Direct cardiac effects of coronary site-directed thiopental and its enantiomers: a comparison to propofol in conscious sheep

BACKGROUND: Previous evidence from laboratory animal studies indicates that R-thiopental has a greater margin of safety than either the more potent S-thiopental or the clinically used rac-thiopental. Although thiopental can cause cardiovascular depression from direct myocardial effects as well as indirect central nervous system and peripheral effects, no studies have yet determined whether its myocardial effects are enantioselective. A lesser direct effect would provide further evidence supporting R-thiopental as a preferred single enantiomer replacement for rac-thiopental. METHODS: The direct myocardial effects of the thiopental enantiomers were compared to those of rac-thiopental and propofol, using a crossover design with small incremental doses infused over 3 min, on separate days, into the left coronary arteries of conscious sheep. Hemodynamic and electrocardiographic measurements were acquired, and serial blood samples were collected during the studies for drug analyses. RESULTS: All three forms of thiopental and propofol produced significant hemodynamic effects consisting of dose-related and rapid-onset decreases in left ventricular dP/dtmax and stroke volume, and increases in left coronary blood flow and heart rate. Cardiac output, mean arterial blood pressure, and central venous pressure remained unaltered. The effects did not differ significantly among rac-thiopental, enantiopure R- or S-thiopental, or propofol. Arterial blood drug concentrations were consistently less than those associated with systemic effects. CONCLUSIONS: Although previous evidence indicates that R-thiopental could make a suitable single-enantiomer replacement for rac-thiopental, the current study did not find a significant difference in direct cardiac effects among the thiopental enantiomers, racemate, or propofol.     

The effects of nicardipine on dynamic cerebral autoregulation in patients anesthetized with propofol and fentanyl

We investigated the effects of nicardipine on dynamic cerebral pressure autoregulation in 13 normal adult patients undergoing gynecologic or orthopedic surgery. Anesthesia was induced and maintained with propofol and fentanyl. Hypotension to a mean arterial pressure of 60-65 mm Hg was induced and maintained with a continuous infusion of nicardipine. Time-averaged mean blood flow velocity in the right middle cerebral artery was measured continuously by using transcranial Doppler ultrasonography. The cerebral autoregulatory responses were activated by releasing thigh cuffs. The actual blood flow velocity in the right middle cerebral artery response to acute change in mean arterial pressure was fitted to 1 of 10 computer-generated curves to determine the dynamic rate of cerebral autoregulation (dRoR), and the best fitting curve was used. The autoregulation test was repeated until two values of dRoR were obtained at baseline and during induced hypotension. Nicardipine significantly reduced dRoR values of 13.1% +/- 3.6%/s at baseline to 8.3% +/- 2.6%/s during hypotension (P: < 0.01). During deliberate hypotension induced by nicardipine, the cerebral dynamic autoregulatory response is impaired in normal adult patients. IMPLICATIONS: During deliberate hypotension induced by nicardipine, the cerebral dynamic autoregulatory response is impaired in normal adult patients.     

Hemodynamic and coronary vascular effects of dexmedetomidine in the anesthetized goat

Background: In phase III trials, the hemodynamic stabilising effect of the α₂-adrenergic agonist dexmedetomidine (DEX) is being investigated in patients with coronary artery disease. Coronary vascular effects of α₂-agonists have been studied in dogs and pigs, but both species have a different hemodynamic response to DEX than man. The aim of this study was to investigate the hemodynamic and coronary vascular effects in goats.
Methods: In 6 open-chest goats anesthetized with halothane, central and coronary hemodynamics and oxygen supply and demand were measured before and following IV bolus infusion of DEX in doses ranging from 0.1 to 10 μg/kg.
Results: With DEX doses of 1 μg/kg or higher, mean arterial pressure (MAP), systemic vascular resistance, coronary vascular resistance and arterio-mixed venous oxygen content increased within 2 min, but returned to baseline within 15 min. In contrast, there was a progressive and cumulative decrease in cardiac output (CO), heart rate, and dP/dt_max. Regional coronary venous oxygen extraction (C(a-cv)O₂) transiently increased after 3 μg/kg DEX and decreased 15 min after 10 μg/kg DEX. LVEDP transiently increased after 3 and 10 μg/kg DEX. The changes after DEX 10 μg/kg differed from those after lower doses: MAP (35%), CO (50%), stroke volume (33%), C(a-cv)O₂ (15%) and myocardial oxygen extraction (33%) were all decreased. Myocardial oxygen supply and demand decreased in parallel.
Conclusions: 1) The cardiovascular response to IV DEX in goats is similar to man. 2) In goats after DEX, systemic and coronary vasoconstriction are short-lived, and 3) the balance between myocardial oxygen supply and demand is maintained.     

Prolonged dysequilibrium between blood and brain concentrations of propofol during infusions in sheep

BACKGROUND: Previous work had shown dysequilibrium between the arterial blood and brain concentrations of the intravenous anaesthetic agent propofol following its rapid administration over 2 min to sheep. The extent of dysequilibrium was examined following slower administration as a constant rate 45-min infusion (10 mg/min). METHODS: Six sheep were prepared with arterial and sagittal sinus (effluent from the brain) blood sampling catheters and a Doppler flow probe for measuring an index of cerebral blood flow. Propofol concentrations in arterial and sagittal sinus blood during and after the infusions were measured using high-performance liquid chromatography with fluorescence detection. Brain concentrations were calculated from these concentrations and cerebral blood flow using direct mass balance methods. RESULTS: There was dysequilibrium between the arterial blood and brain concentrations until approximately 30 min after the start of the infusion, with marked hysteresis between the arterial blood and brain concentrations for the duration of the study. The equilibrium half-life between the blood and the brain was 3.5 min, which is comparable to the value of 4.3 min derived from the earlier rapid administration data, suggesting there was no time dependency in the kinetics of cerebral uptake. The mass of propofol entering the brain via arterial blood was the same as the mass leaving the brain via sagittal sinus blood, suggesting minimal metabolism of propofol in the brain of sheep. CONCLUSION: It is clear that pharmacokinetic analysis based on arterial blood concentrations alone cannot accurately account for the concentrations of propofol at its site of action in the brain.     

丙泊酚复合氯诺昔康预防全麻拔管期心血管反应的临床观察

目的 观察丙泊酚复合氯诺昔康对腹腔镜下胆囊切除术(LC)患者气管拔管时心血管反应的预防作用.方法 LC患者40例随机均分为观察组(T组)和对照组(C组).T组于气管拔管前给予静注丙泊酚0.5～1.0 mg/kg和氯诺昔康8 mg,2～3 min后予吸痰拔管;C组不用药.观察围拔管期BP、RR、HR、SpO2、拔管时间,清醒时间、躁动发生情况及有无恶心、呕吐等不良反应.结果 T组拔管时BP、RR、HR平稳.明显优于C组,躁动发生例数也少于C组(P<0.05或P<0.01);两组间拔管时间、清醒时间差异无统计学意义.结论 LC患者在拔除气管导管前给予丙泊酚复合氯诺昔康能有效预防气管拔管时的心血管反应,且不良反应少.     

On-line monitoring of end-tidal propofol concentration in anesthetized patients

BACKGROUND: Propofol (2,6-diisopropylphenol) has some volatility, so it can be detected in expired breath of individuals receiving intravenous propofol. This study measured volatile propofol exhaled by patients and investigated the relation between exhaled and plasma propofol concentrations. METHODS: Nineteen patients with American Society of Anesthesiologists physical status I or II who were undergoing elective surgery participated in this two-part study. In study 1 (n = 11), anesthesia was induced with 2 mg/kg propofol, 0.1 mg/kg vecuronium, and 2 microg/kg fentanyl. After intubation, propofol was administered continuously for 60 min at each of three rates: 3, 6, and 9 mg x kg(-1) x h(-1). Blood samples were obtained just before each change in the infusion rate, and the plasma concentrations of propofol were measured. The exhaled propofol concentration was measured continuously by means of proton transfer mass spectrometry. End-tidal propofol concentrations during blood sampling were averaged and compared with plasma propofol concentrations. In study 2 (n = 8), after induction of anesthesia, patients received a bolus injection of 2 mg/kg propofol, and the exhaled propofol concentration was measured. RESULTS: Volatile propofol was detected in expired gas from all study patients. From study 1, the authors obtained 24 paired data points, i.e., concentrations of end-tidal and plasma propofol. With Bland-Altman analysis, bias +/- precision was 5.2 +/- 10.4 with 95% limits of agreement of -15.1 and 25.6. In study 2, the exhaled propofol concentration curve showed an obvious peak in all patients. CONCLUSIONS: Agreement between plasma and exhaled propofol concentrations suggests that proton transfer mass spectrometry can be used for real-time propofol monitoring.     

Comparison of the effects of sub-hypnotic concentrations of propofol and halothane on the acute ventilatory response to hypoxia

To compare the effects of sub-anaesthetic concentrations of propofol and halothane on the respiratory control system, we have studied the acute ventilatory response to isocapnic hypoxia (AHVR) in 12 adults with and without three different concentrations of propofol and halothane. Target doses for propofol were 0, 0.05, 0.1 and 0.2 of the effective plasma concentration (EC50 = 8.1 micrograms ml-1). Target doses for halothane were 0, 0.05, 0.1 and 0.2 minimum alveolar concentration (MAC = 0.77%). The doses achieved experimentally were 0.01, 0.06, 0.13 and 0.26 of the EC50 for propofol and 0, 0.05, 0.11 and 0.20 MAC for halothane. During the experiment subjects breathed via a mouthpiece from an end-tidal forcing system. End-tidal PO2 (PE'O2) was held at 13.3 kPa for 5 min, and then at 6.7 kPa for 5 min. End- tidal PCO2 (PE'CO2) was held constant at 0.13-0.27 kPa greater than the subject's natural level throughout. The mean values for AHVR with propofol were: 12.8 (SEM 2.4) litre min-1 (0.01 EC50), 10.0 (1.9) litre min-1 (0.06 EC50), 9.8 (2.3) litre min-1 (0.13 EC50) and 4.9 (1.2) litre min-1 (0.26 EC50). The values for AHVR with halothane were: 11.9 (2.4) litre min-1 (0 MAC), 7.8 (1.6) litre min-1 (0.05 MAC), 5.9 (1.2) litre min-1 (0.11 MAC) and 3.2 (1.6) litre min-1 (0.2 MAC). The decline in AHVR with increasing dose for both drugs was statistically significant (ANOVA, P < 0.001); there was no significant difference between the two drugs with respect to this decline. Normoxic ventilation with propofol declined from 13.2 (1.6) litre min-1 (0.01 EC50) to 8.3 (0.9 litre min-1 (0.26 EC50), and with halothane declined from 13.5 (2.0) litre min-1 (0 MAC) to 11.8 (1.6) litre min-1 (0.2 MAC). This was significant for both drugs (ANOVA, P < 0.001).      

The cerebrovascular effects of adrenaline,noradrenaline and dopamine infusions under propofol and isoflurane anaesthesia in sheep

Infusions of catecholamines are frequently administered to patients receiving propofol or isoflurane anaesthesia. Interactions between these drugs may affect regional circulations, such as the brain. The aim of this animal (sheep) study was to determine the effects of ramped infusions of adrenaline, noradrenaline (10, 20, 40 micrograms/min) and dopamine (10, 20, 40 micrograms/kg/min) on cerebral blood flow (CBF), intracranial pressure (ICP), cerebrovascular resistance (CVR) and cerebral metabolic rate for oxygen (CMRO2). These measurements were made under awake physiological conditions, and during continuous propofol (15 mg/min) or 2% isoflurane anaesthesia. All three catecholamines significantly and equivalently increased mean arterial pressure from baseline in a dose-dependent manner in the three cohorts (P < 0.001). In the awake cohort (n = 8), dopamine (P < 0.01) significantly increased CBF from baseline whilst adrenaline and noradrenaline did not (P > 0.05). Under propofol (n = 6) and isoflurane (n = 6), all three catecholamines significantly increased CBF (P < 0.001). Dopamine caused the greatest increase in CBF, and was associated with significant increases in ICP (awake: P < 0.001; propofol P < 0.05; isoflurane P < 0.001) and CVR (isoflurane P < 0.05). No significant changes in CMRO2 were demonstrated. Under propofol and isoflurane anaesthesia, the cerebrovascular effects of catecholamines were significantly different from the awake, physiological state, with dopamine demonstrating the most pronounced effects, particularly under propofol. Dopamine-induced hyperaemia was associated with other cerebrovascular changes. In the presence of an equivalent effect on mean arterial pressure, the exaggerated cerebrovascular effects under anaesthesia appear to be centrally mediated, possibly induced by propofol- or isoflurane-dependent changes in blood-brain barrier permeability, thereby causing a direct influence on the cerebral vasculature.     

不同靶控浓度反馈输注异丙酚的药效动力学

目的 探讨靶控反馈输注异丙酚的浓度与临床效应的关系,寻求最佳靶控浓度。方法24例ASA Ⅰ～Ⅱ级拟行腹腔镜胆囊切除术(LC)的患者,随机分成三组,每组8例。术中行异丙酚反馈靶控输注。三组靶浓度分别为3.0 μg/ml(A组)、3.5μg/ml(B组)、4.0μg/ml(C组)。术中监测血压(BP)、平均动脉压(MAP)、心率(HR)、脑电双频指数(BIS)。分别于诱导前、异丙酚输注后1、2、3、4、5min、插管后、10、15、20、30、40 min、唤醒时、拔管时抽取桡动脉血,采用反向高效液相色谱分析法测定血药浓度。结果 麻醉诱导期间,A组BIS下降与B组、C组差异有显著性(P<0.05)。各组异丙酚诱导剂量差异均有显著性(P<0.05)。麻醉维持期间,A组用药量少于B组和C组(P<0.05)。B组与C组之间差异无显著性(p>0.05)。A组MAP、HR的波动明显大于B组、C组(P<0.05)。麻醉诱导期C组患者的MAP下降幅度大于B组(P<0.05)。各点实测血药浓度(Cm)低于预测血药浓度(Cp)。B组Cm、Cp的曲线波动均较C组小。三组BIS与Cp均良好负相关。结论 在LC术中3.5μg/m1靶控浓度为异丙酚靶控反馈输注静脉麻醉的推荐浓度。     

Use of propofol in 1350 anesthetized patients for electroconvulsive therapy

Propofol was used for 1,350 sessions of electro-convulsive therapy (ECT). After 0.5 mg of intravenous atropine, patients received 1 to 1.5 mg.kg-1 bolus of propofol over a period of 20 seconds or less. This was convenient for loss of the eye-lash reflex. A bolus of 15 to 20 mg suxamethonium was given, in non allergic patients, to prevent trauma from the seizure. The patient was hyperventilated with pure oxygen through a facial mask. The electric shock was delivered bitemporally after a dental protection had been inserted. For each patient, the following data were noted: sex, use of tricyclic antidepressant drugs, atopy, amount of administered propofol and the effective intensity of the electric shock. The 99 patients were given 16.27 +/- 14 ECT sessions. Among them 26 took antidepressant drugs and 34 were atopic. There was no difference, except for weight, between the 25 men and 74 women. The mean dose of propofol was 1.37 +/- 0.3 mg.kg-1. The dose decreased with increasing age. There was no statistical relationship between the amount of propofol and intensity of the electric shock required to set off a seizure. The use of antidepressant drugs, and atopy did not influence the required amount of propofol. Speed of injection seemed to be the determining factor for narcosis with low doses of propofol. Hyperoxia and hypocapnia induced by hyperventilating with pure oxygen seemed to facilitate occurrence and duration of seizures. Although propofol has been said to reduce the length of seizures, there is controversy concerning the ECT efficacy criteria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial and coronary effects of propofol in rabbits with compensated cardiac hypertrophy

BACKGROUND: Myocardial effects of propofol have been previously investigated but most studies have been performed in healthy hearts. This study compared the cardiac effects of propofol on isolated normal and hypertrophic rabbits hearts. METHODS: The effects of propofol (10-1,000 microM) on myocardial contractility, relaxation, coronary flow and oxygen consumption were investigated in hearts from rabbits with pressure overload-induced left ventricular hypertrophy (LVH group, n = 20) after aortic abdominal banding and from sham-operated control rabbits (SHAM group, n = 10), using an isolated and erythrocyte-perfused heart model. In addition, to assess the myocardial and coronary effects of propofol in more severe LVH, hearts with a degree of hypertrophy greater than 140% were selected (severe LVH group, n = 7). RESULTS: The cardiac hypertrophy model induced significant left ventricular hypertrophy (136+/-21%, P < 0.05). The pressure-volume relation showed normal systolic function but an altered diastolic compliance in hypertrophic hearts. Propofol only decreased myocardial contractility and relaxation at supratherapeutic concentrations (> or = 300 microM) in SHAM and LVH groups. The decrease in myocardial performances was not significantly different in SHAM and LVH groups. Propofol induced a significant increase in coronary blood flow which was not significantly different between groups. In severe LVH group, the degree of hypertrophy reached to 157+/-23%. Similarly, the effects of concentrations of propofol were not significantly different from the SHAM group. CONCLUSIONS: Propofol only decreased myocardial function at supratherapeutic concentrations. The myocardial and coronary effects of propofol were not significantly modified in cardiac hypertrophy.     

The effect of remifentanil on cerebral blood flow velocity in children anesthetized with propofol

BACKGROUND: Cerebrovascular stability and rapid anesthetic emergence are desirable features of a neuroanesthetic regimen. In this randomized crossover study the effect of a low-dose remifentanil infusion on cerebral blood flow velocity (CBFV) in children anesthetized with propofol was evaluated. METHODS: Twenty healthy children aged 1-6 years undergoing urological surgery were enrolled. Following face mask induction with sevoflurane, anesthesia was maintained with a standardized propofol infusion. Rocuronium was used to facilitate tracheal intubation and normothermia, and normocapnia were maintained. All children received a caudal epidural block, and a transcranial Doppler probe was placed to measure middle cerebral artery blood flow velocity (Vmca). Each patient received a remifentanil regimen of 0.5 microg x kg(-1) followed by 0.2 microg x kg(-1) x min(-1) in a predetermined order of remifentanil + propofol or propofol alone. Vmca, mean arterial pressure (MAP) and heart rate (HR) were recorded simultaneously at equilibrium with and without remifentanil. RESULTS: The combination of remifentanil and propofol caused an 8.1% decrease in MAP (P = 0.0005) and an 11.8% decrease in HR (P < 0.0001) compared with propofol alone. Vmca was not different between the two groups (P = 0.4041). CONCLUSION: The addition of remifentanil to propofol anesthesia in children causes a reduction in MAP and HR without affecting CBFV. This may imply that cerebral blood pressure autoregulation is preserved in children under propofol and remifentanil anesthesia.     

Renalase deficiency in chronic kidney disease, and its contribution to hypertension and cardiovascular disease

PURPOSE OF REVIEW: Recent experimental data shed light on the regulation of renalase, a secreted amine oxidase, which circulates in an inactive form (prorenalase). Abnormalities in the renalase pathway are evident not only in animal models of chronic kidney disease, but also during the development of hypertension, at a time when kidney function appears normal. RECENT FINDINGS: Prorenalase is rapidly (30-60 s) activated by increased plasma catecholamines and systolic blood pressure. Catecholamine administration promotes the secretion of preformed renalase within 5 min. Plasma renalase is markedly reduced in patients with chronic kidney disease and end-stage renal disease, and in animal models of chronic kidney disease and salt-dependent hypertension. Rats subjected to subtotal nephrectomy develop hypertension and chronic kidney disease, and exhibit low plasma and cardiac renalase, and abnormal renalase activation. SUMMARY: The renalase pathway is a previously unrecognized mechanism for regulating circulating catecholamines, cardiac function and blood pressure. In this pathway, prorenalase is rapidly activated by increased catecholamines and converted to renalase, which in turn degrades catecholamines. Abnormalities in the renalase pathway are evident in animal models of chronic kidney disease and hypertension. Collectively, these data suggest that renalase plays a key role in the regulation of sympathetic tone, blood pressure and cardiac function.     

The effects of propofol on lipid peroxidation and inflammatory response in elective coronary artery bypass grafting

OBJECTIVE: To determine whether the antioxidant and anti-inflammatory properties of propofol confer benefit in adult patients undergoing elective coronary artery bypass grafting. DESIGN: Prospective, blinded, randomized, controlled clinical investigation. SETTING: Single-center, university teaching hospital and academic research laboratory. PARTICIPANTS: Twenty-one adult patients (11 control, 10 intervention) with chronic stable angina and normal ventricular function scheduled to undergo elective coronary artery bypass grafting. INTERVENTIONS: All patients received a standardized fentanyl-isoflurane anesthetic. Fifteen minutes before reperfusion, patients in the intervention group received a target-controlled infusion of propofol, continued for 4 hours after cross-clamp release. Patients in the control group received saline administered in a similar fashion. MEASUREMENTS: Serum concentration of malondialdehyde (MDA) (from systemic and coronary sinus blood); systemic concentrations of interleukins 4, 6, 8, and 10; and systemic leukocyte functions (respiratory burst, phagocytosis, and beta(2) integrin expression) were measured up to 36 hours after reperfusion. RESULTS: A high serum malondialdehyde concentration was detected in the coronary sinus in control patients, 10 minutes after reperfusion; serum malondialdehyde was not detected in the coronary sinus at this time in patients who received propofol (41.4 [15.6-1,150] micromol/L v 0, p = 0.004). Interleukin-8 concentrations increased 2 and 4 hours after reperfusion in the control group. Interleukin-6 concentrations were greater in the control group than the propofol group 4 hours after clamp release (289.1 [165.2-561] rhog/mL v 153.2 (58.2-280.3) rhog/mL, respectively, p = 0.003). Mean dose of propofol was 31.7 mg/kg during the study period. CONCLUSION: Clinically relevant concentrations of propofol may attenuate free radical-mediated and inflammatory components of myocardial reperfusion injury in patients undergoing elective coronary artery bypass graft surgery.