Assessment of Non-Invasive Ventilation Combined with Naloxone for the Management of Acute Respiratory Failure in Patients with Chronic Obstructive Pulmonary Disease.

Background: Chronic obstructive pulmonary disease (COPD) poses a significant global health burden. Finding effective interventions for COPD is crucial to alleviating this health burden and enhancing patient outcomes and quality of life. Objective: This study aimed to evaluate the therapeutic efficacy of the combination of non-invasive ventilation and naloxone in the management of acute respiratory failure among patients with COPD. Methods: A retrospective analysis was conducted on the clinical data of 102 COPD patients experiencing acute respiratory failure who were treated at our hospital between October 2020 and October 2022. Patients were categorized into an observation group (receiving non-invasive ventilation combined with naloxone) and a control group (receiving non-invasive ventilation alone). Parameters such as lung function, blood gas levels, endocrine hormone concentrations, treatment efficacy, and patient prognosis were carefully recorded and compared. Results: The observation group demonstrated enhanced lung function, optimized endocrine hormone levels, and improved blood gas parameters compared to the control group. Following treatment, the observation group exhibited significant reductions in plasma renin activity (PRA), angiotensin II (AngII), aldosterone (ALD), and norepinephrine (NE) levels. The total effective rate was notably higher in the observation group. This group also presented higher scores for Acute Physiology and Chronic Health Evaluation II (APACHE II) and Chronic Obstructive Pulmonary Disease Assessment Test (CAT). Conclusions: The combination of non-invasive ventilation with naloxone emerged as a significantly effective strategy in managing acute respiratory failure in COPD patients. This approach led to improvements in lung function, endocrine hormone levels, and blood gas parameters and highlights its potential as an impactful treatment strategy for COPD patients experiencing acute respiratory failure.

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.

BACKGROUND AND PURPOSE: Opioid-induced respiratory depression limits the use of µ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti-nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy. EXPERIMENTAL APPROACH: Respiration was measured in awake, freely moving male CD-1 mice using whole body plethysmography. Anti-nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR-17018 were administered orally. Receptor activation and arrestin-3 recruitment were measured in HEK293 cells using BRET assays. KEY RESULTS: Across the dose ranges examined, all opioids studied depressed respiration in a dose-dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR-17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti-nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds. CONCLUSION AND IMPLICATIONS: In addition to providing effective anti-nociception, the novel opioids, oliceridine, tianeptine and SR-17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.

Toxicity assessment of gelsenicine and the search for effective antidotes.

BACKGROUND: Gelsenicine, one of the most toxic alkaloids of Gelsemium elegans Benth (G. elegans), causes severe respiratory depression. However, its toxicity mechanisms are yet to be elucidated and no effective antidotes are available. OBJECTIVE: This study aimed to analyse the toxicity characteristics of gelsenicine. METHODS: Both acute and sub-acute toxicities were evaluated. Gelsenicine distribution and elimination in the central nervous system (CNS) and blood were observed. Effective antidotes for gelsenicine poisoning were screened. RESULTS: In the acute toxicity study, gelsenicine was highly toxic, and female rats exhibited greater sensitivity to gelsenicine than male rats (LD50 0.520 mg/kg vs 0.996 mg/kg, respectively). Death was primarily caused by respiratory failure. However, in the sub-acute toxicity study, no significant organ damage was observed. Gelsenicine was easily absorbed from the gastrointestinal tract and penetrated the blood-brain barrier, reaching peak concentrations in the CNS within 15 min and rapidly decreasing thereafter. Flumazenil or diazepam combined with epinephrine reversed gelsenicine toxicity and significantly improved survival rate in mice. CONCLUSIONS: Gelsenicine is a highly toxic substance that affects nerve conduction without causing damage; the potential toxic mechanism is possibly associated with GABAA receptors. Our findings provide insights into the clinical treatment of gelsenicine-related poisoning and its toxicity mechanisms.

Testing the efficacy and safety of BIO101, for the prevention of respiratory deterioration, in patients with COVID-19 pneumonia (COVA study): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: As of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage. The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia. TRIAL DESIGN: Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts. Part 1: Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2: Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population. The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive - to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial. PARTICIPANTS: Inclusion criteria 1. Age: 45 and above 2. A confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used. 3. Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4. With evidence of pneumonia based on all of the following: a. Clinical findings on a physical examination b. Respiratory symptoms developed within the past 7 days 5. With evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: a. Tachypnea: ≥25 breaths per minute b. Arterial oxygen saturation ≤92% c. A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterion 6. Without a significant deterioration in liver function tests: a. ALT and AST ≤ 5x upper limit of normal (ULN) b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN c. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8. Female participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR a. Have a negative urine pregnancy test at screening b. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product. (Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy). 10. Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention. 11. Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product. 12. For France only: Being affiliated with a European Social Security. Exclusion criteria 1. Not needing or not willing to remain in a healthcare facility during the study 2. Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.). 4. Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water). 5. Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents). 6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101. 7. Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula). 8. In France only: a. Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b. Being under tutelage or legal guardianship. Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients' participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days. INTERVENTION AND COMPARATOR: Two treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., 'negative' or 'positive' event). Participants who are officially discharged from hospital care will no longer receive study medication. MAIN OUTCOMES: Primary study endpoint: The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage). Requiring extracorporeal membrane oxygenation (ECMO). Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min. Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28. Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition. Secondary and exploratory endpoints: In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected. RANDOMIZATION: Randomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above). In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not). BLINDING (MASKING): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacy data, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power. Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients). Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1). TRIAL STATUS: The current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021. TRIAL REGISTRATION: The trial was registered before trial start in trial registries: EudraCT , No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Palliative and end-of-life care in COVID-19 management in sub-Saharan Africa: a matter of concern.

The COVID-19 pandemic has strained health care systems beyond capacity resulting in many people not having access to life-sustaining measures even in well-resourced countries. Palliative and end-of-life care are therefore essential to alleviate suffering and ensure a continuum of care for patients unlikely to survive. This is challenging in sub-Saharan Africa where lack of trained teams on basic palliative care and reduced access to opioids limit implementation of palliative and end-of-life care. At the same time, health care providers have to cope with local cultural conceptions of death and absence of advance care directives.

Cost-Effectiveness of Antiviral Treatments for Pandemics and Outbreaks of Respiratory Illnesses, Including COVID-19: A Systematic Review of Published Economic Evaluations.

OBJECTIVE: To review published economic evaluations of antiviral treatment for pandemics and outbreaks of respiratory illnesses. METHODS: We conducted a systematic review to identify economic evaluations of antiviral treatment for pandemics and outbreaks of respiratory illnesses, including coronavirus disease 2019 (COVID-19). We searched Medline (EBSCOhost), EMBASE (Ovid), EconLit (Ovid), National Health Service Economic Evaluation Database (Ovid), and Health Technology Assessment (Ovid). The search was last rerun on July 5, 2020. Citation tracking and reference checking were used. Only full economic evaluations published as peer-reviewed articles in the last 10 years were included. Studies were quality assessed using the National Institute for Health and Care Excellence economic evaluation checklist. RESULTS: Overall, 782 records were identified, of which 14 studies met the inclusion criteria. The studies were mostly conducted in high-income countries. All were model-based. Seven (50%) were cost-utility analyses, 4 (28.6%) were cost-effectiveness analyses, 2 (14.3%) were cost-consequences analyses, and 1 (7.1%) was a cost-benefit analysis. Strategies including antiviral treatment were found to be either cost-saving or cost-effective, at the study-specific willingness-to-pay thresholds. Empirical treatment was more cost-effective than test-guided treatment for young adults but less so for older adults. CONCLUSIONS: Antiviral treatment for managing pandemics and outbreaks of respiratory illnesses that have very high case fatality rate, similar to COVID-19 pandemic, are likely to be cost-effective either as a standalone intervention or part of a multifaceted strategy. Investing in the development of such curative treatments and promptly evaluating their cost-effectiveness, relative to other strategies in use at the time of their introduction should be the focus going forward to inform resource allocation decisions particularly in low- and middle-income countries.

Forced expiratory volumes in 3 s is a sensitive clinical measure for assessment of bronchodilator reversibility in elderly Chinese with severe lung function impairment.

Purpose: Sensitively assessing bronchial reversibility by spirometry is difficult in patients with serious airflow limitation and the elderly. Some patients cannot exhale for ≥6 s to achieve FVC testing criteria. The aim of this study was to assess if FEV3 could be a more sensitive and an acceptable surrogate for evaluating bronchial reversibility in such patients. Patients and methods: Subjects who had undergone pulmonary function examination in Beijing hospital from July 2003 to April 2015 were included in the study. Patients with FEV1<50% of the predicted value were classified as the severely lung function-impaired group. Correlation between the severity of lung function impairment and changes in FEV1, FEV3 and FVC in response to a bronchodilator was estimated. Results: A total of 7745 tests on elderly subjects with a median age of 71 years were reviewed. The severely lung function-impaired group of 1728 accounted for 22.3% of the total number of subjects. There were significantly more patients in the severely lung function-impaired group who exhibited positive response in FEV3 or FVC and negative response in FEV1 after bronchodilator test (FEV1 negative response but FVC positive response, χ2=626.97, P<0.001; FEV1 negative response but FEV3 positive response, χ2=372.83, P<0.001). With the progressive increase in lung function impairment, ΔFEV1 increased and then declined, while ΔFVC and ΔFEV3 increased progressively. Changes in FEV3 or FVC significantly exceeded the change in FEV1 in the severely lung function-impaired groups (P<0.001). Conclusion: In elderly subjects, especially those with severe lung function impairment, FEV3 combined with FVC is a more effective and sensitive primary clinical outcome measure to detect bronchial reversibility. In subjects who cannot complete ≥6 s forced expiration and whose FVC is unreliable, FEV3 combined with FEV1 might be clinically more valuable in detecting bronchial reversibility.

Economic outcomes of influenza in hospitalized elderly with and without ICU admission.

BACKGROUND: To describe direct medical costs of influenza in hospitalized elderly, with and without intensive care unit (ICU) admission, during the 2014-2015 season in Hong Kong. METHODS: A retrospective study was conducted in 110 inpatients aged ≥65 years with laboratory-confirmed influenza treated by antiviral therapy during season 2014-2015 in a tertiary hospital. Resource utilization of influenza-related diagnostic and laboratory tests, medications for influenza treatment, usage of general medical ward and ICU during the influenza-related length of hospital stay (IR-LOS) were collected. RESULTS: There were 18 (16.4%) and 92 (83.4%) cases with and without ICU admission, respectively. The difference in influenza-related mortality rates between patients with (11.1%) and without ICU admission (2.2%) was not statistically significant (P=0.064). Patients with ICU admission reported longer IR-LOS (12.7 ±6.0 days versus 5.5 ±2.7 days; P<0.001) and higher direct costs (36,588 USD ±21,482 versus 5,773 USD ±2,017; P<0.001; 1 USD=7.8 HKD). Male gender (OR=14.50; 95% CI 1.68, 125.07) and respiratory complications (OR=9.61; 95% CI 1.90, 48.50) were positive predictors of ICU admission. Age ≥70 years (OR=0.09; 95% CI 0.02, 0.46) and antiviral therapy initiation within 7 days (OR=0.05; 95% CI 0.003, 0.79) were negative predictors of ICU admission. Influenza B was a positive predictor of high-cost hospitalization in non-ICU survivors (OR=7.33; 95% CI 1.24, 43.29). No predictor of mortality was identified. CONCLUSIONS: Hospitalization cost in elderly for seasonal influenza was substantial in Hong Kong. The cost in patients with ICU admission was significantly higher than those without ICU care. Respiratory complications and male gender predicted ICU admission. Influenza B infection predicted high-cost hospitalization in non-ICU survivors.

Costo efectividad y análisis de impacto presupuestario del óxido nítrico inhalatorio neonatal en un hospital, desde la perspectiva del sistema público de salud / Cost effectiveness and budget impact analysis of inhaled nitric oxide in a neonatal unit from the perspective of the public health system

El óxido nítrico inhalatorio (ONi) es actualmente la terapia de primera línea en la insuficiencia respiratoria hipoxémica grave del recién nacido; la mayor parte de los centros neonatales de regiones en Chile no cuentan con esta alternativa terapéutica. Objetivo: Determinar el costo-efectividad del ONi en el tratamiento de la insuficiencia respiratoria asociada a hipertensión pulmonar del recién nacido, comparado con el cuidado habitual y el traslado a un centro de mayor complejidad. Pacientes y método: Se modeló un árbol de decisiones clínicas desde la perspectiva del sistema de salud público chileno, se calcularon razones de costo-efectividad incremental (ICER), se realizó análisis de sensibilidad determinístico y probabilístico, se estimó el impacto presupuestario, software: TreeAge Health Care Pro 2014. Resultados: La alternativa ONi produce un aumento promedio en los costos de 11,7 millones de pesos por paciente tratado, con una razón de costo-efectividad incremental comparado con el cuidado habitual de 23 millones de pesos por muerte o caso de oxigenación extracorpórea evitada. Al sensibilizar los resultados por incidencia, encontramos que a partir de 7 casos tratados al año resulta menos costoso el óxido nítrico que el traslado a un centro de mayor complejidad. Conclusiones: Desde la perspectiva de un hospital regional chileno incorporar ONi en el manejo de la insuficiencia respiratoria neonatal resulta la alternativa óptima en la mayoría de los escenarios posibles.

Inhaled nitric oxide (iNO) is currently the first-line therapy in severe hypoxaemic respiratory failure of the newborn. Most of regional neonatal centres in Chile do not have this therapeutic alternative. Objective: To determine the cost effectiveness of inhaled nitric oxide in the treatment of respiratory failure associated with pulmonary hypertension of the newborn compared to the usual care, including the transfer to a more complex unit. Patients and method: A clinical decision tree was designed from the perspective of Chilean Public Health Service. Incremental cost effectiveness rates (ICER) were calculated, deterministic sensitivity analysis was performed, and probabilistic budget impact was estimated using: TreeAge Pro Healthcare 2014 software. Results: The iNO option leads to an increase in mean cost of $ 11.7 million Chilean pesos (€ 15,000) per patient treated, with an ICER compared with the usual care of $ 23 million pesos (€ 30,000) in case of death or ECMO avoided. By sensitising the results by incidence, it was found that from 7 cases and upwards treated annually, inhaled nitric oxide is less costly than the transfer to a more complex unit. Conclusions: From the perspective of a Chilean regional hospital, incorporating inhaled nitric oxide into the management of neonatal respiratory failure is the optimal alternative in most scenarios.

[Cost effectiveness and budget impact analysis of inhaled nitric oxide in a neonatal unit from the perspective of the public health system]. / Costo efectividad y análisis de impacto presupuestario del óxido nítrico inhalatorio neonatal en un hospital, desde la perspectiva del sistema público de salud.

Inhaled nitric oxide (iNO) is currently the first-line therapy in severe hypoxaemic respiratory failure of the newborn. Most of regional neonatal centres in Chile do not have this therapeutic alternative. OBJECTIVE: To determine the cost effectiveness of inhaled nitric oxide in the treatment of respiratory failure associated with pulmonary hypertension of the newborn compared to the usual care, including the transfer to a more complex unit. PATIENTS AND METHOD: A clinical decision tree was designed from the perspective of Chilean Public Health Service. Incremental cost effectiveness rates (ICER) were calculated, deterministic sensitivity analysis was performed, and probabilistic budget impact was estimated using: TreeAge Pro Healthcare 2014 software. RESULTS: The iNO option leads to an increase in mean cost of $ 11.7 million Chilean pesos (€15,000) per patient treated, with an ICER compared with the usual care of $23 million pesos (€30,000) in case of death or ECMO avoided. By sensitising the results by incidence, it was found that from 7 cases and upwards treated annually, inhaled nitric oxide is less costly than the transfer to a more complex unit. CONCLUSIONS: From the perspective of a Chilean regional hospital, incorporating inhaled nitric oxide into the management of neonatal respiratory failure is the optimal alternative in most scenarios.

Assessment of the appropriateness of naloxone administration to patients receiving long-term opioid therapy.

BACKGROUND: The most dangerous adverse effect of opioids is respiratory depression. Naloxone is used to reverse this, although in patients receiving long-term opioid therapy it can cause acute opioid withdrawal and opioid-refractory pain. OBJECTIVE: To determine if naloxone is appropriately administered to patients receiving long-term opioid therapy. METHODS: This retrospective case series based on chart reviews systematically identified patients over one year in a district general hospital. All patients aged 18 years or older receiving long-term opioid therapy admitted to medicine, surgery or the high dependency unit who were administered naloxone during their admission were included. RESULTS: A total of 1206 patient drug administration records were reviewed. Sixteen patients receiving long-term opioid therapy were administered naloxone. Twelve of these did not have opioid-induced respiratory depression and four did not have respiratory rate and oxygen saturations documented in the medical notes. All naloxone doses administered were higher than those recommended by national guidelines for this patient group. CONCLUSIONS: No patient receiving long-term opioid therapy who was administered naloxone had evidence of respiratory depression. More thorough assessment and documentation are needed. Verbal and physical stimulation as well as oxygenation should be considered prior to naloxone administration; this should be followed by close observation, hydration, renal function tests and opioid dose review.

Clinical and Economic Impact of Formulary Conversion From Inhaled Flolan to Inhaled Veletri for Refractory Hypoxemia in Critically Ill Patients.

BACKGROUND: Flolan (iFLO) and Veletri (iVEL) are 2 inhaled epoprostenol formulations. There is no published literature comparing these formulations in critically ill patients with refractory hypoxemia. OBJECTIVE: To compare efficacy, safety, and cost outcomes in patients who received either iFLO or iVEL for hypoxic respiratory failure. METHODS: This was a retrospective, single-center analysis of adult, mechanically ventilated patients receiving iFLO or iVEL for improvement in oxygenation. The primary end point was the change in the PaO2/FiO2 ratio after 1 hour of pulmonary vasodilator therapy. Secondary end points assessed were intensive care unit (ICU) length of stay (LOS), hospital LOS, duration of study therapy, duration of mechanical ventilation, mortality, incidence of adverse events, and cost. RESULTS: A total of 104 patients were included (iFLO = 52; iVEL = 52). More iFLO patients had acute respiratory distress syndrome compared with the iVEL group (61.5 vs 34.6%; P = 0.01). There was no difference in the change in the PaO2/FiO2 ratio after 1 hour of therapy (33.04 ± 36.9 vs 31.47 ± 19.92; P = 0.54) in the iFLO and iVEL groups, respectively. Patients who received iVEL had a shorter duration of mechanical ventilation (P < 0.001) and ICU LOS (P < 0.001) but not hospital LOS (P = 0.86) and duration of therapy (P = 0.36). No adverse events were attributed to pulmonary vasodilator therapy, and there was no difference in cost. CONCLUSIONS: We found no difference between iFLO and iVEL when comparing the change in the PaO2/FiO2 ratio, safety, and cost in hypoxic, critically ill patients. There were differences in secondary outcomes, likely a result of differences in underlying indication for inhaled epoprostenol.

Inhaled nitric oxide in term/late preterm neonates with hypoxic respiratory failure: estimating the financial impact of earlier use.

OBJECTIVE: We reported recently that early use of inhaled nitric oxide therapy (iNO) for term and late preterm infants with hypoxic respiratory failure (HRF) at an oxygenation index (OI) of ≥15 and <20 is associated with earlier discharge from the hospital, relative to babies treated at OI ≥25. The objective of the present analysis is to determine whether earlier use of iNO in this cohort leads to lower cost of medical care. METHODS: We used a decision-analytic model, which was developed to compare hospital resource use and costs associated with early versus standard use of iNO in HRF. The model population included infants with moderate HRF caused by primary pulmonary hypertension with an OI ≥15 and <20. A hypothetical case population of 1000 patients was assumed and probabilistic sensitivity analyses were completed where all the clinical inputs into the model were varied. Two deterministic sensitivity analyses were also completed, one surrounding the hospital cost inputs and another surrounding the cost of iNO. RESULTS: Early iNO was associated with fewer hospital days, fewer days of ventilation and fewer hours on extracorporeal membrane oxygenation (ECMO). In probabilistic sensitivity analyses, total costs per patient were $88,518 ± $7574 and $92,581 ± $9664 for early iNO and standard iNO, respectively. The probability of early iNO being cost-effective was approximately 72%, based on a willingness to pay $100,000 or less to prevent ECMO therapy and/or death. In both deterministic sensitivity analyses, early iNO was cost-saving. CONCLUSION: Our analysis shows that early use of iNO at an OI of ≥15 and <20 may be associated with shorter hospitalizations and a decreased cost of care for term/late preterm infants with HRF associated with pulmonary hypertension. Our results are based on clinical data from a single trial; future research using data from real-world practice is warranted.

Use of inhaled nitric oxide in preterm infants.

Nitric oxide, an important signaling molecule with multiple regulatory effects throughout the body, is an important tool for the treatment of full-term and late-preterm infants with persistent pulmonary hypertension of the newborn and hypoxemic respiratory failure. Several randomized controlled trials have evaluated its role in the management of preterm infants ≤ 34 weeks' gestational age with varying results. The purpose of this clinical report is to summarize the existing evidence for the use of inhaled nitric oxide in preterm infants and provide guidance regarding its use in this population.

Development of neonatal respiratory and intensive care: Chinese perspectives.

Recent economic improvements in China have allowed the development of perinatal-neonatal care in sub-provincial regions. However, variations in neonatal respiratory and intensive care exist, especially in regions with limited resources. We conducted a series of collaborative clinical investigations into neonatal hypoxemic respiratory failure (NRF). In the study period from 2004 to 2005, this nationwide study found an incidence of NRF of 13.4% of total admissions to neonatal intensive care units (NICUs), with a mortality of 32%. Fewer than 30% of infants with respiratory distress syndrome (RDS) received surfactant treatment. Most cases of NRF had birth weights (BWs) of 1,000-1,500 g. Approximately 60% of deaths were due to withdrawal of respiratory support because of economic restraints despite initial response to therapy. Extremely low BW or gestational age accounted for less than 2% of all NRF cases, and their survival rate was less than 50%. A prospective clinical epidemiologic study of NRF in 14 NICUs, mainly sub-provincial centers, in Hebei province was undertaken in the study period from 2007 to 2008. NRF made up 16.9% of total NICU admissions, with increased use of surfactant (>50%) and continuous positive airway pressure (>80%) in this study. However, mortality due to RDS, meconium aspiration syndrome and pulmonary infection/sepsis remained higher than 30%, in part affected by socioeconomic factors. With measures to assist hospitalized neonates from low income families in urban areas, as well as the 'new rural cooperative health care program' to subsidize families from rural areas, the quality and affordability of NICU services may be improved in the forthcoming years.

The INNOVO multicentre randomised controlled trial: neonatal ventilation with inhaled nitric oxide versus ventilatory support without nitric oxide for severe respiratory failure in preterm infants: follow up at 4-5 years.

BACKGROUND: Trials of inhaled nitric oxide (iNO) used short term in preterm infants with severe respiratory failure have to date shown no evidence of benefit, and there have been no trials reporting follow-up to 4 years of age. The INNOVO trial recruited 108 infants (55 iNO arm and 53 controls) from 15 neonatal units. By 1 year of age 59% had died, and 84% of the survivors had signs of impairment or disability. OBJECTIVE: This paper reports the long-term clinical effectiveness and costs of adding NO to the ventilator gases of preterm infants with severe respiratory failure. PATIENTS AND METHODS: Children were assessed at age 4-5 years by interview, examination, cognitive and behavioural assessments. The outcome data were divided into seven domains and were described as normal, impaired or disabled (mild, moderate or severe) by the degree of functional loss. RESULTS: 38 of the 43 survivors had follow-up assessments. In the iNO group 62% (34/55) had died or were severely disabled, compared to 70% (37/53) in the no iNO group (RR 0.89, 95% CI 0.67 to 1.16). There was no evidence of difference in the levels of impairment or disability between the two groups in any of the domains studied, or of cost differences, amongst the survivors. CONCLUSION: For this group of babies with severe respiratory failure there was no evidence of difference in the longer-term outcome between those babies allocated to iNO and those who were allocated to no iNO. The challenge is to identify those premature babies who are able to respond to NO with clinically important health improvements. TRIAL REGISTRATION NUMBER: 17821339.

A 5-year survey of nitric oxide use in a pediatric intensive care unit.

The authors retrospectively reviewed their experience with nitric oxide (NO) in a pediatric ICU. Given its cost ($3000/d), ongoing evaluations are required to ensure its effective use and avoid inappropriate applications. NO use included 4 categories: (1) hypoxemic respiratory failure, (2) pulmonary hypertension following surgery for congenital heart disease (CHD), (3) intraoperatively for surgical procedures such BT shunt placement or 1-lung ventilation, and (4) during ECMO. In the 19 patients with respiratory failure, NO resulted in an increase in oxygenation in 15 of 19 patients (Pao2/Fio2 ratio increased from 83 +/- 60 mm Hg to 188 +/- 105 mm Hg, P = 0.0007). In 4 patients, NO did not improve oxygenation. The 15 patients that responded to NO survived, whereas the 4 patients who did not respond died (P = 0.0003). NO was used to treat pulmonary hypertension in 19 patients following cardiopulmonary bypass (CPB) and surgery for CHD. In 13 of 19 patients, a high pulmonary artery (PA) pressure was documented by direct measurement with a needle inserted into the PA while the chest was open (n = 9) or a postoperative transthoracic PA catheter (n = 4). NO resulted in a decrease in the PA pressure in 9 of 13 patients (37 +/- 5 mm Hg to 21 +/- 3 mm Hg, P < 0.0001). In the one patient in whom NO did not lower intraoperative PA pressure, it was not possible to wean from CPB. For the 10 patients in whom NO was started in the PICU, 4 had PA catheters in place and documented elevated PA pressure. NO resulted in a significant decrease in the PA pressure in only 1 of these 4 patients. The survival of responders was 9 of 9 versus 1 of 4 for nonresponders (P = 0.014). No significant adverse effects requiring therapy other than decreasing the inhaled NO concentration were noted. Potential interventions and practices to limit the unwarranted use of this costly agent are discussed.