piperidines and Hyperventilation

Several treatment strategies for augmenting outcomes with ECT (concurrent antidepressant treatment, frequency of ECT treatments, hyperventilation and use of remifentanil) are discussed in the context of a difficult clinical case, accompanied by a review of the relevant existing literature.. Literature on the above aspects of ECT technique was identified via a PubMed search and was critically reviewed.. There is preliminary evidence that concurrent administration of some antidepressant medications may be useful in the highly treatment resistant patient, though due attention should be given to potential risks in combining these with ECT; reduction of the treatment frequency to twice a week; hyperventilation prior to each treatment; and the use of remifentanil to minimise the dosage of induction anaesthetics with anticonvulsant properties, may be useful strategies to enhance seizure production in cases where a high or rapidly rising seizure threshold is a major impediment to ECT treatment.. It should be noted that empirical evidence for the effectiveness of each of the above strategies in producing better outcomes with ECT is not definitive, pointing to the need for further research in these areas.. The above strategies may be useful in clinical ECT practice, particularly in patients who are apparently treatment resistant, but the practitioner should be aware that the level of evidence underpinning these approaches is at present, preliminary.

Topics: Aged; Anesthesia, General; Anesthetics, Intravenous; Anticonvulsants; Antidepressive Agents; Contraindications; Depressive Disorder, Major; Dominance, Cerebral; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Electroconvulsive Therapy; Electroencephalography; Female; Frontal Lobe; Humans; Hyperventilation; Mental Status Schedule; Piperidines; Recurrence; Remifentanil; Retreatment; Suicide, Attempted; Temporal Lobe

Electroconvulsive therapy (ECT) is a highly effective treatment, but strategies to enhance therapeutic outcomes are occasionally needed. This review examines the evidence for approaches used for enhancing seizure production: hyperventilation, pretreatment with xanthines, and use of remifentanil or ketamine in ECT anesthesia. Hyperventilation may be a useful strategy to enhance seizure production, but its effects on ECT outcomes have not been systematically studied and require further research. Pretreatment with caffeine, theophylline or aminophylline (xanthines) prolongs the duration of ECT seizures but has not been clearly shown in controlled trials to increase efficacy. Caution is also warranted because their use may be associated with significant adverse effects. There are case reports of the usefulness of remifentanil in assisting seizure induction by reducing the dose of barbiturate anesthetic required, but there are no controlled data on whether it independently enhances efficacy outcomes. Preliminary evidence suggests that ketamine and ECT may have synergistic antidepressant effects, although this needs to be further examined in randomized controlled trials.

Topics: Caffeine; Central Nervous System Stimulants; Combined Modality Therapy; Electroconvulsive Therapy; Excitatory Amino Acid Antagonists; Humans; Hyperventilation; Hypnotics and Sedatives; Ketamine; Piperidines; Remifentanil; Treatment Outcome

Topics: Androstanes; Anesthesia; Atropine; Clinical Trials as Topic; Gallamine Triethiodide; Halothane; Humans; Hyperventilation; Injections, Intravenous; Neostigmine; Neuromuscular Nondepolarizing Agents; Nitrous Oxide; Oxygen; Piperidines; Thiopental

While the decrease in blood carbon dioxide (CO2 ) secondary to hyperventilation is generally accepted to play a major role in the decrease of cerebral tissue oxygen saturation (SctO2 ), it remains unclear if the associated systemic hemodynamic changes are also accountable.. Twenty-six patients (American Society of Anesthesiologists I-II) undergoing nonneurosurgical procedures were anesthetized with either propofol-remifentanil (n = 13) or sevoflurane (n = 13). During a stable intraoperative period, ventilation was adjusted stepwise from hypoventilation to hyperventilation to achieve a progressive change in end-tidal CO2 (ETCO2 ) from 55 to 25 mmHg. Minute ventilation, SctO2 , ETCO2 , mean arterial pressure (MAP), and cardiac output (CO) were recorded.. Hyperventilation led to a SctO2 decrease from 78 ± 4% to 69 ± 5% (Δ = -9 ± 4%, P < 0.001) in the propofol-remifentanil group and from 81 ± 5% to 71 ± 7% (Δ = -10 ± 3%, P < 0.001) in the sevoflurane group. The decreases in SctO2 were not statistically different between these two groups (P = 0.5). SctO2 correlated significantly with ETCO2 in both groups (P < 0.001). SctO2 also correlated significantly with MAP (P < 0.001) and CO (P < 0.001) during propofol-remifentanil, but not sevoflurane (P = 0.4 and 0.5), anesthesia.. The main mechanism responsible for the hyperventilation-induced decrease in SctO2 is hypocapnia during both propofol-remifentanil and sevoflurane anesthesia. Hyperventilation-associated increase in MAP and decrease in CO during propofol-remifentanil, but not sevoflurane, anesthesia may also contribute to the decrease in SctO2 but to a much smaller degree.

Topics: Adult; Anesthetics, Inhalation; Anesthetics, Intravenous; Blood Pressure; Carbon Dioxide; Cardiac Output; Cerebrovascular Circulation; Female; Humans; Hyperventilation; Male; Methyl Ethers; Oxygen; Piperidines; Propofol; Remifentanil; Sevoflurane

Traditionally, intraoperative intracranial electroen-cephalography-recordings are limited to the detection of the irritative zone defined by interictal spikes. However, seizure patterns revealing the seizure onset zone are thought to give better localizing information, but are impractical due to the waiting time for spontaneous seizures. Therefore, provocation by seizure precipitants may be used with the precaution that spontaneous and provoked seizures may not be identical.. We present evidence that hyperventilation induced and drug induced focal seizures may arise from different brain regions in the same patient.. Hyperventilation and ultra short acting opioid remifentanil were used separately as intraoperative precipitatants of seizure patterns, while recording from subdural and intraventricular electrodes in a patient with temporal lobe epilepsy. Two different ictal onset zones appeared in response to hyperventilation and remifentanil. Both zones were resected and the patient has remained essentially seizure free for 1 year. Furthermore, this is the first description of hyperventilation used as an intraoperative seizure precipitant in human focal epilepsy.

Topics: Anesthetics, Intravenous; Cerebral Cortex; Child; Electroencephalography; Epilepsy, Temporal Lobe; Female; Humans; Hyperventilation; Intraoperative Care; Piperidines; Remifentanil

A recent study by our laboratory has shown that an increase in intrathoracic temperature activates vagal pulmonary C-fibers. Because these afferents are known to elicit reflex bronchoconstriction upon stimulation, this study was carried out to investigate if an increase in airway temperature within the physiological range alters bronchomotor tone. Adult guinea pigs were anesthetized and mechanically ventilated via a tracheal tube. After the lung had been hyperventilated with humidified hot air (HHA) for 4 min, the tracheal temperature was elevated from 36.4 to 40.5 degrees C, which induced an immediate bronchoconstriction, increasing total pulmonary resistance (R(L)) to 177 +/- 10% and decreasing dynamic lung compliance to 81 +/- 6% of their respective baselines. The increase in R(L) returned spontaneously toward the baseline in <10 min and was reproducible in the same animals. There were no difference in the responses whether the humidity was generated from distilled water or isotonic saline. In contrast, hyperventilation with humidified air at room temperature did not cause any increase in R(L). The increase in R(L) caused by HHA was attenuated by 65.9% after a pretreatment with atropine alone and by 72.0% after a pretreatment with a combination of atropine and neurokinin receptor type 1 and 2 antagonists. In addition, capsazepine, a selective transient receptor potential vanilloid type 1 (TRPV1) antagonist, reduced the HHA-induced increase in R(L) by 64.1% but did not abolish it. However, pretreatment with formoterol, a beta(2)-agonist, completely prevented the HHA-induced bronchoconstriction. These results indicate that the increase in airway temperature induced transient airway constriction in guinea pigs. Approximately two-thirds of the increase in bronchomotor tone was mediated through the cholinergic reflex, which was probably elicited by the activation of TRPV1-expressing airway afferents. The remaining bronchoconstriction was caused by other, yet unidentified factors.

Topics: Airway Resistance; Animals; Atropine; Benzamides; Bronchoconstriction; Bronchodilator Agents; Capsaicin; Disease Models, Animal; Drug Combinations; Ethanolamines; Formoterol Fumarate; Guinea Pigs; Hot Temperature; Humidity; Hyperthermia, Induced; Hyperventilation; Male; Neurons, Afferent; Piperidines; Receptors, Tachykinin; Specific Pathogen-Free Organisms; TRPV Cation Channels; Tryptophan

Rats are most frequently used to fulfill ICH S7A requirements for respiratory safety pharmacology. We hypothesized that the models used to assess respiratory safety pharmacology present different ventilatory responses to bronchoconstriction, bronchodilation and respiratory depression. Respiratory monitoring was performed with head-out plethysmographs for rats, masks for dogs and bias airflow helmets for monkeys. Respiratory rate (RR), tidal volume (TV) and minute volume (MV) were recorded. Forty rats, 18 dogs and 8 monkeys were acclimated to the respiratory monitoring equipment. Animals received saline (IV), albuterol (inhalation), methacholine (IV) and remifentanil (IV). Albuterol increased TV in all species. Methacholine decreased TV and MV in monkeys. In dogs, methacholine increased TV, RR and MV. In rats, methacholine increased TV and decreased RR. Remifentanil induced central respiratory depression in all species with decreased MV, except in rats. Dogs presented a biphasic response to remifentanil with hypoventilation followed by delayed hyperventilation. The monkeys presented similar responses to humans which may be due to biologic similarities. Dogs and rats presented clinically significant ventilatory alterations following positive control drugs. Although, the response to bronchoconstriction in dogs and rats was different from humans, the two species presented ventilatory changes that highlight the potential adverse effect of test articles.

Topics: Albuterol; Animals; Bronchoconstrictor Agents; Bronchodilator Agents; Dogs; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hyperventilation; Hypoventilation; Macaca fascicularis; Male; Methacholine Chloride; Pharmaceutical Preparations; Piperidines; Rats; Remifentanil; Respiration; Respiratory Function Tests; Respiratory Insufficiency; Species Specificity

In vivo anesthetized guinea pigs were used to investigate the effect of tachykinin NK1- and NK2-receptor antagonists, as a single dose or in combination, against hyperventilation-induced bronchoconstriction (HIB). Guinea pigs were ventilated with a rodent ventilator and placed in a whole-body plethysmograph. Hyperventilation was induced by increasing the respiratory rate from 50 to 185 breaths/min for 10 min that produced a 177+/-45% increase in pulmonary resistance (RL) and a 68+/-7% decrease in lung compliance (CDyn). Intravenous (0.03-0.3mg/kg) and oral (0.3-10mg/kg) pretreatments with the tachykinin NK2-antagonist SR 48968 produced a dose-dependent inhibition of HIB whereas pretreatments with the tachykinin NK1-antagonist CP 99994 (1mg/kg intravenously and 30 mg/kg orally) had no effect on HIB. Intravenous and oral combinations of inactive and low doses of CP 99994 and SR 48968 produced a greater inhibition of HIB than SR 48968 alone. Also, the tachykinin NK3-antagonist SB 223412 (1-3mg/kg intravenously and 30 mg/kg orally) did not significantly reduce HIB although a trend was observed at the highest dose tested intravenously (3mg/kg). We conclude that HIB in the guinea pig is mostly mediated by the tachykinin NK2-receptors and to a lesser extent by the tachykinin NK1-receptors. Because the hyperventilation response in guinea pigs may be a surrogate for exercise-induced obstructive airway disease in human, these results suggest that combined use of dual tachykinin NK1- and NK2-receptor antagonists may provide greater benefit than treatment with single activity tachykinin NK-receptor antagonist.

Topics: Administration, Oral; Animals; Benzamides; Bronchoconstriction; Dose-Response Relationship, Drug; Drug Interactions; Guinea Pigs; Hyperventilation; Injections, Intravenous; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinolines; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Respiratory Function Tests

Topics: Aged; Apnea; Brain; Cisapride; Fatal Outcome; Humans; Hyperventilation; Male; Metoclopramide; Neuroleptic Malignant Syndrome; Piperidines

Multiple mediators are involved in the pathophysiology of allergic and inflammatory disorders. Drugs that affect the action of more than one mediator may, therefore, be particularly effective in these disorders. Two such mediators are platelet-activating factor (PAF) and histamine. From a structural series with documented antihistamine activity, Sch 37370 has been identified as a dual antagonist of PAF and histamine. In vitro, Sch 37370 selectively inhibits PAF-induced aggregation of human platelets (IC50 = 0.6 microM) and also competes with PAF binding to specific sites in membrane preparations from human lungs (IC50 = 1.2 microM). Sch 37370 also blocks the binding of [3H]pyrilamine to histamine H1 receptors in rat brain membranes. In guinea pigs, orally administered Sch 37370 is effective against bronchospasm to histamine (ED50 = 2.4 mg/kg), PAF (ED50 = 6.0 mg/kg) or serotonin (ED50 = 9.6 mg/kg). In contrast, it only weakly antagonizes methacholine-induced bronchospasm (ED50 = 51 mg/kg) and is totally inactive at 50 mg/kg against bronchospasm due to leukotriene C4 or substance P. Sch 37370 blocks hypotension in rats and a cutaneous reaction in monkeys induced by either PAF or histamine, as well as PAF-induced edema in the rat pleural cavity. In addition, Sch 37370 blocks bronchospasm induced by either antigen in sensitized guinea pigs or hyperventilation in nonsensitized guinea pigs. Sch 37370 also inhibits antigen-induced lung eosinophilia in sensitized guinea pigs and a reverse passive Arthus reaction in rats. Although Sch 37370 is not the most potent PAF antagonist or antihistamine, it is the first compound that combines these pharmacologically relevant activities and may offer important advantages over currently available antihistamine therapies.

Topics: Animals; Antigens; Bronchial Spasm; Guinea Pigs; Histamine Antagonists; Humans; Hyperventilation; Loratadine; Male; Piperidines; Platelet Activating Factor; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Lew