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The purpose of the Canadian Anesthesia Research Priority Setting Partnership (CAR PSP) was to identify a top ten list of shared priorities for research in anesthesia and perioperative care in Canada.We used the methods of the James Lind Alliance to involve patients, caregivers, healthcare professionals, and researchers in determining the research priorities in Canada. In a first survey, participants submitted questions that they want research to answer about anesthesia and perioperative care. We summarized those responses into a longlist of questions. We reviewed the literature to see if any of those questions were already answered. In a second survey, participants chose up to ten questions from the longlist that they thought were most important to be answered with research. From that list, the highest ranking questions were discussed and assigned a final rank at an in-person workshop.A total of 254 participants submitted 574 research suggestions that were then summarized into 49 questions. Those questions were checked against the literature to be sure they were not already adequately addressed, and in a second survey of those 49 questions, participants chose up to 10 that they thought were most important. A total of 233 participants submitted their priorities, which were then used to choose 24 questions for discussion at the final workshop. At the final workshop, 22 participants agreed on a top ten list of priorities.The CAR PSP top ten priorities reflect a wide variety of priorities captured by a broad spectrum of Canadians who receive and provide anesthesia care. The priorities are a tool to initiate and guide patient-oriented research in anesthesia and perioperative care.RéSUMé: OBJECTIF: L’objectif du Partenariat canadien pour l’établissement des priorités de la recherche en anesthésie (CAR-PSP) était d’établir une liste des dix principales priorités pour la recherche sur les soins anesthésiques et périopératoires au Canada. MéTHODES: Nous avons utilisé la méthodologie de la James Lind Alliance pour impliquer des patients, des aidants, des professionnels de la santé et des chercheurs afin de déterminer quelles étaient les priorités en matière de recherche au Canada. Dans une première enquête, les participants ont envoyé des questions sur les soins anesthésiques et périopératoires auxquelles ils voulaient que la recherche réponde. Nous avons résumé ces envois par une liste exhaustive de questions. Nous avons passé en revue les publications pour voir s’il existait déjà des réponses à ces questions. Dans une deuxième étude, les participants ont choisi dans la liste jusqu’à dix questions qui leur semblaient les plus importantes et pour lesquelles la recherche devrait fournir des réponses. À partir de cette liste, les questions les mieux classées ont été discutées et un classement définitif leur a été attribué au cours d’un atelier où tous les participants étaient présents en personne. RéSULTATS: Au total, 254 participants ont envoyé 574 suggestions de recherche qui ont été résumées en 49 questions. La littérature a été examinée pour s’assurer que ces questions n’avaient pas déjà reçu des réponses adéquates, et dans une seconde étude, les participants ont choisi jusqu’à 10 questions qu’ils jugeaient les plus importantes parmi ces 49 questions. Au total, 233 participants ont communiqué leurs priorités qui ont alors servi à choisir 24 questions ouvertes pour la discussion dans un atelier final. Dans cet atelier, 22 participants se sont mis d’accord sur une liste des dix principales priorités. CONCLUSION: Les dix principales priorités du CAR-PSP sont le reflet d’un grand éventail de priorités venant de Canadiens de tous horizons qui reçoivent ou fournissent des soins d’anesthésie. Ces priorités sont un outil permettant d’entamer et de guider une recherche axée sur le patient dans le domaine des soins anesthésiques et périopératoires.

Ketamine is considered a dissociative anesthetic medication, and it is commonly administered by a parenteral route. It works mainly by blocking the N-methyl-D-aspartate receptor. It inhibits the voltage-gated Na and K channels and serotonin and dopamine reuptake; also, it affects specific receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and aminobutyric acid A receptors. Ketamine appears to have particular mechanisms that are potentially involved during analgesic induction, including enhancing of descending inhibition and antiinflammatory effects. More recently, it has been shown that ketamine has potential in clinical practice for the management of chronic pain, cognitive function, depression, acute brain injury, and disorders of the immune system.

Chronic pain in patients with Alzheimer's disease or dementia is a complex issue in the medical field; these patients suffer from the common causes of chronic pain, especially in geriatric medicine. To ensure the correct type and level of given treatment, medical care should be taken to avoid the contribution of chronic pain and cognitive impairment in the elderly population. Acetylcholinesterase inhibitors (AChE-Is) have been proven as an efficient therapeutic resource for significant improvement in dementia of Alzheimer's disease and chronic pain due to the fact that cholinergic deficit is considered as an early finding in cognitive impairment and persisting pain. Some AChE-Is are investigated here in terms of treatment of dementia and chronic pain management. Neostigmine has been used as an adjunct analgesic in the postoperative period and in combination with other analgesic medications in an intrathecal approach. Rivastigmine has, over the past ten years, become the approved agent for the management of dementia of mild to moderate Alzheimer's disease and has gained approval for treating different types of non-Alzheimer's dementia. In this review, we will focus on the two types of AChE-Is (rivastigmine and neostigmine) in the development of their clinical use and their respective mechanisms of actions on improving cognitive function and managing chronic pain.

Erythropoietin (EPO) is the main regulator of red blood cell production. Since the 1990s, EPO has been used for the treatment of anemia associated with end-stage renal failure and chemotherapy. The erythropoietin receptors were found on other organs such as the brain, spinal cord, heart and skin. In addition, it has been shown that many tissues produce and locally release EPO in response to hypoxic, biochemical and physical stress. In cellular, animal and clinical studies, EPO protects tissues from ischemia and reperfusion injury, has antiapoptotic effects and improves regeneration after injury. In this article, we mainly review the nonhematopoietic effects and new possible clinical indications for EPO.

Objective. This study evaluated subcutaneous injections of tetrodotoxin (TTX) for the treatment of moderate to severe, inadequately controlled cancer-related pain.Methods. Eligible patients were randomized to receive TTX (30 μg) or placebo subcutaneously twice daily for four consecutive days. Efficacy was assessed using pain and composite endpoints (including pain and quality of life measures), and safety was evaluated using standard measures.Results. 165 patients were enrolled at 19 sites in Canada, Australia, and New Zealand, with 149 patients in the primary analysis “intent-to-treat” population. The primary analysis supports a clinical benefit of TTX over placebo based on the pain endpoint alone with a clinically significant estimated effect size of 16.2% (p=0.0460). Thepvalue was nominally statistically significant after prespecified (Bonferroni Holm) adjustment for the two primary endpoints but not at the prespecified two-sided 5% level. The mean duration of analgesic response was 56.7 days (TTX) and 9.9 days (placebo). Most common adverse events were nausea, dizziness, and oral numbness or tingling and were generally mild to moderate and transient.Conclusions. Although underpowered, this study demonstrates a clinically important analgesic signal. TTX may provide clinically meaningful analgesia for patients who have persistent moderate to severe cancer pain despite best analgesic care. This clinical study is registered with ClinicalTrials.gov (NCT00725114).

Context: Hypoventilation and apnea after epidural morphine is a serious concern after surgery and an issue in chronic pain. A low dose of naloxone added to morphine can prevent this complication. Objective: To determine that the low dose of naloxone added to epidural morphine analgesic could change the effect of this opioid in chronic low back pain. In addition, we evaluate its effect on respiratory function and patient satisfaction. Patients: Twenty-seven adults suffering from chronic low back pain (LBP) who were candidates for epidural injection treatment. Intervention: This was a randomized double-blind, uniform crossover, controlled clinical trial. The patients were treated with mixture of morphine-bupivacaine and mixture of morphine-bupivacaine-naloxone. Main outcome measure: The primary goals were to evaluate pain intensity and respiratory function after epidural injection of morphine or morphine combined with naloxone. Secondary end-points were the incidence and the side effects (pruritus, nausea, vomiting, and urinary retention) of neuraxial injection of morphine or morphine combined with naloxone for 14 days after each epidural injection. Results: There was no significant difference between morphine and morphine combined with naloxone on mean peripheral capillary oxygen saturation (SpO2m), the lowest peripheral capillary oxygen saturation (SpO2), and the respiratory disturbance index (RDI). Morphine combined with naloxone seemed to decrease pain more than morphine alone, but the result was not significant (p=0.2116). In the group that received morphine and naloxone, pain decreased sooner by half from baseline pain (at day 2 versus at day 6) than the other group. Vomiting, pruritus, and urinary retention were seen with no significant difference in both groups. Conclusion: We conclude that epidural administration of naloxone can preserve the analgesic effect of morphine in treatment of chronic LBP. Naloxone does not have any effects on respiratory function. It reduces itching, nausea, and pruritus after epidural injection of morphine. We cannot be certain whether this is the ideal dose or whether any changes in the doses might produce fewer side effects without interfering with analgesia.

Ketamine is considered a dissociative anesthetic medication, and it is a commonly administered by a parenteral route. It works mainly by blocking the N-methyl-D-aspartate (NMDA) receptor. It inhibits the voltage-gated Na_ and K_ channels and serotonin and dopamine re-uptake; also, it affects specific receptors, such as α-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA), kainite and amino butyric acid A receptors. Ketamine appears to have particular mechanisms that are potentially involved during analgesic induction, including enhancing of descending inhibition and anti-inflammatory effects. More recently, it has been shown that ketamine has potential in clinical practice for the management of chronic pain, cognitive function, depression, acute brain injury and disorders of the immune system.

Intractable pain that does not respond to conventional analgesic treatments is a clinical challenge, and may occur to a greater extent among elderly individuals or those with end-stage malignancies. This article describes three cases in which such patients were treated with a multidrug infusion to relieve their pain. The successes and challenges encountered in each case are described, and the authors include a discussion regarding the choice of the pharmalogical agents used, as well as their mechanism of action., The aim of the present study was to explore the effectiveness of an alternative method to manage pain based on a time-limited intrathecal (IT) infusion of an analgesic medication mixture. Three patients (69, 64 and 94 years of age) with intractable and poorly controlled pain due to bed sores, pelvic metastatic mass, and thoracic vertebra and rib fractures, respectively, were treated. Daily doses of opioids could not be increased due to side effects. An IT catheter (20 G) was placed by percutaneous approach in the lumbar area while advancing toward the thoracic region, and was then tunnelled and fixed subcutaneously. It was connected to an external infusion pump with a mixture of bupivacaine 1 mg/mL, naloxone 0.02 ng/mL, ketamine 100 μg/mL, morphine 0.01 mg/mL and clonidine 0.75 μg/mL. The starting rate was 1 mL/h. The pain was mostly controlled at a rate of

Complex regional pain syndrome (CRPS) is a condition of neuropathic pain, which is characterized by significant autonomic and inflammatory features. CRPS occurs in patients who have limb surgery, limb fractures, or trauma. Many patients may have pain resolve within twelve months of the inciting incident; however, a small subset progresses to the chronic form. This transitional process often happens by changing from warm CRPS with dominant inflammatory phase to cold CRPS, in which autonomic characteristics or manifestations dominate. Several peripheral and central mechanisms are involved, which might vary among individuals over a period of time. Other contributors include peripheral and central sensitization, autonomic alterations, inflammatory and immune changes, neurochemical changes, and psychological and genetic factors. Although effective management of the chronic CRPS form is often challenging, there are a few high quality randomized controlled trials that support the efficacy of the most commonly used therapeutic approaches., Neuroscience; Health sciences; Neurology; Surgery; Pain research; Pain management, CRPS; Pain; Pathophysiology; Treatment; Future therapy.

Complex regional pain syndrome (CRPS) is a chronic inflammatory pain syndrome that affects one or more extremities of the body. It is characterized by burning pain and abnormalities in the sensory, motor, and autonomic nervous systems. This review illustrates how oxidative stress and nuclear factor erythroid 2-related factor (Nrf2) activation might contribute to understanding the etiopathogenesis of CRPS. The precise cause of CRPS remains unclear, and current treatments are not effective in many patients. The mechanism underlying CRPS may differ across patients and even within a single patient over time. Inflammatory and neuronal mechanisms have been suggested as key contributors to CRPS. Recent evidence demonstrates that oxidative stress is associated with clinical symptoms in patients with CRPS-I. Oxidative stress plays a key role in CRPS pathogenesis. The Nrf2 factor is a master regulator of the transcription of multiple antioxidants, which protects against oxidative stress and inflammation by inducing antioxidant and detoxifying genes through binding with an antioxidant response element. It has antinociceptive effects against inflammatory pain in an animal model. This review summarises the effect of oxidative stress and mitochondrial dysfunction in the pathogenesis of CRPS. It also addresses the question of whether there is a potential role for Nrf2 (activated by pharmacological or nutritional activators) in alleviating the clinical features of CRPS or preventing its progression.

The alpha-2 adrenergic receptor (α-2 AR) agonists have a long history of use in treating different clinical conditions, such as hypertension, psychiatric entities (e.g., attention-deficit hyperactivity disorder), chronic pain, panic disorders, and, lately, for treating opioid withdrawal syndrome. In recent years, α-2 AR medications have been administered as adjuncts for managing inflammatory conditions, depression, chronic pain, sleep and cognitive disorders. This review will provide some clinical applications in neuroscience for this class of drugs. Understanding the pharmacological mechanisms is essential to obtaining neurochemical data that demonstrate that α-2 AR agonists have potential clinical significance in neuroscience.

Introduction: New research shows shown that erythropoietin has neuro-protective effects. In preclinical trial and human clinical trials, it was demonstrated that erythropoietin is effective treatment for spinal cord injury. Early administration of medications after injury increases the hope of attenuating secondary damage and maximizing an improved outcome. Case presentation: A 42-year-old female patient presented with gait instability and progressive weakness in her right leg over a 6-year period. She was diagnosed as myelomalacia and was candidate for cervical discectomy. After surgery, she suffered from right hemiplegia due to spinal cord injury that did not respond well to routine treatment. Darbepoetin alpha (Aranesp) 100 mcg, subcutaneous daily for three days, was added to the patient’s treatment seven days after trauma and resulted in rapid improvement. The patient recovered progressively and was discharged from the hospital ten days after erythropoietin therapy. Conclusions: This case report supports the beneficial role of erythropoietin in function, maintenance, and recovery of neurons. Erythropoietin is a double-edge sword, as long-term erythropoietin therapy has some complications, like thromboembolism and stroke. Recent studies suggested that erythropoietin should be given as single high dose to exert a rapid neuro-protective effect with minimal hematopoietic side effects. We believe that the effects and other adverse consequences of erythropoietin and its non-erythropoietic derivatives should be evaluated in clinical trials.

Prolonged postoperative cognitive dysfunction (POCD) is reported to occur frequently after cardiac surgery. However, it is rarely assessed in routine clinical practice and receives little attention. Although the cerebral consequences of cardiopulmonary bypass have been measured clinically, insights into the resulting molecular and pathologic events within the brain have only begun to be investigated. POCD is likely to impair quality of life and constitutes a large burden on society when elderly patients prematurely lose their independence. Numerous studies have reported that neurocognitive deficit is associated with heightened mortality, increased length of hospital stay, and discharge to a nursing home. This is linked with a tremendous demand for health-care resources. Because of the magnitude of the clinical problem, serious consideration must be directed toward understanding its etiology and the development of neuroprotective strategies. Clearly identifying the mechanisms of POCD is challenging. The purpose of this review is to discuss recent developments in our understanding of the pathophysiologic mechanisms, prevention, and treatments that have been designed to ameliorate brain dysfunction after cardiac surgery.

Purpose: To describe the effects of the combination of several therapies on the pulmonary circulation and cardiac function in a patient with severe pulmonary hypertension. Clinical features: We report the case of a female patient with chronic secondary pulmonary hypertension and cardiac failure who underwent right hemicolectomy under general anesthesia. Insertion of a pulmonary artery catheter before the operation revealed pulmonary artery pressure (PAP) of 55/24 mmHg which was lowered moderately by 40 parts per million (ppm) inhNO. During surgery, the patient presented an episode of atrial fibrillation with a slow, irregular heart rate of 45–50 min−1 and variable systemic pressure. A dipyridamole DPD (0.2 mg·kg−1) bolus stabilized systemic pressure and increased heart rate and cardiac output. However, PAP did not change. Nitroglycerine infusion was started at 10 mg·hr−1 shortly after the initiation of DPD. The patient responded favourably to combined inhNO, intravenous DPD and NTG therapy with a marked and sustained reduction of PAP and a systemic hemodynamic stability. Conclusion: We conclude that: 1) in combination with inhNO, DPD does not augment the inhNO-induced decrease in PAP; 2) DPD improves the hemodynamic profile and elevates cardiac output; 3) therapeutic combination (inhaled NO, NTG, DPD) has a potent effect on pulmonary pressure in cardiac failure patients.

Background: Primary graft failure from right or left ventricular insufficiency remains a serious cause of early death following heart transplantation. Inhaled nitric oxide (NO) is a potent pulmonary vasodilator that could decrease pulmonary pressure and improve right ventricular function. Methods Two cases of early graft failure following orthotopic heart transplantation were treated with NO inhalation. The treatment consisted of inhalation of 20 ppm of NO, introduced 4 to 6 hours following transplantation, in 2 patients supported with high doses of inotropic agents and vasopressors in addition to the intra-aortic balloon pump. Results In the first and second cases, NO inhalation resulted in a decrease in pulmonary artery pressure, in a decrease in pulmonary vascular resistance and in an increase in cardiac index. In the second patient, systemic oxygenation improved markedly 30 minutes after initiation of NO. In the 2 patients, NO inhalation, mechanical ventilation and the intra-aortic balloon pump were weaned 4 days following transplantation. Conclusion Primary graft failure from donor ischemic damage, reperfusion injury or pulmonary hypertension remains a serious complication. The use of an intra-aortic balloon pump, inotropic agents and of inhaled NO appears to offer the best support for recovery of donor heart function. Primary graft failure from right or left ventricular insufficiency remains a serious cause of early mortality following heart transplantation. 1 Ischemic damage of donor heart, reperfusion injury or pulmonary hypertension are the main causes of early graft failure. Although the cause is multifactorial, treatment of primary organ failure remains difficult with dismal results. The objective of the present study was to review the result of 2 patients with donor right heart failure following heart transplantation treated with inhaled nitric oxide (NO).

Acute respiratory distress syndrome (ARDS) was first described about 30 years ago. Modern definitions and statements have recently been proposed to describe ARDS accurately, but none is perfect. Diffuse alveolar damage is the basic pathological pattern most commonly observed in ARDS, and the term includes permeability edema. The alveolar epithelium of the alveolar-capillary barrier is clearly a key component requiring repair, given its multipotent functional activity. Lung inflammation and neutrophil accumulation are essential markers of disease in ARDS, and a wide variety of pro- and anti-inflammatory cytokines have been described in the alveolar fluid and blood of patients. These molecules still have to prove their value as diagnostic or prognostic biomarkers of ARDS.Supportive therapy in ARDS improved in the past decade; mechanical ventilation with lung protective strategies and patient positioning are gaining interest, but the indications for corticosteroids for ARDS are still debated. Nitric oxide may have a place in the treatment of one-third of patients. Novel approaches, such as surfactant replacement and liquid ventilation, may further improve supportive therapy. Innovative interventions may be on the horizon in treatments that help to resolve or modulate common pathways of ARDS, such as inflammation (eg, granulocyte-colony stimulating factor) or epithelial repair (eg, keratinocyte growth factor).

Objectives Clinical applications of inhaled nitric oxide (NO) therapy resulted in the development of delivery systems and monitoring devices applicable to routine clinical care. This article presents the various components necessary for an adequate clinical use of inhaled NO, and discusses the NO gas mixture cylinders, inhaled NO delivery techniques and specifications, monitoring devices, and ending with an exhaustive description of the scavengers of nitrogen oxides (NOx). Data sources Computerized search (CURRENT CONTENTS, MEDLINE) of published original research and review articles (approximately 200), conference abstracts and compendiums up to May 1997 (approximately 50), personal files, and contact with expert informants. Study selection Technical, experimental, and clinical reports were selected from the recent English, French, German, and Spanish literature, if pertinent to the administration or monitoring of inhaled NO. Data extraction The authors extracted all applicable data. Data synthesis The production of NO gas mixture cylinders must be certified with respect to gas purity, stability, and concentration (limits between 100 and 1000 ppm), guaranteed calibration, and specific color. An ideal inhaled NO delivery device requires a synchronized delivery, a minimal production of nitrogen dioxide (NO2), and should be simple to use (verification, calibration, convenient flushing, cylinder change possible while in use and a simple alarm setting) with full information (high and low alarms and available precision monitoring of NO, NO2, and O2). Emergency and transport systems must be readily available. The choice of the monitoring device (chemiluminescence or electrochemistry) should be made based on the knowledge of their strength and weakness for a particular clinical application. Finally, scavengers of NOx should be used with caution until specific filters are proven safe and effective. Conclusions The great expectancies generated by inhaled NO action have led researchers to design personal inhaled NO delivery systems, but only with mitigated results. At present, medical companies are finding a financial interest in designing a delivery system which will suit the needs of clinicians and this, along with official governmental approval, will only then permit the use of inhaled NO safely and on a larger scale.

Nitric oxide (NO) is a powerful vasoactive agent that contributes to the regulation of blood pressure (BP). However, the role of NO in uremic patients and during the course of hemodialysis is still debated. Blood L-arginine concentrations and exhaled NO concentrations were measured in 22 healthy controls and in 22 hemodialysis patients before and after dialysis. On the basis of their BP response during hemodialysis, the patients were divided into three groups: 6 of the 22 patients presented with a decrease in BP during dialysis (group 1), eight presented with a stable BP (group 2), and eight with an increase in BP (group 3). The exhaled NO concentration was higher in dialysis patients than in healthy controls (22.7 +/- 2.6 ppb in dialysis patients v 16.7 +/- 0.9 ppb in controls, mean +/- SEM, P = 0.044). The predialysis and postdialysis exhaled NO concentrations were inversely correlated with the change in BP during hemodialysis (r = -0.47, P = 0.013). Patients with a decrease in BP (group 1) had the highest NO concentrations; patients with an increase in BP (group 3) had the lowest values; and patients with a stable BP during the course of dialysis (group 2) had intermediary values (trend test, P = 0.0291). In addition, both the exhaled NO concentration and the blood L-arginine concentration decreased during dialysis in all patients (P = 0.005 and P = 0.001, respectively). These results provide several novel insights into NO metabolism and BP regulation during hemodialysis: (1) maintenance hemodialysis is associated with a chronic increase in NO concentrations; (2) changes in BP during hemodialysis are inversely correlated with exhaled NO concentrations, higher NO levels being associated with a decrease in BP and lower NO levels with an increase in BP during dialysis; (3) blood L-arginine levels decrease during hemodialysis, and this reduction may in turn influence NO production.

Although the analogy of nitric oxide (NO) to Endothelium-derived Relaxing Factor remains controversial, medical use of exogenous NO gas by inhalation has grown exponentially. This review presents the mechanisms of action of inhaled NO in pulmonary hypertension, hypoxaemia, inflammation and oedema, as well as its therapeutic and diagnostic indications with emphasis on acute respiratory distress syndrome (ARDS) and toxicology.Two medical databases (Current Contents, Medline) were searched for citations containing the above-mentioned key words to December 1996. Moreover, many presentations in congresses such as 4th International Meeting of Biology of Nitric Oxide, 52nd and 53rd Annual Meeting of Canadian Anaesthetists' Society or 10th Annual Meeting of European Association of Cardiothoracic Anaesthesiologists were used.Inhaled NO is now recognized as an invaluable tool in neonatal and paediatric critical care, and for heart/lung surgery. Other clinical applications in adults, such as chronic obstructive pulmonary disease and ARDS, require a cautious approach. The inhaled NO therapy is fairly inexpensive, but it would seem that it is not indicated for everybody with regards to the paradigm of its efficiency and potential toxicity. The recent discovery of its anti-inflammatory and extrapulmonary effects open new horizons for future applications.Clinical use of inhaled NO was mostly reported in case series, properly designed clinical trials must now be performed to establish its real therapeutic role. These trials would permit adequate selection of the cardiopulmonary disorders, and subsequently the patients that would maximally benefit from inhaled NO therapy.

The volatile anaesthetics enflurane and isoflurane inhibit the endothelium dependent-relaxation in some in vitro preparations. To determine their site of action on the endothelium-derived relaxing factor/nitric oxide (EDRF/NO) pathway, experiments were conducted in a bioassay system.Continuously perfused cultured bovine aortic endothelial cells (BAEC) were the source of EDRF/NO while a phenylephrine-precontracted denuded rabbit aortic ring, directly superfused by the BAEC effluent served to detect EDRF/NO. The effect of basal and bradykinin (Bk)-stimulated EDRF/NO release on vascular tension was measured. The effect of 4% enflurane or 2% isoflurane on EDRF/NO-induced relaxation was determined.Enflurane added to the perfusate either upstream or downstream in relation to BAEC attenuated the relaxation induced by Bk at low concentrations. On the other hand, isoflurane, added either upstream or down-stream to BAEC, potentiated the relaxation induced by the basal release of EDRF but attenuated the relaxation induced by the Bk stimulated release of EDRF. Neither enflurane nor isoflurane attenuated the relaxation induced by sodium nitroprusside (SNP), an NO donor.Enflurane decreases the stability of EDRF/NO released after Bk stimulation while isoflurane can have opposite effects depending on whether the relaxation results from basal or Bk-stimulated release of endothelial derived relaxing factor(s). Isoflurane increases the stability or action of the basal relaxing factor, decreases the stability of the Bk-stimulated relaxing factor (which is probably NO).

Recent evidence suggests that newer vasoselective dihydropyridine calcium antagonists are not cardiodepressant and may be useful in the treatment of heart failure. No data are available on the efficacy of clentiazem, a vasoselective benzothiazepine-like calcium antagonist, in this pathological condition. Therefore, our objective was to assess coronary and cardiac sensitivity to clentiazem in an experimental model of chronic heart failure (cardiomyopathic hamster, UM-X7.1, >200 day old). Left ventricular developed pressure (LVP) and coronary flow changes were assessed in isolated, perfused failing hearts and in normal Syrian hamster hearts. Clentiazem dose-response curves for both coronary dilation and negative inotropic effects were determined under control conditions and in the presence of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (L-NAME, 30 μM), and the cyclooxygenase inhibitor, indomethacin (10 μM). Baseline hemodynamics indicate a significant reduction in both LVP and coronary perfusion in failing hearts. Cardiac sensitivity to the negative inotropic effects of clentiazem were similar in normal and failing hearts (IC50 = 677 nM and 734 nM, respectively). However, the clentiazem-induced increase in coronary flow was significantly attenuated in failing hearts (EC50 = 56 ± 9 nM vs. 15 ± 3 nM in normal hearts, p < 0.01). To better characterize the reduced coronary sensitivity to clentiazem in the presence of heart failure, the contributions of the NO synthase and the cyclooxygenase pathways were evaluated. Although coronary sensitivity to clentiazem was significantly reduced in the presence of L-NAME, this attenuation was of the same magnitude in normal and failing hearts, suggesting that coronary desensitization to clentiazem in failing hearts does not involve the NO synthase pathway. Experiments carried in the presence of indomethacin indicate that the reduced coronary sensitivity to clentiazem observed in failing hearts does not involve the cyclooxygenase pathway. In conclusion, reduced coronary sensitivity to the vasoselective calcium antagonist clentiazem was observed in the failing hamster heart, while no exacerbation of clentiazem's cardiodepressant actions was present. Although the mechanisms involved in the vascular desensitization to clentiazem are still unknown, our findings may provide an additional explanation for the variable efficacy of calcium antagonists in the treatment of heart failure.

Pulmonary hypertension is usually treated with intravenous (i.v.) vasodilators, but their use is limited by systemic effects. In the current study, we compared the effects of inhaled nitric oxide and intravenous nitroglycerine on pulmonary and systemic haemodynamic responses as well as on gas exchange measurements in anaesthetized pigs whose pulmonary pressure was increased by hypoxia (FiO2 = 15%). Both treatments reduced pulmonary pressure to the control level. Inhaled nitric oxide did not affect systemic arterial pressure but intravenous nitroglycerine decreased it from 126.2 to 108.8 mmHg (P = 0.04). Unlike intravenous nitroglycerine, inhaled nitric oxide increased arterial PaO2 from 5.3 to 5.9 kPa (P = 0.02). Both treatments diminished central venous pressure and left atrial pressure, suggesting a possible cardiac effect. Inhaled nitric oxide was shown to be a potent pulmonary vasodilator which attenuated pulmonary hypertension and improved arterial oxygenation without important direct effects on systemic pressure in porcine hypoxia-induced pulmonary hypertension.

We have studied the effect of combining inhaled nitric oxide (NO) with an i.v. vasodilator agent, nitroglycerin, or ciloprost, a prostacyclin analogue, during acute pulmonary hypertension in pigs, induced by continuous infusion of a thromboxane analogue (U46619), adjusted to maintain mean pulmonary artery pressure (MPAP) at 40 mm Hg. The effects of the different treatments on MPAP and pulmonary resistances were determined. In the first part of the study, we determined the dose-response to increased NO concentrations from 5 to 40 ppm. This showed a maximum pulmonary effect with NO 5 ppm, but with no systemic effects. The effect of NO 10 ppm was then compared with two i.v. drugs. Nitroglycerin was less effective than NO on pulmonary vessels but induced significant arterial hypotension. Pulmonary vasodilatation induced by ciloprost was greater than that by NO but with the same side effects as nitroglycerin on systemic variables. We also found that the combination of NO and nitroglycerin had the same pulmonary effects as NO 10 ppm but that adding ciloprost to NO decreased pulmonary pressures significantly more than either drug used alone. We conclude that inhaled NO may be usefully combined with i.v. ciloprost but not with i.v. nitroglycerin.

Background Volatile anesthetics, such as halothane and isoflurane, have been reported to affect the endothelium mediated relaxation of vascular smooth muscle cells. Because the activity of the constitutive nitric oxide synthase in endothelial cells depends on the availability of intracellular Ca2+, there is a definite possibility that the observed inhibitory effect of volatile anesthetics involves an action on the agonist-evoked internal Ca2+ mobilization and/or Ca2+ influx in these cells. Therefore, a study was undertaken to determine how halothane and isoflurane affect the Ca2+ signalling process in vascular endothelial cells. Methods The effect of halothane and isoflurane on the Ca2+ response to bradykinin of bovine aortic endothelial (BAE) cells was investigated using the fluorescent Ca2+ indicator fura-2. Halothane or isoflurane was applied either to resting cells or after bradykinin stimulation. The agonist-evoked Ca2+ influx in BAE cells was estimated by measuring either the rate of fura-2 quenching induced by Mn2+ or the increase in cytosolic Ca2+ concentration initiated after readmission of external Ca2+ after a brief exposure of the cells to a Ca(2+)-free external medium. The effects of halothane on cell potential and intracellular Ca2+ concentration were measured in cell-attached patch-clamp experiments in which a calcium-activated K+ channel and an inward rectifying Ca(2+)-independent K+ channel were used as probes to simultaneously monitor the intracellular Ca2+ concentration and the cell transmembrane potential. In addition, combined fura-2 and patch-clamp cell-attached recordings were carried out, to correlate the variations in internal Ca2+ caused by halothane and the activity of the Ca(2+)-dependent K+ channels, which are known in BAE cells to regulate intracellular potential. Finally, a direct action of halothane and isoflurane on the gating properties of the Ca(2+)-activated K+ channel present in these cells was investigated in patch-excised inside-out experiments. Results The results of the current study indicate that the initial Ca2+ increase in response to bradykinin stimulation is not affected by halothane, but that pulse applications of halothane (0.4-2 mM) or isoflurane (0.5-1 mM) reversibly reduce the sustained cytosolic Ca2+ increase initiated either by bradykinin or by the Ca2+ pump inhibitor thapsigargin. In addition, halothane appeared to dose-dependently inhibit the Ca2+ influx evoked by bradykinin, and to cause, concomitant to a decrease in cytosolic Ca2+ concentration, a depolarization of the cell potential. Halothane failed, however, to affect internal Ca2+ concentration in thapsigargin-treated endothelial cells, which were depolarized using a high K+ external solution. Finally, halothane and isoflurane decreased the open probability of the Ca(2+)-dependent K+ channel present in these cells. Conclusions These observations suggest that the effects of halothane and isoflurane on Ca2+ homeostasis in BAE cells reflect, for the most part, a reduction of the thapsigargin- or bradykinin-evoked Ca2+ influx, which would be consequent to a cellular depolarization caused by an inhibition of the Ca(2+)-dependent K+ channel activity initiated after cell stimulation.

Background/Aims: Although the cardiac output is increased in liver cirrhosis, some degree of cardiac failure could coexist as suggested by human investigations showing cardiac enlargement in cirrhosis and by animal studies describing a limited response to fluid loading in the cirrhotic rat. Endotoxemia induces similar hemodynamic changes during the septic shock. This septic cardiomyopathy has been attributed to an increased secretion of nitric oxide by the myocytes. In this study, we aimed to verify if cirrhotic cardiomyopathy was present in the rat with biliary cirrhosis, and if it could be related to abnormal nitric oxide secretion. Methods: We therefore compared the coronary pressure, the systolic ventricular pressure and the peak rate of rise of the left ventricular pressure obtained from isolated hearts perfused with a modified Langedorff apparatus in control rats and in cirrhotic rats obtained by bile duct ligation. The variations occurring after inhibition of nitric oxide synthesis by the addition of N g monomethyl-L-arginine (10 −6 M) to the perfusing Krebs-Ringer solution wee also studied in both groups. Results: We found that the coronary pressure and the contractility of the cirrhotic hearts decreased significantly when compared to the controls. Inhibition of the nitric oxide synthesis increased those values significantly when the hearts were obtained from cirrhotic animals. This was not observed in the control group. Conclusion: Our data suggest that the cardiac modifications induced by the cirrhosis in the studied parameters are related to nitric oxide.

The pathogenesis of the vasodilatation associated with liver cirrhosis is not fully understood, but it has recently been postulated that it may be related to an increase in nitric oxide production. The aim of this study was to compare the response of isolated aortic rings from normal and cirrhotic rats to two vasoconstrictors, phenylephrine and U46619, a thromboxane analogue. Biliary cirrhosis was induced by ligation of the common bile duct; a sham operation was performed in control animals. Five weeks later, the aorta was removed and dissected into rings for study in organ chambers. Concentration-response curves were obtained for the two vasoconstrictors from rings with intact endothelium and from rings denuded of endothelium. We found that the vasoconstriction produced by phenylephrine was decreased in cirrhotic vessels both with and without endothelium, but the response to U46619 was not modified by cirrhosis. Concentration-response curves for phenylephrine were also obtained from rings in which the synthesis of nitric oxide and prostaglandins was inhibited by N-G-monomethyl-L-arginine and indomethacin, respectively. Nitric oxide synthase inhibition restored normal contractility of the rings with and without endothelium. This beneficial effect was not observed when cyclo-oxygenase activity was blocked with indomethacin. This study suggests that cirrhotic vessels are hyporeactive to vasoconstrictors and that this effect is mediated through increased nitric oxide production. The improvement observed after inhibition of the nitric oxide pathway in denuded rings led us to suggest that cirrhosis also induces nitric oxide synthase in smooth muscle cells, as previously observed by others in septic animals.

While an increasing amount of evidence demonstrates the homeostatic functions of the cardiac oxytocin (OT) system, less is known about the role of this hormone in the injured heart. The current study examined the effect of OT infusion on cell apoptosis, expression of proliferating cell nuclear antigen (PCNA) and inflammation in the acute and subacute phases of myocardial infarction (MI). Prior MI male Sprague-Dawley rats were infused subcutaneously with OT 25 or 125 ng/(kg h) for 3 or 7 days. Saline-treated MI and sham-operated rats served as controls. Echocardiography and analysis of cardiac sections were used to disclose OT actions. Left ventricular fractional shortening, estimated to be 46.0 +/- 1.8% in sham controls, declined to 21.1 +/- 3.3% in vehicle-treated MI rats and was improved to 34.2 +/- 2.1 and to 30.9 +/- 2.5% after treatment with OT 25 and 125 ng/(kg h), respectively. OT infusion resulted in: (1) increase of cells expressing PCNA in the infarct zone, diminished cell apoptosis and fibrotic deposits in the remote myocardium; (2) suppression of inflammation by reduction of neutrophils, macrophages and T lymphocytes; (3) depression of the expression of proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 with promotion of transforming growth factor-beta. OT treatment reduced expression of atrial and brain natriuretic peptides in the infarcted ventricle, as well as the concentration of both peptides in the circulation. These results indicate that continuous OT delivery reduces inflammation and apoptosis in infarcted and remote myocardium, thus improving function in the injured heart.

This chapter describes current findings from the research into postoperative cognitive dysfunction (POCD) following cardiac and non-cardiac surgery in older adults. The evidence suggests that a significant proportion of patients show POCD in the early weeks following surgery and anesthesia. Specific domains of cognition are affected, especially memory. Much less evidence supports the presence of POCD several months or years after surgery, suggesting that POCD may be transient. However, several methodological issues make it difficult to compare findings across studies. Increasing age is among the most consistently reported patient-related risk factor. Other factors more directly related to the surgery and anesthesia are likely to contribute to the pathogenesis of POCD, including inflammatory processes triggered by the surgical procedure. Animal studies have provided valuable findings otherwise not possible in human studies; these include a correlation between the inflammatory response in the hippocampus and the development of POCD in rodents.

Experiments were designed to determine the effects of fentanyl on coronary vascular tone and energetic state of the heart. Both arterial and arteriolar responses were assessed; particular attention was directed to epicardial vessels. Four experimental methods and three animal species were used. Isolated canine coronary artery rings with and without endothelium were suspended in organ chambers, and changes in their tension were measured. Fentanyl (100 ng/ml) had no effect on resting tension of unstimulated rings on a contraction evoked by serotonin 10(-8) to 10(-4) M. In rings with endothelium, the opioid had a minimal depressant effect on the contractile response to phenylephrine. Tension of vessels precontracted with serotonin (3 x 10(-7) M), or phenylephrine (10(-5) M) was unchanged following fentanyl at 10, 30, 70, or 150 ng/ml. Computerized quantitative angiography was used in intact pigs anesthetized with ketamine to determine the effects of fentanyl on coronary artery diameters of vessels with or without endothelium. Intravenous fentanyl 50 and 250 micrograms/kg had no effect on vessel diameters. Isolated perfused rat hearts were used to assess fentanyl effects upon coronary flow and arteriolar tone and upon myocardial energy state. Coronary blood flow was not altered by fentanyl (100 ng/ml) and was unchanged following washout of the drug. The heart maintained a normal energy status prior to and following fentanyl treatment. These data demonstrate that, under the conditions tested, fentanyl is devoid of major effects on the coronary circulation and upon myocardial metabolism.

Postpump syndrome is associated with systemic inflammation. Matrix metalloproteinases (MMP)-2 and -9 contribute to proinflammatory and platelet-activator reactions. Nitric oxide (NO) is involved in the regulation of MMPs. The objectives of our study were to investigate the intensity of inflammation induced by 3 different surgical procedures, the effects of inflammation on the activity of MMPs, and the regulation of inflammation by inhaled NO (20 ppm). Inhaled NO was initiated immediately after tracheal intubation and maintained for the total duration of the experiments. Thirty pigs were equally randomized into 6 groups [sham; sham + NO; cardiopulmonary bypass; bypass + NO; bypass + lipopolysaccharide (1 microg/kg for 50 min); bypass + lipopolysaccharide + NO] and animals were subjected to anesthesia and mechanical ventilation up to 24 h. The levels of MMP-2 and MMP-9 in plasma and bronchoalveolar lavage were measured using zymography. Bypass resulted in a time-dependent rise in MMP activity, an effect potentiated by lipopolysaccharide. Inhaled NO attenuated the effects of bypass + lipopolysaccharide. These results confirm that MMP-2 and MMP-9 are associated with the inflammatory process causing the postpump syndrome. Preemptive and continuous administration of inhaled NO helps to prevent increased MMP-2 and MMP-9 activity.

Background Cardiopulmonary bypass (CPB), a procedure often used during cardiac surgery, is associated with an inflammatory process that leads to lung injury. We hypothesized that inhaled nitric oxide (INO), which has anti-inflammatory properties, possesses the ability to modulate lung cell apoptosis and prevent CPB-induced inflammation. Methods Twenty male pigs were randomly classified into four groups: sham, sham plus INO, CPB, and CPB plus INO. INO (20 ppm) was administered for 24 h after anesthesia. CPB was performed 90 min into INO treatment. BAL fluid and blood were collected at time 0 (before CPB), at 4 h after beginning CPB, and 24 h after beginning CPB (T 24 ). Results At T 24 , BAL interleukin (IL)-8 levels and neutrophil percentages were elevated significantly in the CPB group. At T 24 , INO reduced IL-8 concentrations and attenuated the increase of neutrophil percentage in the CPB-plus-INO group. Nitrite-plus-nitrate (NOx) concentrations were decreased significantly in groups without INO. Moreover, animals treated with INO showed higher rates of pulmonary apoptosis compared to their respective control groups except for the sham-plus-INO group, in which they were diminished. Conclusion These results demonstrate that NOx production is reduced after CPB, and that INO acts as an anti-inflammatory agent by decreasing neutrophil numbers and their major chemoattractant, IL-8. INO also increases cell apoptosis in the lungs during inflammatory conditions, which may explain, in part, how it resolves pulmonary inflammation.

Cardiopulmonary bypass (CPB) activates a systemic inflammatory response characterized clinically by alterations in cardiovascular and pulmonary function. The aim of this study was to measure the cardiopulmonary consequences in sham-operated pigs, and in animals subjected to CPB in the presence or absence of lipopolysaccharide (LPS). We also investigated, if the perioperative administration of inhaled NO exerts significant cardiopulmonary effects in an anaesthetized and mechanically ventilated pig model of extracorporeal circulation. Thirty pigs were randomized into six equal groups (sham; sham+INO; CPB; CPB+INO; CPB+LPS; CPB+LPS+INO) and subjected to anaesthesia with mechanical ventilation for up to 24h. We found that CPB+LPS group has the highest degree of lung injury. We also demonstrated that there was a significant difference on the cardiovascular parameters (heart rate, central venous pressure, stroke volume index, and mean systemic arterial blood pressure) between the CPB groups and the sham groups. The deteriorated lung mechanics was associated with a decrease in active subfraction of surfactant (LA) with time during the procedure (P=0.0003), on which inhaled NO had only an initial beneficial effect. In our model, inhaled NO had no long-term beneficial effect on lung mechanics and surfactant homeostasis despite improving lung haemodynamics, inflammation, and oxygenation. We conclude from this study that the use of pre-emptive and continuous inhaled NO therapy has protective and safe effects against lung ischemia/reperfusion associated with CPB.

Cardiopulmonary bypass (CPB) is associated with an inflammatory process that leads to lung injury. In this study, we hypothesized that inhaled nitric oxide (INO) possesses the ability to modulate CPB-induced inflammation. Fifteen male pigs were randomly divided into 3 groups: Sham, CPB+LPS (CPB and lipopolysaccharide), and CPB+LPS+INO. INO (20 parts per million) was administered for 24 h after anesthesia. CPB was performed for 90 min, and LPS was infused (1 µg/kg) after CPB. Bronchoalveolar lavage (BAL) fluid and blood were collected at T0(before CPB), at 4 h, and at 24 h. At 24 h, BAL interleukin-8 (IL-8) levels were not increased as expected in the CPB+LPS group compared with the Sham group, but they were reduced significantly in the CPB+LPS+INO group. Cell hypo reactivity observed in the groups receiving LPS also seemed to downregulate endothelial nitric oxide synthase NOS protein expression relative to the Sham group. Nitrite and nitrate (NOx) concentrations were decreased significantly in the groups without INO. Moreover, animals treated with INO showed higher rates of pulmonary apoptosis compared with their respective controls. These results demonstrate that NOx production is reduced after CPB and that INO acts on the inflammatory process by diminishing neutrophils and their major chemoattractant, IL-8. INO also increases cell apoptosis in the lungs under inflammatory conditions, which may explain, in part, how it resolves pulmonary inflammation.Key words: CPB, nitric oxide, apoptosis, LPS, IL-8.

Objective: Endothelial dysfunction of the pulmonary arterial tree occurring after cardiopulmonary bypass (CPB) contributes to pulmonary hypertension and respiratory failure in the postoperative period. The goal of the present study was to characterize the alterations of endothelial cell signal transduction pathways in pulmonary arteries following CPB, the effect of ventilation and nitric oxide (NO) inhalation on endothelium-dependent relaxations and the alterations in hemodynamics and oxygenation. Methods: Six groups of Landrace swine were compared: control, sham without CPB, CPB 150 min + no reperfusion, CPB 150 min + reperfusion 60 min, CPB 150 min + ventilation (tidal volume 12 ml/kg) + reperfusion 60 min, and CPB 150 min + NO inhalation (with ventilation, NO 40 ppm) + 60 min of reperfusion. No cross-clamping was applied, the heart was left beating, empty. Pulmonary artery reactivity was evaluated in organ chambers to assess the endothelium-dependent relaxations. Results: CPB alone did not alter endothelial function. CPB and pulmonary reperfusion induced a statistically significant decrease in endothelium-dependent relaxations to acetylcholine. Mechanical ventilation during CPB prevented the reduction of relaxations to acetylcholine. Ventilation and NO inhalation during CPB did not differ from ventilation alone in terms of endothelium-dependent relaxations. There were no differences between groups for relaxations to bradykinin. There was a significant increase in arterial oxygen tension in the ventilated group compared to the non-ventilated group. Conclusion: Pulmonary reperfusion after CPB causes a selective dysfunction of Gi-protein-mediated relaxations. Mechanical ventilation prevents the pulmonary endothelial dysfunction due to reperfusion after CPB. Ventilation also improves oxygenation after CPB. Mechanical ventilation could be used as a preventive approach for patients undergoing cardiac surgery with extracorporeal circulation.

Purpose: To review the pulmonary and systemic effects of endogenous nitric oxide and inhaled nitric oxide administered to patients. Source: A systematic search for experimental data, human case reports, and randomized clinical trials since 1980, the year of discovery of endothelium-derived relaxing factor. Principal findings: Nitric oxide has pulmonary and systemic effects. Inhaled nitric oxide not only causes selective pulmonary vasodilation but also results in pulmonary vasoconstriction of the vessels perfusing non-ventilated alveolae. The systemic effects of inhaled nitric oxide, which include modulation of the distribution of systemic blood flow, increase in renal output, interaction with coagulation, fibrinolysis and platelet functions, alteration of the inflammatory response, are described and the mechanisms of nitric oxide transport are explained. The possible toxicity of inhaled nitric oxide is also discussed. Conclusion: The multiple effects of inhaled nitric oxide support its role as a pulmonary and extra-pulmonary medication.

Background: Chronic inflammation integrally related to oxidative stress has been increasingly recognized as a contributing factor in various chronic diseases such as neurodegenerative diseases, pulmonary diseases, metabolic syndrome, and cardiovascular diseases as well as premature aging. Thus, inhibiting this vicious circle has the potential to delay, prevent progression, and treat those diseases. However, adverse effects of current anti-inflammatory drugs and the failure of exogenous antioxidant encourage scientists to develop new therapeutic alternatives. The nuclear factor E2-related factor 2 (Nrf2) is the transcription factor that is responsible for the expression of antioxidant response element (ARE)-regulated genes and have been described as having many therapeutic effects. In this review, we have discussed the role of oxidative stress in various chronic diseases. Furthermore, we have also explored various novel ways to activate Nrf2 either directly or indirectly, which may have therapeutic potential in attenuating oxidative stress, inflammation and mitochondrial dysfunction that contributes to chronic diseases.Keywords: Oxidative stress, Mitochondria, Inflammation, Nrf2, Nutrition, Chronic diseases

This study was designed to determine whether fetal arterial and venous PO2 could be increased by increasing maternal FIO2 in the period between hysterotomy and birth. Two groups of ten patients were studied. All were anaesthetised with the same technique except for the FIO2 after hysterotomy. One group inspired 50% oxygen and the second group inspired 100% oxygen. Although the maternal arterial PO2 was higher at birth in the 100% O2 group (177.4 +/- 42.3 mmHg vs 281.0 +/- 94.2 mmHg), there were no differences between the arterial umbilical cord PO2 (19.3 +/- 5.7 mmHg vs 18.5 +/- 7.3 mmHg) and the venous umbilical cord PO2 (31.1 +/- 7.6 mmHg vs 33.0 +/- 10.8 mmHg). Awareness was present in one patient in the 50% O2 group and in four patients in the 100% O2 group but this difference was not statistically significant. It is concluded that a higher inspired maternal oxygen concentration between hysterotomy and birth does not result in any increase in fetal PO2.

Background Previous works have suggested that the impairment of platelet aggregation by halothane was partly related to a stimulation of cyclic adenosine monophosphate (cAMP) production, to an inhibitory effect on Ca2+ signaling, or both. Intracellular Ca2+ measurements therefore were undertaken, first to determine the critical steps in the platelet CaZ+ signaling cascade most likely to be affected by halothane or by an increase in cAMP production, and second to establish if the effect of halothane involves aggregation-related biochemical pathways triggered by an increase in internal Ca2+. Methods Human washed platelets were treated with halothane or forskolin for 5 min before application of either platelet-activating factor, thrombin, U46619, or thapsigargin. The cytosolic Ca2+ concentration ([Ca2+]i) was measured with the fluorescent Ca2+ indicator fura-2. Nephelometric measurements were also performed to assay the aggregation process. Results Our results indicate that pretreating platelets with halothane leads to a partial impairment of the [Ca2+]i increase induced either by U46619, thrombin, or platelet-activating factor, but this had no significant effect on the [Ca2+]i response triggered by thapsigargin. In addition, our results show that halothane inhibits platelet aggregation triggered by U46619, but not by thapsigargin. Conversely, forskolin completely inhibited the [Ca2+]i response to U46619 and thapsigargin and prevented platelet aggregation induced by both agonists. Conclusions These results suggest that halothane and cAMP exert their effects on platelet aggregation and Ca2+ signaling through different mechanisms, and that halothane cannot impair platelet aggregation independently of phospholipase C stimulation.

Because controversies surround the increased negative inotropic effects of calcium antagonists in heart failure, other mechanisms may explain their lack of efficacy in this condition. We hypothesized that altered coronary sensitivity through endothelial dysfunctions may be involved. Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left ventricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyopathic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem concentration-response curves for both coronary dilation and its negative inotropic effects were charted under control conditions and in the presence of the specific nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Diltiazem concentration-response curves for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 microM, respectively). In contrast, the coronary dilator effects of diltiazem were impaired in failing hearts (EC50 for diltiazem-induced coronary dilation increased from 90 nM in normal hearts to 1.1 microM in failing hearts, p < 0.01). The involvement of endothelial dysfunctions in the observed coronary "desensitization" to diltiazem in heart failure was evaluated through the NO-synthase and cyclooxygenase pathways. Diltiazem concentration-response curves from failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart failure. These findings suggest that coronary "desensitization" to diltiazem occurs through parallel production and/or release of a vasoconstricting factor or factors originating from the cyclooxygenase pathway. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These findings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better understanding of factors modulating the effects of calcium antagonists in heart failure.

The purpose of this study was to verify whether, compared with the introduction of the NO-N2 mixture at the air inlet of the ventilator (classical method), a direct injection of NO-N2 into the inspiratory line of the ventilator circuit with a new injection device (new method), would reduce NO2 formation by reducing contact time between O2 and NO. The effect of two FIO2(0.21 and 0.90) and NO concentrations on NO2 production was determined. In the classical method, NO and O2 were mixed with an air/oxygen blender before the gas mixture entered the ventilator. In the new method, NO was injected directly into the respiratory line with the injection system. Nitric oxide and nitrogen dioxide gases were measured using a chemiluminescence analyzer. For a FI02 of 0.90 and 90 ppm of NO2, the amount of NO2 produced was decreased from 8.9 +/- 0.8 ppm (mean +/- SD) with the classical injection system to 4.4 +/- 0.2 ppm with the new injection system (P = 0.0039, Mann-Whitney test), and NO2 production was decreased from 4.5 +/-0.2 ppm to 2.1 +/- 0.4 ppm (P = 0.02) at 60 ppm of NO. However, at a FIO2, no difference was found in the amount of NO2 produced. We conclude that, compared with the classical method of NO administration, the new NO injection system reduces considerably the concentration of inhaled NO2 when a high FIO2 and a high concentration of NO are used.

Although hypothermia and cardioplegic cardiac arrest provide effective protection during cardiac surgery, ischemia of long duration, poor preoperative myocardial function, and ventricular hypertrophy may lead to heterogeneous delivery of cardioplegic solutions, incomplete protection, and impaired postischemic recovery. Calcium antagonists are potent cardioprotective agents, but their efficacy in the presence of cold cardioplegia is still controversial, especially in heart failure, since it is often believed that failing hearts are more sensitive to their negative inotropic and chronotropic actions. However, recent data have demonstrated that the benzothiazepine-like calcium antagonists diltiazem and clentiazem, in selected dose ranges, elicit significant cardioprotection independently of intrinsic cardiodepression, thus lending support to their use in cardioprotective maneuvers involving the failing heart. We therefore evaluated the cardioprotective interaction of diltiazem, clentiazem, and cold cardioplegia in both normal and failing ischemic hearts. Hearts were excised from 200- to 225-day-old cardiomyopathic hamsters (CMHs) of the UM-X7.1 line and age-matched normal healthy controls. Ex vivo perfusion was performed at a constant pressure (140 cmH2O; 1 cmH2O = 98.1 Pa) according to the method of Langendorff. Heart rate, left ventricular developed pressure (LVDP), and coronary flow were monitored throughout the study. Global ischemia was produced for 90 min by shutting down the perfusate flow, followed by reperfusion for 30 min. Normal and failing CMH hearts were either untreated (control) or perfused at the onset of global ischemia with one of the following combinations: cold cardioplegia alone (St. Thomas' Hospital cardioplegic solution, 4 °C, infused for 2 min), cold cardioplegia + 10 nM diltiazem, or cold cardioplegia + 10 nM clentiazem. The cardiac and coronary dilator properties of 10 nM diltiazem and 10 nM clentiazem alone were investigated in separate groups of isolated preparations. Failing CMH hearts had lower basal LVDP (42 ± 2 vs. 77 ± 2 mmHg (1 mmHg = 133.3 Pa) for normal hearts, p

Diltiazem is known to exert significant cardioprotection, but its efficacy under hypothermic conditions has not been documented. Because of its lipophilicity and its better tissue penetration, clentiazem, a chlorobenzothiazepine derivative of diltiazem, may offer cytoprotection additive to cold cardioplegia. We investigated the cardioprotective actions of clentiazem and diltiazem (10(-8) and 10(-6) M) when added to cold cardioplegia (myocardial temperature of 10 degrees-12 degrees C), in isolated rabbit heart subjected to 90-min global ischemia. Functional recovery was assessed by measuring left ventricular developed pressure (LVDP), coronary flow (CF) and heart rate (HR). To explore the potential beneficial mechanisms of these agents, we measured myocardial lipids and total calcium at the end of a 30-min period of reperfusion as well as their myocardial accumulation. Addition of 10(-8) M clentiazem to cold cardioplegia resulted in significant improvement in mechanical recovery (postischemic LVDP of 88.5 mm Hg with cardioplegia alone vs. 105.5 mm Hg with added clentiazem at 25 mm Hg diastolic pressure, DP). The additive cardioprotection afforded by clentiazem appeared to be concentration dependent since significant cardiodepression (postischemic LVDP of 79.8 mm Hg and 18% reduction in HR) was observed at a higher concentration (10(-6) M) and these effects were correlated with myocardial accumulation of the drug. The additive cardioprotective effect of clentiazem appeared to be structure related because diltiazem at both 10(-8) and 10(-6) M concentrations offered no benefits in addition to cold cardioplegia. These results indicate that the additive cardioprotection observed with 10(-8) M clentiazem could be related to its coronary vasodilator action since it reversed the cold cardioplegia-induced attenuation of hyperemic CF at reperfusion. Other factors must be involved, however, because addition of 10(-6) M diltiazem resulted in increased postischemic CF but without improving myocardial recovery. The functional protection offered by 10(-8) M clentiazem was associated with preservation of myocardial lipid components. Myocardial cholesterol content, which is essential for maintenance of membrane integrity, was preserved in that group, whereas a loss was observed in groups treated with cardioplegia alone and in the other treated groups. Total myocardial phospholipids were preserved in groups receiving 10(-8) M clentiazem plus cold cardioplegia or cold cardioplegia alone. A reduction in plasmalogen content, the predominant myocardial phospholipid species, and an increase in total myocardial calcium were noted only in ischemic hearts that received neither cardioplegia nor benzothiazepines, suggesting that cold cardioplegia is sufficient to prevent irreversible damage. Clentiazem affords cardioprotective benefits additive to cold cardioplegia.(ABSTRACT TRUNCATED AT 400 WORDS)

Background Halothane attenuates endothelium-dependent relaxation. To differentiate halothane's effect on endothelium-derived relaxing factor/nitric oxide (EDRF/NO) production from its effect on nitric oxide action on vascular smooth muscle, halothane's effect on endothelium-dependent relaxation was studied in a bioassay system. Methods Indomethacin-treated, bovine aortic endothelial cells (BAEC) grown on microcarrier beads, continuously perfused by oxygenated and carbonated (95% O2, 5% CO2) Krebs-Ringer solution served as nitric oxide donors while an isolated denuded rabbit aortic ring directly superfused by the effluent of the BAEC and precontracted with phenylephrine was used to detect EDRF/NO release. The effect of basal and bradykininstimulated EDRF release on the tension of the vascular ring was measured. In the bioassay, it was possible to treat either the vascular denuded ring alone or the vascular ring plus the BAEC with halothane by adding it to the perfusate either upstream or downstream from the BAEC. Halothane (final concentration 2.2%) was added to the perfusate at these two positions, and its effect on the relaxation induced by EDRF/NO was determined. In some experiments, the preparations were treated with hemoglobin or L-monomethyl-L-arginine to attenuate the relaxation induced by the EDRF/NO pathway. Finally, halothane's effect on vascular relaxation induced by an increasing concentration of sodium nitroprusside was measured. Halothane's concentration in the perfusate was determined by gas chromatography using electron capture for anesthetic measurement. Results EDRF/NO released by the BAEC was responsible for the relaxation of the vascular ring. Halothane added to the perfusate potentiated the tension induced by phenylephrine (7.1 ± 1.89%) and attenuated the relaxation induced by the release of EDRF/NO. This effect was reversible after discontinuation of halothane. Halothane's effect was present even when the anesthetic was added to the perfusate downstream to the perfusion of the endothelial cells. Halothane had no effect on the vascular relaxation induced by sodium nitroprusside. Conclusions The authors' data demonstrate that halothane does not interfere with endothelial cell release of EDRF/NO and its smooth muscle cell relaxation but seems to modify either EDRF/NO half-life or its activated redox form.

The purpose of this study was to test the hypothesis that isoproterenol could reverse bupivacaine toxicity. In eight isolated rabbit hearts an electrophysiologic evaluation was performed then repeated during infusion of bupivacaine (1 microgram/mL) alone and bupivacaine plus isoproterenol (1-2 micrograms/mL). Bupivacaine alone increased electrocardiographic intervals (P wave, QRS complex, PR, AV, and QTc interval) and refractory periods of the myocardium and atrioventricular junction as well as the Wenckebach cycle and pacing thresholds. The addition of isoproterenol corrected partially or completely all bupivacaine-induced abnormalities, and decreased sinus cycle length, suggesting a potential therapeutic value in the treatment of bupivacaine intoxication.

Nalbuphine hydrochloride, an agonist-antagonist opioid, is reported to reverse the respiratory depression of moderate doses of fentanyl (20 micrograms.kg-1) and still provide good analgesia. We report four patients having abdominal aortic aneurysm repair in which we attempted to reverse the respiratory depression of large doses of fentanyl (50-75 micrograms.kg-1) with nalbuphine (0.3 mg.kg-1, 0.1 mg.kg-1 or 0.05 mg.kg-1). Nalbuphine reversed respiratory depression in all four patients and the respiratory rate increased from 10 to 23 breaths per minute, end-tidal CO2 decreased from 7.0 +/- 0.3 per cent to 5.6 +/- 0.7 per cent, and peak inspiratory pressure after 0.1 seconds increased from 4 +/- 1.4 to 13 +/- 2.6 mmHg. However, hypertension, increased heart rate, and significant increase in analogue pain scores accompanied reversal of respiratory depression. Agitation, nausea, vomiting, and cardiac dysrhythmias also were observed frequently. We do not recommend the use of nalbuphine to facilitate early extubation of the trachea after large doses of fentanyl for abdominal aortic surgery.