RESUMEN
Methylene blue (MB) has been shown to reduce mortality and morbidity in vasoplegic patients after cardiac surgery. Though MB is considered to be safe, extravasation of MB leading to cutaneous toxicity has been reported. In this study, we sought to characterize MB-induced cutaneous toxicity and investigate the underlying mechanisms. To induce MB-induced cutaneous toxicity, we injected 64 adult male Sprague-Dawley rates with 200 µL saline (vehicle) or 1%, 0.1%, or 0.01% MB in the plantar hind paws. Paw swelling, skin histologic changes, and heat and mechanical hyperalgesia were measured. Injection of 1%, but not 0.1% or 0.01% MB, produced significant paw swelling compared to saline. Injection of 1% MB produced heat hyperalgesia but not mechanical hyperalgesia. Pain behaviors were unchanged following injections of 0.1% or 0.01% MB. Global transcriptomic analysis by RNAseq identified 117 differentially expressed genes (111 upregulated, 6 downregulated). Ingenuity Pathway Analysis showed an increased quantity of leukocytes, increased lipids, and decreased apoptosis of myeloid cells and phagocytes with activation of IL-1ß and Fos as the two major regulatory hubs. qPCR showed a 16-fold increase in IL-6 mRNA. Thus, using a novel rat model of MB-induced cutaneous toxicity, we show that infiltration of 1% MB into cutaneous tissue causes a dose-dependent pro-inflammatory response, highlighting potential roles of IL-6, IL-1ß, and Fos. Thus, anesthesiologists should administer dilute MB intravenously through peripheral venous catheters. Higher concentrations of MB (1%) should be administered through a central venous catheter to minimize the risk of cutaneous toxicity.
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Modelos Animales de Enfermedad , Hiperalgesia , Inflamación , Azul de Metileno , Ratas Sprague-Dawley , Piel , Animales , Masculino , Azul de Metileno/farmacología , Azul de Metileno/administración & dosificación , Hiperalgesia/patología , Hiperalgesia/inducido químicamente , Inflamación/patología , Inflamación/inducido químicamente , Piel/efectos de los fármacos , Piel/patología , Relación Dosis-Respuesta a Droga , Calor , Ratas , Interleucina-1beta/metabolismo , Interleucina-1beta/genéticaRESUMEN
Methylene blue (MB) is an effective treatment for methemoglobinemia, ifosfamide-induced encephalopathy, cyanide poisoning, and refractory vasoplegia. However, clinical case reports and preclinical studies indicate potentially neurotoxic activity of MB at certain concentrations. The exact mechanisms of MB neurotoxicity are not known, and while the effects of MB on neuronal tissue from different brain regions and myenteric ganglia have been examined, its effects on primary afferent neurons from dorsal root ganglia (DRG) have not been studied. Mouse DRG were exposed to MB (0.3-10 µM) in vitro to assess neurite outgrowth. Increasing concentrations of MB (0.3-10 µM) were associated with neurotoxicity as shown by a substantial loss of cells with neurite formation, particularly at 10 µM. In parallel experiments, cultured rat DRG neurons were treated with MB (100 µM) to examine how MB affects electrical membrane properties of small-diameter sensory neurons. MB decreased peak inward and outward current densities, decreased action potential amplitude, overshoot, afterhyperpolarization, increased action potential rise time, and decreased action potential firing in response to current stimulation. MB induced dose-dependent toxicity in peripheral neurons, in vitro. These findings are consistent with studies in brain and myenteric ganglion neurons showing increased neuronal loss and altered membrane electrical properties after MB application. Further research is needed to parse out the toxicity profile for MB to minimize damage to neuronal structures and reduce side effects in clinical settings.
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Ganglios Espinales , Azul de Metileno , Ratas , Ratones , Animales , Azul de Metileno/farmacología , Azul de Metileno/metabolismo , Ganglios Espinales/metabolismo , Células Receptoras Sensoriales/metabolismo , Electrofisiología , Técnicas de Cultivo de Célula , Células CultivadasRESUMEN
OBJECTIVE: To analyze industry payments to pain medicine physicians in the United States. DESIGN: Retrospective cohort study using publicly available databases. SUBJECTS: The study includes U.S. pain medicine physicians (PMPs) with reports in the Open Payments program from 2013 to 2018. METHODS: The Centers for Medicare and Medicaid Services Open Payments program was analyzed for general, investment, and ownership payments to PMPs reported from 2013 to 2018. The nature, type, and geographic variation of payments were analyzed. RESULTS: The main findings of the study are as follows: 1) Payments made to PMPs constituted a small proportion of the payments made to all physicians in the United States, and the number of transactions and the total dollar amount seem to have decreased from 2016 to 2018. 2) The median number of payments among physicians with reported payments was around 4 (interquartile range: 18), and the majority of them were under $20. 3) The majority of payments were for in-kind items and services (85%) and were made for food and beverages (91%), travel and lodging (5.5%). 4) Some of the ownership and investment interest payments exceeded $500,000. 5) The top five drugs associated with physician payments included medications with opioids. 6) A very small minority of payments were made for entertainment or gifts. 7) A third of PMPs with reports had payments reported under more than one taxonomy. CONCLUSIONS: Overall payments made to PMPs seem to be decreasing since 2016. The majority of the payments are made for the food, beverage, and travel categories. Public and physician awareness of the Open Payments system reports is essential to promote transparency and to minimize adverse effects of financial relationships on patient care.
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Conflicto de Intereses , Médicos , Anciano , Centers for Medicare and Medicaid Services, U.S. , Revelación , Industria Farmacéutica , Humanos , Medicare , Dolor , Estudios Retrospectivos , Estados UnidosRESUMEN
OBJECTIVES: Chronic pain spinal implantable electronic devices (CPSIEDs) include devices that provide spinal cord stimulation and intrathecal drug therapy. In this study, we sought to evaluate the trends of CPSIED infections, related complications, and outcomes following the treatment of infection. MATERIALS AND METHODS: The Nationwide Inpatient Sample database contains data from 48 states, and the District of Columbia was used to identify patients with a primary diagnosis of CPSIED infection during the years 2005-2014. Patients with intrathecal pumps for the treatment of spasticity were excluded to limit the study population to patients with chronic pain disorders. Treatments were categorized as: 1) without device removal, 2) pulse generator or pump only removal, 3) intrathecal pump system removal, and 4) spinal cord stimulation system removal. Complications associated with CPSIED infections were identified using administrative billing codes. RESULTS: During the study period 2005-2014, a total of 11,041 patients were admitted to the hospital with CPSIED infections. The majority of the patients were treated without surgical intervention (56%), and a smaller proportion underwent complete system explantation (22.7%). In-hospital mortality or permanent disability due to paralysis after CPSIED infection was around 1.83% and 2.77%, respectively. Infectious complications such as meningitis, abscess formation, and osteomyelitis occurred in 4.93%, 5.08%, and 1.5%, respectively. The median cost of hospitalization was around US $14,118.00, and the median length of stay was approximately six days (interquartile range = 4-13 days). CONCLUSIONS: The complications of CPSIED infection were higher among patients that did not undergo device removal.
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Dolor Crónico , Estimulación de la Médula Espinal , Dolor Crónico/epidemiología , Dolor Crónico/terapia , Electrónica , Humanos , Bombas de Infusión Implantables , Pacientes Internos , Espasticidad Muscular , Estimulación de la Médula Espinal/efectos adversosRESUMEN
BACKGROUND: Modern intrathecal drug delivery systems (IDDS) are technologically advanced to deliver medication through various automated and patient-controlled programs. They also are associated with unique complications ranging from post-operative complications, medication-related adverse events (AE), device malfunction, to refill associated AE. OBJECTIVES: To systematically analyze real-world complications and AE reported on the Food and Drug Administration's Manufacturer and User Facility Device Experience database (MAUDE) associated with IDDS among patients predominantly with chronic pain disorders. MATERIALS AND METHODS: MAUDE database was sampled for a month four times a year during the study period, February 2018 to February 2019. The database was resampled every six months till August 2020 to evaluate for any additional reported cases during the index months. The two FDA approved IDDS, were included. AE were broadly classified into causes related to catheter malfunction, pump malfunction, biologic, and medication-related AE. RESULTS: A total of 1001 reports were included in the final analysis. The top three reasons for adverse report are infection/erosion (15.7%, n = 157), motor stall (12.4%, n = 125) and adverse medication reactions (11.8%, n = 119), respectively. There were five deaths among patients with IDDS. Epidural hematoma (n = 3) after IDDS surgery resulted in a death and residual neurological deficits after surgical evacuation. Programming errors, medication concentration discrepancy, and failure to turn on the pump after reprogramming are various preventable causes of medication-related IDDS AEs. CONCLUSIONS: Analysis of AE associated with IDDS from the MAUDE database provided a real-world perspective different from reported registry complications. Awareness and vigilance of preventable IDDS-related complications is the first step toward mitigating risks to provide safe and effective intrathecal drug delivery for chronic pain management.
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Sistemas de Liberación de Medicamentos , Bases de Datos Factuales , HumanosRESUMEN
To develop non-opioid therapies for postoperative incisional pain, we must understand its underlying molecular mechanisms. In this study, we assessed global gene expression changes in dorsal root ganglia neurons in a model of incisional pain to identify pertinent molecular pathways. Male, Sprague-Dawley rats underwent infiltration of 1% capsaicin or vehicle into the plantar hind paw (n = 6-9/group) 30 min before plantar incision. Twenty-four hours after incision or sham (control) surgery, lumbar L4-L6 dorsal root ganglias were collected from rats pretreated with vehicle or capsaicin. RNA was isolated and sequenced by next generation sequencing. The genes were then annotated to functional networks using a knowledge-based database, Ingenuity Pathway Analysis. In rats pretreated with vehicle, plantar incision caused robust hyperalgesia, up-regulated 36 genes and downregulated 90 genes in dorsal root ganglias one day after plantar incision. Capsaicin pretreatment attenuated pain behaviors, caused localized denervation of the dermis and epidermis, and prevented the incision-induced changes in 99 of 126 genes. The pathway analyses showed altered gene networks related to increased pro-inflammatory and decreased anti-inflammatory responses in dorsal root ganglias. Insulin-like growth factor signaling was identified as one of the major gene networks involved in the development of incisional pain. Expression of insulin-like growth factor -2 and IGFBP6 in dorsal root ganglia were independently validated with quantitative real-time polymerase chain reaction. We discovered a distinct subset of dorsal root ganglia genes and three key signaling pathways that are altered 24 h after plantar incision but are unchanged when incision was made after capsaicin infiltration in the skin. Further exploration of molecular mechanisms of incisional pain may yield novel therapeutic targets.
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Capsaicina/farmacología , Ganglios Espinales/metabolismo , Dolor Postoperatorio/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Somatomedinas/metabolismo , Transcriptoma/genética , Animales , Escala de Evaluación de la Conducta , Capsaicina/uso terapéutico , Biología Computacional , Regulación hacia Abajo , Ganglios Espinales/lesiones , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Masculino , RNA-Seq , Ratas , Ratas Sprague-Dawley , Transducción de Señal/genética , Somatomedinas/genética , Herida Quirúrgica/complicaciones , Regulación hacia ArribaAsunto(s)
Analgesia Epidural , Anestesia Epidural , Humanos , Infusiones Intravenosas , Abdomen/cirugía , Lidocaína/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Analgésicos Opioides/uso terapéutico , Anestésicos Locales/uso terapéuticoAsunto(s)
Dolor Crónico , Disfunción Cognitiva , Humanos , Anciano , Disfunción Cognitiva/epidemiologíaAsunto(s)
Anestesiólogos , Betacoronavirus , Infecciones por Coronavirus/prevención & control , Control de Infecciones/métodos , Exposición Profesional/prevención & control , Pandemias/prevención & control , Neumonía Viral/prevención & control , Anestesiólogos/normas , COVID-19 , Infecciones por Coronavirus/transmisión , Humanos , Control de Infecciones/normas , Exposición Profesional/normas , Material Particulado/efectos adversos , Neumonía Viral/transmisión , SARS-CoV-2Asunto(s)
Analgésicos no Narcóticos , Dolor en Cáncer , Neoplasias , omega-Conotoxinas , Analgésicos no Narcóticos/uso terapéutico , Dolor en Cáncer/tratamiento farmacológico , Humanos , Inyecciones Espinales , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , omega-Conotoxinas/uso terapéuticoRESUMEN
BACKGROUND: Nonevoked spontaneous pain is most problematic for postoperative patients. Physicians assess this form of pain using the human visual analog scale or verbal numeric rating scale. Recent studies have proposed that spontaneous foot-lifting (SFL) behaviors are an expression of spontaneous pain in animals after spinal nerve injury or adjuvant-induced inflammation. In the current study, we characterize SFL behaviors in a rat model of acute postoperative pain, which includes comparisons with evoked behaviors to analgesic treatments. METHODS: SFL was manually recorded over four 5-minute periods with 10-minute intervals between each testing session. Paw-withdrawal thresholds were subsequently measured with an electronic von Frey esthesiometer. To evaluate the effects of age, rats were tested in different age groups: 2, 7, and >26 months. The effects of buprenorphine and morphine were tested in a separate group of animals, which received intraperitoneal injections of saline, morphine (0.01, 0.1, 1, or 2 mg/kg), or buprenorphine (0.001, 0.01, or 0.1 mg/kg) before testing. RESULTS: SFL behaviors peaked at 3 hours after incision and significantly recovered by the 3rd or 4th postoperative day (P < 0.0001). The presentation of these behaviors did not significantly vary with animal age (2, 7, and >26 months old; P = 0.30). SFL behaviors, with the exception of rapid SFL at 3 hours after incision, did not show significant correlation with paw-withdrawal threshold behaviors. The median effective dose of buprenorphine for reversal of mechanical hyperalgesia (0.0452 mg/kg; 95% CI, 0.0259-0.0787) was significantly larger than for reversing rapid (0.0027 mg/kg; 95% CI, 0.0009-0.0083; P < 0.0001) and prolonged (0.0004 mg/kg, 95% CI, 0.0000, 0.0035; P = 0.001) SFL at 3 hours after incision. Similarly, the median effective dose of morphine for reversal of mechanical hypersensitivity behaviors (2.901 mg/kg; 95% CI, 1.132-7.436) was larger than for SFL count (0.4044 mg/kg; 95% CI, 0.1048-1.561; P = 0.0103) and SFL duration (0.0309 mg/kg; 95% CI, 0.0095-0.0998; P < 0.0001) at 3 hours after incision. CONCLUSIONS: The present study demonstrates that a hindpaw plantar incision induces SFL behaviors in rats and that these behaviors have higher bioassay sensitivity to analgesic interventions with morphine and buprenorphine compared with mechanically evoked behaviors.
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Analgésicos Opioides/uso terapéutico , Conducta Animal/efectos de los fármacos , Buprenorfina/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Morfina/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/psicología , Dolor Agudo/tratamiento farmacológico , Envejecimiento/psicología , Animales , Estimulación Física , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Especificidad de la EspecieRESUMEN
BACKGROUND: Unrelieved acute postoperative pain can lead to a wide range of adverse effects, such as anxiety, depression, restlessness and sleep deprivation. OBJECTIVE: To investigate anxiety-like behaviour in a postoperative pain model. INTERVENTIONS AND MAIN OUTCOME MEASURES: Mechanical hypersensitivity was assessed with an electronic von Frey device, whereas anxiety-like behaviour was measured with light/dark testing and elevated plus maze testing. RESULTS: Rats developed significant mechanical hyperalgesia on 1, 3 and 8 days postsurgery compared with sham-operated rats. There was no reduction in motility between preincision and postincision when animals were allowed to move freely in an open field locomotion test. In light-dark tests, incised animals spent significantly less time than sham rats in the light compartment on the 1st and 3rd postoperative days. However, in an elevated plus maze test, differences between sham and incised rats were only observed on the 8th postoperative day as they spent significantly more time in the open arms. Pretreatment with morphine significantly increased withdrawal thresholds compared with treatment with saline (0.9% NaCl), but had no effect on light or open arm avoidance behaviour. CONCLUSION: We report that a rat model of acute postoperative pain is associated with anxiety-like increased light and open arm avoidance behaviour.
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Ansiedad/psicología , Conducta Animal , Hiperalgesia/psicología , Dolor Postoperatorio/psicología , Enfermedad Aguda , Analgésicos Opioides/farmacología , Animales , Ansiedad/etiología , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Conducta Exploratoria , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Hiperalgesia/fisiopatología , Masculino , Actividad Motora , Dimensión del Dolor , Percepción del Dolor , Umbral del Dolor , Dolor Postoperatorio/complicaciones , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/fisiopatología , Ratas Sprague-Dawley , Factores de TiempoAsunto(s)
Vértebras Cervicales/diagnóstico por imagen , Hematoma Espinal Epidural/inducido químicamente , Hematoma Espinal Epidural/diagnóstico por imagen , Esteroides/efectos adversos , Anciano de 80 o más Años , Femenino , Hematoma Espinal Epidural/cirugía , Humanos , Inyecciones Epidurales , Esteroides/administración & dosificaciónRESUMEN
Perioperative anaphylaxis is rare but potentially life-threatening. Although the most common causative agents are muscle relaxants and antibiotics, there have been several case reports of sugammadex-induced anaphylactic reactions. Though most cases of perioperative anaphylaxis present after induction, sugammadex anaphylaxis presents at the end of the case, sometimes in unmonitored situations such as after extubation or during transport to the recovery unit. Here we report a case of suspected sugammadex-induced anaphylaxis that led to cardiac arrest. We emphasize that vigilance is required when a high dose of sugammadex is used for the reversal of neuromuscular blockade.
RESUMEN
Background: This study investigated if a localized increase in skin temperature in rat models of incisional and inflammatory pain correlates with the intensity of spontaneous and evoked pain behaviors. Methods: Anesthetized rats received either a 20-mm longitudinal incision made through the skin, fascia, and muscle of the plantar hind paw or an injection of complete Freund adjuvant into the plantar hind paw of anesthetized rats to induce local inflammation. Spontaneous and evoked pain behaviors were assessed, and changes in skin temperature were measured using a noncontact infrared thermometer. Results: There were no differences in skin temperature between the ipsilateral and contralateral hind paw before the incision or inflammation. Skin temperature increased at 2 hours after hind paw plantar incision or 1 day after inflammation of the affected paw, which gradually returned to baseline by the first day and fourth days after treatment, respectively. The increase in skin temperature correlated with the intensity of spontaneous pain behaviors and heat but not with mechanical allodynia. Conclusions: Our results suggest that a simple measurement of localized skin temperature using a noncontact infrared thermometer could measure the extent of spontaneous pain behaviors and heat hyperalgesia following plantar incision or inflammation in animals. In the absence of a reliable objective marker of pain, these results are encouraging. However, studies are warranted to validate our results using analgesics and pain-relieving interventions, such as nerve block on skin temperature changes.
RESUMEN
Among anesthesia-related life-threatening complications, respiratory failure requiring reintubation is common. However, studies evaluating patient characteristics for extubation failure are scarce in the literature. Such knowledge is important to increase awareness and for the development of strategies to improve the safety of anesthesia care. We retrospectively reviewed 196 cases that were reported to our quality assurance (QA) committee from 2004 to 2014 at 3 hospitals. The reintubation rate was 0.09% (n=196). More reintubations occurred in the operating room than the postanesthesia care unit (58% vs 30%). Ninety-three reintubated patients (47%) were 65 years or older. Most patients were in ASA class 3 or 4 (76%) and had a surgical procedure lasting longer than 3 hours. Eleven reintubated patients (5%) died during the hospital course. The exact causes of reintubation could not be determined because of limited data in our QA database. We conclude that although the individual risk of reintubation for each patient is low, the reintubated patients have a higher mortality rate. The study findings emphasize the need for extra vigilance before anesthesia providers attempt extubation of a patient who is elderly, underwent surgery over 3 hours, has chronic obstructive airway disease, or has ASA class 3 or 4 status.