Preoperative pregabalin does not reduce propofol ED(50): a randomized controlled trial.

BACKGROUND: In many studies, gabapentinoids, such as pregabalin, have been shown to reduce preoperative anxiety. This anxiolysis is often accompanied by sedation, one of the most frequent side effects of pregabalin. We hypothesized that pregabalin taken preoperatively could reduce propofol requirements for induction of general anesthesia. METHODS: A randomized double-blind placebo-controlled trial was conducted after approval by the local ethics committee. Fifty women aged 18-40 yr, American Anesthesiologists Society physical status I and II, and scheduled to undergo elective laparoscopic gynecologic procedures were enrolled after written consent. Treatment group patients were given pregabalin 150 mg po one hour before surgery while patients in the control group received a placebo. The primary outcome was the propofol dose required to achieve a targeted anesthetic depth in 50% of the population, i.e., effective dose (ED)50. The ED50 was estimated using Dixon's up-and-down methodology. The targeted anesthetic depth was defined based on predetermined entropy monitoring values (State Entropy [SE] < 50 and Response Entropy [RE]-SE < 10). As a secondary outcome, we tested if pregabalin reduced pre-induction anxiety levels which were measured on a 0-100 scale. RESULTS: The propofol ED50 was not statistically different between the pregabalin group (mean 1.33 mg·kg(-1); 95% confidence interval [CI] 1.23 to 1.43) vs the placebo group (mean 1.37 mg·kg(-1); 95% CI 1.28 to 1.46); P = 0.19. Also, pre-induction anxiety level was not different between groups (median 31; interquartile range [IQR] [10-52] vs median 42; IQR [4-71], respectively; P = 0.41). CONCLUSIONS: Preoperative pregabalin does not reduce propofol requirements in a population of healthy young women undergoing laparoscopic gynecologic procedures. This study failed to show a pre-induction anxiolytic effect of pregabalin in such a population. This trial was registered at www.clinicaltrials.gov (NCT01158859).

Mechanisms of active laryngeal closure during noninvasive intermittent positive pressure ventilation in nonsedated lambs.

The present study stems from our recent demonstration (Moreau-Bussiere F, Samson N, St-Hilaire M, Reix P, Lafond JR, Nsegbe E, Praud JP. J Appl Physiol 102: 2149-2157, 2007) that a progressive increase in nasal intermittent positive pressure ventilation (nIPPV) leads to active glottal closure in nonsedated, newborn lambs. The aim of the study was to determine whether the mechanisms involved in this glottal narrowing during nIPPV originate from upper airway receptors and/or from bronchopulmonary receptors. Two groups of newborn lambs were chronically instrumented for polysomnographic recording: the first group of five lambs underwent a two-step bilateral thoracic vagotomy using video-assisted thoracoscopic surgery (bilateral vagotomy group), while the second group, composed of six lambs, underwent chronic laryngotracheal separation (isolated upper airway group). A few days later, polysomnographic recordings were performed to assess glottal muscle electromyography during step increases in nIPPV (volume control mode). Results show that active glottal narrowing does not develop when nIPPV is applied on the upper airways only, and that this narrowing is prevented by bilateral vagotomy when nIPPV is applied on intact airways. In conclusion, active glottal narrowing in response to increasing nIPPV originates from bronchopulmonary receptors.

Origins of the inhibiting effects of nasal CPAP on nonnutritive swallowing in newborn lambs.

The present study investigated the mechanism by which continuous positive airway pressure (CPAP) suppresses nonnutritive swallowing (NNS) during quiet sleep (QS) in newborn lambs. Eighteen full-term lambs were chronically instrumented and evenly distributed into three separate groups to determine the extent to which modulation of NNS may be attributed to stimulation of upper airway and/or bronchopulmonary mechanoreceptors. Six lambs were tracheotomized, six other lambs underwent a two-step bilateral intrathoracic vagotomy, and the remaining six lambs underwent chronic laryngotracheal separation (isolated upper airway group). Forty-eight hours after surgery, each nonsedated lamb underwent polysomnographic recordings on three consecutive days. States of alertness, NNS and respiratory movements were recorded. Results demonstrate that a CPAP of 6 cmH(2)O inhibited NNS during QS while administered directly on the lower airways and that bivagotomy prevented this inhibition. However, application of CPAP on the upper airways only also inhibited NNS during QS. Finally, the application of a CPAP of 6 cmH(2)O had no systematic effect on NNS-breathing coordination (assessed by the respiratory phase preceding and following NNS). In conclusion, our results suggest that bronchopulmonary receptors are implicated in the inhibiting effects of nasal CPAP of 6 cmH(2)O on NNS in all our experimental conditions, whereas upper airway receptors are only implicated in certain conditions.

Influence of prematurity on postnatal maturation of heart rate and arterial pressure responses to hypoxia in lambs.

BACKGROUND: While hypoxic events with bradycardias are a frequent occurrence during the first weeks of life in preterm infants, the impact of preterm birth on maturation of the cardiovascular response to hypoxia in early postnatal life is unknown. OBJECTIVES: In the present study, we tested the hypothesis that preterm birth influences postnatal maturation of cardiovascular responses to hypoxia. METHODS: 6 preterm lambs (term 132 days, birth weight 2.9 kg) and 6 full-term lambs (term 147 days, birth weight 4.3 kg) were studied without sedation on days 3, 7, 14, 21 and 28 during acute, steady-state hypoxia (FIO(2) = 0.08, 15 min). RESULTS: Results show that full-term lambs increased their heart rate (HR) in response to hypoxia from the first day of life, with no postnatal maturation thereafter. In preterm lambs, HR did not change before day 14 and the full-term-like response was not acquired before 2 weeks after theoretical term. In both groups, mean arterial pressure tended to decrease below baseline, but the amplitude of variations remained of small magnitude. CONCLUSION: The present results bring unique evidence that preterm birth is associated with a blunted heart response to steady-state hypoxia during the first postnatal week and a delay in the maturation of HR response.

Laryngeal response to nasal ventilation in nonsedated newborn lambs.

Although endoscopic studies in adult humans have suggested that laryngeal closure can limit alveolar ventilation during nasal intermittent positive pressure ventilation (nIPPV), there are no available data regarding glottal muscle activity during nIPPV. In addition, laryngeal behavior during nIPPV has not been investigated in neonates. The aim of the present study was to assess laryngeal muscle response to nIPPV in nonsedated newborn lambs. Nine newborn lambs were instrumented for recording states of alertness, electrical activity [electromyograph (EMG)] of glottal constrictor (thyroarytenoid, TA) and dilator (cricothyroid, CT) muscles, EMG of the diaphragm (Dia), and mask and tracheal pressures. nIPPV in pressure support (PS) and volume control (VC) modes was delivered to the lambs via a nasal mask. Results show that increasing nIPPV during wakefulness and quiet sleep led to a progressive disappearance of Dia and CT EMG and to the appearance and subsequent increase in TA EMG during inspiration, together with an increase in trans-upper airway pressure (TUAP). On rare occasions, transmission of nIPPV through the glottis was prevented by complete, active glottal closure, a phenomenon more frequent during active sleep epochs, when irregular bursts of TA EMG were observed. In conclusion, results of the present study suggest that active glottal closure develops with nIPPV in nonsedated lambs, especially in the VC mode. Our observations further suggest that such closure can limit lung ventilation when raising nIPPV in neonates.

Cricothyroid muscle electrical activity during respiration and apneas in lambs.

Respiratory function of the cricothyroid muscle (CT) is virtually unknown in the neonatal period. This study was aimed at assessing CT electrical activity (EMG) during respiration and central apneas in non-sedated lambs. Seven full-term and four preterm lambs were instrumented for polysomnographic recording, including EMG of the diaphragm, thyroarytenoid (TA, a glottal constrictor), posterior cricoarytenoid (PCA, the primary glottal dilator) and CT. Phasic CT EMG was usually observed during inspiration and late expiration, whereas phasic TA EMG was observed during early expiration. While TA EMG virtually disappeared in REM sleep, both inspiratory and expiratory CT EMG increased. Overall, while CT EMG was not frequently observed during central apneas in either full-term (10% of apneas, but never simultaneously with TA EMG) or preterm lambs (30% of apneas), it was associated with decreased lung volume and subglottal pressure when present alone or with PCA EMG. Our results concur with the assumption that CT behaves as a laryngeal dilator in the neonatal period.

Postnatal maturation of laryngeal chemoreflexes in the preterm lamb.

Laryngeal chemoreflexes (LCR) are triggered by the contact of liquids with the laryngeal mucosa. In the mature organism, LCR trigger lower airway protective responses (coughing, effective swallowing, and arousal) to prevent aspiration. General belief holds that LCR are responsible for apnea and bradycardia in the newborn mammal, including humans. Our laboratory has recently shown that LCR in full-term lambs are consistently analogous to the mature LCR reported in adult mammals, without significant apneas and bradycardias (St-Hilaire M, Nsegbe E, Gagnon-Gervais K, Samson N, Moreau-Bussiere F, Fortier PH, and Praud J-P. J Appl Physiol 98: 2197-2203, 2005). The aim of the present study was to assess LCR in nonsedated, newborn preterm lambs born at 132 days of gestation (term = 147 days). The preterm lambs were instrumented for recording glottal adductor electromyogram, electroencephalogram, eye movements, heart rate, respiration, and oximetry. A chronic supraglottal catheter was used for injecting 0.5 ml of saline, distilled water, and HCl (pH 2) during quiet sleep, active sleep, and wakefulness on postnatal days 7 (D7) and 14 (D14). Laryngeal stimulation by water or HCl on D7 induced significant apneas, bradycardia, and desaturation, which, at times, appeared potentially life-threatening. No significant apneas, bradycardias, or desaturation were observed on D14. No consistent effects of sleep state could be shown in the present study. In conclusion, laryngeal stimulation by liquids triggers potentially dangerous LCR in preterm lambs on D7, but not on D14. It is proposed that maturation of the LCR between D7 and D14 is partly involved in the disappearance of apneas/bradycardias of prematurity with postnatal age.

Laryngeal function and nasal ventilatory support in the neonatal period.

Nasal application of positive airway pressure, either intermittently or continuously, is increasingly used in the neonatal period. An important difference however when using a nasal interface as opposed to an endotracheal tube for ventilatory support is the interposition of the larynx. Recent animal studies from our laboratory showed that nasal ventilatory support in the neonatal period can significantly impact laryngeal function. This includes active laryngeal closure against intermittent positive pressure ventilation, which can limit lung ventilation, and inhibition of non-nutritive swallowing, which may delay swallowing maturation. Those novel findings are highly relevant to neonatal respiratory care. Additional studies are underway to uncover both the mechanisms involved and consequences on lung ventilation and swallowing function.

Effect of nasal continuous or intermittent positive airway pressure on nonnutritive swallowing in the newborn lamb.

The present study was aimed at investigating the effects of nasal continuous positive airway pressure (nCPAP; 6 cmH2O) or intermittent positive pressure ventilation (nIPPV; 10/4 cmH2O) on nonnutritive swallowing (NNS) and on the coordination between NNS and phases of the respiratory cycle, while taking into account the potential effects of states of alertness. Twelve full-term lambs were chronically instrumented at 48 h after birth for polysomnographic recordings, including NNS, diaphragm electromyographic activity, respiratory movements, pulse oximetry, and states of alertness. Studies in control conditions, with nCPAP and nIPPV, were performed in random order in nonsedated lambs at 4, 5, and 6 days of life. Results demonstrate that nCPAP significantly decreased overall NNS frequency, more specifically isolated NNS during quiet sleep and bursts of NNS in active sleep. In comparison, the effects of nIPPV on NNS frequency were more variable, with an inhibition of NNS only in wakefulness and an increase in isolated NNS frequency in active sleep. In addition, neither nCPAP nor nIPPV disrupted the coordination between NNS and phases of the respiratory cycle. In conclusion, nCPAP inhibits NNS occurrence in newborn lambs. Clinical relevance of this novel finding is related to the importance of NNS for clearing the upper airways from secretions and gastric content frequently regurgitated in the neonatal period.

Monitoring pulse oximetry via radiotelemetry in freely-moving lambs.

This study was aimed at validating the use of a custom-made wireless pulse oximeter in freely moving lambs, using radiotelemetry transmission. First, measurements obtained simultaneously using the new, wireless oximeter and a standard commercially-available pulse oximeter (Nonin 8500) were compared in five lambs during 5min episodes of normoxia, hypoxia and hyperoxia. Correlation between the two oximeters for both SpO(2) and heart rate was very good, regardless of oxygenation conditions. Secondly, the capabilities of our device were assessed during more than 45h of polysomnographic recordings in seven lambs. According to the plethysmographic pulse waveform, reliable SpO(2) values were obtained in more than 85% of recording time. Multiple decreases in SpO(2) were readily observed after spontaneous apneas in preterm lambs. It is concluded that our wireless pulse oximeter performs as reliably as a standard pulse oximeter for monitoring SpO(2) variations in lambs, and offers new perspectives for researchers interested in continuous monitoring of oxygenation throughout sleep stages and wakefulness.

Laryngeal chemoreflexes induced by acid, water, and saline in nonsedated newborn lambs during quiet sleep.

Laryngeal chemoreflexes (LCR) are triggered by the contact of assorted liquids with the laryngeal mucosa. In the neonatal period, the immature LCR consist primarily of apnea and bradycardia, which at times can be life threatening. The aim of this study was to assess LCR induction in nonsedated, newborn full-term lambs by several acid solutions, compared with distilled water and saline. Twelve lambs were instrumented for recording of glottal adductor and diaphragm EMG, EEG, eye movements, heart rate, systemic arterial pressure, and respiratory movements. LCR were induced during quiet sleep by the injection (0.5 ml) of saline, distilled water or two acid solutions (HCl and citric acid, pH 2, diluted in either water or saline). A chronic supraglottal catheter was used to inject the solutions in a random order. Distilled water and acid solutions did not induce any significant decrease in heart rate or respiratory rate. However, significant lower airway protective responses (swallowing, cough, and arousal) were observed after distilled water and especially acid solution administration. In conclusion, LCR in full-term lambs, particularly with acid solutions, are merely characterized by lower airway protective responses resembling mature LCR reported in adult mammals.

Postnatal maturation of vagal respiratory reflexes in preterm and full-term lambs.

The postnatal development of ventilatory reflexes originating from bronchopulmonary receptors was assessed in preterm vs. full-term lambs. Ventilation and arterial pressure were repeatedly measured in 10 preterm (gestational age, 132 days) and 7 full-term lambs without sedation from day 1 to day 42. The Hering-Breuer inhibitory reflex (slowly adapting stretch receptors) was assessed by the increase in expiratory time during end-inspiratory occlusion. The pulmonary chemoreflex (C-fiber endings) was assessed by the initial apnea + bradycardia + systemic hypotension and the secondary tachypnea after capsaicin intravenous injection. Results show the following. 1) Premature birth did not modify the maturation of the Hering-Breuer reflex. 2) Whereas a classic pulmonary chemoreflex was observed in the very first hours of life in preterm lambs, the tachypneic component of this reflex was weaker than in full-term lambs on day 1. 3) Premature birth led to a reversed postnatal maturation of this tachypneic response (tendency to increase with postnatal age). Our findings suggest that premature birth in lambs modifies postnatal maturation of the pulmonary chemoreflex.

Active glottal closure during central apneas limits oxygen desaturation in premature lambs.

Our laboratory previously reported that active glottal closure was present in 90% of spontaneous central apneas in premature lambs while maintaining a high-apneic lung volume (Renolleau S, Letourneau P, Niyonsenga T, and Praud JP. Am J Respir Crit Care Med 159: 1396-1404, 1999.) The present study aimed at testing whether this mechanism limits postapnea oxygen desaturation. Four premature lambs were instrumented for recording states of alertness, thyroarytenoid muscle and diaphragm electromyographic (EMG) activity, nasal airflow, lung volume changes, and pulse oximetry. One thousand four hundred fifty-two spontaneous central apneas (isolated or during periodic breathing) were analyzed in nonsedated lambs. Apneas, with high lung volume maintained by active glottal closure, were compared with apneas, with a tracheostomy opened at apnea onset. Oxygen desaturation slopes were lower when high-apneic lung volume was actively maintained during both wakefulness and quiet sleep. Furthermore, oxygen desaturation slopes were lower after isolated apneas with continuous thyroarytenoid EMG during wakefulness, compared with apneas with noncontinuous thyroarytenoid EMG (= glottis opened shortly after apnea onset). These results highlight the importance of maintaining high-alveolar oxygen stores during central apneas by active glottal closure to limit desaturation in newborns.