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BACKGROUND Although the package insert clearly states that "the safety and efficacy of sugammadex in pediatric patients have not been established," we hypothesized that sugammadex is used widely in pediatric anesthetic practice supplanting neostigmine as the primary drug for antagonizing neuromuscular blockade (NMB). Additionally, we sought to identify the determinants by which pediatric anesthesiologists choose reversal agents and if and how they assess NMB in their practice. Finally, because of sugammadex's effects on hormonal contraception, we sought to determine whether pediatric anesthesiologists counseled postmenarchal patients on the need for additional or alternative forms of contraception and the risk of unintended pregnancy in the perioperative period. METHODS We e-mailed a questionnaire to all 3245 members of the Society of Pediatric Anesthesia (SPA) requesting demographic data and attitudes regarding use of NMB agents, monitoring, and antagonism practices. To address low initial response rates and quantify nonresponse bias, we sent a shortened follow-up survey to a randomly selected subsample (n = 75) of SPA members who did not initially respond. Response differences between the 2 cohorts were determined. RESULTS Initial questionnaire response rate was 13% (419 of 3245). Overall, 163 respondents (38.9%; 95% confidence interval [CI], 34.2-43.8) used sugammadex as their primary reversal agent, and 106 (25.2%; 95% CI, 21.2-30.0) used it exclusively. Respondents with ≤5 years of practice used sugammadex as their primary reversal agent more often than those with ≥6 years of practice (odds ratio [OR]: 2.08; 95% CI, 1.31-3.31; P = .001). This increased utilization remained after controlling for institutional restriction and practice type (adjusted OR [aOR]: 2.20; 95% CI, 1.38-3.54; P = .001). Only 40% of practitioners always assess NMB (train-of-four), and use was inversely correlated with years of practice (Spearman ρ = -0.11, P = .04). Anesthesiologists who primarily used sugammadex assess NMB less routinely (OR: 0.56; 95% CI, 0.34-0.90; P = .01). A slim majority (52.8%) used sugammadex for pediatric postmenarchal girls; those with less experience used it more commonly (P < .001). Thirty-eight percent did not discuss its effects on hormonal contraception with the patient and/or family, independent of anesthesiologist experience (P = .33) and practice location (P = .38). No significant differences were seen in demographics or practice responses between initial and follow-up survey respondents. CONCLUSIONS Sugammadex is commonly used in pediatric anesthesia, particularly among anesthesiologists with fewer years of practice. Failure to warn postmenarchal adolescents of its consequences may result in unintended pregnancies. Finally, pediatric anesthesia training programs should emphasize objective monitoring of NMB, particularly with sugammadex use.

Enhanced Recovery after Surgery (ERAS) pathways have been shown to decrease length of stay (LOS) after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). The aim of this study was to compare immediate post-operative outcomes following an ERAS pathway with a traditional pathway for AIS. A prospective dual-center study of patients treated using an ERAS pathway (203 patients) or a traditional discharge (TD) pathway (73 patients) was performed with focus on pain at discharge, quality of life at one month, and return to school/work. LOS was 55% less in the ERAS group (4.8 days TD vs. 2.2 days ERAS, p

The coronavirus disease 2019 (COVID-19) pandemic has affected the personal and professional lives of all health care workers. Anesthesiologists frequently perform virus-aerosolizing procedures (eg, intubation and extubation) that place them at increased risk of infection. We sought to determine how the initial COVID-19 outbreak affected members of the Society for Pediatric Anesthesia (SPA) on both personal and professional levels. Specifically, we examined the potential effects of gender and age on personal stress, burnout, sleep deprivation, anxiety, depression, assessed job satisfaction, and explored financial impact.After receiving approval from the SPA Committees for Research and Quality and Safety and the Colorado Multiple Institutional Review Board, we e-mailed a questionnaire to all 3245 SPA members. The survey included 22 questions related to well-being and 13 questions related to effects of COVID-19 on current and future practice, finances, retirement planning, academic time and productivity, and clinical and home responsibilities. To address low initial response rates and quantify nonresponse bias, we sent a shortened follow-up survey to a randomly selected subsample (n = 100) of SPA members who did not respond to the initial survey. Response differences between the 2 cohorts were determined.A total of 561 (17%) members responded to the initial questionnaire. Because of COVID-19, 21.7% of respondents said they would change their clinical responsibilities, and 10.6% would decrease their professional working time. Women were more likely than men to anticipate a future COVID-19-related job change (odds ratio [OR] = 1.92, 95% confidence interval [CI], 1.12-2.63; P = .011), perhaps because of increased home responsibilities (OR = 2.63, 95% CI, 1.74-4.00; P.001). Additionally, 14.2% of respondents planned to retire early, and 11.9% planned to retire later. Women and non-White respondents had higher likelihoods of burnout on univariate analysis (OR = 1.75, 95% CI, 1.06-2.94, P = .026 and OR = 1.82, 95% CI, 1.08-3.04, P = .017, respectively), and 25.1% of all respondents felt socially isolated. In addition, both changes in retirement planning and future occupational planning were strongly associated with total job satisfaction scores (both P.001).The COVID-19 pandemic has affected the personal and professional lives of pediatric anesthesiologists, albeit not equally, as women and non-Whites have been disproportionately impacted. The pandemic has significantly affected personal finances, home responsibilities, and retirement planning; reduced clinical and academic practice time and responsibilities; and increased feelings of social isolation, stress, burnout, and depression/anxiety.

INTRODUCTION Compared with the older pediatric population, neonates have greater perioperative morbidity and mortality. Difficulty with glucose regulation may be a contributing modifiable risk factor during perioperative anesthetic management. To mitigate the risk of hyperglycemia in neonates, some providers empirically halve the preoperative rate of dextrose-containing infusions during surgery. AIM To assess the association between halving the preoperative maintenance dextrose rate and postoperative euglycemia in neonatal intensive care unit patients undergoing exploratory laparotomies. METHODS Neonatal intensive care unit patients who underwent exploratory laparotomy under general anesthesia from 1/1/2014 to 11/21/2019 were included in this analysis. Hyperglycemia and hypoglycemia were defined as >150 mg/dL and

BACKGROUND Pyloromyotomy is one of the most common surgical procedures performed on otherwise healthy infants. Pyloric stenosis results in a hypochloremic, hypokalemic metabolic alkalosis that is considered a medical emergency. This alkalotic state is believed to be associated with an increased incidence of apneic episodes. Because apnea tends to occur during anesthetic emergence, we sought to examine the association between the preoperative serum bicarbonate level and anesthetic emergence time after laparoscopic pyloromyotomy. METHODS Data were collected from patients who underwent laparoscopic pyloromyotomies from April 2014 to October 2018. To estimate the correlation between preoperative bicarbonate level and emergence time while accounting for the positive skew of emergence time and potential confounding variables, a weighted quantile mixed regression was used. Due to a nonlinear association with emergence time, preoperative serum bicarbonate was split into 2 continuous intervals (

Pediatric anesthesiologists are exposed to ionizing radiation from x-rays on an almost daily basis. Our goal was to determine the culture of safety in which they work and how they adhere to preventative strategies that minimize exposure risk in their daily practice.After Institutional Review Board waiver and approval of the Society for Pediatric Anesthesia's research and quality and safety committees, an electronic e-mail questionnaire was sent to the Society's physician, nontrainee members and consisted of questions specific to provider use of protective lead shielding, the routine use of dosimeters, and demographic information. Univariate analyses were performed using the Wilcoxon rank sum test for ordinal variables, the Fisher exact test for categorical variables, and the Spearman test to analyze correlation between 2 ordinal variables, while a proportional odds logistic regression was used for a multivariable ordinal outcome analysis. P values of.05 were considered statistically significant.Twenty-one percent (674/3151) of the surveyed anesthesiologists completed the online questionnaire. Radiation exposure is ubiquitous (98.7%), and regardless of sex, most respondents were either concerned or very concerned about radiation exposure (76.8%); however, women were significantly more concerned than men (proportional odds ratio, 1.66 [95% confidence interval, 1.20-2.31]; P = .002). Despite this and independent of sex, level of concern was not associated with use of a radiation dosimeter (P = .85), lead glasses (odds ratio, 1.07 [95% confidence interval, 0.52-2.39]; P = 1.0), or a thyroid shield (P = .12). Dosimeters were rarely (13%) or never used (52%) and were mandated in only 28.5% of institutions. Virtually none of the respondents had ever taken a radiation safety course, received a personal radiation dose report, notification of their radiation exposure, or knew how many millirem/y was considered safe. Half of the respondents were female, and while pregnant, 73% (151/206) tried to avoid radiation exposure by requesting not to be assigned to cases requiring x-rays. These requests were honored 78% (160/206) of the time.Despite universal exposure to ionizing radiation from x-rays, pediatric anesthesiologists do not routinely adhere to strategies designed to limit the intensity of this exposure and rarely work in institutions in which a culture of radiation safety exists. Our study highlights the need to improve radiation safety education, the need to change the safety culture within the operating rooms and imaging suites, and the need to more fully investigate the utility of dosimeters, lead shielding, and eye safety measures in pediatric anesthesia practice.

The purpose of this study was to determine if a higher dosing of ε-aminocaproic acid (EACA) is associated with less perioperative blood loss than a lower dose. A total of 74 patients having scoliosis surgery were analyzed. Of the 74 patients, 36 patients received EACA (10 mg/kg/h) and 38 patients received EACA (33 mg/kg/h). After controlling for key variables, an infusion of 33 mg/kg/h of EACA was associated with an increase in intraoperative blood loss of 8.1 ml/kg compared with an infusion of 10 mg/kg/h of EACA. A 33 mg/kg/h intraoperative infusion is associated with higher intraoperative blood loss than an infusion at 10 mg/kg/h.

BACKGROUND Surgeons have hesitated to use steroids in patients undergoing posterior spinal fusion because of the risk of wound complications. The literature has supported the use of postoperative steroids in other areas of orthopaedics on the basis of more rapid recovery and improved postoperative pain control. We hypothesized that a short course of postoperative dexamethasone following posterior spinal fusion for the treatment of adolescent idiopathic scoliosis (AIS) would decrease opioid usage without increasing wound-healing problems. METHODS Consecutive patients undergoing posterior spinal fusion for the treatment of AIS from 2015 to 2018 at a single hospital were included. A review of demographic characteristics, curve characteristics, surgical data, and postoperative clinic notes was performed. Opioid usage was determined by converting all postoperative opioids given into morphine milligram equivalents (MME). RESULTS Sixty-five patients underwent posterior spinal fusion for the treatment of AIS without postoperative steroids (the NS group), and 48 patients were managed with 3 doses of postoperative steroids (the WS group) (median, 8.0 mg/dose). There was no difference between the groups in terms of curve magnitude, number of vertebrae fused, or estimated blood loss. There was a 39.6% decrease in total MME used and a 29.5% decrease in weight-based MME used in the group receiving postoperative steroids (82.0 mg [1.29 mg/kg] in the NS group versus 49.5 mg [0.91 mg/kg] in the WS group]; p < 0.001). This difference persisted after accounting for gabapentin, ketorolac, and diazepam usage; surgical time; curve size; levels fused; and number of osteotomies (median decrease, 0.756 mg/kg [95% CI, 0.307 to 1.205 mg/kg]; p = 0.001). Three patients in the NS group (4.6%) and 4 patients in the WS group (8.3%) developed wound dehiscence requiring wound care (p = 0.53). One patient in the NS group required surgical debridement for the treatment of an infection. Patients in the WS group were more likely to walk at the time of the initial physical therapy evaluation (60.4% versus 35.4%; p = 0.013). CONCLUSIONS A short course of postoperative steroids after posterior spinal fusion was associated with a 40% decrease in the use of opioids, with no increase in wound complications. Surgeons may consider the use of perioperative steroids in an effort to decrease the use of postoperative opioids following posterior spinal fusion for the treatment of AIS. LEVEL OF EVIDENCE Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background Infants undergoing pyloromyotomy are at a high risk of aspiration, making rapid sequence induction the preferred method of induction. Since succinylcholine use in infants can be associated with complications, rocuronium is frequently substituted despite its prolonged duration of action. Aims To examine the likelihood of non-reversibility to neostigmine at the end of surgery in laparoscopic pyloromyotomies and its correlation to both rocuronium dose and out of operating room time. Methods Patients who underwent laparoscopic pyloromyotomy for infantile hypertrophic pyloric stenosis, received rocuronium, and were reversed with neostigmine were included. Bayesian multivariable logistic regression was utilized to determine the probability of non-reversibility, and Bayesian multivariable median regression was performed to ascertain the correlation between out of operating room time and non-reversibility. Results 306 patients were analyzed with a median surgical duration of 19 min (interquartile range 16 to 23). 74% received succinylcholine for intubation followed by rocuronium, and the remaining received rocuronium alone. The median rocuronium dose was 0.41 mg/kg (interquartile range 0.27 - 0.56 mg/kg). Prolonged block occurred in 68 (22.2%) patients. There was a non-trivial probability of prolonged block with low rocuronium doses, and each 0.1 mg/kg increase in total rocuronium dose was associated with an odds ratio of 1.36 (95% credible interval: 1.17-1.58) of neostigmine non-reversibility at the end of surgery. Non-reversibility was correlated with a substantial increase in median out of operating room time (13.4 min, 95% credible interval: 5.5-20.8 min), which was compounded by high rocuronium dosing (2.2 min increase per 0.1 mg/kg for doses greater than 0.5 mg/kg, 95% credible interval: 0.7-3.6 min). Conclusion Prolonged blockade can occur from rocuronium administration in infants undergoing pyloromyotomy even at low doses. Therefore, consideration of appropriate rocuronium dosing or the use of sugammadex should be considered.

Study objective Bilateral myringotomy and tympanostomy tube placement (BMT) is one of the most frequently performed pediatric outpatient procedures with 667,000 children receiving tympanostomy tubes annually. Because of this high volume, discovering the ideal analgesic regimen may lead to decreased overall postanesthesia care unit (PACU) costs while increasing patient and parent satisfaction. The purpose of this study is to determine if there is any benefit in supplementing intranasal (IN) fentanyl with intramuscular (IM) ketorolac with regard to immediate recovery characteristics. Design Retrospective, cohort study. Setting University-affiliated teaching hospital. Patients One thousand one hundred forty American Society of Anesthesiologists physical status 1 and 2 pediatric patients scheduled for BMT. Interventions No interventions were performed. Measurements A propensity matched cohort of pediatric patients who underwent BMT at Vanderbilt Children's Hospital from 2011 to 2014 was analyzed. The authors compared PACU recovery time, rescue analgesic administration, maximal PACU pain scores, and maximal PACU agitation scores between subgroups of patients given either IN fentanyl and IM ketorolac or IN fentanyl alone intraoperatively. Main results After adjusting for patient demographics and fentanyl dose, the fentanyl/ketorolac group received rescue analgesics 4.7% (95% confidence interval [CI], 2.0%-7.5%) less often, displayed moderate to severe pain 4.7% (95% CI, 1.5%-8.0%) less often, and experienced emergence agitation 3.6% (95% CI, 1.5%-5.8%) less often than patients in the fentanyl-only group. This corresponded to a relative risk reduction of 127%, 76%, and 200%, respectively. Conclusions Based on our retrospective analysis, adding IM ketorolac to IN fentanyl may be beneficial to pediatric patients undergoing BMT. However, these results should be confirmed with a prospective, double-blinded, randomized study.

BACKGROUND Children undergoing posterior spinal fusion experience high blood loss often necessitating transfusion. An appropriately activated coagulation system provides hemostasis during surgery, but pathologic dysregulation can cause progressive bleeding and increased transfusions. Despite receiving antifibrinolytics for clot stabilization, many patients still require transfusions. AIMS We sought to examine the association of dilutional coagulopathy with blood loss and blood transfusion in posterior spinal fusion for pediatric scoliosis patients. METHODS A retrospective, single institution study of children undergoing posterior spinal fusion >6 levels with a standardized, prospective anesthetic protocol utilizing antifibrinolytics. Blood loss was evaluated using a hematocrit-based calculation. To evaluate transfusions, a normalized Blood Product Transfusion calculation was developed. Factors associated with blood loss and blood transfusions were determined by univariate analysis and multivariate regression modeling with multicollinearity and mediation analysis. RESULTS Patients received 73.7 mL/kg (standard deviation ±30.8) of fluid poor in coagulation factors. Estimated blood loss was 42.6 mL/kg (standard deviation ±18.0). There was a significant association between estimated blood loss and total fluids delivered (Spearman's rho = 0.51, 95% confidence interval 0.33-0.65, P < 0.001). Factors significantly associated with normalized Blood Product Transfusion in this cohort included age, weight, scoliosis type, levels fused, total osteotomies, pelvic fixation, total fluid, maximum prothrombin time, and minimum fibrinogen. Regression modeling showed the best combination of variables for modeling normalized Blood Product Transfusion included patient weight, number of levels fused, total fluid administered, and maximum prothrombin time. CONCLUSION Blood product transfusion remains a frustrating problem in pediatric scoliosis. Identifying and controlling dilutional coagulopathy in these patients may reduce blood loss and the need for blood transfusion.

To compare turnover times for a series of elective cases with surgeons following themselves with turnover times for a series of previously scheduled elective procedures for which the succeeding surgeon differed from the preceding surgeon.Retrospective cohort study.University-affiliated teaching hospital.The operating room (OR) statistical database was accessed to gather 32 months of turnover data from a large academic institution. Turnover time data for the same-surgeon and surgeon-swap groups were batched by month to minimize autocorrelation and achieve data normalization. Two-way analysis of variance (ANOVA) using the monthly batched data was performed with surgeon swapping and changes in procedure category as variables of turnover time. Similar analyses were performed using individual surgical services, hourly time intervals during the surgical day, and turnover frequency per OR as additional covariates to surgeon swapping.The mean (95% confidence interval [CI]) same-surgeon turnover time was 43.6 (43.2 - 44.0) minutes versus 51.0 (50.5 - 51.6) minutes for a planned surgeon swap (P0.0001). This resulted in a difference (95% CI) of 7.4 (6.8 - 8.1) minutes. The exact increase in turnover time was dependent on surgical service, change in subsequent procedure type, time of day when the turnover occurred, and turnover frequency.The investigated institution averages 2.5 cases per OR per day. The cumulative additional turnover time (far less than one hour per OR per day) for switching surgeons definitely does not allow the addition of another elective procedure if the difference could be eliminated. A flexible scheduling policy allowing surgeon swapping rather than requiring full blocks incurs minimal additional staffed time during the OR day while allowing the schedule to be filled with available elective cases.

Trisomy 10 is a rare disorder, with only 35 cases reported in the literature. Anesthetic management may be challenging in this patient population because of craniofacial, cardiac, and renal abnormalities commonly seen in the disorder. We describe a 16-year-old male with an anesthetic history notable for prolonged emergence, postoperative hypoxia, postoperative reintubation, and unexpected hospital admission presenting for dental extraction of impacted teeth. We utilized intravenous caffeine, a respiratory stimulant used in preterm infants, to facilitate recovery from anesthesia.

Cardiofaciocutaneous syndrome is a rare syndrome that is characterized by distinct craniofacial features, cardiac abnormalities, and multiple organ involvement. Patients may present with pulmonary stenosis, hypertrophic cardiomyopathy, micrognathia, a short neck, laryngomalacia, and tracheomalacia; all of which may significantly impact the perioperative course of these patients. We describe a 6-year-old child with cardiofaciocutaneous syndrome presenting for an orthopedic procedure. He had an uneventful perioperative and postoperative course.

Summary Background Craniofacial reconstructive surgery for craniosynostosis is associated with large blood loss and intraoperative transfusion. This blood loss may continue through the initial postoperative period, potentially resulting in transfusion postoperatively. The purpose of this study is to determine if there is an association between any modifiable intraoperative factors and postoperative blood transfusion in this patient population. Methods A cohort of 55 pediatric patients who underwent primary craniofacial reconstruction at Vanderbilt Children's Hospital from January 1, 2013 to April 31, 2014 was analyzed. The authors analyzed 20 different demographic and perioperative variables for statistical associations with postoperative PRBC transfusion using multiple logistic regression with optimal models being selected by Bayesian model averaging. Results The optimal regression model only included initial PACU Hct as a predictor and showed a significant association between this variable and postoperative PRBC transfusion (odds ratio 0.69, 95% CI 0.55–0.87, P = 0.0016). Based on the average decrease in postoperative hematocrit (Hct) and the postoperative transfusion trigger, an initial PACU Hct threshold of 30 was calculated. In our patient sample, an initial PACU Hct above 30 was associated with a 50% decrease in the absolute risk of receiving a PRBC transfusion postoperatively. Conclusions Based on this retrospective analysis, it may be justifiable to transfuse residual volume from previously exposed intraoperative PRBCs to a Hct above 30 to decrease the likelihood of subsequent blood transfusions from different donors in the postoperative period.

A 3-year-old male with isovaleric acidemia presented for dental rehabilitation under general anesthesia. In times of stress, such as in the perioperative period, patients with isovaleric acidemia are at greater risk for morbidity and mortality from disordered metabolism, including glucose disturbances, hyperammonemia, hypocalcemia, and non-anion gap metabolic acidosis. Communication between the anesthesiology, dental, and endocrine teams allowed for safe and successful care of the patient.

Severe pain associated with high doses of bumetanide has been reported sporadically in the literature. We present a report of a patient who developed debilitating pain while receiving bumetanide for treatment of a heart failure exacerbation. We discuss possible etiologies of this effect based on the role of Na-K-2Cl cotransporters (NKCC) and K-Cl cotransporters (KCC) in pain regulation. A 68 year old Caucasian female with chronic diastolic heart failure, aortic and tricuspid valve repair, atrial fibrillation, and stage IV chronic kidney disease (CKD) presented to the hospital with increased shortness of breath for one week. Exam on admission was notable for elevated jugular venous pressure, pulmonary rales, and lower extremity pitting edema. On admission, her brain natriuretic peptide was 1050 pg/mL, troponin-I 0.02 ng/mL, and creatinine 2.36 mg/dL. She was diagnosed with an acute heart failure exacerbation and treated with intravenous furosemide 80 mg every 8 hours. Her home medications including chlorthalidone, amiodarone, and spironolactone were continued. Due to a poor diuretic response after 48 hours her furosemide was converted to a continuous infusion of 10 mg/hour. After an additional 48 hours with poor diuresis, she was converted to IV bumetanide with a 2 mg bolus followed by a continuous infusion titrated up to 2 mg/hr. Approximately 4 hours after starting bumetanide the patient began to experience diffuse pain that worsened over the next 48 hours. The pain was described as a severe, superficial tenderness of the skin. The pain was worsened by any pressure or light touch, including ambulation or even wearing clothing. The patient herself attributed the pain to the bumetanide bolus and infusion during our assessment. During this episode of pain her potassium and magnesium were repleted regularly to maintain a level greater than 4 mmol/L and 2 mg/dL, respectively. Her serum creatinine remained near baseline, between 2.19 and 2.51 mg/dL, throughout this illness (creatinine clearance 33 to 27 mL/min) from a baseline of 2.7 mg/dL (27 mL/min). A CK on admission was 29 IU/L and a recheck after 72 hours on the bumetanide infusion was 95 IU/L. Her albumin was 4.3 g/dL. Her pain was treated with a combination of acetaminophen and narcotics with some relief. Approximately 72 hours after initiation of the bumetanide infusion her pain began to improve and later resolved. No change in the dose of her bumetanide infusion was made during this time. Pain syndromes are a known adverse effect associated with bumetanide whose mechanism is not understood. In all reported cases, the episodes are characterized by generalized musculoskeletal pain, cramping, and/or weakness, sometimes severe enough to limit mobility [1-3]. In one series, nine patients with baseline CKD developed severe pain with oral and IV bolus doses of bumetanide starting 2-4 hours after dosing [2]. Eight patients also had hypoalbuminemia. Another report described similar symptoms in patients receiving continuous bumetanide infusions [1]. However, no laboratory abnormalities were noted to be associated with symptoms, including renal failure or hypoalbuminemia. In all cases the symptoms resolved with discontinuation of bumetanide, and in 2 cases the symptoms recurred during re-challenge with bumetanide. Changing to equivalent or higher doses of furosemide did not cause symptoms to recur. Those prior cases are similar to the case presented above except for our patient’s extreme sensitivity to touch. This presentation of allodynia suggests a possible neuropathic mechanism for bumetanide-induced pain. We speculate that this pain syndrome may be related to bumetanide’s effects on KCC2 and NKCC1, two cation-chloride cotransporters that play important roles in regulating pain transmission (Figure 1). Figure 1 Model of bumetanide interaction with nociception Allodynia is thought to result from a disruption in the way nociceptive neurons respond to non-painful stimuli. Normally these non-painful signals inhibit the transmission of pain by stimulating GABAergic interneurons in the spinal cord. The interneurons alter the intracellular chloride concentration in nociceptive neurons by opening GABA-A ligand-gated chloride channels. NKCC1, a Na-K-2Cl cotransporter sensitive to bumetanide, promotes a high resting chloride concentration in peripheral afferent neurons. Therefore, non-painful stimuli open GABA-mediated chloride channels and the resulting chloride efflux partially depolarizes the cell. This so-called primary afferent depolarization reduces the magnitude of nociceptive action potentials and decreases transmission of pain signals [4-5]. NKCC1 is upregulated in chronic pain and inflammatory conditions resulting in elevated intracellular chloride levels. As a result, normally non-painful stimuli produce a larger chloride efflux and generate sufficient depolarization to induce full action potentials, leading to allodynia [6]. Using bumetanide to block NKCC1 can decrease allodynia in animal models of chronic pain [7]. However, blocking KCC2, a bumetanide-sensitive K-Cl cotransporter located on central ascending afferent neurons, seems to have the opposite effect of inducing allodynia. KCC2 maintains a low resting chloride concentration in ascending neurons such that GABAergic interneurons stimulate chloride influx. This hyperpolarizes the neuron and blocks nociceptive action potentials [5, 8]. Blocking KCC2 reverses this effect by raising chloride concentrations and promoting GABA-induced depolarizations, resulting in hypersensitivity to pain. While blockade of KCC2 provides a possible etiology of bumetanide-induced pain syndromes, bumetanide has an approximately 500 fold higher affinity for NKCC1 than KCC2 [9]. Thus, doses of bumetanide necessary to inhibit KCC2 would also be expected to cause NKCC1 inhibition resulting in ototoxicity, which was not reported by our patient. Yet loop diuretics may have different effects on pain depending on the baseline state of the subject. For example, one study found that intrathecal furosemide increased the pain threshold in rats that had been subjected to trauma but decreased the pain threshold in intact rats [10]. Thus, in the setting of inflammation and NKCC1 upregulation, there may be an increased NKCC1/KCC2 receptor expression and/or activity ratio that would result in a net effect of analgesia after bumetanide exposure. This ratio may be substantially lower under normal physiological conditions, leading to allodynia after administration of bumetanide. Alternatively, as bumetanide-associated pain syndromes are only seen in a subset of patients, these patients may have an isoform of KCC2 that is more sensitive to bumetanide. The mechanisms of bumetanide-associated pain syndromes will need to be more fully elucidated in order to devise strategies to counter-act this effect.

KCC2, a neuronal-specific K-Cl cotransporter, is involved in pain perception physiology through its effects on postsynaptic inhibition in spinal cord neurons. We injected a newly identified, highly potent and selective inhibitor of KCC2 (D4), an inactive structural variant (D4.14), and the Na-K-2Cl cotransporter (NKCC1) inhibitor, bumetanide, into the intrathecal space of mice to measure their effect on heat-evoked nociceptive responses.Commercially available intrathecal catheters were modified and surgically placed into 2 cohorts of 10 mice. After recovery from the procedure, the mice were injected with D4, D4.14, and bumetanide through this catheter. Nociceptive measurements (hotplate assay, tail flick assay) were performed after injection of each of the test drugs and compared with vehicle controls.Two mice in each cohort were omitted because of postprocedure complications. There was a statistically significant decrease (P0.01) in withdrawal latency after injection of the active KCC2 inhibitor but not after injection of the inactive compound (P = 0.78), as measured by hotplate assay at 55°C. Injection of bumetanide significantly increased withdrawal latency (P = 0.02) at the same temperature. These results were confirmed using tail flick assays performed at 49°C.Inhibition of KCC2 by D4 led to decreased heat-evoked withdrawal latency in mice, as measured by hotplate and tail flick assays, whereas inhibition of NKCC1 by bumetanide resulted in increased response latencies to heat stimuli as measured by both of these nociceptive tests.