Electrophysiological, haemodynamic, and mitochondrial alterations induced by levobupivacaine during myocardial ischemia in a pig model: protection by lipid emulsions?

Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into two groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: (i) single IV injection of saline, (ii) lipid emulsion (Intralipid(®) ), (iii) levobupivacaine, (iv) combination levobupivacaine-Intralipid(®) . Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax ). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation, and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins, and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/dtmax . At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid(®) quickly improved haemodynamics. However, beneficial effects of Intralipid(®) were less clear after myocardial ischemia.

T-type calcium current contributes to escape automaticity and governs the occurrence of lethal arrhythmias after atrioventricular block in mice.

BACKGROUND: When complete atrioventricular block (AVB) occurs, infranodal escape rhythms are essential to prevent bradycardic death. The role of T-type Ca(2+) channels in pacemaking outside the sinus node is unknown. We investigated the role of T-type Ca(2+) channels in escape rhythms and bradycardia-related ventricular tachyarrhythmias after AVB in mice. METHODS AND RESULTS: Adult male mice lacking the main T-type Ca(2+) channel subunit Cav3.1 (Cav3.1(-/-)) and wild-type (WT) controls implanted with ECG telemetry devices underwent radiofrequency atrioventricular node ablation to produce AVB. Before ablation, Cav3.1(-/-) mice showed sinus bradycardia (mean±SEM; RR intervals, 148±3 versus 128±2 ms WT; P<0.001). Immediately after AVB, Cav3.1(-/-) mice had slower escape rhythms (RR intervals, 650±75 versus 402±26 ms in WT; P<0.01) but a preserved heart-rate response to isoproterenol. Over the next 24 hours, mortality was markedly greater in Cav3.1(-/-) mice (19/31; 61%) versus WT (8/26; 31%; P<0.05), and Torsades de Pointes occurred more frequently (73% Cav3.1(-/-) versus 35% WT; P<0.05). Escape rhythms improved in both groups during the next 4 weeks but remained significantly slower in Cav3.1(-/-). At 4 weeks after AVB, ventricular tachycardia was more frequent in Cav3.1(-/-) than in WT mice (746±116 versus 214±78 episodes/24 hours; P<0.01). Ventricular function remodeling was similar in Cav3.1(-/-) and WT, except for smaller post-AVB fractional-shortening increase in Cav3.1(-/-). Expression changes were seen post-AVB for a variety of genes; these tended to be greater in Cav3.1(-/-) mice, and overexpression of fetal and profibrotic genes occurred only in Cav3.1(-/-). CONCLUSIONS: This study suggests that T-type Ca(2+) channels play an important role in infranodal escape automaticity. Loss of T-type Ca(2+) channels worsens bradycardia-related mortality, increases bradycardia-associated adverse remodeling, and enhances the risk of malignant ventricular tachyarrhythmias complicating AVB.

Prophylactic pacemaker implantation in familial amyloid polyneuropathy.

BACKGROUND: Familial amyloid polyneuropathy (FAP) is an autosomic dominant disease with a high rate of conduction disorders and increased risk of sudden death. Prophylactic cardiac pacing may be considered in asymptomatic patients with FAP. However, the potential benefits are unknown. OBJECTIVE: To document conduction disorders in a large series of FAP and the incidence of high-degree atrioventricular (AV) block in patients with prophylactic pacemaker (PM). METHODS: From January 1999 to January 2010, 262 patients with FAP were retrospectively evaluated. Prophylactic PM was implanted in patients with His-ventricular interval ≥ 70 ms, His-ventricular interval >55 ms associated with a fascicular block, a first-degree AV block, or a Wenckebach anterograde point ≤ 100 beats/min. The spontaneous AV conduction was then analyzed by temporarily inhibiting the PM. RESULTS: As compared with patients with prophylactic PM (n = 100) and patients implanted given a class I/IIa indication (n = 18), the patients who did not require PM (n = 144) were younger and displayed less severe cardiac involvement. Follow-up after prophylactic PM implantation was analyzed in 95 of the 100 patients over 45 ± 35 months, and a high-degree AV block was documented in 24 of the 95 patients (25%). The risk of high-degree AV block was higher in patients with first-degree AV block or Wenckebach anterograde point ≤ 100 beats/min (hazard ratio 3.5; 95% confidence interval 1.2-10) while microvoltage on surface electrocardiogram reduced the risk (hazard ratio 0.2; 95% confidence interval 0.1-0.7). CONCLUSION: In FAP with conduction disorders, prophylactic PM implantation prevented major cardiac events in 25% of the patients over a 45-month mean follow-up. It is suggested that prophylactic PM implantation prevented symptomatic bradycardia in these patients.

Application of prophylactic gel-pads for transcutaneous pacing in patients with complete right bundle-branch block with axis deviation when surgical procedures are performed: 10-year experience from a single Japanese university hospital.

This retrospective study aimed to determine whether prophylactic transcutaneous pacing is required for patients with complete right bundle-branch block (CRBBB) and axis deviation (AD), so-called bifascicular block, when surgical procedures are performed under general or local anesthesia. The authors reviewed 34 063 anesthesia cases that took place at Nara Medical University Hospital during a 10-year period (1996-2005). The anesthesia records of all identified patients having CRBBB or bifascicular block were retrospectively reviewed and the incidence of block progression to complete heart block or bradycardia requiring temporary transcutaneous pacing served as the primary endpoint. As a secondary endpoint, the incidence of block progression to complete heart block or bradycardia requiring only medical treatment was checked. Seventy of the 34 063 patients (0.2%) had CRBBB with AD. Only 1 patient with CRBBB with left AD, who underwent on-pump aorto-coronary bypass grafting surgery, developed complete heart block at the resumption of heartbeat. None of the other 69 patients, except for this cardiac case, developed complete heart block during surgery. Based on this analysis of 70 cases, prophylactic gel-pad electrode application in patients with CRBBB and AD does not appear to be necessary during surgical procedures.

Percutaneous injection of lidocaine within the carotid body area in carotid artery stenting: an "old-new" technique.

Severe bradycardia is a common untoward effect during balloon angioplasty when performing carotid artery stenting. Therefore atropine injection even before dilatation and the presence of an anesthesiologist are advocated in all patients. In the surgical literature, injection of a local anesthetic agent into the carotid sinus before carotid endarterectomy was performed in an attempt to ameliorate perioperative hemodynamic instability. This study was undertaken to test the hypothesis that percutaneous infiltration of the carotid sinus with local anesthetic immediately before balloon dilatation reduces bradycardia and ameliorates the need for atropine injection or the presence of an anesthesiologist. Infiltration of the carotid sinus with 5 ml of 1% lidocaine, 3 min before dilatation, was performed in 30 consecutive patients. No one exhibited any significant rhythm change that required atropine injection. The anesthesiologist did not face any hemodynamic instability during the carotid artery stenting procedure.

Hemorrhage activates proopiomelanocortin neurons in the rat hypothalamus.

Severe blood loss lowers arterial pressure through a central mechanism that is thought to include opioid neurons. In this study, we investigated whether hemorrhage activates proopiomelanocortin (POMC) neurons by measuring Fos immunoreactivity and POMC mRNA levels in the medial basal hypothalamus. Hemorrhage (2.2 ml/100 g body weight over 20 min) increased the number of Fos immunoreactive neurons throughout the rostral-caudal extent of the arcuate nucleus, the retrochiasmatic area and the peri-arcuate region lateral to the arcuate nucleus where POMC neurons are located. Double label immunohistochemistry revealed that hemorrhage increased Fos expression by beta-endorphin immunoreactive neurons significantly. The proportion of beta-endorphin immunoreactive neurons that expressed Fos immunoreactivity increased approximately four-fold, from 11.7+/-1.4% in sham-operated control animals to 42.0+/-5.2% in hemorrhaged animals. Hemorrhage also increased POMC mRNA levels in the medial basal hypothalamus significantly, consistent with the hypothesis that blood loss activates POMC neurons. To test whether activation of arcuate neurons contributes to the fall in arterial pressure evoked by hemorrhage, we inhibited neuronal activity in the caudal arcuate nucleus by microinjecting the local anesthetic lidocaine (2%; 0.1 or 0.3 microl) bilaterally 2 min before hemorrhage was initiated. Lidocaine injection inhibited hemorrhagic hypotension and bradycardia significantly although it did not influence arterial pressure or heart rate in non-hemorrhaged rats. These results demonstrate that hemorrhage activates POMC neurons and provide evidence that activation of neurons in the arcuate nucleus plays an important role in the hemodynamic response to hemorrhage.

Absence of device-device interaction (DDI) in a patient with cardiac and diaphragmatic pacemakers for congenital central hypoventilation syndrome.

Autonomic control of ventilation is impaired in patients with Ondine's curse or congenital central hypoventilation syndrome (CCHS), but voluntary control remains intact. Bradyarrhythmias can be life threatening. In a patient with CCHS and long sinus pause requiring cardiac pacemaker insertion, a diaphragmatic pacemaker inserted in early childhood caused diaphragmatic pacer spikes observed during the interrogation of the cardiac pacemaker. Diaphragmatic pacing did not interfere with the cardiac pacemaker function.

Anxiolytic-like effect of a serotonergic ligand with high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors.

S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-alpha]-pyrazine (CSP-2503) is a serotonin (5-HT) receptor ligand with selectivity and high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. CSP-2503 reduced rectal temperature and 5-HT neuronal hypothalamic activity in mice, decreased electrical activity of raphe nuclei cells in rats and blocked the enhancement of adenylate cyclase activity induced by forskolin in HeLa cells transfected with the human 5-HT1A receptor. This compound also blocked head-twitches induced by the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Contractions of guinea pig ileum induced by the 5-HT3 receptor agonist 2-methyl-5-HT were prevented by CSP-2503. Moreover, it reduced the bradycardia reflex induced by 2-methyl-5-HT in anaesthetized rats. In the light/dark box and social interaction tests, CSP-2503 presented anxiolytic activity, an action shared by 5-HT1 agonists and 5-HT3 antagonists. Taken together, these results suggest that CSP-2503 is a new 5-HT1 receptor agonist with 5-HT2A and 5-HT3)receptor antagonist activities that might be useful in a number of conditions associated with anxiety.

KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts.

BACKGROUND: A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation. METHODS AND RESULTS: KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-beta1; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720. CONCLUSIONS: These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation.

Atrial septal pacing: a new approach to prevent atrial fibrillation.

Atrial pacing may prevent the onset of atrial fibrillation (AF) because of: (1) prevention of the relative bradycardia that triggers paroxysmal AF; (2) prevention of the bradycardia induced dispersion of refractoriness; (3)suppression or reduction of premature atrial contractions that initiate reentry and predispose to AF; (4) preservation of AV synchrony, which might prevent switch induced changes in atrial repolarization predisposing to AF. Atrial pacing locations that decrease atrial activation and dispersion of refractoriness may be preferable in patients with a history of AF. Two different interatrial septum sites have been proposed: the Bachmann's bundle and the coronary sinus ostium. The results of two prospective randomized studies indicate that septal pacing, when compared to the traditional right atrial appendage pacing, significantly reduces : (1) paroxysmal AF recurrences and burden; and (2) progression to chronic AF.

How do atrial pacing algorithms prevent atrial arrhythmias?

With an ageing population, atrial fibrillation has become an increasing cause of hospital admission and morbidity. Pacemaker implantation may prevent atrial tachyarrhythmias by preventing bradycardia and pauses. Implantable devices are now available with specific atrial pacing algorithms designed to prevent atrial arrhythmias. These algorithms work by increasing the atrial pacing rate to achieve continuous overdrive pacing or by responding to triggers such as premature atrial complexes. This article examines how the algorithms work by describing the functions of one of the new generation of pacemakers in detail. Early studies have indicated that the use of preventative pacing can reduce atrial arrhythmia burden and symptomatic atrial fibrillation in selected patients. There are clearly some patients who benefit from implantation of these devices but what remains unclear is how to identify this patient group.

Pauses after burst pacing provoke afterdepolarizations and torsades de pointes in a patient with long QT syndrome.

A patient with long QT syndrome and syncope underwent electrophysiological testing and recording of monophasic action potentials (MAP). Programmed ventricular stimulation using up to three premature stimuli did not provoke arrhythmias. Transient action potential prolongation and afterdepolarizations were observed during pauses directly after high-rate fix frequent right ventricular burst pacing at 120-160 bpm. During the pause after burst pacing at 180 bpm, afterdepolarizations at 16-19% amplitude of the MAP plateau persisted for several beats and preceded a short episode of torsades de pointes. High-rate burst pacing provoked afterdepolarizations and triggered torsades de pointes in this patient with long QT syndrome.

Sub-Tenon's block reduces both intraoperative and postoperative analgesia requirement in vitreo-retinal surgery under general anaesthesia.

BACKGROUND AND OBJECTIVE: We compared the effects of sub-Tenon's local anaesthetic block and placebo on peri-operative opioid requirement and cardiovascular stability and on postoperative pain, nausea and vomiting in patients undergoing vitreo-retinal surgery under general anaesthesia. METHODS: We studied 43 patients undergoing vitreo-retinal surgery under general anaesthesia in a randomized double blind study. Patients received a standard general anaesthetic followed by a sub-Tenon's injection of 4-5 mL of either bupivacaine 0.75% or saline. We recorded intraoperative invasive arterial pressure, then the incidence and severity of pain and of nausea and vomiting, for 24 h postoperatively. RESULTS: In the sub-Tenon's bupivacaine group, there was a significant reduction in the perioperative opioid use and a reduction in the frequency of bradycardia and hypertensive episodes, defined as a rise > 25% of baseline for a duration of > 3 min. The sub-Tenon's bupivacaine group also had significantly lower pain scores and nausea scores at 12 h, concomitant with a lower consumption of analgesia and antiemetics. CONCLUSIONS: This local anaesthetic technique is effective in vitreo-retinal surgery and can be safely applied to this population of patients regardless of axial length.

[Role of atrial stimulation in the treatment of paroxysmal atrial fibrillation]. / Place de la stimulation auriculaire dans le traitement de la fibrillation auriculaire paroxystique.

Preventive treatments for atrial fibrillation by stimulation have been developed for several years now, mainly due to the relative failure of anti-arrhythmic treatments. They are based on the hypothetical effects of stimulation by controlling cardiac frequency, abolishing bradycardia-dependent extrasystoles, by the inhibition of atrial automatic foci with "overdrive", and by the modification of intra- or inter-atrial conduction delays as well as by remodelling the arrhythmogenic substrate. It is clear that an undeniable effect exists for the prevention of atrial fibrillation, even for the risk of cerebral vascular accident, by physiological stimulation (DDD/DDDR) compared to pure ventricular stimulation (VVI/VVIR) in a heterogenous global population of stimulated patients. For the moment, there is not sufficient proof of a positive effect for the emerging sites of cardiac stimulation, either atrial mono-site or double site in the populations at high risk of atrial fibrillation, with or without associated bradycardia. Some new prevention algorithms by "overdrive" are under development but for the moment only a few preliminary studies seem to show a slight benefit. It is clear that at present stimulation should be reserved only for cases of atrial fibrillation associated with a classic indication for implantation. In these patients it is recommended to position the probes in an optimal manner in order to counteract conduction disorders, choosing an adapted double chamber stimulator with prevention algorithms. That said, the patient should be clearly warned that the long term success rate is no more than 50%.

Oculocardiac reflex during retinal surgery using peribulbar block and nitrous narcotic anesthesia.

BACKGROUND AND OBJECTIVES: This study was designed to examine the effects of local and general anesthesia on the oculocardiac reflex (OCR) in adults during retinal detachment surgery, with an aim of determining the safest type of anesthesia and on which extraocular muscle traction causes a higher incidence of OCR. PATIENTS AND METHODS: The study was performed on 30 American Society of Anesthesiologists-I patients (age range 40-60 years) who were undergoing retinal detachment surgery. Fifteen patients underwent surgery with general anesthesia and 15 were given a local peribulbar block. A fixed traction of 400 g was applied to all the extraocular muscles, and the heart rate, rhythm, and electrocardiogram of each patient was monitored. RESULTS: The overall incidence of OCR was higher with general anesthesia (63.3%) than with local anesthesia (14.4%). There was a significant decrease in heart rate for the rectus muscles (P < .0005) as well as the oblique muscles (P < .005) during traction with general anesthesia. All four rectus muscles were equally sensitive in eliciting the reflex. The incidence of dysrhythmias was 20% with general anesthesia and 6.67% with local anesthesia. CONCLUSION: This study showed that local anesthesia produces less bradycardia and ectopic arrhythmias and, therefore, may be safer and better than general anesthesia for surgeries in which traction of extraocular muscles is required.

Pain and vomiting after vitreoretinal surgery: a potential role for local anaesthesia.

Periconal local anaesthesia with subtenon supplementation was used to provide anaesthesia for 94 patients having vitreoretinal surgery. Of these, 44 patients also received general anaesthesia with neuromuscular block. None of these patients received opioid or antiemetic before or during surgery. In comparison with a retrospective control group, patients who had received local anaesthesia as part of their anaesthetic technique were less likely to be given a parenteral opioid (P < 0.001) or to vomit (P < 0.001) within six hours of the completion of surgery. They also experienced significantly fewer bradycardic episodes during surgery (P = 0.001). For patients having general anaesthesia, administration of an intraoperative antiemetic reduced the incidence of vomiting within six hours of the completion of surgery (P = 0.008). For patients who did not receive local anaesthetic, shorter operating time was a factor associated with both reduced postoperative vomiting (P = 0.0015) and administration of parenteral opioid (P = 0.0014). It is suggested that the use of local anaesthesia as part of the anaesthetic technique for vitreoretinal surgery is associated with improved patient comfort.

Effects of chronic nifedipine treatment on streptozotocin-induced diabetic rats.

We studied the effects of 6-week treatment with nifedipine (35 mg/kg/day orally, p.o.) on streptozotocin (STZ)-induced diabetic rats. Injection of STZ [45 mg/kg intravenously, (i.v.) single dose] produced a significant increase in blood pressure (BP), bradycardia, hyperglycemia, hypoinsulinemia, hyperlipidemia, hypothyroidism, depression in left ventricular developed pressure (LVDP), cardiomyopathy, and nephropathy. Treatment of diabetic rats with nifedipine normalized the BP and prevented bradycardia. Insulin levels were decreased after nifedipine treatment in diabetic as well as nondiabetic rats. However, serum glucose levels were also partially decreased in diabetic animals by nifedipine treatment. In control animals as well, glucose levels were in the normal range despite lower insulin levels observed after nifedipine treatment. Nifedipine treatment significantly prevented STZ-induced increase in cholesterol and triglyceride levels. Nifedipine treatment significantly prevented STZ-induced hypothyroidism and also prevented STZ-induced cardiac depression and cardiomyopathy. Our data indicate that nifedipine increases insulin sensitivity and has some beneficial effects on cardiovascular parameters. It may therefore be considered a preferred drug in the treatment of hypertension associated with diabetes mellitus.