Venous admixture as a measure of pulmonary gas exchange was studied before and during laparascopi... more Venous admixture as a measure of pulmonary gas exchange was studied before and during laparascopic cholecystectomy in 12 patients with normal healthy cardio-pulmonary function. After induction of anaesthesia the patients were studied by radial and pulmonary arterial catheterization and simultaneous arterial and mixed venous blood gas sampling in the horizontal, 15-20 degrees head-down and 15-20 degrees head-up tilt positions. After establishing the pneumoperitoneum (PP) by insufflation of carbon dioxide to an intraabdominal pressure level of 11-12 mmHg, the measurements were repeated in the same positions. The laparoscopic cholecystectomy then started and measurements were repeated every 30 min during surgery. The venous admixture was 4 +/- 0.6% (range 2-6%) in the horizontal position and was not influenced by altered body position. Immediately after establishment of PP, there was a 31 +/- 5% (P < 0.05) reduction of venous admixture and a 15 +/- 3% (P < 0.01) elevation of PaO2...
Scandinavian Journal of Urology and Nephrology, 1989
The effects of diclofenac sodium on the kidneys were studied during 4 1/2 hours in eight patients... more The effects of diclofenac sodium on the kidneys were studied during 4 1/2 hours in eight patients with normal renal function. Urinary output decreased within 10 min after the injection, and maximally by 80%. The renal plasma flow and the glomerular filtration rate initially diminished significantly, by 35%, but began to increase after only 2 hours. The dominant and persistent effect was reduction of free water clearance, with maximum fall from 5.9 to 0.08 ml/min after 2 1/2 hours. The long-lasting increased tubular reabsorption of water probably is important for the lowered intrapelvic pressure that is associated with good analgetic effect of diclofenac in ureteral colic.
The mechanisms underlying the functional effects of neuropeptide Y (NPY)-like immunoreactivity (L... more The mechanisms underlying the functional effects of neuropeptide Y (NPY)-like immunoreactivity (LI) and noradrenaline (NA) and their release evoked by nerve stimulation were studied with the blood-perfused pig spleen in vivo. Infusion of selective agonists and antagonists suggested the presence of alpha 1- and beta 2-adrenoceptors mediating vasoconstriction and vasodilatation, respectively. NPY caused a slight inhibition of stimulation-evoked [3H]NA release and a clearcut non-adrenergic vasoconstriction. Local pretreatment with phentolamine and prazosin as well as with clonidine and UK 14304 reduced the perfusion pressure response to nerve stimulation. Phentolamine, yohimbine and idazoxan enhanced while clonidine and UK 14304 decreased the output of [3H]NA or NA and NPY-LI. The subsequent addition of propranolol to the alpha-adrenoceptor antagonists was followed by reappearance at a considerable portion of the perfusion pressure response while the output of [3H]NA or NA and NPY-LI was slightly reduced. It is concluded that NPY exerts pre- and post-junctional actions in pig spleen that regulate both NA release and vascular tone. alpha 1-Adrenoceptors are mainly involved in vasoconstriction, and prejunctional alpha 2 mechanisms inhibit both NA and NPY release at a low frequency of stimulation. beta 2-Adrenoceptors mediate vasodilatation when NA release is enhanced with a minor effect on mediator secretion.
Endotoxin is a major stimulus for triggering the host response in septicaemia. The pathophysiolog... more 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. 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. 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 &amp;amp;lt; 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. 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.
Background Several animal studies show antinociceptive effects of intrathecally administered aden... more Background Several animal studies show antinociceptive effects of intrathecally administered adenosine and its analogs. However, there is no clinical experience regarding the effects of intrathecal adenosine in humans. Methods The side effects and analgesic effects of intrathecal adenosine (500-2,000 microg) on experimental pain were studied in 12 healthy volunteers. Before and after adenosine was given, the authors evaluated the cold pain rating of the foot (submersion in ice water for 1 min), the forearm ischemic pain rating during a 30-min tourniquet test, and the thermal and tactile pain thresholds on healthy and inflamed skin after application of mustard oil (4 min) to the calf. The areas of secondary allodynia surrounding the inflammation were also determined. The cerebrospinal fluid level of adenosine was determined before and after injection. Results Intrathecal adenosine caused a 1,000- to 2,000-fold elevation of the cerebrospinal fluid concentration. One volunteer experien...
1. Haemodynamic and metabolic effects of intravenous infusion of adenosine, an endogenous vasodil... more 1. Haemodynamic and metabolic effects of intravenous infusion of adenosine, an endogenous vasodilator, were studied in healthy humans. 2. Catheters were inserted into pulmonary and brachial arteries and into the hepatic and subclavian veins. Cardiac output was determined according to the Fick principle, and splanchnic blood flow was measured by using extraction of Indocyanine Green. Skin blood flow was estimated by a laser Doppler technique, calf blood flow by venous occlusion plethysmography and skeletal muscle and adipose tissue blood flow by a local isotope clearance technique. 3. Adenosine (infused in steps from 40 to 80 μg min−-1 kg−-1 into a central vein) elicited a gradual reduction in the peripheral vascular resistance to less than 50% of the basal level. There was a slight increase in the systemic blood pressure, but the pulmonary arterial and the ventricular filling pressures were unchanged. Cardiac output was doubled, accomplished by a combination of a positive chronotrop...
The aim of this in vitro study was to evaluate the effect of a clinical concentration (2 microM) ... more The aim of this in vitro study was to evaluate the effect of a clinical concentration (2 microM) of dipyridamole alone or in combination with adenosine, 5&#39;-N-ethyl-carboxamido-adenosine (NECA), or prostaglandin E2 on ADP-induced whole blood aggregability. Cyclic AMP accumulation in platelet-rich plasma was also evaluated. For comparison, R-E 244 (a dipyridamole analogue with low phosphodiesterase inhibition) was examined. In whole blood, dipyridamole (2 microM), but not R-E 244 (2 microM), had a small inhibitory effect (16% +/- 5%, p less than 0.01) on aggregation. Adenosine (1 or 5 microM) had an inhibitory effect that was enhanced by the combination with dipyridamole or R-E 244. Adenosine + dipyridamole produced an inhibition almost equal to that of adenosine + R-E 244. Dipyridamole and R-E 244 had no influence on the antiaggregatory effect of NECA and prostaglandin E2. In platelet-rich plasma, dipyridamole and R-E 244 did not enhance cyclic AMP, nor did they reinforce the cyclic AMP production during treatment with adenosine, NECA, and prostaglandin E2. Our results suggest that inhibition of the uptake of adenosine into red blood cells may play a more important role than the inhibition of phosphodiesterase as the pharmacological mechanism for the antiaggregatory effect of dipyridamole in clinical treatment.
Adenosine, a potent vasodilator both in animals and in humans, has been used to produce controlle... more Adenosine, a potent vasodilator both in animals and in humans, has been used to produce controlled hypotension in patients, especially during cerebral aneurysm surgery. However, in animals adenosine by intrarenal infusion decreases renal blood flow (RBF), glomerular filtration rate (GFR), urine flow, and causes an inhibition of renin secretion. In this study we evaluated the effect of adenosine on RBF in patients (n = 15) scheduled for cerebral aneurysm surgery who had been anesthetized with a modified neurolept-anesthesia during controlled hyperventilation. Perioperative hypotension was achieved with infusion of adenosine (252.8 +/- 55.8 micrograms.kg-1.min-1) (n = 8) or sodium nitroprusside (2.5 +/- 0.8 micrograms.kg-1.min-1) (n = 7). Mean arterial pressure was lowered by 25%-30%, to approximately 60-70 mm Hg, in both groups. Glomerular filtration rate and RBF were measured using standard renal clearance methods for 51Cr-ethylenediaminetetraacetic acid and paraaminohippuric acid. Urine and blood samples were collected during normotension before and after a bolus dose of hypertonic mannitol, during hypotension, and during normotension after clipping of the aneurysm. Adenosine induced a marked decrease in GFR (-91%) and RBF (-92%), and a pronounced increase in renal vascular resistance. Sodium nitroprusside caused a significantly (P less than 0.01) less pronounced decrease in GFR (-24%) and RBF (-36%), but did not affect renal vascular resistance. After discontinuation of the hypotensive agents, GFR returned to baseline levels in both groups. Renal blood flow, however, increased above baseline after discontinuation of adenosine (+93%) but not after sodium nitroprusside. Sodium nitroprusside increased renin secretion, which was not seen with adenosine. Four patients in the adenosine group developed reversible atrioventricular conduction disturbances.(ABSTRACT TRUNCATED AT 250 WORDS)
The splanchnic region is particularly susceptible to shock. The purpose of this study was to eval... more The splanchnic region is particularly susceptible to shock. The purpose of this study was to evaluate microdialysis of the liver and small intestine as a monitor of splanchnic metabolic deterioration (elevation of lactate and hypoxanthine) in porcine endotoxic shock. Tonometry of the small intestine was used as a reference. Microdialysis probes (liver, ileum, and artery), tonometer, and pulmonary artery catheter were inserted. Eight animals were given Escherichia coli lipopolysaccharide endotoxin (20 μg kg-1 h-1 for 2 h). Five animals served as controls. Measurements were made every half-hour. Three hours after onset of endotoxin challenge, there were significant differences between endotoxin and control groups in intestinal lactate and hypoxanthine, as well as liver lactate, in addition to mucosal pH obtained by tonometry. Lactate elevation in blood was first seen at 4 h, while there was no significant hypoxanthine elevation in arterial blood over 5 h. Hence, data obtained from the splanchnic region became significantly different early, when compared with data obtained from arterial blood. Microdialysis of liver and small intestine as well as intestinal tonometry are sensitive tools for detection of splanchnic metabolic deterioration during endotoxin shock.
Venous admixture as a measure of pulmonary gas exchange was studied before and during laparascopi... more Venous admixture as a measure of pulmonary gas exchange was studied before and during laparascopic cholecystectomy in 12 patients with normal healthy cardio-pulmonary function. After induction of anaesthesia the patients were studied by radial and pulmonary arterial catheterization and simultaneous arterial and mixed venous blood gas sampling in the horizontal, 15-20 degrees head-down and 15-20 degrees head-up tilt positions. After establishing the pneumoperitoneum (PP) by insufflation of carbon dioxide to an intraabdominal pressure level of 11-12 mmHg, the measurements were repeated in the same positions. The laparoscopic cholecystectomy then started and measurements were repeated every 30 min during surgery. The venous admixture was 4 +/- 0.6% (range 2-6%) in the horizontal position and was not influenced by altered body position. Immediately after establishment of PP, there was a 31 +/- 5% (P < 0.05) reduction of venous admixture and a 15 +/- 3% (P < 0.01) elevation of PaO2...
Scandinavian Journal of Urology and Nephrology, 1989
The effects of diclofenac sodium on the kidneys were studied during 4 1/2 hours in eight patients... more The effects of diclofenac sodium on the kidneys were studied during 4 1/2 hours in eight patients with normal renal function. Urinary output decreased within 10 min after the injection, and maximally by 80%. The renal plasma flow and the glomerular filtration rate initially diminished significantly, by 35%, but began to increase after only 2 hours. The dominant and persistent effect was reduction of free water clearance, with maximum fall from 5.9 to 0.08 ml/min after 2 1/2 hours. The long-lasting increased tubular reabsorption of water probably is important for the lowered intrapelvic pressure that is associated with good analgetic effect of diclofenac in ureteral colic.
The mechanisms underlying the functional effects of neuropeptide Y (NPY)-like immunoreactivity (L... more The mechanisms underlying the functional effects of neuropeptide Y (NPY)-like immunoreactivity (LI) and noradrenaline (NA) and their release evoked by nerve stimulation were studied with the blood-perfused pig spleen in vivo. Infusion of selective agonists and antagonists suggested the presence of alpha 1- and beta 2-adrenoceptors mediating vasoconstriction and vasodilatation, respectively. NPY caused a slight inhibition of stimulation-evoked [3H]NA release and a clearcut non-adrenergic vasoconstriction. Local pretreatment with phentolamine and prazosin as well as with clonidine and UK 14304 reduced the perfusion pressure response to nerve stimulation. Phentolamine, yohimbine and idazoxan enhanced while clonidine and UK 14304 decreased the output of [3H]NA or NA and NPY-LI. The subsequent addition of propranolol to the alpha-adrenoceptor antagonists was followed by reappearance at a considerable portion of the perfusion pressure response while the output of [3H]NA or NA and NPY-LI was slightly reduced. It is concluded that NPY exerts pre- and post-junctional actions in pig spleen that regulate both NA release and vascular tone. alpha 1-Adrenoceptors are mainly involved in vasoconstriction, and prejunctional alpha 2 mechanisms inhibit both NA and NPY release at a low frequency of stimulation. beta 2-Adrenoceptors mediate vasodilatation when NA release is enhanced with a minor effect on mediator secretion.
Endotoxin is a major stimulus for triggering the host response in septicaemia. The pathophysiolog... more 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. 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. 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 &amp;amp;lt; 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. 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.
Background Several animal studies show antinociceptive effects of intrathecally administered aden... more Background Several animal studies show antinociceptive effects of intrathecally administered adenosine and its analogs. However, there is no clinical experience regarding the effects of intrathecal adenosine in humans. Methods The side effects and analgesic effects of intrathecal adenosine (500-2,000 microg) on experimental pain were studied in 12 healthy volunteers. Before and after adenosine was given, the authors evaluated the cold pain rating of the foot (submersion in ice water for 1 min), the forearm ischemic pain rating during a 30-min tourniquet test, and the thermal and tactile pain thresholds on healthy and inflamed skin after application of mustard oil (4 min) to the calf. The areas of secondary allodynia surrounding the inflammation were also determined. The cerebrospinal fluid level of adenosine was determined before and after injection. Results Intrathecal adenosine caused a 1,000- to 2,000-fold elevation of the cerebrospinal fluid concentration. One volunteer experien...
1. Haemodynamic and metabolic effects of intravenous infusion of adenosine, an endogenous vasodil... more 1. Haemodynamic and metabolic effects of intravenous infusion of adenosine, an endogenous vasodilator, were studied in healthy humans. 2. Catheters were inserted into pulmonary and brachial arteries and into the hepatic and subclavian veins. Cardiac output was determined according to the Fick principle, and splanchnic blood flow was measured by using extraction of Indocyanine Green. Skin blood flow was estimated by a laser Doppler technique, calf blood flow by venous occlusion plethysmography and skeletal muscle and adipose tissue blood flow by a local isotope clearance technique. 3. Adenosine (infused in steps from 40 to 80 μg min−-1 kg−-1 into a central vein) elicited a gradual reduction in the peripheral vascular resistance to less than 50% of the basal level. There was a slight increase in the systemic blood pressure, but the pulmonary arterial and the ventricular filling pressures were unchanged. Cardiac output was doubled, accomplished by a combination of a positive chronotrop...
The aim of this in vitro study was to evaluate the effect of a clinical concentration (2 microM) ... more The aim of this in vitro study was to evaluate the effect of a clinical concentration (2 microM) of dipyridamole alone or in combination with adenosine, 5&#39;-N-ethyl-carboxamido-adenosine (NECA), or prostaglandin E2 on ADP-induced whole blood aggregability. Cyclic AMP accumulation in platelet-rich plasma was also evaluated. For comparison, R-E 244 (a dipyridamole analogue with low phosphodiesterase inhibition) was examined. In whole blood, dipyridamole (2 microM), but not R-E 244 (2 microM), had a small inhibitory effect (16% +/- 5%, p less than 0.01) on aggregation. Adenosine (1 or 5 microM) had an inhibitory effect that was enhanced by the combination with dipyridamole or R-E 244. Adenosine + dipyridamole produced an inhibition almost equal to that of adenosine + R-E 244. Dipyridamole and R-E 244 had no influence on the antiaggregatory effect of NECA and prostaglandin E2. In platelet-rich plasma, dipyridamole and R-E 244 did not enhance cyclic AMP, nor did they reinforce the cyclic AMP production during treatment with adenosine, NECA, and prostaglandin E2. Our results suggest that inhibition of the uptake of adenosine into red blood cells may play a more important role than the inhibition of phosphodiesterase as the pharmacological mechanism for the antiaggregatory effect of dipyridamole in clinical treatment.
Adenosine, a potent vasodilator both in animals and in humans, has been used to produce controlle... more Adenosine, a potent vasodilator both in animals and in humans, has been used to produce controlled hypotension in patients, especially during cerebral aneurysm surgery. However, in animals adenosine by intrarenal infusion decreases renal blood flow (RBF), glomerular filtration rate (GFR), urine flow, and causes an inhibition of renin secretion. In this study we evaluated the effect of adenosine on RBF in patients (n = 15) scheduled for cerebral aneurysm surgery who had been anesthetized with a modified neurolept-anesthesia during controlled hyperventilation. Perioperative hypotension was achieved with infusion of adenosine (252.8 +/- 55.8 micrograms.kg-1.min-1) (n = 8) or sodium nitroprusside (2.5 +/- 0.8 micrograms.kg-1.min-1) (n = 7). Mean arterial pressure was lowered by 25%-30%, to approximately 60-70 mm Hg, in both groups. Glomerular filtration rate and RBF were measured using standard renal clearance methods for 51Cr-ethylenediaminetetraacetic acid and paraaminohippuric acid. Urine and blood samples were collected during normotension before and after a bolus dose of hypertonic mannitol, during hypotension, and during normotension after clipping of the aneurysm. Adenosine induced a marked decrease in GFR (-91%) and RBF (-92%), and a pronounced increase in renal vascular resistance. Sodium nitroprusside caused a significantly (P less than 0.01) less pronounced decrease in GFR (-24%) and RBF (-36%), but did not affect renal vascular resistance. After discontinuation of the hypotensive agents, GFR returned to baseline levels in both groups. Renal blood flow, however, increased above baseline after discontinuation of adenosine (+93%) but not after sodium nitroprusside. Sodium nitroprusside increased renin secretion, which was not seen with adenosine. Four patients in the adenosine group developed reversible atrioventricular conduction disturbances.(ABSTRACT TRUNCATED AT 250 WORDS)
The splanchnic region is particularly susceptible to shock. The purpose of this study was to eval... more The splanchnic region is particularly susceptible to shock. The purpose of this study was to evaluate microdialysis of the liver and small intestine as a monitor of splanchnic metabolic deterioration (elevation of lactate and hypoxanthine) in porcine endotoxic shock. Tonometry of the small intestine was used as a reference. Microdialysis probes (liver, ileum, and artery), tonometer, and pulmonary artery catheter were inserted. Eight animals were given Escherichia coli lipopolysaccharide endotoxin (20 μg kg-1 h-1 for 2 h). Five animals served as controls. Measurements were made every half-hour. Three hours after onset of endotoxin challenge, there were significant differences between endotoxin and control groups in intestinal lactate and hypoxanthine, as well as liver lactate, in addition to mucosal pH obtained by tonometry. Lactate elevation in blood was first seen at 4 h, while there was no significant hypoxanthine elevation in arterial blood over 5 h. Hence, data obtained from the splanchnic region became significantly different early, when compared with data obtained from arterial blood. Microdialysis of liver and small intestine as well as intestinal tonometry are sensitive tools for detection of splanchnic metabolic deterioration during endotoxin shock.
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