Respiratory depressant effects of fentanyl analogs are opioid receptor-mediated.

Opioid-related fatalities involving synthetic opioids have reached unprecedented levels. This study evaluated the respiratory depressant effects of seven fentanyl analogs that have either emerged in the illicit drug supply or been identified in toxicological analyses following fatal or non-fatal intoxications. Adult male Swiss Webster mice were administered fentanyl analogs (isobutyrylfentanyl, crotonylfentanyl, para-methoxyfentanyl, para-methoxybutyrylfentanyl, 3-furanylfentanyl, thiophenefentanyl, and benzodioxolefentanyl) and their effects on minute volume as compared to mu-opioid receptor (MOR) agonist standards (fentanyl, morphine, and buprenorphine) were measured using whole body plethysmography (WBP). All drugs elicited significant (p ≤ 0.05) hypoventilation relative to vehicle for at least one dose tested: morphine (1, 3.2, 10, 32 mg/kg), buprenorphine, (0.032, 0.1, 0.32, 1, 3.2 mg/kg), fentanyl (0.0032, 0.01, 0.032, 0.1, 1, 32 mg/kg), isobutyrylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), crotonylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxyfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), para-methoxybutyrylfentanyl (0.32, 1, 3.2, 10 mg/kg), 3-furanylfentanyl (0.1, 0.32, 1, 3.2, 10 mg/kg), thiophenefentanyl (1, 3.2, 10, 32, 100 mg/kg), and benzodioxolefentanyl (3.2, 10, 32, 100 mg/kg). The ED50 values for hypoventilation showed a rank order of potency as follows: fentanyl (ED50 = 0.96 mg/kg) > 3-furanylfentanyl (ED50 = 2.60 mg/kg) > crotonylfentanyl (ED50 = 2.72 mg/kg) > para-methoxyfentanyl (ED50 = 3.31 mg/kg) > buprenorphine (ED50 = 10.8 mg/kg) > isobutyrylfentanyl (ED50 = 13.5 mg/kg) > para-methoxybutyrylfentanyl (ED50 = 16.1 mg/kg) > thiophenefentanyl (ED50 = 18.0 mg/kg) > morphine (ED50 = 55.3 mg/kg) > benzodioxolefentanyl (ED50 = 10,168 mg/kg). A naloxone pretreatment (10 mg/kg) attenuated the hypoventilatory effects of all drugs. These results establish that the respiratory depressant effects of these fentanyl analogs are at least in part mediated by the MOR.

Integrated pulmonary index can predict respiratory compromise in high-risk patients in the post-anesthesia care unit: a prospective, observational study.

BACKGROUND: Respiratory compromise (RC) including hypoxia and hypoventilation is likely to be missed in the postoperative period. Integrated pulmonary index (IPI) is a comprehensive respiratory parameter evaluating ventilation and oxygenation. It is calculated from four parameters: end-tidal carbon dioxide, respiratory rate, oxygen saturation measured by pulse oximetry (SpO2), and pulse rate. We hypothesized that IPI monitoring can help predict the occurrence of RC in patients at high-risk of hypoventilation in post-anesthesia care units (PACUs). METHODS: This prospective observational study was conducted in two centers and included older adults (≥ 75-year-old) or obese (body mass index ≥ 28) patients who were at high-risk of hypoventilation. Monitoring was started on admission to the PACU after elective surgery under general anesthesia. We investigated the onset of RC defined as respiratory events with prolonged stay in the PACU or transfer to the intensive care units; airway narrowing, hypoxemia, hypercapnia, wheezing, apnea, and any other events that were judged to require interventions. We evaluated the relationship between several initial parameters in the PACU and the occurrence of RC. Additionally, we analyzed the relationship between IPI fluctuation during PACU stay and the occurrences of RC using individual standard deviations of the IPI every five minutes (IPI-SDs). RESULTS: In total, 288 patients were included (199 elderly, 66 obese, and 23 elderly and obese). Among them, 18 patients (6.3 %) developed RC. The initial IPI and SpO2 values in the PACU in the RC group were significantly lower than those in the non-RC group (6.7 ± 2.5 vs. 9.0 ± 1.3, p < 0.001 and 95.9 ± 4.2 % vs. 98.3 ± 1.9 %, p = 0.040, respectively). We used the area under the receiver operating characteristic curves (AUC) to evaluate their ability to predict RC. The AUCs of the IPI and SpO2 were 0.80 (0.69-0.91) and 0.64 (0.48-0.80), respectively. The IPI-SD, evaluating fluctuation, was significantly greater in the RC group than in the non-RC group (1.47 ± 0.74 vs. 0.93 ± 0.74, p = 0.002). CONCLUSIONS: Our study showed that low value of the initial IPI and the fluctuating IPI after admission to the PACU predict the occurrence of RC. The IPI might be useful for respiratory monitoring in PACUs and ICUs after general anesthesia.

Evaluation of transcutaneous carbon dioxide and saturation monitoring during fiberoptic bronchoscopy.

INTRODUCTION: The aim of the study was to assess the effects of interventions during bronchoscopy on ventilation and determine the risk factors for hypoventilation related to both interventions and patients' demographical and clinical characteristics. MATERIALS AND METHODS: A total of 74 patients who underwent fiberoptic bronchoscopy (FOB) were included in the study. Oxygen saturation (SpO2) and partial carbon dioxide pressure (PCO2) were measured transcutaneously (TcSO2 and TcPCO2) using a sensor consisting of a probe placed on the earlobe. The demographic characteristics and basal, mean, peak and minimum values of TcSO2 and TcPCO2 during FOB were retrospectively analyzed and assessed in terms of the risk factors for hypoventilation. RESULT: During the procedure, the device automatically recorded the TcSO2 and TcPCO2 values. The mean TcPCO2 level was 37.09 ± 5.6 (27.1-60.6) mmHg. The mean increase in the TcPCO2 level from baseline was 3.25 ± 2.12 mmHg. The mean TcSO2 measurement was 95.9 ± 2.27 (80-100%). The measured mean and peak TcPCO2 values were significantly higher in men. In the whole group, the patients with a history of smoking more than 20 packyears also had significantly higher TcPCO2 values compared to the nonsmokers and light smokers. In the patients with endobronchial lesions, the decrease in the TcSO2 level was higher during FOB (p= 0.03), and the mean difference between the lowest and mean TcSO2 levels was significantly greater (6.2 vs 4.55%, p= 0.03). CONCLUSIONS: Changes in ventilation during FOB have multifactorial causes. The best indicator of ventilation is PCO2, and monitorization of PCO2 is very important in detecting hypoventilation. In this study, we determined some risk factors for hypoventilation in order to predict ventilation problems in patients planned to undergo FOB. We recommend that in male patients with endobronchial lesions, those with a longer smoking history, and those with a longer duration of FOB, SpO2 should be monitored together with PCO2.

Sedation for gastrointestinal endoscopy in Australia: what is the same and what is different?

PURPOSE OF REVIEW: The purpose of this article is to review the practice of sedation for adults having gastrointestinal endoscopy in Australia and to compare it with practice in other countries. RECENT FINDINGS: The practice of sedation for endoscopy in Australia is dominated by anaesthesiologists, who have a preference for deep propofol-based sedation. The recent literature includes a number of guidelines for sedation developed by multidisciplinary groups, anaesthesiologists and gastroenterologists in Australia and other countries. The appropriate health practitioner to provide deep sedation and general anaesthesia, to use propofol for sedation and to manage higher risk patients remains controversial. The estimated risks associated with endoscopy vary by provider, sedation technique and study design (prospective or retrospective, single- or multicentre). New airway management techniques are being investigated that may be useful in patients at high risk of hypoventilation and hypoxia. SUMMARY: Endoscopy sedation is safe but more high-quality, multicentre observer-blinded randomized controlled trials are required.

Respiratory Volume Monitoring Reduces Hypoventilation and Apnea in Subjects Undergoing Procedural Sedation.

INTRODUCTION: The use of monitored anesthesia care for endoscopic procedures increases the risk of respiratory depression, necessitating careful monitoring of patient ventilation. We examined the effectiveness of an impedance-based respiratory volume monitor (RVM) in improving the safety of patients undergoing upper and lower gastrointestinal endoscopies under total intravenous anesthesia. We hypothesized that feedback from the RVM would allow anesthesiologists to maintain adequate ventilation, which would reduce the duration of respiratory depression (ie, hypoventilation and apnea) compared to a blinded control group. METHODS: Sixty-five subjects were enrolled in a randomized controlled trial and monitored with a noninvasive impedance-based RVM, which displayed respiratory traces and calculated expiratory minute ventilation (V̇E), tidal volume (VT), and breathing frequency (f) measurements. Prior to induction of anesthesia, a baseline V̇E measurement (V̇E-baseline) was taken as a measurement of normal breathing. V̇E was monitored throughout the procedure for signs of hypoventilation and apnea. Hypoventilation was defined as V̇E < 40% V̇E-baseline, and apneas were defined as V̇E = 0 for > 15 s. RESULTS: Sixty-five subjects were randomly assigned to either a control (n = 38) or RVM intervention group (n = 27). Subjects in the intervention group had a higher V̇E% for the entire procedure (P = .045), as well as the third and fourth quartile of the procedure compared to the control group (P = .01). Likewise, subjects in the RVM intervention group spent significantly less time below 40% V̇E-baseline compared to the control group throughout the entire procedure (12 ± 15% vs 32 ± 24%, respectively) (P < .001). The median number of apneas per subject was greater in the control group (median 2, interquartile range 1-2, maximum 4) compared to the RVM intervention group (median 1, interquartile range 1-2, maximum 3) (P = .037). CONCLUSIONS: The control group had a higher incidence of hypoventilation and apnea compared to the RVM intervention group. Respiratory monitoring using the RVM can potentially be a useful tool for identifying early signs of respiratory depression and for titrating anesthetics to maintain adequate ventilation while minimizing patient risk.

Safety of unsedated PEG placement using transoral ultrathin endoscopy in patients with amyotrophic lateral sclerosis.

BACKGROUND AND AIMS: In patients with amyotrophic lateral sclerosis (ALS), percutaneous endoscopic gastrostomy (PEG) placement under sedation often causes apnea or hypoventilation. The aim of the present study was to assess whether unsedated PEG placement in ALS patients using ultrathin endoscopy (UTE) via the transoral route can improve safety. METHODS: Between 2003 and 2013, PEG placement was identified and reviewed in 45 patients with ALS. PEG was performed in 14 patients using transoral UTE without sedation (UTE group), 17 patients using conventional normal-diameter esophagogastroduodenoscopy (C-EGD) without sedation (unsedated C-EGD group) and 14 patients using C-EGD with sedation (sedated C-EGD group). We compared the clinical features, cardiopulmonary data before and during PEG placement, and complications related to PEG placement among the three groups. RESULTS: There were no significant differences in age, male/female ratio, forced vital capacity, blood pressure, oxygen saturation before and during PEG, or major complications among the three groups. No minor complications were observed in the UTE group, whereas apnea and/or hypoventilation were observed in the sedated C-EGD group and aspiration pneumonia was observed in the unsedated C-EGD group. CONCLUSIONS: Unsedated PEG placement using transoral UTE in ALS patients is a safe method.

Understanding Heroin Overdose: A Study of the Acute Respiratory Depressant Effects of Injected Pharmaceutical Heroin.

Opioids are respiratory depressants and heroin/opioid overdose is a major contributor to the excess mortality of heroin addicts. The individual and situational variability of respiratory depression caused by intravenous heroin is poorly understood. This study used advanced respiratory monitoring to follow the time course and severity of acute opioid-induced respiratory depression. 10 patients (9/10 with chronic airflow obstruction) undergoing supervised injectable opioid treatment for heroin addiction received their usual prescribed dose of injectable opioid (diamorphine or methadone) (IOT), and their usual prescribed dose of oral opioid (methadone or sustained release oral morphine) after 30 minutes. The main outcome measures were pulse oximetry (SpO2%), end-tidal CO2% (ETCO2%) and neural respiratory drive (NRD) (quantified using parasternal intercostal muscle electromyography). Significant respiratory depression was defined as absence of inspiratory airflow >10s, SpO2% < 90% for >10s and ETCO2% per breath >6.5%. Increases in ETCO2% indicated significant respiratory depression following IOT in 8/10 patients at 30 minutes. In contrast, SpO2% indicated significant respiratory depression in only 4/10 patients, with small absolute changes in SpO2% at 30 minutes. A decline in NRD from baseline to 30 minutes post IOT was also observed, but was not statistically significant. Baseline NRD and opioid-induced drop in SpO2% were inversely related. We conclude that significant acute respiratory depression is commonly induced by opioid drugs prescribed to treat opioid addiction. Hypoventilation is reliably detected by capnography, but not by SpO2% alone. Chronic suppression of NRD in the presence of underlying lung disease may be a risk factor for acute opioid-induced respiratory depression.

A randomized controlled trial of capnography during sedation in a pediatric emergency setting.

OBJECTIVE: Data suggest that capnography is a more sensitive measure of ventilation than standard modalities and detects respiratory depression before hypoxemia occurs. We sought to determine if adding capnography to standard monitoring during sedation of children increased the frequency of interventions for hypoventilation, and whether these interventions would decrease the frequency of oxygen desaturations. METHODS: We enrolled 154 children receiving procedural sedation in a pediatric emergency department. All subjects received standard monitoring and capnography, but were randomized to whether staff could view the capnography monitor (intervention) or were blinded to it (controls). Primary outcome were the rate of interventions provided by staff for hypoventilation and the rate of oxygen desaturation less than 95%. RESULTS: Seventy-seven children were randomized to each group. Forty-five percent had at least 1 episode of hypoventilation. The rate of hypoventilation per minute was significantly higher among controls (7.1% vs 1.0%, P = .008). There were significantly fewer interventions in the intervention group than in the control group (odds ratio, 0.25; 95% confidence interval [CI], 0.13-0.50). Interventions were more likely to occur contemporaneously with hypoventilation in the intervention group (2.26; 95% CI, 1.34-3.81). Interventions not in time with hypoventilation were associated with higher odds of oxygen desaturation less than 95% (odds ratio, 5.31; 95% CI, 2.76-10.22). CONCLUSION: Hypoventilation is common during sedation of pediatric emergency department patients. This can be difficult to detect by current monitoring methods other than capnography. Providers with access to capnography provided fewer but more timely interventions for hypoventilation. This led to fewer episodes of hypoventilation and of oxygen desaturation.

The effect of ketamine on hypoventilation during deep sedation with midazolam and propofol: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Hypoventilation is a major cause of morbidity and mortality in patients having procedures under sedation. Few clinical strategies have been evaluated to reduce intraoperative hypoventilation during surgical procedures under deep sedation. OBJECTIVE: The primary objective of this investigation was to examine the effect of ketamine on hypoventilation in patients receiving deep sedation for surgery with midazolam and propofol. DESIGN: The study was a randomised, placebo-controlled, double-blind clinical trial. SETTING: Intraoperative. PATIENTS: Healthy women undergoing breast surgery. INTERVENTION: Randomised to receive ketamine (0.5 mg kg bolus, followed by an infusion of 1.5 µg kg min) or isotonic saline. MAIN OUTCOME MEASURE: Duration of hypercapnia measured continuously with a transcutaneous carbon dioxide (TCO2) monitor. RESULTS: Fifty-four participants were recruited. Patient and surgical characteristics were similar between the study groups. The median percentage of the sedation time with TCO2 more than 6.7 kPa in participants in the ketamine group, 1.2% (95% confidence interval, CI, 0 to 83), was less than that in the isotonic saline group (65%, 95% CI, 0 to 88; P = 0.01). Severe hypoventilation (TCO2 >8.0 kPa) was also less in the ketamine group, median 0% (95% CI, 0 to 11.7) compared with 28% (95% CI, 0 to 79.3; P = 0.0002) for the isotonic saline group. The ketamine group required less airway manoeuvres (chin lift) to keep the SaO2 greater than 95% median (95% CI) [0 (0 to 3) compared with 3 (0 to 16) in the isotonic saline group] (P = 0.004). CONCLUSION: Ketamine decreased the duration and severity of hypercapnia in patients undergoing deep sedation with propofol. The addition of ketamine may reduce hypoventilation and adverse effects in patients having procedures under sedation. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01535976.

Clinical review: long-term noninvasive ventilation.

Noninvasive positive ventilation has undergone a remarkable evolution over the past decades and is assuming an important role in the management of both acute and chronic respiratory failure. Long-term ventilatory support should be considered a standard of care to treat selected patients following an intensive care unit (ICU) stay. In this setting, appropriate use of noninvasive ventilation can be expected to improve patient outcomes, reduce ICU admission, enhance patient comfort, and increase the efficiency of health care resource utilization. Current literature indicates that noninvasive ventilation improves and stabilizes the clinical course of many patients with chronic ventilatory failure. Noninvasive ventilation also permits long-term mechanical ventilation to be an acceptable option for patients who otherwise would not have been treated if tracheostomy were the only alternative. Nevertheless, these results appear to be better in patients with neuromuscular/-parietal disorders than in chronic obstructive pulmonary disease. This clinical review will address the use of noninvasive ventilation (not including continuous positive airway pressure) mainly in diseases responsible for chronic hypoventilation (that is, restrictive disorders, including neuromuscular disease and lung disease) and incidentally in others such as obstructive sleep apnea or problems of central drive.

Programa de asistencia ventilatoria no invasiva en atención primaria de salud: normas técnicas / Noninvasive ventilatory support progam in primary health care: technical standards

En el presente documento se incluye la Normativa Técnica diseñada para la ejecución de un Programa Nacional de Asistencia Ventilatoria no Invasiva Domiciliaria en niños con hipoventilación crónica nocturna. Se proponen las soluciones para que los requerimientos de estos niños sean cubiertos transfiriendo tecnología, prestaciones derivadas y también la capacitación y supervisión necesaria en sus domicilios, por equipos regionales especializados de profesionales de la Atención Primaria de Salud (modalidad 1), o por un diseño de externalización de servicios equivalentes y con una estrategia similar a la utilizada en otros Programas Nacionales (modalidad 2).

Cardiac tamponade complicating postpericardiotomy syndrome.

We present 2 children who developed postpericardiotomy syndrome (PPS) and the rare complication of cardiac tamponade after cardiac surgery, each requiring life-saving pericardiocentesis in the emergency department (ED). Each child presented with vomiting as a chief complaint, an initial sign that has not been reported previously. As the frequency of orthotopic heart transplants and other cardiac surgeries among children increases, it is likely that ED physicians will encounter PPS and cardiac tamponade with greater frequency, and it is imperative that it be recognized promptly and treated appropriately. We review PPS, cardiac tamponade, and the proper performance of a pericardiocentesis.

Uso de máscara laríngea en fibrobroncoscopía / Use of laryngeal mask in fiberoptic bronchoscopy

La eficacia del uso de la máscara laríngea en la realización de fibrobroncoscopías fue evaluada en cien procedimientos endoscópicos diagnósticos efectuados en pacientes ambulatorios. El procedimiento fue realizado con anestesia general intravenosa con fentanilo y propofol, ventilándose a los pacientes en forma asistida con oxígeno al 100 por ciento. La eficacia de la ventilación pulmonar fue evaluada a través del registro de la oxicapnometría medida en forma continua durante todo el acto endoscópico. Durante éste, todos los pacientes presentaron una SaO2 promedio del 98 por ciento y una capnometría media de 37 mmHg (rango entre 33 y 45) registrada en los intervalos libres de aspiración endoscópica. La posición de la máscara laríngea fue evaluada a través de la clasificación endoscópica de Brimacombe. El 94 por ciento de los pacientes presentó una óptima visualización endoscópica de la laringe y las cuerdas vocales (grados 4 y 3 de la clasificación), que permitió una excelente evaluación funcional de las mismas. En el 6 por ciento restante se produjo una interposición parcial de la epiglotis anterior (grado 2 de la clasificación), la cual no impidió, sin embargo, la visualización de las cuerdas luego de eludir la epiglotis con el endoscopio. El análisis del score Mallampati de los pacientes fue registrado y correlacionado con la posición final de la máscara laríngea, evaluada endoscópicamente con la clasificación de Brimacombe, con el fin de determinar la eficacia de la técnica en los pacientes con vía aérea dificultosa. Dicho análisis permite sugerir una dificultad creciente en la colocación de la máscara laríngea así como una disminución en la calidad de su posición y, consecuentemente, de la visualización endoscópica de la laringe, a medida que aumenta el score Mallampati de los pacientes. Sin embargo, el escaso número de éstos con score Mallampati elevado en nuestra muestra de pacientes no nos permite arribar a una conclusión definitiva al respecto. Creemos que el uso de la máscara laríngea para la ejecución de fibrobroncoscopías es un método seguro y eficaz que permite una ventilación adecuada de los pacientes a la vez que ofrece a los endoscopistas una excelente visualización y evaluación funcional de las cuerdas vocales y demás estructuras de la vía aérea superior.

A randomized, controlled trial of transcutaneous carbon dioxide monitoring during ERCP.

BACKGROUND: Pulse oximetry, used to monitor oxygen saturation during endoscopy, does not directly measure hypoventilation. Study goals were to determine whether transcutaneous carbon dioxide (PtcCO(2)) monitoring during endoscopic retrograde cholangiopancreatography (ERCP) prevents severe hypoventilation and to assess the accuracy of clinical observation and pulse oximetry in detecting hypoventilation. METHODS: All patients received intensive clinical and electronic monitoring including pulse oximetry. Supplemental oxygen was administered for pulse oximetry < 90%. Patients were randomized to a treatment arm (group 1) where PtcCO(2) monitoring guided sedation or a control arm (group 2) where PtcCO(2) was recorded but unavailable for guiding sedation. RESULTS: Group 1 had significantly fewer episodes of severe carbon dioxide retention (rise in PtcCO(2) >/=40 mm Hg above baseline) than group 2 (0 of 199 versus 5 of 196, respectively, p = 0.03), as well a shorter mean duration of procedure discomfort (8.3% of procedure duration rated as "uncomfortable" versus 11.5%, p = 0.04). Correlations between clinical observation and objective measures of ventilation were poor: level of sedation versus PtcCO(2) (R = 0.3) or pulse oximetry (R = 0.06); slowest respiratory rate versus PtcCO(2) (R = 0.4) or pulse oximetry (R = -0.4). PtcCO(2) rises of greater than 20 mm Hg occurred without oxygen desaturation in 10.7% of patients receiving supplemental oxygen. CONCLUSIONS: Carbon dioxide retention during ERCP is not reliably detected by clinical observation or by pulse oximetry in patients receiving supplemental oxygen. The addition of PtcCO(2) monitoring prevents severe carbon dioxide retention more effectively than intensive clinical monitoring and pulse oximetry alone. The clinical relevancy of this observation needs to be determined in an appropriately designed outcome study.

Ketamine antagonises alfentanil-induced hypoventilation in healthy male volunteers.

BACKGROUND: The effects of ketamine on respiration, alone, or in combination with opioids, have not been completely clarified. Both stimulant and depressant effects have been reported, as well as attenuation of opioid-induced hypoventilation at the expense of increased oxygen consumption. These conflicting results might partly be due to dose-dependent mechanisms. We have, therefore, determined the ventilatory effects of ketamine, in combination with alfentanil, using infusions to different pseudo steady-state concentrations. METHODS: On two separate days, eight healthy male volunteers were given alfentanil as a continuous computer-controlled infusion, aiming at a plasma concentration of 50 ng x mL(-1). After reaching apparent steady-state for alfentanil, racemic ketamine or placebo was administered in a protocol randomised for the two days. On the ketamine days a computer-controlled infusion, aiming for escalating ketamine plasma concentrations of 50, 100 and 200 ng x mL(-1), was added to the alfentanil infusion. On the placebo days saline was added. Using a face-mask with an occlusion valve, respiratory parameters were measured during air-breathing and after 6 repetitive 30-s CO2 challenges. RESULTS: The alfentanil infusion induced hypoventilation by decreasing respiratory rate, while tidal volume and respiratory drive were unaffected. This hypoventilation was antagonised by ketamine in a concentration-dependent manner mainly through an increase in respiratory rate. The CO2 response was not affected by alfentanil or ketamine. CONCLUSION: In the dose range of interest for postoperative, intensive-care and pain-clinic settings, ketamine antagonises the resting hypoventilation induced by alfentanil.