Caffeine is a respiratory stimulant without effect on sleep in the short-term in late-preterm infants

Background Caffeine is widely used in preterm infants for apnea control. It has no effect on sleep in the only existing polysomnographic study including ten preterm infants Behavioral and polygraphic studies have conflicting results. Methods We studied 21 late-preterm infants at a median gestational age of 36 weeks. Polysomnography was performed twice, at baseline on day 1 and on the day after the onset of caffeine treatment (20 mg/kg loading and 5 mg/kg morning maintenance dose). Results Caffeine acted short term as a breathing stimulant with reduction of apneas, improved baseline SpO2 (p < 0.001), and decreased 95 percentile of end-tidal carbon dioxide level (p < 0.01). It also increased arousal frequency to SpO2 desaturations of more than 5% (p < 0.001). Caffeine did not affect sleep stage distribution, sleep efficiency, frequency of sleep stage transitions, appearance of REM periods, or the high number of spontaneous arousals. The median spontaneous arousal count was 18 per hour at baseline, and 16 per hour during caffeine treatment (p = 0.88). Conclusions In late-preterm infants, caffeine has a clear short-term respiratory stimulant effect, and it increases the arousal frequency to hypoxia. However, caffeine does not appear to act as a central nervous system stimulant, and it has no acute effect on sleep quality. Impact Effects of caffeine on sleep in preterm infants has previously been investigated with only one full polysomnographic study including ten preterm infants. The study showed no effect. The current study shows that caffeine acts short term as a respiratory stimulant and increases arousal frequency to hypoxia. Although a potent central nervous system (CNS) stimulant in adults, caffeine does not seem to have similar acute CNS effect in late-preterm infants. The onset of caffeine treatment has no short-term effect on sleep stage distribution, sleep efficiency, frequency of sleep stage transitions, appearance of REM periods, or the high number of spontaneous arousals.

The Effect of DREADD Activation of Leptin Receptor Positive Neurons in the Nucleus of the Solitary Tract on Sleep Disordered Breathing

Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway due to the loss of upper airway muscle tone during sleep. OSA is highly prevalent, especially in obesity. There is no pharmacotherapy for OSA. Previous studies have demonstrated the role of leptin, an adipose-tissue-produced hormone, as a potent respiratory stimulant. Leptin signaling via a long functional isoform of leptin receptor, LEPRb, in the nucleus of the solitary tract (NTS), has been implicated in control of breathing. We hypothesized that leptin acts on LEPRb positive neurons in the NTS to increase ventilation and maintain upper airway patency during sleep in obese mice. We expressed designer receptors exclusively activated by designer drugs (DREADD) selectively in the LEPRb positive neurons of the NTS of Leprb-Cre-GFP mice with diet-induced obesity (DIO) and examined the effect of DREADD ligand, J60, on tongue muscle activity and breathing during sleep. J60 was a potent activator of LEPRb positive NTS neurons, but did not stimulate breathing or upper airway muscles during NREM and REM sleep. We conclude that, in DIO mice, the stimulating effects of leptin on breathing during sleep are independent of LEPRb signaling in the NTS.

Almitrine: a possible therapeutic strategy for COVID-19?

Coronavirus disease 2019 (COVID‐19) remains with no specific treatment, despite the efforts of many scientists around the world. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) penetrates human host banknotes through interaction with angiotensin-converting enzyme 2 and transmembrane protease, serine 2 (TMPRSS2) receptors, located at respiratory tract (upper and lower) and the olfactory epithelium (pathway to the Central Nervous System). The virus causes COVID-19 and sometimes a Severe Acute Respiratory Syndrome (SARS). Several neurological manifestations can be associated with the infection. The SARS-COV-2 neurotropism for cardiorespiratory centers, causing autonomic damage, may contribute to respiratory failure. Almitrine is a respiratory stimulant drug, used in chronic hypoxemic diseases. Almitrine acts in peripheral chemoreceptors and could be a potential treatment for the optimization of chemoreceptors, improving the respiratory control affected by the SARS‐CoV‐2 in patients with COVID-19.

Is the “respiratory stimulant, Acetazolamide” add-on therapy suitable to relieve mild respiratory insufficiency in stable COVID-19 out/inpatients?

Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) and its related disease, COVID-19 is terribly spreading to 202 countries, areas or territories. Till March 29th, 2020 the values of confirmed cases and total deaths were more than 575,000 and ~ 26,500. Due to epithelial injury, as a critical event both in early stages of the disease and specifically in the development of acute respiratory distress syndrome (ARDS), patients encounter rapid vasoconstriction in the pulmonary circulation, followed by ventilation/perfusion mismatch. Acetazolamide-medaited carbonic anhydrase (CA) inhibition may attenuate the effects of hyperventilation-induced respiratory alkalosis. The evidences on chronic obstructive pulmonary disease (COPD) and acute mountain sickness (AMS) support our proposition that low doses of acetazolamide appear to stimulate ventilation in stable patients with COVID-19.

Doxapram alleviates low SpO2 induced by the combination of propofol and fentanyl during painless gastrointestinal endoscopy

Background Painless gastrointestinal endoscopy under intravenous propofol anesthesia is widely applied in the clinical scenario. Despite the good sedation and elimination of anxiety that propofol provides, low SpO2 may also result. Doxapram is a respiratory stimulant with a short half-life. The primary aim of this study was to investigate the effects of doxapram on alleviating low SpO2 induced by the combination of propofol and fentanyl during painless gastrointestinal endoscopy. Methods In this prospective study, patients scheduled for painless gastrointestinal endoscopy were randomly assigned to group D or S with 55 patients per group. Initially, both groups received a combination of propofol and fentanyl. Patients in group D received 50 mg doxapram after propofol injection, while patients in group S received an equal volume of saline. Vital signs of the patients, propofol dose, examination duration, and incidences of low SpO2 were recorded. Results There were no statistical differences in propofol consumption and examination duration between the two groups. Twenty-six patients in group S experienced low SpO2 versus 10 in group D (P = 0.001). Nineteen patients in group S underwent oxygenation with a face mask in contrast to 8 in group D (P = 0.015). Eighteen patients in group S were treated with jaw lifting compared to 5 in group D (P = 0.002). Four patients in group S underwent assisted respiration compared to 2 in group D (without statistical difference). The average oxygen saturation in group S was significantly lower than that in group D at 1, 2 and 3 min after propofol injection (P < 0.001, P = 0.001 and P = 0.020, respectively). There were no statistical differences in oxygen saturation at other time points. There were no statistical differences in MAP and HR (except for the time point of 1 min after the induction) between the two groups. Conclusions Low dose of doxapram can effectively alleviate low SpO2 in painless gastrointestinal endoscopy with intravenous propofol, without affecting propofol consumption, examination duration, MAP, or HR. Trail registration The study was approved by the Institutional Ethics Committee of Clinical and New Technology of Wuxi People’s Hospital on 20th July, 2018 (KYLLH2018029) and registered in the Chinese Clinical Trial Register on 16th August, 2018 (ChiCTR1800017832).

Doxapram stimulates respiratory activity through distinct activation of neurons in the nucleus hypoglossus and the pre-Bötzinger complex

Doxapram is a respiratory stimulant used for decades as a treatment option in apnea of prematurity refractory to methylxanthine treatment. Its mode of action, however, is still poorly understood. We investigated direct effects of doxapram on the pre-Bötzinger complex (PreBötC) and on a downstream motor output system, the hypoglossal nucleus (XII), in the transverse brainstem slice preparation. While doxapram has only a modest stimulatory effect on frequency of activity generated within the PreBötC, a much more robust increase in the amplitude of population activity in the subsequent motor output generated in the XII was observed. In whole cell patch-clamp recordings of PreBötC and XII neurons, we confirmed significantly increased firing of evoked action potentials in XII neurons in the presence of doxapram, while PreBötC neurons showed no significant alteration in firing properties. Interestingly, the amplitude of activity in the motor output was not increased in the presence of doxapram compared with control conditions during hypoxia. We conclude that part of the stimulatory effects of doxapram is caused by direct input on brainstem centers with differential effects on the rhythm generating kernel (PreBötC) and the downstream motor output (XII). NEW & NOTEWORTHY The clinically used respiratory stimulant doxapram has distinct effects on the rhythm generating kernel (pre-Bötzinger complex) and motor output centers (nucleus hypoglossus). These effects are obliterated during hypoxia and are mediated by distinct changes in the intrinsic properties of neurons of the nucleus hypoglossus and synaptic transmission received by pre-Bötzinger complex neurons.