Search

While consensus exists regarding risk factors for priapism, predictors of operative intervention are less well established. We assessed patient and hospital-level predictors associated with penile surgical intervention (PSI) for patients admitted with acute priapism, as well as length of stay (LOS) and total hospital charges using the National Inpatient Sample (2010-2015). Inpatients with acute priapism were stratified by PSI, defined as penile shunts, incisions, and placement of penile prostheses, exclusive of irrigation procedures. Survey-weighted logistic regression models were utilized to assess predictors of PSI. Negative binomial regression and generalized linear models with logarithmic transformation were used to compare PSI to LOS and total hospital charges, respectively. Among 14,529 weighted hospitalizations, 4,953 underwent PSI. Non-Medicare insurances, substance abuse, and ≥3 Elixhauser comorbidities had increased odds of PSI. Conversely, Black patients, sickle cell disease, alcohol abuse, neurologic diseases, malignancies, and teaching hospitals had lower odds. PSI coincided with shorter median LOS (adjusted IRR: 0.62; p < 0.001) and lower ratio of the mean hospital charges (adjusted Ratio: 0.49; p < 0.001). Additional subgroup analysis revealed penile incisions and shunts primarily associated with reduced LOS (adjusted IRR: 0.66; p < 0.001) and total hospital charges (adjusted Ratio: 0.49; p < 0.001). Further work is required to understand predictors of poor outcomes in these populations., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Radiation-induced hemorrhagic cystitis is a complication of pelvic radiotherapy, with an incidence of up to 5%. The resultant hematuria may be severe and refractory to conservative measures. Our objective was to describe the pattern of inpatient treatments among a cohort of patients with radiation-induced hemorrhagic cystitis requiring pharmacological management., Methods: We conducted a retrospective case series to identify all inpatient admissions at a single institution during which patients with radiation cystitis underwent pharmacological intervention for refractory hematuria between 2004 and 2019. Patient demographics, medical history, details of radiation therapy, and relevant admission data were collected. Details of treatment, including the use of pharmacotherapy and surgical treatment, were reviewed and summarized., Results: We identified 21 patients who were treated during 26 admissions. Most were male (91%) with a history of external beam radiation therapy (86%), primarily for prostate cancer (85%), and a median age of 73 (IQR: 67-85). Most patients received continuous bladder irrigation as the first intervention during their admission (65%), for a median duration of 40 hours (IQR: 25-59). Eleven separate pharmacologic agents were used, with variations in initial pharmacotherapy utilization over time. Most patients were treated with a combination of surgical and pharmacological interventions (85%). The median length of stay was 9 days (IQR: 5-17) and the 90-day readmission rate was 35%., Conclusions: Pharmacologic treatment for refractory radiation-induced hemorrhagic cystitis is inconsistent and lacks evidence to support treatment strategies. Further work is needed to determine the optimal management for this morbid complication., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: In the absence of overt infection signs, clinical criteria for early intervention in patients with ureteral stones are poorly defined. We aimed to develop a model that can identify patients who are at risk for developing sepsis if discharged home from the emergency department (ED). Materials and Methods: We retrospectively reviewed patients between January 2010 and December 2019 who were discharged from the ED after diagnosis of ureteral stones. The primary outcome was sepsis requiring urgent surgical decompression. We used multivariable logistic regression to identify predictors of sepsis. We refined the model using backward stepwise regression with a threshold p -value of 0.05. Results: We identified 1331 patients who were discharged from the ED with ureteral stones. Of these patients, 22 (2%) subsequently developed sepsis requiring urgent decompression. In the initial multivariable model, female gender (odds ratio [OR]: 2.82, p  = 0.039) and urine white blood cells (WBCs) (OR: 1.02 per cell count, p  < 0.001) were predictive of sepsis. After performing backward stepwise regression, female gender, urine WBCs, and leukocytosis (WBCs >15,000/mm 3 ) met criteria for inclusion in the model. A logistic model including these variables predicted sepsis with an internally cross-validated area under the curve (AUC) of 0.79. Among patients with urine cultures completed in the ED, rates of sepsis were 9% in patients with positive cultures and 1% in patients with negative cultures ( p  < 0.001). Antibiotic usage was not protective against developing sepsis. Conclusions: Sepsis is a rare complication among patients with ureteral stones selected for conservative management. The presence of elevated urine WBCs and female gender can help identify patients who are at risk of developing sepsis. Patients with risk factors should be managed with an increased index of suspicion for infection and may benefit from early intervention to reduce the risk of sepsis. Sepsis is more common in patients with positive urine cultures.

Objective: Male adolescents frequently present to the emergency department (ED) and many participate in behaviors increasing their risk of sexually transmitted infections and unintended pregnancies. Although the ED visit may represent an intervention opportunity, how best to design and deliver a sexual health intervention matching the preferences of adolescent male users is unclear. Our objective was to explore receptivity to and preferences for sexual health interventions among adolescent male ED patients., Methods: In this qualitative study, we asked sexually active male ED patients aged 14 to 21 years about their attitudes toward ED-based sexual health interventions and preferences for intervention modalities. Participants interacted with an early prototype of a digital intervention to gather specific feedback. Enrollment continued until saturation of key themes. Interviews were recorded, transcribed, and coded based on thematic analysis using NVivo., Results: Participants (n = 42) were predominantly 18 to 21 years (63%) and Hispanic (79%). Although most (71%) had sex in the prior 3 months, 45% did not use a condom at last intercourse and 17% had impregnated a partner. Participants viewed the ED visit as unused time without distracting influences, suitable for educational sexual health interventions. They considered ED-based digital interventions a reliable and confidential source of information. Engaging interventions allowed user control and provided novel and relatable content., Conclusions: Adolescent male ED patients are receptive to ED-based digital sexual health interventions. These identified preferences should be considered when designing future user-informed sexual health interventions for the ED setting., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The acute care surgery model has led to improved outcomes for emergent surgical conditions, but similar models of care have not been implemented in urology. Our department implemented an acute care urology (ACU) service in 2015, and the service evolved in 2018. We aimed to evaluate the impact of the ACU model on the management of nephrolithiasis. Materials and Methods: We conducted a retrospective review of all patients with urology consults in the emergency department for nephrolithiasis, who required surgical intervention from 2013 to 2019. Patients were divided into three cohorts based on date of consultation: Pre-ACU (2013-2014), Phase 1 (2015-2017), and Phase 2 (2018-2019). Results: We identified 733 patients with nephrolithiasis requiring intervention (162 pre-ACU, 334 Phase 1, and 237 Phase 2). Before ACU implementation, median time from consult to definitive intervention was 36 days. After ACU implementation, median time to intervention decreased to 22 days in Phase 1 ( p  < 0.001) and 15 days in Phase 2 ( p  < 0.001). On multivariable Cox regression, the hazard of definitive intervention improved in Phase 1 (hazard ratio [HR] 1.90, p  < 0.001) and in Phase 2 (HR 1.80, p  < 0.001). Rates of primary definitive intervention without initial decompression and loss to follow-up were also significantly improved, compared to the pre-ACU cohort. Conclusions: Implementation of a structured ACU service was associated with improved time to treatment for patients with acute nephrolithiasis, as well as increased primary definitive intervention and improved follow-up care. This model of care has potential to improve patient outcomes for nephrolithiasis and other acute urological conditions.

Introduction: Partial nephrectomy (PN) is the preferred treatment for localized renal masses (LRM), however its use is not uniform across patient socioeconomic (SES) factors. Our hypothesis is that the effect of increased SES on surgical management of LRMs in New York City (NYC) will not be the same for Black and White patients., Patients and Methods: Patients were identified from the New York State Cancer Registry (NYSPACED) treated for LRMs with PN or radical nephrectomy from 2004 to 2016. We identified patients' home neighborhoods through Public Use Microdata Areas (PUMA) in NYSCAPED and used a US Census SES index. Logistic regression was used to determine the association of race and SES on receipt of PN, controlling for age, ethnicity, gender, and diagnosis year., Results: On unadjusted analyses, patients from higher PUMA SES quartiles were more likely to receive PN (OR = 1.07, P < 0.05), while Black patients were less likely to receive PN as compared to White patients (OR = 0.66, P < 0.001). Multivariable analysis showed a significant interaction between race and SES quartile (interaction P = 0.005) such that the effect of PUMA SES on receipt of PN was modified by race. PN receipt for Black vs. White patients was significantly different within the highest SES quartile (OR = 0.44, P < 0.001), but not within the lowest., Conclusion: In NYC, patients from higher SES quartile neighborhoods had significantly increased odds for receipt of PN for LRMs. As neighborhood SES quartile increased, White patients were significantly more likely to receive PN, while Black patients were not., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: In the United States, New York State's health care system experienced unprecedented stress as an early epicenter of the coronavirus disease 2019 (COVID-19) pandemic. This study aims to assess the level of hopelessness in New York State physicians working on the frontlines during the first wave of the COVID-19 outbreak., Methods: A confidential online survey sent to New York State health care workers by the state health commissioner's office was used to gather demographic and hopelessness data as captured by a brief Hopelessness Scale. Adjusted linear regression models were used to assess the associations of physician age, sex, and number of triage decisions made, with level of hopelessness., Results: In total, 1330 physicians were included, of whom 684 were male (51.4%). Their average age was 52.4 years (SD=12.7), with the majority of respondents aged 50 years and older (55.2%). Almost half of the physician respondents (46.3%) worked directly with COVID-19 patients, and 163 (12.3%) were involved in COVID-19-related triage decisions. On adjusted analysis, physicians aged 40 to 49 years had significantly higher levels of hopelessness compared with those aged 50 years or more (μ=0.441, SD=0.152, P=0.004). Those involved in 1 to 5 COVID-19-related triage decisions had a significantly lower mean hopelessness score (μ=-0.572, SD=0.208, P=0.006) compared with physicians involved in none of these decisions., Conclusion: Self-reported hopelessness was significantly higher among physicians aged 40 to 49 years and those who had not yet been involved in a life or death triage decision. Further work is needed to identify strategies to support physicians at high risk for adverse mental health outcomes during public health emergencies such as the COVID-19 pandemic., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: It has been hypothesized that polypharmacy may increase the frequency of multidrug interactions (MDIs) where one drug interacts with two or more other drugs, amplifying the risk of associated adverse drug events (ADEs). The main objective of this study was to determine the prevalence of MDIs in medication lists of elderly ambulatory patients and to identify the medications most commonly involved in MDIs that amplify the risk of ADEs., Methods: Medication lists stored in the electronic health record (EHR) of 6,545 outpatients ≥60 years old were extracted from the enterprise data warehouse. Network analysis identified patients with three or more interacting medications from their medication lists. Potentially harmful interactions were identified from the enterprise drug-drug interaction alerting system. MDIs were considered to amplify the risk if interactions could increase the probability of ADEs., Results: MDIs were identified in 1.3 % of the medication lists, the majority of which involved three interacting drugs (75.6 %) while the remainder involved four (15.6 %) or five or more (8.9 %) interacting drugs. The average number of medications on the lists was 3.1 ± 2.3 in patients with no drug interactions and 8.6 ± 3.4 in patients with MDIs. The prevalence of MDIs on medication lists was greater than 10 % in patients prescribed bupropion, tramadol, trazodone, cyclobenzaprine, fluoxetine, ondansetron, or quetiapine and greater than 20 % in patients prescribed amiodarone or methotrexate. All MDIs were potentially risk-amplifying due to pharmacodynamic interactions, where three or more medications were associated with the same ADE, or pharmacokinetic, where two or more drugs reduced the metabolism of a third drug. The most common drugs involved in MDIs were psychotropic, comprising 35.1 % of all drugs involved. The most common serious potential ADEs associated with the interactions were serotonin syndrome, seizures, prolonged QT interval and bleeding., Conclusions: An identifiable number of medications, the majority of which are psychotropic, may be involved in MDIs in elderly ambulatory patients which may amplify the risk of serious ADEs. To mitigate the risk, providers will need to pay special attention to the overlapping drug-drug interactions which result in MDIs., (© 2021. The Author(s).)

Introduction: Priapism is a urologic emergency that may require surgical intervention in cases refractory to supportive care. Exchange transfusion (ET) has been previously used to manage sickle cell disease (SCD), including in priapism; however, its utilization in the context of surgical intervention has not been well-established., Aim: To explore the utilization of ET, as well as other patient and hospital-level factors, associated with surgical intervention for SCD-induced priapism METHODS: Using the National Inpatient Sample (2010-2015), males diagnosed with SCD and priapism were stratified by need for surgical intervention. Survey-weighted regression models were used to analyze the association of ET to surgical intervention. Furthermore, negative binomial regression and generalized linear models with logarithmic transformation were used to compare ET vs surgery to length of hospital stay (LOS) and total hospital charges, respectively., Main Outcome Measures: Predictors of surgical intervention among patients with SCD-related priapism RESULTS: A weighted total of 8,087 hospitalizations were identified, with 1,782 (22%) receiving surgical intervention for priapism, 484 undergoing ET (6.0%), and 149 (1.8%) receiving combined therapy of both ET and surgery. On multivariable regression, pre-existing Elixhauser comorbidities (e.g. ≥2 Elixhauser: OR: 2.20; P < 0.001), other forms of insurance (OR: 2.12; P < 0.001), and ET (OR: 1.99; P = 0.009) had increased odds of undergoing surgical intervention. In contrast, Black race (OR: 0.45; P < 0.001) and other co-existing SCD complications (e.g. infectious complications OR: 0.52; P < 0.001) reduced such odds. Compared to supportive care alone, patients undergoing ET (adjusted IRR: 1.42; 95% CI: 1.10-1.83; P = 0.007) or combined therapy (adjusted IRR: 1.42; 95% CI: 111-1.82; P < 0.001) had a longer LOS vs. surgery alone (adjusted IRR: 0.85; 95% CI: 0.74-0.97; P = 0.017). Patients receiving ET (adjusted Ratio: 2.39; 95% CI: 1.52-3.76; P < 0.001) or combined therapy (adjusted Ratio: 4.42; 95% CI: 1.67-11.71; P = 0.003) had higher ratio of mean hospital charges compared with surgery alone (adjusted Ratio: 1.09; 95% CI: 0.69-1.72; P = 0.710)., Conclusions: Numerous factors were associated with the need for surgical intervention, including the use of ET. Those receiving ET, as well as those with combined therapy, had a longer LOS and increased total hospital charges. Ha AS, Wallace BK, Miles C, et al. Exploring the Use of Exchange Transfusion in the Surgical Management of Priapism in Sickle Cell Disease: A Population-Based Analysis. J Sex Med 2021;18:1788-1796., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To describe contemporary perioperative outcomes for octogenarians managed under an Enhanced Recovery After Surgery (ERAS) protocol. ERAS protocols have improved outcomes in radical cystectomy (RC), though outcomes for octogenarian patients undergoing RC in the modern ERAS era are not well researched. ERAS components have been gradually implemented into our clinical care pathways over the past 10 years., Methods and Materials: Octogenarians undergoing RC at our institution were retrospectively identified between 2009 and 2019. Cox proportional hazards models examined changes in time to hospital discharge and time to bowel movement over time, and logistic regression models examined differences in 90-day readmissions and discharge dispositions over time. Secondary analyses examined the effect of alvimopan on time to hospital discharge and time to bowel movement using log-rank tests, along with 90-day readmissions and discharge dispositions using Chi-squared tests., Results: Seventy octogenarian patients underwent RC during the study period. Median time to bowel movement was 6 days, while median time to hospital discharge was 9 days. Two-thirds of patients were discharged to home and 22% were readmitted within 90 days. There were no statistically significant associations between year of surgery and perioperative outcomes. Patients taking alvimopan had decreased time to hospital discharge (hazard ratio = 2.7, 95% confidence interval [1.5, 5.0], P = 0.002), but showed no difference in other perioperative outcomes., Conclusions: Octogenarians treated with RC had no significant changes in perioperative outcomes during the implementation of ERAS components at our institution. However, octogenarians taking alvimopan were observed to have decreased time to hospital discharge., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Socioeconomic factors may impact how a patient is treated for prostate cancer (CaP). Our objective was to determine if county of residence or neighborhood socioeconomic characteristics were associated with treatment for CaP in New York City (NYC)., Materials and Methods: We used the NYSPACED database to identify men aged 40 to 80 years with localized CaP in NYC between 2004 and 2016. We categorized patients into receiving either aggressive local therapy (ALT) or non-aggressive treatment (NT). We identified borough of residence through NYSPACED and used Public Use Microdata Area (PUMA) designation to define neighborhood characteristics using United States Census data. We hypothesized that differences exist in use of ALT according to county of residence and neighborhood characteristics. We used multivariable logistic regression to test the association between county of residence and ALT as well as between ALT and PUMA characteristics., Results: Our cohort included 40,668 patients. Overall, 80% had ALT, and 21% had NT. NT use increased over time from 16% in 2004 to 32% in 2016 (P < .001). On multivariable logistic regression, patients in Manhattan were less likely to receive ALT compared with those in other boroughs (P < .001). PUMAs with lower education attainment, larger foreign-born populations, lower crime rate, and higher median income were significantly associated with receipt of ALT (P < .05)., Conclusions: We observed significant differences in use of treatment for men with newly diagnosed CaP in NYC. The ability to receive this treatment was associated with borough of residence as well as neighborhood socioeconomic characteristics. Additional research is required to identify barriers in access to NT within NYC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: This study aimed to examine whether changes in intracranial pressure (ICP) waveform morphologies can be used as a biomarker for early detection of ventriculitis., Methods: Consecutive patients (N = 1653) were prospectively enrolled in a hemorrhage outcomes study from 2006 to 2018. Of these, 435 patients (26%) required external ventricular drains (EVDs) and 76 (17.5% of those with EVDs) had ventriculitis treated with antibiotics. Nineteen patients (25% of those with ventriculitis) showed culture-positive cerebrospinal fluid (CSF) and were included in the present analysis. CSF was routinely cultured three times per week and additionally if infection was suspected. EVDs were left open for drainage, with ICP assessed hourly by clamping. Using wavelet analysis, we extracted uninterrupted segments of ICP waveforms. We extracted dominant pulses from continuous high-resolution data, using morphological clustering analysis of intracranial pressure (MOCAIP). Then we applied k-means clustering, using the dynamic time warping distance to obtain morphologically similar groupings. Finally, metaclusters and further-split clusters (when equipoise existed) were categorized for broad comparison by clinician consensus., Results: We extracted 275,911 dominant pulses from 459.9 h of EVD data. Of these, 112,898 pulses (40.9%) occurred before culture positivity, 41,300 pulses (15.0%) occurred during culture positivity, and 121,713 pulses (44.1%) occurred after it. K-means identified 20 clusters, which were further grouped into metaclusters: tri-/biphasic, single-peak, and artifactual waveforms. Prior to ventriculitis, 61.8% of dominant pulses were tri-/biphasic; this percentage reduced to 22.6% during ventriculitis and 28.4% after it (p < 0.0001). One day before the first positive cultures were collected, the distribution of metaclusters changed to include more single-peak and artifactual ICP waveforms (p < 0.0001)., Conclusion: The distribution of ICP waveform morphology changes significantly prior to clinical diagnosis of ventriculitis and may be a potential biomarker.

The association between impaired brain perfusion, cerebrovascular reactivity status and the risk of ictal events in patients with subarachnoid hemorrhage is unknown. We identified 13 subarachnoid hemorrhage (SAH) patients with seizures and 22 with ictal-interictal continuum (IIC), and compared multimodality physiological recordings to 38 similarly poor-grade SAH patients without ictal activity. We analyzed 10,179 cumulative minutes of seizure and 12,762 cumulative minutes of IIC. Cerebrovascular reactivity (PRx) was not different between subjects with seizures, IIC, or controls. Cerebral perfusion pressure (CPP) was higher in patients with seizures [99 ± 6.5, p  = .005] and IIC [97 ± 8.5, p  = .007] when compared to controls [89 ± 12.3]. DeltaCPP, defined as actual CPP minus optimal CPP (CPPopt), was also higher in the seizure group [8.3 ± 7.9, p  = .0003] and IIC [8.1 ± 10.3, p  = .0006] when compared to controls [-0.1 ± 5]. Time spent with supra-optimal CPP was higher in the seizure group [342 ± 213 min/day, p  = .002] when compared to controls [154 ± 120 min/day]. In a temporal examination, a supra-optimal CPP preceded increased seizures and IIC in SAH patients, an hour before and continued to increase during the events [ p  < .0001].

Objective: Intracranial pressure (ICP) is an important and established clinical measurement that is used in the management of severe acute brain injury. ICP waveforms are usually triphasic and are susceptible to artifact because of transient catheter malfunction or routine patient care. Existing methods for artifact detection include threshold-based, stability-based, or template matching, and result in higher false positives (when there is variability in the ICP waveforms) or higher false negatives (when the ICP waveforms lack complete triphasic components but are valid)., Approach: We hypothesized that artifact labeling of ICP waveforms can be optimized by an active learning approach which includes interactive querying of domain experts to identify a manageable number of informative training examples., Main Results: The resulting active learning based framework identified non-artifactual ICP pulses with a superior AUC of 0.96 + 0.012, compared to existing methods: template matching (AUC: 0.71 + 0.04), ICP stability (AUC: 0.51 + 0.036) and threshold-based (AUC: 0.5 + 0.02)., Significance: The proposed active learning framework will support real-time ICP-derived analytics by improving precision of artifact-labelling.

Background and Objectives: Despite extensive examination of physician self-disclosure to patients and colleagues, no studies have directly investigated if physician faculty disclose personal health information to trainees for clinical teaching purposes. This study examines the types of personal medical information (personal health narratives) family medicine faculty use during resident teaching encounters and the beliefs of family medicine faculty about such disclosure., Methods: Due to the exploratory nature of this study, the authors relied upon the triangulation of qualitative research methods to verify the use of and purpose for sharing personal health narratives by family physician faculty during teaching encounters. Direct observation, depth interviews, an attitude survey, and focus groups were sequentially used to evoke their beliefs about the purpose, benefits, and risks of sharing personal health narratives with residents., Results: Ninety-eight percent of survey respondents acknowledged using personal health narratives in teaching, and half reported doing so infrequently. A large majority considered the practice an effective teaching method, but respondents were divided on potential risks. Focus group participants believed that disclosing health information is a powerful teaching method that should be utilized purposefully. Participants identified a need for guidance on how to effectively incorporate personal health narratives during teaching., Conclusions: The use of personal health narratives in teaching is well accepted among the physician faculty in this study. Although participants endorsed the practice, none had been trained to integrate self-disclosure in teaching, and most had not consciously considered the limits and risks of sharing their health histories with residents. Further research is needed to determine the prevalence, range, and depth of faculty disclosure in teaching and to assess the impact on learners.

Background and Purpose: KCa3.1, a calcium-activated potassium channel, regulates ion and fluid secretion in the lung and gastrointestinal tract. It is also expressed on vascular endothelium where it participates in blood pressure regulation. However, the expression and physiological role of KCa3.1 in blood-brain barrier (BBB) endothelium has not been investigated. BBB endothelial cells transport Na(+) and Cl(-) from the blood into the brain transcellularly through the co-operation of multiple cotransporters, exchangers, pumps, and channels. In the early stages of cerebral ischemia, when the BBB is intact, edema formation occurs by processes involving increased BBB transcellular Na(+) transport. This study evaluated whether KCa3.1 is expressed on and participates in BBB ion transport., Methods: The expression of KCa3.1 on cultured cerebral microvascular endothelial cells, isolated microvessels, and brain sections was evaluated by Western blot and immunohistochemistry. Activity of KCa3.1 on cerebral microvascular endothelial cells was examined by K(+) flux assays and patch-clamp. Magnetic resonance spectroscopy and MRI were used to measure brain Na(+) uptake and edema formation in rats with focal ischemic stroke after TRAM-34 treatment., Results: KCa3.1 current and channel protein were identified on bovine cerebral microvascular endothelial cells and freshly isolated rat microvessels. In situ KCa3.1 expression on BBB endothelium was confirmed in rat and human brain sections. TRAM-34 treatment significantly reduced Na(+) uptake, and cytotoxic edema in the ischemic brain., Conclusions: BBB endothelial cells exhibit KCa3.1 protein and activity and pharmacological blockade of KCa3.1 seems to provide an effective therapeutic approach for reducing cerebral edema formation in the first 3 hours of ischemic stroke., (© 2014 American Heart Association, Inc.)

Brain edema forms rapidly in the early hours of ischemic stroke by increased secretion of Na, Cl, and water into the brain across an intact blood-brain barrier (BBB), together with swelling of astrocytes as they take up the ions and water crossing the BBB. Our previous studies provide evidence that luminal BBB Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) participate in ischemia-induced edema formation. NKCC1 and two NHE isoforms, NHE1 and NHE2, reside predominantly at the luminal BBB membrane. NKCC and NHE activities of cerebral microvascular endothelial cells (CMEC) are rapidly stimulated by the ischemic factors hypoxia, aglycemia, and AVP, and inhibition of NKCC and NHE activities by bumetanide and HOE642, respectively, reduces brain Na uptake and edema in the rat middle cerebral artery occlusion model of stroke. The present study was conducted to further explore BBB NHE responses to ischemia. We examined whether ischemic factor-stimulated NHE activity is sustained over several hours, when the majority of edema forms during stroke. We also examined whether ischemic factors alter NHE1 and/or NHE2 protein abundance. Finally, we conducted initial studies of ERK1/2 MAP kinase involvement in BBB NHE and NKCC responses to ischemic factors. We found that hypoxia, aglycemia, and AVP increase CMEC NHE activity through 5 h and that NHE1, but not NHE2, abundance is increased by 1- to 5-h exposures to these factors. Furthermore, we found that these factors rapidly increase BBB ERK1/2 activity and that ERK1/2 inhibition reduces or abolishes ischemic factor stimulation of NKCC and NHE activities., (Copyright © 2014 the American Physiological Society.)

Previous studies have provided evidence that, in the early hours of ischemic stroke, a luminal membrane blood-brain barrier (BBB) Na-K-Cl cotransporter (NKCC) participates in ischemia-induced cerebral edema formation. Inhibition of BBB NKCC activity by intravenous bumetanide significantly reduces edema and infarct in the rat permanent middle cerebral artery occlusion model of ischemic stroke. We demonstrated previously that the BBB cotransporter is stimulated by hypoxia, aglycemia, and AVP, factors present during cerebral ischemia. However, the underlying mechanisms have not been known. Ischemic conditions have been shown to activate p38 and JNK MAP kinases (MAPKs) in brain, and the p38 and JNK inhibitors SB-239063 and SP-600125, respectively, have been found to reduce brain damage following middle cerebral artery occlusion and subarachnoid hemorrhage, respectively. The present study was conducted to determine whether one or both of these MAPKs participates in ischemic factor stimulation of BBB NKCC activity. Cultured cerebral microvascular endothelial cell NKCC activity was evaluated as bumetanide-sensitive (86)Rb influx. Activities of p38 and JNK were assessed by Western blot and immunofluorescence methods using antibodies that detect total vs. phosphorylated (activated) p38 or JNK. We report that p38 and JNK are present in cultured cerebral microvascular endothelial cells and in BBB endothelial cells in situ and that hypoxia (7% O(2) and 2% O(2)), aglycemia, AVP, and O(2)-glucose deprivation (5- to 120-min exposures) all rapidly activate p38 and JNK in the cells. We also provide evidence that SB-239063 and SP-600125 reduce or abolish ischemic factor stimulation of BBB NKCC activity. These findings support the hypothesis that ischemic factor stimulation of the BBB NKCC involves activation of p38 and JNK MAPKs.

Increased blood-brain barrier (BBB) Na-K-Cl cotransporter activity appears to contribute to cerebral edema formation during ischemic stroke. We have shown previously that inhibition of BBB Na-K-Cl cotransporter activity reduces edema and infarct in the rat middle cerebral artery occlusion (MCAO) model of ischemic stroke. We have also shown that the BBB cotransporter is stimulated by the ischemic factors hypoxia, aglycemia, and arginine vasopressin (AVP), although the mechanisms responsible are not well understood. AMP-activated protein kinase (AMPK), a key mediator of cell responses to stress, can be activated by a variety of stresses, including ischemia, hypoxia, and aglycemia. Previous studies have shown that the AMPK inhibitor Compound C significantly reduces infarct in mouse MCAO. The present study was conducted to evaluate the possibility that AMPK participates in ischemic factor-induced stimulation of the BBB Na-K-Cl cotransporter. Cerebral microvascular endothelial cells (CMEC) were assessed for Na-K-Cl cotransporter activity as bumetanide-sensitive (86)Rb influx. AMPK activity was assessed by Western blot analysis and immunofluorescence methods using antibodies that detect total versus phosphorylated (activated) AMPK. We found that hypoxia (7% and 2% O(2)), aglycemia, AVP, and oxygen-glucose deprivation (5- to 120-min exposures) increase activation of AMPK. We also found that Compound C inhibition of AMPK reduces hypoxia-, aglycemia-, and AVP-induced stimulation of CMEC Na-K-Cl cotransporter activity. Confocal immunofluorescence of perfusion-fixed rat brain slices revealed the presence of AMPK, both total and phosphorylated kinase, in BBB in situ of both control and ischemic brain. These findings suggest that ischemic factor stimulation of the BBB Na-K-Cl cotransporter involves activation of AMPK.

In the early hours of ischemic stroke, cerebral edema forms as Na, Cl, and water are secreted across the blood-brain barrier (BBB) and astrocytes swell. We have shown previously that ischemic factors, including hypoxia, aglycemia, and arginine vasopressin (AVP), stimulate BBB Na-K-Cl cotransporter (NKCC) and Na/H exchanger (NHE) activities and that inhibiting NKCC and/or NHE by intravenous bumetanide and/or HOE-642 reduces edema and infarct in a rat model of ischemic stroke. Estradiol also reduces edema and infarct in this model and abolishes ischemic factor stimulation of BBB NKCC and NHE. There is evidence that NKCC and NHE also participate in ischemia-induced swelling of astrocytes. However, little is known about estradiol effects on astrocyte cell volume. In this study, we evaluated the effects of AVP (100 nM), hypoxia (7.5% O(2)), aglycemia, hypoxia (2%)/aglycemia [oxygen glucose deprivation (OGD)], and estradiol (1-100 nM) on astrocyte cell volume using 3-O-methyl-d-[(3)H]glucose equilibration methods. We found that AVP, hypoxia, aglycemia, and OGD (30 min to 5 h) each significantly increased astrocyte cell volume, and that estradiol (30-180 min) abolished swelling induced by AVP or hypoxia, but not by aglycemia or OGD. Bumetanide and/or HOE-642 also abolished swelling induced by AVP but not aglycemia. Abundance of aquaporin-4, known to participate in ischemia-induced astrocyte swelling, was significantly reduced following 7-day but not 2- or 3-h estradiol exposures. Our findings suggest that hypoxia, aglycemia, and AVP each contribute to ischemia-induced astrocyte swelling, and that the edema-attenuating effects of estradiol include reduction of hypoxia- and AVP-induced astrocyte swelling and also reduction of aquaporin-4 abundance.