Neuroinvasion of SARS-CoV-2 may play a role in the breakdown of the respiratory center of the brain.

The recent outbreak of the novel coronavirus, SARS-CoV-2, has emerged to be highly pathogenic in nature. Although lungs are considered as the primary infected organs by SARS-CoV-2, some of the other organs, including the brain, have also been found to be affected. Here, we have discussed how SARS-CoV-2 might infect the brain. The infection of the respiratory center in the brainstem could be hypothesized to be responsible for the respiratory failure in many COVID-19 patients. The virus might gain entry through the olfactory bulb and invade various parts of the brain, including the brainstem. Alternatively, the entry might also occur from peripheral circulation into the central nervous system by compromising the blood-brain barrier. Finally, yet another possible entry route could be its dispersal from the lungs into the vagus nerve via the pulmonary stretch receptors, eventually reaching the brainstem. Therefore, screening neurological symptoms in COVID-19 patients, especially toward the breakdown of the respiratory center in the brainstem, might help us better understand this disease.

Respiratory Drive in Critically Ill Patients. Pathophysiology and Clinical Implications.

Respiratory drive, the intensity of the respiratory center's output, determines the effort exerted in each breath. The increasing awareness of the adverse effects of both strong and weak respiratory efforts during mechanical ventilation on patient outcome brings attention to the respiratory drive of the critically ill patient. Critical illness can affect patients' respiratory drive through multiple pathways, mainly operating through three feedback systems: cortical, metabolic, and chemical. The chemical feedback system, defined as the response of the respiratory center's output to changes in arterial blood gases and pH, is one of the most important determinants of respiratory drive. The purpose of this state-of-the-art review is to describe the determinants of respiratory drive in critically ill patients, review the tools available to assess respiratory drive at the bedside, and discuss the implications of altered respiratory drive during mechanical ventilation. An analysis that relates arterial carbon dioxide levels with brain's response to this stimulus will be presented, contrasting the brain's responses to the patient's ability to generate effective alveolar ventilation, both during unassisted breathing and with different modes of ventilatory assist. This analysis may facilitate comprehension of the pathophysiology of respiratory drive in critically ill patients. As we aim to avoid both over- and under-assistance with mechanical ventilation, considering the patients' respiratory drive at the bedside may improve clinical assessment and management of the patient and the ventilator.

Obstructive sleep apnea and respiratory center regulation abnormality.

PURPOSE: Obstructive sleep apnea (OSA) is a complex disease in which phenotypic analysis and understanding pathological mechanisms facilitate personalized treatment and outcomes. However, the pathophysiology responsible for this robust observation is incompletely understood. The objective of the present work was to review how respiratory center regulation varies during sleep and wakeness in patients with OSA. DATA SOURCES: We searched for relevant articles up to December 31, 2019 in PubMed database. METHODS: This review examines the current literature on the characteristics of respiratory center regulation during wakefulness and sleep in OSA, detection method, and phenotypic treatment for respiratory center regulation. RESULTS: Mechanisms for ventilatory control system instability leading to OSA include different sleep stages in chemoresponsiveness to hypoxia and hypercapnia and different chemosensitivity at different time. One can potentially stabilize the breathing center in sleep-related breathing disorders by identifying one or more of these pathophysiological mechanisms. CONCLUSIONS: Advancing mechanism research in OSA will guide symptom research and provide alternate and novel opportunities for effective treatment for patients with OSA.

Evaluation of respiratory center function in congenital central hypoventilation syndrome by monitoring electrical activity of the diaphragm.

BACKGROUND: A definitive diagnosis of congenital central hypoventilation syndrome (CCHS) is made by genetic testing. However, there are only a few examinations that warrant genetic testing. Electrical activity of the diaphragm (Edi) reflects neural respiratory drive from respiratory center to diaphragm. We evaluated the function of the respiratory center in CCHS by Edi monitoring. METHODS: Monitoring of Edi was performed in six CCHS cases without mechanical ventilation. The monitoring time was 30 consecutive minutes from wakefulness to sleep. The TcPCO2 or EtCO2 and SpO2 were recorded simultaneously. RESULTS: The Edi peak during wakefulness was 14.0 (10.3-21.0) µV and the Edi peak during sleep was 6.7 (3.8-8.0) µV. The Edi peak during sleep was significantly lower than the Edi peak during wakefulness, and patients were in a state of hypoventilation. Although TcPCO2 or EtCO2 increased due to hypoventilation, an increase in the Edi peak that reflects central respiratory drive was not observed. ΔEdi/ΔCO2 was -0.06µV/mmHg. Maximum EtCO2 or TcPco2 was 51 mmHg, and the average SpO2 was 91.5% during monitoring. CONCLUSIONS: We confirmed that Edi monitoring could evaluate the function of the respiratory center and reproduce the hypoventilation of CCHS. The present study suggested that Edi monitoring is a useful examination in deciding whether to perform genetic testing or not and it may lead to an early diagnosis of CCHS.

[The pH-Sensitive Potassium Channel TASK-1 Is a Chemosensor for Central Respiratory Regulation in Rats].

TWIK-related acid-sensitive potassium channel-1 (TASK-1) is a "leak" potassium channel sensitive to extracellular protons. It contributes to setting the resting potential in mammalian neurons. TASK-1 channels are widely expressed in respiratory-related neurons in the central nervous system. Inhibition of TASK-1 by extracellular acidosis can depolarize and increase the excitability of these cells. Here we describe the distribution of TASK-1 in the rat brainstem and show that TASK-1 mRNAs are present in respiratory-related nuclei in the ventrolateral medulla, which have been proposed as neural substrates for central chemo-reception in rats. After inhalation of 8% CO2 for 30 and 60 min, TASK-1 mRNA levels in positive-expression neurons were remarkably upregulated. Injection of the TASK-1 blocker anandamide (AEA) into the rat lateral cerebral ventricle, showed a significant excitement of respiratory at 10 min posttreatment, with a marked decrease in inspiratory and expiratory durations and an increased frequency of respiration. We suggest that TASK-1 channel may serve as a chemosensor for in central respiration and may contribute to pH-sensitive respiratory effects. TASK-1 channel might be an attractive candidate for sensing H^(+)/CO2 in several respiratory-related nuclei in the brainstem. It is likely that TASK-1 participates in pH-sensitive chemical regulation in the respiratory center under physiological and pathological conditions.

Respiratory CO2 response depends on plasma bicarbonate concentration in mechanically ventilated patients.

OBJECTIVE: There is controversy about the effects of high plasma bicarbonate concentration ([HCO3(-)]) and the CO2 response test. We analyzed the relationship between [HCO3(-)] and the variation in hydrogen ion concentration (pH) for a given change in PaCO2, and its effects upon CO2 response. DESIGN: A retrospective study was carried out. SETTING: Two intensive care units. PATIENTS: Subjects with and without chronic obstructive pulmonary disease (COPD), at the beginning of weaning from mechanical ventilation. INTERVENTIONS: The CO2 response was evaluated by the re-inhalation of expired air method, measuring the hypercapnic ventilatory response (ΔVE/ΔPaCO2) and hypercapnic drive response (ΔP01/ΔPaCO2), where VE is minute volume and P0.1 is airway occlusion pressure 0.1s after the initiation of inspiration. MAIN OUTCOME MEASURES: [HCO3(-)] and CO2 response. RESULTS: A total of 120 patients in the non-COPD group and 48 in the COPD group were studied. COPD patients had higher mean [HCO3(-)] than non-COPD patients (33.2 ± 5.4 vs. 25.7 ± 3.7 mmol/l, p<0.001). In both non-COPD and COPD patients we observed a significant inverse linear relationship between [HCO3(-)] and pH change per mmHg of PaCO2 (p<0.001), ΔVE/ΔPaCO2 (p<0.001) and ΔP0.1/ΔPaCO2 (p<0.001). CONCLUSIONS: There is an inverse linear relationship between [HCO3(-)] and the variation of pH for a given change in PaCO2 and the CO2 response.

Respiratory Center Function and Its Impact in Obesity Hypoventilation Syndrome Treatment.

INTRODUCTION: Patients with obesity hypoventilation syndrome (OHS) need treatment with positive pressure either with continuous (CPAP) or double pressure (NIV). The apnea-hypopnea index (AHI) is considered a key data for making therapeutic decisions. We hypothesized that HR may be an useful tool to establish different phenotypes and individualize treatment in patients with OHS. Our objective was to analyze the role of the respiratory center response to hypercapnia (HR) in the adequacy of positive airway pressure therapy. METHOD: We included subjects with OHS treated with CPAP or NIV according to AHI and baseline pCO2. We analyzed therapeutic effectiveness and treatment changes prioritizing CPAP if AHI>30/h. Therapy was considered adequate if it was effective after two years. HR was measured with the p0.1/pEtCO2 ratio and its capability to select therapy was analyzed. The statistical study was performed by means comparison (Student's t) and multivariate analysis (logistic regression). RESULTS: 67 subjects were included of 68(11) years old, 37 (55%) males, initially 45 (67%) treated with NIV and 22 (33%) with CPAP, one case was excluded and in 25 (38%) the treatment was changed. Finally, CPAP was adequate for 29 subjects (44%) and NIV for 37 (56%). The CPAP group showed AHI 57/h (24) and p0.1/pEtCO2 0.37cmH2O/mmHg (0.23), NIV group AHI 43/h (35) and p0.1/pEtCO2 0.24 (0.15) with p=0.049 and 0.006. In multivariate analysis, p0.1/pEtCO2 (p=0.033) and AHI>30 (p=0.001) were predictors of adequate therapy. CONCLUSION: Measuring the RH of the respiratory center helps to select the most appropriate treatment for patients with OHS.

Effect of vocal respiratory training on respiratory function and respiratory neural plasticity in patients with cervical spinal cord injury: a randomized controlled trial.

In previous studies, researchers have used singing to treat respiratory function in patients with spinal cord injury. However, few studies have examined the way in which vocal training affects respiratory neural plasticity in patients with spinal cord injury. Vocal respiratory training (VRT) is a type of vocal muscle-related treatment that is often a component of music therapy (MT) and focuses on strengthening respiratory muscles and improving lung function. In this randomized controlled study, we analyzed the therapeutic effects of VRT on respiratory dysfunction at 3 months after cervical spinal cord injury. Of an initial group of 37 patients, 26 completed the music therapy intervention, which comprised five 30-minute sessions per week for 12 weeks. The intervention group (n = 13) received VRT training delivered by professional certified music therapists. The control group (n = 13) received respiratory physical therapy delivered by professional physical therapists. Compared with the control group, we observed a substantial increase in respiratory function in the intervention group after the 12-week intervention. Further, the nerve fiber bundles in the respiratory center in the medulla exhibited a trend towards increased diversification, with an increased number, path length, thickness, and density of nerve fiber bundles. These findings provide strong evidence for the effect of music therapeutic VRT on neural plasticity. This study was approved by the Ethics Committee of China Rehabilitation Research Center (approval No. 2020-013-1) on April 1, 2020, and was registered with the Chinese Clinical Trial Registry (registration No. ChiCTR2000037871) on September 2, 2020.

Obstructive sleep apnea -consideration of its pathogenesis.

The pathogenesis of obstructive sleep apnea (OSA) is characterized not only by obstruction of the pharynx, but also by repeated obstruction. OSA onset is thought to involve four phenotypic traits: pharyngeal muscle responsiveness, respiratory center instability (loop gain), arousal threshold, and anatomical factors. Patients with lower muscle responsiveness are likely to have OSA, whereas those with higher responsiveness are not. When the loop gain is relatively high, reaction and suppression of the respiratory drive are repeated, decreasing ventilation and pharyngeal muscle activity and leading to mixed or central apnea events. Patients with a low arousal threshold tend to have frequent respiratory events and less severe respiratory efforts, whereas those with a high arousal threshold tend to have fewer respiratory events and more severe respiratory efforts. Pharyngeal muscle activity, as well as respiratory drive, increases during apnea and decreases after its release. Patients with a low arousal threshold have lower muscle responsiveness and instability of the respiratory center control, whereas those with a high arousal threshold have higher muscle responsiveness and relatively stable respiratory control. The overshoot and undershoot responses of the chemical drive and pharyngeal muscle tone characterize the periodic repetition of obstructive events, which are enhanced by the arousal response. The presence of certain anatomical factors is prerequisite for the onset of OSA. Also, not only volume and flow, but also stiffness and elasticity may contribute to the pathogenesis of OSA. Mouth breathing also plays an important role in the mechanism of pharyngeal collapse. These four factors influence each other, with the first three-muscle responsiveness, loop gain, and arousal threshold-in particular in a trinity. The era is already close in which not only anatomical treatment, but also treatments for other traits can be selected and combined according to the individual pathophysiological condition of each patient with OSA.

A Shift in SARS-CoV-2 Omicron Variant's Entry Pathway Might Explain Different Clinical Outcomes.

Globally, SARS CoV-2 omicron variant has led to a notable increase of COVID-19 diagnoses, although with less severe clinical manifestations and decreased hospitalizations. The omicron wave swelled faster than previous waves, completely displacing the delta variant within weeks, and creating worldwide concern about final, successful pandemic control. Some authors contend that symptoms associated to omicron differ from 'traditional' symptoms and more closely resemble those of the common cold. One major COVID-19 symptom frequent with other variants-loss of taste and smell-is rarely present with omicron. This may be of interest, since it has also been suggested that direct SARS-CoV-2 invasion into the brainstem through the olfactory nerves by transsynaptic pathways could provide one explanation for the acute respiratory distress syndrome refractory to treatment. Brainstem infection by SARS-CoV-2 can severely damage the respiratory center, triggering functional deviations that affect involuntary respiration, leading to acute respiratory distress syndrome refractory to treatment, the main cause of death in COVID-19 patients. A shift in the omicron SARS-CoV-2 entry pathway from cell-surface fusion, triggered by TMPRSS2, to cathepsin-dependent fusion within the endosome, may affect transmission, cellular tropism and pathogenesis. Therefore, we can hypothesize that this entrance modification may impact transmission from the olfactory nerve to the brainstem through transsynaptic pathways. A decrement of the virus's direct invasion into the brainstem could diminish respiratory center dysfunction, reducing acute respiratory distress syndrome and the need for mechanical ventilation.

Respiratory disturbances and high risk of sudden death in the neonatal connexin-36 knockout mouse.

Neural circuits at the brainstem involved in the central generation of the motor patterns of respiration and cardiorespiratory chemoreflexes organize as cell assemblies connected by chemical and electrical synapses. However, the role played by the electrical connectivity mainly mediated by connexin36 (Cx36), which expression reaches peak value during the postnatal period, is still unknown. To address this issue, we analyzed here the respiratory phenotype of a mouse strain devoid constitutively of Cx36 at P14. Male Cx36-knockout mice at rest showed respiratory instability of variable degree, including a periodic Cheyne-Stokes breathing. Moreover, mice lacking Cx36 exhibited exacerbated chemoreflexes to normoxic and hypoxic hypercapnia characterized by a stronger inspiratory/expiratory coupling due to an increased sensitivity to CO2 . Deletion of Cx36 also impaired the generation of the recurrent episodes of transient bradycardia (ETBs) evoked during hypercapnic chemoreflexes; these EBTs constituted a powerful mechanism of cardiorespiratory coupling capable of improving alveolar gaseous exchange under hypoxic hypercapnia conditions. Approximately half of the homo- and heterozygous Cx36KO, but none WT, mice succumbed by respiratory arrest when submitted to hypoxia-hypercapnia, the principal exogenous stressor causing sudden infant death syndrome (SIDS). The early suppression of EBTs, which worsened arterial O2  saturation, and the generation of a paroxysmal generalized clonic-tonic activity, which provoked the transition from eupneic to gasping respiration, were the critical events causing sudden death in the Cx36KO mice. These results indicate that Cx36 expression plays a pivotal role in respiratory control, cardiorespiratory coordination, and protection against SIDS at the postnatal period.

Ablation of Zfhx4 results in early postnatal lethality by disrupting the respiratory center in mice.

Breathing is an integrated motor behavior that is driven and controlled by a network of brainstem neurons. Zfhx4 is a zinc finger transcription factor and our results showed that it was specifically expressed in several regions of the mouse brainstem. Mice lacking Zfhx4 died shortly after birth from an apparent inability to initiate respiration. We also found that the electrical rhythm of brainstem‒spinal cord preparations was significantly depressed in Zfhx4-null mice compared to wild-type mice. Immunofluorescence staining revealed that Zfhx4 was coexpressed with Phox2b and Math1 in the brainstem and that Zfhx4 ablation greatly decreased the expression of these proteins, especially in the retrotrapezoid nucleus. Combined ChIP‒seq and mRNA expression microarray analysis identified Phox2b as the direct downstream target gene of Zfhx4, and this finding was validated by ChIP‒qPCR. Previous studies have reported that both Phox2b and Math1 play key roles in the development of the respiratory center, and Phox2b and Math1 knockout mice are neonatal lethal due to severe central apnea. On top of this, our study revealed that Zfhx4 is a critical regulator of Phox2b expression and essential for perinatal breathing.

Ventilatory response to CO2 with Read's rebreathing method in normal infants.

BACKGROUND: Methods of evaluating the ventilatory response to CO2 (VRCO2 ) of the respiratory center include the steady-state and the rebreathing method. Although the rebreathing method can evaluate the ventilatory response continuously to gradually increasing CO2 , the rebreathing method has been rarely performed in infants. The aim of this study was to investigate whether we could perform the VRCO2 with the rebreathing method in normal infants. METHODS: The subjects were 80 normal infants. The gestational age was 39.9 (39.3-40.3) weeks, and the birth body weight was 3142 (2851-3451) grams. We performed the VRCO2 with Read's rebreathing method, measuring the increase in minute volume (MV) in response to the increase in EtCO2 by rebreathing a closed circuit. The value of VRCO2 was calculated as follow: VRCO2 (ml/min/mmHg/kg) = ΔMV/ΔEtCO2 /body weight. RESULTS: We performed the examination without adverse events. The age in days at examination was 3 (2-4), and the examination time was 150 ± 38 s. The maximum EtCO2 was 51.1 (50.5-51.9) mmHg. The value of VRCO2 was 34.6 (29.3-42.8). The intraclass correlation coefficient of the VRCO2 of cases with multiple measurements was 0.79. CONCLUSION: This study suggests that the rebreathing method can evaluate the ventilatory response to high blood CO2 in a short examination time. We conclude that the rebreathing method is useful even in infants. In the future, we plan to measure the VRCO2 of preterm infants, and evaluate the respiratory center of infants in more detail.

Is the Collapse of the Respiratory Center in the Brain Responsible for Respiratory Breakdown in COVID-19 Patients?

Following the identification of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, we are now again facing a global highly pathogenic novel coronavirus (SARS-CoV-2) epidemic. Although the lungs are one of the most critically affected organs, several other organs, including the brain may also get infected. Here, we have highlighted that SARS-CoV-2 might infect the central nervous system (CNS) through the olfactory bulb. From the olfactory bulb, SARS-CoV-2 may target the deeper parts of the brain including the thalamus and brainstem by trans-synaptic transfer described for many other viral diseases. Following this, the virus might infect the respiratory center of brain, which could be accountable for the respiratory breakdown of COVID-19 patients. Therefore, it is important to screen the COVID-19 patients for neurological symptoms as well as possibility of the collapse of the respiratory center in the brainstem should be investigated in depth.

Brainstem Dysfunction in SARS-COV-2 Infection can be a Potential Cause of Respiratory Distress.

BACKGROUND: A terrible pandemic, Covid-19, has captivated scientists to investigate if SARS-CoV-2 virus infects the central nervous system (CNS). A crucial question is if acute respiratory distress syndrome (ARDS), the main cause of death in this pandemic, and often refractory to treatments, can be explained by respiratory center dysfunction. OBJECTIVE: To discuss that ARDS can be caused by SARS-CoV-2 infection of the respiratory center in the brainstem. MATERIALS AND METHODS: I reviewed literature about SARS-CoV-2 mechanisms to infect the respiratory center in the brainstem. RESULTS AND CONCLUSIONS: An increasing amount of reports demonstrates that neurotropism is a common feature of coronavirus, which have been found in the brains of patients and experimental models, where the brainstem was severely infested. Recent studies have provided tremendous indication of the incidence of acute respiratory failure due to SARS-CoV-2 infection of the brainstem. SARS-CoV-2 might infect the CNS through the olfactory bulb, spreading from the olfactory nerves to the rhinencephalon, and finally reaching the brainstem. Hence, the virus infection causes respiratory center dysfunctions, leading to ARDS in COVID-19 patients. I conclude that acute ARDS in Covid-19 can be caused by SARS-CoV-2 invasion of brainstem respiratory center, suggesting the needs of more specific and aggressive treatments, with the direct participation of neurologists and neurointensivists.

Changes in the Morphology of Hypoglossal Motor Neurons in the Brainstem of Developing Rats.

The autonomic brainstem generates breathing rhythm by integrating inputs from chemosensors and mechanosensors in the viscera and coordinating descending outputs from higher structures in the central nervous system. Hypoglossal motoneurons (XII MNs) receive inputs from respiratory premotor neurons, important for maintaining airway patency. Previous studies in rodents report significant changes in breathing control during the first 3 weeks of life, with a sensitive period at 10 to 13 days postbirth (P10-P13) characterized by pronounced changes in neurotransmitters, excitation-inhibition balance, and breathing physiology. However, age-dependent morphological changes of XII MNs during the first 3 weeks postbirth and especially this sensitive period are under-studied. Here, we comprehensively characterize and quantify the early morphological changes in rat XII MNs. We hypothesized that morphological changes in XII MNs correspond to the functionally defined sensitive period observed at postnatal day 10-13 (P10-P13). To test this hypothesis, we used an innovative contemporary statistical approach to analyze Golgi-Cox stained XII MNs at nine postnatal ages between P1 and P21. Our findings reveal two subpopulations of XII MNs, which are dependent on age and morphological features. Soma size increased approximately 40% from P1 to P21, without changing shape. However, dendritic arborization increased in extent/distance and complexity. Dendritic branching of developing neurons significantly increased from P1 through P13, with the greatest increase at P10-P13 based on the Sholl method. Our detailed characterization of XII MN morphological development establishes a foundation for the study and elucidation of morphological changes caused by maternal and perinatal conditions. Anat Rec, 302:869-892, 2019. © 2018 Wiley Periodicals, Inc.

Structural and functional defects of the respiratory neural system in the medulla and spinal cord of Pax6 mutant rats.

Pax6 is an important transcription factor expressed in several discrete domains of the developing central nervous system. It has been reported that Pax6 is involved in the specification of subtypes of hindbrain motor neurons. Pax6 homozygous mutant (rSey2/rSey2) rats die soon after birth, probably due to impaired respiratory movement. To determine whether the respiratory center in the medulla functions normally, we analyzed the histological and neurophysiological properties of the medulla and spinal cord in fetal rats with this mutation. First, the medulla of rSey2/rSey2 at embryonic (E) 21.5-E22.5 tended to be smaller than those from heterozygous mutant (rSey2/+) and wild-type (+/+) littermates. Through immunohistochemical analysis, we confirmed normal distribution of Phox2b-expressing cells in the parafacial respiratory group (pFRG) of rSey2/rSey2 rats. Expression of neurokinin-1 receptor (NK-1R) was weak and dispersed in rSey2/rSey2 rats. In addition, rSey2/rSey2 rats have a defect of the hypoglossal nerve root. Electrophysiological analysis using brainstem-spinal cord preparations (E21.5-E22.5) revealed that rSey2/rSey2 rats showed larger fluctuation of the amplitude of inspiratory activity monitored from the fourth cervical root although there was no significant difference in the respiratory rate among rSey2/rSey2, rSey2/+, and +/+ littermates. The response of respiratory rhythm to high CO2 was similar among all genotypes. Optical recordings of neuronal activity revealed that the activity of the pFRG tended to be weaker and inspiratory activity appeared in more scattered areas in the caudal ventral medulla in the rSey2/rSey2 rats. These results suggest that the basal activity of the respiratory system was preserved with mild impairment of the inspiratory activity in the rSey2/rSey2 rats and that the Pax6 gene is involved in the functional development of the neuronal system producing effective inspiratory motor outputs for survival.

Effect of caffeine on superior mesenteric artery blood flow velocities in preterm neonates.

OBJECTIVE: To investigate the effect of caffeine infusion on superior mesenteric artery (SMA) blood flow velocities (BFV) in preterm infants. METHODS: Prospective observational study on 38 preterm neonates 28-33+6 weeks gestation, who developed apnea on their first day of life, and caffeine citrate infusion was initiated at a loading dose of 20 mg/kg, followed by a maintenance dose of 5-10 mg/kg/day. Duplex ultrasound measurements of SMA BFV were recorded: peak systolic velocity (PSV), end diastolic velocity (EDV) and resistive index (RI), at 15 min before, 1-, 2- and 6-h after caffeine loading dose, and 2 h after two maintenance doses. RESULTS: There was a significant reduction in PSV 1-h (p = .008), a significant decrease in EDV 1- and 2-h (p = .000 and p = .005, respectively) and a significant increase in RI 1- and 2-h (p = .003 and p = .005, respectively) following caffeine loading dose, as compared to values before caffeine infusion. No significant effect of caffeine maintenance doses on SMA BFV was observed (p > .05). CONCLUSION: Blood flow in SMA is significantly reduced after caffeine citrate infusion at a loading dose of 20 mg/kg. This effect continues for at least 2 h. Meanwhile, SMA BFV seems not affected by maintenance doses.

Dysregulation of Respiratory Center Drive (P0.1) and Muscle Strength in Patients With Early Stage Idiopathic Parkinson's Disease.

Objective: The goal of this study is to evaluate pulmonary function and respiratory center drive in patients with early-stage idiopathic Parkinson's disease (IPD) to facilitate early diagnosis of Parkinson's Disease (PD). Methods: 43 IPD patients (Hoehn and Yahr scale of 1) and 41 matched healthy individuals (e.g., age, sex, height, weight, BMI) were enrolled in this study. Motor status was evaluated using the Movement Disorders Society-Unified PD Rating Scale (MDS-UPDRS). Pulmonary function and respiratory center drive were measured using pulmonary function tests (PFT). All IPD patients were also subjected to a series of neuropsychological tests, including Non-Motor Symptoms Questionnaire (NMSQ), REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ), Beck Depression Inventory (BDI) and Mini Mental State Examination (MMSE). Results: IPD patients and healthy individuals have similar forced vital capacity (FVC), forced expiratory volume in 1s (FEV1), forced expiratory volume in 1s/forced vital capacity (FEV1/FVC), peak expiratory flow (PEF), and carbon monoxide diffusion capacity (DLCOcSB). Reduced respiratory muscle strength, maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) was seen in IPD patients (p = 0.000 and p = 0.002, respectively). Importantly, the airway occlusion pressure after 0.1 s (P0.1) and respiratory center output were notably higher in IPD patients (p = 0.000) with a remarkable separation of measured values compared to healthy controls. Conclusion: Our findings suggest that abnormal pulmonary function is present in early stage IPD patients as evidenced by significant changes in PImax, PEmax, and P0.1. Most importantly, P0.1 may have the potential to assist with the identification of IPD in the early stage.

Asociación entre impulso respiratorio y profundidad de sedación en sujetos bajo ventilación mecánica invasiva: estudio observacional / Association between respiratory drive and depth of sedation in subjects under invasive mechanical ventilation: an observational study

RESUMEN Objetivo: El objetivo de este estudio es determinar si existe asociación entre el impulso respiratorio, evaluado a través de la presión de oclusión (P0.1), y la profundidad de sedación, medida a través de la escala de agitación-sedación de Richmond (RASS, por sus siglas en inglés), en sujetos adultos sometidos a ventilación mecánica invasiva e internados en la unidad de cuidados intensivos del Hospital de Clínicas José de San Martín (HCJSM) en Buenos Aires. Como objetivo secundario, se planteó analizar el comportamiento de variables que pudieran tener impacto en el impulso respiratorio. Materiales y método: Se realizó un estudio observacional en un hospital universitario de la Ciudad Autónoma de Buenos Aires entre el 1 de abril de 2023 y el 28 de mayo de 2023. Las variables analizadas fueron P0.1, RASS, dolor, delirio, exposición a analgésicos y sedantes, estado ácido-base, presión arterial de oxígeno/fracción inspirada de oxígeno (PaO2/FiO2), evaluación de falla orgánica relacionada con la sepsis (SOFA, por sus siglas en inglés) e índice de masa corporal (IMC). Resultados: Se recolectaron 71 mediciones correspondientes a 33 sujetos. La mediana de P0.1 fue de 0,13 cmH20 (0-0,97). En el análisis univariado, se encontró una asociación inversamente proporcional entre la P0.1 y el puntaje RASS (β=-0,4068 y p=0,0435). Los resultados del análisis multivariado mostraron que ninguna de las variables contempladas se asoció con la P0.1 cuando fueron ajustadas entre sí. Conclusión: En este estudio, encontramos una asociación entre la P0.1 y el puntaje RASS, así como una asociación independiente entre la P0.1 y la exposición a la combinación de analgesia y sedación. Sin embargo, al ajustar estas variables en el análisis multivariado, no se encontró asociación.

ABSTRACT Objective: The objective of this study is to determine whether there is an association between respiratory drive, assessed through P0.1, and depth of sedation, measured through the Richmond agitation-sedation scale (RASS), in adult subjects undergoing invasive mechanical ventilation and admitted to the intensive care unit of Hospital de Clínicas José de San Martín (HCJSM) in Buenos Aires. As a secondary objective, we aim to analyze the behavior of variables that may have an impact on respiratory drive. Materials and method: An observational study was conducted at a university hospital in the Autonomous City of Buenos Aires between April 1, 2023, and May 28, 2023. The analyzed variables included P0.1, RASS, pain, delirium, exposure to analgesics and sedatives, acid-base status, pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2), sepsis-related organ failure assessment (SOFA), and body mass index (BMI). Results: A total of 71 measurements were collected from 33 subjects. The median P0.1 was 0.13 cmH20 (0-0.97). In the univariate analysis, an inversely proportional association was found between P0.1 and RASS score (β=-0.4068 and p=0.0435). The results of the multivariate analysis showed no association between P0.1 and any of the considered variables when adjusted for each other. Conclusion: In this study, we found an association between P0.1 and RASS score, along with an independent association between P0.1 and exposure to the combination of analgesia and sedation. However, when adjusting these variables in the multivariate analysis, no association was found.