Transplantation Outcomes with Donor Hearts after Circulatory Death.

BACKGROUND: Data showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited. METHODS: We conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation. RESULTS: A total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, -3 percentage points; 90% CI, -10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation. CONCLUSIONS: In this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.).

Dual-Organ Transplantation: Indications, Evaluation, and Outcomes for Heart-Kidney and Heart-Liver Transplantation: A Scientific Statement From the American Heart Association.

Although heart transplantation is the preferred therapy for appropriate patients with advanced heart failure, the presence of concomitant renal or hepatic dysfunction can pose a barrier to isolated heart transplantation. Because donor organ supply limits the availability of organ transplantation, appropriate allocation of this scarce resource is essential; thus, clear guidance for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation is urgently required. The purposes of this scientific statement are (1) to describe the impact of pretransplantation renal and hepatic dysfunction on posttransplantation outcomes; (2) to discuss the assessment of pretransplantation renal and hepatic dysfunction; (3) to provide an approach to patient selection for simultaneous heart-kidney transplantation and simultaneous heart-liver transplantation and posttransplantation management; and (4) to explore the ethics of multiorgan transplantation.

Hydrostatic mechanical stress regulates growth and maturation of the atrioventricular valve.

During valvulogenesis, cytoskeletal, secretory and transcriptional events drive endocardial cushion growth and remodeling into thin fibrous leaflets. Genetic disorders play an important role in understanding valve malformations but only account for a minority of clinical cases. Mechanical forces are ever present, but how they coordinate molecular and cellular decisions remains unclear. In this study, we used osmotic pressure to interrogate how compressive and tensile stresses influence valve growth and shape maturation. We found that compressive stress drives a growth phenotype, whereas tensile stress increases compaction. We identified a mechanically activated switch between valve growth and maturation, by which compression induces cushion growth via BMP-pSMAD1/5, while tension induces maturation via pSer-19-mediated MLC2 contractility. The compressive stress acts through BMP signaling to increase cell proliferation and decrease cell contractility, and MEK-ERK is essential for both compressive stress and BMP mediation of compaction. We further showed that the effects of osmotic stress are conserved through the condensation and elongation stages of development. Together, our results demonstrate that compressive/tensile stress regulation of BMP-pSMAD1/5 and MLC2 contractility orchestrates valve growth and remodeling.

Neighborhood Socioeconomic Status and Readmission in Acute Type A Aortic Dissection Repair.

INTRODUCTION: We examined the association of socioeconomic status as defined by median household income quartile (MHIQ) with mortality and readmission patterns following open repair of acute type A aortic dissection (ATAAD) in a nationally representative registry. METHODS: Adults who underwent open repair of ATAAD were selected using the US Nationwide Readmissions Database and stratified by MHIQ. Patients were selected based on diagnostic and procedural codes. The primary endpoint was 30-d readmission. RESULTS: Between 2016 and 2019, 10,288 individuals (65% male) underwent open repair for ATAAD. Individuals in the lowest income quartile were younger (median: 60 versus 64, P < 0.05) but had greater Elixhauser comorbidity burden (5.9 versus 5.7, P < 0.05). Across all groups, in-hospital mortality was approximately 15% (P = 0.35). On multivariable analysis adjusting for baseline comorbidity burden, low socioeconomic status was associated with increased readmission at 90 d, but not at 30 d. Concomitant renal disease (odds ratio [OR], 1.68; P < 0.001), pulmonary disease (OR, 1.26; P < 0.001), liver failure (OR 1.2, P = 0.04), and heart failure (OR, 1.17; P < 0.001) were all associated with readmission at 90 d. The primary indication for readmission was most commonly cardiac (33%), infectious (16.5%), and respiratory (9%). CONCLUSIONS: In patients who undergo surgery for ATAAD, lower MHIQ was associated with higher odds of readmission following open repair. While early readmission for individuals living in the lowest income communities is likely attributable to greater baseline comorbidity burden, we observed that 90-d readmission rates are associated with lower MHIQ regardless of comorbidity burden. Further investigation is required to determine which patient-level and system-level interventions are needed to reduce readmissions in the immediate postoperative period for resource poor areas.

Peak insulin drip rate associated with decreased infections post-solid organ transplant.

Infection and rejection outcomes were retrospectively analyzed in patients following liver transplant and separately following heart transplant with patients being stratified by their severity of immediate postoperative insulin resistance as measured by the peak insulin drip rate that was required to reduce glucose levels. For each group, these peak insulin drip rates were divided into quartiles (Q). In liver transplant patients (n = 207), those in Q4 (highest infusion rate) had significantly fewer infections up to 6 months post-transplant (42.3% vs. 60.0%, p = .036) and borderline fewer rejection episodes (25.0% vs. 40.0%, p = .066) compared to Q1-Q3 patients. To confirm these unexpected results, a subsequent similar analysis in heart transplant (n = 188) patients again showed that Q4 patients had significantly fewer infections up to 6 months (19.1% vs. 53.9%, p < .0001) compared to Q1-Q3 patients. Logistic regression in a subset of 103 cardiac transplant patients showed that the maximum glucose during surgery, prior MI, and hypertension were associated with severe insulin resistance (SIR) status, while the presence of pre-existing diabetes and BMI were not. We hypothesize that patients are who are able to mount a more robust counter-regulatory response that causes the insulin resistance may be healthier and thus able to mount a better response to infections.

Modulation of NLRP3 inflammasomes activation contributes to improved survival and function of mesenchymal stromal cell spheroids.

Mesenchymal stem cells (MSCs) are ubiquitous multipotent cells that exhibit significant therapeutic potentials in a variety of disorders. Nevertheless, their clinical efficacy is limited owing to poor survival, low rate of engraftment, and impaired potency upon transplantation. Spheroidal three-dimensional (3D) culture of MSCs (MSC3D) has been proven to better preserve their in vivo functional properties. However, the molecular mechanisms underlying the improvement in MSC function by spheroid formation are not clearly understood. NLRP3 inflammasomes, a key component of the innate immune system, have recently been shown to play a role in cell fate decision of MSCs. The present study examined the role of NLRP3 inflammasomes in the survival and potency of MSC spheroids. We found that MSC3D led to decreased activation of NLRP3 inflammasomes through alleviation of ER stress in an autophagy-dependent manner. Importantly, downregulation of NLRP3 inflammasomes signaling critically contributes to the enhanced survival rate in MSC3D through modulation of pyroptosis and apoptosis. The critical role of NLRP3 inflammasome suppression in the enhanced therapeutic efficacy of MSC spheroids was further confirmed in an in vivo mouse model of DSS-induced colitis. These findings suggest that 3D culture confers survival and functional advantages to MSCs by suppressing NLRP3 inflammasome activation.

Bio-Guided Isolation of Alpha-Glucosidase Inhibitory Compounds from Vietnamese Lichen Roccella Montagnei.

A bio-guided isolation was applied to the Vietnamese lichen Roccella montagnei based on alpha-glucosidase inhibition. Six compounds were isolated and structurally elucidated, including a new ortho depside, montagneside A (1), together with five known compounds, sekikaic acid (2), lanost-7-en-3ß-ol (3), ethyl orsellinate (4), D-montagnetol (5), and D-erythrin (6). Their chemical structures were identified by extensive 1D and 2D NMR analysis, high-resolution mass spectroscopy, and comparisons with those reported in the literature. D-Erythrin (6), a major component, was selected for further modification using Smiles rearrangement. Three erythritol derivatives 6a-6c were synthesized. Compounds 1-3, 6, and 6a-6c were evaluated for alpha-glucosidase inhibition. Compounds 2 and 6a-6c showed significant alpha-glucosidase inhibition with IC50 values ranging from 7.9 to 149 µM, respectively. Molecular docking was applied to the most active compound 6a to clarify the inhibitory mechanism.

Seroepidemiology and Carriage of Diphtheria in Epidemic-Prone Area and Implications for Vaccination Policy, Vietnam.

In 2019, a community-based, cross-sectional carriage survey and a seroprevalence survey of 1,216 persons 1-55 years of age were conducted in rural Vietnam to investigate the mechanism of diphtheria outbreaks. Seroprevalence was further compared with that of an urban area that had no cases reported for the past decade. Carriage prevalence was 1.4%. The highest prevalence, 4.5%, was observed for children 1-5 years of age. Twenty-seven asymptomatic Coerynebacterium diphtheriae carriers were identified; 9 carriers had tox gene-bearing strains, and 3 had nontoxigenic tox gene-bearing strains. Child malnutrition was associated with low levels of diphtheria toxoid IgG, which might have subsequently increased child carriage prevalence. Different immunity patterns in the 2 populations suggested that the low immunity among children caused by low vaccination coverage increased transmission, resulting in symptomatic infections at school-going age, when vaccine-induced immunity waned most. A school-entry booster dose and improved infant vaccination coverage are recommended to control transmissions.

Implementation of a direct-to-operating room aortic emergency transfer program: Expedited management of type A aortic dissection.

INTRODUCTION: Type A Aortic Dissection (TAAD) is a surgical emergency with a time-dependent rate of mortality. We hypothesized that a direct-to-operating room (DOR) transfer program for patients with TAAD would reduce time to intervention. METHODS: A DOR program was started at an urban tertiary care hospital in February 2020. We performed a retrospective study of adult patients undergoing treatment for TAAD before (n = 42) and after (n = 84) implementation of DOR. Expected mortality was calculated using the International Registry of Acute Aortic Dissection risk prediction model. RESULTS: Median time from acceptance of transfer from emergency physician to operating room arrival was 1.37 h (82 min) faster in DOR compared to pre-DOR (1.93 h vs 3.30 h, p < 0.001). Median time from arrival to operating room was 1.14 h (72 min) faster after DOR compared to pre-DOR (0.17 h vs 1.31 h, p < 0.001). In-hospital mortality was 16.2% in pre-DOR, with an observed-to-expected (O/E) ratio of 1.03 (p = 0.24) and 12.0% in the DOR group, with an O/E ratio of 0.59 (p < 0.001). CONCLUSION: Creation of a DOR program resulted in decreased time to intervention. This was associated with a decrease in observed-to-expected operative mortality. The transfer of patients with acute type A aortic dissection to centers with direct-to-OR programs may result in decreased time from diagnosis to surgery.

New Halogenated Flavonoids from Adenosma bracteosum and Vitex negundo and Their α-Glucosidase Inhibition.

Adenosma bracteosum and Vitex negundo are natural sources of methoxylated flavonoids. Little is known about the α-glucosidase inhibition of multi-methoxylated flavonoid derivatives. Eighteen natural flavonoids were isolated from A. bracteosum and V. negundo. Seven halogenated derivatives were synthesized. Their chemical structures were elucidated by extensive NMR analysis and high-resolution mass spectroscopy as well as comparisons in literature. All compounds were evaluated for their α-glucosidase inhibition. Most compounds showed good activity with IC50 values ranging from 16.7 to 421.8 µM. 6,8-Dibromocatechin was the most active compound with an IC50 value of 16.7 µM. A molecular docking study was conducted, indicating that those compounds are potent α-glucosidase inhibitors.

Improving Text-Independent Forced Alignment to Support Speech-Language Pathologists with Phonetic Transcription.

Problem: Phonetic transcription is crucial in diagnosing speech sound disorders (SSDs) but is susceptible to transcriber experience and perceptual bias. Current forced alignment (FA) tools, which annotate audio files to determine spoken content and its placement, often require manual transcription, limiting their effectiveness. Method: We introduce a novel, text-independent forced alignment model that autonomously recognises individual phonemes and their boundaries, addressing these limitations. Our approach leverages an advanced, pre-trained wav2vec 2.0 model to segment speech into tokens and recognise them automatically. To accurately identify phoneme boundaries, we utilise an unsupervised segmentation tool, UnsupSeg. Labelling of segments employs nearest-neighbour classification with wav2vec 2.0 labels, before connectionist temporal classification (CTC) collapse, determining class labels based on maximum overlap. Additional post-processing, including overfitting cleaning and voice activity detection, is implemented to enhance segmentation. Results: We benchmarked our model against existing methods using the TIMIT dataset for normal speakers and, for the first time, evaluated its performance on the TORGO dataset containing SSD speakers. Our model demonstrated competitive performance, achieving a harmonic mean score of 76.88% on TIMIT and 70.31% on TORGO. Implications: This research presents a significant advancement in the assessment and diagnosis of SSDs, offering a more objective and less biased approach than traditional methods. Our model's effectiveness, particularly with SSD speakers, opens new avenues for research and clinical application in speech pathology.

Local fluid shear stress operates a molecular switch to drive fetal semilunar valve extension.

BACKGROUND: While much is known about the genetic regulation of early valvular morphogenesis, mechanisms governing fetal valvular growth and remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it is unknown whether or how they interact with valvulogenic signaling programs. Side-specific activity of valvulogenic programs motivates the hypothesis that shear stress pattern-specific endocardial signaling controls the elongation of leaflets. RESULTS: We determined that extension of the semilunar valve occurs via fibrosa sided endocardial proliferation. Low OSS was necessary and sufficient to induce canonical Wnt/ß-catenin activation in fetal valve endothelium, which in turn drives BMP receptor/ligand expression, and pSmad1/5 activity essential for endocardial proliferation. In contrast, ventricularis endocardial cells expressed active Notch1 but minimal pSmad1/5. Endocardial monolayers exposed to LSS attenuate Wnt signaling in a Notch1 dependent manner. CONCLUSIONS: Low OSS is transduced by endocardial cells into canonical Wnt signaling programs that regulate BMP signaling and endocardial proliferation. In contrast, high LSS induces Notch signaling in endocardial cells, inhibiting Wnt signaling and thereby restricting growth on the ventricular surface. Our results identify a novel mechanically regulated molecular switch, whereby fluid shear stress drives the growth of valve endothelium, orchestrating the extension of the valve in the direction of blood flow.

Deleterious Variants in ABCC12 are Detected in Idiopathic Chronic Cholestasis and Cause Intrahepatic Bile Duct Loss in Model Organisms.

BACKGROUND & AIMS: The etiology of cholestasis remains unknown in many children. We surveyed the genome of children with chronic cholestasis for variants in genes not previously associated with liver disease and validated their biological relevance in zebrafish and murine models. METHOD: Whole-exome (n = 4) and candidate gene sequencing (n = 89) was completed on 93 children with cholestasis and normal serum γ-glutamyl transferase (GGT) levels without pathogenic variants in genes known to cause low GGT cholestasis such as ABCB11 or ATP8B1. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing was used to induce frameshift pathogenic variants in the candidate gene in zebrafish and mice. RESULTS: In a 1-year-old female patient with normal GGT cholestasis and bile duct paucity, we identified a homozygous truncating pathogenic variant (c.198delA, p.Gly67Alafs∗6) in the ABCC12 gene (NM_033226). Five additional rare ABCC12 variants, including a pathogenic one, were detected in our cohort. ABCC12 encodes multidrug resistance-associated protein 9 (MRP9) that belongs to the adenosine 5'-triphosphate-binding cassette transporter C family with unknown function and no previous implication in liver disease. Immunohistochemistry and Western blotting revealed conserved MRP9 protein expression in the bile ducts in human, mouse, and zebrafish. Zebrafish abcc12-null mutants were prone to cholangiocyte apoptosis, which caused progressive bile duct loss during the juvenile stage. MRP9-deficient mice had fewer well-formed interlobular bile ducts and higher serum alkaline phosphatase levels compared with wild-type mice. They exhibited aggravated cholangiocyte apoptosis, hyperbilirubinemia, and liver fibrosis upon cholic acid challenge. CONCLUSIONS: Our work connects MRP9 with bile duct homeostasis and cholestatic liver disease for the first time. It identifies a potential therapeutic target to attenuate bile acid-induced cholangiocyte injury.

Fucose-Rich Sulfated Polysaccharides from Two Vietnamese Sea Cucumbers Bohadschia argus and Holothuria (Theelothuria) spinifera: Structures and Anticoagulant Activity.

Fucosylated chondroitin sulfates (FCSs) FCS-BA and FCS-HS, as well as fucan sulfates (FSs) FS-BA-AT and FS-HS-AT were isolated from the sea cucumbers Bohadschia argus and Holothuria (Theelothuria) spinifera, respectively. Purification of the polysaccharides was carried out by anion-exchange chromatography on DEAE-Sephacel column. Structural characterization of polysaccharides was performed in terms of monosaccharide and sulfate content, as well as using a series of non-destructive NMR spectroscopic methods. Both FCSs were shown to contain a chondroitin core [→3)-ß-d-GalNAc-(1→4)-ß-d-GlcA-(1→]n bearing sulfated fucosyl branches at O-3 of every GlcA residue in the chain. These fucosyl residues were different in pattern of sulfation: FCS-BA contained Fuc2S4S, Fuc3S4S and Fuc4S at a ratio of 1:8:2, while FCS-HS contained these residues at a ratio of 2:2:1. Polysaccharides differed also in content of GalNAc4S6S and GalNAc4S units, the ratios being 14:1 for FCS-BA and 4:1 for FCS-HS. Both FCSs demonstrated significant anticoagulant activity in clotting time assay and potentiated inhibition of thrombin, but not of factor Xa. FS-BA-AT was shown to be a regular linear polymer of 4-linked α-L-fucopyranose 3-sulfate, the structure being confirmed by NMR spectra of desulfated polysaccharide. In spite of considerable sulfate content, FS-BA-AT was practically devoid of anticoagulant activity. FS-HS-AT cannot be purified completely from contamination of some FCS. Its structure was tentatively represented as a mixture of chains identical with FS-BA-AT and other chains built up of randomly sulfated alternating 4- and 3-linked α-L-fucopyranose residues.

Evaluating the Safety and Quality of Life of Colorectal Cancer Patients Treated by Autologous Immune Enhancement Therapy (AIET) in Vinmec International Hospitals.

(1) Colorectal cancer (CRC) is an increasingly prevalent disease with a high mortality rate in recent years. Immune cell-based therapies have received massive attention among scientists, as they have been proven effective as low-toxicity treatments. This study evaluated the safety and effectiveness of autologous immune enhancement therapy (AIET) for CRC. (2) An open-label, single-group study, including twelve patients diagnosed with stages III and IV CRC, was conducted from January 2016 to December 2021. Twelve CRC patients received one to seven infusions of natural killer (NK)-cell and cytotoxic T-lymphocyte (CTL). Multivariate modelling was used to identify factors associated with health-related quality-of-life (HRQoL) scores. (3) After 20−21 days of culture, the NK cells increased 3535-fold, accounting for 85% of the cultured cell population. Likewise, CTLs accounted for 62.4% of the cultured cell population, which was a 1220-fold increase. Furthermore, the QoL improved with increased EORTC QLQ-C30 scores, decreased symptom severity, and reduced impairment in daily living caused by these symptoms (MDASI-GI report). Finally, a 14.3 ± 14.1-month increase in mean survival time was observed at study completion. (4) AIET demonstrated safety and improved survival time and HRQoL for CRC patients in Vietnam.

Risk Factors for Tuberculosis (TB) Among Household Contacts of Patients With Smear-Positive TB in 8 Provinces of Vietnam: A Nested Case-Control Study.

BACKGROUND: Tuberculosis (TB) continues to account for significant morbidity and mortality annually. Household contacts (HHCs) of persons with TB are a key population for targeting prevention and control interventions. We aimed to identify risk factors associated with developing TB among HHCs. METHODS: We conducted a nested case-control study among HHCs in 8 provinces in Vietnam enrolled in a randomized controlled trial of active case finding for TB. Cases were any HHCs diagnosed and registered with TB within the Vietnam National TB Program during 2 years of follow-up. Controls were selected by simple random sampling from the remaining HHCs. Risk factor data were collected at enrollment and during follow-up. A logistic regression model was developed to determine predictors of TB among HHCs. RESULTS: We selected 1254 HHCs for the analysis: 214 cases and 1040 controls. Underlying characteristics varied between both groups; cases were older, more likely to be male, with a higher proportion of reported previous TB and diabetes. Risk factors associated with a TB diagnosis included being male (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.03-2.0), residing in an urban setting (aOR, 1.8; 1.3-2.5), prior TB (aOR, 4.6; 2.5-8.7), history of diabetes (aOR, 3.1; 1.7-5.8), current smoking (aOR, 3.1; 2.2-4.4), and prolonged history of coughing in the index case at enrollment (OR , 1.6; 1.1-2.3). CONCLUSIONS: Household contacts remain an important key population for TB prevention and control. TB programs should ensure effective contact investigations are implemented for household contacts, particularly those with additional risk factors for developing TB.

Cardiac transplantation outcomes in patients with amyloid cardiomyopathy.

OBJECTIVE: Amyloid cardiomyopathy (ACM) is a progressive and life-threatening disease caused by abnormal protein deposits within cardiac tissue. The most common forms of ACM are caused by immunoglobulin derived light chains (AL) and transthyretin (TTR). Orthotopic heart transplantation (OHT) remains the definitive treatment for patients with end stage heart failure. In this study, we perform a contemporary multicenter analysis evaluating post OHT survival in patients with ACM. METHODS: We conducted a multicenter analysis of 40,044 adult OHT recipients captured in the United Network for Organ Sharing (UNOS) registry from 1987-2018. Patients were characterized as ACM or non-ACM. Baseline characteristics were obtained, and summary characteristics were calculated. Outcomes of interest included post-transplant survival, infection, treated rejection, and the ability to return to work. Racial differences in OHT survival were also analyzed. Unadjusted associations between ACM and non-ACM survival were determined using the Kaplan-Meier estimations and confounding was addressed using multivariable Cox proportional hazards models. RESULTS: Three hundred ninety-eight patients with a diagnosis of ACM were identified of which 313 underwent heart only OHT. ACM patients were older (61 vs 53; P < .0001) and had a higher proportion of African Americans (30.7% vs 17.6%; P < .0001). Median survival for ACM was 10.2 years vs 12.5 years in non-ACM (P = .01). After adjusting for confounding, ACM patients had a higher likelihood of death post-OHT (HR 1.39 CI: 1.14, 1.70; P = .001). African American ACM patients had a higher likelihood of survival compared to White ACM patients (HR 0.51 CI 0.31-0.85; P = .01). No difference was observed in episodes of treated rejection (OR 0.63 CI 0.23, 1.78; P = .39), hospitalizations for infections (OR 1.24 CI: 0.85, 1.81; P = .26), or likelihood of returning to work for income (OR 1.23 CI: 0.84, 1.80; P = .30). CONCLUSIONS: In this analysis of OHT in ACM, ACM was associated with a higher likelihood of post-OHT mortality. Racial differences in post-OHT were observed with African American patients with ACM having higher likelihood of survival compared to White patients with ACM. No differences were observed in episodes of treated rejection, hospitalization for infection, or likelihood to return to work for income.

Limb ischemia and bleeding in patients requiring venoarterial extracorporeal membrane oxygenation.

OBJECTIVE: Acute limb ischemia (ALI) and cannulation site bleeding are frequent complications of venoarterial (VA) extracorporeal membrane oxygenation (ECMO) and are associated with worse outcomes. The goals of this study were to assess our rates of ECMO-related ALI and bleeding and to evaluate the efficacy of strategies to prevent them, such as distal perfusion cannula (DPC) and ultrasound-guided cannulation. METHODS: This is a single-center retrospective cohort study of adult patients placed on peripheral VA-ECMO at a tertiary medical center between 2014 and 2018. ALI was defined as new ischemia of the extremity ipsilateral to arterial cannulation. Significant cannulation site bleeding was defined as excessive bleeding requiring intervention (eg, transfusion or reoperation). Univariate analyses were used to identify factors associated with ALI, bleeding, and in-hospital mortality. RESULTS: During the study period, 105 patients were placed on peripheral VA-ECMO (61.3% female; mean age, 54.9 ± 14.8 years). Nearly half (46.6%) had ECMO implantation in an extracorporeal cardiopulmonary resuscitation setting and 37 (44.0%) had a DPC. Average duration of support was 5.6 ± 5.0 days. Overall in-hospital mortality and death on ECMO support were 65.1% and 50%, respectively. ALI occurred in 21 (20%) and cannulation-related bleeding occurred in 24 (22.9%) patients who were treated with a total of 27 procedures, including thromboembolectomy (22.2%), vascular repair (18.5%), and fasciotomy (25.9%). On univariate analysis, cannulation in the operating room (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.08-0.77; P = .02) was associated with decreased risk of ALI, whereas cannulation in the operating room (OR, 2.65; 95% CI, 1.09-6.45; P = .03) and cutdown approach (OR, 4.96; 95% CI, 2.32-10.61; P < .0001) were associated with increased risk of bleeding. Ultrasound-guided placement was associated with decreased risk of bleeding (OR, 0.81; 95% CI, 0.04-0.84; P = .03). DPC was not associated with either ALI (P = .47) or bleeding (P = .06). ALI (OR, 2.68; 95% CI 1.03-6.98; P = .04), age (OR, 1.94; 95% CI, 1.03-3.69; P = .04), and worse baseline heart failure (OR, 2.01; 95% CI, 1.02-3.97; P = .04) were associated with greater risk of in-hospital mortality. Ultrasound-guided cannulation (OR, 0.41; 95% CI, 0.20-0.87; P = .02) was associated with decreased risk of in-hospital mortality. CONCLUSIONS: ALI and significant bleeding are common occurrences after peripheral VA-ECMO cannulation. Whereas DPC placement did not significantly decrease risk of ALI, ultrasound-guided cannulation decreased the risk of bleeding. Cannulation in the operating room is associated with decreased risk of ALI at the expense of increased risk of bleeding. ALI, older age (≥65 years), and worse heart failure increased risk of in-hospital mortality.

Prothrombin Complex Concentrate for Emergent Reversal of Intracranial Hemorrhage in Patients with Ventricular Assist Devices.

BACKGROUND: Intracranial hemorrhage (ICH) is a devastating complication for patients with ventricular assist devices (VADs). The safety of emergent anticoagulation reversal with four-factor prothrombin complex concentrate (PCC) and optimal timing of anticoagulation resumption are not clear. In addition, lactate dehydrogenase (LDH) is used as a biomarker for thromboembolic risk, but its utility in guiding anticoagulation management after reversal with PCC has not be described. METHODS: We retrospectively reviewed a consecutive series of patients with VADs presenting with ICH between 2014 and 2020 who received four-factor PCC for rapid anticoagulation reversal. We collected the timing of PCC administration, timing of resumption of anticoagulation, survival, occurrence of thromboembolic events, and LDH levels throughout hospitalization. RESULTS: We identified 16 ICH events in 14 patients with VADs treated with rapid anticoagulation reversal using four-factor PCC (11 intraparenchymal, 4 subdural, 1 subarachnoid hemorrhage). PCC was administered at a mean of 3.3 ± 0.3 h after imaging diagnosis of ICH. Overall mortality was 63%. Survivors had higher presenting Glasgow Coma Scale (median 15, interquartile range [IQR] 15-15 versus 14, IQR 8-14.7, P = 0.041). In all six instances where the patient survived, anticoagulation was resumed on average 9.16 ± 1.62 days after reversal. There were no thromboembolic events prior to resumption of anticoagulation. Three events occurred after anticoagulation resumption and within 3 months of reversal: VAD thrombosis in a patient with thrombosis at the time of reversal, ischemic stroke, and readmission for elevated LDH in the setting of subtherapeutic international normalized ratio. CONCLUSIONS: Our limited series found no thromboembolic complications immediately following anticoagulation reversal with PCC prior to resumption of anticoagulation. LDH trends may be useful to monitor thromboembolic risk after reversal.

Ankle-brachial index to monitor limb perfusion in patients with femoral venoarterial extracorporeal membrane oxygenation.

BACKGROUND: Limb ischemia is a major complication of femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO). Use of ankle-brachial index (ABI) to monitor limb perfusion in VA-ECMO has not been described. We report our experience monitoring femoral VA-ECMO patients with serial ABI and the relationships between ABI and near infrared spectroscopy (NIRS). METHODS: This is a retrospective single-center review of consecutive adult patients placed on femoral VA-ECMO between January 2019 and October 2019. Data were collected on patients with paired ABI and NIRS values. Relationships between NIRS and ABI of the cannulated (E-NIRS and E-ABI) and non-cannulated legs (N-NIRS and N-ABI) along with the difference between legs (d-NIRS and d-ABI) were determined using Pearson correlation. RESULTS: Overall, 22 patients (mean age 56.5 ± 14.0 years, 72.7% male) were assessed with 295 E-ABI and E-NIRS measurements, and 273 N-ABI and N-NIRS measurements. Mean duration of ECMO support was 129.8 ± 78.3 h. ECMO-mortality was 13.6% and in-hospital mortality was 45.5%. N-ABI and N-NIRS were significantly higher than their ECMO counterparts (ABI mean difference 0.16, 95% confidence interval [CI]: 0.13-0.19, p < .0001; NIRS mean difference 2.51, 95% CI: 1.48-3.54, p < .0001). There was no correlation between E-ABI versus E-NIRS (r = .032, p = .59), N-ABI versus N-NIRS (r = .097, p = .11), or d-NIRS versus d-ABI (r = .11, p = .069). CONCLUSION: ABI is a quantitative metric that may be used to monitor limb perfusion and supplement clinical exams to identify limb ischemia in femorally cannulated VA-ECMO patients. More studies are needed to characterize the significance of ABI in femoral VA-ECMO and its value in identifying limb ischemia in this patient population.