A locally optimised machine learning approach to early prognostication of long-term neurological outcomes after out-of-hospital cardiac arrest.

Background: Out-of-hospital cardiac arrest (OHCA) represents a major burden for society and health care, with an average incidence in adults of 67 to 170 cases per 100,000 person-years in Europe and in-hospital survival rates of less than 10%. Patients and practitioners would benefit from a prognostication tool for long-term good neurological outcomes. Objective: We aim to develop a machine learning (ML) pipeline on a local database to classify patients according to their neurological outcomes and identify prognostic features. Methods: We collected clinical and biological data consecutively from 595 patients who presented OHCA and were routed to a single regional cardiac arrest centre in the south of France. We applied recursive feature elimination and ML analyses to identify the main features associated with a good neurological outcome, defined as a Cerebral Performance Category score less than or equal to 2 at six months post-OHCA. Results: We identified 12 variables 24 h after admission, capable of predicting a six-month good neurological outcome. The best model (extreme gradient boosting) achieved an AUC of 0.96 and an accuracy of 0.92 in the test cohort. Conclusion: We demonstrated that it is possible to build accurate, locally optimised prediction and prognostication scores using datasets of limited size and breadth. We proposed and shared a generic machine-learning pipeline which allows external teams to replicate the approach locally.

Postoperative outcomes after total sevoflurane inhalation sedation using a disposable delivery system (Sedaconda-ACD) in cardiac surgery.

Introduction: The COVID-19 pandemic prompted our team to develop new solutions for performing cardiac surgery without intravenous anesthetics due to a shortage of these drugs. We utilized an anesthetic conserving device (Sedaconda-ACD) to administer total inhaled anesthesia because specific vaporizers were unavailable for administering inhaled agents during cardiopulmonary bypass (CPB) in our center. We documented our experience and postoperative cardiovascular outcomes. The primary outcome was the peak level of troponin, with secondary outcomes encompassing other cardiovascular complications. Material and methods: A single-center retrospective study was conducted. We performed a multivariate analysis with a propensity score. This investigation took place at a large university referral center. Participants: Adult patients (age ≥ 18) who underwent elective cardiac surgery with CPB between June 2020 to March 2021. Intervention: During the inclusion period, two anesthesia protocols for the maintenance of anesthesia coexisted-total inhaled anesthesia with Sedaconda-ACD and our classic protocol with intravenous drugs during and after CPB. Primary endpoint: Troponin peak level recorded after surgery (highest level recorded within 48 h following the surgery). Results: Out of the 654 included patients, 454 were analyzed after matching (intravenous group = 297 and inhaled group = 157). No significant difference was found between the groups in postoperative troponin peak levels (723 ng/l vs. 993 ng/l-p = 0.2). Total inhaled anesthesia was associated with a decreased requirement for inotropic medications (OR = 0.53, 95% CI 0.29-0.99, p = 0.04). Conclusion: In our cohort, the Sedaconda-ACD device enabled us to achieve anesthesia without intravenous agents, and we did not observe any increase in postoperative complications. Total inhaled anesthesia with sevoflurane was not associated with a lower incidence of myocardial injury assessed by the postoperative troponin peak level. However, in our cohort, the use of inotropic drugs was lower.

The real incidence of sudden death: Fair estimations or futile speculations?

BACKGROUND: The true incidence of sudden death remains undetermined, with controversial results from various publications over time and countries. AIM: To investigate if different estimations would reach the values usually reported for France. METHODS: Three different kinds of estimations were used. First, the number of resuscitated sudden deaths and necropsies for sudden death in the Haute-Garonne French administrative department (i.e. county) over the last 10years was expanded to the national level. Second, sudden death coding of death certificates was collected at the national level. Third, the total number of out-of-hospital cardiac arrests leading to any emergency call (with/without intervention) in Haute-Garonne over the last 10years was expanded to the national level. RESULTS: There was a mean of 26 resuscitated sudden deaths and 145 necropsies for sudden death each year in Haute-Garonne, i.e. 12 to 14 sudden deaths for 100,000 inhabitants, and 7700 to 9400 sudden deaths yearly when related to the whole French population, according to the year of inclusion. Based on death certificates, a mean of 6584 sudden deaths was registered each year in France. Finally, there were about 600 yearly calls/interventions for out-of-hospital cardiac arrests in Haute-Garonne, i.e. 40 to 50 sudden deaths for 100,000 inhabitants, and 16,000 to 27,000 sudden deaths yearly for the whole French territory, according to the year of inclusion. CONCLUSIONS: The incidence of sudden death ranges from 6500 to 27,000 in France according to the calculation methods. This huge difference raises the question of the true current incidence of sudden death, which may have been overestimated previously or may be underestimated in France. More straight prospective surveys are needed to solve this question, because of relevant implications for priorities that should be given to sudden death.

Assessing feasibility and satisfaction in third-trimester pre-anaesthetic teleconsultations: A prospective observational study.

Background and Aims: Pregnancy presents risks, particularly for women with pre-existing health problems. Pre-anaesthetic consultations can help anticipate these risks and establish a medical management strategy on the delivery day. While teleconsultations gained popularity during the coronavirus disease 2019 (COVID-19) pandemic, research on pre-anaesthetic teleconsultations during pregnancy is limited. This study aimed to assess patient satisfaction and physician perception of teleconsultations for third-trimester pre-anaesthetic consultations. Methods: A prospective observational study included pregnant women who opted for teleconsultations for pre-anaesthetic consultations. Patient satisfaction was assessed using Likert scale questions and the System Use Scale. Anaesthetist satisfaction was evaluated using a Likert scale and by considering changes in anaesthetic techniques and missing clinical data in the pre-anaesthetic assessment. Data analysis utilised SPSS Statistics for Windows, Version 20.0. encompassing descriptive statistics, hypothesis testing and odds ratio calculations. This approach explored the correlation between patient and anaesthetist satisfaction and pertinent risk factors. Results: The study enroled 99 patients, with 85% expressing satisfaction and high satisfaction on the Likert scale and 88% finding the teleconsultation acceptable based on the System Use Scale (score ≥ 70). Anaesthetists reported being satisfied with the pre-anaesthetic consultations in 94% of cases. Conclusion: This study demonstrates the feasibility and effectiveness of telemedicine consultations in obstetric anaesthesia, showing high patient and anaesthetist satisfaction rates.

Neuroimmune activation is associated with neurological outcome in anoxic and traumatic coma.

The pathophysiological underpinnings of critically disrupted brain connectomes resulting in coma are poorly understood. Inflammation is potentially an important but still undervalued factor. Here, we present a first-in-human prospective study using the 18-kDa translocator protein (TSPO) radioligand 18F-DPA714 for PET imaging to allow in vivo neuroimmune activation quantification in patients with coma (n = 17) following either anoxia or traumatic brain injuries in comparison with age- and sex-matched controls. Our findings yielded novel evidence of an early inflammatory component predominantly located within key cortical and subcortical brain structures that are putatively implicated in consciousness emergence and maintenance after severe brain injury (i.e. mesocircuit and frontoparietal networks). We observed that traumatic and anoxic patients with coma have distinct neuroimmune activation profiles, both in terms of intensity and spatial distribution. Finally, we demonstrated that both the total amount and specific distribution of PET-measurable neuroinflammation within the brain mesocircuit were associated with the patient's recovery potential. We suggest that our results can be developed for use both as a new neuroprognostication tool and as a promising biometric to guide future clinical trials targeting glial activity very early after severe brain injury.

Perioperative pain management models in four European countries: A narrative review of differences, similarities and future directions.

There is general agreement that acute pain management is an important component of perioperative medicine. However, there is no consensus on the best model of care for perioperative pain management, mainly because evidence is missing in many aspects. Comparing the similarities and differences between countries might reveal some insights into different organisational models and how they work. Here, we performed a narrative review to describe and compare the structures, processes and outcomes of perioperative pain management in the healthcare systems of four European countries using Donabedian's framework as a guide. Our comparison revealed many similarities, differences and gaps. Different structures of acute pain services in the four countries with no common definition and standards of care were found. Protocols have been implemented in all countries and guidelines in some. If outcome is assessed, it is mainly pain intensity, and many patients experiencing more intense pain than others have common risk factors (e.g. preoperative pain, preoperative opioid intake, female sex and young age). Outcome assessment beyond pain intensity (such as pain-related physical function, which is important for early rehabilitation and recovery) is currently not well implemented. Developing common quality indicators, a European guideline for perioperative pain management (e.g. for patients at high risk for experiencing severe pain and other outcome parameters) and common criteria for acute pain services might pave the way forward for improving acute pain management in Europe. Finally, the education of general and specialist staff should be aligned in Europe, for example, by using the curricula of the European Pain Federation (EFIC).

Does spinal anesthesia for total hip or knee arthroplasty entail longer operating room occupancy compared to general anesthesia? Case-control study of 337 spinal versus 243 general anesthesias.

BACKGROUND: Treatment protocols, including anesthesia, are constantly progressing to improve rapid early postoperative recovery in lower-limb arthroplasty. To the best of our knowledge, however, no studies compared general versus spinal anesthesia (GA vs. SA) in the surgical pathway of patients undergoing total knee or hip arthroplasty (TKA, THA). Better knowledge of the processes should improve efficacy in theater and optimize surgical planning. The present study comparing GA and SA in the operating room aimed to assess (1) theater occupancy times, and (2) times for each step in a surgery day according to type of anesthesia. HYPOTHESIS: SA leads to longer theater occupancy than GA in TKA and THA. METHODS: A single-center retrospective case-control study analyzed data for the period January 2019 to December 2020 in 303 TKAs (100 GA, 203 SA) and 277 THAs (143 GA, 134 SA), comparing times for all perioperative steps and particularly theater occupancy. RESULTS: In TKA, occupancy did not differ between GA and SA: 98±16min versus 98±14min respectively; Δ=0min (p=0.78). In THA, occupancy was shorter with SA than GA: 117±23min versus 123±26min respectively; Δ=-6min (p=0.02). In THA, time to perform SA was longer than induction of GA: 28±13min versus 23±12min respectively; Δ=+5min (p<0.001). In TKA, time to leaving the operating room was shorter with SA than GA: 8±5min versus 14±7min respectively; Δ=-6min (p<0.001). DISCUSSION/CONCLUSION: SA did not involve longer mean theater occupancy than GA for TKA, and reduced it by 6minutes for THA. LEVEL OF EVIDENCE: III; case-control study.

Comparing COVID-19 and influenza: Epidemiology, clinical characteristics, outcomes and mortality in the ICU.

RATIONALE: Several authors have compared COVID-19 infection with influenza in the ICU. OBJECTIVE: This study aimed to compare the baseline clinical profiles, care procedures, and mortality outcomes of patients admitted to the intensive care unit, categorized by infection status (Influenza vs. COVID-19). METHODS: Retrospective observational study. Data were extracted from the Toulouse University Hospital from March 2014 to March 2021. To compare survival curves, we plotted the survival at Day-90 using the Kaplan-Meier curve and conducted a log-rank test. Additionally, we performed propensity score matching to adjust for confounding factors between the COVID-19 and influenza groups. Furthermore, we use the CART model for multivariate analysis. RESULTS: The study included 363 patients admitted to the ICU due to severe viral pneumonia: 152 patients (41.9 %) with influenza and 211 patients (58.1 %) with COVID-19. COVID-19 patients exhibited a higher prevalence of cardiovascular risk factors, whereas influenza patients had significantly higher severity scores (SOFA: 10 [6-12] vs. 6 [3-9], p<0.01 and SAPS II: 51 [35-67] vs. 37 [29-50], p<0.001). Overall mortality rates were comparable between the two groups (27.6 % (n = 42) in the influenza group vs. 21.8 % (n = 46) in the COVID-19 group, p=NS). Mechanical ventilation was more commonly employed in the influenza group (76.3 % (n = 116) vs. 59.7 % (n = 126), p<0.001); however, COVID-19 patients required longer durations of mechanical ventilation (18 [9-29] days vs. 13 [5-24] days, p<0.006) and longer hospital stays (23 [13-34] days vs. 18.5 [9-34.5] days, p = 0.009). The CART analysis revealed that the use of extra renal replacement therapy was the most influential prognostic factor in the influenza group, while the PaO2/FiO2-PEEP ratio played a significant role in the COVID-19 group. CONCLUSIONS: Despite differences in clinical presentation and prognostic factors, the mortality rates at 90 days, after adjusting for confounding factors, were similar between COVID-19 and influenza patients.

Influence of arterial blood gases on the renal arterial resistive index in intensive care unit.

BACKGROUND: Renal artery Doppler sonography with resistive index (RI) determination is a noninvasive, fast, and reliable diagnostic tool increasingly used in the intensive care unit (ICU) to predict and assess the reversibility of acute kidney injury (AKI). However, interpreting the RI can be challenging due to numerous influencing factors. While some studies have explored various confounding factors, arterial blood gases have received limited attention. Therefore, our study aims to evaluate the impact of arterial blood gases on the RI in the ICU setting. METHODS: This prospective observational study enrolled ICU patients who required blood gas analysis and had not experienced significant hemodynamic changes recently. The RI was measured using standardized Doppler ultrasound within an hour of the arterial blood gases sampling and analysis. RESULTS: A total of sixty-four patients were included in the analysis. Univariate analysis revealed a correlation between the RI and several variables, including PaCO2 (R = 0.270, p = 0.03), age (R = 0.574, p < 0.0001), diastolic arterial pressure (DAP) (R = - 0.368, p = 0.0028), and SaO2 (R = - 0.284, p = 0.0231). Multivariate analysis confirmed that age > 58 years and PaCO2 were significant factors influencing the RI, with respective odds ratios of 18.67 (p = 0.0003) and 1.132 (p = 0.0267). CONCLUSION: The interpretation of renal arterial RI should take into account thresholds for PaCO2, age, and diastolic arterial pressure. Further studies are needed to develop a comprehensive scoring system that incorporates all these cofactors for a reliable analysis of RI levels. Trial registration This observational study, registered under number 70-0914, received approval from local Ethical Committee of Toulouse University Hospital.

Postoperative delirium is a risk factor of institutionalization after hip fracture: an observational cohort study.

Introduction: Hip fracture is a common clinical problem in geriatric patients often associated with poor postoperative outcomes. Postoperative delirium (POD) and postoperative neurocognitive disorders (NCDs) are particularly frequent. The consequences of these disorders on postoperative recovery and autonomy are not fully described. The aim of this study was to determine the role of POD and NCDs on the need for institutionalization at 3 months after hip fracture surgery. Method: A population-based prospective cohort study was conducted on hip fracture patients between March 2016 and March 2018. The baseline interview, which included a Mini-Mental State Examination (MMSE), was conducted in the hospital after admission for hip fracture. NCDs were appreciated by MMSE scoring evolution (difference between preoperative MMSE and MMSE at day 5 >2 points). POD was evaluated using the Confusion Assessment Method. The primary endpoint was the rate of new institutionalization at 3 months. We used a multivariate analysis to assess the risk of new institutionalization. Results: A total of 63 patients were included. Thirteen patients (20.6%) were newly institutionalized at 3 months. Two factors were significantly associated with the risk of postoperative institutionalization at 3 months: POD (OR = 5.23; 95% CI 1.1-27.04; p = 0.04) and IADL evolution (OR = 1.8; 95% CI 1.23-2.74; p = 0.003). Conclusion: Only POD but not NCDs was associated with the risk of dependency and institutionalization after hip fracture surgery. The prevention of POD appears to be essential for improving patient outcomes and optimizing the potential for returning home.

Teleconsultation in pediatric anesthesia: First assessment of feasibility, quality, and satisfaction in France.

INTRODUCTION: The COVID-19 pandemic has prompted the development of anesthesia teleconsultation in many countries. In pediatric anesthesia, data about anesthesia teleconsultation are scarce. The main objective of this prospective descriptive study was to provide an evaluation of the feasibility of pediatric anesthesia teleconsultation. Perception of the safety and quality, parental and medical satisfaction were also assessed. METHODS: From September to December 2020, patients undergoing a pediatric anesthesia teleconsultation in Toulouse University Hospital, using the TeleO™ dedicated teleconsultation platform were prospectively included. Feasibility was defined as the rate of anesthesia teleconsultations successfully performed using the TeleO™ platform alone. Questionnaires regarding the quality, safety, and satisfaction were filled in by physicians and families. RESULTS: A total of 114 children (3 months-17 years) were included in the study. Feasibility was 82%, failure was mainly caused by technical issues. Physicians estimated that the safety and quality of anesthetic preparation were optimal in 100% of cases. Anesthetists were satisfied (VAS ≥70/100) with the medical, technical, and relational (child/parents) aspects of anesthesia teleconsultation in 91%, 64%, and 84%/90% of cases respectively. Almost all parents (97%) stated that they would agree to anesthesia teleconsultation for a future procedure. CONCLUSION: In this first assessment, pediatric anesthesia teleconsultation appears to be feasible, with high rates of medical and parental satisfaction. Physicians' perception of the safety and quality of this process were positive. Improving the technical process might be a key determinant to promote further development of pediatric anesthesia teleconsultation.

Perioperative Risk Assessment of Patients Using the MyRISK Digital Score Completed Before the Preanesthetic Consultation: Prospective Observational Study.

BACKGROUND: The ongoing COVID-19 pandemic has highlighted the potential of digital health solutions to adapt the organization of care in a crisis context. OBJECTIVE: Our aim was to describe the relationship between the MyRISK score, derived from self-reported data collected by a chatbot before the preanesthetic consultation, and the occurrence of postoperative complications. METHODS: This was a single-center prospective observational study that included 401 patients. The 16 items composing the MyRISK score were selected using the Delphi method. An algorithm was used to stratify patients with low (green), intermediate (orange), and high (red) risk. The primary end point concerned postoperative complications occurring in the first 6 months after surgery (composite criterion), collected by telephone and by consulting the electronic medical database. A logistic regression analysis was carried out to identify the explanatory variables associated with the complications. A machine learning model was trained to predict the MyRISK score using a larger data set of 1823 patients classified as green or red to reclassify individuals classified as orange as either modified green or modified red. User satisfaction and usability were assessed. RESULTS: Of the 389 patients analyzed for the primary end point, 16 (4.1%) experienced a postoperative complication. A red score was independently associated with postoperative complications (odds ratio 5.9, 95% CI 1.5-22.3; P=.009). A modified red score was strongly correlated with postoperative complications (odds ratio 21.8, 95% CI 2.8-171.5; P=.003) and predicted postoperative complications with high sensitivity (94%) and high negative predictive value (99%) but with low specificity (49%) and very low positive predictive value (7%; area under the receiver operating characteristic curve=0.71). Patient satisfaction numeric rating scale and system usability scale median scores were 8.0 (IQR 7.0-9.0) out of 10 and 90.0 (IQR 82.5-95.0) out of 100, respectively. CONCLUSIONS: The MyRISK digital perioperative risk score established before the preanesthetic consultation was independently associated with the occurrence of postoperative complications. Its negative predictive strength was increased using a machine learning model to reclassify patients identified as being at intermediate risk. This reliable numerical categorization could be used to objectively refer patients with low risk to teleconsultation.

Is there a benefit for anesthesiologists of adding difficult airway scenarios for learning fiberoptic intubation skills using virtual reality training? A randomized controlled study.

Fiberoptic intubation for a difficult airway requires significant experience. Traditionally only normal airways were available for high fidelity bronchoscopy simulators. It is not clear if training on difficult airways offers an advantage over training on normal airways. This study investigates the added value of difficult airway scenarios during virtual reality fiberoptic intubation training. A prospective multicentric randomized study was conducted 2019 to 2020, among 86 inexperienced anesthesia residents, fellows and staff. Two groups were compared: Group N (control, n = 43) first trained on a normal airway and Group D (n = 43) first trained on a normal, followed by three difficult airways. All were then tested by comparing their ORSIM® scores on 5 scenarios (1 normal and 4 difficult airways). The final evaluation ORSIM® score for the normal airway testing scenario was significantly higher for group N than group D: median score 76% (IQR 56.5-90) versus 58% (IQR 51.5-69, p = 0.0039), but there was no difference in ORSIM® scores for the difficult intubation testing scenarios. A single exposure to each of 3 different difficult airway scenarios did not lead to better fiberoptic intubation skills on previously unseen difficult airways, when compared to multiple exposures to a normal airway scenario. This finding may be due to the learning curve of approximately 5-10 exposures to a specific airway scenario required to reach proficiency.

A quadruple peripheral nerve block outside the OR for anterior cruciate ligament reconstruction reduces the OR occupancy time.

PURPOSE: The use of regional anesthesia (RA) for anterior cruciate ligament (ACL) reconstruction reduces morphine consumption, the time spent in the post-anesthesia care unit (PACU) and the hospital readmission rate. However, RA failures due to delays in the induction of anesthesia and its unpredictable success rate (Cuvillon et al. Ann Fr Anesth 29:710-715, 2010; Jankowski et al. Anesth Analg 10.1213/01.ANE.0000081798.89853.E7) can lead to disorganization of the operating room (OR) schedule. The hypothesis is that performing RA outside the OR will significantly reduce the OR occupancy time relative to using general anesthesia (GA). The primary objective was to compare the OR occupancy time between RA and GA when performing ACL reconstruction. METHODS: This was a retrospective, single-center study of data collected prospectively from consecutive patients operated by a single surgeon between January 2019 and December 2020. The patients undergoing ACL reconstruction were divided into two groups based on the type of anesthesia they received (GA, RA). RA consisted of a quadruple peripheral nerve block (femoral, sciatic, obturator and lateral femoral cutaneous nerves). The durations of the perioperative stages of the patient's journey in the OR suite were compared between these two groups. RESULTS: The analysis involved 469 ACL reconstructions: 356 GA and 113 RA. The two groups were comparable in age, gender and ASA score (American Society of Anesthesiologists). The OR occupancy time for ACL reconstruction with RA was reduced by a mean of 13 min (70 ± 12 SD vs. 83 ± 14 SD; P < 0.0001) and the PACU time by 41 min relative to GA (P < 0.0001). The entry-incision time was reduced by an average of 8 min and the end-exit time by 3 min (P < 0.0001). The care time in the PACU was reduced from 84 ± 35 to 46 ± 26 min (P < 0.0001). However, performing anesthesia outside the OR (i.e., in a RA block room) did not reduce the turnover time (n.s). CONCLUSION: Performing RA outside the OR reduced the OR occupancy time by nearly 20% relative to using GA for ACL reconstructions. LEVEL OF EVIDENCE: Level IV.

A universal predictive and mechanistic urinary peptide signature in acute kidney injury.

BACKGROUND: The delayed diagnosis of acute kidney injury (AKI) episodes and the lack of specificity of current single AKI biomarkers hamper its management. Urinary peptidome analysis may help to identify early molecular changes in AKI and grasp its complexity to identify potential targetable molecular pathways. METHODS: In derivation and validation cohorts totalizing 1170 major cardiac bypass surgery patients and in an external cohort of 1569 intensive care unit (ICU) patients, a peptide-based score predictive of AKI (7-day KDIGO classification) was developed, validated, and compared to the reference biomarker urinary NGAL and NephroCheck and clinical scores. RESULTS: A set of 204 urinary peptides derived from 48 proteins related to hemolysis, inflammation, immune cells trafficking, innate immunity, and cell growth and survival was identified and validated for the early discrimination (< 4 h) of patients according to their risk to develop AKI (OR 6.13 [3.96-9.59], p < 0.001) outperforming reference biomarkers (urinary NGAL and [IGFBP7].[TIMP2] product) and clinical scores. In an external cohort of 1569 ICU patients, performances of the signature were similar (OR 5.92 [4.73-7.45], p < 0.001), and it was also associated with the in-hospital mortality (OR 2.62 [2.05-3.38], p < 0.001). CONCLUSIONS: An overarching AKI physiopathology-driven urinary peptide signature shows significant promise for identifying, at an early stage, patients who will progress to AKI and thus to develop tailored treatments for this frequent and life-threatening condition. Performance of the urine peptide signature is as high as or higher than that of single biomarkers but adds mechanistic information that may help to discriminate sub-phenotypes of AKI offering new therapeutic avenues.

The oxygen carrier M101 alleviates complement activation, which may be beneficial for donor organ preservation.

During organ transplantation, ischemia/reperfusion injury and pre-formed anti-HLA antibodies are the main cause of delayed graft function and recovery through the activation of the complement system. By supplying oxygen during transplantation, M101 is suspected to avoid complement activation, however, a direct effect exerted by M101 on this pathway is unknown. This was tested by using functional assays (lymphocytotoxic crossmatch test, C3d Luminex-based assay, 50% complement hemolysis [CH50], and 50% alternative complement pathway [AP50/AH50]), and quantitative assays (C3, C3a, C4, C5, C5a, C6, C7, C8, C9 and sC5b-9). M101 interferes with the anti-HLA lymphocytotoxic crossmatch assay, and this effect is complement-dependent as M101 inhibits the classical complement pathway (CH50) in a dose-dependent and stable manner. Such inhibition was independent from a proteolytic effect (fractions C3 to C9) but related to a dose-dependent inhibition of the C3 convertase as demonstrated by exploring downstream the release of the anaphylatoxins (C3a and C5a), C3d, and sC5b-9. The C3 convertase inhibition in the presence of M101 was further demonstrated in the AP50/AH50 assay. In conclusion, the use of M101 avoids the activation of the complement pathway, which constitutes an additional advantage for this extracellular hemoglobin to preserve grafts from ischemia/reperfusion injury and preformed anti-HLA antibodies.