Respiratory Suppression Research Articles

On Arrival Blocks: Resuscitation of an Obese Patient Following Vehicular Accident in a Resource Poor Setting

Road traffic accidents has been reported to be on the increase, leaving patients with diverse orthopaedic injuries as well as traumatic brain injury. The accidents and emergencies unit continues to struggle during resuscitation and offer inadequate analgesia to these patients who also may be in shock or not fully resuscitated, owing to fear of worsening the haemodynamics, or the respiratory suppression from opioids, most trauma physicians refrain from using strong opioids. Intravenous access in the polytraumatized patients is usually challenging, even more so in obese patients, putting them to greater morbidity or mortality according to some published articles. This case report expresses the importance of prompt management, multi-disciplinary care of an obese polytraumatized patient, which led to shorter hospital stay and reduction in morbidity and mortality. A multi-disciplinary approach with quick involvement of the Anaesthetists made a big difference in establishing venous access promptly to commence resuscitation, preventing onset of morbidity such as acute kidney injury due to hypovolaemia. On arrival blocks, a technique developed by anesthesiologist Ravindra and plastic and hand surgeon Raja is a situation where the skilled Anaesthetist blocks different regions in order to offer patient excellent analgesia without compromising the haemodynamic or respiratory drive is important to note and emphasize.

Reconsidering the usefulness of long-term high-dose buprenorphine.

Buprenorphine has been successfully used for decades in the treatment of opioid use disorder, yet there are complexities to its use that warrant attention to maximize its utility. While the package insert of the combination product buprenorphine\naloxone continues to recommend a maximum dose of 16 mg daily for maintenance, the emergence of fentanyl and synthetic analogs in the current drug supply may be limiting the effectiveness of this standard dose. Many practitioners have embraced and appropriately implemented novel practices to mitigate the sequelae of our current crisis. It has become common clinical practice to stabilize patients with 24 - 32 mg of buprenorphine daily at treatment initiation. Many of these patients, however, are maintained on these high doses (>16 mg/d) indefinitely, even after prolonged stability. Although this may be a necessary strategy in the short term, there is little evidence to support its safety and efficacy, and these high doses may be exposing patients to more complications and side effects than standard doses. Commonly known side effects of buprenorphine that are likely dose-related include hyperhidrosis, sedation, decreased libido, constipation, and hypogonadism. There are also complications related to the active metabolite of buprenorphine (norbuprenorphine) which is a full agonist at the mu opioid receptor and does not have a ceiling on respiratory suppression. Such side effects can lead to medical morbidity as well as decreased medication adherence, and we, therefore, recommend that after a period of stabilization, practitioners consider a trial of decreasing the dose of buprenorphine toward standard dose recommendations. Some patients' path of recovery may never reach this stabilization phase (i.e., several months of adherence to medications, opioid abstinence, and other clinical indicators of stability). Side effects of buprenorphine may not have much salience when patients are struggling for survival and safety, but for those who are fortunate enough to advance in their recovery, the side effects become more problematic and can limit quality of life and adherence.

Management of post-extubation anxiety in the intensive care unit

Post-extubation anxiety causes significant distress in intensive care unit patients. This review provides treatment recommendations for managing anxiety during weaning and extubation from mechanical ventilation. Factors predisposing to anxiety include cerebral vascular disease, endocrine disorders, cardiopulmonary decompensation, disrupted sleep-wake cycles, and the stressful ICU environment. This review analyzed 21 articles sourced from Google Scholar and PubMed, focusing on case reports, case series, systematic reviews, and meta-analyses. These studies reported that dexmedetomidine effectively reduces extubation time and ICU length of stay through its anxiolytic properties. Antipsychotics, like quetiapine, showed potential in managing anxiety during ventilator weaning, but high-dose haloperidol posed risks. Benzodiazepines were linked to paradoxical agitation and respiratory suppression. Non-pharmacological treatments, such as aromatherapy, music therapy, and massage therapy, appeared to reduce anxiety and improve sleep quality. Caregiver approaches, including parental presence and psychological training, also reduced anxiety. In conclusion, non-pharmacological approaches should be prioritized, and pharmacological treatments considered when necessary. More research is essential to identify optimal treatments for post-extubation anxiety with minimal patient risk and effective symptom control. Keywords: Anxiety, ICU patients, critically ill patients, post-extubation

Effects of different doses of alfentanil combined with target-controlled infusion (TCI) of propofol for daytime hysteroscopy

BackgroundDaytime hysteroscopy requires anesthesia that offers rapid onset and clearance, with minimal respiratory and cardiovascular suppression. This study compared the effects of different doses of alfentanil combined with propofol target-controlled infusion (TCI) for such procedures. MethodsWe randomized 240 patients undergoing daytime hysteroscopy into three groups to receive alfentanil at doses of 5 μg/kg, 10 μg/kg, and 15 μg/kg, combined with propofol TCI. We meticulously recorded complications and perioperative vitals to evaluate the safety and efficacy of each dosage regimen. ResultsThe 10 μg/kg dose of alfentanil, used in conjunction with propofol, required lower propofol dosages and resulted in quicker recovery time and fewer intraoperative movements. However, higher doses of 15 μg/kg led to a significant increase in hypoxemia and instability in hemodynamics and oxygenation. ConclusionCombining alfentanil at 10 μg/kg with propofol TCI for daytime hysteroscopy results in high effectiveness. A lower incidence of complications, a reduced propofol requirement, and rapid emergence from sedation characterize this regimen.

Sodium Leak Channel in Glutamatergic Neurons of the Lateral Parabrachial Nucleus Helps to Maintain Respiratory Frequency Under Sevoflurane Anesthesia.

The lateral parabrachial nucleus (PBL) is implicated in the regulation of respiratory activity. Sodium leak channel (NALCN) mutations disrupt the respiratory rhythm and influence anesthetic sensitivity in both rodents and humans. Here, we investigated whether the NALCN in PBL glutamatergic neurons maintains respiratory function under general anesthesia. Our results showed that chemogenetic activation of PBL glutamatergic neurons increased the respiratory frequency (RF) in mice; whereas chemogenetic inhibition suppressed RF. NALCN knockdown in PBL glutamatergic neurons but not GABAergic neurons significantly reduced RF under physiological conditions and caused more respiratory suppression under sevoflurane anesthesia. NALCN knockdown in PBL glutamatergic neurons did not further exacerbate the respiratory suppression induced by propofol or morphine. Under sevoflurane anesthesia, painful stimuli rapidly increased the RF, which was not affected by NALCN knockdown in PBL glutamatergic neurons. This study suggested that the NALCN is a key ion channel in PBL glutamatergic neurons that maintains respiratory frequency under volatile anesthetic sevoflurane but not intravenous anesthetic propofol.

Characteristics of Cardiorespiratory Failure Preceding Seizure-Induced Mortality in SSKcnj16−/− Rats

Epilepsy is a common, chronic neurological condition characterized by repeated, uncontrolled seizures. These patients are at high risk for cardiorespiratory failure (CRF) and Sudden Unexpected Death in Epilepsy (SUDEP) — the mechanisms of which remain unknown. Most SUDEP events are unwitnessed at night suggesting a circadian influence on seizure-induced mortality. Here we studied cardiorespiratory (CR) function continuously (24/7) in a rat model of audiogenic seizures (SSKcnj16−/− rats) in which repeated seizures have been shown to cause progressive respiratory suppression and mortality. We hypothesized repeated seizures in SSKcnj16−/− rats also lead to 1) progressive dysfunction of post-ictal heart rate (HR) and blood pressure (BP) responses, and 2) cause death via cardiorespiratory failure most frequently when seizures occur after the onset of the inactive period (8am) or prior to the onset of the active phase (4pm). Age matched male and female SSKcnj16−/− rats were implanted with a carotid pressure telemeter and housed in a chronic monitoring plethysmograph with HD video to continuously measure breathing, BP, and HR. Audiogenic seizures (1/day (d) for up to 10d) were induced at a specific time of day and the physiologic data analyzed. Consistent with previous findings, repeated generalized tonic-clonic seizures (GTCSs) caused acute ictal/post-ictal apnea and transient respiratory rate suppression for ~5 minutes post-ictal which was exacerbated with additional seizures (n=6). In addition, GTCSs induced progressively greater transient post-ictal HR suppression and increased BP (n=3; p<0.05 on days 8-10 compared to days 1-3). When seizures occurred at either 8am or 4pm, female SSKcnj16−/− rats had a 10% survival probability (18/20 died) and males had a 40% survival probability (12/20 died). These data combined with previous studies in which seizures were induced throughout the light period showed a higher percentage of deaths at specific times of day: <10am (14%; n=81), 10am-2pm (3%; n=225), 2pm-7pm (8%; n=338). On average seizure-related mortality occurred 2-3 hours after seizures (20 of 30 events) and occurred throughout the 10-day protocol resulting from either moderate (score 2; 53%) or severe (score 3-4; 47%) seizures (Modified Racine Scale). Specific characteristics of death events (n=11-19) included transiently increased BP (+20mmHg) and tidal volume (+0.5 mL/100g; VT) but decreased HR (-50 beats/min), breathing frequency (-50 breaths/min; FB) and ventilation (-20 mL/min/100g; VE). These CR measures then returned to baseline until ~60 minutes post-seizure when there was a secondary decline in BP (-80 mmHg), elevated HR (+100 beats/min), and a concomitant progressive decline in VT and VE prior to terminal apnea/asystole. These data show acute progressive CR suppression with repeated seizures and seizure-induced CRF (tidal volume-mediated decreased ventilation and severe hypotension) leading to death, where time of day for seizure induction contributed to higher mortality rates. This model provides useful insight into the effects of seizures on CR function and understanding the mechanisms of SUDEP, with the ultimate goal of reducing the risk of SUDEP in patients with epilepsy. Supported by NIH HL122358 (MRH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of the State of Emergency Declaration for Severe Acute Respiratory Syndrome Coronavirus-2 Pandemic Suppression on Individuals with Type 1 Diabetes Mellitus.

Objective To examine the impact of lifestyle changes caused by the first emergency declaration issued in 2020 on glycemic control and body weight changes in Japanese individuals with type 1 diabetes mellitus. Methods This study included Japanese individuals with type 1 diabetes mellitus who visited Tokyo Women's Medical University Hospital between January 2019 and September 2020 (n=278). Seasonal changes in glycated hemoglobin (HbA1c) levels and the body mass index (BMI) were compared. A self-administered questionnaire regarding changes in treatment, diet, exercise, sleep, and telecommuting was used to assess lifestyle changes. Results Although HbA1c levels decreased from winter to summer in 2019 and 2020, the annual change was slightly but significantly greater in 2020 than in 2019. Seasonal changes in the BMI between 2019 and 2020 were also significantly different. An increase in the daily insulin dose, overall blood glucose level, diurnal change in blood glucose level, and food intake were significantly associated with increased HbA1c levels. Furthermore, HbA1c levels decreased with increasing moderate physical activity and sleep duration. The change in the BMI increased with increasing insulin dose, overall high blood glucose levels, and food intake. However, an increase in moderate physical activity was associated with a decrease in the BMI. HbA1c levels were significantly lower after the first emergency declaration in individuals with type 1 diabetes mellitus than that before the emergency declaration, even after accounting for seasonal variations. Conclusion Decreased HbA1c levels were associated with a decreased food intake, increased moderate exercise, and increased sleep duration during the state of emergency. The BMI remained relatively unchanged.

Optogenetic stimulation of Phox2b-expressing neurons in the respiratory parafacial region rescue fentanyl-induced respiratory depression

The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), which results in substantial suppression of respiratory rate, destabilization of breathing patterns, severe hypercapnia, and a heightened risk for life-threatening apnea. A crucial chemosensitive brainstem region, located in the rostral ventrolateral medullary reticular formation, contains a bilateral cluster of approximately 800 non-opioid receptor-expressing glutamatergic, non-catecholaminergic, Phox2b+ propriobulbar neurons. These neurons are stimulated by CO2 and acidification and play a vital role in regulating breathing to prevent respiratory acidosis. Under normal circumstances, opioid induced hypercapnia should stimulate these cells to restore ventilation and prevent disturbances in arterial blood gases. However, during OIRD, it remains unclear whether these neurons can effectively rescue breathing in the response to opioid induced hypercapnia. The present study aims to address this question by investigating whether the ability of these neurons to stimulate breathing is significantly altered during opioid-induced respiratory depression. Using optogenetic stimulation, we stimulated these Phox2b+ cells before and after fentanyl to test for whether their ability to stimulate ventilation is reduced during OIRD. As expected, fentanyl (500 μg/kg, ip) resulted in respiratory rate suppression and destabilization of breathing pattern. Before fentanyl administration optogenetic stimulation of Phox2b+ cells increased breathing activity in a pulse stimulation frequency dependent (5-20Hz) manner. Unexpectedly, following fentanyl administration, similar optogenetic stimulation of Phox2b+ cells resulted in a significantly greater frequency dependent (5-20Hz) increase in breathing activity compared to pre-fentanyl levels. Additionally, both hypercapnia (FiCO2 = 0.1) or hypoxia (FiO2 = = 0.1) produced an increase breathing activity in a similar manner in pre- and post-fentanyl conditions. The results suggest that fentanyl paradoxically increases the ability of Phox2b+ cells to stimulate breathing but shifts the steady-state relationship between ventilation and arterial blood gases, such that resting ventilation is reduced. FAPESP, NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Seizures and Post-Ictal Respiratory Recovery in Kcnj16−/− Sprague-Dawley Rats

Epilepsy is a common neurological disorder (3.5 million in the US), of which ~1/3 continue to experience repeated seizures failing to benefit from anti-seizure medication. Poor seizure control puts patients with drug-resistant epilepsies at increased risk of Sudden Unexpected Death in Epilepsy (SUDEP), which is thought to result from severe post-ictal cardiorespiratory suppression. We’ve previously shown that Salt-Sensitive (SS) rats lacking 18 base pairs in the Kcnj16 gene (SS Kcnj16−/−), corresponding to a 6 amino acid (AA163-168) deletion in the second TM domain of Kir5.1, are susceptible to audiogenic seizures. Repeated seizures (1/day for 10 days) in this rat model resulted in ictal apnea, post-ictal respiratory suppression, diminished chemoreflexes, and high spontaneous mortality (PMID: 33232300). Here we generated additional Kcnj16−/− mutants on the outbred Sprague Dawley (SD Kcnj16−/−) genetic background to test the hypothesis that Kcnj16 mutations (T64I substitution; AA64-68 deletion (M7), and AA64-81 deletion (M8)) in the first TM domain of Kir5.1 causes: 1) audiogenic seizures, 2) progressive exacerbation of post-ictal ventilatory dysfunction, and 3) seizure-induced mortality. Ventilation (whole-body plethysmography) and seizure severity (Racine Score; HD video) were measured in male and female SD Kcnj16−/− rats for 20 minutes (min; baseline (BL)) before exposure to an auditory stimulus (2 min) and for 20 min of recovery. Mixed frequency white noise (WN) or a 10 kHz tone (85-95 dB) reproducibly elicited generalized tonic-clonic seizures (GTCSs) in all three SD mutants (T64I, M7, and M8). In SD Kcnj16−/− rats (T64I n=2, M7 n=3, M8 n=7, wild type n=2), 1 seizure/day for 10 days led to ictal apneas and transient post-ictal respiratory changes along with increases in body temperature (+1°C) following seizures, where breath frequency initially decreased (-25% of BL) before increasing (+40%) at 5 min post-stimulus and normalizing by 20 min. Tidal volume increased ~+80% from BL in the first 5 min and returned to BL by 20 min post-ictal. Minute ventilation was decreased (-10%) from BL within 1 min, increased to +60% by 5 minutes and returned to BL within 20 min post-stimulus. In contrast to previous SS Kcnj16−/− rat data, SD Kcnj16−/− rat post-ictal breathing patterns were unchanged across the 10-day seizure protocol, and we observed 100% survival. Our preliminary data suggests that Kcnj16 mutations at multiple sites can elicit the audiogenic seizure phenotype, but that SD Kcnj16−/− mutant rats appear resistant to repeated seizure-induced post-ictal ventilatory dysfunction and mortality — i.e. a potentially useful SUDEP-resistant model of repeated seizures. Funded by NIH HL122358. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Advancing airway management for enhanced patient outcomes: a narrative review

Airway management evidence has primarily been gathered within the operating room, particularly during the induction of anesthesia. The introduction of newly developed supraglottic devices and videolaryngoscopes have significantly impacted the guidelines for managing difficult airways, prompting the need for new evaluation criteria. Moreover, airway complications such as accidental extubation may occur during surgery, while aspiration or respiratory suppression can manifest during the recovery period following extubation. In this review, I will explore the potential future standards for airway management and potential indications for its application. Additionally, I will underscore the significance of emergency airway management during both the surgical procedure and the recovery phase. It is imperative that we not only accumulate knowledge related to managing difficult airways but also focus on emergency airway management in the future. This calls for interprofessional airway management training for all members of the perioperative team. Key words: Airway Management; Videolaryngoscope; Supraglottic Device; Future Direction Abbreviations: DAM - Difficult Airway Management; DAS - Difficult Airway Society; OR - operating room; SGD - Supraglottic Device; VLS – videolaryngoscope Citation: Komasawa N. Advancing airway management for enhanced patient outcomes: a narrative review. Anaesth. pain intensive care 2024;28(1):171−176; DOI: 10.35975/apic.v28i1.2391 Received: December 12, 2023; Reviewed: December 16, 2023; Accepted: December 16, 2023

Anesthetic Methods for Hip Fracture.

To review the benefits, risks, and contraindications of traditional and new anesthesia approaches for hip fracture surgery and describe what is known about the impact of these approaches on postoperative outcomes. This review describes general and spinal anesthesia, peripheral nerve block techniques used for pain management, and novel, local anesthesia approaches which may provide significant benefit compared with traditional approaches by minimizing high-risk induction time and decreasing respiratory suppression and short- and long-term cognitive effects. Hip fracture surgery places a large physiologic stress on an already frail patient, and anesthesia choice plays an important role in managing risk of perioperative morbidity. New local anesthesia techniques may decrease morbidity and mortality, particularly in higher-risk patients.

Prevention of new-onset atrial fibrillation in elderly patients undergoing anatomic pulmonary resection by infusion of magnesium sulfate: protocol for a randomized controlled trial.

Atrial fibrillation (AF) is the most commonly sustained arrhythmia after pulmonary resection, which has been shown to predict higher hospital morbidity and mortality. The lack of strong evidence-based medical evidence makes doctors have very few options for medications to prevent new-onset AF following thoracic surgery. Magnesium can prevent perioperative AF in patients undergoing cardiac surgery. However, this has not yet been fully studied in patients undergoing non-cardiac thoracic surgery, which is the aim of this study. This is a single-center, prospective, double-blind, randomized controlled trial. In total, 838 eligible patients were randomly assigned to one of two study groups, namely, the control group or the magnesium group. The patients in the magnesium group preoperatively received 80 mg magnesium sulfate/kg ideal weight in 100 ml normal saline 30 min. The control group received the same volumes of normal saline simultaneously. The primary outcome is the incidence of new-onset AF intra-operative and on the first, second, and third postoperative days. The secondary outcomes are bradycardia, hypertension, hypotension, and flushing. The occurrence of stroke or any other type of arrhythmia is also recorded. Postoperative respiratory suppression and gastrointestinal discomfort, intensive care unit stays and total duration of hospital stays, in-hospital mortality, and 3-month all-cause mortality are also recorded as important outcomes. This study aims to prospectively evaluate the prophylactic effects of magnesium sulfate against AF compared with a placebo control group during and following anatomic pulmonary resection. The results may provide reliable evidence for the prophylactic value of magnesium against AF in patients with lung cancer. The trial was approved by the Clinical Research Ethics Committee of Shanghai Pulmonary Hospital and has been registered at Chinese Clinical Trial Registry: www.chictr.org.cn, identifier: ChiCTR2300068046.

Repeated seizures lead to progressive ventilatory dysfunction in SSKcnj16-/- rats.

Patients with uncontrolled epilepsy experience repeated seizures putting them at increased risk for sudden unexpected death in epilepsy (SUDEP). Data from human patients have led to the hypothesis that SUDEP results from severe cardiorespiratory suppression after a seizure, which may involve pathological deficiencies in the brainstem serotonin (5-HT) system. Rats with a genomic Kcnj16 mutation (SSKcnj16-/- rats) are susceptible to sound-induced generalized tonic-clonic seizures (GTCS) which, when repeated once daily for up to 10 days (10-day seizure protocol), increased mortality, particularly in male rats. Here, we test the hypothesis that repeated seizures across the 10-day protocol will cause a progressive ventilatory dysfunction due to time-dependent 5-HT deficiency. Initial severe seizures led to ictal and postictal apneas and transient decreases in breathing frequency, ventilatory drive, breath-to-breath variability, and brief hypoventilation. These seizure-induced effects on ventilation were exacerbated with increasing seizures and ventilatory chemoreflexes became further impaired after repeated seizures. Tissue analyses of key brainstem regions controlling breathing showed time-dependent 5-HT system suppression and increased immunoreactivity for IBA-1 (microglial marker) without changes in overall cell counts at 3, 7, and 10 days of seizures. Fluoxetine treatment in SSKcnj16-/- rats prevented repeated seizure-induced progressive respiratory suppression but failed to prevent seizure-related mortality. We conclude that repeated seizures cause a progressive compromise of ventilatory control in the immediate postictal period largely mediated by serotonin system suppression in brainstem regions of respiratory control. However, other unknown factors contribute to overall survival following repeated seizures in this model.NEW & NOTEWORTHY This study demonstrated that repeated seizures in a novel rat model (SSKcnj16-/- rats) caused a progressively greater ventilatory dysfunction in the immediate postictal period associated with brainstem serotonin (5-HT) suppression. Augmenting brain 5-HT with a selective serotonin reuptake inhibitor prevented the progressive ventilatory dysfunction induced by repeated seizures but failed to prevent seizure-related mortality, suggesting that repeated seizures may lead to cardiorespiratory suppression and failure through multiple mechanisms.

Fearing Pain at the End of Life: A Review of Advance Directives.

Patients, caregivers, and healthcare professionals often describe a "good death" as a pain-free process. However, many patients experience pain during their last weeks of life. Advance directives (ADs) are legally binding documents that allow individuals to express their wishes for end-of-life care which should include management of their pain. An interprofessional team conducted a comprehensive analysis of ADs from all 50 states and the District of Columbia to assess the inclusion of language that reflects patients' wishes for pain relief at the end of life. Thirty-seven (73%) of the 51 entities examined reflected the prototypical directive, containing explicit instructions for withholding or withdrawing interventions that may prolong suffering rather than options for treating pain. Of these, 12 (24%) did not include the word "pain". Only 14 states (27%) provided clear guidance for managing pain. Unexpectantly, researchers found that 13 (25%) addressed the common fears of patients, caregivers, and healthcare teams when using opioids to relieve suffering, such as addiction, sedation, appetite, or respiratory suppression, and hastening death. The majority of ADs reviewed lacked clear and comprehensive measures for addressing pain relief. This deficiency may contribute to the undertreatment of pain and amplify the anxiety felt by patients, families, and healthcare providers when making end-of-life decisions. The results highlight the need for improvements in ADs to help ensure that patients' wishes regarding pain management are adequately addressed, documented and respected.

Oxycodone-induced dopaminergic and respiratory effects are modulated by deep brain stimulation.

Introduction: Opioids are the leading cause of overdose death in the United States, accounting for almost 70,000 deaths in 2020. Deep brain stimulation (DBS) is a promising new treatment for substance use disorders. Here, we hypothesized that VTA DBS would modulate both the dopaminergic and respiratory effect of oxycodone. Methods: Multiple-cyclic square wave voltammetry (M-CSWV) was used to investigate how deep brain stimulation (130Hz, 0.2ms, and 0.2mA) of the rodent ventral segmental area (VTA), which contains abundant dopaminergic neurons, modulates the acute effects of oxycodone administration (2.5mg/kg, i.v.) on nucleus accumbens core (NAcc) tonic extracellular dopamine levels and respiratory rate in urethane-anesthetized rats (1.5g/kg, i.p.). Results: I.V. administration of oxycodone resulted in an increase in NAcc tonic dopamine levels (296.9 ± 37.0nM) compared to baseline (150.7 ± 15.5nM) and saline administration (152.0 ± 16.1nM) (296.9 ± 37.0 vs. 150.7 ± 15.5 vs. 152.0 ± 16.1, respectively, p = 0.022, n = 5). This robust oxycodone-induced increase in NAcc dopamine concentration was associated with a sharp reduction in respiratory rate (111.7 ± 2.6min-1 vs. 67.9 ± 8.3min-1; pre- vs. post-oxycodone; p < 0.001). Continuous DBS targeted at the VTA (n = 5) reduced baseline dopamine levels, attenuated the oxycodone-induced increase in dopamine levels to (+39.0% vs. +95%), and respiratory depression (121.5 ± 6.7min-1 vs. 105.2 ± 4.1min-1; pre- vs. post-oxycodone; p = 0.072). Discussion: Here we demonstrated VTA DBS alleviates oxycodone-induced increases in NAcc dopamine levels and reverses respiratory suppression. These results support the possibility of using neuromodulation technology for treatment of drug addiction.

Hybrid Biomimetic Membrane Coated Particles-Mediated Bacterial Ferroptosis for Acute MRSA Pneumonia.

Acute methicillin resistant Staphylococcus aureus (MRSA) pneumonia is one of the most frequently seen lung infection diseases with high morbidity and mortality. It is urgent to explore an efficient antibacterial strategy owing to the increase of drug resistance, virulence, and pathogenicity of MRSA. It was found that Fe3O4 can induce ferroptosis in MRSA, but its effect was inhibited by glutathione (GSH) to a certain extent, while cinnamaldehyde (CA) can enhance ferroptosis by consuming GSH. As a bacterial quorum sensing (QS) inhibitor, CA can suppress the QS system and further exert its antibacterial and antibiofilm effects. Here, we developed an Fe3O4-based ferroptosis inducer to promote ferroptosis in MRSA, interrupt the QS, destroy biofilm, and thus effectively treat acute MRSA pneumonia. We used sodium alginate (SA) to wrap Fe3O4 and CA to form particles, and then coated the surface with a hybrid biomimetic membrane composed of an erythrocyte membrane and platelet membrane to obtain lung targeted antibacterial particles (mFe-CA). Under ultrasonic (US) stimulation, mFe-CA can efficiently release Fe3O4 and CA, thereby synergically inducing MRSA death with the characteristics of ferroptosis, including mass ROS production, lipid peroxidation, GSH depletion, and respiratory chain suppression. Furthermore, mFe-CA + US can inhibit the QS system, remove biofilms, and reduce strain virulence. In the mouse model of MRSA pneumonia, mFe-CA + US treatment markedly advanced the survival rate of the mice, reduced the bacterial load in the lungs, and alleviated the inflammatory damage, but there was no obvious toxicity. This study proposes an antibacterial substitute to induce ferroptosis of MRSA, which may provide a foreground for overcoming microbial drug resistance and fighting biofilm-associated infections and also provides a target and theoretical basis for clinical treatment of acute MRSA pneumonia.

Reproductive and developmental toxicity assessments of LPM3480392, a novel mu opioid receptor biased agonist in rats

Opioids remain the most powerful analgesics for moderate to severe pain but their clinical use, misuse and abuse has been an alarming medical problem, especially for those users at child-bearing age. Mu-opioid receptor (MOR) biased agonists have been suggested as superior alternatives with better therapeutic ratios. We recently discovered and characterized a novel MOR biased agonist, LPM3480392, which demonstrates robust analgesic effect, favorable pharmacokinetic performance, and mild respiratory suppression in vivo. To understand the safety profile of LPM3480392 on the reproductive system and embryonic development, this study evaluated the effects of LPM3480392 on the fertility and early embryonic development, embryo-fetal development, and pre- and postnatal development in rats. Results showed that LPM3480392 had mild effects on parental male and female animals, accompanied by subtle early embryonic loss and delayed ossification of fetal development during organogenesis period. In addition, although minor effects were found on normal developmental milestones and behaviors in the pups, there was no evidence of malformed effect. In conclusion, these results suggest that LPM3480392 has a favorable safety profile with only minor effects on the reproductive and developmental outcomes in animals, which support the development of LPM3480392 as a novel analgesic.

Comparative analysis of opioid use in sickle cell crisis in an urban facility in Ghana.

Vaso-occlusive crises (VOC) is common and opioids are the treatment of choice.This study compared parenteral pethidine and morphine in the elimination/reduction of pain in acute VOC to tolerable levels. This open-label randomized study compared intravenous morphine 5mg 4 hourly to intramuscular pethidine 75mg 4 hourly. Eighty-two consenting adult sickle cell disease participants were recruited from the Korle-Bu Polyclinic. (Forty-one participants in each arm). There were 42 male and 40 female participants. Median age was 25 years. Pethidine participants totalling 31.7% (13/41) and 53.7% (22/41) in the morphine arm had a sustained response within 6h, p=0.027. In the pethidine and morphine arms 60.0% (24/40) and 62.5% (25/40) of participants respectively achieved adequate pain control within 72h of initiating therapy, p=0.296. Most participants, 96.3% (79/82) had no side effects to opioids. The commonest side effects were generalized pruritus, nausea and vomiting, and headaches. More pethidine than morphine participants experienced side effects 29.3% and 22.0% respectively; p=0.448. In conclusion, more morphine participants achieved a sustained pain response compared to the pethidine participants. There was no difference in the tolerability and side effect profile of the opioids. No participant experienced respiratory suppression.

Neural and physiological state dependency of opioid induced respiratory depression

Opioid induced respiratory depression (OIRD) is the major cause of death associated with opioid overdose. Within the brainstem, respiratory activity is generated within the ventrolateral medulla in an opioid-sensitive region known as the PreBötzinger Complex (PreBötC). Within the PreBötC a heterogenous network of neurons under continuous influence by excitatory and inhibitory neuromodulators culminate to form synchronized bursting that results in inspiratory activity. Additionally, the PreBötC network dynamically interacts with the physiological processes that give rise to ventilation. Understanding the interplay between neural and physiological states of the in-vivo system will be key to overcoming OIRD. Here, we tested whether increasing the excitatory state of the PreBötC in-vivo by non-specific K + channel inhibition, or elevated norepinephrine destabilizes breathing, but creates a network state resistant to OIRD. Further, we tested whether the state of upper airway patency following opioid administration influences sensitivity of the PreBötC to OIRD. Following microdialysis into the PreBötC of the non-specific K + channel antagonist, tetraethylammonium (TEA)(10mM), or 1mM norepinephrine ventilation increased and breathing became erratic with variable frequency and tidal volume. However, following 150mg/kg morphine, breathing re-stabilized and returned to near control levels. These results demonstrate that determining the neuromodulatory state of excitability within the PreBötC prior to opioid administration may help to better predict and prevent OIRD. To determine whether the physiological state of the upper-airway following opioid administration can affect sensitivity of the PreBötC to OIRD we tested the ventilatory response to opioids in both airway-intact and tracheostomized mice in-vivo. For these experiments we utilized fentanyl, due to it’s known effects on disrupting upper airway function. Following administration of 500μg/kg fentanyl airway in-tact mice displayed increased upper airway resistance with regular periods of obstructive apnea, severe hypoxemia and reduced breathing frequency that eventually resulted in complete cessation of respiratory activity. Conversely, mice receiving 500μg/kg fentanyl following tracheostomy showed significantly less respiratory suppression and no apneic periods, compared to airway in-tact mice. However, following administration of a hypoxic gas mixture (10% O2) tracheostomized mice experienced terminal apnea in the presence of 500μg/Kg fentanyl. These results demonstrate that hypoxemia experienced following fentanyl administration, which is exacerbated by upper airway constriction may increase the risk of fatal OIRD in-vivo. Together our data suggest that understanding OIRD within the in-vivo system requires the careful investigation of integrative mechanisms between the neural and physiological processes that give rise to overall ventilation. This work was supported by NIH grants: HL154558 (NJB), HL145004 (NEB), HL126523 (JMR), HL144801 (JMR) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ventral and dorsal cervical spinal cord electrical epidural stimulation facilitated respiration differently in the presence of opioids in human via different neural circuits

Opioid overdose is one of the leading causes of overdose related deaths in the United States of America, accounting for 70.6% of overdose fatalities in 2019 alone. A leading cause of death among opioid overdoses is respiratory depression. Epidural electrical stimulation (EES) emerges as a novel approach of facilitating rhythmic motor activities such as locomotion and respiration. Previous studies conducted in humans and rodent models demonstrated respiratory augmentations induced by EES delivered to the dorsal cervical spinal cord. Importantly, EES at the dorsal cervical spinal cord opposes opioid-induced respiratory depression in human. To reveal the mechanism underpins how cervical EES modulate the respiratory neural circuit, we conducted this comparative study between dorsal cervical EES to the ventral EES in patients with opioid-induced respiratory suppression or depression. We hypothesize that the ventral cervical EES activates the local motor neuronal pools while the dorsal EES recruits both sensory and motor cervical circuits as well as accesses supraspinal structures such as medulla. We recruited and consented 25 patients who underwent anterior (ventral) cervical spinal cord surgery and compared the effect of ventral cervical EES to to the effect of dorsal cervical ESS in a dataset that we collected from 18 patients undergoing cervical spinal surgery. In the 25 patients, the EES was deliver to the ventral surface of spinal cord ranging from cervical level 3 to 7 (C3 to C7) for no more than 90 seconds at the optimal intensity ranging from 0.5 mA to 5 mA with stimulation frequencies 5 Hz or 30 Hz. In both the dorsal and ventral EES groups, the subjects were anesthetized with low dose or high dose remifentanil that partially or completely depressed voluntary respiration. We observed three main differences between the dorsal and ventral cervical EEST in regulating respiration in the presence of remifentanil. First, dorsal cervical EES induced the resetting of inspiratory rhythm while ventral cervical EES did not. Second, dorsal but not ventral cervical EES induced longer lasting respiratory modulation after the stimulation stopped. Third, dorsal cervical EES induced both frequency and amplitude changes of respiration while ventral cervical EES modulated the amplitude of the respiration more significantly. These observations suggest that the dorsal and ventral cervical EES facilitate respiration via different neural circuits. This work was supported by the National Institute of Drug Abuse in the National Institutes of Health: R01 DA047637, Louis and Harold Price Foundation, H &amp; H Evergreen Foundation, and J. Yang Family Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.