New frontiers in intraoperative neurophysiologic monitoring: a narrative review.

Background and Objective: Neurological insults during surgery arise from anatomic and/or physiologic perturbations. Intraoperative neurophysiologic monitoring (IONM) fills a critical role of ensuring that any neurological insults during certain surgical procedures are caught in real-time to prevent patient harm. IONM provides immediate feedback to the surgeon and anesthesiologist about the need for an intervention to prevent a neurologic deficit postoperatively. As important as it seems to have IONM available to any patient having surgery where a neurological injury is possible, the truth is that IONM is unavailable to large swaths of people around the world. This review is intended to bring attention to all of the ways IONM is critically important for a variety of surgeries and highlight the barriers preventing most patients around the world from benefiting from the technology. Expansion of IONM to benefit patients from all over the world is the new frontier. Methods: We searched all English language original papers and reviews using Embase and MEDLINE/PubMed databases published from 1995 to 2022. Different combinations of the following search terms were used: intraoperative neuromonitoring, neurosurgery, low-income countries, cost, safety, and efficacy. Key Content and Findings: We describe common IONM modalities used during surgery as well as explore barriers to implementation of IONM in resource-limited regions. Additionally, we describe ongoing efforts to establish IONM capabilities in new locations around the world. Conclusions: In this paper, we performed a review of the literature on IONM with an emphasis on the basic understanding of clinical applications and the barriers for expansion into resource-limited settings. Finally, we provide our interpretation of "new frontiers" in IONM quite literally facilitating access to the tools and education so a hospital in Sub-Saharan Africa can incorporate IONM for their high-risk surgeries.

Toxicology Screening Testing in Patients Undergoing Spine Surgery: A Prospective Observational Pilot Study.

BACKGROUND: Chronic opioid use and polypharmacy are commonly seen in chronic pain patients presenting for spine procedures. Substance abuse and misuse have also been reported in this patient population. Negative perioperative effects have been found in patients exposed to chronic opioid, alcohol, and recreational substances. Toxicology screening testing (TST) in the perioperative period provides useful information for adequate preoperative optimization and perioperative planning. METHODS: We designed a pilot study to understand this population's preoperative habits including accuracy of self-report and TST-detected prescribed and unprescribed medications and recreational substances. We compared the results of the TST to the self-reported medications using Spearman correlations. RESULTS: Inconsistencies between TST and self-report were found in 88% of patients. Spearman correlation was 0.509 between polypharmacy and intraoperative propofol use, suggesting that propofol requirement increased as the number of substances used increased. CONCLUSIONS: TST in patients presenting for spine surgery is a useful tool to detect substances taken by patients because self-report is often inaccurate. Discrepancies decrease the opportunity for preoperative optimization and adequate perioperative preparation.

Neuroanesthesia Guidelines for Optimizing Transcranial Motor Evoked Potential Neuromonitoring During Deformity and Complex Spinal Surgery: A Delphi Consensus Study.

STUDY DESIGN: Expert opinion-modified Delphi study. OBJECTIVE: We used a modified Delphi approach to obtain consensus among leading spinal deformity surgeons and their neuroanesthesiology teams regarding optimal practices for obtaining reliable motor evoked potential (MEP) signals. SUMMARY OF BACKGROUND DATA: Intraoperative neurophysiological monitoring of transcranial MEPs provides the best method for assessing spinal cord integrity during complex spinal surgeries. MEPs are affected by pharmacological and physiological parameters. It is the responsibility of the spine surgeon and neuroanesthesia team to understand how they can best maintain high-quality MEP signals throughout surgery. Nevertheless, varying approaches to neuroanesthesia are seen in clinical practice. METHODS: We identified 19 international expert spinal deformity treatment teams. A modified Delphi process with two rounds of surveying was performed. Greater than 50% agreement on the final statements was considered "agreement"; >75% agreement was considered "consensus." RESULTS: Anesthesia regimens and protocols were obtained from the expert centers. There was a large amount of variability among centers. Two rounds of consensus surveying were performed, and all centers participated in both rounds of surveying. Consensus was obtained for 12 of 15 statements, and majority agreement was obtained for two of the remaining statements. Total intravenous anesthesia was identified as the preferred method of maintenance, with few centers allowing for low mean alveolar concentration of inhaled anesthetic. Most centers advocated for <150 µg/kg/min of propofol with titration to the lowest dose that maintains appropriate anesthesia depth based on awareness monitoring. Use of adjuvant intravenous anesthetics, including ketamine, low-dose dexmedetomidine, and lidocaine, may help to reduce propofol requirements without negatively effecting MEP signals. CONCLUSION: Spine surgeons and neuroanesthesia teams should be familiar with methods for optimizing MEPs during deformity and complex spinal cases. Although variability in practices exists, there is consensus among international spinal deformity treatment centers regarding best practices. LEVEL OF EVIDENCE: 5.

A Sensitive LC-MS/MS Assay for the Quantification of Methadone and its Metabolites in Dried Blood Spots: Comparison With Plasma.

INTRODUCTION: Methadone, a synthetic narcotic, is widely used both in adults and children for pain control and as a replacement drug in opioid use disorder to prevent craving and withdrawal. To support clinical pharmacokinetic trials in neonates, infants, and children, the authors developed and validated a novel, automated, highly sensitive liquid chromatography-electrospray-tandem mass spectrometry ionization (LC-ESI-MS/MS) method for the quantification of methadone and its metabolites, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP), in samples collected as dried blood spots. METHODS: Blood was spiked with different concentrations of methadone, EDDP, and EMDP, and blood drops were applied to filter paper cards. Punches of 6.4 mm were removed from the cards, and 600 µL of protein precipitation solution (methanol/0.2M ZnSO4, 7:3, vol/vol) containing the internal standards (methadone-d9 and EDDP-d5) at a concentration of 1 mcg/L was added. The extracts were analyzed using LC-ESI-MS/MS in combination with online extraction. The mass spectrometer was run in the positive multiple reaction monitoring mode, and the total run time was 3.2 minutes. RESULTS: For the dried blood spots, the assay has a lower limit of quantification of 0.1 mcg/L for methadone, EDDP, and EMDP. The range of reliable response for methadone for the ion transition m/z = 310.2→265.1 was 0.1-100 mcg/L and for the ion transition m/z = 310.2→223.1 5-1000 mcg/L. For EDDP, on the range of reliable response for the ion transition, m/z = 278.2→234.3 was 0.1-100 mcg/L and for the ion transition m/z = 278.2→186.1 5-1000 mcg/L. The calibration range for EMDP was 0.1-100 mcg/L. Accuracy (85%-115%) and imprecision (<15%) met predefined acceptance criteria. DISCUSSION: This assay allows for the measurement of small volume blood samples without the need for an intravenous blood draw, and thus, it is suitable for pharmacokinetics studies and therapeutic drug monitoring in pediatric patients.

Quantification of the 5-lipoxygenase inhibitor zileuton in human plasma using high performance liquid chromatography-tandem mass spectrometry.

Zileuton is an orally active, selective inhibitor of 5-lipoxygenase, which catalyzes the first step in the conversion of arachadonic acid into leukotrienes. Given the important role of leukotrienes in inflammation and cell signaling, multiple studies have investigated the efficacy of zileuton in the treatment of human disease. Examples of disease targets include asthma, ulcerative colitis, rheumatoid arthritis, and more recently, acne, ischemic/reperfusion injury, inflammatory pain, and sickle cell anemia. Zileuton is currently approved for the prophylaxis and chronic treatment of asthma. We report the development and validation of a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the quantification of zileuton in human EDTA plasma. The range of reliable response was 3.05-20,000ng/mL in human plasma. The calibration curves had a correlation coefficient of r(2)>0.99. The intra-day precision was 3.4-5.3%. The inter-day precision ranged from 4.5% to 7.3% and inter-day accuracy from 100% to 107%. No matrix interferences, ion suppression/enhancement, or carry-over was observed. The assay met all predefined acceptance criteria and was subsequently employed to measure plasma zileuton concentrations in a clinical trial.

A low blood volume LC-MS/MS assay for the quantification of fentanyl and its major metabolites norfentanyl and despropionyl fentanyl in children.

Preterm and term neonates often require surgical procedures and analgesia. However, our knowledge about neonatal pharmacokinetics of fentanyl, the most commonly used drug for these procedures, and its metabolites is still incomplete. To facilitate pharmacokinetic studies of fentanyl and its metabolites in neonates and other children, we developed and validated an LC-MS/MS method based on minimally invasive, low blood volume sampling. LC-MS/MS was used for the simultaneous analysis of fentanyl, despropionyl fentanyl (DPF), and norfentanyl from dried blood samples (DBS) collected on filter paper. Positive ions were monitored using multiple reaction monitoring. Since the standard matrix for measuring fentanyl blood concentrations is plasma, the assay was developed and validated in plasma, whole blood, and then DBS. Our method was able to measure clinically relevant levels of fentanyl and its metabolites. In DBS, the lower limits of quantification were 100 pg/mL for fentanyl with a range of reliable response from 0.1 to 100 ng/mL (r(2)>0.99) and 250 pg/mL for both DPF and norfentanyl with a range of reliable response from 0.25 to 100 ng/mL (r(2)>0.99). In plasma and in DBS inter-day accuracy and precisions of fentanyl met predefined acceptance criteria and also indicated comparable assay performance in both matrices.

Prior epidural lidocaine alters the pharmacokinetics and drug effects of extended-release epidural morphine (DepoDur®) after cesarean delivery.

BACKGROUND: A potential physicochemical interaction between epidural local anesthetics and extended-release epidural morphine (EREM) could negate the sustained release. In this study, we sought to determine the pharmacokinetic and drug effects of prior epidural lidocaine administration on EREM. METHODS: Thirty healthy women undergoing cesarean delivery were enrolled in this randomized study. Patients received 8 mg EREM 1 hour after either a combined spinal-epidural (intrathecal bupivacaine and fentanyl 20 µg with no epidural medication; group SE) or an epidural anesthetic (epidural 2% lidocaine with fentanyl 100 µg; group E). Maximal concentration (Cmax), time to Cmax (Tmax), and AUC(0-last) (area under the concentration-time curve until the last plasma concentration that was below the limit of quantitation) for morphine levels were determined from a plasma sample at 0, 5, 10, 15, and 30 minutes, and 1, 4, 8, 12, 24, 36, 48, and 72 hours. Drug effects including pain, analgesic use, and side effects were measured for 72 hours after cesarean delivery. RESULTS: Epidural lidocaine administration (20-35 mL) 1 hour before epidural EREM administration increased the Cmax in group E (11.1 ± 4.9) compared with group SE (8.3 ± 7.1 ng/mL) (P = 0.038). There were no significant effects on Tmax and AUC(0-last) of venous morphine between the groups (P > 0.05). There was an increased incidence in vomiting, oxygen use, and hypotension in group E (patients who received lidocaine before EREM). CONCLUSION: A large dose of epidural lidocaine 1 hour before EREM administration alters the pharmacokinetics and drug effects of EREM. Clinicians must apply caution when EREM is administered even 1 hour after an epidural lidocaine "top-up" for cesarean delivery.

A sensitive assay for the quantification of morphine and its active metabolites in human plasma and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry.

Opioids such as morphine are the cornerstone of pain treatment. The challenge of measuring the concentrations of morphine and its active metabolites in order to assess human pharmacokinetics and monitor therapeutic drugs in children requires assays with high sensitivity in small blood volumes. We developed and validated a semi-automated LC-MS/MS assay for the simultaneous quantification of morphine and its active metabolites morphine 3ß-glucuronide (M3G) and morphine 6ß-glucuronide (M6G) in human plasma and in dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the internal standards were the only manual steps. Morphine and its metabolites were separated on a Kinetex 2.6-µm PFP analytical column using an acetonitrile/0.1% formic acid gradient. The analytes were detected in the positive multiple reaction mode. In plasma, the assay had the following performance characteristics: range of reliable response of 0.25-1000 ng/mL (r(2) > 0.99) for morphine, 1-1,000 ng/mL (r(2) > 0.99) for M3G, and 2.5-1,000 ng/mL for M6G. In DBS, the assay had a range of reliable response of 1-1,000 ng/mL (r(2) > 0.99) for morphine and M3G, and of 2.5-1,000 ng/mL for M6G. For inter-day accuracy and precision for morphine, M3G and M6G were within 15% of the nominal values in both plasma and DBS. There was no carryover, ion suppression, or matrix interferences. The assay fulfilled all predefined acceptance criteria, and its sensitivity using DBS samples was adequate for the measurement of pediatric pharmacokinetic samples using a small blood of only 20-50 µL.

Bioequivalence testing of immunosuppressants: concepts and misconceptions.

Immunosuppressants are considered critical dose/narrow therapeutic index drugs and there is the lingering suspicion among physicians and patients that generic versions may differ in quality and therapeutic efficacy from the brand name drug. The innovator's and the generic active drug molecule are exactly the same and are produced following exactly the same tight rules of good manufacturing practice. Upon oral administration, the drug molecule separates from the formulation and passes the membranes of gut mucosa cells; from this point on, the formulation has no influence on the kinetics of a drug and its biological effects. As formulations may differ, bioequivalence testing in healthy volunteer studies establishes equal relative oral bioavailability. Due to the number of patients required to achieve sufficient statistical power, to test the therapeutic equivalence of two formulations of the same drug with the same bioavailability is an unrealistic goal. An often overlooked fact is that the approval by drug regulatory agencies of several post-approval versions of the innovators' immunosuppressants is based on the identical guidelines used for approval of generics. The FDA has issued specific guidelines describing the requirements for approval of generic versions of tacrolimus, sirolimus, and mycophenolic acid. The standard average bioequivalence approach is recommended and in the cases of tacrolimus and sirolimus, the effect of food should also be tested. No studies in the patient population are requested. Immunosuppressants are not regarded as drugs that require a special status to establish bioequivalence between generic and the innovator's versions.