , Rapport ventilation-perfusion/physiologie , Adulte , Anesthésie , Volume sanguin/physiologie , Cathétérisme , Femelle , Hémodynamique/physiologie , Humains , Concentration en ions d'hydrogène , Hypercapnie/sang , Mâle , Adulte d'âge moyen , Gaz rares , Échanges gazeux pulmonaires , Tests de la fonction respiratoireRÉSUMÉ
The present study assessed the efficacy and potency of intrathecal (i.t.) administration of the opiate morphine, the gamma-aminobutyric acid-B (GABA(B)) receptor agonist baclofen, the alpha2-adrenoceptor agonist clonidine and the adenosine A1-receptor agonist R-phenylisopropyl-adenosine (R-PIA) on the acute allodynia-like behaviour after photochemically induced spinal cord injury (SCI) in rats. Rats displaying allodynia-like behaviours to brushing, von Frey hairs and cold stimulation 1-2 days after photochemically induced SCI were studied. In a cumulative dose regime, morphine (0.1-10 micrcog), baclofen (0.1-1 microg), clonidine (0.1-10 microg) and R-PIA (0.01-10 nmol) were administered i.t. through an implanted catheter at the lumbar spinal cord. All tested drugs dose-dependently reduced the brushing, von Frey hairs and cold stimulation-induced allodynia-like behaviour. No increase in adverse effects such as motor deficits was found for morphine, clonidine and R-PIA. There was a slight increase in motor impairments at the highest dose of baclofen. For the mechanical allodynia, morphine appeared to be most effective, whereas baclofen, clonidine and R-PIA only provided a partial alleviation. For the cold allodynia, morphine and baclofen were more effective than clonidine and R-PIA. In relieving acute mechanical and cold allodynia-like behaviours in rats 1-2 days after SCI, i.t. morphine and baclofen were superior to clonidine and R-PIA.
Sujet(s)
Adénosine/analogues et dérivés , Adénosine/pharmacologie , Agonistes alpha-adrénergiques/pharmacologie , Analgésiques morphiniques/pharmacologie , Baclofène/pharmacologie , Clonidine/pharmacologie , Agonistes GABA/pharmacologie , Morphine/pharmacologie , Névralgie/traitement médicamenteux , Neuroprotecteurs/pharmacologie , Animaux , Comportement animal/effets des médicaments et des substances chimiques , Femelle , Injections rachidiennes , Ischémie/complications , Ischémie/traitement médicamenteux , Névralgie/étiologie , Rats , Rat Sprague-Dawley , Chlorure de sodium/pharmacologie , Moelle spinale/vascularisation , Moelle spinale/physiopathologieRÉSUMÉ
The influence of adenosine infusion (40 microg/kg/min for 4 h) on inflammatory and hemostatic parameters was investigated in healthy males without (n = 10) or with (n = 11) intravenous endotoxin injection (4 ng/kg). Without endotoxin, adenosine elevated circulating leukocytes and circulating platelet-leukocyte aggregates. Endotoxin activated platelets and leukocytes in vivo. Platelet activation was seen as slightly increased platelet P-selectin expression, decreased platelet counts, and elevated plasma soluble P-selectin (from 39.6 +/- 3.4 to 68.9 +/- 6.6 ng/ml, P<0.01). Leukocyte activation was evidenced by increased CD1 lb expression (from MFI of 0.54 +/- 0.02 to 2.21 +/- 0.17; P<0.01) and plasma elastase levels (from 25.3 +/- 2.5 to 169.3 +/- 22.5 ng/ml: P <0.01). Endotoxin also enhanced platelet and leukocyte responsiveness to in vitro stimulation. Endotoxin induced von Willebrand factor secretion (from 92 +/- 8 units to 265 +/- 19 units at 4 h; P <0.001) and enhanced thrombin generation in vivo. Endotoxin induced leukocytosis and thus increased circulating platelet-leukocyte, mainly platelet-neutrophil, aggregates. Adenosine caused slight attenuation of platelet reactivity to agonist stimulation, enhanced the endotoxin-induced leukocytosis, and detained more platelet-leukocyte aggregates in circulation, but did not attenuate endotoxin-induced neutrophil elastase secretion, von Willebrand factor secretion, or thrombin generation. Thus, endotoxemia induces multi-cellular activation in vivo. Adenosine inhibits leukocyte adhesion and extravasation, and mildly attenuates platelet responsiveness and soluble P-selectin release. Adenosine has the potential of becoming a therapeutic antiinflammatory drug, but an optimal treatment strategy needs to be developed.
Sujet(s)
Adénosine/administration et posologie , Endotoxines/pharmacologie , Activation plaquettaire/effets des médicaments et des substances chimiques , Adénosine/pharmacologie , Adulte , Adhérence cellulaire/effets des médicaments et des substances chimiques , Études croisées , Méthode en double aveugle , Tests hématologiques , Hémodynamique , Humains , Inflammation , Perfusions veineuses , Leucocytes/effets des médicaments et des substances chimiques , Antigène macrophage 1/sang , Antigène macrophage 1/effets des médicaments et des substances chimiques , Mâle , Sélectine P/effets des médicaments et des substances chimiques , Sélectine P/métabolisme , Fragments peptidiques/sang , Fragments peptidiques/effets des médicaments et des substances chimiques , Placebo/administration et posologie , Prothrombine/effets des médicaments et des substances chimiques , Facteur de von Willebrand/effets des médicaments et des substances chimiques , Facteur de von Willebrand/métabolismeRÉSUMÉ
BACKGROUND: N-methyl-D-aspartate-receptor antagonists may be useful in pain management. The aim of this study was to evaluate dextromethorphan (DEX), a commonly used oral antitussive drug with NMDA-receptor antagonistic properties, in respect of its analgesic properties as single drug and co-administered with morphine (MO) on experimental ischemic pain. In addition, the analgesic effects of another clinically available NMDA-receptor antagonist, ketamine (KET) as well as of morphine (MO) were tested as active controls. METHODS: Nineteen healthy volunteers were included in the study. Experimental ischemic pain was induced using the forearm tourniquet test. Placebo (PLAC), oral DEX (30 and 90 mg, respectively), KET (9 microg kg(-1) min(-1) i.v.), MO (0.1 mg kg(-1), i.v.) and the DEX+MO and KET+MO combinations were evaluated during eight separate experiments. Development of ischemic pain was rated by visual analog scale (VAS) every minute over 30 min and ratings were summed as sum of pain scores (SPS). RESULTS: DEX by itself did not influence SPS compared to PLAC. The DEX+MO co-administration did not enhance MO-induced analgesia. MO and KET reduced pain ratings by 27% and 39%, respectively. The KET+MO combination showed no enhancement of the analgesic effect in comparison with the respective drugs in monotherapy. CONCLUSION: DEX in clinical doses has no effect on the present acute ischemic pain model and does not influence MO-induced analgesia. Further studies on other pain modalities are needed in order to evaluate the potential use of DEX in pain treatment.
Sujet(s)
Analgésiques/pharmacologie , Dextrométhorphane/pharmacologie , Mesure de la douleur , Douleur/traitement médicamenteux , Récepteurs du N-méthyl-D-aspartate/antagonistes et inhibiteurs , Adulte , Analgésiques/effets indésirables , Analgésiques morphiniques/effets indésirables , Analgésiques morphiniques/usage thérapeutique , Dextrométhorphane/effets indésirables , Association médicamenteuse , Femelle , Humains , Ischémie , Contraction isotonique/effets des médicaments et des substances chimiques , Mâle , Morphine/effets indésirables , Morphine/usage thérapeutique , Douleur/étiologieRÉSUMÉ
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 microg 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.
Sujet(s)
Adénosine/usage thérapeutique , Analgésiques non narcotiques/usage thérapeutique , Hystérectomie , Douleur postopératoire/traitement médicamenteux , Adénosine/administration et posologie , Adénosine/effets indésirables , Adulte , Sujet âgé , Analgésie autocontrôlée , Analgésiques non narcotiques/administration et posologie , Analgésiques non narcotiques/effets indésirables , Anesthésie , Méthode en double aveugle , Femelle , Hémodynamique/effets des médicaments et des substances chimiques , Humains , Injections rachidiennes , Période peropératoire , Adulte d'âge moyen , Mesure de la douleurRÉSUMÉ
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.