Cardioprotection with Intralipid During Coronary Artery Bypass Grafting Surgery on Cardiopulmonary Bypass: A Randomized Clinical Trial.

PURPOSE: Coronary artery bypass grafting (CABG) on cardiopulmonary bypass (CPB) is associated with myocardial ischemia-reperfusion injury (IRI), which may limit the benefit of the surgery. Both experimental and clinical studies suggest that Intralipid, a lipid emulsion commonly used for parenteral nutrition, can limit myocardial IRI. We therefore aimed to investigate whether Intralipid administered at reperfusion can reduce myocardial IRI in patients undergoing CABG on CPB. METHODS: We conducted a randomized, double-blind, pilot trial in which 29 adult patients scheduled for CABG were randomly assigned (on a 1:1 basis) to receive either 1.5 ml/kg Intralipid 20% or Ringer's Lactate 3 min before aortic cross unclamping. The primary endpoint was the 72-h area under the curve (AUC) for troponin I. RESULTS: Of the 29 patients randomized, 26 were included in the study (two withdrew consent and one was excluded before surgery). The 72-h AUC for troponin I did not significantly differ between the control and Intralipid group (546437 ± 205518 versus 487561 ± 115724 arbitrary units, respectively; P = 0.804). Other outcomes (including 72-h AUC for CK-MB, C-reactive protein, need for defibrillation, time to extubation, length of ICU and hospital stay, and serious adverse events) were similar between the two groups. CONCLUSION: In patients undergoing CABG on CPB, Intralipid did not limit myocardial IRI compared to placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02807727 (registration date: 16 June 2016).

The elephant in the room: Exploring the influence and participation of patients in infection-related care across surgical pathways in South Africa and India.

OBJECTIVE: The irrational use of antibiotics is a leading contributor to antibiotic resistance. Antibiotic stewardship (AS) interventions predominantly focus on prescribers. This study investigated the influence and participation of inpatients in infection-related care, including antibiotic decision-making, within and across two tertiary hospitals in South Africa (Cape Town) and India (Kerala). METHODS: Through ethnographic enquiry of clinical practice in surgical pathways, including direct nonparticipant observation of clinical practices, healthcare worker (HCW), patient and carer interactions in surgical ward rounds and face-to-face interviews with participants (HCWs and patients), we sought to capture the implicit and explicit influence that patients and carers have in infection-related care. Field notes and interview transcripts were thematically coded, aided by NVivo 12® Pro software. RESULTS: Whilst observational data revealed the nuanced roles that patients/carers play in antibiotic decision-making, HCWs did not recognize these roles. Patients and carers, though invested in patient care, are not routinely involved, nor are they aware of the opportunities for engagement in infection-related decision-making. Patients associated clinical improvement with antibiotic use and did not consider hospitalization to be associated with infection acquisition or transmission, highlighting a lack of understanding of the threat of infection and antibiotic resistance. Patients' economic and cultural positionalities may influence their infection-related behaviours. In the study site in India, cultural norms mean that carers play widespread but unrecognized roles in inpatient care, participating in infection prevention activities. CONCLUSION: For patients to have a valuable role in AS and make informed decisions regarding their infection-related care, a mutual understanding of their role in this process among HCWs and patients is crucial. The observed differences between the two study sites indicate the critical need for understanding and addressing the contextual drivers that impact effective patient-centred healthcare delivery. PATIENT OR PUBLIC CONTRIBUTION: Ethnographic observations and interviews conducted in this study involved patients as participants. Patients were recruited for interviews after obtaining signed informed consent forms. Patients' identities were completely anonymized when presenting the study findings.

Outcomes of patients undergoing lung resection for drug-resistant TB and the prognostic significance of pre-operative positron emission tomography/computed tomography (PET/CT) in predicting treatment failure.

Background: Surgery remains an adjunctive treatment for drug-resistant tuberculosis (DR-TB) treatment failure despite the use of bedaquiline. However, there are few data about the role of surgery when combined with newer drugs. There are no outcome data from TB endemic countries, and the prognostic significance of pre-operative PET-CT remains unknown. Methods: We performed a prospective observational study of 57 DR-TB patients referred for surgery at Groote Schuur Hospital between 2010 and 2016. PET-CT was performed if there was nodal disease or disease outside the area of planned resection but did not influence treatment decisions. 24-month treatment success post-surgery (cure or treatment completion), including all-cause mortality, was determined. Findings: 35/57 (61.4%) patients (median age 40 years; 26% HIV-infected) underwent surgery and 22/57 (38.6%) did not (11 patients were deemed unsuitable due to bilateral cavitary disease and 11 patients declined surgery). Treatment failure was significantly lower in those who underwent surgery compared to those eligible but declined surgery [15/35 (43%) versus 11/11 (100%); relative risk 0.57 (0.42-0.76); p < 0.01). In patients treated with surgery, a post-operative regimen containing bedaquiline was associated with a lower odds of treatment failure [OR (95%CI) 0.06 (0.00-0.48); p = 0.007]. Pre-operative PET-CT (n = 25) did not predict treatment outcome. Interpretation: Resectional surgery for DR-TB combined with chemotherapy was associated with significantly better outcomes than chemotherapy alone. A post-operative bedaquiline-containing regimen was associated with improved outcome; however, this finding may have been confounded by higher use of bedaquiline and less loss to follow-up in the surgical group. However, PET-CT had no prognostic value. These data inform clinical practice in TB-endemic settings. Funding: This work was supported by the South African MRC (RFA-EMU-02-2017) and the EDCTP (TMA-2015SF-1043 & TMA- 1051-TESAII).

PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation: Part 2: Study results-prostheses, positions, and economic development.

Objectives: The Prospective Randomized On-X Mechanical Prosthesis Versus St Jude Medical Mechanical Prosthesis Evaluation (PROSE) trial purpose was to investigate whether a current-generation mechanical prosthesis (On-X; On-X Life Technologies/Artivion Inc) reduced the incidence of thromboembolic-related complications compared with a previous-generation mechanical prosthesis (St Jude Medical Mechanical Prosthesis; Abbott/St Jude Medical). This second report documents the valve-related complications by individual prostheses and by Western and Developing populations. Methods: The PROSE trial study was conducted in 28 worldwide centers and incorporated 855 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The study protocol, and analyses of 10 demographic variables and 24 risk factors were published in detail in 2021. Results: The total patient population (N = 855) included patients receiving an On-X valve (n = 462) and a St Jude Medical valve (n = 393). The overall freedom evaluation showed no differences at 5 years between the prostheses for thromboembolism or for valve thrombosis. There were also no differences in mortality. There were several differences between Developing and Western populations. The freedom relations at 5 years for mortality favored Western over Developing populations. Valve thrombosis was differentiated by position and site: aortic < mitral (P = .007) and Western < Developing (P = .005). In the mitral position there were no cases in Western populations, whereas there were 8 in Developing populations (P = .217). Conclusions: The On-X valve and St Jude Medical valve performed equally well in the study with no differences found. The only differentiation occurred with valve thrombosis in the mitral position more than the aortic position and occurring in Developing more than Western populations. The occurrence of valve thrombosis was also related to a younger population possibly due to anticoagulation compliance based on record review.

PROSE: Prospective Randomized Trial of the On-X Mechanical Prosthesis and the St Jude Medical Mechanical Prosthesis Evaluation : Part 1(Patient Dynamics): Preoperative demographics and preoperative and operative risk factors.

OBJECTIVES: The PROSE trial purpose is to investigate whether the incidence of thromboembolic-related complications is reduced with a current generation mechanical prosthesis (On-X Life Technologies/CryoLife Inc.-On-X) compared with a previous generation mechanical prosthesis (St Jude Medical-SJM). The primary purpose of the initial report is to document the preoperative demographics, and the preoperative and operative risk factors by individual prosthesis and by Western and Developing populations. METHODS: The PROSE study was conducted in 28 worldwide centres and incorporated 855 subjects randomized between 2003 and 2016. The study enrollment was discontinued on August 31, 2016. The preoperative demographics incorporated age, gender, functional class, etiology, prosthetic degeneration, primary rhythm, primary valve lesion, weight, height, BSA and BMI. The preoperative and operative evaluation incorporated 24 risk factors. RESULTS: The total patient population (855) incorporated On-X population (462) and the St Jude Medical population (393). There was no significant difference of any of the preoperative demographics between the On-X and SJM groups. The preoperative and operative risk factors evaluation showed there was no significant difference between the On-X and St Jude Medical populations. The preoperative and operative risk factors by valve position (aortic and mitral) also documented no differentiation. The dominant preoperative demographics of the Western world population were older age, male gender, sinus rhythm, aortic stenosis, congenital aortic lesion, and mitral regurgitation. The dominant demographics of the Developing world population were rheumatic etiology, atrial fibrillation, aortic regurgitation, mixed aortic lesions, mitral stenosis and mixed mitral lesions. The Developing world group had only one significant risk factor, congestive heart failure. The majority of the preoperative and operative risk factors were significant in the Western world population. CONCLUSIONS: The preoperative demographics do not differentiate the prostheses but do differentiate the Western and Developing world populations. The preoperative and operative risk factors do not differentiate the prostheses BUT do differentiate the Western and Developing world populations.

Patient understanding of and participation in infection-related care across surgical pathways: a scoping review.

OBJECTIVE: To explore the existing evidence on patient understanding of and/or participation in infection-related care in surgical specialties. METHOD: A scoping review of the literature was conducted. PubMed, Web of Science, Scopus, and grey literature sources were searched using predefined search criteria for policies, guidelines, and studies in the English language. Data synthesis was done through content and thematic analysis to identify key themes in the included studies. RESULTS: The initial search identified 604 studies, of which 41 (36 from high-income and five from low- and middle-income countries) were included in the final review. Most of the included studies focused on measures to engage patients in infection prevention and control (IPC) activities, with few examples of antimicrobial stewardship (AMS) engagement strategies. While patient engagement interventions in infection-related care varied depending on study goals, surgical wound management was the most common intervention. AMS engagement was primarily limited to needs assessment, without follow-up to address such needs. CONCLUSION: Existing evidence highlights a gap in patient participation in infection-related care in the surgical pathway. Standardization of patient engagement strategies is challenging, particularly in the context of surgery, where several factors influence how the patient can engage and retain information. Infection-related patient engagement and participation strategies in surgery need to be inclusive and contextually fit.

Neurologic recovery after ten minutes of absent cerebral blood flow at normothermia.

Prolonged normothermic cardiac arrest is associated with a high incidence of neurological morbidity and mortality. Whole body temperature-controlled perfusion has been applied to limit reperfusion injury and minimize ischemia. We describe the full recovery of a patient after the application of rapid hypothermia following an intraoperative aortic rupture with ten minutes of absent cerebral blood flow.

Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing.

Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis.Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity.Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection (n = 14) and healthy lung tissue from control subjects without tuberculosis (n = 10). RNA sequencing, immunohistochemistry, and bacterial load determination were performed at each cavity position. Differentially expressed genes were normalized to control subjects without tuberculosis, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways.Measurements and Main Results: The median (range) lung cavity volume on positron emission tomography/computed tomography scans was 50 cm3 (15-389 cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple proinflammatory pathways were upregulated in the cavity wall, whereas a downregulation "sink" in the central caseum-fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r > 0.6), whereas T-helper effector systems did not.Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.

Isolated mechanical aortic valve replacement in rheumatic patients in a low- to middle-income country.

OBJECTIVE: Although the results of aortic valve replacement are well documented for industrialized countries, the outcome in patients with rheumatic aortic valve disease in low- to middle-income countries is less well explored. The aim of this study was to determine the long-term survival and clinical outcomes after isolated aortic valve replacement in patients with rheumatic heart disease in a Sub-Saharan country where follow-up of indigent patients is often challenging. METHODS: A retrospective review of 969 aortic valve replacements performed between 2003 and 2013 was conducted at Cape Town's Groote Schuur Hospital. Patients who underwent concomitant procedures (n = 664) or had nonrheumatic valve pathology (n = 185) were excluded. The mean age of the rheumatic cohort (n = 121) was 43.1 ± 11.6 years with a mean follow-up period of 6.14 ± 3.44 years. The primary end points were survival and valve-related complications. RESULTS: A 15% cardiac- or valve-related 10-year mortality after receiving a mechanical prosthesis corresponded with a significantly higher mortality rate than that of a matched population. Overall cumulative survival at 1, 5, and 10 years was 93.5% (87.0-96.9), 86.4% (78.4-91.8), and 78.1% (67.5-86.0), respectively, and the corresponding cumulative freedom from combined thromboembolism and bleeding was 94.4% (88.2-97.5), 87.4% (79.4-92.5), and 86.1% (77.9-91.6), respectively. CONCLUSIONS: In low- to middle-income countries, with their unique mix of indigent and "First World" patients, rheumatic heart disease still accounts for a significant proportion of patients requiring isolated aortic valve replacement. Although mechanical prostheses are often selected in these young adults, survival remains suboptimal. Major bleeding and thromboembolic events account for the majority (77%) of the reported valve-related complications.

Drug-Penetration Gradients Associated with Acquired Drug Resistance in Patients with Tuberculosis.

RATIONALE: Acquired resistance is an important driver of multidrug-resistant tuberculosis (TB), even with good treatment adherence. However, exactly what initiates the resistance and how it arises remain poorly understood. OBJECTIVES: To identify the relationship between drug concentrations and drug susceptibility readouts (minimum inhibitory concentrations [MICs]) in the TB cavity. METHODS: We recruited patients with medically incurable TB who were undergoing therapeutic lung resection while on treatment with a cocktail of second-line anti-TB drugs. On the day of surgery, antibiotic concentrations were measured in the blood and at seven prespecified biopsy sites within each cavity. Mycobacterium tuberculosis was grown from each biopsy site, MICs of each drug identified, and whole-genome sequencing performed. Spearman correlation coefficients between drug concentration and MIC were calculated. MEASUREMENTS AND MAIN RESULTS: Fourteen patients treated for a median of 13 months (range, 5-31 mo) were recruited. MICs and drug resistance-associated single-nucleotide variants differed between the different geospatial locations within each cavity, and with pretreatment and serial sputum isolates, consistent with ongoing acquisition of resistance. However, pretreatment sputum MIC had an accuracy of only 49.48% in predicting cavitary MICs. There were large concentration-distance gradients for each antibiotic. The location-specific concentrations inversely correlated with MICs (P < 0.05) and therefore acquired resistance. Moreover, pharmacokinetic/pharmacodynamic exposures known to amplify drug-resistant subpopulations were encountered in all positions. CONCLUSIONS: These data inform interventional strategies relevant to drug delivery, dosing, and diagnostics to prevent the development of acquired resistance. The role of high intracavitary penetration as a biomarker of antibiotic efficacy, when assessing new regimens, requires clarification.

Transmural capillary ingrowth is essential for confluent vascular graft healing.

Spontaneous endothelialization of synthetic vascular grafts may occur via three independent or concurrent modalities: transanastomotic (TA) outgrowth, transmural (TM) ingrowth or fallout (FO) from the blood. The limited TA and FO endothelialization, which occurs in humans, results in poor long-term patency in the small diameter position, where TM ingrowth may offer a clinically relevant alternative. To achieve sequential analysis of each mode of healing, loop grafts comprising anastomotically isolated angiopermissive polyurethane control grafts were abluminally sealed using either ePTFE wraps or solid polyurethane skins and implanted in the rat infrarenal aortic loop model for twelve weeks. Positive control grafts showed improved endothelialization and patency compared to the abluminally isolated mid-grafts. Furthermore, the mid-graft healing was accelerated with surface heparin and heparin-growth factor (VEGF, PDGF) modification in a three-week sub-study. We are thus able to distinguish between the three vascular graft endothelialization modes, and conclude that fallout plays a secondary role to TM healing. The increased endothelialisation for growth factor presenting grafts indicates the promise of this simple approach but further optimization is required. STATEMENT OF SIGNIFICANCE: In addition to the full elucidation of, and differentiation between, the three healing/endothelialisation modes of vascular grafts, the significance of the work relates to the near-complete lack of endothelialisation of small diameter vascular grafts in humans (1-2 cm transanastomotic outgrowth on a graft that may be 60 cm long) even after decades of implantation. The concomitant retained midgraft thrombogenicity leads, together with anastomotic hyperplastic responses, to poor long-term outcomes. The large impact of successful translation of the current research to the achievement of full endothelialisation of long peripheral grafts in humans via transmural ingrowth (half a millimetre distance; thickness of the graft wall), is evident, and supported by the large improvements in clinical patencies achievable in by pre-seeding of ePTFE grafts with confluent endothelia.

The performance of cross-linked acellular arterial scaffolds as vascular grafts; pre-clinical testing in direct and isolation loop circulatory models.

There is a significant need for small diameter vascular grafts to be used in peripheral vascular surgery; however autologous grafts are not always available, synthetic grafts perform poorly and allografts and xenografts degenerate, dilate and calcify after implantation. We hypothesized that chemical stabilization of acellular xenogenic arteries would generate off-the-shelf grafts resistant to thrombosis, dilatation and calcification. To test this hypothesis, we decellularized porcine renal arteries, stabilized elastin with penta-galloyl glucose and collagen with carbodiimide/activated heparin and implanted them as transposition grafts in the abdominal aorta of rats as direct implants and separately as indirect, isolation-loop implants. All implants resulted in high patency and animal survival rates, ubiquitous encapsulation within a vascularized collagenous capsule, and exhibited lack of lumen thrombogenicity and no graft wall calcification. Peri-anastomotic neo-intimal tissue overgrowth was a normal occurrence in direct implants; however this reaction was circumvented in indirect implants. Notably, implantation of non-treated control scaffolds exhibited marked graft dilatation and elastin degeneration; however PGG significantly reduced elastin degradation and prevented aneurismal dilatation of vascular grafts. Overall these results point to the outstanding potential of crosslinked arterial scaffolds as small diameter vascular grafts.

Differentiating transmural from transanastomotic prosthetic graft endothelialization through an isolation loop-graft model.

BACKGROUND: In humans, transanastomotic endothelial outgrowth onto the surface of prosthetic vascular grafts is limited to the immediate perianastomotic region, even after years of implantation. In contrast, continual transanastomotic outgrowth together with short graft lengths has led to early endothelial confluence in most animal models pre-empting endothelialization through transmural capillary sprouting. We describe an isolation loop-graft model that clearly separates these distinctly different events. METHODS: Baseline transanastomotic endothelialization was assessed by implanting low-porosity expanded polytetrafluoroethylene grafts (ePTFE; internal diameter 1.7 mm; internodal distance 15-25 µm; 14.2 ± 1.6 mm long) for 2, 4, and 6 weeks (n = 6/time point) in the abdominal aorta of Wistar rats. High-porosity polyurethane (internal diameter 1.7 mm-150 µm pore size) grafts were then interposed ("welded") into the midsection of the ePTFE grafts for 2, 4, 6, and 8 weeks (n = 6/time point). Looping the interposition grafts increased their length to 70.3 ± 8.3 mm. After implantation periods of 6, 8, 12, and 24 weeks (n = 8/time point) isolation loop grafts were analyzed by light, immune-fluorescence (CD31) and scanning electron microscopy, and endothelialization was expressed as maximal transanastomotic endothelial outgrowth (I(max)), mean transanastomotic outgrowth (I(mean)), and segmental graft coverage (GSE). RESULTS: Transanastomotic outgrowth slowed down between 2 and 6 weeks of implantation (proximal: [I(max) from 0.9 ± 0.5 to 0.3 ± 0.3 mm/wk; P < .04; I(mean) from 0.3 ± 0.1 to 0.2 ± 0.1 mm/wk; nonsignificant (NS)]; distal: [I(max) from 0.7 ± 0.3 to 0.3 ± 0.2 mm/wk; P < .02; I(mean) from 0.3 ± 0.2 to 0.2 ± 0.0 mm/wk; NS]) but remained constant thereafter (I(max) = 0.5 ± 0.2 mm/wk; I(mean) = 0.4 ± 0.2 mm/wk at 24 weeks NS). In straight composite grafts, the ePTFE separation zones were too short to isolate transmural ingrowth beyond week 4. In contrast, a broad endothelial-free separation zone was preserved in all looped composite grafts even after half a year of implantation (25.9 ± 5.9 vs 8.7 ± 4.9 mm proximally and 21.9 ± 13.4 vs 12.3 ± 6.2 mm distally at 6 and 24 weeks, respectively). Ninety-three percent of patent loop-grafts showed isolated transmural midgraft endothelium after 4 weeks and 97% after 6 weeks. Midgraft preconfluence was reached by 6 weeks (GSE = 55 ± 45%) and confluence between week 12 and 24 (GSE = 95.0 ± 10.0% and 84.0 ± 30.13%). The subintimal thickness stayed constant with a nonsignificant trend toward regression (91.8 ± 93.9 mm vs 71.4 ± 59.4 mm at 6 and 24 weeks, respectively; NS). CONCLUSIONS: Transmural endothelialization can be clearly distinguished from transanastomotic outgrowth in a high throughput rat model. A looped interposition graft model provides sufficient isolation length to separate the two events for up to half a year and does not result in an increase in intimal hyperplasia. CLINICAL RELEVANCE: Although the mode of graft deployment has changed over the years, the problem of an absent surface endothelium remains, whether small- to medium-diameter grafts are surgically implanted or placed endovascularly as "covered stents." In contrast to humans, most animal models experience progressive transanastomotic endothelial outgrowth. Together with graft lengths that were too short, the clinically irrelevant transanastomotic endothelialization inadvertently led to early endothelial confluence in the vast majority of experimental vascular graft studies pre-empting or concealing alternative modes of endothelialization. The isolation loop-graft model we propose allows the long-term differentiation of the different modes of endothelialization in a small animal screening model.