Pain assessment and management is a fundamental part of nursing care. Opioids are 1 of the interventions utilized to manage pain within the hospital setting and have a known adverse effect called opioid-induced sedation and respiratory depression (OSRD). The purpose of this quantitative study was to create a prediction model with the known risk factors present on admission, to determine how well they predict OSRD. This served as a first step in the creation of a risk screen tool, supported by the cognitive continuum theory, in understanding the judgment and decision-making process to provide safe care. The combination of factors that most accurately predicted the risk of OSRD in patients on admission to an acute care healthcare institution was determined through a retrospective case control analysis. Risk factors present on admission of a case group of 100 patients who had succumbed to OSRD after an opioid administration were matched and compared to a control group of 100 who did not. A binary logistic regression analysis was used to determine how well age, body mass index, obstructive sleep apnea, pulmonary disease, respiratory disease, renal failure, and no opioid use (i.e., being opioid na�ve) predicted OSRD. The presence of pulmonary disease, renal disease, cardiac disease, diabetes, and being opioid na�ve most accurately predicted OSRD. Although only pulmonary disease and renal disease were statistically significant, the final model included other factors that increase the odds of OSRD, which are encompassed in the proposed tool for future research. Through understanding the factors that predict OSRD, a screening tool was created that could save lives in hospital institutions and lead to positive social change by supporting clinical decision making and care.

La douleur est un enjeu majeur de santé publique. Les prescriptions, et par voie de conséquence les intoxications au tramadol ont explosé récemment. Cet opioïde atypique présente des effets adverses variés, incluant dépression respiratoire, convulsions et syndrome sérotoninergique. Nos travaux chez le rat nous ont permis de montrer que la toxicité respiratoire induite par le tramadol était modérée mais aggravée en cas de co-administration de diazépam. Concernant les convulsions, celles-ci apparaissaient rapidement, étaient généralisées et accompagnées d’un état de mal épileptique. Ces convulsions n’étaient pas liées au syndrome sérotoninergique puis qu’indépendantes de la sérotonine. Nous avons suggéré à l’origine des convulsions induites par le tramadol, une modulation allostérique par cet opioïde des récepteurs GABAA entraînant probablement leur inhibition. Enfin, le syndrome sérotoninergique induit par le tramadol était caractérisé par des manifestations cliniques typiques accompagnées d’une encéphalopathie modérée à l’EEG. Nos résultats suggéraient aussi la nécessité d’une approche EEG systématique en complément des observations cliniques pour un diagnostic plus juste du syndrome sérotoninergique d’origine toxique. Pour reverser la toxicité neuro-respiratoire du tramadol, l’association diazépam/naloxone semblait être le traitement le plus efficace à proposer, abolissant les convulsions électro-cliniques, réduisant significativement les effets respiratoires délétères et faisant disparaître les signes sérotoninergiques. KGNOP1, un hybride bifonctionnel opioïde/anti-nociceptine, proposé comme alternative au tramadol pour traiter les douleurs neuropathique et par excès de nociception, présentait une efficacité et une sécurité d’emploi meilleures que le tramadol et la morphine, malgré des effets respiratoires délétères importants. En revanche, une tolérance rapide à ses effets analgésiques pourrait questionner son utilisation chez l’homme / Pain is a major public health issue. Tramadol prescriptions and their consequent poisonings have increased recently. This atypical opioid has various adverse effects including respiratory depression, seizures and serotonin syndrome. In our rat study, we demonstrated that tramadol-induced respiratory toxicity was moderate and worsened by diazepam co-administration. Tramadol-induced seizures were of rapid onset, generalized and accompanied by status epilepticus. Seizures were not related to serotonin syndrome since not induced by serotonin. We suggested tramadol-induced allosteric modulation of GABAA receptors resulting in its inhibition to explain tramadol-attributed seizures. Finally, tramadol-induced serotonin syndrome was responsible for well-characterized clinical symptoms accompanied by mild encephalopathy on the EEG. Interestingly, our results suggested that EEG study was required for an accurate diagnosis of serotonin syndrome in addition to the clinical observations. In order to treat tramadol-induced toxicity, diazepam/naloxone combination appears to be the best treatment to abolish tramadol-induced electro-clinic seizures, to reduce its deleterious respiratory effects, and to reverse its serotonin toxicity. KGNOP1, a bi-functional opioid/anti-nociceptin hybrid suggested as alternative compound to tramadol in the treatment of neuropathic and nociceptive pains, showed advantages with improved efficacy and safety in comparison to tramadol and morphine, despite important deleterious respiratory effects. However, the onset of rapid tolerance to its analgesic effects questioned the possible administration of this hybrid to humans

Background: Opioid-induced respiratory depression (OIRD) is a life-threatening complication of opioid analgesia. Failure to recognize and respond to OIRD may result in respiratory arrest, anoxic brain injury, and death. Measuring end-tidal carbon dioxide through the use of capnography has been shown to detect early signs of OIRD. Early detection of OIRD facilitates the timely rescue of patients on medical-surgical units where critical patient events are less likely to be witnessed. Purpose: The goal of this quality improvement project was to enhance patient safety by decreasing the incidence of OIRD. The aim was to design, implement, and evaluate a multifaceted intervention to improve patient monitoring for OIRD on medical-surgical units through the use of capnography. The intervention included an updated nursing protocol, an electronic order trigger, improved access to capnography monitors, and education to nurses about OIRD and the use of capnography. Methods: The project was conducted over twelve months on ten medical-surgical units at a 489-bed academic medical center in Southern Arizona. Outcomes were measured using pre- and post-intervention point prevalence surveys. Indicators included the number of patients being monitored with capnography and the number of cases of OIRD. A survey of medical-surgical RNs was also conducted to gather their perceptions on the ease of use and effectiveness of capnography. Results: Twelve months after introducing the intervention, there was a statistically significant increase in monitoring frequency, with 2.56 times more patients at high risk for OIRD being monitored with capnography than at baseline (p = .006). Of the 167 RNs surveyed during this project, 99% perceived the portable capnography monitors as easy to use and interpret. However, 71% reported systems issues in obtaining the monitoring equipment, and 65% reported problems with patient adherence. Preliminary data suggest that the incidence of OIRD decreased after one year, although not by a statistically significant amount (p = .876). Implications for Practice: The intervention succeeded in increasing the number of high-risk patients being monitored with capnography, though the increased monitoring did not improve patient outcomes. The RN survey highlighted areas in need of further improvement, such as the supply of monitors and patient education.

A tese desenvolvida neste estudo é que a depressão respiratória em pacientes queimados que utilizam opiódes como terapeutica farmacológica da dor, pode ser prevenida por meio de ações de enfermagem que identifiquem os fatores predisponentes para a depressão respiratória, que considerem na rotina de aprazamento da terapeutica farmacológica da dor, as características farmacológicas dos medicamentos, para evitar interações medicamentosas e que monitorem adequadamente o paciente queimado para identificar precocemente sinais de depressão respiratória. Para tanto, este estudo teve como objetivo desenvolver barreiras de segurança com foco em ações de enfermagem, para prevenção de depressão respiratória em pacientes queimados em uso de opióides. Trata-se de um estudo restrospectivo, em que foram analisados 272 prontuários de pacientes queimados internados em um Centro de Tratamento de Queimados (CTQ), de um hospital público federal de grande porte, no município do Rio de Janeiro. nos anos de 2011 a 2013. Dentre os 272 prontuários 42 atenderam os critérios de seleção da pesquisa, e destes, em 28,58% (n=12) foi identificada a ocorrência de depressão respiratória. Predominaram pacientes adultos jovens do sexo masculino. O óbito predominou no grupo com DR, assim como, queimaduras de 2 e 3 graus, e superfície corporal queimada com mediana de 50%. Os fatores predominantes para depressão respiratória foram insuficiencia renal, hipoalbuminemia e hipertensão arterial. Na terapia medicamentosa dos pacientes queimados, os analgésicos opióides são os mais utilizados, predominando o tramadol (45,49%) e a metadona (18,45%). Diazepam é o benzodiazepínico de escolha, entre os antidepressivos a imipramina é o mais utilizado, apesar de classificada como anticonvulsivantes a gabapentina, nos queimados é utilizada em dose analgésica. Tanto no grupo de pacientes com ou sem DR, os horários de adiministração de medicamentos que predominaram foram 22h e 06h. Foi evidenciado PIM em 66,6% dos pacientes estudados. A associação entre a ocorrência de PIM e a DR demonstrou-se positiva; os pacientes com que apresentaram PIM têm 2,5 vezes mais risco de apresentar DR. Os pares de medicamentos prevalentes e que apresentaram PIM no grupo com DR foram, metadona com diazepam (n=5), tramadol com fentanil (4), metadona com impramina e metadona com tramadol (n=3). No grupo sem DR foram metadona e tramadol (n=8), tramadol com fentanil (4), e metadona com diazepam (3). As vias oral e intravenosa predominaram nos pacientes com e sem DR, e não houve associação positiva entre a administração por essas vias e a oorrência de DR, constatando-se que a via de administração não é tão relevante para a DR. Nos pacientes com DR, 83,3% apresentaram PIM, principalmente nos horários 22h e 06h, horários próximos aos de ocorrência de DR. Espera-se que este estudo contribua para a segurança medicamentosa no uso de opióides, e na prevenção do eventos adverso grave como a depressão respiratória em pacientes queimados. / The thesis developed in this study considers that the respiratory depression (RD) in burned patients using opioids as pharmacological therapeutic for pain can be prevented through nursing actions that identify its predisposing factors; also, nurses should consider the pharmacological characteristics of drugs during the routine schedule to apply pharmacological therapeutic for pain, aiming to prevent drug interactions; and adequately they should monitor the burned patient to identify early signs of respiratory depression. Therefore, this study had as general objective to develop safety barriers with a focus on nursing actions to prevent respiratory depression in burned patients in use of opioids; those barriers were related to the pharmacology of opioids, to the predisposing factors for respiratory depression by opioid, and to the monitoring of respiratory depression. This is a retrospective study that analyzed 272 medical records of burned patients admitted into a Burn Treatment Center (BTC) of large federal public hospital in the city of Rio de Janeiro, Brazil, from 2011 to 2013. Among those records, 42 records met the selection criteria of this research; and the occurrence of respiratory depression was identified in 28.58% (n=12) of them. Young adult male patients were prevalent. The death predominated in the group with RD, as well as, in the group with burns of 2nd and 3rd degrees and about 50% burned body surface. The prevalent factors for respiratory depression were renal failure, hypoalbuminemia, and high blood pressure. In drug therapy of burn patients, opioid analgesics are the most used, predominantly tramadol (45.49%) and methadone (18.45%). Diazepam is the chosen benzodiazepine; and among antidepressants, imipramine is the most used, although gabapentin is classified as anticonvulsant; in burned patients, it is used in analgesic dose. Either in patients with or without RD, the prevalent drugs administration schedule was made at 10:00 p.m. and 6:00 a.m. Potential Drug Interaction (PDI) was evidenced in 66.6% of studied patients. Correlation between the PDI occurrence and the RD proved to be positive; patients who presented PDI have 2.5 times higher risk for developing RD. The pairs of prevalent drugs and that presented PDI in the group with RD were methadone with diazepam (n=5), tramadol with fentanyl (4), methadone with imipramine, and methadone with tramadol (n=3). In group without DR, the prevalent drugs were methadone and tramadol (n=8), tramadol with fentanyl (4), and methadone with diazepam (3). The oral and intravenous drugs administration was prevalent in patients with and without RD, and no positive correlation between the administration by these forms and the occurrence of RD was found, evidencing up that the administration form is not so important to the RD. In patients with RD, 83.3% had PDI, mainly in the schedules of 10:00 p.m. and 6:00 a.m., close to the occurrence times of RD. It is expected that this study can contribute to safe drug administration when using opioids, and in the prevention of serious adverse events like respiratory depression in burned patients.

A tese desenvolvida neste estudo é que a depressão respiratória em pacientes queimados que utilizam opiódes como terapeutica farmacológica da dor, pode ser prevenida por meio de ações de enfermagem que identifiquem os fatores predisponentes para a depressão respiratória, que considerem na rotina de aprazamento da terapeutica farmacológica da dor, as características farmacológicas dos medicamentos, para evitar interações medicamentosas e que monitorem adequadamente o paciente queimado para identificar precocemente sinais de depressão respiratória. Para tanto, este estudo teve como objetivo desenvolver barreiras de segurança com foco em ações de enfermagem, para prevenção de depressão respiratória em pacientes queimados em uso de opióides. Trata-se de um estudo restrospectivo, em que foram analisados 272 prontuários de pacientes queimados internados em um Centro de Tratamento de Queimados (CTQ), de um hospital público federal de grande porte, no município do Rio de Janeiro. nos anos de 2011 a 2013. Dentre os 272 prontuários 42 atenderam os critérios de seleção da pesquisa, e destes, em 28,58% (n=12) foi identificada a ocorrência de depressão respiratória. Predominaram pacientes adultos jovens do sexo masculino. O óbito predominou no grupo com DR, assim como, queimaduras de 2 e 3 graus, e superfície corporal queimada com mediana de 50%. Os fatores predominantes para depressão respiratória foram insuficiencia renal, hipoalbuminemia e hipertensão arterial. Na terapia medicamentosa dos pacientes queimados, os analgésicos opióides são os mais utilizados, predominando o tramadol (45,49%) e a metadona (18,45%). Diazepam é o benzodiazepínico de escolha, entre os antidepressivos a imipramina é o mais utilizado, apesar de classificada como anticonvulsivantes a gabapentina, nos queimados é utilizada em dose analgésica. Tanto no grupo de pacientes com ou sem DR, os horários de adiministração de medicamentos que predominaram foram 22h e 06h. Foi evidenciado PIM em 66,6% dos pacientes estudados. A associação entre a ocorrência de PIM e a DR demonstrou-se positiva; os pacientes com que apresentaram PIM têm 2,5 vezes mais risco de apresentar DR. Os pares de medicamentos prevalentes e que apresentaram PIM no grupo com DR foram, metadona com diazepam (n=5), tramadol com fentanil (4), metadona com impramina e metadona com tramadol (n=3). No grupo sem DR foram metadona e tramadol (n=8), tramadol com fentanil (4), e metadona com diazepam (3). As vias oral e intravenosa predominaram nos pacientes com e sem DR, e não houve associação positiva entre a administração por essas vias e a oorrência de DR, constatando-se que a via de administração não é tão relevante para a DR. Nos pacientes com DR, 83,3% apresentaram PIM, principalmente nos horários 22h e 06h, horários próximos aos de ocorrência de DR. Espera-se que este estudo contribua para a segurança medicamentosa no uso de opióides, e na prevenção do eventos adverso grave como a depressão respiratória em pacientes queimados. / The thesis developed in this study considers that the respiratory depression (RD) in burned patients using opioids as pharmacological therapeutic for pain can be prevented through nursing actions that identify its predisposing factors; also, nurses should consider the pharmacological characteristics of drugs during the routine schedule to apply pharmacological therapeutic for pain, aiming to prevent drug interactions; and adequately they should monitor the burned patient to identify early signs of respiratory depression. Therefore, this study had as general objective to develop safety barriers with a focus on nursing actions to prevent respiratory depression in burned patients in use of opioids; those barriers were related to the pharmacology of opioids, to the predisposing factors for respiratory depression by opioid, and to the monitoring of respiratory depression. This is a retrospective study that analyzed 272 medical records of burned patients admitted into a Burn Treatment Center (BTC) of large federal public hospital in the city of Rio de Janeiro, Brazil, from 2011 to 2013. Among those records, 42 records met the selection criteria of this research; and the occurrence of respiratory depression was identified in 28.58% (n=12) of them. Young adult male patients were prevalent. The death predominated in the group with RD, as well as, in the group with burns of 2nd and 3rd degrees and about 50% burned body surface. The prevalent factors for respiratory depression were renal failure, hypoalbuminemia, and high blood pressure. In drug therapy of burn patients, opioid analgesics are the most used, predominantly tramadol (45.49%) and methadone (18.45%). Diazepam is the chosen benzodiazepine; and among antidepressants, imipramine is the most used, although gabapentin is classified as anticonvulsant; in burned patients, it is used in analgesic dose. Either in patients with or without RD, the prevalent drugs administration schedule was made at 10:00 p.m. and 6:00 a.m. Potential Drug Interaction (PDI) was evidenced in 66.6% of studied patients. Correlation between the PDI occurrence and the RD proved to be positive; patients who presented PDI have 2.5 times higher risk for developing RD. The pairs of prevalent drugs and that presented PDI in the group with RD were methadone with diazepam (n=5), tramadol with fentanyl (4), methadone with imipramine, and methadone with tramadol (n=3). In group without DR, the prevalent drugs were methadone and tramadol (n=8), tramadol with fentanyl (4), and methadone with diazepam (3). The oral and intravenous drugs administration was prevalent in patients with and without RD, and no positive correlation between the administration by these forms and the occurrence of RD was found, evidencing up that the administration form is not so important to the RD. In patients with RD, 83.3% had PDI, mainly in the schedules of 10:00 p.m. and 6:00 a.m., close to the occurrence times of RD. It is expected that this study can contribute to safe drug administration when using opioids, and in the prevention of serious adverse events like respiratory depression in burned patients.

La buprénorphine (BUP) peut être responsable d’une dépression respiratoire à l’origine d’intoxications graves parfois mortels. Cependant, les mécanismes exacts de ces effets respiratoires délétères ne sont pas encore clairement établis. Les objectifs de cette thèse étaient d’analyser la variabilité des effets respiratoires de la BUP en y intégrant : 1) le rôle exact de la P-glycoprotéine (P-gp) 2) le rôle de l’acquisition d’une tolérance aux opioïdes, tout en précisant les différences potentielles entre tolérance aux effets analgésiques et respiratoires et les mécanismes moléculaires mis en jeu. Pour cela, nous avons étudié en pléthysmographie les effets respiratoires de la BUP et de son métabolite actif la norbuprénorphine (NBUP) chez la souris Fvb femelle. Nous avons mesuré leur transport par la P-gp à la barrière hémato-encéphalique (BHE) en perfusion cérébrale in situ, après inhibition pharmacologique ou suppression du gène codant pour la P-gp. Nous avons étudié la part de variabilité dans ces effets, attribuable au sexe et à la souche de souris. Nous avons ainsi démontré que la P-gp exprimée à la BHE joue un rôle-clé dans la protection contre les effets respiratoires délétères induits par la BUP, en empêchant l’entrée dans le compartiment encéphalique de son métabolite, la NBUP. Nous avons observé que les souris Fvb femelles sont plus sensibles à la toxicité respiratoire de la BUP que les souris Fvb mâles qui sont, eux-mêmes plus sensibles à ces effets que les souris Swiss mâles, sans que la P-gp ne soit à aucun moment impliquée dans cette variabilité. Enfin, nous avons montré qu’une tolérance aux effets analgésiques et respiratoires de la BUP se développe de façon significativement plus réduite chez les souris Fvb déficientes en P-gp, suggérant un rôle crucial pour ce transporteur dans l’acquisition et l’expression de la tolérance à la BUP. Par ailleurs, nous avons montré qu’après administration répétée de morphine, apparait une tolérance plus faible à ses effets respiratoires qu’à ses effets analgésiques. La mise en évidence d’une superactivation de l’adénylate cyclase dans la région périaqueducale impliquée dans les effets antinociceptifs des opioïdes, et non dans le tronc cérébral qui contient les centres de régulation de la ventilation, pourrait au moins en partie, expliquer cette différence d’intensité de tolérance observée. Enfin, pour compléter nos travaux expérimentaux, nous avons réalisé deux mini-revues bibliographiques pour, d’une part faire la synthèse des mécanismes de la tolérance aux opioïdes et de leur rôle dans la dépression respiratoire et d’autre part, analyser les situations déjà rapportées d’effets cliniques nés d’interactions médicamenteuses médiées par la P-gp. / Buprenorphine (BUP) may be responsible for respiratory depression resulting in serious andsometimes fatal poisonings. However, the exact mechanisms leading to these deleterious respiratoryeffects still remain unclear. The objectives of this thesis were to study the variability of BUP-inducedrespiratory effects by focusing on: 1) the involvement of P-glycoprotein 2) the role of tolerance to opioids in addition to investigating possible differences among tolerance to opioid-related antinociceptive and respiratory effects as well as the involved molecular mechanisms. We studied the respiratory effects of BUP and its active metabolite, norbuprenorphine (NBUP) using plethysmography in female Fvb mice. We measured P-gp-related transport of BUP and NBUP at the blood-brain barrier (BBB) using in situ brain perfusion after pharmacological P-gp inhibition as well as in P-gp knock-out mice. We also studied the role of gender and mice strain in the variability of BUP-related respiratory effects. We showed that P-gp at the BBB plays a key-protective role against BUP-related respiratory effects by limiting NBUP distribution into the brain. We observed that female Fvb mice are more sensitive to BUP-induced deleterious respiratory effects than male Fvb mice thatare more sensitive than male Swiss mice. Furthermore, we assessed that gender- and strain-attributedvariability is not related to P-gp. Finally, we demonstrated that tolerance to BUP-induced antinociceptive and respiratory effects is significantly reduced in P-gp knockout mice in comparison to controls, suggesting a critical role for P-gp in tolerance to BUP. In parallel, we showed that repeated administration of morphine results in reduced tolerance to its respiratory effects in comparison to its antinociceptive effects. Adenylate cyclase super-activation that we evidenced in the periaqueductal grey matter, the area involved in opioid-related analgesia control, but not in the brainstem, the area that contains centres of ventilation regulation, may at least in part be responsible for these observed differences in tolerance. Finally, to complete our experimental researches, we performed two mini-reviews, aiming at summarizing the various mechanisms of tolerance and their involvement in respiratory depression in addition to highlighting the importance of drug-drug interactions leading to P-glycoprotein inhibition in the occurrence of deleterious clinical effects.

No description available.