A comparison of the effects of propofol and sevoflurane on the systemic toxicity of intravenous bupivacaine in rats

We compared the effects of propofol and sevoflurane on bupivacaine-induced central nervous system and cardiovascular toxicity in rats. Thirty-four male Sprague-Dawley rats were anesthetized with 70% N2O/30% O2 plus the 50% effective dose (ED50) of propofol (propofol group, n = 12); 70% N2O/30% O2 plus ED50 of sevoflurane (sevoflurane group, n = 11); or 70% N2O/30% O2 (control group, n = 11). Bupivacaine was infused at a constant rate of 2 mg x kg(-1) x min(-1) while electrocardiogram, electroencephalogram, and invasive arterial pressure were continuously monitored. The cumulative doses of bupivacaine that induced dysrhythmias, seizures, and 50% reduction of heart rate were larger in the propofol and sevoflurane groups than in the control group. The cumulative dose of bupivacaine that induced a 50% reduction in the mean arterial blood pressure was larger in the propofol group than in the sevoflurane and control groups. The margin of safety, assessed by the time between the onset of dysrhythmias and 50% reduction of mean arterial blood pressure, was wider in the propofol group than in the sevoflurane group. We conclude that propofol and sevoflurane attenuate bupivacaine-induced dysrhythmias and seizures and that propofol has a wider margin of safety than sevoflurane. IMPLICATIONS: In anesthetized patients, dysrhythmias may be the only warning sign of intravascular injection of bupivacaine. Because propofol has a wider margin of safety than sevoflurane, life-threatening cardiovascular depression may be prevented by stopping the injection of bupivacaine at the onset of dysrhythmias during propofol anesthesia.     

Cardiopulmonary and anesthetic effects of propofol in wild turkeys

OBJECTIVE: To determine safety, anesthetic variables, and cardiopulmonary effects of i.v. infusion of propofol for induction and maintenance of anesthesia in wild turkeys. ANIMALS: 10 healthy, adult wild turkeys. PROCEDURE: Anesthesia was induced by i.v. administration of propofol (5 mg/kg of body weight) over 20 seconds and was maintained for 30 minutes by constant i.v. infusion of propofol at a rate of 0.5 mg/kg/min. Heart and respiratory rates, arterial blood pressures, and arterial blood gas tensions were obtained prior to propofol administration (baseline values) and again at 1, 2, 3, 4, 5, 10, 15, 20, 25, and 30 minutes after induction of anesthesia. All birds were intubated immediately after induction of anesthesia, and end-tidal CO2 concentration was determined at the same time intervals. Supplemental oxygen was not provided. RESULTS: Apnea was observed for 10 to 30 seconds after propofol administration, which induced a decrease in heart rate; however, the changes were not significant. Compared with baseline values, respiratory rate was significantly decreased at 4 minutes after administration of propofol and thereafter. Systolic, mean, and diastolic pressures decreased over the infusion period, but the changes were not significant. Mean arterial blood pressure decreased by 30% after 15 minutes of anesthesia; end-tidal CO2 concentration increased from baseline values after 30 minutes; PO2 was significantly decreased at 5 minutes after induction and thereafter; PCO2 was significantly (P < 0.05) increased after 15 minutes of anesthesia; and arterial oxygen saturation was significantly (P < 0.05) decreased at the end of anesthesia. Two male turkeys developed severe transient hypoxemia, 1 at 5 and the other at 15 minutes after induction. Time to standing after discontinuation of propofol infusion was 11 +/- 6 minutes. Recovery was smooth and unremarkable. CONCLUSION: Propofol is an effective agent for i.v. induction and maintenance of anesthesia in wild turkeys, and is useful for short procedures or where the use of inhalational agents is contraindicated.     

Relationship between auditory intensity discrimination in noise and olivocochlear efferent system activity in humans

The intravenous (i.v.) steroid anesthetic, eltanolone, compares favorably to propofol with respect to its induction characteristics. This double-blind investigation was designed to compare the induction and recovery profile of eltanolone (versus propofol) when it was used for both induction and maintenance of ambulatory anesthesia. Eighty-three consenting ASA physical status I-III outpatients undergoing minor gynecologic or urologic procedures lasting 10-40 min were randomly assigned to one of three anesthetic treatment groups. All patients received midazolam, 2 mg i.v., and fentanyl, 50 micrograms i.v., before induction of anesthesia. The control group (Group 1) was induced with propofol, 2.4 mg/kg i.v. (18-60 yr or ASA physical status I or II) or 1.6 mg/kg i.v. (61-80 yr and/or ASA physical status III), followed by intermittent bolus doses of 0.6 mg/kg i.v. in combination with N2O 67% for maintenance of anesthesia. In Group 2, anesthesia was induced with eltanolone, 0.75 mg/kg i.v., (18-60 yr and/or ASA physical status I or II) or 0.5 mg/kg i.v. (61-80 yr and/or ASA physical status III), and maintained with intermittent bolus injections of 0.2 mg/kg i.v. and N2O 67%. Group 3 received eltanolone, 1.0 mg/kg i.v. (18-60 yr and/or ASA physical status I or II), or 0.75 mg/kg i.v. (61-80 yr and/or ASA physical status III), followed by intermittent bolus injections of 0.2 mg/kg i.v. and N2O 67%. In addition to recording the induction and recovery times and side effects, psychomotor testing was performed before and at 30-min intervals after anesthesia. Induction times (57 +/- 23, 67 +/- 26, and 61 +/- 22s, respectively) were similar in all three groups. Although eltanolone produced no pain on injection (versus 52% in the propofol group), 10% of the eltanolone-treated patients (versus none in the propofol group) developed transient cutaneous (rash-like) reactions. The total dose of study medication used during the anesthetic period was 9.2 +/- 3.7 mg.kg-1.h-1 in the propofol group compared with 3.3 +/- 1.4 mg.kg-1.h-1 and 3.3 +/- 1.9 mg.kg-1.h-1 in Groups 2 and 3, respectively. Early recovery times were significantly shorter after propofol anesthesia. However, times to ambulation, micturition, and being judged "fit for discharge," as well as recovery of cognitive function, were similar in all three groups. Although ethanolone seems to be a safe and effective i.v. anesthetic, these data suggest that it is unlikely to replace propofol in the ambulatory setting. Implications: Eltanolone is an investigational steroid anesthetic that causes less pain on injection and less cardiovascular depression than propofol (the most widely used intravenous anesthetic in the outpatient setting). Unfortunately, emergence from anesthesia after ambulatory surgery is slower with eltanolone compared with propofol. Therefore, it is unlikely that eltanolone will replace propofol for outpatient anesthesia.     

Changes in serum levels of N-terminal procollagen type III propeptide as an index of postinfarction ventricular remodeling

The cardiovascular effects of slow (over two minutes) intravenous infusions of thiopentone 750 mg in conscious instrumented sheep breathing 100% oxygen were examined for 30 minutes following the start of the infusion. The maximum rate of rise of left ventricular pressure (an index of myocardial contractility) decreased significantly from 1 to 10 minutes, to a minimum of 45% of baseline. Heart rate increased by up to 33% above baseline from 0.5 min onwards. Both mean arterial pressure and cardiac output were decreased from between 1 and 7 min. Left ventricular minute work was transiently decreased, but left coronary blood flow and myocardial oxygen consumption showed little or no change from baseline. We conclude that in vivo, thiopentone administered at a relatively slow rate caused large reductions in myocardial contractility, and therefore cardiac reserve, in the absence of significant changes in myocardial blood flow or oxygen consumption.     

Susceptibility changes following bolus injections

The general mechanism of bulk magnetic susceptibility (BMS) induced MRI contrast following a bolus injection is elaborated. Combining radiolabeled tracer data for the first pass of a bolus injection through the human brain with the application of Wiedemann's law allows us to calculate the lower limit for the time course of the vascular BMS following the injection of any contrast agent. Superparamagnetic iron oxide particles produce a much larger effect than any mononuclear Ln(III) chelate. We also calculate the BMS changes occurring after a dilution bolus injection (of isosmolal physiological saline) subsequent to a prior slow infusion of an intravascular contrast agent. This technique bears some resemblance to the increasingly important approach that exploits changes in only the level of blood oxygenation. The calculation indicates that contrast changes after the dilution bolus injection are smaller than those following Ln(III) agent injections but larger than those due to changes in blood oxygenation and suggests a way to possibly enhance the latter. We present an in vivo study demonstrating the dilution bolus injection technique in the mouse brain, and that features its rapid repeatability. Extrapolation of these results to the human, however, indicates that the saline volumes required for venous injections, except possibly for cardiac studies, would be prohibitively large. Smaller, catheter-delivered arterial bolus injections are feasible. We also suggest a method for using an agent bolus injection to measure the parenchymal BMS, and thus the iron content, of pathologically iron-loaded tissue.     

Inhibition of presenilin 1 expression is promoted by p53 and p21WAF-1 and results in apoptosis and tumor suppression

Pain on injection is one of the well-known side effects of propofol. Previous studies have shown several methods to alleviate this discomfort. We employed all these methods together to clarity whether pain-free injection of propofol was possible. Sixty adult patients premedicated with midazolam were studied. Control group patients (n = 20) received an induction dose of propofol via a vein on the dorsum of the hand at a slow injection speed with carrier i.v. fluid. Study group patients (n = 40) received i.v. fentanyl 0.1 mg, followed by bolus injection of cold propofol premixed with lidocaine (final concentration of lidocaine was 0.2%) in a forearm vein without carrier i.v. fluid. Eighteen patients (90%) in the control group experienced injection pain. In the study group, however, no patients complained of pain or discomfort. In conclusion, pain-free injection of propofol was possible when prior-administration of fentanyl, premixing of lidocaine, cooling to 4 degrees C, and rapid injection via a forearm vein without carrier i.v. fluid was the adopted precedure.     

Primary anastomosis of the trachea: management and pitfalls

The potentiating activity of SG-86[N-(2-hydroxyethyl)nicotinamide], a denitrated metabolite of nicorandil, on the adenosine-induced vasodepression was compared with that of nicorandil in anesthetized rats. Single bolus i.v. adenosine (3-100 micrograms/kg) produced dose-dependent reductions of blood pressure, accompanied by slight decreases (except for 100 micrograms/kg) in heart rate. The adenosine-induced vasodepression was significantly enhanced during i.v. infusion of either SG-86 (100 micrograms/kg per min) as well as nicorandil (10 micrograms/kg per min). The enhancement of adenosine action by them did not occur in the presence of glibenclamide (20 mg/kg i.v.). Single bolus i.v. injections of SG-86 (0.3-30 mg/kg), except for 30 mg/kg, which caused a glibenclamide-sensitive decrease by about 5-10 mmHg in mean arterial blood pressure, had no effects on blood pressure and heart rate, whereas those of nicorandil (30-300 micrograms/kg) elicited overt reduction of blood pressure, accompanied by decreases in heart rate. The present results revealed that SG-86, like nicorandil, significantly enhanced the vasodepressor response to adenosine, probably in part through KATP channel activation, and that the activity of SG-86 was about 10 times less potent than that of nicorandil.     

Is patient-controlled sedation good for elderly patients?

The purpose of this study was to evaluate the safety and advantage of intra-operative patient-controlled sedation (PCS) in elderly patients. Propofol PCS was compared with anesthesiologist-controlled sedation (ACS) during knee arthroplasty under epidural anesthesia. Eleven elderly patients scheduled for unilateral knee total or partial arthroplasty were divided randomly into PCS group (n = 6) and ACS group (n = 5). Epidural anesthesia was performed to produce an appropriate level of sensory block (T 10 through S). Firstly a mixture of pentazocine 0.2 mg.kg-1 and 2% mepivacaine 6-9 ml was injected to the epidural space, and anaesthesia was maintained using 2% mepivacaine afterward. Patients in both groups received propofol 0.3 mg.kg-1 i.v. as a loading dose and 0.6 mg.kg-1.h-1 continuous infusion. Furthermore patients in PCS group received propofol PCS (bolus: 0.2 mg.kg-1, lockout time: 3 min). Patients in ACS group were administered propofol continuously and infusion rates were regulated to maintain a sedation score 3 (Wilson et al) by anesthesiologist. Respiratory rate, blood pressure, heart rate, SpO2, arterial blood gas analysis and plasma levels of propofol were measured 4 times during and after the surgery. Satisfaction of patients and surgeons was questioned. Patients in PCS group received a mean propofol dose of 1.9 +/- 0.1 mg.kg-1 during procedures with a mean duration of 147 min. On the other hand patients in ACS group received propofol 2.9 +/- 0.3 mg.kg-1 with 142 min of procedures. Satisfaction of patients and surgeons, the incidence of complication were similar between the groups. For elderly patients who undergo epidural anesthesia, PCS is a safe and effective technique providing similar good sedation as with ACS.     

Gentamicin intravenous infusion rate: effect on interstitial fluid concentration

To assess the possible role of intravenous (i.v.) infusion rate as a determinant of degree and rate of interstitial fluid penetration, six rabbits, each with four intraperitoneal implanted capsules, were studied by crossover design after a single dose of 1.7 mg of gentamicin per kg by either slow 2.5-min i.v. bolus or 30 min i.v. infusion. The mean serum peak antibiotic level after slow bolus was 17.4 mug/ml. After 30 min of infusion, mean serum peak was 8.3 mug/ml (P < 0.025). Mean capsule fluid antibiotic levels at 30 min, 1, and 2 h were 0.9 mug/ml, 1.6 mug/ml, and 1.8 mug/ml, respectively, after slow bolus and 0.6 mug/ml, 0.9 mug/ml, and 1.3 mug/ml after 30-min infusion (P < 0.05 at 30 min, P < 0.001 at 1 h, and P < 0.05 at 2 h). Comparison of capsule levels beyond 2 h revealed no significant differences, and peak capsular concentrations achieved by the two methods were similar. Slow 2.5-min i.v. bolus administration of gentamicin established higher interstitial fluid levels during the first 2 h of therapy and may be the preferred mode of delivery when rapid extravascular penetration is desired.     

Safety and cost of rapid i.v. injection of famotidine in critically ill patients

The safety and cost of famotidine in intensive care patients given the drug by rapid i.v. injection or slow i.v. infusion were studied. All patients admitted to the medical-coronary care and surgical intensive care units (ICUs) at a university teaching hospital over a two-month period who had orders for at least one dose of famotidine injection for any indication were randomly assigned to receive the drug by rapid i.v. injection or slow i.v. infusion via volumetric chamber. Data on patient demographics, drug administration time, adverse effects, cardiovascular variables, and costs (including drug acquisition, supply, and nursing personnel costs) were collected prospectively. Fifty-three patients received famotidine by i.v. injection (a total of 1041 doses) and 52 by i.v. infusion (1006 doses). The mean +/- S.D. duration of famotidine administration was 44 +/- 12 seconds in the i.v.-injection group and 19 +/- 5 minutes in the i.v.-infusion group. Adverse effects possibly related to famotidine occurred in three injection-group patients and two infusion-group patients. No significant difference between the groups in cardiovascular variables (mean arterial pressure, heart rate, and respiratory rate) was noted. Cost savings for the injection group relative to the infusion group totaled $2886 for the two-month study period. Half of the savings came from reduced supply costs and half from reduced personnel costs. The annualized savings to the institution would be about $17,300. Rapid i.v. injection of famotidine appeared to be as safe in ICU patients as giving the drug by slow i.v. infusion and was less costly.     

Effectiveness of polyclonal and monoclonal antibodies prepared for an immunoassay of the etofenprox insecticide

The aim of this study was to compare hemodynamic responses to intubation and pin head-holder application in two groups of neurosurgical patients given oral clonidine (3 microg/kg) or oral temazepam (10-20 mg) 90 min before the induction of anesthesia. Fifty patients undergoing elective craniotomy were randomized to either group. Anesthesia was induced with i.v. propofol 1500 mg/h, fentanyl 4 microg/kg, vecuronium 0.15 mg/kg, and lidocaine 1.5 mg/kg and was maintained with propofol 6 mg x kg(-1) x h(-1). Mean arterial blood pressure (MAP) and heart rate were recorded before the induction of anesthesia and before and after intubation and application of the pin head holder. Interventions required to maintain hemodynamic stability were compared between groups. Preinduction sedation scores and MAP values were similar between groups. MAP was significantly lower (P = 0.031) in the clonidine group after pin head-holder application. Interventions to stabilize MAP were not significantly different between groups (P = 0.11). We conclude that clonidine is effective in reducing the MAP increase with pin head-holder application in patients undergoing craniotomy. Implications: In this study, we investigated an approach to the prevention of increased blood pressure often seen during the early part of anesthesia for brain surgery. Oral clonidine was effective in reducing the mean arterial blood pressure increase resulting from pin head-holder application. Clonidine, a blood pressure-reducing drug, was given to 25 patients before anesthesia. Their blood pressure measurements were then compared with those of 25 patients not given clonidine.     

Help for women refugees

A randomized crossover study was designed using the chronically instrumented pregnant sheep preparation to study the possible effects of epidural injection of adrenaline as a single compound on the circulation of mother and fetus. Three consecutive identical doses of adrenaline were administered epidurally with a 30 min interval between treatments. In a randomized crossover fashion two dosages (10 and 15 micrograms) were tested on different days. The day after the last epidural experiment the same doses of adrenaline were given intravenously (i.v.). Between the two i.v. doses a 30 min interval was allowed for values to return to baseline. Twenty-seven experiments were performed in eight ewes. Epidural administration of adrenaline did not affect maternal mean arterial pressure, maternal heart rate, uterine blood flow, fetal mean arterial pressure, fetal heat rate, or maternal and fetal blood gases and acid-base status. After i.v. administration of adrenaline the uterine blood flow decreased in a dose-dependent fashion, but the other haemodynamic variables were not affected. In conclusion, this study indicates that consecutive epidural injections of adrenaline have no significant effect on maternal and fetal haemodynamic responses, uterine blood flow, blood gases and acid-base status in the gravid ewe. However, an i.v. injection of 10 or 15 micrograms adrenaline decreases the uterine blood flow and could compromise the fetus.     

Complete reversal of ischemic wall motion abnormalities by combined use of gene therapy with transmyocardial laser revascularization

1. The effects of the various doses of NG-nitro-L-arginine methyl ester (L-NAME, 10 and 30 mg/kg) on some cardiovascular and biochemical parameters during the early posthemorrhagic period were studied in anesthetized rabbits subjected to hemorrhagic hypovolemia. 2. Hemorrhagic shock was produced by intermittent bleeding of 40% of the estimated blood volume for 15 min. Blood samples were taken before and after bleeding (0, 15 and 60 min). Simultaneously, the mean arterial pressure (MAP) and the heart rate (HR) were measured. Hemorrhaged rabbits were treated by L-NAME10 or L-NAME30 (10 or 30 mg/kg, i.v. bolus injection, respectively) or the corresponding volumes of saline (0.6 ml, i.v. bolus) immediately after the end of bleeding. 3. The observed cardiovascular parameters (MAP, HR) were significantly reduced after the end of bleeding in all rabbits. 4. The rise of the MAP was significantly more pronounced 30 min after the injection of L-NAME30 in comparison with the corresponding values in the saline (S) group. In contrast, L-NAME10 produced only a small, insignificant increase in the MAP in hemorrhaged rabbits. 5. The L-NAME30-induced rise of the MAP was accompanied by a severe bradycardia, hyperkalemia and an aggravated metabolic acidosis, more severe than the corresponding disturbance of the acid-base status in the S group. The changes in the acid-base parameters were observed both in arterial (pH, excess base) and in venous blood (pH) of hemorrhaged rabbits. 6. In conclusion, the i.v. bolus injection of L-NAME30 (immediately after the end of bleeding) produced a significant increase in the MAP during the first hour after the injury, but the presumable inhibition of the endothelial constitutive nitric oxide synthase during the early posthemorrhagic period resulted in severe cardiovascular and metabolic disturbances.     

Determination of plasma concentrations of propofol associated with 50% reduction in postoperative nausea

BACKGROUND: Subhypnotic doses of propofol possess direct antiemetic properties. The authors sought to determine the plasma concentration of propofol needed to effectively manage postoperative nausea and vomiting. METHODS: Patients aged 18-70 yr who were classified as American Society of Anesthesiologists physical status 1 or 2 and had surgery during general anesthesia were approached for the study. Only patients who had nausea (verbal rating score > 5 on a 0- to 10-point scale), retching, or vomiting in the postanesthetic care unit participated. Propofol was administered to these patients to achieve target plasma concentrations of 100, 200, 400, and 800 ng/ml using a computer-assisted continuous infusion device. Target concentrations were increased every 15 min until patients described at least a 50% reduction in symptoms on the verbal rating score. An arterial blood sample was obtained at each step. The measured plasma propofol concentrations were used to analyze data. Blood pressure, heart and respiratory rates, arterial blood saturation, sedation score, and overall satisfaction with treatment were recorded. RESULTS: Of the 89 patients who consented to the study, 15 patients met entry criteria and were enrolled. Five of these patients also had retching or vomiting when they entered the study. Fourteen patients responded successfully to treatment. One patient did not achieve the required response at plasma concentrations of 830 ng/ml. Hence the success rate for the treatment of postoperative nausea and vomiting was 93%. Among patients who responded, the median plasma concentration associated with an antiemetic response was 343 ng/ml. There was no difference in sedation scores from baseline and no episodes of desaturation. Hemodynamic parameters were stable during the study. CONCLUSIONS: Propofol is generally efficacious in treating postoperative nausea and vomiting at plasma concentrations that do not produce increased sedation. Simulations indicate that to achieve antiemetic plasma propofol concentrations of 343 ng/ml, a bolus dose of 10 mg followed by an infusion of approximately 10 microg x kg(-1) x min(-1) are necessary.     

Helicobacter pylori eradication in the healing and recurrence of benign gastric ulcer: a two-year, double-blind, placebo controlled study

STUDY OBJECTIVE: To evaluate the safety and efficacy of monitored anesthesia care (MAC) in patients who undergo a novel treatment for hepatocellular cancer in which procedure-related hemodynamic instability is problematic. DESIGN: Nonrandomized open study. SETTING: University cancer center operating room. PATIENTS: Nine patients scheduled for hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration (no more than 3 procedures per patient). INTERVENTIONS: Hepatic venous isolation was achieved with a dual-balloon inferior vena cava catheter connected to an extracorporeal circuit containing chemofilters. Doxorubicin was infused through the hepatic artery and filtered from the venous blood, which was returned to the patient through an internal jugular venous catheter. Each patient received a bolus of propofol (200 micrograms/kg) and one of alfentanil (2 micrograms/kg) followed by simultaneous infusions of propofol and alfentanil for percutaneous placement of the catheters and operation of the extracorporeal circuit. Drug rates were varied to maintain a sedative-analgesic state of calm, comfort, minimal movement, and adequate respiratory function. Prior to circuit initiation, patients were preloaded with crystalloid. During circuit operation, hypotension was treated with intravenous (IV) phenylephrine and crystalloid. MEASUREMENTS AND MAIN RESULTS: End-tidal CO2 (PETCO2), respiratory rate, oxygen saturation (SaO2), arterial blood pressure (BP), and heart rate (HR) were monitored. Systolic, diastolic, and mean arterial pressure (MAP), and HR were compared before, during, and after hepatic venous isolation and chemofiltration. Doses and infusion rates of propofol, alfentanil, and phenylephrine were recorded for each treatment. Hypotension occurred in 11 of 13 procedures when blood was directed through the chemofilters and was successfully treated with phenylephrine (dose range 40 to 5,733 micrograms) and crystalloid. Blood pressure returned to the baseline value on termination of the circuit. Throughout the sedation, patients were easily arousable, analgesia was adequate, and PETCO2 level of 38 +/- 4 mmHg and SaO2 greater than 94% were maintained. Mean doses and infusion rates of MAC drugs were, respectively: propofol, 261 +/- 88 mg and 23.7 +/- 3.6 micrograms/kg/min; alfentanil, 3,350 +/- 1,468 micrograms and 0.32 +/- 0.14 microgram/kg/min. CONCLUSIONS: Patients undergoing this novel cancer treatment are safely and effectively managed by MAC achieved with simultaneous infusions of alfentanil and propofol. Procedure-associated hypotension is easily treated with IV phenylephrine and crystalloid.     

The optimal test dose of epinephrine for epidural injection with lidocaine solution in awake patients premedicated with oral clonidine

We attempted to determine the optimal test dose of epinephrine for use with epidural anesthesia in awake patients premedicated with clonidine. Eighty-eight adult patients were randomized into two groups [oral premedication with clonidine 5 microg/kg (CLON) or no premedication (CONT)]. Before induction of general anesthesia, heart rate (HR) and blood pressure (BP) were measured for 3 min after the i.v. injection of 3 mL of 1.5% lidocaine containing epinephrine (0, 1.25, 2.5, 5, 7.5, or 15 microg) in a randomized, double-blind manner. We calculated 95% confidence intervals for the peak HR and BP increases induced by each dose of epinephrine. At 7.5 microg, epinephrine induced a significantly greater increase in HR and BP in CLON than in CONT. The 95% confidence interval for the HR change induced by 7.5 microg of epinephrine in CLON was nearly the same as the accepted standard dose of epinephrine (15 microg) in CONT. We conclude that premedication with clonidine enhances HR and BP responses to the i.v. administration of epinephrine-containing epidural test solutions. Consequently, 7.5 microg of epinephrine may be sufficient to enable detection of accidental injection into a blood vessel in awake patients premedicated with clonidine 5 microg/kg. Implications: Clonidine, a commonly used preanesthetic medication, alters patients' cardiovascular responses to drugs such as epinephrine. Our randomized, double-blind study suggests that, in awake patients receiving oral clonidine premedication, 7.5 microg of epinephrine (half the usual dose) is adequate as an indicator of accidental injection into the epidural vessels during epidural anesthesia.     

Effects of cisatracurium on cerebral and cardiovascular hemodynamics in patients with severe brain injury

BACKGROUND: For neuroanesthesia and neurocritical care the use of drugs that do not increase or preferentially decrease intracranial pressure (ICP) or change cerebral perfusion pressure (CPP) and cerebral blood flow (CBF) are preferred. The current study investigates the effects of a single rapid bolus dose of cisatracurium on cerebral blood flow velocity, ICP, CPP, mean arterial pressure (MAP) and heart rate (HR) in 24 mechanically ventilated patients with intracranial hypertension after severe brain trauma (Glasgow coma scale <6) under continuous sedation with sufentanil and midazolam. METHODS: Patients were randomly assigned to receive either 2xED95 (n=12) or 4xED95 (n=12) of cisatracurium as a rapid i.v. bolus injection. Before and after bolus administration mean cerebral blood flow velocity (BFV, cm/s) was measured in the middle cerebral artery using a 2-MHz transcranial Doppler sonography system, ICP (mm Hg) was measured using an extradural probe, and MAP (mm Hg) and HR (b/min) were measured during a study period of 20 min. Cerebral perfusion pressure (CPP=MAP-ICP) was also calculated. RESULTS: Our data show that a single bolus dose of up to 4xED95 cisatracurium caused no significant (P<0.05) changes in BFV, ICP, CPP, MAP and HR. Possible histamine-related events were not observed during the study. CONCLUSIONS: The results from this study suggest that cisatracurium is a safe neuromuscular blocking agent for use in adult severe brain-injured patients with increased ICP under mild hyperventilation and continuous sedation.     

Tachycardia alone fails to change the myocardial pharmacokinetics and dynamics of lidocaine, thiopental, and verapamil after intravenous bolus administration in sheep

Previous reports have suggested that tachycardia alone can increase the rate of myocardial uptake of some drugs. As part of a systematic study of the determinants of the myocardial uptake and effects of drugs in critical illness, the effect of tachycardia induced by intracardiac pacing on the myocardial disposition and effects of lidocaine, verapamil, and thiopental were studied in chronically instrumented sheep. For each drug, seven sheep received either 100 mg of lidocaine, 10 mg of verapamil, or 750 mg of thiopental over 2 min in unpaced and paced (140 beats/min) states on separate occasions and in random order. Arterial and coronary sinus (effluent from the heart) blood samples were taken at regular intervals for 30 min, and the maximum rate of change of left ventricular pressure (LV dP/dtmax) was measured as an index of myocardial contractility. There were no differences between unpaced and paced studies in the time courses of arterial and coronary sinus concentrations, or the time-courses of myocardial contractility and blood flow, after bolus iv injections of these drugs. Tachycardia alone does not appear to influence the myocardial kinetics or dynamics of lipophilic drugs that can rapidly diffuse into the heart.     

pR plasmid replication provides evidence that single-stranded DNA induces the SOS system in vivo

The aim of this study was to quantitate factors affecting the initial "peak" of the pulmonary artery (PA) drug concentrations after i.v. bolus drug administration, which is a determinant of the subsequent drug uptake into both the lungs and other well-perfused organs. Indocyanine green (ICG) was used as a marker drug in anaesthetized (1.5% halothane) sheep prepared with an inferior vena cava injection catheter and a large-gauge pulmonary artery blood sampling catheter. For three ranges of cardiac output, 2.5-mg doses of ICG were injected in the following combinations: 10 ml injected over 1, 5 or 10 s; 5 or 25 ml injected over 1 s. On-line PA ICG concentrations were recorded for approximately 60 s using a densitometer. The mean maximum PA ICG concentrations (2-8 mg litre-1), the mean times at which they occurred (7-18 s after injection) and the time lags before ICG was detected in the PA (4-9 s), were inversely related to cardiac output, but linearly related to the time over which the injection was made. The area under the curve of the peak was related inversely to cardiac output only, while the aspect ratio of the peak was related inversely to the time over which the injection was made only. The injectate volume had no effect on any of the measured values. We conclude that, in some circumstances, the rate of injection of drugs with narrow margins of safety should be tailored to the cardiac output of an individual.     

Effect of intracerebroventricular and intravenous administration of nitric oxide donors on blood pressure and heart rate in anaesthetized rats

1. The effects of nitric oxide (NO) releasing substances, sodium nitroprusside, 3-morpholino sydnonimine (SIN-1) and a novel oxatriazole derivative, GEA 3162, on blood pressure and heart rate were studied after peripheral or central administration in anaesthetized normotensive Wistar rats. 2. Given as cumulative intravenous injections, both nitroprusside and GEA 3162 (24-188 nmol kg-1) induced short-lasting and dose-dependent decreases in mean arterial pressure, while SIN-1 decreased blood pressure only slightly even after larger doses (94-3000 nmol kg-1). Heart rate increased concomitantly with the hypotensive effect of the NO-releasing substances. 3. Cumulative intracerebroventricular administration of GEA 3162 (24-188 nmol kg-1) induced a dose-dependent hypotension with slight but insignificant increases in heart rate. In contrast, intracerebroventricular nitroprusside induced little change in blood pressure, while a large dose of SIN-1 (3000 nmol kg-1, i.c.v.) slightly increased mean arterial pressure. However, intracerebroventricular nitroprusside and SIN-1 increased heart rate at doses that did not significantly affect blood pressure. 4. To determine whether the cardiovascular effects of GEA 3162 were attributable to an elevation of cyclic GMP levels, pretreatments with methylene blue, a putative guanylate cyclase inhibitor, were performed. This substance failed to attenuate the cardiovascular effects of peripherally or centrally administered GEA 3162, suggesting that the effects were independent of guanylate cyclase. 5. In conclusion, the centrally administered NO-donor, GEA 3162, induced a dose-dependent. hypotensive response without significant changes in heart rate. Furthermore, intracerebroventricular injections of nitroprusside and SIN-1 increased heart rate without affecting blood pressure. These results suggest that NO released by these drugs may affect central mechanisms involved in cardiovascular regulation independently of cyclic GMP.