Methylene blue dose-dependently induces cutaneous inflammation and heat hyperalgesia in a novel rat model.

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.

Increases in local skin temperature correlate with spontaneous foot lifting and heat hyperalgesia in both incisional inflammatory models of pain.

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.

Adverse Effects of Sugammadex on the Cardiovascular System.

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.

Adverse effects of methylene blue in peripheral neurons: An in vitro electrophysiology and cell culture study.

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.

A Predictive Model for Developing Long Term Opioid Use After Neurosurgery and Orthopedic Surgery.

This study aimed to identify patient characteristics that predict long-term opioid use after an orthopedic or neurosurgery procedure. Long-term opioid use was defined as opioid use for 90 or more days following the surgical procedure. A retrospective analysis was conducted of orthopedic and neurosurgery patients 18 years and older from 01/01/2011 through 12/31/2017 (n = 12,301). Characteristics included age, sex, race, length of hospital stay, body mass index, surgical procedure specialty, presence of opioid use before and after surgery, and opioid use 90 days or more after surgery. A multiple logistic regression model was used to model characteristics predictive of long-term use of opioids. In this cohort, 32.0% of patients had prescriptions for opioids 90 or more days after surgery. Statistically significant risk factors for long-term opioid use were being Caucasian, younger (18-25 years age group) or older than age 45 and being obese. People who were African American or Black, in the 25-45 years age group, underweight, and used opioids before surgery were less likely to use opioids 90 days after surgery. Nurse anesthetist awareness of predictive characteristics of long-term opioid use can lead to alternative options to prevent opioid abuse.

Incidence and Mortality Rate of Perioperative Reintubation: Case Series of 196 Patients.

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.

In Vivo Calcium Imaging Visualizes Incision-Induced Primary Afferent Sensitization and Its Amelioration by Capsaicin Pretreatment.

Previous studies have shown that infiltration of capsaicin into the surgical site can prevent incision-induced spontaneous pain like behaviors and heat hyperalgesia. In the present study, we aimed to monitor primary sensory neuron Ca2+ activity in the intact dorsal root ganglia (DRG) using Pirt-GCaMP3 male and female mice pretreated with capsaicin or vehicle before the plantar incision. Intraplantar injection of capsaicin (0.05%) significantly attenuated spontaneous pain, mechanical, and heat hypersensitivity after plantar incision. The Ca2+ response in in vivo DRG and in in situ spinal cord was significantly enhanced in the ipsilateral side compared with contralateral side or naive control. Primary sensory nerve fiber length was significantly decreased in the incision skin area in capsaicin-pretreated animals detected by immunohistochemistry and placental alkaline phosphatase (PLAP) staining. Thus, capsaicin pretreatment attenuates incisional pain by suppressing Ca2+ response because of degeneration of primary sensory nerve fibers in the skin.SIGNIFICANCE STATEMENT Postoperative surgery pain is a major health and economic problem worldwide with ∼235 million major surgical procedures annually. Approximately 50% of these patients report uncontrolled or poorly controlled postoperative pain. However, mechanistic studies of postoperative surgery pain in primary sensory neurons have been limited to in vitro models or small numbers of neurons. Using an innovative, distinctive, and interdisciplinary in vivo populational dorsal root ganglia (DRG) imaging (>1800 neurons/DRG) approach, we revealed increased DRG neuronal Ca2+ activity from postoperative pain mouse model. This indicates widespread DRG primary sensory neuron plasticity. Increased neuronal Ca2+ activity occurs among various sizes of neurons but mostly in small-diameter and medium-diameter nociceptors. Capsaicin pretreatment as a therapeutic option significantly attenuates Ca2+ activity and postoperative pain.

Industry Payments to Pain Medicine Physicians: An Analysis of the Centers for Medicare and Medicaid Services Open Payments Program.

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.

Outcomes Associated With Infection of Chronic Pain Spinal Implantable Electronic Devices: Insights From a Nationwide Inpatient Sample Study.

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.

Adverse Events and Complications Associated With Intrathecal Drug Delivery Systems: Insights From the Manufacturer and User Facility Device Experience (MAUDE) Database.

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.

Anesthetic consideration for patients with micra leadless pacemaker.

MICRA, miniaturized leadless single chamber pacemaker, is inserted directly into the right ventricular myocardium via transcatheter approach. We present a case of a 66-year-old patient with a Micra pacemaker scheduled for kidney-pancreas transplant. The patient is pacemaker dependent. The preoperative cardiology consult did not comment on the need of reprogramming. One hour prior to the surgery, the anesthesia team was unable to locate the pacemaker on the chest wall. The Medtronic hotline was called, and the caregivers learned that the particular pacemaker is buried within the ventricular wall and is not responsive to an external magnet. Thus, the case was delayed and a cardiac electrophysiology team was contacted to reprogram the pacemaker to VOO (fixed ventricular pacing) mode. We suggest that the pacemaker can pose perioperative challenges due to its novelty, paucity of report, and guidelines.

Anesthetic Management for Emergent Repair of Tracheoinnominate Fistula.

We present a case of a 30-year-old female, who had tracheostomy revision complicated by false passage into the subcutaneous space and pneumothorax. Six days later, she developed massive bleeding from the mouth, nose, and tracheostomy site. Approximately 2 liters of blood was lost. With high suspicion for tracheo-innominate fistula, she was emergently brought to the operating room for fistula repair. Her anesthetic management was initially focused on maintaining spontaneous ventilation with inhalation agents until surgical exposure was adequate. An endotracheal tube was then placed under guidance of a video-laryngoscope. The tracheostomy tube was then removed over a Cook catheter to maintain secure passage in case of airway collapse. The oral endotracheal tube was then inserted distal to the arterial and tracheal defect. The patient's bleeding was stopped, the fistula was repaired, and she was transferred back to the intensive care unit, but she died several days later due to multi-organ failure.

Global transcriptome analysis of rat dorsal root ganglia to identify molecular pathways involved in incisional pain.

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.