Prolonged dialysis during ex vivo lung perfusion promotes inflammatory responses.

Ex-vivo lung perfusion (EVLP) has extended the number of transplantable lungs by reconditioning marginal organs. However, EVLP is performed at 37°C without homeostatic regulation leading to metabolic wastes' accumulation in the perfusate and, as a corrective measure, the costly perfusate is repeatedly replaced during the standard of care procedure. As an interesting alternative, a hemodialyzer could be placed on the EVLP circuit, which was previously shown to rebalance the perfusate composition and to maintain lung function and viability without appearing to impact the global gene expression in the lung. Here, we assessed the biological effects of a hemodialyzer during EVLP by performing biochemical and refined functional genomic analyses over a 12h procedure in a pig model. We found that dialysis stabilized electrolytic and metabolic parameters of the perfusate but enhanced the gene expression and protein accumulation of several inflammatory cytokines and promoted a genomic profile predicting higher endothelial activation already at 6h and higher immune cytokine signaling at 12h. Therefore, epuration of EVLP with a dialyzer, while correcting features of the perfusate composition and maintaining the respiratory function, promotes inflammatory responses in the tissue. This finding suggests that modifying the metabolite composition of the perfusate by dialysis during EVLP can have detrimental effects on the tissue response and that this strategy should not be transferred as such to the clinic.

Epidemiology of perioperative anaphylaxis in France in 2017-2018: the 11th GERAP survey.

BACKGROUND: Perioperative anaphylaxis is rare but is associated with significant morbidity. This complication has been well described in France by the GERAP (Groupe d'Etude des Réactions Anaphylactiques Périopératoires), a network focused on its study. The epidemiology of perioperative anaphylaxis is evolving, influenced by environmental factors and clinical practice. The aim of this study was to update the epidemiology of perioperative anaphylaxis in France. METHODS: This multicentre retrospective study was performed in 26 allergy clinics of the GERAP network in 2017-8. RESULTS: There were 765 patients with perioperative anaphylaxis included. Most cases were severe, with 428 (56%) reactions graded as 3 or 4 according to the Ring and Messmer classification. Skin test results were available for 676 patients, with a culprit agent identified in 471 cases (70%). Neuromuscular blocking agents were the main cause of perioperative anaphylaxis (n=281; 60%), followed by antibiotics (n=118; 25%) and patent blue dye (n=11; 2%). Cefazolin was the main antibiotic responsible for perioperative anaphylaxis (52% of antibiotic-related reactions). Suxamethonium and rocuronium were the main neuromuscular blocking agents responsible for perioperative anaphylaxis with 7.1 (6.1-8.4) and 5.6 (4.2-7.4) reactions per 100,000 vials sold, respectively, whereas cefazolin-related cases were estimated at 0.7 (0.5-0.9) reactions per 100,000 vials sold. CONCLUSIONS: Our results confirm that most commonly identified triggering agents remain neuromuscular blocking agents. Reactions to antibiotics, particularly cefazolin, are becoming increasingly frequent. The origin of sensitisation to cefazolin is unknown, as no cross-sensitisation has been described, and it should be the subject of further study. Perioperative anaphylaxis should be followed over the years and understood given the changing triggers. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT04654923).

Association of severe postpartum hemorrhage and development of psychological disorders: Results from the prospective and multicentre HELP MOM study.

OBJECTIVE: Post-partum hemorrhage (PPH) is the leading preventable cause of worldwide maternal morbidity and mortality. Risk factors for psychological disorders following PPH are currently unknown. HELP-MOM study aimed to determine the incidence and identify risk factors for psychological disorders following PPH. METHODS: HELP-MOM study was a prospective, observational, national, and multicentre study including patients who experienced severe PPH requiring sulprostone. The primary endpoint was the occurrence of psychological disorders (anxiety and/or post-traumatic disorder and/or depression) following PPH, assessed at 1, 3, and 6 months after delivery using HADS, IES-R, and EPDS scales. RESULTS: Between November 2014 and November 2016, 332 patients experienced a severe PPH and 236 (72%) answered self-questionnaires at 1, 3, and 6 months. A total of 161 (68%) patients declared a psychological disorder following severe PPH (146 (90.1%) were screened positive for anxiety, 96 (58.9%) were screened positive for post-traumatic stress disorder, and 94 (57.7%) were screened positive for post-partum depression). In multivariable analysis, the use of intra-uterine tamponnement balloon was associated with a lower risk to be screened positive for psychological disorder after severe PPH (OR = 0.33 [IC95% 0.15-0.69], p = 0.004, and after propensity score matching (OR=0.34 [IC95% 0.12-0.94], p = 0.04)). Low hemoglobin values during severe PPH management were associated with a higher risk of being screened positive for psychological disorders. Finally, we did not find differences in desire or pregnancy between patients without or with psychological disorders occurring in the year after severe PPH. DISCUSSION: Severe PPH was associated with significant psychosocial morbidity including anxiety, post-traumatic disorder, and depression. This should engage a psychological follow-up. Large cohorts are urgently needed to confirm our results. REGISTRATION: ClinicalTrials.gov under number NCT02118038.

Interest in the new thromboelastometry device, Clot Pro®, for predicting thrombocytopenia and hypofibrinogenemia during lung transplantation.

INTRODUCTION: Lung transplantation is associated with high proportion of transfusion. Monitoring of coagulopathy using viscoelastic tests could aid in the perioperative management of bleeding. The aim of the study was to assess the predictive cut-off values for thrombocytopenia and hypofibrinogenemia using the new thromboelastography analyzer, ClotPro. METHODS: We retrospectively enrolled 65 patients who underwent lung transplantation and were sampled for both viscoelastic assays and conventional coagulation assays simultaneously during the procedure. We characterized the correlation between the EX-test (extrinsic pathway) and platelet count as well as between the FIB-test (extrinsic pathway after platelet inhibition) and fibrinogen concentration. Then, we used ROC curve analysis to determine the optimal EX-test and FIB-test values for predicting thrombocytopenia and hypofibrinogenemia. RESULTS: All the amplitude values of the EX-test (A5, A10, A20, MCF) showed correlation with platelets count (Spearman's rank correlation coefficient ranging from 0.75 to 0.77, all p < 0.0001). We also observed a strong correlation between the amplitude values of the FIB-test (A5, A10, A20 and MCF) and the fibrinogen concentration (Spearman's rank correlation coefficient ranging from 0.68 to 0.71, all p < 0.0001). The AUCs of the EX-test values for thrombocytopenia <100 G/L and <80 G/L ranged from 0.80 to 0.93. Similarly, the AUCs of the FIB-test values for hypofibrinogenemia <1.5 g/L and <2 g/L ranged from 0.74 to 0.83. These results indicate that only the five-minute parameter of thromboelastometry is sufficient for detecting thrombocytopenia and hypofibrinogenemia in patients undergoing lung transplantation. The proposed cut off values for the EX-test to predict thrombocytopenia <80 G/L showed high sensitivity (>86 %), high specificity (>89 %) and high negative predictive value (>95 %). FIB-test cut off values predictive of fibrinogen below 1.5 g/L showed sensitivity (>78 %), specificity (>55 %) and negative predictive value (>88 %). CONCLUSIONS: Our study provided preliminary results that are useful for developing a ClotPro-based algorithm to guide transfusion in lung transplantation. Future interventional studies will be necessary to validate these cut-off values of ClotPro for guiding transfusion.

Survey of the Impact of Decision Support in Preoperative Management of Anemia (i-Anemia): Survey Study.

BACKGROUND: Major surgery on patients with anemia has demonstrated an increased risk of perioperative blood transfusions and postoperative morbidity and mortality. Recent studies have shown that integrating preoperative anemia treatment as a component of perioperative blood management may reduce blood product utilization and improve outcomes in both cardiac and noncardiac surgery. However, outpatient management of anemia falls outside of daily practice for most anesthesiologists and is probably weakly understood. OBJECTIVE: We conducted a simulated case survey with anesthesiologists to accomplish the following aims: (1) evaluate the baseline knowledge of the preoperative optimization of anemia and (2) determine the impact of real-time clinical decision support on anemia management. METHODS: We sent a digital survey (i-Anemia) to members of the French Society of Anaesthesia and Critical Care. The i-Anemia survey contained 7 simulated case vignettes, each describing a patient's brief clinical history and containing up to 3 multiple-choice questions related to preoperative anemia management (12 questions in total). The cases concerned potential situations of preoperative anemia and were created and validated with a committee of patient blood management experts. Correct answers were determined by the current guidelines or by expert consensus. Eligible participants were randomly assigned to control or decision support groups. In the decision support group, the primary outcome measured was the correct response rate. RESULTS: Overall, 1123 participants were enrolled and randomly divided into control (n=568) and decision support (n=555) groups. Among them, 763 participants fully responded to the survey. We obtained a complete response rate of 65.6% (n=364) in the group receiving cognitive aid and 70.2% (n=399) in the group without assistance. The mean duration of response was 10.2 (SD 6.8) minutes versus 7.8 (SD 5) minutes for the decision support and control groups, respectively (P<.001). The score significantly improved with cognitive aid (mean 10.3 out of 12, SD 2.1) in comparison to standard care (mean 6.2 out of 12, SD 2.1; P<.001). CONCLUSIONS: Management strategies to optimize preoperative anemia are not fully known and applied by anesthesiologists in daily practice despite their clinical importance. However, adding a decision support tool can significantly improve patient care by reminding practitioners of current recommendations.

Differential early response of monocyte/macrophage subsets to intra-operative corticosteroid administration in lung transplantation.

Introduction: Lung transplantation often results in primary and/or chronic dysfunctions that are related to early perioperative innate allo-responses where myeloid subsets play a major role. Corticosteroids are administered upon surgery as a standard-of-care but their action on the different myeloid cell subsets in that context is not known. Methods: To address this issue, we used a cross-circulatory platform perfusing an extracorporeal lung coupled to cell mapping in the pig model, that enabled us to study the recruited cells in the allogeneic lung over 10 hours. Results: Myeloid cells, i.e. granulocytes and monocytic cells including classical CD14pos and non-classical/intermediate CD16pos cells, were the dominantly recruited subsets, with the latter upregulating the membrane expression of MHC class II and CD80/86 molecules. Whereas corticosteroids did not reduce the different cell subset recruitment, they potently dampened the MHC class II and CD80/86 expression on monocytic cells and not on alveolar macrophages. Besides, corticosteroids induced a temporary and partial anti-inflammatory gene profile depending on cytokines and monocyte/macrophage subsets. Discussion: This work documents the baseline effects of the standard-of-care corticosteroid treatment for early innate allo-responses. These insights will enable further optimization and improvement of lung transplantation outcomes.

An observational study of gastric content in women scheduled for cesarean section or operative hysteroscopy.

BACKGROUND: The estimation of gastric content in third trimester pregnant women has already been studied, conclusions remain contradictory. The aim of this study was to compare gastric content in pregnant and non-pregnant women using gastric ultrasound. We performed an observational two-center study of women scheduled for a cesarean section (CS group) and of non-pregnant women scheduled for hysteroscopy (HS group). METHODS: Ultrasound evaluation was performed before surgery with measurement of antral cross-sectional area (CSA) in the semi-recumbent position (SRP), primary outcome, and in the right lateral position (RLD). Gastric fluid volume (GFV) was calculated. Results are expressed as medians (25th and 75th percentiles). Perlas Score was evaluated and expressed as number (percentage). RESULTS: Sixty patients in the CS group and 64 in the HS group were analyzed. Antral CSA (SRP) was greater in the CS group (350 mm2 [236-415] vs. 247 mm2 [180-318]; P=0.001). Antral CSA (RLD) was also significantly greater in the CS group (P=0.027). GFV was not different between groups whether expressed in absolute value (P=0.516) or relative to weight (P=0.946) mL.kg-1. Perlas Score repartition was similar in both groups (P=0.860). Kappa coefficients of concordance between CSA, GFV and Perlas Score were slight or at best fair. CONCLUSIONS: Our study confirmed that antral CSA is increased among pregnant women and outlined that antral CSA should not be used alone in the decision-making process especially when the results of indicators (antral CSA, GFV, and Perlas Grading Score) are discordant.

Chronic pain after posterolateral and axillary approaches to lung surgery: a monocentric observational study.

PURPOSE: Post-thoracotomy pain syndrome (PTPS) and chronic postsurgical neuropathic pain (CPNP) were evaluated 4 months after thoracic surgery whether the approach was a posterolateral (PL) incision or the less invasive axillary (AX) one. METHODS: Patients, 79 in each group, undergoing a thoracotomy between July 2014 and November 2015 were analyzed 4 months after surgery in this prospective monocentric cohort study. RESULTS: More PL patients suffered PTPS (60.8% vs. 40.5%; p = 0.017) but CPNP was equally present (45.8% and 46.9% in the PL and AX groups). Patients with PTPS have more limited daily activities (p < 0.001) but a similar psychological disability (i.e., catastrophism). Patients with CPNP have an even greater limitation of daily activities (p = 0.007) and more catastrophism (p = 0.0002). Intensity of pain during mobilization of the homolateral shoulder at postoperative day 6 (OR = 1.40, CI 95% [1.13-1.75], p = 0.002); age (OR = 0.97 [0.94-1.00], p = 0.022), and presence of pain before surgery (OR = 2.22 [1.00-4.92], p = 0.049) are related to the occurrence of PTPS; while, height of hypoesthesia area on the breast line measured 6 days after surgery is the only factor related to that of CPNP (OR = 1.14 [1.01-1.30], p = 0.036). CONCLUSION: Minimally invasive surgery was associated with less frequent PTPS, but with equal risk of CPNP. Pain before surgery and its postoperative intensity are associated with PTPS. This must lead to a more aggressive care of pain patients before surgery and of a better management of postoperative pain. CPNP can be forecasted according to the early postoperative height of hypoesthesia area on the breast line.

Results of Lung Transplantation for Cystic Fibrosis With Selected Donors Over 65 Years Old.

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65 years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65 years or ≥65 years). The primary objective was to assess the survival rate at 3 years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65 years, and 30 had donors over 65 years. Donors' characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5 years, the percentage of predicted forced expiratory volume in 1 s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65 years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice.

Cell type- and time-dependent biological responses in ex vivo perfused lung grafts.

In response to the increasing demand for lung transplantation, ex vivo lung perfusion (EVLP) has extended the number of suitable donor lungs by rehabilitating marginal organs. However despite an expanding use in clinical practice, the responses of the different lung cell types to EVLP are not known. In order to advance our mechanistic understanding and establish a refine tool for improvement of EVLP, we conducted a pioneer study involving single cell RNA-seq on human lungs declined for transplantation. Functional enrichment analyses were performed upon integration of data sets generated at 4 h (clinical duration) and 10 h (prolonged duration) from two human lungs processed to EVLP. Pathways related to inflammation were predicted activated in epithelial and blood endothelial cells, in monocyte-derived macrophages and temporally at 4 h in alveolar macrophages. Pathways related to cytoskeleton signaling/organization were predicted reduced in most cell types mainly at 10 h. We identified a division of labor between cell types for the selected expression of cytokine and chemokine genes that varied according to time. Immune cells including CD4+ and CD8+ T cells, NK cells, mast cells and conventional dendritic cells displayed gene expression patterns indicating blunted activation, already at 4 h in several instances and further more at 10 h. Therefore despite inducing inflammatory responses, EVLP appears to dampen the activation of major lung immune cell types, what may be beneficial to the outcome of transplantation. Our results also support that therapeutics approaches aiming at reducing inflammation upon EVLP should target both the alveolar and vascular compartments.

Auriculotherapy in prevention of migraine attacks: an open randomized trial.

Use of auriculotherapy to prevent episodic migraine pain has seldom been reported. The aim of this open study was to show that three sessions of auriculotherapy, 1 month apart, using semi-permanent needles decrease frequency and intensity of an attack in patients presenting episodic migraine. A total of 90 patients were randomized to the treatment group (AUR group, n = 58) or the control group (C group, n = 32). Four patients dropped out during the study (three in the AUR group and one in the C group). The number of days with migraine and non-migraine headache was similar when the analysis focused on the 3 months of the study or on the difference in each group of this number between the 3 months preceding the inclusion and the 3 months of the study (p = 0.123). AUR group patients had fewer days with non-migraine headache (p = 0.011) and took less Triptans (p = 0.045) than group C. Number of days with migraine, sum of the pain intensities of all migraines and non-migraine headaches, and total number of analgesics taken, other than triptan, were similar between groups. MIDAS score decreased with time in the AUR group while it increased in the C group whether in absolute values (p = 0.035) or as categories (p = 0.037). These contrasted results should lead to further study of the effectiveness of auriculotherapy for the prevention of migraine. Clinical trail registration: Protocol registered on the Clinicaltrials.gov, website (January 30, 2017, NCT03036761).

Guidelines on perioperative optimization protocol for the adult patient 2023.

OBJECTIVE: The French Society of Anesthesiology and Intensive Care Medicine [Société Française d'Anesthésie et de Réanimation (SFAR)] aimed at providing guidelines for the implementation of perioperative optimization programs. DESIGN: A consensus committee of 29 experts from the SFAR was convened. A formal conflict-of-interest policy was developed at the outset of the process and enforced throughout. The entire guidelines process was conducted independently of any industry funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence. METHODS: Four fields were defined: 1) Generalities on perioperative optimization programs; 2) Preoperative measures; 3) Intraoperative measures and; 4) Postoperative measures. For each field, the objective of the recommendations was to answer a number of questions formulated according to the PICO model (population, intervention, comparison, and outcomes). Based on these questions, an extensive bibliographic search was carried out using predefined keywords according to PRISMA guidelines and analyzed using the GRADE® methodology. The recommendations were formulated according to the GRADE® methodology and then voted on by all the experts according to the GRADE grid method. As the GRADE® methodology could have been fully applied for the vast majority of questions, the recommendations were formulated using a "formalized expert recommendations" format. RESULTS: The experts' work on synthesis and application of the GRADE® method resulted in 30 recommendations. Among the formalized recommendations, 19 were found to have a high level of evidence (GRADE 1±) and ten a low level of evidence (GRADE 2±). For one recommendation, the GRADE methodology could not be fully applied, resulting in an expert opinion. Two questions did not find any response in the literature. After two rounds of rating and several amendments, strong agreement was reached for all the recommendations. CONCLUSIONS: Strong agreement among the experts was obtained to provide 30 recommendations for the elaboration and/or implementation of perioperative optimization programs in the highest number of surgical fields.

A cross-circulatory platform for monitoring innate allo-responses in lung grafts.

Lung transplantation is the only curative option for end-stage chronic respiratory diseases. However the survival rate is only about 50% at 5 years. Although experimental evidences have shown that innate allo-responses impact on the clinical outcome, the knowledge of the involved mechanisms involved is limited. We established a cross-circulatory platform to monitor the early recruitment and activation of immune cells in an extracorporeal donor lung by coupling blood perfusion to cell mapping with a fluorescent marker in the pig, a commonly-used species for lung transplantation. The perfusing pig cells were easily detectable in lung cell suspensions, in broncho-alveolar lavages and in different areas of lung sections, indicating infiltration of the organ. Myeloid cells (granulocytes and monocytic cells) were the dominant recruited subsets. Between 6 and 10 h of perfusion, recruited monocytic cells presented a strong upregulation of MHC class II and CD80/86 expression, whereas alveolar macrophages and donor monocytic cells showed no significant modulation of expression. This cross-circulation model allowed us to monitor the initial encounter between perfusing cells and the lung graft, in an easy, rapid, and controllable manner, to generate robust information on innate response and test targeted therapies for improvement of lung transplantation outcome.

Complementary Therapy Learning in the Setting of Lung Transplantation: A Single-Center Observational Study of Appropriation and Efficacy.

Transplanted patients could benefit from complementary techniques. This prospective single-center, open study, performed in a tertiary university hospital, evaluates the appropriation and efficacy of a toolbox-kit of complementary techniques. Self-hypnosis, sophrology, relaxation, holistic gymnastics, and transcutaneous electric nerve stimulation (TENS) were taught to adult patients scheduled for double-lung transplantation. Patients were asked to use them before and after transplantation, as needed. The primary outcome was appropriation of each technique within the first three postoperative months. Secondary outcomes included efficacy on pain, anxiety, stress, sleep, and quality-of-life. Among the 80 patients included from May 2017 to September 2020, 59 were evaluated at the 4th postoperative month. Over the 4359 sessions performed, the most frequent technique used before surgery was relaxation. After transplantation, the techniques most frequently used were relaxation and TENS. TENS was the best technique in terms of autonomy, usability, adaptation, and compliance. Self-appropriation of relaxation was the easiest, while self-appropriation of holistic gymnastics was difficult but appreciated by patients. In conclusion: the appropriation by patients of complementary therapies such as mind-body therapies, TENS and holistic gymnastics is feasible in lung transplantation. Even after a short training session, patients regularly practiced these therapies, mainly TENS and relaxation.

Goal-Directed Fluid Therapy and major postoperative complications in elective craniotomy. A retrospective analysis of a before-after multicentric study.

BACKGROUND: Goal-Directed Fluid Therapy (GDFT) is recommended to decrease major postoperative complications. However, data are lacking in intra-cranial neurosurgery. METHODS: We evaluated the efficacy of a GDFT protocol in a before/after multi-centre study in patients undergoing elective intra-cranial surgery for brain tumour. Data were collected during 6 months in each period (before/after). GDFT was performed in high-risk patients: ASA score III/IV and/or preoperative Glasgow Coma Score (GCS) < 15 and/or history of brain tumour surgery and/or tumour greater size ≥ 35 mm and/or mid-line shift ≥ 3 mm and/or significant haemorrhagic risk. Major postoperative complication was a composite endpoint: re-intubation after surgery, a new onset of GCS < 15 after surgery, focal motor deficit, agitation, seizures, intra-cranial haemorrhage, stroke, intra-cranial hypertension, hospital-acquired related pneumonia, surgical site infection, cardiac arrythmia, invasive mechanical ventilation ≥ 48 h and in-hospital mortality. RESULTS: From July 2018 to January 2021, 344 patients were included in 3 centers: 171 in the before and 173 in the after (GDFT) period. Thirty-six (21.1%) patients displayed a major postoperative complication in the Before period, and 50 (28.9%) in the After period (p = 0.1). In the propensity score analysis, we matched 48 patients in each period: 9 (18.8%) patients in the After period and 14 (29.2%) patients in the Before period displayed a major perioperative complication (p = 0.2). Sixty-two (35.8%) patients received GDFT in the After period, with great heterogeneity among centers (p < 0.05). CONCLUSIONS: In our before-after study, GDFT was not associated with a decrease in postoperative major complications in elective intra-cranial neurosurgery.