Tropine exacerbates the ventilatory depressant actions of fentanyl in freely-moving rats.

Our lab is investigating the efficacy profiles of tropine analogs against opioid-induced respiratory depression. The companion manuscript reports that the cell-permeant tropeine, tropine ester (Ibutropin), produces a rapid and sustained reversal of the deleterious actions of fentanyl on breathing, alveolar-arterial (A-a) gradient (i.e., index of alveolar gas exchange), and arterial blood-gas (ABG) chemistry in freely-moving male Sprague Dawley rats, while not compromising fentanyl analgesia. We report here that in contrast to Ibutropin, the injection of the parent molecule, tropine (200 µmol/kg, IV), worsens the adverse actions of fentanyl (75 µg/kg, IV) on ventilatory parameters (e.g., frequency of breathing, tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives), A-a gradient, ABG chemistry (e.g., pH, pCO2, pO2, and sO2), and sedation (i.e., the righting reflex), while not affecting fentanyl antinociception (i.e., the tail-flick latency) in freely-moving male Sprague Dawley rats. These data suggest that tropine augments opioid receptor-induced signaling events that mediate the actions of fentanyl on breathing and alveolar gas exchange. The opposite effects of Ibutropin and tropine may result from the ability of Ibutropin to readily enter peripheral and central cells. Of direct relevance is that tropine, resulting from the hydrolysis of Ibutropin, would combat the Ibutropin-induced reversal of the adverse effects of fentanyl. Because numerous drug classes, such as cocaine, atropine, and neuromuscular blocking drugs contain a tropine moiety, it is possible that their hydrolysis to tropine has unexpected/unintended consequences. Indeed, others have found that tropine exerts the same behavioral profile as cocaine upon central administration. Together, these data add valuable information about the pharmacological properties of tropine.

L-cysteine ethylester reverses the adverse effects of morphine on breathing and arterial blood-gas chemistry while minimally affecting antinociception in unanesthetized rats.

L-cysteine ethylester (L-CYSee) is a membrane-permeable analogue of L-cysteine with a variety of pharmacological effects. The purpose of this study was to determine the effects of L-CYSee on morphine-induced changes in ventilation, arterial-blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient (i.e., a measure of the index of alveolar gas-exchange), antinociception and sedation in male Sprague Dawley rats. An injection of morphine (10 mg/kg, IV) produced adverse effects on breathing, including sustained decreases in minute ventilation. L-CYSee (500 µmol/kg, IV) given 15 min later immediately reversed the actions of morphine. Another injection of L-CYSee (500 µmol/kg, IV) after 15 min elicited more pronounced excitatory ventilatory responses. L-CYSee (250 or 500 µmol/kg, IV) elicited a rapid and prolonged reversal of the actions of morphine (10 mg/kg, IV) on ABG chemistry (pH, pCO2, pO2, sO2) and A-a gradient. L-serine ethylester (an oxygen atom replaces the sulfur; 500 µmol/kg, IV), was ineffective in all studies. L-CYSee (500 µmol/kg, IV) did not alter morphine (10 mg/kg, IV)-induced sedation, but slightly reduced the overall duration of morphine (5 or 10 mg/kg, IV)-induced analgesia. In summary, L-CYSee rapidly overcame the effects of morphine on breathing and alveolar gas-exchange, while not affecting morphine sedation or early-stage analgesia. The mechanisms by which L-CYSee modulates morphine depression of breathing are unknown, but appear to require thiol-dependent processes.

The ventilatory depressant actions but not the antinociceptive effects of morphine are blunted in rats receiving intravenous infusion of L-cysteine ethyl ester.

This study demonstrates that intravenous infusion of the cell-penetrant thiol ester, L-cysteine ethyl ester (L-CYSee), to adult male Sprague-Dawley rats elicited (a) minor alterations in frequency of breathing, expiratory time, tidal volume, minute ventilation, or expiratory drive but pronounced changes in inspiratory time, end-inspiratory and expiratory pauses, peak inspiratory and expiratory flows, EF50, relaxation time, apneic pause, inspiratory drive and non-eupneic breathing index, (b) minimal changes in arterial blood-gas (ABG) chemistry (pH, pCO2, pO2, SO2) and Alveolar-arterial (A-a) gradient (index of alveolar gas exchange), and (c) minimal changes in antinociception (tail-flick latency). Subsequent injection of morphine (10 mg/kg, IV) elicited markedly smaller effects on the above parameters, ABG chemistry, and A-a gradient in rats receiving L-CYSee, whereas morphine antinociception was not impaired. Infusions of L-cysteine or L-serine ethyl ester (oxygen rather than sulfur moiety), did not affect morphine actions on ABG chemistry or A-a gradient. L-CYSee (250 µmol/kg, IV) injection elicited dramatic changes in ventilatory parameters given 15 min after injection of morphine in rats receiving L-CYSee. Our findings suggest that (a) L-CYSee acts in neurons that drive ventilation, (b) L-CYSee reversal of the adverse actions of morphine on ventilation, ABG chemistry and A-a gradient may be via modulation of intracellular signaling pathways activated by morphine rather than by direct antagonism of opioid receptors since morphine antinociception was not diminished by L-CYSee, and (c) the thiol moiety of L-CYSee is vital to efficacy, (d) intracellular conversion of L-CYSee to an S-nitrosylated form may be part of its mechanism of action.

L-cysteine methyl ester overcomes the deleterious effects of morphine on ventilatory parameters and arterial blood-gas chemistry in unanesthetized rats.

We are developing a series of thiolesters that produce an immediate and sustained reversal of the deleterious effects of opioids, such as morphine and fentanyl, on ventilation without diminishing the antinociceptive effects of these opioids. We report here the effects of systemic injections of L-cysteine methyl ester (L-CYSme) on morphine-induced changes in ventilatory parameters, arterial-blood gas (ABG) chemistry (pH, pCO2, pO2, sO2), Alveolar-arterial (A-a) gradient (i.e., the index of alveolar gas-exchange within the lungs), and antinociception in unanesthetized Sprague Dawley rats. The administration of morphine (10 mg/kg, IV) produced a series of deleterious effects on ventilatory parameters, including sustained decreases in tidal volume, minute ventilation, inspiratory drive and peak inspiratory flow that were accompanied by a sustained increase in end inspiratory pause. A single injection of L-CYSme (500 µmol/kg, IV) produced a rapid and long-lasting reversal of the deleterious effects of morphine on ventilatory parameters, and a second injection of L-CYSme (500 µmol/kg, IV) elicited pronounced increases in ventilatory parameters, such as minute ventilation, to values well above pre-morphine levels. L-CYSme (250 or 500 µmol/kg, IV) also produced an immediate and sustained reversal of the deleterious effects of morphine (10 mg/kg, IV) on arterial blood pH, pCO2, pO2, sO2 and A-a gradient, whereas L-cysteine (500 µmol/kg, IV) itself was inactive. L-CYSme (500 µmol/kg, IV) did not appear to modulate the sedative effects of morphine as measured by righting reflex times, but did diminish the duration, however, not the magnitude of the antinociceptive actions of morphine (5 or 10 mg/kg, IV) as determined in tail-flick latency and hindpaw-withdrawal latency assays. These findings provide evidence that L-CYSme can powerfully overcome the deleterious effects of morphine on breathing and gas-exchange in Sprague Dawley rats while not affecting the sedative or early stage antinociceptive effects of the opioid. The mechanisms by which L-CYSme interferes with the OR-induced signaling pathways that mediate the deleterious effects of morphine on ventilatory performance, and by which L-CYSme diminishes the late stage antinociceptive action of morphine remain to be determined.

The effect of hyperoxia on ventilation during recovery from general anesthesia: A randomized pilot study for a parallel randomized controlled trial.

STUDY OBJECTIVE: While supplemental O2 inhalation corrects hypoxemia, its effect on post-anesthesia ventilation remains unknown. This pilot trial tested the hypothesis that hyperoxia increases the time spent with a transcutaneous PCO2 (TcPCO2) > 45 mmHg, compared with standard O2 supplementation. DESIGN: Single-blinded, parallel two-arm randomized pilot trial. SETTING: University hospital. PATIENTS: 20 patients undergoing robotic-assisted laparoscopic nephrectomy. MEASUREMENTS: After institutional approval and informed consent, patients were randomized to receive O2 titrated to arterial saturation (SpO2): 90-94% (Conservative O2, N =10), or to SpO2 > 96% (Liberal O2, N = 10) for up to 90 min after anesthesia. Continuous TcPCO2, respiratory inductance plethysmography (RIP), and SpO2, were recorded. We calculated the percentage of time at TcPCO2 > 45 mmHg for each patient and compared the two groups using analysis of covariance, adjusting for sex, age, and body mass index. We also estimated the sample size required to detect the between-group difference observed in this pilot trial. RIP signals were used to calculate apnea/hypopnea index (AHI), which was then compared between two groups. MAIN RESULTS: The mean percentage of time with a TcPCO2 > 45 mmHg was 80.6% for the Conservative O2 (N=9) and 61.2% for the Liberal O2 (N=10) group [between-group difference of 19.4% (95% CI: -18.7% to 57.6%), P = 0.140]. With an observed effect size of 0.73, we estimated that 30 participants per group are required, to demonstrate this difference with a power of 80% at a two-sided alpha of 5%. Means SpO2 were 94.5% and 99.9% for the Conservative O2 and the Liberal O2 groups, respectively. AHI was significantly higher in the Conservative O2, compared with the Liberal O2 group (median AHI: 16 vs. 3; P = 0.0014). CONCLUSIONS: Hyperoxia in the post-anesthesia period reduced the time spent at TcPCO2 > 45 mmHg and significantly decreased AHI, while mean SpO2 ranged inside the a priori defined limits. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04723433.

Evaluation of Monitored Anesthesia Care Involving Sedation and Axillary Nerve Block for Day-Case Hand Surgery.

BACKGROUND: Ultrasound-guided axillary brachial plexus block (ABPB) is a technique of choice for regional anesthesia during hand and forearm surgery. Intravenous sedation may facilitate this procedure, particularly for those suffering from anxiety; however, it can also be associated with respiratory, cardiovascular, and neurological side effects. The objective of this study was to evaluate the effect of intravenous sedation on perioperative respiratory depression for patients undergoing day-case hand surgery under ABPB. METHODS: A prospective, observational, single-center study was conducted between 1 May and 1 November 2016. RESULTS: A total of 2318 patients were included, with 501 patients in the group with IV sedation and 1817 in the group without. A multivariable propensity-score matched analysis showed that the variables associated with the number of desaturation were: (i) sedation (aRR 1.534 [95% CI: 1.283 to 1.836]), (ii) age and sex, (iii) type of surgery, and iv) Body Mass Index (BMI). CONCLUSIONS: Supplementing ABPB with IV sedation was associated with an increased rate of respiratory depression (episodes of desaturation) compared to fully awakened patients. The rate of oxygen administration was also higher in sedated patients even though they had fewer cases of chronic respiratory diseases and fewer were active smokers than non-sedated patients. Future research should consider precisely evaluating patient satisfaction, as well as the differences between sedation and drug-free approaches.

Blockade of astrocytic activation delays the occurrence of severe hypoxia-induced seizure and respiratory arrest in mice.

Seizures are induced when subjects are exposed to severe hypoxia. It is followed by ventilatory fall-off and eventual respiratory arrest, which may underlie the pathophysiology of death in patients with epilepsy and severe respiratory disorders. However, the mechanisms of hypoxia-induced seizures have not been fully understood. Because astrocytes are involved in various neurological disorders, we aimed to investigate whether astrocytes are operational in seizure generation and respiratory arrest in a severe hypoxic condition. We examined the effects of astrocytic activation blockade on responses of EEG and ventilation to severe hypoxia. Adult mice were divided into two groups; in one group (n = 24) only vehicle was injected, and in the other group (n = 24) arundic acid, an inhibitory modulator of astrocytic activation, was administered before initiation of recording. After recording EEG and ventilation by whole body plethysmography in room air, the gas in the recording chamber was switched to 5% oxygen (nitrogen balanced) until a seizure and ventilatory depression occurred, followed by prompt switch back to room air. Severe hypoxia initially increased ventilation, followed by a seizure and ventilatory suppression in all mice examined. Fourteen mice without arundic acid showed respiratory arrest during loading of hypoxia. However, 22 mice pretreated with arundic acid did not suffer from respiratory arrest. Time from the onset of hypoxia to the occurrence of seizures was significantly longer in the group with arundic acid than that in the group without arundic acid. We suggest that blockade of astrocytic activation delays the occurrence of seizures and prevents respiratory arrest.

Related factors for ProSeal™ laryngeal mask airway failure / Factores relacionados con insuficiencia de las vías respiratorias con el uso de ProSeal™ laryngeal mask

Abstract Introduction: The laryngeal mask airway (LMA) is a device for airway management that is easy to insert, safe, and efficient. However, there are associated complications that can lead to important patient morbidity and mortality, as ventilator failure, can occur with reported incidence between 0.2% and 4.7%. Male gender, advanced age, obesity, short thyromental distance, and poor dentition are known related factors to LMA failure. Objective: Determine the incidence of ProSeal™ LMA ventilatory failure and identify clinical related conditions. Materials and methods: Observational analytic study a group of adult patients with ProSealTM laryngeal mask for airway management. Statistical analysis was performed using STATA 12.1 software. Bivariate analysis was done using Fisher's exact test or Chi2 as it corresponded with statistical significance defined as P value <0.05. Skewed logistic regression for multivariate analysis was performed for estimating adjusted odd ratios (ORs). Results: Incidence of ProSealTM LMA ventilatory failure was 5.2%. In the group of patients that presented failure, 69 were older than 75 years (OR=1.06, 95% confidence interval [CI] 1.03-1.09, P < 0.001), 6 (23.1%) thyromental distance less than 6 x0200A;cm (OR = 2.48, 95% CI 0.93-6.62, P = 0.069), 5 (19.2%), inadequate anesthetic depth and/or laryngospasm (OR=5.78, 95% CI 2.23-14.96, P< 0.001) and 9 (34.6%) vintraoperative use of neuromuscular blockers (NMB) (OR=2.35, 95% CI 1.06-5.21, P=0.035). Conclusion: In patients with LMA management, the age, intraoperative use of NMB and inadequate anesthetic depth and/ or laryngospasm are clinical related conditions for ProSealTMLMA ventilatory failure.

Resumen Introducción: La mascarilla laríngea de vía aérea (LMA) es un dispositivo para el manejo de la vía aérea fácil de insertar, seguro y eficiente. Sin embargo, hay complicaciones asociadas que pueden llevar a morbilidad y mortalidad del paciente, como la falla del respirador, con una incidencia reportada de entre el 0.2% y el 4.7%. El sexo masculino, la edad avanzada, la obesidad, la corta distancia tiromentoniana y la mala dentición son factores conocidos relacionados con el fracaso de la LMA. Objetivo: Determinar la incidencia de la insuficiencia respiratoria con ProSeal™ LMA e identificar las condiciones clínicas relacionadas. Materiales y métodos: Estudio analítico observacional de un grupo de pacientes adultos con uso de ProSeal™ Laryngeal Mask para el manejo de las vías respiratorias. El análisis estadístico se realizó utilizando el software STATA 12.1©. El análisis bivariado se realizó utilizando la prueba exacta de Fisher o Chi2, ya que correspondía a la significación estadística definida como valor de p < 0.05. Se realizó una regresión logística sesgada para el análisis multivariado, con el fin de estimar las proporciones impares ajustadas (OR). Resultados: La incidencia de fallo ventilatorio de ProSeal™ LMA fue del 5.2%. En el grupo de pacientes que presentaron fracaso, 69 eran mayores de 75 años (OR = 1.06; IC del 95%: 1.03 a 1.09; p < 0.001), 6 pacientes (23.1%) tenían distancia tiromentoniana inferior a 6 cm (OR = 2.48; IC del 95%: 0.93 a 6.62, p = 0.069), 5 (19.2%) presentaron profundidad inadecuada del anestésico y/o laringoespasmo (OR = 5.78; IC del 95%: 2.23 a 14.96; p < 0.001) y en 9 (34.6%) hubo uso intraoperatorio de NMB (OR = 2.35; IC del 95%: 1.06 a 5.21; p = 0.035). Conclusión: En pacientes con manejo de la LMA, la edad, el uso intraoperatorio de la NMB y la profundidad anestésica inadecuada y/o laringoespasmo son condiciones clínicas relacionadas con la insuficiencia respiratoria de la LMA ProSeal™.

Rubral modulation of breathing.

NEW FINDINGS: What is the topic of this review? Rubral modulation of pontomedullary respiratory rhythm and pattern generating circuitry powerfully contributes to regulation of breathing. What advances does it highlight? Studies have demonstrated extensive rubromedullary and rubrospinal projections to zones generating and organizing the respiratory rhythm and pattern. Rubral modulation of respiratory output effects inspiratory expiratory phase transitions with stimulation generating inhibitory or excitatory responses of medullary inspiratory and expiratory units. The red nucleus mediates hypoxic ventilatory depression, integrates respiratory output with oromotor and locomotor activity, and modulates respiratory output during noxious stimulation. ABSTRACT: Although normal triphasic eupnoea can be produced by the pontomedullary respiratory network after pontomesencephalic transection, the midbrain provides important modulation of respiration. Specifically, stimulation of the red nucleus elicits inspiratory inhibition, as manifest in the phrenic neurogram, in addition to excitation and inhibition of individual medullary respiratory-related units, with the majority of premotor units that receive rubral modulation being inhibited. Stimulation of the red nucleus also induces respiratory phase transitions, which appear to be pontine independent. These effects might be mediated by rubrobulbar and/or rubrospinal tracts. Although lesioning of the red nucleus does not alter respiration in normoxic conditions, it eliminates hypoxic ventilatory depression, which is the second phase of the biphasic ventilatory response to low oxygen tension. The finding that the red nucleus also plays a role in anti-nociception suggests that it might coordinate respiratory responses during noxious stimulation and, given that the red nucleus regulates upper limb flexors, it might represent one region in a distributed bulbar network contributing to respiratory-locomotor integration. Modulation of jaw opening by the red nucleus would support a model whereby it coordinates oromotor activity with breathing. Thus, the multiplicity of roles played by the red nucleus aptly position it to coordinate respiration in a variety of behavioural states. In this review, we seek to highlight the different features and regional specializations of the rubral contribution to respiratory control and underscore its vital importance to breathing in the freely behaving mammal.

Do we feel pain during anesthesia? A critical review on surgery-evoked circulatory changes and pain perception.

The difficulty of defining the three so-called components of « an-esthesia ¼ is emphasized: hypnosis, absence of movement, and adequacy of anti-nociception (intraoperative « analgesia ¼). Data obtained from anesthetized animals or humans delineate the activation of cardiac and vasomotor sympathetic reflex (somato-sympathetic reflex) and the cardiac parasympathetic deactivation observed following somatic stimuli. Sympathetic activation and parasympathetic deactivation are used as monitors to address the adequacy of intraoperative anti-nociception. Finally, intraoperative nociception through the administration of nonopioid analgesics vs. opioid analgesics is considered to achieve minimal postoperative side effects.

Key Brainstem Structures Activated during Hypoxic Exposure in One-day-old Mice Highlight Characteristics for Modeling Breathing Network in Premature Infants.

We mapped and characterized changes in the activity of brainstem cell groups under hypoxia in one-day-old newborn mice, an animal model in which the central nervous system at birth is particularly immature. The classical biphasic respiratory response characterized by transient hyperventilation, followed by severe ventilation decline, was associated with increased c-FOS immunoreactivity in brainstem cell groups: the nucleus of the solitary tract, ventral reticular nucleus of the medulla, retrotrapezoid/parafacial region, parapyramidal group, raphe magnus nucleus, lateral, and medial parabrachial nucleus, and dorsal subcoeruleus nucleus. In contrast, the hypoglossal nucleus displayed decreased c-FOS immunoreactivity. There were fewer or no activated catecholaminergic cells activated in the medulla oblongata, whereas ~45% of the c-FOS-positive cells in the dorsal subcoeruleus were co-labeled. Approximately 30% of the c-FOS-positive cells in the parapyramidal group were serotoninergic, whereas only a small portion were labeled for serotonin in the raphe magnus nucleus. None of the c-FOS-positive cells in the retrotrapezoid/parafacial region were co-labeled for PHOX2B. Thus, the hypoxia-activated brainstem neuronal network of one-day-old mice is characterized by (i) the activation of catecholaminergic cells of the dorsal subcoeruleus nucleus, a structure implicated in the strong depressive pontine influence previously reported in the fetus but not in newborns, (ii) the weak activation of catecholaminergic cells of the ventral reticular nucleus of the medulla, an area involved in hypoxic hyperventilation, and (iii) the absence of PHOX2B-positive cells activated in the retrotrapezoid/parafacial region. Based on these results, one-day-old mice could highlight characteristics for modeling the breathing network of premature infants.

Reversal of morphine-induced respiratory depression by doxapram in anesthetized rats.

The present study was undertaken to investigate whether doxapram, a blocker of tandem pore K(+) (TASK-1/-3) channels, is a useful tool for recovery from morphine-induced ventilatory disturbances. Spontaneous ventilation and the hind leg withdrawal response against noxious thermal stimulation were recorded simultaneously in anesthetized rats. Morphine (1.0mg/kg, i.v.) decreased the minute volume resulting from depression of the ventilatory rate and tracheal airflow. Concomitantly, it prolonged the latency of withdrawal response against the thermal stimulation. Subsequent intravenous injection of doxapram recovered the morphine-induced ventilatory depression. This effect of doxapram declined rapidly after a single injection (1.0-3.0mg/kg, i.v.) but persisted with a continuous infusion (0.33mg/kg/min). Neither single injection nor continuous infusion of doxapram had any detectable effect on the analgesic potency of morphine. The central respiratory activity was recorded from the phrenic nerve in anesthetized, vagotomized, paralyzed and artificially ventilated rats. Morphine (3.0mg/kg, i.v.) induced respiratory depression, characterized by a prolonged plateau-like inspiratory discharge (apneustic discharge) in the phrenic nerve. Doxapram (10mg/kg, i.v.) restored the morphine-induced apneustic discharge to an augmenting inspiratory discharge. This study demonstrated that doxapram counteracted morphine-induced respiratory depression by stimulating the central respiratory network without compromising morphine antinociception. These results support the clinical use of doxapram for amelioration of ventilatory disturbances in patients treated with opioids.

Mechanisms of pentazocine-induced ventilatory depression and antinociception in anesthetized rats.

This study was performed to clarify mechanisms underlying pentazocine-induced ventilatory depression and antinociception. Spontaneous ventilation and hind leg withdrawal response against nociceptive thermal stimulation were simultaneously recorded in anesthetized rats. Pentazocine decreased minute volume resulting from depression of the ventilatory rate and tracheal airflow, and prolonged the latency of withdrawal response. Pre-treatment of ß-funaltorexamine, but not nor-binaltorphimine, significantly attenuated pentazocine-induced ventilatory depression, while either antagonist weakened its analgesic potency. Comparing with effects of fentanyl and U50488, the present results suggest that ventilatory depression induced by pentazocine is mediated by mainly µ receptors and analgesia by both µ and κ receptors.

Effects of arundic acid, an astrocytic modulator, on the cerebral and respiratory functions in severe hypoxia.

Mild hypoxia increases ventilation, but severe hypoxia depresses it. The mechanism of hypoxic ventilatory depression, in particular, the functional role of the cerebrum, is not fully understood. Recent progress in glial physiology has provided evidence that astrocytes play active roles in information processing in various brain functions. We investigated the hypothesis that astrocytic activation is necessary to maintain the cerebral function and ventilation in hypoxia, by examining the responses of EEG and ventilation to severe hypoxia before and after administration of a modulator of astrocytic function, arundic acid, in unanesthetized mice. Ventilatory parameters were measured by whole body plethysmography. When hypoxic ventilatory depression occurred, gamma frequency band of EEG was suppressed. Arundic acid further suppressed ventilation, and the EEG power was suppressed in a dose-dependent manner. Arundic acid also suppressed hypoxia-induced c-Fos expression in the hypothalamus. We conclude that severe hypoxia suppresses the cerebral function which could reduce the stimulus to the brainstem resulting in ventilatory depression. Astrocytic activation in hypoxia may counteract both cerebral and ventilatory suppression.

Hyperoxia-induced developmental plasticity of the hypoxic ventilatory response in neonatal rats: contributions of glutamate-dependent and PDGF-dependent mechanisms.

Rats reared in hyperoxia exhibit a sustained (vs. biphasic) hypoxic ventilatory response (HVR) at an earlier age than untreated, Control rats. Given the similarity between the sustained HVR obtained after chronic exposure to developmental hyperoxia and the mature HVR, it was hypothesized that hyperoxia-induced plasticity and normal maturation share common mechanisms such as enhanced glutamate and nitric oxide signaling and diminished platelet-derived growth factor (PDGF) signaling. Rats reared in 21% O2 (Control) or 60% O2 (Hyperoxia) from birth until 4-5 days of age were studied after intraperitoneal injection of drugs targeting these pathways. Hyperoxia rats receiving saline showed a sustained HVR to 12% O2, but blockade of NMDA glutamate receptors (MK-801) restored the biphasic HVR typical of newborn rats. Blockade of PDGF-ß receptors (imatinib) had no effect on the pattern of the HVR in Hyperoxia rats, although it attenuated ventilatory depression during the late phase of the HVR in Control rats. Neither nitric oxide synthase inhibitor used in this study (nNOS inhibitor I and l-NAME) altered the pattern of the HVR in Control or Hyperoxia rats. Drug-induced changes in the biphasic HVR were not correlated with changes in metabolic rate. Collectively, these results suggest that developmental hyperoxia hastens the transition from a biphasic to sustained HVR by upregulating glutamate-dependent mechanisms and downregulating PDGF-dependent mechanisms, similar to the changes underlying normal postnatal maturation of the biphasic HVR.

Developmental hyperoxia alters CNS mechanisms underlying hypoxic ventilatory depression in neonatal rats.

Newborn mammals exhibit a biphasic hypoxic ventilatory response (HVR), but the relative contributions of carotid body-initiated CNS mechanisms versus central hypoxia on ventilatory depression during the late phase of the HVR are not well understood. Neonatal rats (P4-5 or P13-15) were treated with a nonselective P2 purinergic receptor antagonist (pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, or PPADS; 125mgkg(-1), i.p.) to pharmacologically denervate the peripheral chemoreceptors. At P4-5, rats reared in normoxia showed a progressive decline in ventilation during a 10-min exposure to 12% O2 (21-28% decrease from baseline). No hypoxic ventilatory depression was observed in the older group of neonatal rats (i.e., P13-15), suggesting that the contribution of central hypoxia to hypoxic ventilatory depression diminishes with age. In contrast, rats reared in moderate hyperoxia (60% O2) from birth exhibited no hypoxic ventilatory depression at either age studied. Systemic PPADS had no effect on the ventilatory response to 7% CO2, suggesting that the drug did not cross the blood-brain barrier. These findings indicate that (1) CNS hypoxia depresses ventilation in young, neonatal rats independent of carotid body activation and (2) hyperoxia alters the development of CNS pathways that modulate the late phase of the hypoxic ventilatory response.

Animal and clinical trials on a prototype, pressure limited, time cycled Philippine ventilator (PhilVent)

OBJECTIVE:To test the efficacy and safety of PhilVent™, a pressure limited, time cycled, Philippine ventilator through animal and clinical studies. METHODS AND RESULTS: Animal study: Term, newborn piglets (N=8) were intubated and alternately cycled to the PhilVent™ or to a pressure limited, time cycled, commercial ventilator (Sechrist) at peak inspiratory pressures of 10, 13 and 15 cm H20 and rates of 15, 20, 25 breaths per min and constant FiO2 (0.40) and positive end expiratory pressure (+4). Blood gases and adverse events (pneumothorax, sudden deterioration, death) were monitored. Results show no significant difference in blood gases on either machine at the various ventilator settings. No adverse events occurred. Clinical study: Prospective, randomized, controlled trial of 90 preterm infants with respiratory distress, randomized either to PhilVent™ (N=45) or Sechrist (N=45). Ventilator settings were adjusted to achieve predetermined range of blood gases. Arterial blood gases and any adverse events e.g., pneumothorax, pulmonary hemorrhage were monitored. There were no clinically significant differences in the ventilator settings or blood gases of the infants on the PhilVent™ or Sechrist. No increase in adverse events were noted with the PhilVent™. CONCLUSION: In animal and clinical studies, the efficacy and safety of the PhilVent were comparable to the Sechrist. The PhilVent™ is an effective, alternative ventilator for the treatment of respiratory insufficiency in newborn infants.

Effects of four volatile anesthesics on postanesthetic ventilation: a comparison of halothane, enflurane, isoflurane, and sevoflurane.

To investigate the effects of four volatile anesthetics (halothane, enflurane, isoflurane, and sevoflurane) on postanesthetic ventilation and levels of consciousness, we enrolled 24 patients undergoing tympanoplasty in this study. Anesthesia was maintained with 67% nitrous oxide and one of four volatile anesthetics. We measured end-tidal carbon dioxide concentration (CETco2), minute volume ([Formula: see text]) and respiratory rate (RR), and determined the volatile anesthetic concentration in whole arterial blood (CBAnesth) and arterial carbon dioxide tension (Paco2) at 20 min and 2h after tracheal extubation. We also observed the level of consciousness (awake, drowsy, and asleep) before the measurement. Ventilatory variables were similar among the four groups at 20 min, although the ratio of volatile anesthetic concentration in the alveoli to the minimum alveolar concentration (MAC) (CAAnesth/MAC ratio) calculated from CBAnesth in the halothane group was twice those in the other groups. In the halothane group, Paco2 was significantly higher, and[Formula: see text] and RR were significantly lower compared with the isoflurane and sevoflurane groups at 2h. Halothane tended to prolong the recovery of levels of consciousness. We conclude that isoflurane and sevoflurane provide clinical advantages over halothane on postanesthetic ventilation and recovery of levels of consciousness.