Brain injury plasma biomarkers in patients on veno-arterial extracorporeal membrane oxygenation: A pilot prospective observational study.

INTRODUCTION: Early diagnosis of acute brain injury (ABI) is critical for patients on veno-arterial extracorporeal membrane oxygenation (V-A ECMO) to guide anticoagulation strategy; however, neurological assessment in ECMO is often limited by patient sedation. METHODS: In this pilot study of adults from June 2018 to May 2019, plasma samples of glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and tubulin associated unit (Tau) were collected daily after V-A ECMO cannulation and measured using a multiplex platform. Primary outcomes were occurrence of ABI, assessed clinically, and neurologic outcome, assessed by modified Rankin Scale (mRS). RESULTS: Of 20 consented patients (median age = 48.5°years; 55% female), 8 (40%) had ABI and 15 (75%) had unfavorable neurologic outcome at discharge. 10 (50%) patients were centrally cannulated. Median duration on ECMO was 4.5°days (IQR: 2.5-9.5). Peak GFAP, NFL, and Tau levels were higher in patients with ABI vs. without (AUC = 0.77; 0.85; 0.57, respectively) and in patients with unfavorable vs. favorable neurologic outcomes (AUC = 0.64; 0.59; 0.73, respectively). GFAP elevated first, NFL elevated to the highest degree, and Tau showed limited change regardless of ABI. CONCLUSION: Further studies are warranted to determine how plasma biomarkers may facilitate early detection of ABIs in V-A ECMO to assist timely clinical decision-making.

Plasma biomarkers for brain injury in extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for patients with refractory cardiorespiratory failure. Despite its benefits, ECMO carries a significant risk of neurological complications, including acute brain injury (ABI). Although standardized neuromonitoring and neurological care have been shown to improve early detection of ABI, the inability to perform neuroimaging in a timely manner is a major limitation in the accurate diagnosis of neurological complications. Therefore, blood-based biomarkers capable of detecting ongoing brain injury at the bedside are of great clinical significance. This review aims to provide a concise review of the current literature on plasma biomarkers for ABI in patients on ECMO support.

The influence of elevated international normalized ratio on complications following total shoulder arthroplasty.

Background: Identifying preoperative risk factors for complications following total shoulder arthroplasty (TSA) has both clinical and financial implications. The purpose of this study was to determine the influence of different degrees of preoperative INR elevation on complications following TSA. Methods: Patients undergoing primary TSA from 2007 to 2018 were identified in a national database. Patients were stratified into 4 cohorts: INR of <1.0, INR of >1.0 to 1.25, INR of >1.25 to 1.5, and INR of >1.5. Postoperative complications were assessed. Multivariate logistic regressions were performed to adjust for differences in demographics and comorbidities among the INR groups. Results: Following adjustment and relative to patients with an INR of <1.0, those with INR of >1.0-1.25, >1.25-1.5, and >1.5 had 1.6-times, 2.4-times, and 2.8-times higher odds of having postoperative bleeding requiring transfusion, respectively (p < 0.05 for all). Relative to patients with INR <1.0, those with INR of > 1.25-1.5 and INR of >1.5 had 7.8-times and 7.0-times higher odds of having pulmonary complications, respectively (p < 0.05 for both). Discussion: With increasing INR levels, there is an independent and step-wise increase in odd ratios for postoperative complications. Current guidelines for preoperative INR thresholds may need to be adjusted for more predictive risk-stratification for TSA. Level of Evidence: III.

Patient, provider, and system-level factors associated with preoperative cardiac testing: A systematic review.

BACKGROUND: Overuse of preoperative cardiac testing contributes to high healthcare costs and delayed surgeries. A large body of research has evaluated factors associated with variation in preoperative cardiac testing. However, patient, provider, and system-level factors associated with variation in testing have not been systematically studied. OBJECTIVE: To conduct a systematic review to better delineate the patient, provider, and system-level factors associated with variation in preoperative cardiac testing. METHODS: We included studies of an adult US population evaluating a patient, provider, or system-level factor associated with variation in preoperative cardiac testing for noncardiac surgery since 2012. Our search strategy used terms related to preoperative testing, diagnostic cardiac tests, and care variation with Ovid MEDLINE and Embase from inception through January 2023. We extracted study characteristics and factors associated with variation and qualitatively analyzed them. We assessed risk of bias using the Newcastle-Ottawa Scale and Evidence Project Risk of Bias tool. RESULTS: Twenty-eight articles met inclusion criteria. Older age and higher comorbidity were strongly associated with higher-intensity testing. The evidence for provider and system-level covariates was weaker. However, there was strong evidence that a focus on primary care and away from preoperative clinic and cardiac consultations was associated with less testing and that interventions to reduce low-value testing can be successful. CONCLUSIONS: There is significant interprovider and interhospital variation in preoperative cardiac testing, the correlates of which are not well-defined. Further work should aim to better understand these factors.

Temporal trends in the rate of complications and prolonged length of stay relative to body mass index in patients undergoing total knee arthroplasty from 2012 to 2020.

BACKGROUND: Elevated body mass index (BMI) is a risk factor for complications following total knee arthroplasty (TKA). Thus, we believe it is important to constantly re-evaluate the relationship between BMI and complication risk following TKA. METHOD: Patients undergoing primary TKA were identified in a national database from 2012-2020. Rates of major complications, minor complications, and length of stay (LOS) greater than 2 days were calculated. The prevalence of postoperative outcomes were calculated per unit of BMI and then multiplied by a factor of 10^2 or 10^3 in order to create adjusted-BMI (aBMI). To isolate the effect of aBMI on postoperative outcomes, changes over time were analyzed using linear regression analysis controlling for age, sex, American Society of Anesthesiology (ASA) classification and smoking status. RESULTS: 365,333 patients were included. Mean BMI 33 ± 6.8. 10,616 (2.9%) of patients had a major postoperative complication, 9,345 (2.6%) minor complications, 3,277 (0.9%) had a deep or superficial surgical site infection (SSI). 133,563 (37%) of patients had LOS > 2 days. From 2012-2020, the ratio of major complications to aBMI decreased significantly by an average of -2.7% per year. The ratio of patients with LOS > 2 days to aBMI decreased significantly by -27% per year. The ratio of SSI to aBMI increased significantly by 10.8% per year. CONCLUSIONS: From 2012 to 2020, the ratio of major complications and extended LOS following TKA as a function of BMI has decreased significantly, while the ratio of SSI as a function of BMI has doubled.

Sublingual immunotherapy persistence and adherence in real-world settings: A systematic review.

BACKGROUND: Sublingual immunotherapy (SLIT) adherence in the literature is often evaluated in closely monitored trials that may impact patient behavior; real-world SLIT adherence is relatively unknown. This systematic review intends to assess SLIT adherence in studies that reflect real-world settings. METHODS: A literature search of PubMed, Embase, Cochrane, Web of Science, and Scopus for real-world studies examining SLIT adherence was performed. Monitored clinical trials were excluded. Paired investigators independently reviewed all articles. For this review, "persistence" was defined as continuing therapy and not being lost to follow-up and "adherence" as persistence in accordance with prescribed SLIT dose, dosing schedule, and duration. Article quality was assessed using a modified Newcastle-Ottawa scale and then converted to AHRQ standards (good, fair, and poor). RESULTS: The search yielded 1596 nonduplicate abstracts, from which 32 articles (n = 63,683 patients) met criteria. Twenty-six (81%) studies reported persistence rates ranging from 7.0% to 88.7%, and 18 (56%) reported adherence rates ranging from 9.6% to 97.0%. Twenty-one (66%) studies surveyed reasons for discontinuing SLIT. All studies were Oxford level of evidence 2b and of good (n = 12) to fair (n = 20) quality. CONCLUSION: Reported rates of real-world SLIT persistence and adherence varied widely by study methodology (e.g., follow-up duration, objective vs. subjective assessment). Studies with longer follow-up generally reported lower rates; 3-year persistence ranged from 7% to 59.0% and 3-year adherence from 9.6% to 49.0%. Future studies of SLIT adherence would benefit from following concordant definitions of persistence/adherence and standardized reporting metrics.

Systematic review of real-world persistence and adherence in subcutaneous allergen immunotherapy.

BACKGROUND: Given that subcutaneous immunotherapy (SCIT) adherence in the literature is often studied in closely monitored trials, few studies report real-world SCIT adherence. The purpose of this review is to assess SCIT adherence in real-world settings. METHODS: A literature search of PubMed, Embase, Cochrane Library, Web of Science, and Scopus for real-world studies examining SCIT adherence was performed. Paired investigators independently reviewed all articles. For this review, "persistence" was defined as continuing therapy and not being lost to follow-up after initiating SCIT, and "adherence" defined as persistence in accordance with prescribed SCIT dose, dosing schedule, and duration. Article quality was first assessed using a modified Newcastle-Ottawa scale and then converted to Agency for Healthcare Research and Quality standards (good, fair, and poor). RESULTS: The search yielded 1596 nonduplicate abstracts, from which 17 articles (n = 263,221 patients) met inclusion criteria. Fourteen (82%) studies reported persistence rates, ranging from 16.0% to 93.7%. Seven (41%) studies reported adherence rates, ranging from 15.1% to 99%. Five (29%) studies (n = 416 patients) collected original data on reasons for discontinuing SCIT, of which inconvenience was most cited. All studies were Oxford level of evidence 2b and of good (n = 10) to fair (n = 7) quality. CONCLUSION: Real-world SCIT persistence and adherence rates are poor, with the majority of included studies reporting rates <80%; however, they range widely, explained in part by inter-study differences in measuring and reporting adherence-related findings. Future studies on SCIT adherence may benefit from following concordant definitions of persistence and adherence in addition to standardized reporting metrics.

Patent anomalous circumflex coronary artery stent occlusion following aortic valve replacement with coronary artery bypass.

An anomalous left circumflex artery branching arising from the right coronary artery is one of the most common congenital coronary artery abnormalities. Despite this, the incidence is low and our clinical understanding of the nuances in patients with such abnormalities remains limited. We present a case of a 73-year-old male with coronary artery disease status-post stenting of an anomalous circumflex artery who subsequently underwent coronary artery bypass grafting and surgical aortic valve replacement with EKG changes post-operatively. He was emergently taken to the cardiac catheterization lab, where catheterization revealed total occlusion of the proximal circumflex artery, just distal to the previous stent. Acute inferior ST-elevation myocardial infarction was suspected to be secondary to intraoperative external manipulation at the site of occlusion in the retro-aortic segment of the vessel. In patients with abnormal coronary artery anatomy, it is imperative to monitor for new EKG changes that may be indicative of new ischemia requiring further intervention.

Transcranial Doppler microemboli and acute brain injury in extracorporeal membrane oxygenation: A prospective observational study.

Objective: Extracorporeal membrane oxygenation (ECMO) carries a high morbidity of acute brain injury (ABI) with resultant mortality increase. Transcranial Doppler (TCD) allows real-time characterization of regional cerebral hemodynamics, but limited data exist on the interpretation of microembolic signals (MES) in ECMO. Methods: This prospective cohort study was conducted at a single tertiary care center, November 2017 through February 2022, and included all adult patients receiving venoarterial (VA) and venovenous (VV) ECMO undergoing TCD examinations, which all included MES monitoring. Results: Of 145 patients on ECMO who underwent at least 1 TCD examination, 100 (68.9%) patients on VA-ECMO received 187 examinations whereas 45 (31.1%) patients on VV-ECMO received 65 examinations (P = .81). MES were observed in 35 (35.0%) patients on VA-ECMO and 2 (4.7%) patients on VV-ECMO (P < .001), corresponding to 46 (24.6%) and 2 (3.1%) TCD examinations, respectively. MES were present in 29.4% of patients on VA-ECMO without additional cardiac support, compared with 38.1% with intra-aortic balloon pump and 57.1% with left ventricular assist device, but these differences were not statistically significant (P = .39; P = .20, respectively). Presence or number of MES was not associated with VA-ECMO cannulation mode (23.4% MES presence in peripheral cannulation vs 25.8% in central cannulation, P = .80). In both VA- and VV-ECMO, MES presence or number was not associated with presence of clot or fibrin in the ECMO circuit or with any studied hemodynamic, laboratory, or ECMO parameters at the time of TCD. ABI occurred in 38% and 31.1% of patients on VA- and VV-ECMO, respectively. In multivariable logistic regression analyses, neither ABI nor a composite outcome of arterial thromboembolic events was associated with presence or number of MES in VA- ECMO. Conclusions: TCD analysis in a large cohort of patients on ECMO demonstrates a significant number of MES, especially in patients on VA-ECMO with intra-aortic balloon pump, and/or left ventricular assist device. However, clinical associations and significance of TCD MES remain unresolved and warrant further correlation with systematic imaging and long-term neurologic follow-up.

Myocardial fibrosis by T1 mapping magnetic resonance imaging predicts incident cardiovascular events and all-cause mortality: the Multi-Ethnic Study of Atherosclerosis.

AIMS: To evaluate whether myocardial fibrosis predicts cardiovascular events (CVEs) and mortality in the Multi-Ethnic Study of Atherosclerosis. METHODS AND RESULTS: Cardiac magnetic resonance (CMR) T1 mapping with gadolinium administration for assessment of extracellular volume fraction (ECV) was performed in 1326 participants, in whom myocardial scar was assessed by late gadolinium enhancement (LGE). The clinical outcomes were defined as all-cause mortality, atherosclerotic CVEs, and incident heart failure (HF) during an average of 8 years of follow-up after the scan. Participants' mean native T1 time was 971 ms [standard deviation (SD) 45.5], ECV was 27 (SD 2.9), and 117 (8.8%) of them had LGE. At the time of the CMR exam, participant age was 68 years (SD 9) and 48% of them were women. Ideal cut-offs were identified using classification and regression trees accounting for time-to-event outcomes for ECV (30%) and native T1 time (954 ms). Over the follow-up period, 106 participants died, 78 developed CVE, and 23 developed HF. After adjustment for risk factors, ECV >30% was associated with death [hazard ratio (HR): 1.67, P < 0.05], incident CVE (HR: 2.02, P < 0.05), and incident HF (HR: 2.85, P < 0.05). After adjustments, native T1 >954 ms was associated with incident CVE (HR: 2.09, P < 0.05). Myocardial scar by LGE was not predictive of clinical outcomes after adjustments. CONCLUSION: ECV is an independent prognostic marker of incident HF, atherosclerotic CVEs, and all-cause mortality. ECV, with its ability to characterize both diffuse and focal fibrosis processes, better predicted incident events than regional myocardial abnormalities as visualized by LGE imaging in a large multi-ethnic population.

Fluorescent Molecular Imaging Can Improve Intraoperative Sentinel Margin Detection in Oral Squamous Cell Carcinoma.

In head and neck cancer, a major limitation of current intraoperative margin analysis is the ability to detect areas most likely to be positive based on specimen palpation, especially for larger specimens where sampling error limits detection of positive margins. This study aims to prospectively examine the clinical value of fluorescent molecular imaging to accurately identify "the sentinel margin," the point on a specimen at which the tumor lies closest to the resected edge in real-time during frozen section analysis. Methods: Eighteen patients with oral squamous cell carcinoma were enrolled into a prospective clinical trial and infused intravenously with 50 mg of panitumumab-IRDye800CW 1-5 d before surgery. Resected specimens were imaged in a closed-field near-infrared optical imaging system in near real-time, and custom-designed software was used to identify locations of highest fluorescence on deep and peripheral margins. The surgeon identified the sentinel margin masked to optical specimen mapping, and then the regions of highest fluorescence were identified and marked for frozen analysis. Final pathology based on specimen reconstruction was used as reference standard. Results: Resected specimens were imaged in the operating room, and fluorescence had a higher interobserver agreement with pathology (Cohen κ value 0.96) than the surgeon (Cohen κ value of 0.82) for the location of the closest margin. Plotting margin distance at the predicted sentinel margin location of each observer versus the actual closest margin distance at pathology demonstrated best correlation between fluorescence and pathology (R2 = 0.98) with surgeon (R2 = 0.75). Conclusion: Fluorescence imaging can improve identification of the sentinel margin in head and neck cancer resections, holding promise for rapid identification of positive margins and improved oncologic outcomes.

Intraoperative Fluorescence-Guided Surgery in Head and Neck Squamous Cell Carcinoma.

The rate of positive margins in head and neck cancers has remained stagnant over the past three decades and is consistently associated with poor overall survival. This suggests that significant improvements must be made intraoperatively to ensure negative margins. We discuss the important role of fluorescence imaging to guide surgical oncology in head and neck cancer. This review includes a general overview of the principles of fluorescence, available fluorophores used for fluorescence imaging, and specific clinical applications of fluorescence-guided surgery, as well as challenges and future directions in head and neck surgical oncology. Laryngoscope, 131:529-534, 2021.

Effect of Formalin Fixation for Near-Infrared Fluorescence Imaging with an Antibody-Dye Conjugate in Head and Neck Cancer Patients.

PURPOSE: This study evaluated the effect of formalin fixation for near-infrared (NIR) fluorescence imaging of an antibody-dye complex (panitumumab-IRDye800CW) that was intravenously administered to patients with head and neck squamous cell carcinoma (HNSCC) scheduled to undergo surgery of curative intent. PROCEDURES: HNSCC patients were infused with 25 or 50 mg of panitumumab-IRDye800CW followed by surgery 1-5 days later. Following resection, primary tumor specimens were imaged in a closed-field fluorescence imaging device, before and after formalin fixation. The fluorescence images of formalin-fixed specimens were compared with images prior to formalin fixation. Regions of interest were drawn on the primary tumor and on the adjacent normal tissue on the fluorescence images. The mean fluorescence intensity (MFI) and tumor-to-background ratios (TBRs) of the fresh and formalin-fixed tissues were compared. RESULTS: Of the 30 enrolled patients, 20 tissue specimens were eligible for this study. Formalin fixation led to an average of 10 % shrinkage in tumor specimen size (p < 0.0001). Tumor MFI in formalin-fixed specimens was on average 10.9 % lower than that in the fresh specimens (p = 0.0002). However, no statistical difference was found between the TBRs of the fresh specimens and those of the formalin-fixed specimens (p = 0.85). CONCLUSIONS: Despite the 11 % decrease in MFI between fresh and formalin-fixed tissue specimens, the relative difference between tumor and normal tissue as measured in TBR remained unchanged. This data suggests that evaluation of formalin-fixed tissue for assessing the accuracy of fluorescence-guided surgery approaches could provide a valid, yet more flexible, alternative to fresh tissue analysis. TRIAL REGISTRATION: NCT02415881.

Safety and Stability of Antibody-Dye Conjugate in Optical Molecular Imaging.

PURPOSE: The development of molecularly targeted tracers is likely to improve the accuracy of diagnostic, screening, and therapeutic tools. Despite the many therapeutic antibodies that are FDA-approved with known toxicity, only a limited number of antibody-dye conjugates have been introduced to the clinic. Thorough evaluation of the safety, stability, and pharmacokinetics of antibody conjugates in the clinical setting compared with their parental components could accelerate the clinical approval of antibodies as agents for molecular imaging. Here we investigate the safety and stability of a near-infrared fluorescent dye (IRDye800CW) conjugated panitumumab, an approved therapeutic antibody, and report on the product stability, pharmacokinetics, adverse events, and QTc interval changes in patients. PROCEDURES: Panitumumab-IRDye800CW was made under good manufacturing practice (GMP) conditions in a single batch on March 26, 2014, and then evaluated over 4.5 years at 0, 3, and 6 months, and then at 6-month intervals thereafter. We conducted early phase trials in head and neck, lung, pancreas, and brain cancers with panitumumab-IRDye800CW. Eighty-one patients scheduled to undergo standard-of-care surgery were infused with doses between 0.06 to 2.83 mg/kg of antibody. Patient ECGs, blood samples, and adverse events were collected over 30-day post-infusion for analysis. RESULTS: Eighty-one patients underwent infusion of the study drug at a range of doses. Six patients (7.4 %) experienced an adverse event that was considered potentially related to the drug. The most common event was a prolonged QTc interval which occurred in three patients (3.7 %). Panitumumab-IRDye800CW had two OOS results at 42 and 54 months while meeting all other stability testing criteria. CONCLUSIONS: Panitumumab-IRDye800CW was safe and stable to administer over a 54-month window with a low rate of adverse events (7.4 %) which is consistent with the rate associated with panitumumab alone. This data supports re-purposing therapeutic antibodies as diagnostic imaging agents with limited preclinical toxicology studies.