AcumenTM hypotension prediction index guidance for prevention and treatment of hypotension in noncardiac surgery: a prospective, single-arm, multicenter trial.

BACKGROUND: Intraoperative hypotension is common during noncardiac surgery and is associated with postoperative myocardial infarction, acute kidney injury, stroke, and severe infection. The Hypotension Prediction Index software is an algorithm based on arterial waveform analysis that alerts clinicians of the patient's likelihood of experiencing a future hypotensive event, defined as mean arterial pressure < 65 mmHg for at least 1 min. METHODS: Two analyses included (1) a prospective, single-arm trial, with continuous blood pressure measurements from study monitors, compared to a historical comparison cohort. (2) A post hoc analysis of a subset of trial participants versus a propensity score-weighted contemporaneous comparison group, using external data from the Multicenter Perioperative Outcomes Group (MPOG). The trial included 485 subjects in 11 sites; 406 were in the final effectiveness analysis. The post hoc analysis included 457 trial participants and 15,796 comparison patients. Patients were eligible if aged 18 years or older, American Society of Anesthesiologists (ASA) physical status 3 or 4, and scheduled for moderate- to high-risk noncardiac surgery expected to last at least 3 h. MEASUREMENTS: minutes of mean arterial pressure (MAP) below 65 mmHg and area under MAP < 65 mmHg. RESULTS: Analysis 1: Trial subjects (n = 406) experienced a mean of 9 ± 13 min of MAP below 65 mmHg, compared with the MPOG historical control mean of 25 ± 41 min, a 65% reduction (p < 0.001). Subjects with at least one episode of hypotension (n = 293) had a mean of 12 ± 14 min of MAP below 65 mmHg compared with the MPOG historical control mean of 28 ± 43 min, a 58% reduction (p< 0.001). Analysis 2: In the post hoc inverse probability treatment weighting model, patients in the trial demonstrated a 35% reduction in minutes of hypotension compared to a contemporaneous comparison group [exponentiated coefficient: - 0.35 (95%CI - 0.43, - 0.27); p < 0.001]. CONCLUSIONS: The use of prediction software for blood pressure management was associated with a clinically meaningful reduction in the duration of intraoperative hypotension. Further studies must investigate whether predictive algorithms to prevent hypotension can reduce adverse outcomes. TRIAL REGISTRATION: Clinical trial number: NCT03805217. Registry URL: https://clinicaltrials.gov/ct2/show/NCT03805217 . Principal investigator: Xiaodong Bao, MD, PhD. Date of registration: January 15, 2019.

E-cigarette use-associated lung injury (EVALI).

The prevalence of vaping has overtaken conventional cigarettes as the most frequent form of nicotine consumption among 15-24-year olds. There are currently a large number of both legitimate and illegitimate products and suppliers offering more than 8000 different flavors of vape on the market, whose additives are not tested, studied or regulated and whose safety and toxicity profile remains unknown. In vitro studies have demonstrated a dose-dependent decrease in the viability of normal human bronchial epithelial cells after exposure to vapor from electronic vape devices.Short- and medium-term studies to date indicate that vapor-induced pulmonary lesions are the most serious and commonly reported side effect; such lesions include bilateral ground glass opacities in lung bases with subpleural preservation, bilateral infiltrates, pleural effusion, pneumomediastinum and nodular opacities. Cases of EVALI have been described in patients with daily exposure, as well as in users who reported having been exposed to these substances at least once a month. The most frequently inhaled substances are THC, flavored liquids of unknown content, and nicotine.The clinical manifestations of dyspnea and cough are the most frequent respiratory symptomatology, in addition to constitutional manifestations such as fever and chills, and gastrointestinal manifestations such as vomiting, nausea, abdominal pain and diarrhea. To these can be added the presence of tachypnea, tachycardia, elevated blood pressure, hypoxia, leukocytosis with neutrophilia and elevated ESR.

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.

Incidence of Postoperative Cognitive Dysfunction Following Inhalational vs Total Intravenous General Anesthesia: A Systematic Review and Meta-Analysis.

Postoperative cognitive dysfunction (POCD) has been increasingly recognized as a contributor to postoperative complications. A consensus-working group recommended that POCD should be distinguished between delayed cognitive recovery, ie, evaluations up to 30 days postoperative, and neurocognitive disorder, ie, assessments performed between 30 days and 12 months after surgery. Additionally, the choice of the anesthetic, either inhalational or total intravenous anesthesia (TIVA) and its effect on the incidence of POCD, has become a focus of research. Our primary objective was to search the literature and conduct a meta-analysis to verify whether the choice of general anesthesia may impact the incidence of POCD in the first 30 days postoperatively. As a secondary objective, a systematic review of the literature was conducted to estimate the effects of the anesthetic on POCD between 30 days and 12 months postoperative. For the primary objective, an initial review of 1913 articles yielded ten studies with a total of 3390 individuals. For the secondary objective, four studies with a total of 480 patients were selected. In the first 30 days postoperative, the odds-ratio for POCD in TIVA group was 0.46 (95% CI = 0.26-0.81; p = 0.01), compared to the inhalational group. TIVA was associated with a lower incidence of POCD in the first 30 days postoperatively. Regarding the secondary objective, due to the small number of selected articles and its high heterogeneity, a metanalysis was not conducted. Given the heterogeneity of criteria for POCD, future prospective studies with more robust designs should be performed to fully address this question.

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.

Echocardiographic parameters, speckle tracking, and brain natriuretic peptide levels as indicators of progression of indeterminate stage to Chagas cardiomyopathy.

BACKGROUND: Chronic Chagas cardiomyopathy (CCM) is characterized by a unique type of cardiac involvement. Few studies have characterized echocardiographic (Echo) transitions from the indeterminate Chagas disease (ChD) form to CCM. The objective of this study was to identify the best cutoffs in multiple Echo parameters, speckle tracking, and N-terminal pro B-type natriuretic peptide (NT-proBNP) to distinguish patients without CCM (stage A) vs patients with myocardial involvement (stages B, C, or D). METHODS: Cross-sectional study conducted in 273 consecutive patients with different CCM stages. Echo parameters, NT-proBNP, and other clinical variables were measured. Logistic regression models (dichotomized in stage A versus B, C, and D) adjusted for age, sex, body mass index, and NT-proBNP were performed. RESULTS: Left ventricular global longitudinal strain (LV-GLS), mitral flow E velocity, LV mass index, and NT-proBNP identified early changes that differentiated stages A vs B, C, and D. The LV-GLS with a cutoff -20.5% showed the highest performance (AUC 92.99%; accuracy 84.56% and negative predictive value (NPV) 88.82%), which improved when it was additionally adjusted by NT-proBNP with a cutoff -20.0% (AUC 94.30%; accuracy 88.42% and NPV 93.55%). CONCLUSIONS: Our findings suggest that Echo parameters and NT-proBNP may be used as diagnostic variables in detecting the onset of myocardial alterations in patients with the indeterminate stage of ChD. LV-GLS was the more accurate measurement regarding stage A differentiation from the stages B, C, and D. Prospective longitudinal studies are needed to validate these findings.

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.

Preoperatively Screened Obstructive Sleep Apnea Is Associated With Worse Postoperative Outcomes Than Previously Diagnosed Obstructive Sleep Apnea.

BACKGROUND: Obstructive sleep apnea (OSA) affects up to 26% of US adults, is often undiagnosed, and increases perioperative morbidity. We hypothesized that patients screened on the day of surgery as moderate/high risk for OSA (S-OSA) present similar perioperative respiratory complications, hospital use, and mortality than patients with previously diagnosed OSA (D-OSA). Second, we hypothesized that both OSA groups have more respiratory complications than No-OSA patients. METHODS: The electronic medical database from 1 academic and 2 community hospitals was retrospectively queried to identify adults undergoing nonemergent inpatient surgery (January 1, 2012, to December 31, 2014). Based on the day-of-surgery preoperative assessment and STOP-BANG (Snoring, Tiredness, Observed apnea during sleep, high blood Pressure, Body mass index >35, Age >50 years, thick Neck, Gender male) score, they were classified as D-OSA, S-OSA, or No-OSA. Perioperative respiratory events and interventions, hospital use, and mortality were measured. The primary outcome composite (adverse respiratory events [AREs]) included perioperative hypoxemic events and difficult airway management. Hypoxemic event was defined as peripheral saturation of oxygen (SpO2) <90% by continuous pulse oximetry for ≥3 minutes, or if validated and/or manually entered into the medical chart. Hypoxemia was classified as mild (lowest SpO2 86%-89%) or moderate/severe (lowest SpO2 ≤85%). Secondary outcomes included postoperative respiratory interventions, intensive care unit admission, hospital length of stay, and 30-day and 1-year all-cause mortality. Outcomes were compared using linear and logistic regression analyses. RESULTS: A total of 28,912 patients were assessed: 3432 (11.9%) D-OSA; 1546 (5.3%) S-OSA; and 23,934 (82.8%) No-OSA patients. At least 1 ARE was present in 68.0% of S-OSA; 71.0% of D-OSA; and 52.1% of No-OSA patients (unadjusted P < .001), primarily ≥1 moderate/severe hypoxemic event after discharge from the postanesthesia care unit (PACU; 39.9% in S-OSA; 39.5% in D-OSA; and 27.1% in No-OSA patients). S-OSA patients compared to D-OSA patients presented lower rates of moderate/severe hypoxemia in the PACU but similar intraoperatively and postoperatively, higher difficult mask ventilation rates, and similar difficult intubation reports. After adjusting for demographic, health, and surgical differences and hospital type, the likelihood of ≥1 ARE was not different in S-OSA and D-OSA patients (adjusted odds ratio 0.90 [99% confidence interval, 0.75-1.09]; P = .15). S-OSA patients compared to D-OSA patients had significantly increased postoperative reintubation, mechanical ventilation, direct intensive care unit admission after surgery, hospital length of stay, and 30-day all-cause mortality. CONCLUSIONS: Patients classified as S-OSA have similar rates of AREs to D-OSA patients, but increased postoperative respiratory interventions, hospital use, and 30-day all-cause mortality. These worse postoperative outcomes in S-OSA patients than D-OSA patients could reflect the lack of awareness and appropriate management of this bedside S-OSA diagnosis after PACU discharge. Multidisciplinary interventions are needed for these high-risk patients.

Características clínicas de pacientes llevados a monitoría externa de eventos / Clinical characteristics of patients undergoing external monitoring of events

Para la evaluación del paciente con síntomas que sugieran arritmia cardiaca existen varios métodos que pueden ser utilizados. En ese sentido, los monitores externos de eventos pueden mejorar la sensibilidad del diagnóstico. Se realizó un estudio descriptivo, retrospectivo y transversal, que incluyó la revisión de resultados de la monitoría externa de eventos de 203 pacientes. El motivo más común por el cual se solicitó el monitor externo de eventos fueron las palpitaciones en 161 pacientes (79,3%), seguidas por síncope en 21 pacientes (10,3%). El diagnóstico más habitual fue el ritmo sinusal normal sin otras alteraciones en 59 pacientes (29%), seguido por taquicardia sinusal en 54 (26,6%), extrasistolia ventricular en 24 (11,8%), extrasistolia auricular en 17 (8,3%), taquicardia auricular no sostenida en 12 (5,9%) y, en forma menos frecuente, taquicardia supraventricular en 8 (3,94%), taquicardia ventricular no sostenida en 5 (2,4%) y trastorno de la conducción interventricular en 6 (2,9%). Este es el primer estudio descriptivo de la monitoría externa de eventos llevado a cabo en Colombia. Desde el punto de vista epidemiológico y de diagnóstico electrocardiográfico, los hallazgos son similares a los resultados de estudios previos, con las limitaciones que ofrece un análisis de este tipo.

There are a variety of methods that can be used for the evaluation of patients with symptoms suggestive of cardiac arrhythmia; in this regard, external monitoring of events can improve the sensitivity of diagnosis. A descriptive, retrospective and cross-sectional study, which included review of the results of external monitoring of events of 203 patients was performed. The most common reason for requesting external monitoring of events was palpitations in 161 patients (79.3%), followed by syncope in 21 patients (10.3%). The most common diagnosis was normal sinus rhythm with no other abnormalities in 59 patients (29%), followed by sinus tachycardia in 54 (26.6%), ventricular extrasystoles in 24 (11.8%), atrial extrasystoles in 17 (8.3%), non-sustained atrial tachycardia in 12 (5.9%), and less frequently supraventricular tachycardia in 8 (3.94%), non-sustained ventricular tachycardia in 5 patients (2.4%) and interventricular conduction disturbance in 6 (2.9%). This is the first descriptive study of external monitoring of events held in Colombia. From the epidemiological and diagnosis electrocardiographic point of view, the findings are similar to results of previous studies, with the limitations that provides this type of analysis.

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.

Comparison of the quantification of acetaminophen in plasma, cerebrospinal fluid and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry.

Acetaminophen (paracetamol, N-(4-hydroxyphenyl) acetamide) is one of the most commonly prescribed drugs for the management of pain in children. Quantification of acetaminophen in pre-term and term neonates and small children requires the availability of highly sensitive assays in small volume blood samples. We developed and validated an LC-MS/MS assay for the quantification of acetaminophen in human plasma, cerebro-spinal fluid (CSF) and dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the deuterated internal standard were the only manual steps. Extracted samples were analyzed on a Kinetex 2.6 µm PFP column using an acetonitrile/formic acid gradient. The analytes were detected in the positive multiple reaction mode. Alternatively, DBS were automatically processed using direct desorption in a sample card and preparation (SCAP) robotic autosampler in combination with online extraction. The range of reliable response in plasma and CSF was 3.05-20,000 ng/ml (r(2)>0.99) and 27.4-20,000 ng/ml (r(2)>0.99) for DBS (manual extraction and automated direct desorption). Inter-day accuracy was always within 85-115% and inter-day precision for plasma, CSF and manually extracted DBS were less than 15%. Deming regression analysis comparing 167 matching pairs of plasma and DBS samples showed a correlation coefficient of 0.98. Bland Altman analysis indicated a 26.6% positive bias in DBS, most likely reflecting the blood: plasma distribution ratio of acetaminophen. DBS are a valid matrix for acetaminophen pharmacokinetic studies.

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.

Randomized, double-blind, placebo-controlled, single intravenous dose-escalation study to evaluate the safety, tolerability, and pharmacokinetics of the novel coronary smooth muscle cell proliferation inhibitor Biolimus A9 in healthy individuals.

Biolimus A9 (BA9) is a novel proliferation inhibitor of coronary smooth muscle cells that has been specifically designed for coating drug-eluting stents. The goals of this study were to identify the highest safe intravenous dose of BA9, to evaluate the dose-dependent pharmacokinetics of BA9 after intravenous administration in humans, and to characterize early clinical symptoms of BA9 toxicity in healthy subjects. This phase 1 trial in healthy subjects was designed as a double-blind, placebo-controlled, randomized, ascending single-dose study. After screening and randomization, 28 volunteers received either placebo (n = 7) or BA9 (n = 21) in a double-blinded fashion. Doses from 0.0075 mg/kg were escalated to 0.25 mg/kg in 4 cohorts. BA9 concentrations were measured using liquid chromatography-tandem mass spectrometry. BA9 doses up to 0.075 mg/kg were well tolerated. Only the highest BA9 dose of 0.25 mg/kg produced reversible drug-related adverse events. The most frequent adverse events were headache, nausea, and mouth ulcers, most likely due to immunosuppression. Exposure to BA9 did not result in electrocardiographic or clinical laboratory changes. BA9 had a terminal half-life of 90.0 ± 40.0 hours (all n = 21, mean ± standard deviation), an apparent clearance from blood of 0.96 ± 1.07 L/kg/h, and a volume of distribution of 96.5 ± 72.6 L/kg.

Polymer-free biolimus a9-coated stent demonstrates more sustained intimal inhibition, improved healing, and reduced inflammation compared with a polymer-coated sirolimus-eluting cypher stent in a porcine model.

BACKGROUND: Drug-eluting stents effectively reduce restenosis but may increase late thrombosis and delayed restenosis. Persistent polymer, the drug, or a combination of both could be responsible. Local delivery of Biolimus A9, a rapamycin derivative, from a polymer-free BioFreedom stent (Biosensors International) may prevent these complications. METHODS AND RESULTS: We compared high-dose (HD) (225 microg/14 mm Biolimus A9) and low-dose (LD) (112 microg/14 mm Biolimus A9) BioFreedom stents with a polymer-coated sirolimus-eluting Cypher stent (SES) and a bare-metal stent (BMS) at 28 days and 180 days in an overstretch coronary mini-swine model with histomorphometric and histological analysis. At 28 days, there was a reduction in neointimal proliferation by HD, LD, and SES compared with BMS (neointimal thickness: HD, 0.080+/-0.032; LD, 0.085+/-0.038; SES, 0.064+/-0.037; BMS, 0.19+/-0.111 mm; P<0.001; BMS > HD/LD/SES). At 180 days, both BioFreedom stents were associated with reduced neointimal proliferation, whereas SES exhibited increased neointima (neointimal thickness: HD, 0.12+/-0.034; LD, 0.10+/-0.040; SES, 0.20+/-0.111; BMS, 0.17+/-0.099 mm; P<0.001; SES > HD/LD; BMS > LD). At 180 days, BioFreedom stents showed decreased fibrin and inflammation, including granuloma and giant cells, compared with SES. CONCLUSIONS: The polymer-free Biolimus A9-coated stent demonstrates equivalent early and superior late reduction of intimal proliferation compared with SES in a porcine model. After implantation of BioFreedom stent, delayed arterial healing was minimal, and there was no increased inflammation at 180 days compared with SES implantation. The use of polymer-free stents may have a potential long-term benefit over traditional polymeric-coated drug-eluting stents.

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.

Development and validation of a semi-automated assay for the highly sensitive quantification of Biolimus A9 in human whole blood using high-performance liquid chromatography-tandem mass spectrometry.

Drug-eluting stents are sustained-release intra-coronary devices that are usually coated with a few hundred micrograms of drug. Measuring the drugs that are released over weeks in order to assess human pharmacokinetics is a challenge that requires assays with high sensitivity. We developed and validated a semi-automated LC-MS/MS assay for the quantification of Biolimus A9, a proliferation signal inhibitor that was specifically developed for coating on drug-eluting stents in human EDTA blood. The only manual step was the addition of a zinc sulfate/methanol protein precipitation solution which included the internal standard. Samples were injected into the HPLC and extracted online. The assay had the following performance characteristics: range of reliable response 0.01-100 ng/mL (r(2)>0.99), inter-day accuracy (0.033 ng/mL): 111.7%, and inter-day precision: 8.6%. There was no ion suppression, matrix interferences or carry-over. Extracted samples were stable in the autosampler at +4 degrees C for at least 24 h and could undergo three freeze-thaw cycles. The assay, with a lower limit of detection of 333 fg/mL and a lower limit of quantitation of 10 pg/mL, was sufficiently sensitive and robust for quantifying Biolimus A9 in clinical trials after i.v. injection and after stent implantation.

Embolismo paradójico inminente evidenciado por ecocardiografía en pacientes con foramen ovale persistente / Imminent paradoxical embolism evidenced by echocardiography in patients with patent foramen ovale

Paciente de género masculino, de 72 años de edad, con antecedente de trombo-embolismo pulmonar, quien ingresó por evento cerebro-vascular isquémico y en quien en el ecocardiograma trans-torácico y luego en el trans-esofágico, se encontró una masa móvil que sugería un trombo que traspasaba el foramen ovale permeable. Ante el diagnóstico de embolismo paradójico inminente, se consideró realizar trombectomía quirúrgica, la cual se difirió por infección y se inició anticoagulación con heparina de bajo peso molecular. Se realizó un ecocardiograma de control y se observó que la masa había desaparecido por completo. Se dio de alta con anticoagulación oral.