Role of epigenetic mechanisms in transmitting the effects of neonatal sevoflurane exposure to the next generation of male, but not female, rats.

BACKGROUND: Clinical studies report learning disabilities and attention-deficit/hyperactivity disorders in those exposed to general anaesthesia early in life. Rats, primarily males, exposed to GABAergic anaesthetics as neonates exhibit behavioural abnormalities, exacerbated responses to stress, and reduced expression of hypothalamic K+-2Cl- Cl- exporter (Kcc2). The latter is implicated in development of psychiatric disorders, including male predominant autism spectrum disorders. We tested whether parental early life exposure to sevoflurane, the most frequently used anaesthetic in paediatrics, affects the next generation of unexposed rats. METHODS: Offspring (F1) of unexposed or exposed to sevoflurane on postnatal day 5 Sprague-Dawley rats (F0) were subjected to behavioural and brain gene expression evaluations. RESULTS: Male, but not female, progeny of sevoflurane-exposed parents exhibited abnormalities in behavioural testing and Kcc2 expression. Male F1 rats of both exposed parents exhibited impaired spatial memory and expression of hippocampal and hypothalamic Kcc2. Offspring of only exposed sires had abnormalities in elevated plus maze and prepulse inhibition of startle, but normal spatial memory and impaired expression of hypothalamic, but not hippocampal, Kcc2. In contrast to exposed F0, their progeny exhibited normal corticosterone responses to stress. Bisulphite sequencing revealed increased CpG site methylation in the Kcc2 promoter in F0 sperm and F1 male hippocampus and hypothalamus that was in concordance with the changes in Kcc2 expression in specific F1 groups. CONCLUSIONS: Neonatal exposure to sevoflurane can affect the next generation of males through epigenetic modification of Kcc2 expression, while F1 females are at diminished risk.

Feasibility and accuracy of nasal alar pulse oximetry.

BACKGROUND: The nasal ala is an attractive site for pulse oximetry because of perfusion by branches of the external and internal carotid arteries. We evaluated the accuracy of a novel pulse oximetry sensor custom designed for the nasal ala. METHODS: After IRB approval, healthy non-smoking subjects [n=12; aged 28 (23-41) yr; 6M/6F] breathed hypoxic mixtures of fresh gas by a facemask to achieve oxyhaemoglobin saturations of 70-100% measured by traditional co-oximetry from radial artery samples. Concurrent alar and finger pulse oximetry values were measured using probes designed for these sites. Data were analysed using the Bland-Altman method for multiple observations per subject. RESULTS: Bias, precision, and accuracy root mean square error (ARMS) over a range of 70-100% were significantly better for the alar probe compared with a standard finger probe. The mean bias for the alar and finger probes was 0.73% and 1.90% (P<0.001), respectively, with corresponding precision values of 1.65 and 1.83 (P=0.015) and ARMS values of 1.78% and 2.72% (P=0.047). The coefficients of determination were 0.96 and 0.96 for the alar and finger probes, respectively. The within/between-subject variation for the alar and finger probes were 1.14/1.57% and 1.87/1.47%, respectively. The limits of agreement were 3.96/-2.50% and 5.48/-1.68% for the alar and finger probes, respectively. CONCLUSIONS: Nasal alar pulse oximetry is feasible and demonstrates accurate pulse oximetry values over a range of 70-100%. The alar probe demonstrated greater accuracy compared with a conventional finger pulse oximeter.

Transfusion has no effect on recurrence in hepatitis C after liver transplantation.

BACKGROUND: The literature suggests that blood product transfusions have a negative impact on the survival of liver transplant patients. We investigated the impact of intraoperative blood product usage on the survival of liver transplantation patients being transplanted for hepatitis C-related end-stage liver disease. In addition, we analyzed a potentially more sensitive metric, namely disease recurrence and fibrosis progression, obtained from follow-up liver biopsies. METHODS: We retrospectively studied 194 consecutive patients with hepatitis C virus (HCV) undergoing liver transplantation. To investigate the effect of red blood cell (RBC) or platelet transfusions on post-transplant HCV recurrence, hepatic biopsy data from 4 months and 1 year after transplantation were studied. In addition, survival data were analyzed. RESULTS: There was no effect of intraoperative RBC or platelet transfusion on either 1- or 5-year patient survival following liver transplantation. There was no difference in HCV disease recurrence or progression of hepatic fibrosis at 4 months or 1 year attributable either to RBC or to platelet transfusion. CONCLUSION: This study was not able to confirm an effect on the survival of HCV-infected liver transplant patients related to intraoperative transfusion of RBCs or platelets. In addition, these transfusions had no effect on HCV recurrence or fibrosis progression. This is not to condone a liberal transfusion practice, but rather to reassure that when clinically indicated, transfusion does not have a significant impact on patient survival or disease recurrence in HCV-infected liver transplant patients.

Specific inhibition of N-methyl-D-aspartate receptor function in rat hippocampal neurons by L-phenylalanine at concentrations observed during phenylketonuria.

Hippocampal N-methyl-D-aspartate receptors (NMDARs) are thought to be involved in the regulation of memory formation and learning. Investigation of NMDAR function during experimental conditions known to be associated with impaired cognition in vivo may provide new insights into the role of NMDARs in learning and memory. Specifically, the mechanism whereby high concentrations of L-phenylalanine (L-Phe) during phenylketonuria (>1.2 mM) cause mental retardation remains unknown. Therefore, the effects of L-Phe on NMDA-activated currents (I(NMDA)) were studied in cultured hippocampal neurons from newborn rats using the patch-clamp technique. L-Phe specifically and reversibly attenuated I(NMDA) in a concentration-dependent manner (IC(50) = 1.71 +/- 0.24 mM). In contrast, L-tyrosine (L-Tyr), an amino acid synthesized from L-Phe in normal subjects, did not significantly change I(NMDA). Although the L-Phe-I(NMDA) concentration-response relationship was independent of the concentration of NMDA, it was shifted rightward by increasing the concentration of glycine. Consistent with an effect of L-Phe on the NMDAR glycine-binding site, L-Phe (1 mM) did not attenuate I(NMDA) in the presence of D-alanine (10 microM). Furthermore, L-Phe significantly attenuated neither glutamate-activated current in the presence of MK-801, nor current activated by AMPA. The finding that L-Phe inhibits specifically NMDAR current in hippocampal neurons by competing for the glycine-binding site suggests a role for impaired NMDAR function in the development of mental retardation during phenylketonuria and accordingly an important role for NMDARs in memory formation and learning.

Structure-activity relationships and electrophysiological effects of short-acting amiodarone homologs in guinea pig isolated heart.

Antiarrhythmic agents with amiodarone-like electrophysiological actions, but with a more favorable pharmacokinetic profile than amiodarone would be extremely useful for the treatment of many tachyarrhythmias. We designed a series of amiodarone homologs with an alkyl ester group at position 2 of the benzofurane moiety. It was hypothesized that the electrophysiological and pharmacokinetic properties of these compounds are closely related to the size and branching of the ester group. The magnitude and time course of electrophysiological effects caused by methyl (ATI-2001), ethyl (ATI-2010), isopropyl (ATI-2064), sec-butyl (ATI-2042), and neopentyl (ATI-2054) homologs, and their common metabolite (ATI-2000) were investigated in guinea pig isolated heart. In paced hearts (atrial cycle length = 300 ms), each homolog (1 microM) was infused for 90 min followed by a 90-min washout. The stimulus-to-atrium (St-A), atrium-to-His bundle (AH), His bundle-to-ventricle (HV), QRS, and QT intervals, and ventricular monophasic action potential duration at 90% repolarization (MAPD(90)) were measured every 10 min. ATI-2001 and ATI-2064 significantly lengthened the St-A, HV, and QRS intervals, whereas ATI-2042 and ATI-2054 prolonged only the St-A interval. All compounds except the metabolite prolonged the AH interval. The relative rank order for the homologs to lengthen ventricular repolarization (MAPD(90)) was ATI-2042 > or = 2001 = 2010 = 2064 > 2054 > or = 2000. The metabolite was electrophysiologically inactive. Thus, modification of the benzofurane moiety ester group size and branching markedly altered the magnitude and time course of the electrophysiological effects caused by the ATI compounds. The different structure-activity relationships among the amiodarone homologs may have important consequences for further development of amiodarone-like antiarrhythmic agents.

Potent and reversible effects of ATI-2001 on atrial and atrioventricular nodal electrophysiological properties in guinea pig isolated perfused heart.

We recently demonstrated that the short-acting analog of amiodarone, ATI-2001, caused favorable effects in guinea pig ventricular myocardium on electrophysiological substrates underlying tachyarrhythmia initiation, perpetuation, and termination. Here, the acute effects of 1.0 microM ATI-2001 and 1.0 microM amiodarone (90-min infusion followed by 90-min washout period) on atrial and atrioventricular (AV) nodal electrophysiological properties were studied in guinea pig isolated hearts. Neither ATI-2001 nor amiodarone significantly prolonged atrial conduction time. Compared with amiodarone, ATI-2001 caused significantly more rapid and greater prolongation of atrial monophasic action potential duration at 90% repolarization (maximal change 21.4 +/- 3.7 versus 19.0 +/- 4.0 ms) and atrial effective refractory period (ERP, 27.8 +/- 6.1 versus 9.2 +/- 2.3 ms). Shortening of the atrial cycle length from 250 to 200 ms did not significantly alter drug-induced changes in atrial repolarization and refractoriness. ATI-2001 prolonged the atrium-to-His bundle interval (22.1 +/- 2.6 versus 8.8 +/- 2.3 ms), His bundle-to-ventricle interval (2.8 +/- 0.4 versus 0.9 +/- 0.3 ms), AV nodal ERP (72.5 +/- 7.3 versus 31.4 +/- 4.1 ms), and Wenckebach cycle length (69.6 +/- 5.2 versus 35.8 +/- 4.1 ms) significantly more than did amiodarone. Unlike amiodarone, the effects of ATI-2001 were markedly reversed upon discontinuation of drug infusion. Given these data, ATI-2001 should not only be useful for terminating ongoing and preventing reoccurrence of atrial tachyarrhythmias but also to treat supraventricular tachycardias involving the AV node and to control ventricular rate during atrial tachyarrhythmias. Whether the observed differences in the pharmacokinetic properties render ATI-2001 superior to amiodarone in acute tachyarrhythmia management and less likely to accumulate into tissues during chronic therapy remains to be established.

Antagonism of the positive dromotropic effect of isoproterenol by adenosine: role of nitric oxide, cGMP-dependent cAMP-phosphodiesterase and protein kinase G.

We hypothesized that nitric oxide (NO) plays an important role in mediating the anti-adrenergic effect of adenosine on atrioventricular (AV) nodal conduction. In guinea-pig hearts instrumented for measurement of AV nodal conduction time (atrium-to-His bundle, A-H, interval), the NO synthase (NOS) inhibitor, l-NMMA (100 microm), reversibly inhibited 80% (P=0.009, n=6) of adenosine's anti-adrenergic action on the positive dromotropic effect of isoproterenol (0.01 microm). In parallel studies carried out in rabbit AV nodal myocytes, intracellular mechanisms whereby NO mediates the inhibitory effect of adenosine on isoproterenol-induced A-H interval shortening were studied. Adenosine (3 microm) inhibited isoproterenol-stimulated (0.1 microm) I(Ca,L)(beta -I(Ca,L)) by 46+/-6% (P<0.001, n=17). Consistent with isolated heart data, the NOS inhibitors, l -NMMA (100 microm) and L-NNA (500 microm) attenuated the effect of adenosine on beta -I(Ca,L)by 69+/-8% (P<0.001, n=16) and 69+/-7% (P<0.001, n=10), respectively. An inhibitor of NO-stimulated guanylyl cyclase LY83538 (40 microm) reduced the inhibitory effect of adenosine on beta -I(Ca,L)by 97+/-6% (P=0.004, n=15). Similarly, the non-specific inhibitor of cAMP-phosphodiesterases IBMX (50 microm) decreased the anti-adrenergic effect of adenosine by 60% (P=0.02, n=6), whereas the extracellular application of the non-hydrolyzeable cAMP analog 8-Br-cAMP (500 microm) prevented this action of adenosine. Activation of cGMP-dependent protein kinase (PKG) by CPT-cGMP (300 microm) diminished beta -I(Ca,L), but to a significantly smaller degree (16+/-4%, P=0.025, n=12) than that caused by adenosine. NO mediates the anti-adrenergic effect of adenosine on AV nodal conduction by a mechanism predominately involving activation of cGMP-dependent cAMP-phosphodiesterase and to a lesser extent activation of PKG.

Midazolam selectively potentiates the A(2A) - but not A1- receptor--mediated effects of adenosine: role of nucleoside transport inhibition and clinical implications.

BACKGROUND: Inhibition of adenosine metabolism offers a unique approach to harness the cardioprotective properties of adenosine in a site- and event-specific manner. Benzodiazepines inhibit adenosine metabolism by blocking nucleoside transporter. Therefore, the authors studied the binding affinities of structurally different benzodiazepines to nucleoside transporter and benzodiazepine-induced potentiation of A1-adenosine (negative dromotropy) and A2A-adenosine (coronary vasodilation) receptor-mediated effects. METHODS: In membranes from porcine striatum and guinea pig ventricle, competition binding assays to displace [3H]nitrobenzylmercaptopurine riboside ([3H]NBMPR) from nucleoside transporter were performed using alprazolam, chlorodiazepoxide, diazepam, flurazepam, and midazolam. The augmentation by the most potent benzodiazepine of A1- and A2A-adenosine receptor-mediated responses, elicited by exogenous administration of adenosine or brief periods of global hypoxia, was subsequently studied in guinea pig Langendorff-perfused hearts. RESULTS: All benzodiazepines completely displaced [3H]NBMPR in a concentration-dependent manner with Hill coefficients not significantly different from unity in both striatal and ventricular membranes. Midazolam was the most potent inhibitor of nucleoside transporter (ventricle:pKi = 5.22+/-0.41, Ki = 6 microM). In isolated hearts, midazolam (5, 10, 20 microM) significantly augmented coronary flow in a concentration-dependent manner in the presence of adenosine (30 nM), an effect reversed by ZM 241385, a selective A2A-receptor antagonist. In contrast, midazolam did not increase the effect of adenosine (30 nM) on atrioventricular conduction. Similarly, midazolam potentiated A2A- but not A1-receptor-mediated effects of endogenous adenosine released during hypoxia. CONCLUSIONS: Structurally distinct benzodiazepines inhibit nucleoside transporter to different degrees. Midazolam selectively augments A2A- but not A1-receptor-mediated effects of adenosine by inhibiting nucleoside transporter.

Cross-sectional area of the right and left internal jugular veins.

OBJECTIVE: To compare the cross-sectional area (CSA) of the right internal jugular vein (RIJV) with the left internal jugular vein (LIJV) using two-dimensional ultrasound and to measure the response to the Valsalva maneuver in both the supine and Trendelenburg positions. DESIGN: Prospective and randomized. SETTING: University-affiliated hospital. PARTICIPANTS: Fifty healthy adult volunteers. INTERVENTIONS: The CSA of both the RIJV and LIJV was measured with a 5-MHz, two-dimensional surface transducer before and during a 10-second Valsalva maneuver with the subjects in the supine position, and then with the subjects in a 10 degree Trendelenburg tilt. MEASUREMENTS AND MAIN RESULTS: After the baseline measurements were performed, the subjects were divided into two groups based on the CSA of the RIJV and LIJV. Group 1 had an LIJV CSA equal to or greater than that of the RIJV (n = 10) and group 2 had an LIJV CSA less than that of the RIJV (n = 40). Of the latter 40 patients, 17 (34%) had an LIJV CSA less than 50% of that of the RIJV. In both groups, the CSA of both veins increased significantly with the Valsalva maneuver, Trendelenburg tilt, and both maneuvers combined. CONCLUSION: The findings suggest that in one third of adults (34%), the LIJV is significantly smaller compared with the RIJV and, combined with operator inexperience, may influence the success rate and risk for complications. Thus, the use of ultrasound and maneuvers that increase CSA is suggested during LIJV cannulation.

Ionic mechanisms mediating the differential effects of methohexital and thiopental on action potential duration in guinea pig and rabbit isolated ventricular myocytes.

BACKGROUND: Commonly used barbiturate anesthetics may significantly influence cardiac electrophysiologic characteristics. The authors evaluated thiopental (a thiobarbiturate) and methohexital (an oxybarbiturate), two compounds with similar physicochemical properties but different structures, to determine whether they have distinct effects on the major ionic currents that determine action potential duration (APD) in ventricular myocytes. METHODS: The effects of thiopental and methohexital (50 microM) on APD at 50% (APD50) and 90% (APD90) repolarization were studied in guinea pig and rabbit single ventricular myocytes using the patch-clamp technique in a whole-cell configuration. The ionic mechanisms underlying the APD changes were evaluated by measuring the anesthetics' effects on the L-type calcium inward current, the inward rectifier potassium current, and the delayed rectifier potassium current in guinea pig cells and on the transient outward potassium current in rabbit cells. RESULTS: Thiopental and methohexital caused opposite effects on APD. Whereas thiopental prolonged APD50 and APD90 in guinea pig and rabbit ventricular myocytes, methohexital shortened them. Thiopental markedly depressed both the inward and outward components of the inward rectifier potassium current, whereas methohexital caused minimal inhibition of the inward component and no change in the outward component. The delayed rectifier potassium current was inhibited by thiopental but significantly potentiated by methohexital. Neither thiopental nor methohexital significantly affected the transient outward potassium current or the L-type calcium inward current. CONCLUSIONS: Despite their similar lipid solubilities, molecular weights, and pKa values, thiopental increased and methohexital decreased the APD in ventricular myocytes by predominantly inhibiting the inward rectifier potassium current and the delayed rectifier potassium current and by increasing the delayed rectifier potassium current, respectively. These characteristics suggest distinct structure-specific actions of barbiturates on the function of myocardial ionic channels.

Hyperkalemia enhances the effect of adenosine on IK,ADO in rabbit isolated AV nodal myocytes and on AV nodal conduction in guinea pig isolated heart.

BACKGROUND: The atrioventricular (AV) node is insensitive to changes in extracellular potassium concentration, [K+]o, because of the absence of the inward rectifier potassium current (IK1). However, we propose that in the presence of adenosine, elevated [K+]o should increase the adenosine-activated inward rectifier potassium current (IK,ADO) in AV nodal myocytes and hence augment the negative dromotropic effect of the nucleoside. METHODS AND RESULTS: The effects of normal (4.8 mmol/L) and high (8.0 mmol/L) [K+]o on adenosine-induced changes in resting membrane potential (Vm), IK,ADO, and membrane resistance (Rm) in rabbit isolated AV nodal myocytes and in AV nodal conduction delay (atrium-to-His bundle, AH, interval) in guinea pig isolated hearts were determined with the use of whole-cell patch-clamp and His bundle electrogram techniques, respectively. High [K+]o alone did not significantly affect membrane current, Rm, or Vm in AV nodal myocytes. However, high [K+]o in the presence of adenosine (3 micromol/L) markedly increased Im (-0. 249+/-0.038 to -0.571+/-0.111 nA, P<0.05) at -100 mV and reduced Rm (151+/-21 to 77+/-8 MOmega, P<0.02). Adenosine still hyperpolarized Vm from -48+/-2 to -65+/-1 mV (P<0.001). High [K+]o alone did not significantly affect the AH interval in isolated hearts. However, high [K+]o markedly lengthened the AH interval prolongation caused by adenosine (4 micromol/L, 7.9+/-0.8 vs 22.1+/-3.0 ms, P<0.001). The potentiating effect of high [K+]o on adenosine-induced delay in AV nodal conduction was abolished by BaCl2 (100 micromol/L). CONCLUSIONS: By increasing IK,ADO and decreasing Rm of AV nodal myocytes, elevated [K+]o, augments the depressant effect of adenosine on AV nodal conduction.

Effects of volatile anesthetics on atrial and AV nodal electrophysiological properties in guinea pig isolated perfused heart.

BACKGROUND: Knowledge of the anesthetic effects on atrial and atrioventricular (AV) nodal electrophysiologic properties is fundamental to understand the modulatory role of anesthetics on the pathogenesis of supraventricular tachycardias, and to individualize the perioperative management of patients with supraventricular tachycardias or AV nodal conduction disturbances. Therefore the authors studied the effects of three commonly used volatile anesthetics on the electrophysiologic properties of the atrium and AV node. METHODS: The concentration-dependent electrophysiologic effects of halothane, isoflurane, and desflurane (0-2 minimum alveolar concentration [MAC]) were studied in guinea pig Langendorff-perfused hearts fit with instruments to simultaneously measure atrial and AV nodal conduction times and atrial monophasic action potential duration. Atrial and AV nodal effective refractory periods were measured simultaneously using a computer-assisted premature stimulation protocol. The concentrations of anesthetics in the gas phase were monitored by an infrared gas analyzer. RESULTS: Volatile anesthetics caused markedly different concentration-dependent effects on atrial conduction, repolarization, and refractoriness, and on AV nodal function. At equianesthetic concentrations, halothane depressed atrial conduction the most, whereas desflurane caused the greatest shortening of atrial monophasic action potential duration. Halothane had no significant effect on atrial refractoriness, whereas at 2 MAC desflurane significantly shortened and isoflurane significantly prolonged atrial effective refractory periods by 18.1+/-13.5% and 13.2+/-14.7%, respectively. On an equi-MAC basis, the rank order of potency for the anesthetics to prolong AV nodal conduction time and AV nodal ERP was halothane > desflurane > isoflurane. CONCLUSION: The different electrophysiologic effects of volatile anesthetics in the atrium and AV node suggest that these agents may modulate atrial dysrhythmogenesis in distinctly different ways.

Validation of Furchgott's method to determine agonist-dependent A1-adenosine receptor reserve in guinea-pig atrium.

1. The ubiquitous distribution of A1-adenosine receptors (A1AdoR) represents an impediment to achieve organ and/or response selectivity of A1AdoR agonists. Differential receptor reserve may be exploited to overcome this problem. We hypothesize that A1AdoR reserve is agonist-dependent and can be accurately estimated with Furchgott's method. 2. Concentration-response curves were constructed from measurement of the atrial monophasic action potential duration in guinea-pig, isolated hearts treated with R(-) N6-(2-phenylisopropyl)adenosine (R-PIA) or 2-chloro-N6-cyclopentyl-adenosine (CCPA) before and after treatment with the selective, irreversible A1AdoR antagonist 8-cyclopentyl-3-[3-[[4-(fluorosulphonyl)benzoyl]oxy]propyl]-1-prop ylxanthine (FSCPX). Using Furchgott's method, we determined the equilibrium dissociation constant (KA) of R-PIA and CCPA, and the fraction of non-inactivated A1AdoRs remaining after FSCPX treatment (q(functional)). Values of q(functional) were correlated to the fraction of specific binding sites after FSCPX treatment labelled by [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]-CPX) derived from saturation binding normalized to control (q(binding)). 3. Both R-PIA and CCPA are full A1AdoR agonists, but have significantly different potencies (pD2 [EC50]=6.84+/-0.04 [145 nM] vs 7.36+/-0.04 [44 nM], respectively), receptor affinities (pKA [KA]= 6.54+/-0.10 [288 nM] vs 6.13+/-0.03 [734 nM]), and pharmacological shift ratios defined as KA/EC50 (2.2+/-0.6 vs 15.9+/-1.5). Values for q(functional) and q(binding) were highly correlated (r2=0.96). The ratio between the intrinsic efficacies of CCPA and R-PIA derived from Furchgott's analysis was 5.9, a value similar to the ratio of 6.2-6.6 calculated from previously obtained binding data. 4. Radioligand binding studies validated the use of Furchgott's method to estimate A1AdoR reserve. A1AdoR reserve was agonist-dependent. CCPA was shown to be a high intrinsic efficacy, low affinity agonist, whereas R-PIA was found to be a low intrinsic efficacy, high affinity agonist.

Cross-sectional area and intravascular pressure of the right internal jugular vein during anesthesia: effects of Trendelenburg position, positive intrathoracic pressure, and hepatic compression.

STUDY OBJECTIVE: To determine changes in the cross-sectional area of the right internal jugular vein (RIJV) in response to positive intrathoracic pressure and hepatic compression in mechanically ventilated patients during general anesthesia. DESIGN: Prospective, nonrandomized study. SETTING: A university medical center. PATIENTS: 15 ASA physical status II and III adult patients undergoing RIJV cannulation after anesthetic induction and endotracheal intubation. INTERVENTIONS: Patients were studied first supine and then at a 10 degrees and 20 degrees Trendelenburg tilt. The cross-sectional area of the RIJV was determined by two-dimensional ultrasound before and during 1) an end-inspiratory hold of 20 cm H2O; 2) hepatic compression for 10 seconds; and 3) both maneuvers applied simultaneously. Subsequently, the RIJV was cannulated and the intravascular pressure was measured during the same sequence of maneuvers. MEASUREMENTS AND MAIN RESULTS: In supine patients, the cross-sectional area of the RIJV significantly increased during the end-inspiratory hold, during hepatic compression, and with both maneuvers performed simultaneously (p < 0.05). With a 10 degrees Trendelenburg tilt, only both maneuvers applied simultaneously increased the cross-sectional area of the RIJV significantly, and with the 20 degrees Trendelenburg tilt, no further increase was seen. Intravascular pressure of the RIJV consistently increased with each maneuver in all positions. CONCLUSION: Hepatic compression and positive inspiratory hold effectively dilate the RIJV in supine patients and can be used when the Trendelenburg position is not advisable or possible. Performing these maneuvers with patients in the Trendelenburg position may facilitate cannulation, possibly by making the vein less collapsible due to increased intravascular pressure.

Ionic basis of the differential effects of intravenous anesthetics on erythromycin-induced prolongation of ventricular repolarization in the guinea pig heart.

BACKGROUND: Dysrhythmias and death occur in patients with acquired long QT syndrome (LQTS). Little information exists regarding interactions between anesthetics and drugs that prolong ventricular repolarization. Therefore the effects of three commonly used intravenous anesthetics on ventricular repolarization were investigated in the setting of drug-induced, long QT syndrome. METHODS: The effects of increasing concentrations (0, 10, 25, and 50 microM) of propofol, ketamine, and thiopental on ventricular repolarization were evaluated by measuring the monophasic action potential duration at 90% repolarization (MAPD90) in guinea pig Langendorff-perfused hearts in the absence or presence of erythromycin (100 microM). If an anesthetic enhanced erythromycin-induced prolongation of MAPD90, its effects on the delayed rectifier (I[K]) and inward rectifier (I[Kl]) potassium currents were measured using the whole-cell patch-clamp technique. RESULTS: At clinically relevant concentrations, only thiopental significantly modulated erythromycin's effect on MAPD90. Thiopental at 10, 25, and 50 microM prolonged MAPD90 from a control of 163 +/- 6 ms by 18 +/- 4, 30 +/- 3, and 31 +/- 4 ms, respectively. In a separate group, erythromycin prolonged MAPD90 from 155 +/- 2 ms to 171 +/- 2 ms (n = 21, P < 0.001). In the presence of erythromycin, thiopental at 10, 25, and 50 microM caused significantly greater prolongation from a control of 171 +/- 2 ms by 39 +/- 2, 58 +/- 3, and 72 +/- 6 ms, respectively. Whole-cell patch-clamp experiments indicated that thiopental inhibited I(K) and I(Kl). CONCLUSIONS: Intravenous anesthetics caused markedly different effects on ventricular repolarization. Thiopental, unlike propofol and ketamine, potentiated the effects of erythromycin on ventricular repolarization by inhibiting I(K) and I(Kl).