The CHARTER-Ireland trial: can nebulised heparin reduce acute lung injury in patients with SARS-CoV-2 requiring advanced respiratory support in Ireland: a study protocol and statistical analysis plan for a randomised control trial.

BACKGROUND: COVID-19 pneumonia is associated with the development of acute respiratory distress syndrome (ARDS) displaying some typical histological features. These include diffuse alveolar damage with extensive pulmonary coagulation activation. This results in fibrin deposition in the microvasculature, leading to the formation of hyaline membranes in the air sacs. Well-conducted clinical trials have found that nebulised heparin limits pulmonary fibrin deposition, attenuates progression of ARDS, hastens recovery and is safe in non-COVID ARDS. Unfractionated heparin also inactivates the SARS-CoV-2 virus and prevents entry into mammalian cells. Nebulisation of heparin may therefore limit fibrin-mediated lung injury and inhibit pulmonary infection by SARS-CoV-2. Based on these findings, we designed the CHARTER-Ireland Study, a phase 1b/2a randomised controlled study of nebulised heparin in patients requiring advanced respiratory support for COVID-19 pneumonia. METHODS: This is a multi-centre, phase 1b/IIa, randomised, parallel-group, open-label study. The study will randomise 40 SARs-CoV-2-positive patients receiving advanced respiratory support in a critical care area. Randomisation will be via 1:1 allocation to usual care plus nebulised unfractionated heparin 6 hourly to day 10 while receiving advanced respiratory support or usual care only. The study aims to evaluate whether unfractionated heparin will decrease the procoagulant response associated with ARDS up to day 10. The study will also assess safety and tolerability of nebulised heparin as defined by number of severe adverse events; oxygen index and respiratory oxygenation index of intubated and unintubated, respectively; ventilatory ratio; and plasma concentration of interleukin (IL)-1ß, IL6, IL-8, IL-10 and soluble tumour necrosis factor receptor 1, C-reactive protein, procalcitonin, ferritin, fibrinogen and lactate dehydrogenase as well as the ratios of IL-1ß/IL-10 and IL-6/IL-10. These parameters will be assessed on days 1, 3, 5 and 10; time to separation from advanced respiratory support, time to discharge from the intensive care unit and number tracheostomised to day 28; and survival to days 28 and 60 and to hospital discharge, censored at day 60. Some clinical outcome data from our study will be included in the international meta-trials, CHARTER and INHALE-HEP. DISCUSSION: This trial aims to provide evidence of potential therapeutic benefit while establishing safety of nebulised heparin in the management of ARDS associated with SARs-CoV-2 infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT04511923 . Registered on 13 August 2020. Protocol version 8, 22/12/2021 Protocol identifier: NUIG-2020-003 EudraCT registration number: 2020-003349-12 9 October 2020.

Insights Regarding the Berlin Definition of ARDS from Prospective Observational Studies.

The definition of acute respiratory distress syndrome (ARDS), has evolved since it was first described in 1967 by Ashbaugh and Petty to the current "Berlin" definition of ARDS developed in 2012 by an expert panel, that provided clarification on the definition of "acute," and on the cardiac failure criteria. It expanded the definition to include patients receiving non-invasive ventilation, and removed the term "acute lung injury" and added a requirement of patients to be receiving a minimum 5 cmH2O expiratory pressure.Since 2012, a series of observational cohort studies have generated insights into the utility and robustness of this definition. This review will examine novel insights into the epidemiology of ARDS, failures in ARDS diagnosis, the role of lung imaging in ARDS, the novel ARDS cohort that is not invasively ventilated, lung compliance profiles in patients with ARDS, sex differences that exist in ARDS management and outcomes, the progression of ARDS following initial diagnosis, and the clinical profile and outcomes of confirmed versus resolved ARDS. Furthermore, we will discuss studies that challenge the utility of distinguishing ARDS from other causes of acute hypoxemic respiratory failure (AHRF) and identify issues that may need to be addressed in a revised definition.

Association of postoperative complications with persistent post-surgical pain: a multicentre prospective cohort study.

BACKGROUND: Persistent post-surgical pain is an important and under-recognised problem that is difficult to treat. Postoperative complications have been identified as possible risk factors for persistent post-surgical pain. We conducted a secondary analysis of the Measurement of Exercise Tolerance before Surgery (METS) cohort study to characterise the association of major postoperative complications with post-surgical pain at 30 days and 1 yr after major surgery. METHODS: The analysis included 1313 participants (≥40 yr old) who had inpatient noncardiac surgery and survived for 1 yr. The co-primary outcomes were 30-day post-surgical pain and 1-yr post-surgical pain. Post-surgical pain was defined as pain or discomfort that was of moderate or severe intensity (EuroQoL-5D [EQ-5D] instrument) and unimproved compared with preoperative pain or discomfort. The principal exposure was major in-hospital complications (moderate or severe by modified Clavien-Dindo criteria). Multivariable logistic regression modelling was used to characterise the adjusted association of major complications with outcomes. RESULTS: Of the cohort, 12% (n=163) experienced major complications, 51% (n=674) reported 30-day post-surgical pain, and 42% (n=545) reported 1-yr post-surgical pain. Major complications were associated with 30-day post-surgical pain (adjusted odds ratio [aOR]=1.54; 95% confidence interval [CI], 1.05-2.23) and possibly 1-yr post-surgical pain (aOR=1.42; 95% CI, 0.98-2.06). When analyses were repeated after multiple imputation of missing covariate and outcome data, complications were associated with both 30-day and 1-yr post-surgical pain. CONCLUSIONS: Patients who developed major complications were more likely to report pain at 30 days and possibly 1 yr after surgery. Research is necessary to validate these findings and delineate underlying mechanisms.

Albumin use in bleeding cardiac surgical patients and associated patient outcomes.

PURPOSE: Albumin solution is a colloid used for resuscitation in cardiac surgical patients, but it is unclear if it offers advantages over crystalloids. We examined current clinical practice across 11 cardiac surgical centres and the association of albumin with outcomes in a cohort of bleeding cardiac surgical patients. METHODS: This was a post hoc analysis of data from the Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery (FIBRES) trial. Multivariable regression models adjusted for demographic and surgical characteristics were used to examine predictors of early albumin administration (within the initial 24 perioperative hours), late albumin administration (from 24 hr to seven days after cardiopulmonary bypass), and the association of albumin use with 28-day acute kidney injury, mortality, and length of hospital and intensive care unit (ICU) stay. RESULTS: Of the 735 patients included, 525 (71%) received albumin, ranging from 4.8% to 97.4% of patients across institutions, with 475 (64.6%) receiving albumin early (5% or 25% solution). In the adjusted models, female sex and preoperative hospital admission were associated with early use, while heart failure, female sex, bleeding severity, older age, and prior albumin use were predictors of later administration. Early albumin use was not associated with differences in acute kidney injury (adjusted odds ratio [aOR] 1.77; 95% confidence interval [CI], 0.96 to 3.27; P = 0.07), mortality (aOR 1.66; 95% CI, 0.99 to 2.78; P = 0.05), or length of ICU stay (P = 0.11) or hospital stay (P = 0.67). CONCLUSIONS: Albumin use is common but highly variable within and across sites. Albumin use was not associated with improved outcomes. High quality randomized controlled trials should clarify its role in cardiac surgical patients.

RéSUMé: OBJECTIF: La solution d'albumine est un colloïde utilisé pour la réanimation des patients chirurgicaux cardiaques, mais nous ne savons pas si elle est avantageuse par rapport aux cristalloïdes. Nous avons examiné la pratique clinique actuelle dans 11 centres de chirurgie cardiaque et l'association entre l'albumine et les devenirs dans une cohorte de patients chirurgicaux cardiaques en état d'hémorragie. MéTHODE: Il s'agissait d'une analyse post hoc des données de l'étude FIBRES (Effect of Fibrinogen Concentrate vs Cryoprecipitate on Blood Component Transfusion After Cardiac Surgery, soit 'Effet du concentré de fibrinogène vs cryoprécipité sur la transfusion de composants sanguins après une chirurgie cardiaque'). Des modèles de régression multivariée ajustés pour tenir compte des caractéristiques démographiques et chirurgicales ont été employés pour examiner les facteurs prédictifs d'une administration précoce d'albumine (dans les premières 24 heures périopératoires), d'une administration tardive d'albumine (entre 24 heures et sept jours après la circulation extracorporelle), et l'association entre l'utilisation d'albumine et l'insuffisance rénale aiguë à 28 jours, la mortalité, et la durée de séjour à l'hôpital et à l'unité de soins intensifs (USI). RéSULTATS: Parmi les 735 patients inclus, 525 (71 %) ont reçu de l'albumine, allant de 4,8 % à 97,4 % des patients dans tous les établissements, et 475 (64,6 %) ont reçu de l'albumine de manière précoce (solution à 5 % ou 25 %). Dans les modèles ajustés, le sexe féminin et l'admission préopératoire à l'hôpital ont été associés à une utilisation précoce, tandis que l'insuffisance cardiaque, le sexe féminin, la gravité des saignements, un âge plus avancé et l'utilisation antérieure d'albumine étaient des prédicteurs d'une administration tardive. L'utilisation précoce d'albumine n'a pas été associée à des différences en matière d'insuffisance rénale aiguë (rapport de cotes ajusté [RCA] 1,77; intervalle de confiance [IC] à 95 %, 0,96 à 3,27; P = 0,07), de mortalité (RCA = 1,66; IC 95 %, 0,99 à 2,78; P = 0,05), ou de durée de séjour à l'USI (P = 0,11) ou à l'hôpital (P = 0,67). CONCLUSION: L'utilisation de l'albumine est fréquente mais très variable au sein des établissements et entre ceux-ci. L'utilisation de l'albumine n'a pas été associée à une amélioration des devenirs. Des études randomisées contrôlées de haute qualité devraient clarifier son rôle chez les patients de chirurgie cardiaque.

Perioperative risk assessment - focus on functional capacity.

PURPOSE OF REVIEW: This review examines how functional capacity informs preoperative risk stratification, as well as strengths and limitations of options for estimating functional capacity. RECENT FINDINGS: Functional capacity (or cardiopulmonary fitness) overlaps with other important characteristics, including muscular strength, balance, and frailty. Poor functional capacity is associated with postoperative morbidity, especially noncardiovascular complications. Both patient interviews and exercise tests are used to assess functional capacity. The usual approach of an unstructured patient interview does not predict outcomes. Structured interviews that incorporate validated questionnaires (Duke Activity Status Index) or standardized questions about physical activity (ability to climb stairs) do predict moderate-or-severe complications and cardiovascular complications. Among exercise tests, cardiopulmonary exercise testing (CPET) has shown the most consistent association with risks of complications. Other tests (6-min walk test, incremental shuttle walk test, stair climbing) might predict complications, but still require further high-quality evaluation. SUMMARY: A straightforward way to better assess functional capacity is a structured interview with validated questionnaires or standardized questions about physical activities. Functional capacity can also be assessed by exercise tests, with the strongest evidence supporting CPET. Although some simpler exercise tests have shown promise, more research remains needed to better define their role in preoperative evaluation.

Tranexamic acid: current use in obstetrics, major orthopedic, and trauma surgery.

PURPOSE: In this Continuing Professional Development module, we review the practical pharmacology of tranexamic acid and its clinical use in trauma, obstetrics, and major orthopedic surgery. PRINCIPAL FINDINGS: Tranexamic acid is a synthetic drug that inhibits fibrinolysis. Multiple clinical trials in various clinical settings have shown that it can reduce blood loss, transfusion rates, and bleeding-associated mortality. In trauma and obstetrical bleeding, early tranexamic acid administration (< three hours) may have greater clinical benefits. Overall, tranexamic acid use appears safe with no significant increase of thromboembolic or seizure events. Nevertheless, current evidence has limitations related to wide heterogeneity in dose, route, and timing of drug administration, as well as generalizability of the large-scale trial findings to higher income nations. CONCLUSIONS: Tranexamic acid is an efficacious and safe pharmacological-based blood conservation technique in the management of clinically significant hemorrhage. All anesthesiologists should have a good understanding of the pharmacotherapeutic properties and perioperative role of tranexamic acid therapy both inside and outside of the operating room. The use of tranexamic acid is likely to continue to rise with endorsement by various clinical guidelines and healthcare organizations. Further quantitative research is needed to evaluate optimal dosing and drug efficacy in these clinical scenarios.

RéSUMé: OBJECTIF: Dans ce module de Développement professionnel continu, nous passons en revue la pharmacologie pratique de l'acide tranexamique et son utilisation clinique dans le trauma, l'obstétrique, et les chirurgies orthopédiques majeures. CONSTATATIONS PRINCIPALES: L'acide tranexamique est un médicament synthétique inhibant la fibrinolyse. Plusieurs essais cliniques dans divers contextes cliniques ont montré qu'il peut réduire les pertes de sang, les taux de transfusion et la mortalité associée aux saignements. Dans les cas de saignement traumatologique et obstétrical, l'administration précoce d'acide tranexamique (< trois heures) pourrait avoir de plus grands bienfaits cliniques. Globalement, l'utilisation d'acide tranexamique semble sécuritaire et n'entraîne pas d'augmentation significative des complications thromboemboliques ou de convulsions. Néanmoins, les données probantes actuelles comportent des limites liées à une grande hétérogénéité dans la posologie, la voie et le moment d'administration du médicament, ainsi qu'à l'aspect généralisable des résultats des études à grande échelle pour les pays à revenu élevé. CONCLUSION: L'acide tranexamique est une technique pharmacologique de conservation du sang efficace et sécuritaire pour la prise en charge de l'hémorragie cliniquement significative. Les anesthésiologistes devraient tous posséder une bonne compréhension des propriétés pharmacothérapeutiques et du rôle périopératoire de la thérapie par acide tranexamique, tant à l'intérieur qu'à l'extérieur de la salle d'opération. L'utilisation de l'acide tranexamique continuera vraisemblablement à augmenter au fur et à mesure de l'obtention de son approbation par diverses lignes directrices cliniques et organismes de soins de santé. D'autres recherches quantitatives sont nécessaires pour évaluer le dosage optimal et l'efficacité du médicament dans ces scénarios cliniques.

Albumin in adult cardiac surgery: a narrative review.

PURPOSE: Intravascular fluids are a necessary and universal component of cardiac surgical patient care. Both crystalloids and colloids are used to maintain or restore circulating plasma volume and ensure adequate organ perfusion. In Canada, human albumin solution (5% or 25% concentration) is a colloid commonly used for this purpose. In this narrative review, we discuss albumin supply in Canada, explore the perceived advantages of albumin, and describe the clinical literature supporting and refuting albumin use over other fluids in the adult cardiac surgical population. SOURCE: We conducted a targeted search of PubMed, Embase, Medline, Web of Science, ProQuest Dissertations and Theses Global, the Cochrane Central Register of Controlled trials, and the Cochrane Database of Systematic Reviews. Search terms included albumin, colloid, cardiac surgery, bleeding, hemorrhage, transfusion, and cardiopulmonary bypass. PRINCIPAL FINDINGS: Albumin is produced from fractionated human plasma and imported into Canada from international suppliers at a cost of approximately $21 million CAD per annum. While it is widely used in cardiac surgical patients across the country, it is approximately 30-times more expensive than equivalent doses of balanced crystalloid solutions, with wide inter-institutional variability in use and no clear association with improved outcomes. There is a general lack of high-quality evidence for the superiority of albumin over crystalloids in this patient population, and conflicting evidence regarding safety. CONCLUSIONS: In cardiac surgical patients, albumin is widely utilized despite a lack of high- quality evidence supporting its efficacy or safety. A well-designed randomized controlled trial is needed to clarify the role of albumin in cardiac surgical patients.

RéSUMé: OBJECTIF: Les liquides intravasculaires sont une composante nécessaire et universelle des soins aux patients de chirurgie cardiaque. Les cristalloïdes et les colloïdes sont utilisés pour maintenir ou restaurer le volume plasmatique en circulation et assurer une perfusion adéquate des organes. Au Canada, les solutions d'albumine humaine (concentration de 5 % ou 25 %) constituent un colloïde couramment utilisé à cette fin. Dans ce compte rendu narratif, nous discutons de l'approvisionnement en albumine au Canada, explorons les avantages perçus de l'albumine et décrivons la littérature clinique soutenant ou réfutant l'utilisation de l'albumine par rapport à d'autres solutions pour la population chirurgicale cardiaque adulte. SOURCES: Nous avons effectué une recherche ciblée dans les bases de données PubMed, Embase, Medline, Web of Science, ProQuest Dissertations and Theses Global, le Cochrane Central Register of Controlled trials et la Cochrane Database of Systematic Reviews. Les termes de recherche (en anglais) incluaient albumine, colloid, cardiac surgery, bleeding, hemorrhage, transfusion, et cardiopulmonary bypass (soit albumine, colloïde, chirurgie cardiaque, saignement, hémorragie, transfusion et circulation extracorporelle). CONSTATATIONS PRINCIPALES: L'albumine est fabriquée à partir de plasma humain fractionné et importée au Canada à partir de fournisseurs internationaux au coût d'environ 21 millions CAD par année. Bien qu'elle soit largement utilisée chez les patients de chirurgie cardiaque à travers le pays, elle est environ 30 fois plus coûteuse que des doses équivalentes de solutions cristalloïdes équilibrées, avec une grande variabilité interinstitutionnelle quant à son utilisation et aucune association claire avec des devenirs améliorés. Il n'existe en général pas de données probantes de qualité élevée confirmant la supériorité de l'albumine par rapport aux cristalloïdes dans cette population de patients, et les données probantes quant à son innocuité sont contradictoires. CONCLUSION: Chez les patients de chirurgie cardiaque, l'albumine est largement utilisée en dépit d'un manque de données probantes de haute qualité soutenant son efficacité ou son innocuité. Une étude randomisée contrôlée bien conçue est nécessaire pour clarifier le rôle de l'albumine chez les patients de chirurgie cardiaque.

"Fit for Surgery? What's New in Preoperative Assessment of the High-Risk Patient Undergoing Pulmonary Resection".

Advances in perioperative assessment and diagnostics, together with developments in anesthetic and surgical techniques, have considerably expanded the pool of patients who may be suitable for pulmonary resection. Thoracic surgical patients frequently are perceived to be at high perioperative risk due to advanced age, level of comorbidity, and the risks associated with pulmonary resection, which predispose them to a significantly increased risk of perioperative complications, increased healthcare resource use, and costs. The definition of what is considered "fit for surgery" in thoracic surgery continually is being challenged. However, no internationally standardized definition of prohibitive risk exists. Perioperative assessment traditionally concentrates on the "three-legged stool" of pulmonary mechanical function, parenchymal function, and cardiopulmonary reserve. However, no single criterion should exclude a patient from surgery, and there are other perioperative factors in addition to the tripartite assessment that need to be considered in order to more accurately assess functional capacity and predict individual perioperative risk. In this review, the authors aim to address some of the more erudite concepts that are important in preoperative risk assessment of the patient at potentially prohibitive risk undergoing pulmonary resection for malignancy.

Efficacy of Glyceryl trinitrate (GTN) to facilitate the rewarming process during cardiopulmonary bypass.

BACKGROUND: Does Glyceryl trinitrate (GTN) administered during rewarming on cardiopulmonary bypass (CPB) impact: time to completion of rewarming prior to separation from CPB circuit, early post-op patient peripheral - core temperature gradient, time to maintenance of normothermia (core temperature > 36.5 °C) for minimum of 2 h in the initial post-op period, and plasma lactate concentrations initially post-CPB. METHODS: Single centre prospective randomized trial conducted in the Mater Misericordiae University teaching hospital in Dublin Ireland. TRIAL REGISTRATION: ISRCTN registry, ISRCTN10480871 , registered 16th of August 2017. 82 patients enrolled. Patients randomised to low dose GTN infusion (0.01 mcg/kg/min) or higher dose GTN infusion (0.5 mcg/kg/min) during rewarming on CPB. MEASUREMENTS AND MAIN RESULTS: There was no significant difference between the treatment arms for the total time to being rewarmed, U = 759.0, p = 0.84. There were also no differences between the treatment arms for the time to achieve core temperature greater than 36.5 after two hours, U = 714.0, p = 0.52, the time to achieve plateau core skin temperature, U = 688.0, p = 0.37, and the post-intervention protamine lactate, U = 721.0, p = 0.56. CONCLUSIONS: Higher dose GTN infusion during rewarming on CPB does not improve peripheral-core temperature gradient post operatively and has no effect on post-operative lactate concentrations.

Ultrasound-guided continuous deep serratus anterior plane block versus continuous thoracic paravertebral block for perioperative analgesia in videoscopic-assisted thoracic surgery.

BACKGROUND: The deep serratus anterior plane block (SAPB) is a promising novel regional anaesthesia technique for blockade of the anterolateral chest wall. Evidence for the efficacy of SAPB versus other analgesic techniques in thoracic surgery remains inadequate. AIMS: This study compared ultrasound-guided continuous SAPB with a surgically placed continuous thoracic paravertebral block (SPVB) technique in patients undergoing videoscopic-assisted thoracic surgery (VATS). METHODS: In a single-centre, double-blinded, randomized, non-inferiority study, we allocated 40 patients undergoing VATS to either SAPB or SPVB, with both groups receiving otherwise standardized treatment, including multimodal analgesia. The primary outcome was 48-hr opioid consumption. Secondary outcomes included numerical rating scale (NRS) for postoperative pain, patient-reported worst pain score (WPS) as well as functional measures (including mobilization distance and cough strength). RESULTS: A 48-hr opioid consumption for the SAPB group was non-inferior compared with SPVB. SAPB was associated with improved NRS pain scores at rest, with cough and with movement at 24 hr postoperatively (p = .007, p = .001 and p = .012, respectively). SAPB was also associated with a lower WPS (p = .008). Day 1 walking distance was improved in the SAPB group (p = .012), whereas the difference in cough strength did not reach statistical significance (p = .071). There was no difference in haemodynamics, opioid side effects, length of hospital stay or patient satisfaction between the two groups. CONCLUSIONS: The SAPB, as part of a multimodal analgesia regimen, is non-inferior in terms of 48-hr opioid consumption compared to SPVB and is associated with improved functional measures in thoracic surgical patients. ClinicalTrials.gov Identifier: NCT03768193. SIGNIFICANCE: The SAPB interfascial plane block is an efficacious alternative method of opioid-sparing analgesia in high-risk thoracic surgical patients as part of an enhanced recovery programme.

The prognostic significance of nodal ratio on breast cancer recurrence and its potential for incorporation in a new prognostic index.

Axillary nodal status is an inherent part of prognostic tools such as the Nottingham Prognostic Index (NPI). Literature suggests that nodal ratio is a stronger predictive parameter than the total number of positive nodes sampled. Studies also note improved survival in node-negative patients with a larger proportion of nodes excised. The aim of this study was to assess disease-free survival (DFS) comparing the number of negative and positive nodes excised and nodal ratio as the predictive parameters. Consecutive axillary lymph node dissections (ALND) were analyzed over a 25-year period. Data were analyzed using Cox Regression and Kaplan-Meier survival curves. Eight hundred and forty-nine ALNDs were identified, with 327 positive ALNDs and 268 node negative ALNDs incorporated in the study following exclusions. A prognostic index based on nodal ratio was devised and applied retrospectively to 327 positive ALNDs prior to 2002. This index was then prospectively validated in 116 consecutive positive ALNDs from 2002 to 2005. In node negative ALNDs, no significant difference in DFS was noted in patients having