Advanced Respiratory Failure Requiring Tracheostomy-A Marker of Unfavourable Prognosis after Heart Transplantation.

Advanced respiratory failure with tracheostomy requirement is common in heart recipients. The aim of the study is to assess the tracheostomy rate after orthotopic heart transplantation and identify the subgroups of patients with the highest need for tracheostomy and these groups' association with mortality at a single centre through a retrospective analysis of 140 consecutive patients transplanted between December 2012 and July 2018. As many as 28.6% heart recipients suffered from advanced respiratory failure with a need for tracheostomy that was performed after a median time of 11.5 days post-transplant. Tracheostomy was associated with a history of stroke (OR 3.4; 95% CI) 1.32-8.86; p = 0.012), previous sternotomy (OR 2.5; 95% CI 1.18-5.32; p = 0.017), longer cardiopulmonary bypass time (OR 1.01; 95% CI 1.00-1.01; p = 0.007) as well as primary graft failure (OR 6.79; 95% CI2.93-15.71; p < 0.001), need of renal replacement therapy (OR 19.2; 95% 2.53-146; p = 0.004) and daily mean SOFA score up to 72 h (OR 1.50; 95% 1.23-1.71; p < 0.01). One-year mortality was significantly higher in patients requiring a tracheostomy vs. those not requiring one during their hospital stay (50% vs. 16%, p < 0.001). The need for tracheostomy in heart transplant recipients was 30% in our study. Advanced respiratory failure was associated with over 3-fold greater 1-year mortality. Thus, tracheostomy placement may be regarded as a marker of unfavourable prognosis.

The Active-Site [4Fe-4S] Cluster in the Isoprenoid Biosynthesis Enzyme IspH Adopts Unexpected Redox States during Ligand Binding and Catalysis.

(E)-4-Hydroxy-3-methylbut-2-enyl diphosphate reductase, or IspH (formerly known as LytB), catalyzes the terminal step of the bacterial methylerythritol phosphate (MEP) pathway for isoprene synthesis. This step converts (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) into one of two possible isomeric products, either isopentenyl diphosphate (IPP) or dimethylallyl diphosphate (DMAPP). This reaction involves the removal of the C4 hydroxyl group of HMBPP and addition of two electrons. IspH contains a [4Fe-4S] cluster in its active site, and multiple cluster-based paramagnetic species of uncertain redox and ligation states can be detected after incubation with reductant, addition of a ligand, or during catalysis. To characterize the clusters in these species, 57Fe-labeled samples of IspH were prepared and studied by electron paramagnetic resonance (EPR), 57Fe electron-nuclear double resonance (ENDOR), and Mössbauer spectroscopies. Notably, this ENDOR study provides a rarely reported, complete determination of the 57Fe hyperfine tensors for all four Fe ions in a [4Fe-4S] cluster. The resting state of the enzyme (Ox) has a diamagnetic [4Fe-4S]2+ cluster. Reduction generates [4Fe-4S]+ (Red) with both S = 1/2 and S = 3/2 spin ground states. When the reduced enzyme is incubated with substrate, a transient paramagnetic reaction intermediate is detected (Int) which is thought to contain a cluster-bound substrate-derived species. The EPR properties of Int are indicative of a 3+ iron-sulfur cluster oxidation state, and the Mössbauer spectra presented here confirm this. Incubation of reduced enzyme with the product IPP induced yet another paramagnetic [4Fe-4S]+ species (Red+P) with S = 1/2. However, the g-tensor of this state is commonly associated with a 3+ oxidation state, while Mössbauer parameters show features typical for 2+ clusters. Implications of these complicated results are discussed.

Comment on Oehler et al. Outcome and Midterm Survival after Heart Transplantation Is Independent from Donor Length of Stay in the Intensive Care Unit. Life 2022, 12, 1053.

Oehler et al. described an interesting finding, stating that length of stay (LOS) of the donors in the intensive care unit (ICU) did not have an impact on the outcomes and survival of recipients up to 5 years after heart transplantation (HTx) [...].

Enhanced Recovery After Surgery (ERAS®) Society Consensus Guidelines for Emergency Laparotomy Part 3: Organizational Aspects and General Considerations for Management of the Emergency Laparotomy Patient.

BACKGROUND: This is Part 3 of the first consensus guidelines for optimal care of patients undergoing emergency laparotomy using an enhanced recovery after surgery (ERAS) approach. This paper addresses organizational aspects of care. METHODS: Experts in management of the high-risk and emergency general surgical patient were invited to contribute by the International ERAS® Society. PubMed, Cochrane, Embase, and MEDLINE database searches were performed for ERAS elements and relevant specific topics. Studies were selected with particular attention to randomized clinical trials, systematic reviews, meta-analyses and large cohort studies, and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation system. Recommendations were made on the best level of evidence, or extrapolation from studies on elective patients when appropriate. A modified Delphi method was used to validate final recommendations. RESULTS: Components of organizational aspects of care were considered. Consensus was reached after three rounds of a modified Delphi process. CONCLUSIONS: These guidelines are based on best current available evidence for organizational aspects of an ERAS® approach to patients undergoing emergency laparotomy and include discussion of less common aspects of care for the surgical patient, including end-of-life issues. These guidelines are not exhaustive but pull together evidence on important components of care for this high-risk patient population. As much of the evidence is extrapolated from elective surgery or emergency general surgery (not specifically laparotomy), many of the components need further evaluation in future studies.

Consensus Guidelines for Perioperative Care for Emergency Laparotomy Enhanced Recovery After Surgery (ERAS®) Society Recommendations Part 2-Emergency Laparotomy: Intra- and Postoperative Care.

BACKGROUND: This is Part 2 of the first consensus guidelines for optimal care of patients undergoing emergency laparotomy (EL) using an Enhanced Recovery After Surgery (ERAS) approach. This paper addresses intra- and postoperative aspects of care. METHODS: Experts in aspects of management of high-risk and emergency general surgical patients were invited to contribute by the International ERAS® Society. PubMed, Cochrane, Embase, and Medline database searches were performed for ERAS elements and relevant specific topics. Studies on each item were selected with particular attention to randomized clinical trials, systematic reviews, meta-analyses, and large cohort studies and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Recommendations were made on the best level of evidence, or extrapolation from studies on elective patients when appropriate. A modified Delphi method was used to validate final recommendations. Some ERAS® components covered in other guideline papers are outlined only briefly, with the bulk of the text focusing on key areas pertaining specifically to EL. RESULTS: Twenty-three components of intraoperative and postoperative care were defined. Consensus was reached after three rounds of a modified Delphi Process. CONCLUSIONS: These guidelines are based on best available evidence for an ERAS® approach to patients undergoing EL. These guidelines are not exhaustive but pull together evidence on important components of care for this high-risk patient population. As much of the evidence is extrapolated from elective surgery or emergency general surgery (not specifically laparotomy), many of the components need further evaluation in future studies.

Impact of negative pressure wound therapy on enteroatmospheric fistulation in the septic open abdomen.

AIM: The effect of negative pressure wound therapy (NPWT) on the pathogenesis and outcome of enteroatmospheric fistulation (EAF) in the septic open abdomen (OA) is unclear. This study compares the development and outcome of EAF following NPWT with that occurring in the absence of NPWT. METHODS: Consecutive patients admitted with EAF following abdominal sepsis at a National Reference Centre for intestinal failure between 01 January 2005 and 31 December 2015 were included in this study. Patients were divided into two groups based on those that had been treated with NPWT and those that had not (non-NPWT) and characteristics of their fistulas compared. Clinical outcomes concerning nutritional autonomy at 4 years and time to fistula development, size of abdominal wall defect and complete fistula closure were compared between groups. RESULTS: A total of 160 patients were admitted with EAF following a septic abdomen (31-NPWT and 129-non-NPWT). Median (range) time taken to fistulation after OA was longer with NPWT (18 [5-113] vs. 8 [2-60] days, p = 0.004); these patients developed a greater number of fistulas (3 [2-21] vs. 2 [1-10], p = 0.01), involving a greater length of small bowel (42.5 [15-100] cm vs. 30 [3.5-170] cm, p = 0.04) than those who did not receive NPWT. Following reconstructive surgery, nutritional autonomy was similar in both groups (77% vs. 72%) and a comparable number of patients were also fistula-free (100% vs. 97%). CONCLUSIONS: Negative pressure wound therapy appears to be associated with more complex and delayed intestinal fistulation, involving a greater length of small intestine in the septic OA. This did not, however, appear to adversely affect the overall outcome of intestinal and abdominal wall reconstruction in this study.

The Role of Cytochrome†P450 AbyV in the Final Stages of Abyssomicin†C Biosynthesis.

Abyssomicin C and its atropisomer are potent inhibitors of bacterial folate metabolism. They possess complex polycyclic structures, and their biosynthesis has been shown to involve several unusual enzymatic transformations. Using a combination of synthesis and in vitro assays we reveal that AbyV, a cytochrome P450 enzyme from the aby gene cluster, catalyses a key late-stage epoxidation required for the installation of the characteristic ether-bridged core of abyssomicin C. The X-ray crystal structure of AbyV has been determined, which in combination with molecular dynamics simulations provides a structural framework for our functional data. This work demonstrates the power of combining selective carbon-13 labelling with NMR spectroscopy as a sensitive tool to interrogate enzyme-catalysed reactions in vitro with no need for purification.

The Role of Cytochrome†P450 AbyV in the Final Stages of Abyssomicin†C Biosynthesis.

Abyssomicin C and its atropisomer are potent inhibitors of bacterial folate metabolism. They possess complex polycyclic structures, and their biosynthesis has been shown to involve several unusual enzymatic transformations. Using a combination of synthesis and in vitro assays we reveal that AbyV, a cytochrome P450 enzyme from the aby gene cluster, catalyses a key late-stage epoxidation required for the installation of the characteristic ether-bridged core of abyssomicin C. The X-ray crystal structure of AbyV has been determined, which in combination with molecular dynamics simulations provides a structural framework for our functional data. This work demonstrates the power of combining selective carbon-13 labelling with NMR spectroscopy as a sensitive tool to interrogate enzyme-catalysed reactions in vitro with no need for purification.

Perioperative care for older people.

Increasing numbers of older people are undergoing surgery with benefits including symptom relief and extended longevity. Despite these benefits, older people are more likely than younger patients to experience postoperative complications, which are predominantly medical as opposed to surgical. Comprehensive Geriatric Assessment and optimisation offers a systematic approach to risk assessment and risk modification in the perioperative period. Clinical evidence shows that Comprehensive Geriatric Assessment and optimisation reduces postoperative medical complications and is cost effective in the perioperative setting. These benefits have been observed in patients undergoing elective and emergency surgery. Challenges in the implementation of perioperative Comprehensive Geriatric Assessment and optimisation services are acknowledged. These include the necessary involvement of a wide stakeholder group, limited available geriatric medicine workforce and ensuring fidelity to Comprehensive Geriatric Assessment methodology with adaptation to the local context. Addressing these challenges needs a cross-specialty, interdisciplinary approach underpinned by evidence-based medicine and implementation science with upskilling to facilitate innovative use of the extended workforce. Future delivery of quality patient-centred perioperative care requires proactive engagement with national audit, collaborative guidelines and establishment of networks to share best practice.

Prognostic significance of serum lactate following cardiac transplantation.

Aim: Hyperlactatemia is common post-heart transplantation. Lactate measurements in the first 24 h were analyzed with respect to mortality. Methods: A total of 153 consecutive cardiac transplant patients were reviewed. Recipients of organs maintained in a state of ex vivo perfusion were included. Results: A total of 143 heart recipients were included. Hyperlactatemia (>2 mmol/l) was present in all patients. Despite maximum lactate and lactate clearance being significantly higher in nonsurvivors (p = 0.002, p = 0.004), neither receiver operator curve analysis nor multivariate logistic regression showed association with 1-year mortality. In comparison, the minimum lactate was significantly associated with mortality (area under the curve 0.728 [p < 0.001]; odds ratio 1.28 [95% 1.01-162; p = 0.04]). Conclusion: The minimum lactate, a surrogate of persistent hyperlactatemia, was demonstrated to be superior compared with maximum lactate and lactate clearance in determining patient prognosis.

Midterm outcomes of venovenous extracorporeal membrane oxygenation as a bridge to lung transplantation: Comparison with nonbridged recipients.

OBJECTIVES: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is increasingly being used in acutely deteriorating patients with end-stage lung disease as a bridge to transplantation (BTT). It can allow critically ill recipients to remain eligible for lung transplants (LTx) while reducing pretransplant deconditioning. We analyzed early- and midterm postoperative outcomes of patients on VV-ECMO as a BTT and the impact of preoperative VV-ECMO on posttransplant survival outcomes. METHODS: All consecutive LTx performed at our institution between January 2012 and December 2018 were analyzed. After matching, BTT patients were compared with nonbridged LTx recipients. RESULTS: Out of 297 transplanted patients, 21 (7.1%) were placed on VV-ECMO as a BTT. After matching, we observed similar 30-day mortality between BTT and non-BTT patients (4.6% vs. 6.6%, p = .083) despite a higher incidence of early postoperative complications (need for ECMO, delayed chest closure, and acute kidney injury). Furthermore, preoperative VV-ECMO did not appear associated with 30-day or 1-year mortality in both frequentist and Bayesian analysis (odds ratio [OR]: 0.35, 95% confidence interval: 0.03-3.49, p = .369; OR: 0.27, 95% credible interval: 0.01-3.82, p = 84.7%, respectively). In sensitivity analysis, both subgroups were similar in respect to 30-day (7.8% vs. 6.5%, p = .048) and 1-year mortality (12.5% vs. 18%, p = .154). CONCLUSIONS: Patients with acute refractory respiratory failure while waiting for LTx represent a high-risk cohort of patients. VV-ECMO as a BTT is a reasonable strategy in adult patients with acceptable operative mortality and 1-year survival comparable to non-BTT patients.

Postoperative acute kidney injury and renal replacement therapy after DCD lung transplantation.

Acute kidney injury (AKI) after lung transplantation (LTx) is a common complication. We aimed to assess whether donation after circulatory death (DCD) is associated with an increased risk of AKI and renal replacement therapy (RRT) in the early postoperative period compared to the donation after brain death (DBD). Retrospective data on a cohort (N = 95) of LTx patients (DCD n = 17, DBD n = 78) characterized by no use of ex-vivo lung perfusion were analyzed for the incidence of AKI within 30 postoperative days and incidence of RRT within 7 and 30 days. After optimal full matching, an imbalance remained between the DCD and DBD patients in respect to intraoperative use of cardiopulmonary bypass (CPB). Therefore, a further subset (n = 77) was defined that excluded CPB patients, and matching was repeated (DCD n = 13 vs. DBD n = 63) resulting in a fair balance on a range of preoperative characteristics and intraoperative use of ECMO. In both matched subsets, DCD was associated with around twice higher risk of AKI and RRT within 7 and 30 postoperative days. In conclusion, data suggest that DCD could be associated with worse early renal outcomes in a subset of LTx patients and justify further studies on the topic in order to refine further renal care pathways perioperatively.

Echocardiography in the intensive care unit: An essential tool for diagnosis, monitoring and guiding clinical decision-making.

In the last years, new trends on patient diagnosis for admission in cardiac intensive care unit (CICU) have been observed, shifting from acute myocardial infarction or acute heart failure to non-cardiac diseases such as sepsis, acute respiratory failure or acute kidney injury. Moreover, thanks to the advances in scientific knowledge and higher availability, there has been increasing use of positive pressure mechanical ventilation which has its implications on the heart. Therefore, there is a growing need for Cardiac intensivists to quickly, noninvasively and repeatedly evaluate various hemodynamic conditions and the response to therapy. Transthoracic critical care echocardiography (CCE) currently represents an essential tool in CICU, as it is used to evaluate biventricular function and complications following acute coronary syndromes, identify the mechanisms of circulatory failure, acute valvular pathologies, tailoring and titrating intravenous treatment or mechanical circulatory support. This could be completed with trans-esophageal echocardiography (TOE), advanced echocardiography and lung ultrasound to provide a thorough evaluation and monitoring of CICU patients. However, CCE could sometimes be challenging as the acquisition of good-quality images is limited by mechanical ventilation, suboptimal patient position or recent surgery with drains on the chest. Moreover, there are some technical caveats that one should bear in mind while performing CCE in order to optimize its use and avoid misleading findings. The aim of this review is to highlight the key role of CCE, providing an updated overview of its main applications and possible pitfalls in order to facilitate its use in CICU for clinical decision-making.

Enantioselective Organocatalytic Synthesis of Bicyclic Resorcinols via an Intramolecular Friedel-Crafts-Type 1,4-Addition: Access to Cannabidiol Analogues.

The organocatalytic transformation of resorcinols is extremely rare. In this article, we report a highly enantioselective, organocatalytic intramolecular cyclization of these systems by a Friedel-Crafts-type 1,4-addition using a Jørgensen-Hayashi-like organocatalyst with a large silyl protecting group, and show that heat improves reaction yield with virtually no detriment to enantioselectivity. A variety of bicyclic resorcinols were obtained with excellent enantioselectivities (up to 94%). To show the utility of these constructs, and as part of a wider project involving the synthesis of cannabinoid-like compounds, the resorcinol formed was used to generate both 'normal' and 'abnormal' cannabidiol (CBD) derivatives which were shown to have anticonvulsant activity.

The Role of Mechanical Circulatory Support in Patients With Severe Left Ventricular Impairment Treated With Transcatheter Aortic Valve Implantation and Percutaneous Coronary Intervention.

Transcatheter aortic valve implantation (TAVI) has become an established treatment for patients with severe aortic stenosis (AS) in an ever-growing patient population. It is not uncommon for patients who are undergoing TAVI to have technically difficult anatomy, simultaneous severe left ventricular (LV) impairment and/or extensive coronary artery disease. In this case series we present examples where the use of mechanical circulatory support (MCS) facilitated a safe aortic and coronary intervention in extremely complex patients who would have otherwise carried prohibitive procedural risk.

Guidelines for Perioperative Care for Emergency Laparotomy Enhanced Recovery After Surgery (ERAS) Society Recommendations: Part 1-Preoperative: Diagnosis, Rapid Assessment and Optimization.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) protocols reduce length of stay, complications and costs for a large number of elective surgical procedures. A similar, structured approach appears to improve outcomes, including mortality, for patients undergoing high-risk emergency general surgery, and specifically emergency laparotomy. These are the first consensus guidelines for optimal care of these patients using an ERAS approach. METHODS: Experts in aspects of management of the high-risk and emergency general surgical patient were invited to contribute by the International ERAS® Society. Pubmed, Cochrane, Embase, and MEDLINE database searches on English language publications were performed for ERAS elements and relevant specific topics. Studies on each item were selected with particular attention to randomized controlled trials, systematic reviews, meta-analyses and large cohort studies, and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Recommendations were made on the best level of evidence, or extrapolation from studies on non-emergency patients when appropriate. The Delphi method was used to validate final recommendations. The guideline has been divided into two parts: Part 1-Preoperative Care and Part 2-Intraoperative and Postoperative management. This paper provides guidelines for Part 1. RESULTS: Twelve components of preoperative care were considered. Consensus was reached after three rounds. CONCLUSIONS: These guidelines are based on the best available evidence for an ERAS approach to patients undergoing emergency laparotomy. Initial management is particularly important for patients with sepsis and physiological derangement. These guidelines should be used to improve outcomes for these high-risk patients.

General Method for the Synthesis of α- or ß-Deoxyaminoglycosides Bearing Basic Nitrogen.

The introduction of glycosides bearing basic nitrogen is challenging using conventional Lewis acid-promoted pathways owing to competitive coordination of the amine to the Lewis acid promoter. Additionally, because many aminoglycosides lack a C2 substituent, diastereomeric mixtures of O-glycosides are often produced. Herein, we present a method for the synthesis of α- or ß- 2,3,6-trideoxy-3-amino- and 2,4,6-trideoxy-4-amino O-glycosides from a common precursor. Our strategy proceeds by the reductive lithiation of thiophenyl glycoside donors and trapping of the resulting anomeric anions with 2-methyltetrahydropyranyl peroxides. We apply this strategy to the synthesis of α- and ß-forosamine, pyrrolosamine, acosamine, and ristosamine derivatives using primary and secondary peroxides as electrophiles. α-Linked products are obtained in 60-96% yield and with >50:1 selectivity. ß-Linked products are obtained in 45-94% yield and with 1.7->50:1 stereoselectivity. Contrary to donors bearing an equatorial amine substituent, donors bearing an axial amine substituent favored ß-products at low temperatures. This work establishes a general strategy to synthesize O-glycosides bearing a basic nitrogen.

Valvular complications following the Impella device implantation.

BACKGROUND: Despite clear clinical benefits, there is limited evidence regarding possible complications of the novel mechanical support device Impella. Aortic and mitral valve regurgitation or injury are rare but potential complications following implantation of the Impella device. METHODS: To evaluate valvular complications after the Impella device implantation, we have performed a comprehensive search of literature on multiple sites on this topic. RESULTS AND CONCLUSION: Ten case reports and one observational retrospective study were identified, with a total number of 19 patients identified. This article aims to draw attention to potential periprocedural complications relating to the Impella, in particular iatrogenic aortic and mitral valve injuries. Moreover, we have summarized our recommendations emphasizing the need for careful management and meticulous follow-up of these patients to avoid such potentially devastating complications.

Veno-arterial mechanical support as bridge to surgery in a patient with severe aortic regurgitation: a case report.

In this case report, we describe the successful application of veno-arterial extracorporeal membrane oxygenation support in a young patient with severe aortic regurgitation caused by a blocked mechanical valve. In this situation, extracorporeal membrane oxygenation mechanical support was used as a bridge to the prompt replacement of the diseased valve. Aortic regurgitation is commonly recognized as a contraindication to extracorporeal membrane oxygenation support because of the risk of ventricular distension, pulmonary oedema and further organ failure. However, in certain cases and with a rapid decision making, extracorporeal membrane oxygenation can be used as a bridge to treatment and recovery.

Addendum: Synthesis and reactivity of precolibactin 886.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.