Mechanisms involved in the relaxing effect of midazolam on coronary arteries.

BACKGROUND AND OBJECTIVE: Hypotension, especially in elderly and hypovolaemic patients, is frequently associated with intravenous midazolam administration. The mechanisms are not completely understood. This study was designed to investigate the mechanisms involved in the relaxing effect of midazolam on coronary arteries. METHODS: The substance was studied in isolated porcine coronary artery rings precontracted by either potassium chloride or prostaglandin F2alpha. RESULTS: Midazolam caused vasodilatation in a concentration-dependent manner. Relaxation was more pronounced in prostaglandin F2alpha precontracted segments than in those treated with potassium chloride (P < 0.001). Vasodilatation was unaffected by Nomega-nitro-L-arginine, indomethacin and glibenclamide. Tetraethylammonium chloride, an inhibitor of the BK(Ca) K+ channel (a high conductance Ca(2+)-sensitive K+ channel), dose dependently attenuated the vasodilating effect of midazolam (P < 0.01). CONCLUSIONS: Hyperpolarization of the smooth muscle cell in the vessel wall, elicited by the activation the BK(Ca) K+ channel, may contribute to the vasorelaxing effect of midazolam.

Ketamine enantiomers differentially relax isolated coronary artery rings.

BACKGROUND AND OBJECTIVE: It has been shown that racemic ketamine increases coronary blood flow and that this effect is at least in part due to a direct vasorelaxing effect of this substance. This study was designed to determine whether ketamine might stereoselectively relax isolated porcine coronary arteries. METHODS: Using the model of isolated vessels we studied the effects of S(+) ketamine, R(-) ketamine, and racemic ketamine (5-500 microg mL(-1)) on artery strips pre-contracted by either potassium chloride (KCl) or prostaglandin F2alpha (PGF2alpha). To elucidate possible mechanisms of action these experiments were repeated in the presence of one of the following compounds: N(omega)-nitro-L-arginine (L-NNA), indomethacin, glibenclamide, and tetraethylammonium (TEA) chloride, an inhibitor of the BK(Ca) K+ channel. RESULTS: Both isoforms and racemic ketamine relaxed isolated coronary arteries in a concentration-dependent manner in concentrations beyond those used in clinical practice. S(+) ketamine exerted the strongest vasorelaxing effect, followed by racemic ketamine and R(-) ketamine. Pretreatment with L-NNA, indomethacin, or glibenclamide did not alter the vasodilating properties of ketamine, whereas TEA chloride significantly attenuated the vasorelaxing effects of all the three forms of ketamine. CONCLUSIONS: Ketamine dilates coronary arteries in vitro when administered in high concentrations. There is a stereoselective difference with a stronger vasorelaxing effect of S(+) ketamine compared to racemic and R(-) ketamine. The impact of TEA chloride suggests that the activation of the BK(Ca) channel may contribute to the vasodilating effect of ketamine.

[Tracheotomy for the long-term ventilator-dependent patient?]. / Tracheotomie - Luftweg der Wahl für den langzeitbeatmeten Patienten?

OBJECTIVE: Tracheotomy is commonly performed in long-term ventilated patients. The aim of this review is to discuss the advantages and disadvantages of tracheotomy. METHODS: Review of the literature. RESULTS: Disadvantages of tracheotomy include the risk of bleeding, infection, injury of the truncus brachiocephalicus, and of long-term tracheal injury. These risks must be compared with the risk of vocal cord trauma, laryngeal trauma, and subglottic stenosis following translaryngeal intubation. Despite a number of disadvantages and potentially even life-threatening complications, however, tracheotomy is a well-established technique for long-term airway management in critically ill patients. Potential advantages of tracheotomy include enhanced patient comfort, reduced airway resistance and dead space, a lower incidence of ventilator-associated pneumonia and a shorter duration of mechanical ventilation and hospital stay. Patient comfort before and after tracheotomy has not yet been seriously evaluated, using modern ventilators airway resistance does not longer play a major role. No data from randomized controlled trials actually support the thesis that tracheotomy reduces the incidence of ventilator-associated pneumonia. There is weak evidence for the concept that the duration of mechanical ventilation can be reduced in patients while using tracheotomy. Patients undergoing percutaneous dilational tracheotomy seem to have a reduced risk of bleeding and site infection and a shorter duration of the procedure when compared to those with conventional surgical tracheotomy. CONCLUSIONS: Many clinicians perform tracheotomies on the basis of expert opinion and clinical experience. So far, the benefits, however, have not been proven in large-scale randomized trials. Many of these studies suffer from design flaws, insufficient randomization and the absence of blinding. On the other hand, the lack of positive results do not rule out that tracheotomy may be beneficial for the ventilator-dependent patient. Percutaneous tracheotomy procedures may be superior to conventional surgical tracheotomies. Long-term results, however, will have to prove this preliminary observation.

[Malposition of a central venous catheter in a patient with severe chest trauma]. / Fehllage eines zentralen Venenkatheters bei einem Patienten mit schwerem Thoraxtrauma.

The placement of a central venous catheter is associated with specific risks including malposition of the catheter. We report the case of a 32 year old man who suffered from a severe thoracic trauma including haematopneumothorax on his left side. In the emergency room a large-bore central venous catheter was placed in the left subclavian vein, after blood had been aspirated successfully. Later, the haemodynamic state of the patient deteriorated, so that cardiopulmonary resuscitation had to be started. While great amounts of blood transfusions were applied via the catheter using a rapid transfusion device, the blood loss over the left sided chest tube increased rapidly. Emergency thoracotomy was performed, revealing that the catheter was not in intravenous position, but in intrapleural malposition. Haematothorax was caused by a laceration of the upper lobe of the left lung with severe bleeding from great vessels. This case shows that successful aspiration of blood does not exclude malposition of a central venous catheter. Correct position of the catheter must be verified using appropriate methods including chest X-ray, intracardiac ECG tracing or display of the central venous pressure curve on a monitor.

Activation of the K+ channel BK(Ca) is involved in the relaxing effect of propofol on coronary arteries.

BACKGROUND AND OBJECTIVE: Propofol may cause undesirable hypotension due to vasodilation. The underlying mechanisms are not completely understood. We investigated the mechanisms by which propofol relaxes vascular segments. METHODS: We studied the effect of propofol on isolated porcine coronary artery rings precontracted with potassium chloride or prostaglandin F2alpha. RESULTS: Propofol, in a concentration-dependent manner, relaxed all segments at concentrations of 5 microg mL(-1) and above. This relaxation was unaltered in the presence of N(omega)-nitro-L-arginine, indomethacin, diltiazem and glibenclamide. Tetraethylammonium chloride, an inhibitor of the BK(Ca) K+ channel (a high conductance Ca2+-sensitive K+ channel), dose-dependently attenuated the vasodilating effect of propofol (P < 0.001). CONCLUSIONS: Our results suggests that the activation of the BK(Ca) channel may contribute to the vasodilating effect of propofol, hereby causing hyperpolarization of the smooth muscle membrane and reduction of smooth muscle tone.

[Ketamine attenuates the contractile response to vasoconstrictors in isolated coronary artery rings]. / Ketamin hemmt die Wirkung von Vasokonstriktoren an isolierten Koronararterien.

OBJECTIVE: Ketamine was shown to increase coronary blood flow. It was the aim of this study to answer the question whether ketamine directly dilates coronary arteries. METHODS: Using the model of isolated vessel rings we studied the effects of ketamine (2.5, 25, and 250 microg ml(-1)) on the contractile response to three vasoconstrictors, acetylcholine, histamine, and serotonin in porcine coronary artery segments. Other rings were contracted with KCl or PGF (2a) and then treated with ketamine (5 up to 500 microg ml(-1) added cumulatively). RESULTS: Ketamine dose-dependently dilated coronary arteries in concentrations beyond those used in clinical practice. In intact rings ketamine racemate (250 microg ml(-1)) attenuated contractions mediated by acetylcholine by 38.8 +/- 2.8%, histamine by 33.0 +/- 4.4% and serotonin by 42.1 +/- 3.7% (p < 0.05). There were no differences between intact and denuded rings (acetylcholine 38.5 +/- 2.8%, histamine 26.6 +/- 4.7%, serotonin 30.0 +/- 3.2%). With low concentrations of ketamine (2.5 microg ml(-1)) a slight tendency towards a contraction was recorded (n. s.). In rings precontracted with either KCl or PGF (2a) ketamine caused a small enhancement of contraction (KCl: 101.4 +/- 0.4%, PGF (2a): 101.3 +/- 1.4%) when administered in low concentration (5 microg ml(-1)), but almost complete relaxation (KCl: 0.4 +/- 1.3%, PGF (2a): 0.0 +/- 5.4%) in high concentration (500 microg ml(-1)). CONCLUSIONS: It is concluded that ketamine dose-dependently dilates porcine coronary arteries in concentrations beyond those used in clinical practice and that this effect is independent of endothelial function.

High-dose midazolam and the attenuation of the contractile response to vasoconstrictors in coronary artery segments.

BACKGROUND AND OBJECTIVE: Benzodiazepines may cause hypotension and are reported to interfere with smooth vascular muscle activity. The aim was to elucidate the influence of three different benzodiazepines on the vascular reactivity of coronary arteries. METHODS: Using the model of isolated vessels, we studied the impact of midazolam (0.15, 1.5, 15 microg mL(-1)), diazepam (0.1, 1.0, 10 microg mL(-1)) and flunitrazepam (0.01, 0.1, 1.0 microg mL(-1)) on the contractile responses to histamine (2 x 10(-5) mol L(-1)) and serotonin (3 x 10(-5) mol L(-1)) in isolated intact and denuded coronary arteries. RESULTS: Midazolam significantly attenuated the contractile response when administered in high concentrations (15 microg mL(-1)). This effect was more pronounced in intact than in denuded preparations (histamine: -22.7 versus -7.3%, P = 0.0079; serotonin: -47.1 versus -15.9%, P < 0.0001). Diazepam and flunitrazepam exerted no significant effects on the vascular tone of coronary arteries. CONCLUSIONS: Midazolam, but not diazepam or flunitrazepam, attenuates the contractile responses to vasoconstrictors in concentrations beyond those used in clinical practice. This effect is in part mediated by endothelial factors.

[Opioid intoxication following transdermal administration of fentanyl]. / Opioidintoxikation durch transdermales Fentanyl.

The case of a 77-year-old woman is described, who was found unconscious, with decreased respiration and miotic pupils, having previously experienced dizziness, nausea and drowsiness before. In the emergency room a fentanyl patch was detected, which had obviously been mistakenly applied by the patient the day before. Opioid intoxication was assumed and successfully treated with naloxon. The patient was supervised in an ICU for 24 h and sent home the next day without serious sequelae. The consequences following inappropriate use of transdermal fentanyl are discussed.

[F. W. Sertürner and the discovery of morphine. 200 years of pain therapy with opioids]. / F. W. Sertürner und die Entdeckung des Morphins - 200 Jahre Schmerztherapie mit Opioiden -

Since many centuries mankind has been aware of the poppy (papaver somniferum) and has known its product opium as an analgesic drug. Until the beginning of the 19 (th) century its compounds were not known, making it almost impossible to apply the substance in exact doses. 1803/04, Friedrich Wilhelm Sertürner (1783 - 1841) succeeded in isolating a crystalline substance from opium in the test tube, which he called morphium. In animals and in man he was able to prove that this new compound he had discovered was the principium somniferum of opium. He isolated morphine, the first pure opioid available for calculated pain therapy with one defined compound. Moreover, he laid the foundations of a new class of pharmaceutical drugs, the alcaloids.

Influence of opioids on the vascular tone of isolated porcine coronary artery segments.

BACKGROUND: It was the aim of this study to elucidate the influence of opioids on coronary vascular tone using the model of isolated porcine coronary artery segments. METHODS: We studied the effects of fentanyl (0.01, 0.1, 1.0 microg ml(-1)), alfentanil (0.1, 1.0, 10 microg ml(-1)), and sufentanil (0.01, 0.1, 1.0 microg ml(-1)) on the contractile response to three vasoconstrictors, acetylcholine, histamine and serotonin. RESULTS: Fentanyl (0.1, 1.0 microg x ml(-1)) dose-dependently attenuated the contractile response to acetylcholine, but not to histamine and serotonin. There were no differences in fentanyl's vasorelaxing potency between rings with intact and denuded endothelium. Alfentanil and sufentanil did not exert any significant influence on any of the vasoconstrictors tested. CONCLUSION: It is concluded that, in isolated porcine coronary artery rings, fentanyl at high concentrations has an attenuating effect on acetylcholine-induced contractions, which is independent of endothelial function, whereas alfentanil and sufentanil do not influence coronary vascular tone.

Do muscle relaxants influence vascular tone in isolated coronary artery segments?

The aim of this study was to elucidate the influence of four neuromuscular blocking substances on coronary vascular tone using the model of isolated porcine coronary artery segments. We studied the effects of four muscle relaxants, atracurium, pancuronium, rocuronium, and vecuronium (0.1, 1, and 10 microg mL-1 each), on the contractile response to three vasoconstrictors: acetylcholine, histamine, and serotonin. None of the neuromuscular blocking agents under investigation exerted a significant influence on the vasoconstricting effects of these mediators except for pancuronium, which dose-dependently attenuated acetylcholine-mediated contractions (-10.8% attenuation for 10 microg mL-1 pancuronium, P < 0.05). There was no difference between vessels with intact endothelium and denuded preparations. It is concluded that high-dose pancuronium exerts an antimuscarinic effect in vascular smooth muscle. The other neuromuscular agents studied do not alter vascular reactivity of isolated porcine coronary arteries.

Propofol and thiopental attenuate the contractile response to vasoconstrictors in human and porcine coronary artery segments.

The effects of propofol and thiopental on three vasoconstrictors, acetylcholine, histamine, and serotonin were studied in isolated porcine and human coronary artery rings. Propofol and thiopental attenuated the contractile response to all mediators in a dose-dependent manner. This dilating effect was fairly weak using low concentrations (propofol 1 microg mL-1 and 10 microg mL-1, thiopental 5 microg mL-1 and 10 microg mL-1). In the presence of high concentrations (propofol 100 microg mL-1, thiopental 50 microg mL-1) marked relaxation was observed (propofol -32% up to -49%, P < 0,05; thiopental -23% up to -67%, P < 0.05). These dilating effects were seen both in intact and denuded rings, the differences were not significant. Human coronary artery segments were relaxed by thiopental (-22% to -76%) and propofol (-11% to -67%) to a similar extent. Our data indicate that propofol and thiopental relax isolated coronary segments in a dose-dependent manner, and that there is no evidence that these effects are dependent of endothelial factors.