Effects of intravenous nonopioid anesthetics on the Cardiovascular System :Effects of intravenous nonopioid anesthetics on the Cardiovascular System Theodoros Aslanidis 2006 a review to the new and old facts


Nonopioid intravenous anesthetics :Nonopioid intravenous anesthetics 1. Propofol 2. Thiopental 3. Methohexital 4. Diazepam 5. Lorazepam 6. Midazolam 7. Ketamine ? Phencyclidines 8. Etomidate 9. Dexmedetomidine 10. Clonidine* 11. Droperidol ? Butyrophenones Barbiturates Bensodiazepines a2 -antagonists


Propofol :Propofol * -AuonC,Major E Anaesthesia 1984 ,39:1096-1100 - Grounds RM et al, Anaesthesia 1985,40:735-740 -Al-Khudhairi etal, Anaesthesia 1982,37:1007-1010 - Coates DP. Et al , Anesth. Analg. 1987 66:64-70 - Larsen R et all, Anaesthesia 1988, Suppl:35-31


Propofol (cont’d) :Propofol (cont’d) Clinically ,the myocardial depressant effect and the vasodilatation appear to be dependent on both the dose and the plasma concentration - Pagel M. and Wartlier DC., Anesthesiology 1993,78:100-108 -


Propofol (cont’d) :Propofol (cont’d) Possible mechanisms of vasodilatation: 1. Due to a reduction in Sympathetic activity - Ebert T.,Muzi M.,Goff D., Anesthesiology 1992,77:A337 2. A direct effect on intracellular smooth muscle Ca +2 -mobilization -Xuan YT.,Glass PS.,Br J Pharmacology 1996, 117:5-12 -Chang KS,Davis RF.,Anesth. Anelg 1993, 73:24-32 3. Inhibition of PC synthesis in endothelial cells -Yamashita et al., Anesthesiology 1999, 91:1080-1089


Propofol (cont’d) :Propofol (cont’d) Possible mechanisms of vasodilatation: (cont’d) ?4. Reduction of AT II – elicited Ca+2-entry -Samain et al., Anesth. Analg 2000, 90:546-552 ?5. Activation of K+ ATP channels, especially the high-conductance Ca+2 – sensitive K+ - channels -Schulze H. et al.,Eur J Anaesthesiol. 2004 Mar;21(3):226-30


Propofol (cont’d) :Propofol (cont’d) ?It has been suggested that propofol reset or inhibits the baroreflex ,thus reducing the tachycardiac response to atropine. -Ebert et al.,Anestesiology 1992, 76:725-733 ?It has minimal direct effect on SA node or on AV or accessory pathway conduction. However it is not a good choice for anaesthesia in congenital central hypoventilation syndrome. -Sochala C. et al. Paediatr Anaesth. 1999;9(4):349-51 -Sharpe MD. Et al., Anesthesiology 1995,82:888-895 ?It suppress SVRT (atrial) and should probably be avoided in electrophysiological studies. Wu M, Anest. Analg 1998,86:914 ?It inhibit the PS cardiac tone in proportion to the degree of sedation that it produces. -Kanaya N. et al., Anesthesiology 2003, 98:34-40


Propofol (cont’d) :Propofol (cont’d) Maintenance of Anaesthesia ? SAP remains between 20% and 30% below preinduction levels -Clayes MA et al., Br J Anaesth 1983,60:3-9 ? HR may increase, decrease or remain unchanged. Propofol may vary heart rate by modulating GABrgic neurotransmission to cardiac parasympathetic neurons -Patric MR et al, Postgrad Med J 1985,61(3):23-27 -Vermeyn KM st al., Br J Anaesth 1987,59:1115-1120 -Wang X. et al, Anesthesiology. 2004 May;100(5):1198-205 ? Results a significant reduction in both myocardial blood flow and MVO2 , a finding that suggests prevention of global supply-demand ratio -Stephan et al., Br J Anaesth 1986, 58:969-975


Propofol (cont’d) :Propofol (cont’d) ? On experimental models (isolated rat preparations) seemed to provide myocardial protection after ischemia and reperfusion. -Ko SH et al., Anesth Analg 1997,85:719-724 -Kokita et al.,Anesth Anlg 1998, 86:252-258 ?It seems that it has strong antioxidative activity .It seems that propofol provides dose-dependent protection primarily by enhancing tissue antioxidant capacity and reducing lipid peroxidation. -Masahiko T.et al, Am J Respir Crit Care Med 2001,163:26-31 -Godin DV. Et al, Can J Physiol Pharmacol. 2003 Jan;81(1):14-21 ?It is suggested as a useful adjunct to cardioplegic solutions as well as being an appropriate -Lim KH. Et al, Exp Biol Med (Maywood). 2005 Jun;230(6):413-20


Propofol (cont’d) :Propofol (cont’d) ? during a brief period of ischemia in patients undergoing MIDCAB surgery, sevoflurane preserved myocardial function better than propofol! - Bein B. et al., Anesth Analg. 2005 Mar;100(3):610-6, table of contents ? Trials in animal models suggest that propofol potentiates alpha-adrenoreceptor-mediated pulmonary vasoconstriction by inhibiting the concomitant production of prostacyclin by cyclooxygenase II. -Ogawa K. et al.,Anesthesiology. 2001 May;94(5):833-9. ?It increases the metabolism and oxygen consumption in the liver , expressed by decreased ShvO2 and increased OERspl (hepato-splanchnic oxygen extraction ratio ). -Fukuda I., Masui. 2005 Jul;54(7):736-41.


Barbiturates :Barbiturates ? Peripheral vasodilatation resulting in pooling blood in the venous system ?Decrease in CO due to : (1) direct negative inotropic effect* (2) decreased ventricular filling because of increased capacitance (3) decreased sympathetic outflow from CNS *In vitro myocardial depression by thiopental is dependent on the underlying beta-adrenergic tone. -Thurston T.,Mathew BP., Acta Anaesthesiol Scand. 1996 Mar;40(3):338-41


Barbiturates (cont’d) :Barbiturates (cont’d) ? Increase in HR (10 – 36%) *: probably due to baroreceptor-mediated sympathetic reflex stimulation of the heart in response to the drop of CO and BP. It leads to increase in MVO2 (NB! In patients with CAD). In hypovolemia it can cause a drop in CO up to 69%. -Dandee JW et al, Anaestesia 1961,16:50-61 -Sonntag et al. ,Acta Anaesthisiol Scand 1975,19:69-78 * it can be attenuated with fentanyl 1-3 µg/kgr ?Comparison of the effects of propofol and pentobarbital on left ventricular adaptation to an increased afterload showed that pentobarbital at 3 mg /kgr/h has less deleterious hemodynamic effects than propofol at 10 mg /kgr/h. -Kohl P et al.,J Cardiovasc Pharmacol. 2004 Sep;44(3):294-301


Benzodiazepines :Benzodiazepines * -Rao et al.,Clin Pharmacol Therap 1973,14182-189 -Dhalphale P et al., ASA 1977 ,paper -Jacson et al., Br J Anaesth 1978,50:375-378 -Sauelson et al.South Med J 1980,73:332-334 -Samuelson et al.,Anesth Analg. 1981,60:802-809


Benzodiazepines (cont’d) :Benzodiazepines (cont’d) * - Ruff R, Reves JG, J Cardiothorac Anesth.1990, 4:314-317


Benzodiazepines (cont’d) :Benzodiazepines (cont’d) * - Lebowitz et al.,Anest analg 1982,61:771-775 -Lebowitz P ,Cote M.,Can J Anaesth.1983, 30:19-23 - Marty J et al.. Anestesiology 1986,64:206-210


Benzodiazepines (cont’d) :Benzodiazepines (cont’d) ? Their peak haemodynamic effect is 10 min. after administration -Reves J et al. Can Anaest Soc j 1979,26:681-687 ?It predominates the decrease in SAP due to decrease in SVR. ? These effects are dose related, however there is a plateau plasma drug effect above which little in BP occurs -Sunzel M et al., Br J Clin Pharmacol 1988,42:101-1089


Benzodiazepines (cont’d) :Possible mechanism of the relative stable hemodynamics of benzodiazepines: -The prevention of homeostatic reflex mechanisms* ? In patients with elevated LV filling pressure, diazepam and midazolam produce a “nitroglycerine-like” effect by lowering the filling pressure and increasing CO. ?The stresses of endotracheal intubation and surgery are not blocked by midazolam. ?The combination with opioids have a supra-additive effect. -Reves J et al,Common problems in anaest. Year book 1987 ?There is evidence that diazepam and midazolam decrease catecholamines. - Marty J et al. Anesth Analg 1986,65:113-119 Benzodiazepines (cont’d)


Ketamine :Ketamine * - Tweed WA et al.,Anesthesiology 1972,37:613-619 - Nishimura K et al, Osaka city Med J 1973,19:17-26 - Tweed WA et al.,Anesthesiology 1974,41:49-52


Ketamine (cont’d) :Ketamine (cont’d) ? It stimulates the cardiovascular system . ? The haemodynamic changes are not related to the dose of ketamine (no difference between administration of 0.5 and 1.5 mg/kg i.v) -Zigmond E. et al ,Year book of anesthesia 1980,pg.283 ?It inhibits the K+ ATP – mediated vasorelaxation ,a direct effect on pulmonary vascular smooth muscle.* -Shon J.,Murray P. Anesthesiology. 2003 Jan;98(1):104-13 ? The 2nd dose of ketamine produces less or even the opposite haemodynamic effects. -Savege TM. Anesth Analg 1976,48:1071-1081


Ketamine (cont’d) :Possible mechanism for its actions 1. It inhibits baroreflexor function trough an effect on NMDA –R in n. tractus soliltarius. Injected directly to CNS produces an immediate S-nervous system hemodynamic effect. -Ogawa A.,Anestesiology 1993,78:163-167 -Ivankovich AD, Anest Analg 1974,53:924-933 2.It causes S-neuronal release of catecholamines. -Zigmond E. et al,Clin Pharmcol Ther 1974,15:223 3.It inhibits the intraneuronal uptake of catecholamines in a cocaine-like effect and the extraneuronal norepinephrine uptake. -Hill G.E. et al, Anesthesiology 48:315-319,1978 -Cook DJ. et al, J Pharmacol Exp Ther 261:101-107,1992 Ketamine (cont’d)


Ketamine (cont’d) :Ketamine (cont’d) -It can cause haemodynamic depression in the setting of deep anaesthesia when S - responses do not accompany its administration. -Stimulation of the cardiovascular system is not always desirable. Successful methods of blocking ketamine-related tachycardia and hypertension is co-administration of adrenergic blockers, vasodilatators, clonidine, benzodiazepines and inhaled anesthetics.


Etomidate :Etomidate * - Gooding JM. Et al, Anesth Analg 56:717-719,1977 - Gooding Jm. Et al., Anesth Analg 58:40-41,1979 - Kettler D. et al ., Anaesthesist 35:116-121,1974


Etomidate (cont’d) :? In patients with mitral or aortic valvular disease it may produce greater chamges in MAP (approx. 20% decrease) -Lindeburg T.et al, Acta Anaesthesiol Scand 26:205-208,1982 ? After induction (18mg) and infusion (2.4mg/min) it produces a 50% decrease in myocardial blood flow and oxygen consumption and a 20-30% increase in coronary blood flow.The oxygen demand-supply ratio is well maintained. -Larsen R. et al., Anaesthesia 43(Suppl):25-31,1988 ?It minimal effect on QT interval. -Lischke V. et al, Acta Anaesthesiol Scand 38:144-148,1994 Etomidate (cont’d)


Etomidate (cont’d) :Etomidate (cont’d) ?It has minimal negative inotropic effect. -Sprung J. et al, Anesth Analg 91:38-75,2000 ?In vascular procedures, it may inhibit the PLT function and thus result blood loss -Gries A. et al, Acta Anaesthesiol Scand 45:449-457,2001 ?It inhibits the K+ ATP – mediated vasorelaxation ,a direct effect on pulmonary vascular smooth muscle. -Shon J.,Murray P.. Anesthesiology. 2003 Jan;98(1):104-13. ?It LACKS ANALGESIC effect, and may not totally ablate S- response to laryngoscopy and intubation -Giese JL. Et al,Anesth Analg 64:871-876,1985


Dexmedetomidine :Dexmedetomidine ?The general effect of a2 – agonists are DECREASED HR,SVR and indirectly SBP,CO, myocardial contractility. Bolus dose: biphasic response ? i.v. 2 µgr/kgr ? ?HR by 27% ?BP by 22% in the first 5min. The HR returns to baseline 15min after, and the BP gradually to 15% of baseline by 1h. ? i.m. 2 µgr/kgr ? HR and BP within 10% of baseline. -Dyck J. et al., Anesthesiology 78:813-820,1993


Dexmedetomidine (cont’d) :Dexmedetomidine (cont’d) Infusion (target 0.7-1.5ng/ml): The lowest 2 concentrations? Decrease in MAP (13%) followed by progressive increase(12%). Increased concentrations caused a decrease in HR (max 29%) and CO(33%) -Ebert Tj. Et al, Anesthesiology 93:A1357,2000 ?Infusion has shown to result a compensated reduction of systemic S- tone without changes in baroreflex sensitivity


Dexmedetomidine (cont’d) :? It blunts the HR and systemic S-response to sweating but it’s less effective in blunting the cardiac S-response to shivering -Hogue CW et al., Anesthesiology 8:813-820,2002 In animal models: ? beneficial effect on the ischaemic heart through decreased oxygen consumption and redistribution of coronary blood flow from nonischaemic to ischaemic zones after artery occlusion -Roeckets P. et al.,J Cardiothorac Anesth 8:58,1994 ? decreased serum Lac. levels in coronary ischemia (decrease in HR and measured catecholamines) .and produced a 35% increase in the endocardial/ epicardial blood flow ratio. -Willigers H. et al., Anesth Analg. 96:657-764,2003 Dexmedetomidine (cont’d)


Droperidol :Droperidol * - Prys-Roberts C.et al.,Anesthesiology 39:134-145,1967 - Israel J. et al., Anesthesiology 26:253,1965


Droperidol (cont’d) :? It causes dose – dependent QT interval prolongation (!risk of torsades de pointes). It lengthens cardiac repolarization due to block of the rapid component of the delayed rectifier potassium current (I(K)r) -Drolet B. et al, J Car diovasc Electrophysiol. Dec;10(12):1597-604,1999 -Wooltorton E. et al, CMAJ 166:932,2002 ?It may have some quinidine –like (class IA) antiarrhythmic effect -Dich-Nielsen J. et al.,Acta Anaesthesiol Scand 36:583-587,1992 ?It produces vasodilatation with a decrease in blood pressure, an effect considered to be result from a moderate a-adrenergic blockade -Janssen P. et al., Arzneimittelforschung 13:205-211,1963 -Stanley T et al.,Can Anaesth Soc J 25:26-29,1978 Droperidol (cont’d)


Droperidol (cont’d) :Droperidol (cont’d) ? It has little effect on myocardial contractility - Yelonsky J. et al., Toxixol Appl Pharmacol 6:37-47,1964 ?It does not impair the dopamine-induced increase in renal blood flow. - Birch AA. Et al,Anesthesiology 47:70-71,1977 ? It causes rapid and marked ocular hypotension after i.v. administration .The retrobulbar changes consequent to the ocular tension reduction likely represent autoregulatory responses to altered ocular perfusion pressure. This agent may prove useful in the management of acute ocular hypertension -Hurris H. Eur J Ophthalmol. 2002 May-Jun;12(3):193-9.


Droperidol (cont’d) :Droperidol (cont’d) In animal models: ?It inhibits intracellular Ca2+, myofilament Ca2+ sensitivity, and contraction in ventricular myocytes - Shiga T. et al, Anesthesiology. 2005 Jun;102(6):1165-73


CNS hemodynamics during nonopioid i.v. anesthetic agents :CNS hemodynamics during nonopioid i.v. anesthetic agents *Protection against cerebral ischemia: pentobarbital>midazolam>diazepam