Depression Of Breathing Research Articles

Fentanyl activates opposing opioid and non-opioid receptor systems that control breathing.

Fentanyl elicits profound disturbances in ventilatory control processes in humans and experimental animals. The traditional viewpoint with respect to fentanyl-induced respiratory depression is that once the effects on the frequency of breathing (Freq), tidal volume (TV), and minute ventilation (MV = Freq × TV) are resolved, then depression of breathing is no longer a concern. The results of the present study challenge this concept with findings, as they reveal that while the apparent inhibitory effects of fentanyl (75μg/kg, IV) on Freq, TV, and MV in adult male rats were fully resolved within 15 min, many other fentanyl-induced responses were in full effect, including opposing effects on respiratory timing parameters. For example, although the effects on Freq were resolved at 15 min, inspiratory duration (Ti) and end inspiratory pause (EIP) were elevated, whereas expiratory duration (Te) and end expiratory pause (EEP) were diminished. Since the effects of fentanyl on TV had subsided fully at 15 min, it would be expected that the administration of an opioid receptor (OR) antagonist would have minimal effects if the effects of fentanyl on this and other parameters had resolved. We now report that the intravenous injection of a 1.0mg/kg dose of the peripherally restricted OR antagonist, methyl-naloxone (naloxone methiodide, NLXmi), did not elicit arousal but elicited some relatively minor changes in Freq, TV, MV, Te, and EEP but pronounced changes in Ti and EIP. In contrast, the injection of a 2.5mg/kg dose of NLXmi elicited pronounced arousal and dramatic changes in many variables, including Freq, TV, and MV, which were not associated with increases in non-apneic breathing events such as apneas. The two compelling conclusions from this study are as follows: 1) the blockade of central ORs produced by the 2.5mg/kg dose of NLXmi elicits pronounced increases in Freq, TV, and MV in rats in which the effects of fentanyl had apparently resolved, and 2) it is apparent that fentanyl had induced the activation of two systems with counter-balancing effects on Freq and TV: one being an opioid receptor inhibitory system and the other being a non-OR excitatory system.

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

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

Age-related differences in symptom distress among patients with cancer

IntroductionDifferences in symptom distress among older (age 65–74) and very old (age 75+) patients with cancer, compared to younger patients, remain to be well explored. These differences are important to understand given the heterogeneity of older populations and may have implications for age-appropriate symptom detection and management. Materials and MethodsWe examined routinely collected Edmonton Symptom Assessment System Revised (ESAS-r) scores from 9,143 patients age 40+ initiating chemotherapy for solid malignancies at a single academic cancer centre, between September 2011 and May 2019. We used multivariable logistic regression models to determine associations between the most common symptoms and age group (ages 40–64, 65–74, 75–84, and 85+), cancer site, clinical stage, sex, and income levels. We focused our findings on patients with the five most common cancers, breast (n = 1,532), prostate (n = 923), lung (n = 889), pancreatic (n = 429), and colorectal (n = 368), prior to receiving treatment. ResultsWithin our sample, 58.0% were age 40–64, 27.3% age 65–74, 11.8% age 75–84, and 2.9% age 85+. Among the nine symptoms in the ESAS-r (anxiety, depression, tiredness, wellbeing, nausea, pain, drowsiness, appetite, and shortness of breath), the most common symptoms overall were anxiety (moderate-severe scores [ESAS-r 4 or higher] were reported by 33.8% of patients), lack of well-being (38.3%), and tiredness (38.3%). Older age was associated with lower odds of moderate/severe anxiety (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.73–0.90 for age 65–74; OR 0.81, 95%CI 0.70–0.93 for age 75–84; OR 0.62, 95%CI 0.47–0.82 for age 85+; referent is 40–64-year-olds for all analyses), and increased odds of tiredness (OR 1.00, 95%CI 0.90–1.11 for age 65–74; OR 1.19, 95%CI 1.04–1.37 for age 75–84; and OR 1.34, 95%CI 1.04–1.72 for age 85+). Advanced stage, female sex, and lower income levels were associated with higher odds of moderate/severe tiredness, anxiety, and lack of well-being in adjusted models. Patients with pancreatic and lung cancers reported worse scores for these three symptoms than patients with other cancers. DiscussionOlder age was associated with differences in symptom experiences such as increased tiredness and reduced anxiety. Supportive care interventions and future research should focus on addressing these symptoms to improve patient quality of life.

Retrospective Outcomes of a New Acupuncture Service at a Comprehensive Cancer Center.

Introduction: Among cancer centers, patients' interest in acupuncture is growing, in addition to clinical research in the intervention. Their National Cancer Institute-designated comprehensive cancer center piloted an acupuncture service. Their aim was to assess whether acupuncture impacted patient self-reported symptoms as delivered clinically and discuss their implementation strategy. Methods: Patients undergoing acupuncture at a comprehensive cancer center from June 2019 to March 2020 were asked to complete a modified Edmonton Symptom Assessment Scale (ESAS) before and after each session. The authors evaluated symptom changes after acupuncture in both outpatient and inpatient settings. A change of ≥1 U, on the 0-10 scale, was considered clinically significant. Results: Three hundred and nine outpatient and 394 inpatient acupuncture sessions were provided to patients at the comprehensive cancer center during this period, of which surveys from 186 outpatient (34 patients) and 124 inpatient (57 patients) sessions were available for analysis. The highest pretreatment symptoms reported by outpatients were neuropathy (5.78), pain (5.58), and tiredness (5.59). Outpatients receiving acupuncture reported clinically significant improvements in pain (ESAS score change of -2.97), neuropathy (-2.68), decreased lack of well-being (-2.60), tiredness (-1.85), nausea (-1.83), anxiety (-1.56), activities of daily living issues (-1.32), depression (-1.23), anorexia (-1.19), insomnia (-1.14), and shortness of breath (-1.14). The most severe pretreatment symptoms reported by inpatients were pain (6.90), insomnia (6.16), and constipation (5.44). Inpatients receiving acupuncture reported clinically significant improvements in anxiety (-3.69), nausea (-3.61), insomnia (-3.26), depression (-2.98), pain (-2.77), neuropathy (-2.68), anorexia (-2.20), constipation (-1.95), and diarrhea (-1.26). Conclusion: Both outpatient and inpatient participants in this pilot acupuncture program reported clinically significant improvements in symptoms after a single acupuncture treatment. Some differences between the outpatient and inpatient settings warrant further investigation.

Effect of Walking Exercise with Breathing Control on the Degree of Shortness of Breath, Anxiety, and Depression in COPD: A Systematic Review

Introduction: Chronic obstructive pulmonary disease (COPD) is a high disease burden and negatively impacts the bio-psycho-social well-being of patients, such as anxiety, depression, and shortness of breath. Anxiety and depression can increase morbidity and worsen the condition and health status of the patient. This systematic review aimed to analyze the effect of walking exercises with breathing control on the degree of shortness of breath, anxiety, and depression in COPD patients. Methods: The data sources were taken from EBSCO, PubMed, and ProQuest using related keywords. Articles were selected using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram method. Results: Ten articles in this systematic review obtained three intervention categories: 1) intervention combined walking exercises with breathing control can be performed 30 minutes per session 2-3 times a week; 2) walking exercise intervention is performed thrice a week for 30-45 minutes per session; 3) breathing control exercise intervention is performed 10-30 minutes with a duration of 2 times a day in the morning and night or can be performed three times a week. Those three intervention categories significantly reduced the degree of shortness of breath, anxiety, and depression in COPD patients. Conclusion: Findings from this systematic review suggest that walking exercise intervention in COPD patients can help reduce the degree of shortness of breath, anxiety, and depression.

Viminol hydroxybenzoate as a non-narcotic analgesic pharmacological choic

Acute postoperative pain is a constant challenge for medical professionals, who seek to choose drugs capable of generating a high degree of analgesia, without, however, inducing adverse effects, such as: intense sedation, gastrointestinal effects, addiction and breathing depression, inherent to opioids. It is already well known that narcotic analgesics constitute the pharmacological group most used in the immediate postoperative period. Here we present Viminol Hydroxybenzoate which has peculiar analgesic characteristics, being considered a potent non-narcotic analgesic of central action and equipotent to codeine. The aim of this study was to highlight the prescriptive importance of Viminol Hydroxybenzoate in the context of acute postoperative pain, explore its pharmacological aspects and warn about the prescriptive risk of opioids. Thus, we suggest the use of Viminol Hydroxybenzoate as an interesting therapeutic alternative to replace opioids, especially in conditions of mild to moderate acute postoperative pain, capable of providing a reduction in pain and, consequently, a better quality of life for patients, without the deleterious effects of opioids.

LYTIC COCKTAIL ATTENUATES CATECHOLAMINE SURGE AFTER SEVERE BURNS BY BLOCKING HISTAMINE H1 RECEPTOR/PKA/CREB/TYROSINE HYDROXYLASE SIGNALING IN CHROMAFFIN CELLS.

Severe burns develop a catecholamine surge, inducing severe damage to the organism, raising the possibility of multisystem organ failure, and even death. The mechanisms of catecholamine surge have not been fully elucidated, and few strategies are generally acceptable to reduce catecholamine surge postburn. Thus, it is valuable to investigate the underlying mechanisms of catecholamine surge postburn to develop targeted interventions to attenuate it. We have found that the lytic cocktail alleviates the surge of catecholamine and organ injury after severe burn; however, the underlying mechanisms were still unclear. Moreover, the lytic cocktail has side effects, such as significant arterial hypotension and breathing depression, limiting its clinical application. This study aims to investigate the therapeutic mechanism of the lytic cocktail in regulating catecholamine levels postburn. We find that promethazine, a classic histamine H1 receptor blocker and a component of the lytic cocktail, can effectively reduce catecholamine surge and organ injury postburn. Our study confirms that blood histamine levels increase after severe burns. We find that histamine can amplify the catecholamine surge by elevating tyrosine hydroxylase expression and catecholamine synthesis in chromaffin cells through the histamine H1 receptor/Protein Kinase A /cAMP-response element binding protein signaling pathway. In summary, for the first time, we find that histamine plays a vital role in catecholamine surge postburn. We also confirm that the lytic cocktail effectively alleviates catecholamine surge and organ injury postburn through promethazine.

Perioperative pharmacological interventions for fetal immobilisation during fetal surgery and invasive procedures.

Developments in ultrasound assessment of pregnancy has resulted in the increasing diagnosis of antenatal fetal issues. Many structural fetal conditions as well as complications associated with multiple pregnancies have the potential for in-utero treatment to improve both pregnancy and neonatal outcomes. Procedures such as laser ablation for twin-twin syndrome or cord occlusion for selective fetal termination require fetal immobilisation. Immobilisation of the fetus can occur through administration of medication to the mother or directly to the fetus. This improves procedural success and reduces the ongoing risk to the pregnancy. Evidence regarding the best medication and mode of delivery helps to ensure the optimal decision is made for both the mother and the fetus. To assess the effects of perioperative pharmacological interventions for fetal immobilisation during fetal surgery and invasive procedures on fetal, neonatal, and maternal outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 May 2021), and reference lists of retrieved studies. We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) which compared different classes of medication administered to the mother or fetus to allow in-utero procedures to be performed. We also included cluster-randomised trials but excluded cross-over trials. We used the standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. One study with three trial reports met the inclusion criteria. This involved 54 women with a multiple pregnancy. The study was conducted in a tertiary European hospital maternal-fetal medicine unit and compared remifentanil to diazepam for fetal immobilisation and maternal sedation during fetoscopic surgery. Low-certainty evidence suggested that remifentanil may reduce fetal movement more than diazepam for two outcomes of fetal movement, one of fetal immobilisation at 40 minutes using a visual analogue score (VAS) (where 0 = immobile and 100 = baseline mobility), and one of gross body and limb movements (score was absolute number of movements), both assessed by a sonographer evaluating a taped ultrasound sequence (mean difference (MD) -65.00, 95% confidence interval (CI) -69.38 to -60.62 and MD -10.00, 95% CI -11.62 to -8.38; 1 study, 50 women). Surgeons may also report being more satisfied with the procedure when using remifentanil rather than diazepam (risk ratio (RR) 2.88, 95% CI 1.60 to 5.15; 1 study, 50 women; low-certainty evidence). However, maternal respiratory rate may decrease more during the surgical procedure with remifentanil compared with diazepam (MD -6.00, 95% CI -8.29 to -3.71; 1 study, 50 women; low-certainty evidence). Maternal sedation may also be worse with remifentanil compared with diazepam (RR 0.09, 95% CI 0.01 to 0.65; 1 study, 50 women; low-certainty evidence) measured using an observer assessment of alertness/sedation (where a score of < 4 equates to profound sedation and > 4 equates to insufficient sedation). Perinatal mortality and time taken to perform the procedure were not reported in the trial. We prespecified 20 outcomes and planned to use GRADE for 6 of them, all other outcomes were not able to be reported against for the purpose of meta-analysis due to data not being provided or unable to be interpreted. We assessed the included study at low risk of selection bias (appropriate random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (outcome assessors were blinded), attrition bias (incomplete outcome data minimal), and reporting bias. Our GRADE assessment for certainty of the evidence indicates that there is low certainty of the evidence. We were only able to include one study with a small number of women, from a single centre, a European tertiary hospital. This study was published in 2005 with an abstract of this trial published in 2004. This study evaluated two intravenous medications administered to the mother - remifentanil and diazepam. This study reported our prespecified primary outcome but only evaluated several of our secondary outcomes, which limited further assessment.Low-certainty evidence suggested that remifentanil may be better at reducing fetal movements and surgeons were more satisfied with the procedure. However, maternal sedation and depression of breathing may be worse with remifentanil. Further high-quality RCTs assessing both fetal and maternal medications are required to evaluate their efficacy for fetal immobilisation as well as safety for both mother and fetus.

Tac1‐expressing cells in the pre‐Bötzinger complex are potential targets to prevent opioid‐induced respiratory depression

RationalOpioids are extensively used for their analgesic properties but present a variety of unwanted side effects, including tolerance, dependence and respiratory depression. The analgesic effect of opioids is due to activation of µ‐opioid receptors (MOR) in the central nervous system and no treatments are currently available to prevent respiratory depression without reducing their analgesic properties. The neural circuits and mechanisms regulating respiratory depression, sedation, and analgesia by opioids often overlap, therefore making challenging the identification of the mechanisms regulating respiratory depression. Neurons expressing tachykinin precursor 1 peptide (Tac1) located in the pre‐Bötzinger complex (preBötC) also co‐express neurokinin‐1 receptors (NK1R) and MORs. NK1R neurons are preferentially inhibited by opioids and play an essential role in mediating opioid‐induced respiratory depression.ObjectiveHere, we tested the hypothesis that optogenetic activation of Tac1‐expressing preBötC cells in freely behaving mice will modulate breathing and prevent respiratory depression by opioids.MethodsUsing a Cre‐loxP recombination approach, we injected in Tac1 Cre recombinase mice the adeno‐associated virus containing the gene cassette of the excitatory channelrhodopsin‐2 ChETA flanked between loxP sites. A 200 µm optical fiber was then fixed above the preBötC for laser stimulation with blue light (wavelength: 480 nm). After a four weeks period to allow ChETA expression in targeted cells, the mouse was placed in a plethysmographic chamber and breathing was measured while laser stimulations were performed under baseline conditions (30 Hz). Following baseline measurements, the clinically relevant µ‐opioid drug fentanyl was administered by intraperitoneal injection (0.3 mg/Kg). About 5 minutes after fentanyl injection, targeted preBötC cells were activated using laser stimulations (30 Hz).ResultsData show that stimulation of Tac1‐expressing cells increased respiratory frequency under baseline conditions. Fentanyl depressed breathing in 5 minutes and stimulation of Tac1 cells prevented opioid‐induced respiratory depression; an effect that was reversible.ConclusionTac1‐expressing preBötC cells may constitute a target to prevent depression of breathing by opioids. These results will help identify the cells mediating opioid‐induced respiratory depression, an essential step toward the development of therapeutic targets to reduce the risk of opioids overdose and associated mortality.

Association of Patient-Reported Outcomes With Subsequent Nonfatal Self-injury After a New Cancer Diagnosis

Nonfatal self-injury (NFSI) is a patient-centered manifestation of severe distress occurring in 3 out of 1000 patients after cancer diagnosis. How to identify patients at risk for NFSI remains unknown. To examine the associations between patient-reported outcome measures and subsequent NFSI in patients with cancer. This population-based matched case-control study included adults with a new cancer diagnosis reporting an Edmonton Symptom Assessment System (ESAS) score within 36 months of diagnosis in Ontario, Canada, 2007 to 2019. Data analysis was performed January 2007 to December 2019. Cases included patients with NFSI, and controls were patients without NFSI. Cases and controls were matched 1:4. Multivariable conditional logistic regression assessed the association between moderate to severe ESAS symptom scores and total ESAS (t-ESAS, range 0-90) score with NFSI in the subsequent 180 days. Of 408 858 patients reporting 1 or more ESAS assessments, 425 patients experienced NFSI and reported an ESAS score in the preceding 180 days. Of those, 406 cases were matched to 1624 control patients without an NFSI. Cases reported a higher proportion of moderate to severe symptoms and higher t-ESAS score than controls prior to the event. After adjustment, moderate to severe anxiety (odds ratio [OR], 1.61; 95% CI, 1.14-2.27), depression (OR, 1.66; 95% CI, 1.20-2.31), and shortness of breath (OR, 1.65; 95% CI, 1.18-2.31) and each 10-point increase in t-ESAS score (OR, 1.51; 95% CI, 1.40-1.63) were independently associated with higher odds of subsequent NFSI. In this case-control study, reporting moderate to severe anxiety, depression, and shortness of breath and an increasing t-ESAS score after cancer diagnosis were associated with higher odds of NFSI in the following 180 days. These data support the prospective use of routine ESAS screening as a means of identifying patients at higher risk for NFSI to improve supportive care.

Virtual Reality in Home Palliative Care: Brief Report on the Effect on Cancer-Related Symptomatology.

Virtual reality (VR) has been used as a complementary therapy for managing psychological and physical symptoms in cancer patients. In palliative care, the evidence about the use of VR is still inadequate. This study aims to assess the effect of an immersive VR-based intervention conducted at home on anxiety, depression, and pain over 4days and to evaluate the short-term effect of VR sessions on cancer-related symptomatology. Participants were advanced cancer patients assisted at home who were provided with a VR headset for 4days. On days one and four, anxiety and depression were measured by the Hospital Anxiety and Depression Scale (HADS) and pain by the Brief Pain Inventory (BPI). Before and after each VR session, symptoms were collected by the Edmonton Symptom Assessment Scale (ESAS). Participants wore a smart wristband measuring physiological signals associated with pain, anxiety, and depression. Fourteen patients (mean age 47.2±14.2years) were recruited. Anxiety, depression (HADS), and pain (BPI) did not change significantly between days one and four. However, the ESAS items related to pain, depression, anxiety, well-being, and shortness of breath collected immediately after the VR sessions showed a significant improvement (p<0.01). A progressive reduction in electrodermal activity has been observed comparing the recordings before, during, and after the VR sessions, although these changes were not statistically significant. This brief research report supports the idea that VR could represent a suitable complementary tool for psychological treatment in advanced cancer patients assisted at home.

Living with long COVID

Post-COVID syndrome, or long COVID, is an increasing problem. Debbie Duncan looks at the evidence for management in primary care One in five people have symptoms that persist after 5 weeks, and one in ten have symptoms for 12 weeks or longer after an acute COVID-19 infection ( Office for National Statistics [ONS], 2020 ). NICE ( National Institute for Health and Care Excellence, 2020 ) defines this condition as post-COVID syndrome or long COVID. Common symptoms vary from fatigue, shortness of breath, palpitations, insomnia and anxiety and depression and encompasses a plethora of debilitating symptoms ( Dani et al, 2021 ). The new guideline for NICE (2021) recommends that patients presenting with new or ongoing symptoms 4 weeks or later after an initial COVID infection should have the investigations done to rule out acute, life-threatening complications or identify any unrelated diagnosis ( NICE, 2021 ). Garg et al (2020) suggests that long COVID is a multisystem syndrome and needs a multifaceted approach to tackle the physical, cognitive, psychological, social, and vocational aspects of this condition. This article looks at the literature about long COVID and suggests there is a clear pathway for treatment in primary care. All physicians should be equipped to recognise long-COVID and provide supportive management ( Dani et al, 2021 ).

Living with long COVID

One in five people have symptoms that persist after 5 weeks, and one in ten have symptoms for 12 weeks or longer after an acute COVID-19 infection ( Office for National Statistics [ONS], 2020 ). NICE ( National Institute for Health and Care Excellence, 2020 ) defines this condition as post-COVID syndrome or long COVID. Common symptoms vary from fatigue, shortness of breath, palpitations, insomnia and anxiety and depression and encompasses a plethora of debilitating symptoms ( Dani et al, 2021 ). The new guideline for NICE (2021) recommends that patients presenting with new or ongoing symptoms 4 weeks or later after an initial COVID infection should have the investigations done to rule out acute, life-threatening complications or identify any unrelated diagnosis ( NICE, 2021 ). Garg et al (2020) suggests that long COVID is a multisystem syndrome and needs a multifaceted approach to tackle the physical, cognitive, psychological, social, and vocational aspects of this condition. This article looks at the literature about long COVID and suggests there is a clear pathway for treatment in primary care. Certainly that all physicians should be equipped to recognise long-COVID and provide supportive management ( Dani et al, 2021 ).

An Effective and Safe Enkephalin Analog for Antinociception.

Opioids account for 69,000 overdose deaths per annum worldwide and cause serious side effects. Safer analgesics are urgently needed. The endogenous opioid peptide Leu-Enkephalin (Leu-ENK) is ineffective when introduced peripherally due to poor stability and limited membrane permeability. We developed a focused library of Leu-ENK analogs containing small hydrophobic modifications. N-pivaloyl analog KK-103 showed the highest binding affinity to the delta opioid receptor (68% relative to Leu-ENK) and an extended plasma half-life of 37 h. In the murine hot-plate model, subcutaneous KK-103 showed 10-fold improved anticonception (142%MPE·h) compared to Leu-ENK (14%MPE·h). In the formalin model, KK-103 reduced the licking and biting time to ~50% relative to the vehicle group. KK-103 was shown to act through the opioid receptors in the central nervous system. In contrast to morphine, KK-103 was longer-lasting and did not induce breathing depression, physical dependence, and tolerance, showing potential as a safe and effective analgesic.

Patient-reported outcomes predicting non-fatal self-injury after a cancer diagnosis: A population-based case-control study.

e18583 Background: Psychological distress is key in cancer care. Non-fatal self-injury (NFSI) represents a patient-centred, objectively measured manifestation of the greatest level of distress occurring in 3 out of 1,000 patients after a new cancer diagnosis. How to identify patients at high risk for NFSI remains unknown. We examined the relationships between routinely collected patient-reported outcomes measures and the risk of subsequent NFSI following a cancer diagnosis. Methods: We conducted a population-based case-control study of patients with a new cancer diagnosis (2007-2019) reporting a Edmonton Symptom Assessment (ESAS) score within 36 months of diagnosis. Cases were patients with NFSI within 36 months of diagnosis and controls those without NFSI (assigned a dummy index date corresponding to the case’s NFSI). Cases and controls were matched 1:4 on time from cancer diagnosis, ESAS record in 180 days prior index, age, sex, cancer site, and history of self-injury. Multivariable conditional logistic regression assessed the association between moderate-to-severe ESAS symptoms and total ESAS (t-ESAS) score with NFSI within 180 days. Results: Of 408,858 patients reporting &gt;1 ESAS within 36 months of cancer diagnosis, 748 patients had a NFSI, including 425 patients with an ESAS score within 180 days preceding the NFSI event. Of those 406 cases were matched to 1,624 controls without NFSI. Cases reported a higher proportion of moderate-to-severe symptoms and higher t-ESAS than controls prior to the event (p &lt; 0.01 for all). After adjusting for psychiatric illness history and cancer therapy received, reporting of moderate-to-severe anxiety (odds ratio – OR 1.61, 95%CI 1.14-2.27), depression (OR 1.66, 95%CI 1.2-2.31), and shortness of breath (OR 1.65, 955CI 1.18-2.31) were independently associated with higher risk of NFSI within 180 days. Each 10-point increase in t-ESAS (score 0-90) was independently associated with increased risk of NFSI within 180 days (OR 1.51; 95%CI 1.40-1.63). Conclusions: Reporting moderate-to-severe anxiety, depression, and shortness of breath, and increasing t-ESAS after cancer diagnosis are associated with higher odds of NFSI in the following 180 days. These data support the prospective identification of patients at high risk for NFSI via routine ESAS screening to improve supportive care. Patients with at-risk ESAS scores should receive tailored assessment, management, and longitudinal follow-up.

Limited Capacity for Clearance of Adenosine from the preBötzinger Complex Inspiratory Network Contributes to the Profound Depression of Breathing by Hypoxia in the Very Young

Breathing in premature infants often stops briefly (apnea) because the brainstem network that controls breathing is immature (apnea of prematurity, AOP). Apneas cause hypoxia, triggering the hypoxic ventilatory response (HVR), which comprises an initial increase in ventilation followed by a centrally mediated 2° decrease. In adults, breathing remains above baseline during this 2° phase, but in the very young it falls below baseline leading to a life-threatening feedback loop where apnea causes hypoxia, respiratory depression, further hypoxia and so on. Understanding the cause of this powerful hypoxic inhibition of breathing in the very young, a major question in perinatal physiology, could inform new therapies for AOP. The transmitter ATP is released in the preBötzinger Complex (preBötC, site of inspiratory rhythm generation) during hypoxia where it increases breathing and attenuates the 2° depression. However, extracellular ATP (ATPe) is degraded to adenosine (ADO), which inhibits breathing and is implicated in AOP; e.g., caffeine blocks ADOe actions and is the first line treatment for AOP. We hypothesize that the greater 2° inhibition of breathing in prematurity is due to an immature system for clearing ADOe. ADOe-mediated inhibition stops with its removal from the extracellular space, which depends on i) equilibrative nucleoside transporters (ENTs) that move ADOe across cell membranes down its concentration gradient, and ii) ADO kinase (ADK), an enzyme that keeps the level of ADO inside cells lower than outside so ENTs clear ADOe. How ENT activity develops in the preBötC is unknown. However, the form of ADK that influences ADOe in the brain is minimally functional until 2 weeks of age in rodents. To assess the importance of ADOe clearance in the development of the HVR, we used plethysmography to measure the HVR (10% O2) in 0-56 day old (P0-14) wild-type (WT), ENT knockout (KO), and ADKtg mice engineered to have functional ADK throughout life. In WT and ENT KO neonates (P0-2), ventilation fell below baseline after ~7 min in hypoxia, but the hypoxia-evoked frequency increase was markedly reduced in the ENT KO. Strikingly, P0-2 ADKtg mice showed the mature breathing response; ventilation remained above baseline levels throughout hypoxia. At P12 in WT and ENT KO, the HVR had still not matured; ventilation fell below baseline during the 2° phase, yet it remained above baseline in P12 ADKtg mice. To assess the importance of ENT and ADK specifically in the preBötC, we isolated the preBötC network in rhythmic brain slices from P0-12 mice. The ADO inhibition of preBötC frequency lasted twice as long in P0-12 ENT KO mice compared to WT. Conversely, the decrease in basal frequency caused by ADK inhibition (ABT-702) increased with age (P0-2, 15%; P9-11, 23%). These data suggest that i) ENTs are important for ADO clearance in the preBötC after birth and ii) low ADK activity at birth is a major contributor to the greater hypoxic respiratory depression in early development.

170P Predictors for cancer-related fatigue among patients with advanced lung cancer attending palliative care department: A prospective observational study

Background: Cancer-related fatigue (CRF) among patients with lung cancer (LC) is present before and after treatment and present in about three fourth of cases. CRF is often a common unmet need affecting the quality of life of patients with LC. We conducted this study to understand the predictors for CRF among patients with LC attending the palliative care department in our center. Methods: A prospective observational study was conducted among patients having LC. The study was conducted on patients referred to the palliative care department of Tata Medical Center, Kolkata from January 2019 to June 2019. Those patients whose Karnofsky status is less than 40, with a history of diabetes, heart disease, psychiatric disease, and psychotropic drugs were excluded from the study. Edmonton Symptom Scale was used to assess the various symptoms like pain, fatigue, nausea, depression, anxiety, appetite, well-being, cough, and shortness of breath. History of any surgery, chemotherapy, or radiotherapy along with blood investigations like serum albumin, hemoglobin, and white blood cell count was documented. Results: Eighty-four patients with LC with a mean age of 61.5 years were included in the present study. The prevalence of CRF was 48.80%. Univariate analysis revealed that the presence of cough (p < 0.001), breathlessness (p < 0.001), hemoglobin levels (p = 0.012), and radiotherapy treatment (p = 0.038) to be associated with fatigue. After multiple logistic regression analysis with fatigue as outcome variable, revealed that presence of cough [OR = 3.80; 95% CI = 1.13 to 12.80;(p = 0.031)] and breathlessness [OR = 3.57; 95% CI = 1.19 to 10.73; (p = 0.023)] as significant predictors affecting fatigue among lung cancer patients. Conclusions: Half of our patients with LC had CRF. The presence of cough and breathlessness were significant factors that affected the CRF in the present study after the confounding factors were adjusted. Further studies on this associated symptom cluster of fatigue, breathlessness, and cough have to be conducted. While managing the patients with fatigue it is important that these associated symptoms like cough and breathlessness have to be handled. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Time-dependent Patient-reported Outcomes As Predictors of the Survival of Patients With Lung Cancer

Background: The importance of patient-reported outcomes (PROs) has been increasingly recognized in cancer care. No study has investigated how changes in PROs after completion of cancer treatment affect survival. Objective: To investigate the predictive value of patient characteristics, including PROs, for cancer survival. Methods: A total of 86 patients with a confirmed diagnosis of lung cancer were recruited. Data on PROs including sleep disturbance, anxiety, depression, fatigue, nausea, pain, weight loss, cough, good appetite, chest tightness, and ease of breathing were collected through self-reported questionnaires at 5 time points for each patient: before treatment and 6, 12, 24, and 48 weeks after treatment. Results: Bivariate time-dependent Cox regression revealed the following variables to be significant: small-cell, stage IV lung cancer; pretreatment pneumonia; treatment type; and several PRO variables, including sleep disturbance (hazard ratio [HR] = 1.10, P &lt; .001), anxiety (HR = 1.15, P &lt; .001), depression (HR = 1.11, P &lt; .001), weight loss (HR = 0.71, P &lt; .001), chest tightness (HR = 0.83, P = .029), and ease of breathing (HR = 0.62, P &lt; .001). Multivariable time-dependent Cox regression revealed that only stage IV (HR = 7.33, P = .029) and weight loss (HR = 0.76, P = .006) were significant variables associated with survival. Conclusions: Patient-reported weight loss was independently associated with shortened survival in patients with lung cancer. Implications for Practice: Health care professionals should closely monitor the PROs of patients with lung cancer. In cases of self-reported weight loss, further investigation and appropriate interventions are necessary. What is Foundational: Patient-reported weight loss has been recognized in our research as a modifiable risk factor in lung cancer survival. PROs have potential predictive value in cancer survival.

Early ethanol pre-exposure alters breathing patterns by disruptions in the central respiratory network and serotonergic balance in neonate rats

Early ethanol exposure alters neonatal breathing plasticity. Respiratory EtOH's effects are attributed to central respiratory network disruptions, particularly in the medullary serotonin (5HT) system. In this study we evaluated the effects of neonatal pre-exposure to low/moderate doses upon breathing rates, activation patterns of brainstem’s nuclei and expression of 5HT 2A and 2C receptors. At PD9, breathing frequencies, tidal volumes and apneas were examined in pups pre-exposed to vehicle or ethanol (2.0 g/kg) at PDs 3, 5 and 7. This developmental stage is equivalent to the 3rd human gestational trimester, characterized by increased levels of synaptogenesis. Pups were tested under sobriety or under the state of ethanol intoxication and when subjected to normoxia or hypoxia. Number of c-Fos and 5HT immunolabelled cells and relative mRNA expression of 5HT 2A and 2C receptors were quantified in the brainstem. Under normoxia, ethanol pre-exposed pups exhibited breathing depressions and a high number of apneas. An opposite phenomenon was found in ethanol pre-treated pups tested under hypoxia where an exacerbated hypoxic ventilatory response (HVR) was observed. The breathing depression was associated with an increase in the neural activation levels of the raphe obscurus (ROb) and a high mRNA expression of the 5HT 2A receptor in the brainstem while desactivation of the ROb and high activation levels in the solitary tract nucleus and area postrema were associated to the exacerbated HVR. In summary, early ethanol experience induces respiratory disruptions indicative of sensitization processes. Neuroadaptive changes in central respiratory areas under consideration appear to be strongly associated with changes in their respiratory plasticity.

Disparity in the effect of morphine on eupnea and gasping in anesthetized spontaneously breathing adult rats.

The goal of this study was to examine the effects of systemic morphine on the pattern and morphology of gasping breathing during respiratory autoresuscitation from transient anoxia. We hypothesized that systemic morphine levels sufficient to cause significant depression of eupnea would also cause depression of gasping breathing. Respiratory and cardiovascular variables were studied in 20 spontaneously breathing pentobarbital-anaesthetized adult male rats. Sham (saline) injections caused no significant change in resting respiratory or cardiovascular variables (n = 10 rats). Morphine, on the other hand, caused significant depression of eupneic breathing, with ventilation and peak inspiratory flow decreased by ∼30-60%, depending on the background condition (n = 10 rats). In contrast, morphine did not depress gasping breathing. Duration of primary apnea, time to restore eupnea, the number and amplitude of gasping breaths, average and maximum peak flows, and volume of gasping breaths were not significantly different postinjection in either condition. Blood pressures were all significantly lower following morphine injection at key time points in the process of autoresuscitation. Last, rate of successful recovery from anoxia was 80% in the morphine group (8/10 rats) compared with 100% (10/10 rats) in the sham group, postinjection. We conclude that the mechanisms and/or anatomic correlates underlying generation of gasping rhythm are distinct from those underlying eupnea, allowing gasping to remain robust to systemic morphine levels causing significant depression of eupnea. Morphine nevertheless decreases likelihood of recovery from transient anoxia, possibly as a result of decreased tissue perfusion pressures at critical time points during the process of respiratory autoresuscitation.