The effect of tranexamic acid on blood loss in orthognathic surgery: a randomized, placebo-controlled, equivalence study.

Orthognathic surgery can cause substantial bleeding. Recent meta-analyses concluded that there is a statistically significant reduction in perioperative blood loss with the preventive use of tranexamic acid (TA). However, the mean reported difference in bleeding was moderate, and the clinical relevance of this blood-sparing effect remains debated. We therefore conducted a prospective, double-blind, randomized, placebo-controlled equivalence study of the effect of TA in patients undergoing Lefort I or bimaxillary osteotomies. Our main outcome measure was total blood loss on postoperative day 1. The equivalence margin was ± 250 ml for the difference in blood loss and its 95% confidence interval. One hundred and forty-seven patients were randomized, of which 122 underwent bimaxillary osteotomies. Blood loss in the treatment group was 682 ± 323 vs. 875 ± 492 ml. The mean difference in bleeding was -132 [-243; -21] ml as per-protocol, but -193 [-329; -57] ml in intention-to-treat: the limits of this confidence interval exceeded the margin of equivalence. Similar results were obtained when analysing only patients undergoing bimaxillary osteotomy. Haemoglobin decreased by 1.8 ± 1.2 g/dl with TA, vs. 2.6 ± 1.1 g/dl with placebo (p<0.001). Our study did not demonstrate equivalence between TA and placebo on perioperative blood loss in orthognathic surgery. TA may reduce blood loss but without evidence of clinical consequences.

A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

[Factors related to severe neonatal acidosis in planned cesarean section. A case-control study]. / Facteurs liés à la survenue d'une acidose néonatale sévère en cas de césarienne programmée. Une étude cas-témoins.

OBJECTIVES: To identify factors related to the occurrence of severe neonatal acidosis in case of planned caesarean section. METHODS: Case-control study conducted between 1997 and 2016 among women with planned caesarean delivery at term. Cases were women whose neonates had neonatal arterial pH<7,0. For each case, two planned caesarean sections with neonatal pH≥7,0 were selected as controls. Women whose fetus had a congenital malformation and those whose anesthesia was not spinal anesthesia were excluded. RESULTS: Among the 5014 planned cesarean sections of the study period, 38 severe neonatal acidosis were observed (incidence of 0,76% CI95 [0,54-1,04]). Compared to 72 controls, the 36 caesareans with severe neonatal acidosis were associated with more frequent maternal obesity (BMI≥30kg/m2), higher ephedrine doses, longer time from skin incision to infant delivery, and more extraction difficulties. After logistic regression, only maternal obesity remained associated with a significant increase in the risk of severe neonatal acidosis, ORa=3,73, 95%CI (1,11-12,56). CONCLUSIONS: In case of planned cesarean section, the main risk factor for severe neonatal acidosis is the existence of maternal obesity.

Real-time polymerase chain reaction detection of Lichtheimia species in bandages associated with cutaneous mucormycosis in burn patients.

BACKGROUND: Cutaneous mucormycoses, mainly due to Lichtheimia (Absidia), have occurred on several occasions in the Burn Unit of the University Hospital of Lille, France. AIM: To investigate the potential vector role of non-sterile bandages used to hold in place sterile gauze used for wound dressing. METHODS: Mycological analysis by conventional culture, Mucorales real-time polymerase chain reaction (qPCR), and Lichtheimia species-specific qPCR were performed on eight crepe and six elasticized bandages that were sampled on two independent occasions in March 2014 and July 2016. Characteristics of the seven Lichtheimia mucormycoses which occurred in burn patients between November 2013 and July 2016 were also collected to assess the epidemiological relationship between potentially contaminated bandages and clinical infections. FINDINGS: One Lichtheimia corymbifera strain was isolated from a crepe bandage by culture, and Lichtheimia spp. qPCR was positive in six out of eight crepe and four out of six elasticized bandages. Using species-specific qPCR, Lichtheimia ramosa, Lichtheimia ornata, and L. corymbifera were identified in six out of ten, five out of ten, and four out of ten bandages, respectively. In patients with mucormycosis, L. ramosa and L. ornata were present in five and two cases, respectively. CONCLUSION: Our data support the utility of Mucorales qPCR for epidemiological investigations, the potential role of these bandages in cutaneous mucormycoses in burn patients in our centre, and, consequently, the need for sterile bandages for the dressing of extensive wounds.

French lyophilized plasma versus fresh frozen plasma for the initial management of trauma-induced coagulopathy: a randomized open-label trial.

Essentials An immediate supply of plasma in case of trauma-induced coagulopathy is required. The Traucc trial compared French Lyophilised Plasma (FLyP) and Fresh Frozen Plasma (FFP). FLyP achieved higher fibrinogen concentrations compared with FFP. FLyP led to a more rapid coagulopathy improvement than FFP. SUMMARY: Background Guidelines recommend beginning hemostatic resuscitation immediately in trauma patients. We aimed to investigate if French lyophilized plasma (FLyP) was more effective than fresh frozen plasma (FFP) for the initial management of trauma-induced coagulopathy. Methods In an open-label, phase 3, randomized trial (NCT02750150), we enrolled adult trauma patients requiring an emergency pack of 4 plasma units within 6 h of injury. We randomly assigned patients to receive 4-FLyP units or 4-FFP units. The primary endpoint was fibrinogen concentration at 45 min after randomization. Secondary outcomes included time to transfusion, changes in hemostatic parameters at different time-points, blood product requirements and 30-day in-hospital mortality. Results Forty-eight patients were randomized (FLyP, n = 24; FFP, n = 24). FLyP reduced the time from randomization to transfusion of first plasma unit compared with FFP (median[IQR],14[5-30] vs. 77[64-90] min). FLyP achieved a higher fibrinogen concentration 45 min after randomization compared with FFP (baseline-adjusted mean difference, 0.29 g L-1 ; 95% confidence interval [CI], 0.08-0.49) and a greater improvement in prothrombin time ratio, factor V and factor II. The between-group differences in coagulation parameters remained significant at 6 h. FLyP reduced fibrinogen concentrate requirements. Thirty-day in-hospital mortality rate was 22% with FLyP and 29% with FFP. Conclusion FLyP led to a more rapid, pronounced and extended increase in fibrinogen concentrations and coagulopathy improvement compared with FFP in the initial management of trauma patients. FLyP represents an attractive option for trauma management, especially when facing logistical issues such as combat casualties or mass casualties related to terror attacks or disasters.

Compliance with evidence-based clinical management guidelines in bleeding trauma patients.

BACKGROUND: In 2007, the multidisciplinary European Task Force for Advanced Bleeding Care in Trauma published guidelines for the management of the bleeding trauma patient. The present study aimed to assess compliance with the European guidelines during the first 24 h in a level I trauma centre and to determine whether compliance impacts mortality. METHODS: This was a retrospective study of consecutive bleeding trauma patients referred to a university hospital in France between 2010 and 2014. A reference document was developed on the basis of the European guidelines to transform the guidelines pragmatically into 22 objectively measurable criteria. We measured per-patient and per-criterion compliance rates and assessed the impact of guideline compliance on mortality. RESULTS: A total of 121 bleeding trauma patients were included. The median (interquartile range) per-patient compliance rate was 75 (65-82)% and the per-criterion compliance rate 64 (57-81)%. Mortality rates were 18 and 32% at 24 h and 30 days, respectively. After adjusting for injury severity, per-patient compliance rates were associated with decreased mortality at 24 h (odds ratio per 10% increase in patient compliance score, 0.43; 95% confidence interval 0.26-0.71; P = 0.0001) and at 30 days (odds ratio per 10% increase in patient compliance score, 0.47; 95% confidence interval 0.31-0.72; P = 0.0004). CONCLUSIONS: We found that compliance with protocols based on European guidelines impacts trauma outcome, because patient compliance was associated with survival. Further work is needed to improve adherence to these guidelines, with ongoing monitoring to ensure best practice and optimal patient outcome.

Decrease in pulse pressure and stroke volume variations after mini-fluid challenge accurately predicts fluid responsiveness†.

BACKGROUND: Dynamic indices, such as pulse pressure variation (PPV), are inaccurate predictors of fluid responsiveness in mechanically ventilated patients with low tidal volume. This study aimed to test whether changes in continuous cardiac index (CCI), PPV, and stroke volume variation (SVV) after a mini-fluid challenge (100 ml of fluid during 1 min) could predict fluid responsiveness in these patients. METHODS: We prospectively studied 49 critically ill, deeply sedated, and mechanically ventilated patients (tidal volume <8 ml kg(-1) of ideal body weight) without cardiac arrhythmias, in whom a fluid challenge was indicated because of circulatory failure. The CCI, SVV (PiCCO™; Pulsion), and PPV (MP70™; Philips) were measured before and after 100 ml of colloid infusion during 1 min, and then after the additional infusion of 400 ml during 14 min. Responders were defined as subjects with a ≥15% increase in cardiac index (transpulmonary thermodilution) after the full (500 ml) fluid challenge. Areas under the receiver operating characteristic curves (AUCs) and the grey zones were determined for changes in CCI (ΔCCI100), SVV (ΔSVV100), and PPV (ΔPPV100) after 100 ml fluid challenge. RESULTS: Twenty-two subjects were responders. The ΔCCI100 predicted fluid responsiveness with an AUC of 0.78. The grey zone was large and included 67% of subjects. The ΔSVV100 and ΔPPV100 predicted fluid responsiveness with AUCs of 0.91 and 0.92, respectively. Grey zones were small, including ≤12% of subjects for both indices. CONCLUSIONS: The ΔSVV100 and ΔPPV100 predict fluid responsiveness accurately and better than ΔCCI100 (PiCCO™; Pulsion) in patients with circulatory failure and ventilated with low volumes.

Variations of the analgesia nociception index during general anaesthesia for laparoscopic abdominal surgery.

The analgesia nociception index (ANI) is an online heart rate variability analysis proposed for assessment of the antinociception/nociception balance. In this observational study, we compared ANI with heart rate (HR) and systolic blood pressure (SBP) during various noxious stimuli in anaesthetized patients. 15 adult patients undergoing laparoscopic appendectomy or cholecystectomy were studied. Patients received target controlled infusions of propofol (adjusted to maintain the Bispectral index in the range [40-60]) and remifentanil (with target increase in case of haemodynamic reactivity [increase in HR and/or SBP >20% of baseline]), and cisatracurium. Medical staff was blind to the ANI monitor. ANI and haemodynamic data were recorded at predefined times before and during surgery, including tetanic stimulation of the ulnar nerve before start of surgery. Anaesthesia induction decreased HR and SBP, while high ANI values (88 [17]) were recorded, indicating parasympathetic predominance. In 10 out of 11 patients, tetanic stimulation led to a transient (<5 min) decrease in ANI to 48 (40) whereas HR and SBP did not change. After start of surgery, ANI decreased to 60 (39) and decreased further to 50 (15) after the pneumoperitoneum was inflated, while there was no significant change in HR or SBP. When haemodynamic reactivity occurred, ANI had further decreased to 40 (15). After completion of surgery, ANI returned to 90 (34). ANI seems more sensitive than HR and SBP to moderate nociceptive stimuli in propofol-anaesthetized patients. Whether ANI monitoring may allow preventing haemodynamic reactivity to noxious stimuli remains to be demonstrated.

[Organ donation: point of view of private practice physicians in the region Nord-Pas de Calais in France]. / Le don d'organes : point de vue des médecins libéraux de la région Nord-Pas de Calais en France.

BACKGROUND: In 2008, in France, 222 patients died because they did not receive the graft they expected. The main objective of this study was to determine the attitude of private practice physicians concerning organ donation. METHODS: A postal questionnaire was sent to all private practice office-based physicians in the Nord-Pas de Calais region. This questionnaire was elaborated with a panel of physicians and sociologists. It was sent with the monthly journal of the regional union of private physicians of June 2008. RESULTS: Two hundred and seventy eight questionnaires were returned. One hundred and thirty four (48.2%) respondents declared they knew what the regulations about organ donation were. The majority of respondents approved organ donation. Information to patients was provided during visits by 34.53% (96) of practitioners. For those who were knowledgeable about regulations, 50.75% of them talked about organ donation. Physicians who had already had experience with organ donation were more inclined to talk about it with other patients. The practitioners described three actions they felt could have a positive influence on family acceptance: providing information before death, talking about organ donation in an appropriate sensitive way, and relying on the confidence established by a solid patient-physician relationship. CONCLUSION: Almost 90% of private physicians who responded to the survey were in favor of organ donation but only 34.5% delivered information and discussed the issue with their patients. The physicians coped with the topics more easily when they had experienced cases and when they were informed about existing regulations. A specific educational program on the current regulations and how to interact with patients on this subject during a visit could be a first answer to the problem and would be welcomed by practitioners.

Heart rate variability analysis for arterial hypertension etiological diagnosis during surgical procedures under tourniquet.

Pneumatic tourniquets are widely used to provide a bloodless operative field during upper or lower limb surgery. If tourniquet inflation during general anesthesia is initially a mild stimulus, a long duration of inflation can imply heart rate and blood pressure increasing. However, heart rate or blood pressure increasing can also be caused by other external stimuli. Indeed, in the case of an insufficient analgesia, painful surgical stimuli can also cause an increase in heart rate and blood pressure. Therefore, in the case of the use of a tourniquet during surgery, it's very difficult for the anesthesiologist to distinguish hypertension caused by pain from hypertension caused by tourniquet inflation. In such a case, an efficient and reliable hypertension diagnosis could help the anesthesiologist in the medication choice. We have previously developed and evaluated an Analgesia / Nociception Index (ANI) based on the magnitude analysis of the respiratory patterns on the RR series. We hypothesize that the use of such an index could help in the arterial hypertension etiological diagnosis during surgical procedures under tourniquet.

PhysioDoloris: a monitoring device for analgesia / nociception balance evaluation using heart rate variability analysis.

Continuous Analgesia / Nociception balance evaluation during general anesthesia could be of precious help for the optimization of analgesic drugs delivery, limiting the risk of toxicity due to the use of opioid drugs, limiting the risk of post operative hyper algesia, and, probably, reducing time of recovery after surgical procedure. Heart Rate Variability analysis has been shown in several studies to measure the Autonomic Nervous System tone, which is strongly influenced by anesthetic drugs. Recording RR series during general anesthesia enabled us to observe that the Respiratory Sinus Arrhythmia pattern changed when a surgical stimulation was painful, even though the patient was not conscious. We have previously developed and evaluated a pain / analgesia measurement algorithm based on the magnitude analysis of the respiratory patterns on the RR series. In this paper, we present the development of a monitoring device (PhysioDoloris), based on the previously described technology, giving in real time an Analgesia Nociception Index (ANI) which can be used during general anesthesia in order to give to the anesthetist, a complementary tool for optimized drug delivery.

Goitre and difficulty of tracheal intubation.

OBJECTIVES: To assess the difficulty in both laryngoscopy and tracheal intubation related to goitre and to identify factors predictive of difficult intubation due to this condition. STUDY DESIGN: Prospective observational. METHODS: We used the Intubation Difficulty Scale (IDS) in 80 consecutive patients with large goitre (defined by the inability to palpate the cricoid cartilage, the presence of endothoracic goitre, tracheal deviation of more than 1cm or tracheal stenosis on the chest x-ray) and 77 control patients. RESULTS: Cormack grades 3-4 were more frequent at initial laryngoscopy in patients with goitre (23/80 vs. 9/77; p<0.05), but the difference was no longer significant after application of an external laryngeal pressure (8/80 vs. 5/77). IDS scores (median [25th-75th percentiles]) were higher in the goitre group (1 [0 - 4]) than in the control group (0 [0 - 1]; p=0.001), corresponding to an increase in slightly difficult intubation (IDS 1-5: 36/80 vs. 15/77; p<0.05). However, incidence of moderate to major difficulty in intubation (IDS>5: 8/80 vs. 7/77) as well as time to completion of intubation were similar in both groups. Tracheal stenosis (> or =30%) and reduced mouth opening (<4.4cm) were the only significant predictors of increased difficulty in intubation in patients with a goitre. CONCLUSION: Large goitres are usually associated with slight difficulty in intubation only. Increased difficulty should be expected when severe tracheal stenosis is present on chest x-ray, especially when associated with a reduced mouth opening.

Sevoflurane pre- and post-conditioning protect the brain via the mitochondrial K ATP channel.

BACKGROUND: This study aimed to evaluate whether exposure to sevoflurane at the onset of reperfusion provides protection similar to sevoflurane preconditioning and whether the effect depends on mitochondrial potassium ATP-dependent channel (mitoK(ATP)) in a rat model of focal cerebral ischaemia. METHODS: Adult Wistar male rats were subjected to focal cerebral ischaemia for 1 h followed by 24 h or 7 days of reperfusion. Preconditioning consisted of 15 min exposure to sevoflurane at 1 minimum alveolar concentration (2.6%) 72 h before ischaemia. Post-conditioning was performed by exposure to sevoflurane immediately at the onset of reperfusion or by a delayed exposure 5 min after the onset of reperfusion. The role of the mitoK(ATP) channel was assessed by i.p. injection of the selective blocker 5-hydroxydecanoate before each sevoflurane administration or by the mitoK(ATP) channel opener, diazoxide (DZX), given in place of sevoflurane. Cerebral infarct size, neurological deficit score, and motor coordination were evaluated 24 h and 7 days after reperfusion. RESULTS: Sevoflurane preconditioning and early post-conditioning reduced both cerebral infarct size and neurological defect score at 24 h of reperfusion whereas the sole sevoflurane post-conditioning improved motor coordination. At 7 days, only infarct volume remained lower in pre- and post-conditioned animals. Neuroprotection mediated by sevoflurane was lost when it was given 5 min after the onset of reperfusion and was abolished by inhibition of mitoK(ATP). DZX alone mimicked sevoflurane-induced pre- and post-conditioning. CONCLUSIONS: The pretreatment with sevoflurane or its early administration at reperfusion provides neuroprotection via mitoK(ATP) in a rat model of focal cerebral ischaemia.

Validation of a graphic measurement of heart rate variability to assess analgesia/nociception balance during general anesthesia.

The optimization of analgesic drugs delivery during general anesthesia (GA) requires to evaluate the pain/analgesia balance. Heart Rate Variability (HRV) analysis has long been shown to measure the autonomic nervous system tone, which is strongly influenced by anesthetic drugs. Power spectrum measurements are widely used to assess HRV low (LF) and high frequency (HF) ranges, related to the sympathetic and parasympathetic systems. We have developed an original graphic measurement technique (EnvTOT) of the ventilatory influence on the RR series. Measurements on simulated RR series showed that the graphic assessment is independent from respiratory rate, while LF and HF spectral measurements are over- and underestimated for respiratory rates lower than 12 cycles min Clinical measurements on 49 patients during GA showed that normalized HF power was strongly related to hemodynamic responsiveness during GA, and was strongly correlated with normalized EnvTOT measurements. A real time computation of the RR series could therefore help medical staff to anticipate hemodynamic responsiveness and the analgesia/nociception balance during GA.

Automated pulse pressure and stroke volume variations from radial artery: evaluation during major abdominal surgery.

BACKGROUND: Off-line calculation of the pulse pressure variation (PPV(ref)) has repeatedly been shown to be a reliable predictor of fluid responsiveness in mechanically ventilated patients. This study was designed to assess the ability of two algorithms for automated calculation of PPV (PPV(auto)) (Intellivue MP 70) and stroke volume variation (SVV(auto)) (FloTrac/Vigileo) to predict fluid responsiveness during abdominal surgery. METHODS: We conducted a prospective study of 56 fluid challenges given for haemodynamic instability in 11 patients undergoing major abdominal surgery. Fluid responsiveness was defined as an increase in stroke volume index (SVI) >10%. PPV(ref), PPV(auto), SVV(auto), and SVI (oesophageal Doppler) were recorded simultaneously before and after each fluid challenge. RESULTS: PPV(auto) and SVV(auto) both correlated with PPV(ref) [r(corr)=0.87 (P<0.0001) and 0.84 (P<0.0001), respectively; n=77]. All three indices measured before fluid challenges were higher in responder (n=32) than in non-responder (n=24) fluid challenges (P < or = 0.02). The mean areas under the receiver operating characteristic curves were 0.96 (PPV(ref)), 0.96 (PPV(auto)), and 0.95 (SVV(auto)), and the optimal threshold value for each variable was 13%, 13%, and 12%, respectively. All indices correlated with the fluid challenge-induced changes in SVI (PPV(ref): r(corr)=0.65; PPV(auto): r(corr)=0.58; SVV(auto): r(corr)=0.58, P<0.001 for all). CONCLUSIONS: PPV(auto) and SVV(auto) predict fluid responsiveness as accurately as off-line PPV(ref) in patients with haemodynamic instability during major abdominal surgery.

[Contribution of central venous oxygen saturation in postoperative blood transfusion decision]. / Apport de la saturation veineuse centrale en oxygène dans la décision transfusionnelle postopératoire.

OBJECTIVE: The aim of this study was to assess the value of central venous oxygen saturation (ScvO(2)) for the decision of blood transfusion in comparison with the criteria of the French guidelines for blood transfusion (2003). STUDY DESIGN: Prospective, observational. PATIENTS AND METHODS: Sixty patients, haemodynamically stable, for whom a blood transfusion (BT) was discussed in the postoperative course of general surgery, were included. ScvO(2) (%) and haemoglobin (g/dl) were measured before and after BT. Patients were retrospectively divided into two groups according to ScvO(2) measured before BT (< or >or=70%). Results are expressed as median. RESULTS: The ScvO(2) before transfusion was greater or equal to 70% in 25 (47.2%) patients. Following BT, the ScvO(2) increased significantly (from 57.8 to 68.5%) in the group with initial ScvO(2) less than 70% whereas it was unchanged in patients with initial ScvO(2) greater or equal 70% (from 76.8 to 76.5%). Twenty patients (37.7%) did not meet the French guidelines for BT criteria. Eighteen patients out of 33 that met the criteria had ScvO(2) greater or equal 70% before BT while 13 patients with ScvO(2) less than 70% were not detected by these same criteria. CONCLUSION: ScvO(2) could be a relevant biological parameter to complete the current guidelines for BT in stable patient with a central venous catheter during the postoperative period.