Pharmacokinetics, Bioavailability, and Swallowing Safety With Riluzole Oral Film.

Dysphagia is highly prevalent in patients with amyotrophic lateral sclerosis (ALS). Riluzole is a US Food and Drug Administration-approved treatment for ALS. Riluzole oral film (ROF; Exservan™) contains riluzole in a polymer-based film matrix. The ROF is administered by placing on the tongue, where it dissolves and the drug is ingested with the saliva. Two clinical trials assessed the safety and tolerability of the ROF. Bioavailability and pharmacokinetics (PK) were evaluated in an open-label, randomized, single-dose, replicate crossover study of 50 mg of ROF and riluzole 50-mg tablets in 32 healthy volunteers. The second study was a videofluoroscopic swallowing examination conducted with nine patients with ALS before and after receiving a single dose of 50 mg of ROF. The primary outcome was change on penetration-aspiration scale (PAS) scores from pre- to post-dose. Overall, the PK parameters for ROF and riluzole tablets were comparable between treatments and administrations when administered under fasting conditions. Administration of ROF with food resulted in a 15% reduction in area under the curve and a 45% reduction in maximum serum concentration. A total of 44 treatment-emergent adverse events (AEs) were reported in the study; all were mild in severity. No serious AEs were observed and no subjects discontinued due to AEs. In the swallowing study, very little numerical or categorical change was observed following the dose of ROF. No evidence of deterioration of swallowing function was observed post-dose. The ROF was bioequivalent to riluzole tablets, was well tolerated, and had no detrimental effect on swallowing.

Hepatic Resection and Transplant in Glycogen Storage Diseases.

Patients with glycogen storage diseases pose unique management challenges to clinicians.These challenges are exacerbated wheneverthey undergo surgery as the basic anomaly in their glycogen storage pathways make them susceptible to organic acidosis, which may in turn complicate their preoperative, intraoperative, and postoperative course. Because of the rarity of these diseases, clinicians may not be aware of the specific management concerns. In the case reported here, a 37-year-old patient with glycogen storage disease type 1 underwentleft hepatectomy for hepatic adenomatosis, which was complicated by intraoperative severe lactic acidosis that was successfully treated. After successful hepatectomy, the patient underwent liver transplant without major lactic acidosis or hemodynamic instability. Early recognition and aggressive management of blood sugar and lactic acidosis in patients with glycogen storage diseases can allow for successful outcomes even when complex surgical procedures are required.

Rescue Hepatectomy and Anhepatic Phase Management After Primary Nonfunction in a Liver Transplant.

Primary nonfunction is a rare but lethal complication that occurs in a small number of liver transplants. When primary nonfunction occurs, the only definite treatment is retransplant; however, another liver might not be readily available at that time. Hence, a surgeon should be aware of the various options available at hand for patient care during the time interval between the primary nonfunction and retransplant. Here, we describe the management strategy that was devised to take care of an unstable anhepatic patient in the intensive care unit, care of the patient during anhepatic phase, and successful outcome with a second liver transplant. Our index patient was a recipient of a liver donated after cardiac death. While in the operating room, after reperfusion of the liver, the patient had right heart dysfunction leading to hemodynamic instability and congestion of the liver, which culminated in primary nonfunction. Graft hepatectomy had to be done on postoperative day 1 because of deteriorating condition of the patient, and the patient was maintained in anhepatic phase in the intensive care unit for 27 hours.

Intraoperative Cardiac Arrest During Adult Liver Transplantation: Incidence and Risk Factor Analysis From 7 Academic Centers in the United States.

BACKGROUND: Intraoperative cardiac arrest (ICA) has a reported frequency of 1 in 10,000 anesthetics but has a much higher estimated incidence in orthotopic liver transplantation (OLT). Single-center studies of ICA in OLT are limited by small sample size that prohibits multivariable regression analysis of risks. METHODS: Utilizing data from 7 academic medical centers, we performed a retrospective, observational study of 5296 adult liver transplant recipients (18-80 years old) between 2000 and 2017 to identify the rate of ICA, associated risk factors, and outcomes. RESULTS: ICA occurred in 196 cases (3.7% 95% confidence interval [CI], 3.2-4.2) and mortality occurred in 62 patients (1.2%). The intraoperative mortality rate was 31.6% in patients who experienced ICA. In a multivariable generalized linear mixed model, ICA was associated with body mass index (BMI) <20 (odds ratio [OR]: 2.04, 95% CI, 1.05-3.98; P = .0386), BMI ≥40 (2.16 [1.12-4.19]; P = .022), Model for End-Stage Liver Disease (MELD) score: (MELD 30-39: 1.75 [1.09-2.79], P = .02; MELD ≥40: 2.73 [1.53-4.85], P = .001), postreperfusion syndrome (PRS) (3.83 [2.75-5.34], P < .001), living donors (2.13 [1.16-3.89], P = .014), and reoperation (1.87 [1.13-3.11], P = .015). Overall 30-day and 1-year mortality were 4.18% and 11.0%, respectively. After ICA, 30-day and 1-year mortality were 43.9% and 52%, respectively, compared to 2.6% and 9.3% without ICA. CONCLUSIONS: We established a 3.7% incidence of ICA and a 1.2% incidence of intraoperative mortality in liver transplantation and confirmed previously identified risk factors for ICA including BMI, MELD score, PRS, and reoperation and identified new risk factors including living donor and length of surgery in this multicenter retrospective cohort. ICA, while rare, is associated with high intraoperative mortality, and future research must focus on therapy to reduce the incidence of ICA.

Examination of sulfonamide-based inhibitors of MMP3 using the conditioned media of invasive glioma cells.

Glioblastoma multiforme (GBM) is the deadliest and the most common primary malignant brain tumour. The median survival for patients with GBM is around one year due to the nature of glioma cells to diffusely invade that make the complete surgical resection of tumours difficult. Based upon the connexin43 (Cx43) model of glioma migration we have developed a computational framework to evaluate MMP inhibition in materials relevant to GBM. Using the ilomastat Leu-Trp backbone, we have synthesised novel sulphonamides and monitored the performance of these compounds in conditioned media expressing MMP3. From the results discussed herein we demonstrate the performance of sulfonamide based MMPIs included AP-3, AP-6, and AP-7.

Influence of the urethral pressure transducer in measuring Valsalva leak point pressure in women undergoing multichannel urodynamic testing.

AIMS: To determine if the air-charged urethral sensor balloon currently used in urodynamic testing (UDS) significantly impacts Valsalva leak point pressure (VLPP) measurements. METHODS: This is a prospective cohort study of women undergoing UDS at an academic institution. VLPPs were obtained at 150 mL and urodynamic capacity with and without the urethral pressure sensor in the urethra. VLPP measurements were analyzed using a Wilcoxon signed-rank test. Median and interquartile range are presented. RESULTS: Sixty-three patients were enrolled in the study, 53 were included in the primary analysis. The mean age of the subjects was 56.2 ± 12.1 years. Nine patients (16%) solely leaked when the balloon was not present in the urethra either with cough or during VLPP measurement. At both 150 mL and urodynamic capacity, when VLPP testing was performed, there was a significant difference (cmH2 O) between the control and intervention values, (76.2 [55.0, 97.0] vs 68.8 [46.3, 93.3], P = .0012; 79.3 [53, 96.5] vs 72.5 [50.8, 92.3], P = .04). There was also a statistically significant difference between the control and intervention values for the lowest leak value at 150 mL and capacity (70.5 [51, 94.5] vs 60.0 [40, 88] P = .002; 73.5 [49.5, 91.5] vs 61 [45, 88], P = .017). CONCLUSIONS: The higher VLPPs obtained with the urethral balloon in place indicate that the balloon may be the cause of falsely elevated VLPPs during urodynamic testing. Additionally, the balloon may mask a diagnosis of stress urinary incontinence in some patients.

Profound Intraoperative Hypotension Associated With Transfusion via the Belmont Fluid Management System.

This retrospective observational case series conducted at 2 large academic centers over a 4-year period consists of 15 cases of profound hypotension in surgical patients immediately after initiation of the Belmont Fluid Management System for rapid transfusion of blood products. Halting the infusion and administering vasoactive agents led to resolution of hypotension. Repeat transfusion with the Belmont system resulted in repeat hypotension unless counteracted with vasopressors. No etiology was elucidated. This represents the largest documented association of acute hypotensive transfusion reaction with any rapid infusion system in surgical patients.

Mild hypothermia is associated with improved outcomes in patients undergoing microvascular head and neck reconstruction.

OBJECTIVE: Microvascular free tissue transfer has become the standard for reconstruction for large defects. With long operative times and an increased surface area exposed, transient hypothermia is common, but it is unclear how this impacts surgical outcomes. This study evaluated the impact of core body temperature on free tissue flap outcomes in patients undergoing microvascular reconstruction. STUDY DESIGN: Retrospective data analysis. SETTING: Mount Sinai Hospital; NYC, NY; 2007-2016. SUBJECTS AND METHODS: Demographic information, mean/minimum/maximum body temperatures, and the presence of flap complications (venous thrombosis, arterial insufficiency, flap death, wound infection/dehiscence, fistula, chyle leak, hematoma/seroma) of 519 free tissue transfer patients were documented. Binomial logistic regression was used to examine associations between the presence of flap complications and mean temperature. Statistical analysis used SPSS, with p-values ≤0.05 deemed statistically significant. RESULTS: 393 soft-tissue and 125 osteocutaneous flaps were included. 19.8% (n = 103) patients had the presence of ≥1 flap complication, while 80.2% (n = 416) did not. Average temperature for all patients was 36.12 ±â€¯0.84 °C, with minimum at 34.43 ±â€¯0.97 °C and maximum at 37.24 ±â€¯1.23 °C. After controlling for several factors including: tumor stage, radiation, diabetes, BMI, age, sex, and flap type, there was a significant association between flap complications and mean intraoperative temperature (Exp(B) = 1.559, p = 0.004). CONCLUSION: Higher intraoperative temperatures were associated with worse outcomes. A mild relative hypothermia may improve flap outcomes in this population. This represents the largest study to date evaluating the impact of intraoperative temperature on free tissue transfer outcomes.

Intrathecal Morphine Administration Does Not Affect Survival After Liver Resection for Hepatocellular Carcinoma.

Introduction. Opioids may influence tumor recurrence and cancer-free survival in hepatocellular carcinoma (HCC). The relationship between intrathecal morphine administration, tumor recurrence, and patient survival after hepatectomy for HCC is unknown. Patients and Methods. This single-center, retrospective study included 1837 liver resections between July 2002 and December 2012; 410 cases were incorporated in the final univariate and multivariate analysis. Confirmatory propensity matching yielded 65 matched pairs (intrathecal morphine vs none). Primary outcomes were recurrence of HCC and survival. Secondary outcomes included characterization of factors associated with recurrence and survival. Results. Groups were similar except for increased coronary artery disease in the no intrathecal morphine group. All patients received volatile anesthesia. Compared with no intrathecal morphine (N = 307), intrathecal morphine (N = 103) was associated with decreased intraoperative intravenous morphine administration (median difference = 12.5 mg; 95% confidence interval [CI] = 5-20 mg). There was no difference in blood loss, transfusion, 3- or 5-year survival, or recurrence in the univariate analysis. Multivariate analysis identified covariates that significantly correlated with 5-year survival: intrathecal morphine (hazard ratio [HR] = 0.527, 95% CI = 0.296-0.939), lesion diameter (HR = 1.099, 95% CI = 1.060-1.141), vascular invasion (HR = 1.658, 95% CI = 1.178-2.334), and satellite lesions (HR = 2.238, 95% CI = 1.447-3.463). Survival analysis on the propensity-matched pairs did not demonstrate a difference in 5-year recurrence or survival. Discussion and Conclusion. Multivariate analysis revealed a significant association between intrathecal morphine and 5-year survival. This association did not persist after propensity matching. The association between intrathecal morphine and HCC recurrence and survival remains unclear and prospective work is necessary to determine whether an association exists.

Persistent acidosis after reperfusion-A prognostic indicator of increased 30-day and in-hospital postoperative mortality in liver transplant recipients.

During liver transplantation, the patient is at risk of developing progressive lactic acidosis. Following reperfusion, correction of acidosis may occur. In some patients, acidosis will worsen, a phenomenon referred to as persistent acidosis after reperfusion (PAAR). We compared postoperative outcomes in patients who manifested PAAR vs those that did not. All adult patients undergoing liver transplantation from 2002 to 2015 were included. PAAR is defined by the presence of a significant negative slope coefficient for base excess values measured after hepatic artery anastomosis through 72 hours postoperatively. Primary outcome was a composite of 30-day and in-hospital mortality. Secondary outcomes included: ICU LOS, total hospital LOS, and re-transplantation rate within 7 days. PAAR occurred in 10% of the transplant recipients. Patients with PAAR had higher MELD, BMI, and eGFR and demonstrated a longer median ICU LOS and hospital median LOS with a trend toward mortality difference. But, after propensity matching, the mortality rate difference became significantly higher in patients with PAAR compared with matched controls while the ICU LOS differences disappeared. The re-transplantation rates were similar also between the PAAR and no PAAR groups. The cohort with PAAR had a significant 30-day and in-hospital increase in mortality after propensity score matching.

Volume at First Leak Is Associated With Sling Failure Among Women With Stress Urinary Incontinence.

INTRODUCTION: Stress urinary incontinence at a low bladder volume is a clinically observed phenomenon that is not well studied with regard to treatment outcomes. The primary aim of our study was to determine if the volume at first leak is associated with sling outcome. METHODS: This is a retrospective cohort study evaluating whether urodynamic stress urinary incontinence observed at low volumes is associated with sling failure using the Synthetic Derivative database. Sling failure was defined as (1) undergoing a subsequent surgery for stress incontinence (eg, urethral bulking agent, repeat sling) or (2) leakage that was subjectively worse or unchanged from baseline. Sling success was defined as subjective improvement in incontinence or being dry. Intrinsic sphincter deficiency was defined as maximum urethral closure pressure 20 cm H20 or less or abdominal leak point pressure less than 60 cm H20. RESULTS: Outcome data were available for 168 of 206 women who underwent a sling after urodynamic testing from 2006 to 2014. Of the 168 women, 80 were transobturator, 79 were retropubic, 8 lacked data regarding the approach to the midurethral sling, and 1 was an autologous pubovaginal sling. Similar failure rates were seen for transobturator (10%) and retropubic slings (7.6%). Preoperative urodynamic parameters, such as cystometric capacity and intrinsic sphincter deficiency, were similar among failed and successful slings. For every additional 50 mL in bladder volume at first leak (SUIvol), there was a 1.6 increased odds of having a successful sling (odds ratio, 1.576; 95% confidence interval, 1.014-2.450; P = 0.04). There was no statistically significant association between maximum urethral closure pressure, abdominal leak point pressure, body mass index, age, sling type, or whether a prior anti-incontinence procedure had been performed and sling success. CONCLUSIONS: Bladder volume at first leak is a strong predictor of sling failure.

Preoperative QTc Interval is Not Associated With Intraoperative Cardiac Events or Mortality in Liver Transplantation Patients.

OBJECTIVES: The primary objective of this study was to determine whether liver transplantation recipients with preoperative prolonged corrected (QTc) intervals have a higher incidence of intraoperative cardiac events and/or postoperative mortality compared with their peers with normal QTc intervals. DESIGN: This was a retrospective cohort study. SETTING: Single academic hospital in New York, NY. PARTICIPANTS: Patients undergoing liver transplantation between 2007 and 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data relating to all liver transplantation recipients with preoperative electrocardiograms were queried from an institutional anesthesia data warehouse and electronic medical records. Primary outcomes were a composite outcome of intraoperative cardiac events and postoperative mortality. Patients with a prolonged QTc interval (>450 ms for men, >470 ms for women) did not demonstrate an association with intraoperative cardiac events, 30- or 90-day mortality, in-hospital mortality, or overall mortality compared with recipients in the normal QTc interval group. A prolonged QTc was found to be associated with increased anesthesia time, surgical time, length of hospital stay, and incidence of fresh frozen plasma and platelets transfusion. CONCLUSIONS: Prolonged QTc interval is not associated with an increased incidence of intraoperative cardiac events or mortality in liver transplantation recipients. The demonstrated correlation among QTc length and Model for End-stage Liver Disease score, blood component requirements, surgical and anesthetic times, and hospital length of stay likely represents the association between QTc length and severity of liver disease.

Use, Training, and Opinions About Effectiveness of Transesophageal Echocardiography in Adult Liver Transplantation Among Anesthesiologists in the United States.

STUDY OBJECTIVE: Describe transesophageal echocardiography (TEE) use, preparatory training and opinions about clinical importance, and future training pathways in a sample of liver transplant anesthesiologists. DESIGN: Online survey questionnaire. SETTING: Liver Transplant Centers in the United States. PARTICIPANTS: Director of Liver Transplant Anesthesia or designated alternate respondent. RESULTS: A total of 79 Directors or alternates from 111 (71%) centers were identified. There were 56 responses (71%) representing 433 transplant anesthesiologists who cared for 63.3% of liver transplant cases performed in 2015. Basic TEE certification was reported more frequently (64%) than advanced (53.6%). At least one team member used TEE in over 90% of responding centers. Most respondents (83.9%) agreed TEE provided unique and valuable clinical information but were equally divided about future training pathways (on the job learning vs basic TEE certification). CONCLUSION: TEE use in liver transplantation is growing with a substantial increase in basic TEE certified users. Transplant anesthesiologists support basic certification but an equal number believe there should be more applied training at the site of care.

Transfusion-Related Acute Lung Injury (TRALI) and Transfusion-Associated Circulatory Overload (TACO) in Liver Transplantation: A Case Report and Focused Review.

Liver transplantation (LT) is a complex procedure in a patient with multi-organ system dysfunction and coagulation defects. The surgical procedure involves dissection, major vessel manipulation, and pathophysiologic effects of graft storage and reperfusion. As a result, LT frequently involves significant hemorrhage. Subsequent massive transfusion carries high risk of transfusion-associated complications. Transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO) are the leading causes of transfusion associated mortality. In this case report and focused review, we present data that suggest that patients undergoing liver transplantation may be at higher risk for TRALI and TACO than the general population. Anesthesiologists can play a role in decreasing these risks by increasing recognition and reporting of TRALI and TACO, using point of care testing with thromboelastography to guide and decrease transfusion, and considering alternatives to traditional blood products like solvent/detergent plasma.

Anesthetic considerations for a novel anterior surgical approach to pediatric scoliosis correction.

BACKGROUND: Idiopathic scoliosis is a condition that may require surgical correction. Limitations of previous surgical modalities, however, created the need for novel methods of repair. One such technique, a newer form of anterolateral scoliosis correction, has shown considerable promise, which our center has had substantial experience performing. AIM: In this article, we present the case details of our first 105 patients for the purposes of describing the evolution and details of the anesthetic management and considerations for this procedure. METHODS: A retrospective review of medical records for 105 patients undergoing anterolateral instrumentation procedure for idiopathic scoliosis correction done at a single institution from May 2014 to June 2016 was performed. The details of perioperative management as well as surgical technique were reported for all patients. RESULTS: The mean age for patients was 14.8 years (range 10-18); the mean weight was 49.9 kg (range 25-82). Unilateral procedures were performed on 46.7%, with bilateral and hybrid procedures performed on 50.5% and 4.7%, respectively. The median number of levels corrected was 8 (interquartile range [IQR] 7-9) for unilateral, right 7 (IQR 6-7) and left 5 (IQR 4-5) for bilateral, and 4 (IQR 4-4.5) for hybrids. The average estimated blood loss (EBL) was 310 mL±138, with cell salvaged blood transfused in 61% of patients, and allogenic blood transfusion required in only two patients. CONCLUSIONS: The described anesthetic and analgesic management provides a framework for delivering perioperative care for this challenging procedure, which is gaining popularity as a modality for scoliosis correction.

Anesthetic management for intestinal transplantation: A decade of experience.

BACKGROUND: Intestinal transplantation (ITx) is the definitive therapy for patients suffering from intestinal failure. Previously published reports suggest that these cases should be managed perioperatively with the same intensive monitors and techniques as in liver transplantation. METHODS: We retrospectively reviewed the anesthetic management of 67 isolated intestinal, intestinal-pancreas, and intestinal-kidney transplants over the previous decade (2005-2015) in our tertiary care institution. RESULTS: Patients were typically managed with a single arterial line, a single central venous catheter, and rarely intensive modalities such as a pulmonary artery catheter, a transesophageal echocardiography, a second arterial catheter or central venous catheter, a rapid infusion system, a cell salvage device, or viscoelastic testing. Significant hemodynamic derangements were rare, and the rate of postreperfusion syndrome was 8.96%. Our fluid administration type and volume and transfusion type and volume were similar to previous reports in which more intensive anesthetic management was employed. CONCLUSION: We demonstrate that ITx can safely occur without utilizing the intensive resources requisite for a liver transplant.

Ventilator Data Extraction with a Video Display Image Capture and Processing System.

Medical hardware and software device interoperability standards are not uniform. The result of this lack of standardization is that information available on clinical devices may not be readily or freely available for import into other systems for research, decision support, or other purposes. We developed a novel system to import discrete data from an anesthesia machine ventilator by capturing images of the graphical display screen and using image processing to extract the data with off-the-shelf hardware and open-source software. We were able to successfully capture and verify live ventilator data from anesthesia machines in multiple operating rooms and store the discrete data in a relational database at a substantially lower cost than vendor-sourced solutions.

Variables affecting maximum urethral closure pressure (MUCP) and abdominal leak point pressure (ALPP) measurements.

INTRODUCTION AND HYPOTHESIS: The relationship between pelvic floor muscles and measurements of urethral function is not well studied. It is not known whether adjusting for clinical, demographic and urodynamic parameters would improve the association between MUCP and ALPP. Our hypothesis was that pelvic floor muscle strength (PFMS) influences the relationship between MUCP and ALPP. METHODS: This was a retrospective study of women who underwent a complex urodynamic study with evaluation of MUCP and ALPP using ICD-9 codes with documentation of PFMS. RESULTS: Urodynamic stress incontinence was confirmed in 478 patients, of whom 323 had MUCP recorded and 263 had both MUCP and ALPP recorded. Women with higher PFMS had a higher MUCP. In regression analysis ALPP at 150 mL and MUCP were weakly associated (coefficient 0.43, 95% CI 0.08-0.78; p = 0.02), whereas ALPP at capacity and MUCP were moderately associated (coefficient 0.60, 95% CI 0.25-0.95; p < 0.001). CONCLUSIONS: This study showed that MUCP and ALPP at 150 mL were weakly associated and that this improved to a moderate association for ALPP at capacity. MUCP increased with increasing PFMS among women with stress urinary incontinence and decreased with increasing age. There was no evidence that ALPP was associated with PFMS or age. The relationship between MUCP and ALPP was unchanged when accounting for covariates of PFMS (age, parity, BMI, prior procedure, urethral mobility, bladder capacity, stage of cystocele, or stage of uterine or apical prolapse).