In silico evidence that substitution of glycine for valine (p.G8V) in a common variant of TMPRSS2 isoform 1 increases accessibility to an endocytic signal: Implication for SARS-cov-2 entry into host cells and susceptibility to COVID-19.

The TMPRSS2 protease plays a key role in the entry of the SARS-CoV-2 into cells. The TMPRSS2 gene is highly polymorphic in humans, and some polymorphisms may affect the susceptibility to COVID-19 or disease severity. rs75603675 (c.23G > T) is a missense variant that causes the replacement of glycine with valine at position 8 (p.G8V) in the TMPRSS2 isoform 1. According to GnomAD v4.0.0 database, the allele frequency of the rs75603675 on a global scale is 38.10 %, and range from 0.92 % in East Asian to 40.77 % in non-Finnish European (NFE) population. We analyzed the occurrence of the rs75603675 in two cohorts of patients, the first with severe/critical COVID-19 enrolled in a French hospital (42 patients), and the second with predominantly asymptomatic/pauci-symptomatic/mild COVID-19 enrolled in an Italian hospital (69 patients). We found that the TMPRSS2-c.23T minor allele frequency was similar in the two cohorts, 46.43 % and 46.38 %, respectively, and higher than the frequency in the NFE population (40.77 %). Chi-square test provided significant results (p < 0.05) when the genotype data (TMPRSS2-c.23T/c.23T homozygotes + TMPRSS2-c.23G/c.23T heterozygotes vs. TMPRSS2-c.23G/c.23G homozygotes) of the two patient groups were pooled and compared to the expected data for the NFE population, suggesting a possible pathogenetic mechanism of the p.G8V substitution. We explored the possible effects of the p.G8V substitution and found that the N-terminal region of the TMPRSS2 isoform 1 contains a signal for clathrin/AP-2-dependent endocytosis. In silico analysis predicted that the p.G8V substitution may increase the accessibility to the endocytic signal, which could help SARS-CoV-2 enter cells.

Reactivation of Epstein-Barr virus among intensive care patients: a prospective observational study.

PURPOSE: Herpesvirus reactivation has been documented among patients in the intensive care unit (ICU) and is associated with increased morbidity and mortality, particularly for cytomegalovirus (CMV). Epstein-Barr virus (EBV) has been poorly studied despite >95% of the population being seropositive. Our preliminary study suggested an association between EBV reactivation and increased morbidity and mortality. This study aimed to investigate this association among patients admitted to the ICU. METHODS: In this multicenter prospective study, polymerase chain reaction was performed to quantify EBV in patients upon ICU admission and then twice a week during their stay. Follow-up was 90 days. RESULTS: The study included 129 patients; 70 (54.3%) had EBV reactivation. On day 90, there was no difference in mortality rates between patients with and without reactivation (25.7% vs 15.3%, p = 0.22). Patients with EBV reactivation at admission had increased mortality compared with those without reactivation and those with later reactivation. EBV reactivation was associated with increased morbidity. Patients with EBV reactivation had fewer ventilator-free days at day 28 than those without reactivation (18 [1-22] vs. 21 days [5-26], p = 0.037) and a higher incidence of acute respiratory distress syndrome (34.3% vs. 17%, p = 0.04), infections (92.9% vs. 78%, p = 0.03), and septic shock (58.6% vs. 32.2%, p = 0.004). More patients with EBV reactivation required renal replacement therapy (30% vs. 11.9%, p = 0.02). EBV reactivation was also associated with a more inflammatory immune profile. CONCLUSION: While EBV reactivation was not associated with increased 90-day mortality, it was associated with significantly increased morbidity.

Severe hypocalcemia at admission is associated with increased transfusion requirements: A retrospective study in a level 1 trauma center.

INTRODUCTION: In recent years, hypocalcemia has been added to the "lethal triad" of the trauma patient, thus constituting the "lethal diamond". Nevertheless, its proper role remains debated. The aim of this study is to evaluate the association between severe hypocalcemia at admission and 24 h- transfusion requirements in severe trauma patients in a level 1 trauma center. STUDY DESIGN AND METHODS: In a monocentric retrospective observational study from January 2015 to May 2021, 137 traumatized adult patients transfused within 24 h after hospital admission was included in the study. The threshold for severe hypo ionized calcemia was ≤ 0.9 mmol/L. RESULTS: 137 patients were included in the study, 23 presented with severe hypo-iCa at admission, 111 moderate hypo-iCa (0.9-1.2 mmol/L) and 3 normal iCa (≥ 1.2 mmol/L). Patients with severe hypo-iCa at admission had higher severity scores (SAPSII 58 IQR [51-70] vs. 45 IQR [32-56]; p = 0.001 and ISS 34 IQR [26-39] vs. 26 IQR [17-34]; p = 0.003). 24 h-transfusion requirements were greater for patients with severe hypo-iCa, regardless of the type of blood products transfused. There was a significant negative correlation between admission iCa and 24 h-transfusion (r = -0.45, p < 0.001). The difference in mortality was not significant between the two groups (24 h mortality: 17 % (4/23) for severe hypo-iCa vs. 8 % (9/114) for non-severe hypo-iCa; p = 0.3). DISCUSSION: This study highlights the high prevalence of severe hypocalcemia in trauma patients and its association with increased 24 h- transfusion requirements.

Study of the Relationship Between Liver Function Markers and Traumatic Rhabdomyolysis: A Retrospective Study of Hemorrhagic Patients Admitted to Intensive Care Unit in a Level I Trauma Center.

BACKGROUND: Traumatic rhabdomyolysis (RM) is common and contributes to the development of medical complications, of which acute renal failure is the best described. Some authors have described an association between elevated aminotransferases and RM, suggesting the possibility of associated liver damage. Our study aims to evaluate the relationship between liver function and RM in hemorrhagic trauma patients. METHODS: This is a retrospective observational study conducted in a level 1 trauma center analyzing 272 severely injured patients transfused within 24 hours and admitted to intensive care unit (ICU) from January 2015 to June 2021. Patients with significant direct liver injury (abdominal Abbreviated Injury Score [AIS] >3) were excluded. Clinical and laboratory data were reviewed, and groups were stratified according to the presence of intense RM (creatine kinase [CK] >5000 U/L). Liver failure was defined by a prothrombin time (PT)-ratio <50% and an alanine transferase (ALT) >500 U/L simultaneously. Correlation analysis was performed using Pearson's or Spearman's coefficient depending on the distribution after log transformation to evaluate the association between serum CK and biological markers of hepatic function. Risk factors for the development of liver failure were defined with a stepwise logistic regression analysis of all relevant explanatory factors significantly associated with the bivariate analysis. RESULTS: RM (CK >1000 U/L) was highly prevalent in the global cohort (58.1%), and 55 (23.2%) patients presented with intense RM. We found a significant positive correlation between RM biomarkers (CK and myoglobin) and liver biomarkers (aspartate transferase [AST], ALT, and bilirubin). Log-CK was positively correlated with log-AST (r = 0.625, P < .001) and log-ALT (r = 0.507, P < .001) and minimally with log-bilirubin (r = 0.262, P < .001). Intensive care unit stays were longer for intense RM patients (7 [4-18] days vs 4 [2-11] days, P < .001). These patients required increased renal replacement therapy use (4.1% vs 20.0%, P < .001) and transfusion requirements. Liver failure was more common (4.6% vs 18.2%, P < .001) for intense RM patients. It was associated with bivariate and multivariable analysis with intense RM (odds ratio [OR], 4.51 [1.11-19.2]; P = .034), need for renal replacement therapy, and Sepsis-Related Organ Failure Assessment Score (SOFA) score on day 1. CONCLUSIONS: Our study established the presence of an association between trauma-related RM and classical hepatic biomarkers. Liver failure was associated with the presence of intense RM in bivariate and multivariable analysis. Traumatic RM could have a role in the development of other system failures, specifically at the hepatic level, in addition to the already known and well-described renal failure.

Analysis of mortality over 7 years in a mature trauma center: evolution of preventable mortality in severe trauma patients.

PURPOSE: The study of preventable trauma deaths is one mechanism used to examine the quality of care and outcomes of a trauma system. The present study aims to define the rate of preventable (PD) and potentially preventable death (PPD) in our mature trauma center, determine its leading causes, and evaluate the evolution of this rate over the years. METHODS: We performed a retrospective observational study in the Sainte Anne Military Teaching Hospital, Toulon (Var), France. From January 2013 to December 2020, all patients with severe trauma admitted to our trauma center and who died were analyzed. An independent group of 4 experts in the management of severe trauma performed the classification of deaths using a DELPHI method. RESULTS: During the study period, 180 deaths occurred among 2642 consecutive severe trauma patients (overall mortality 6.8%). 169 deaths were analyzed, Eleven (6.5%) were considered PD, and thirty-eight (22.1%) were PPD. 69 errors were identified. The most frequent errors were in pre-hospital (excessive pre-hospital times 33.3% and inadequate management 29%). Time before surgery was considered excessive in 15.9% of cases. Over the study period, the rates of PD and PPD deaths remained stable. CONCLUSION: PD and PPD rates are still high and do not decrease over the years in our mature trauma center. It confirms the need for progress in the management of severe trauma patients. Reducing the time to provide care seems to be the main area for improvement. Further studies will be necessary to better target the points to be improved.

Step by step transfusion timeline and its challenges in trauma: A retrospective study in a level one trauma center.

BACKGROUND: Hemorrhagic shock is the leading cause of preventable early death in trauma patients. Transfusion management is guided by international guidelines promoting early and aggressive transfusion strategies. This study aimed to describe transfusion timelines in a trauma center and to identify key points to performing early and efficient transfusions. METHODS: This is a monocentric retrospective study of 108 severe trauma patients, transfused within the first 48 h and hospitalized in an intensive care unit between January 2017 and May 2019. RESULTS: One hundred and eight patients were transfused with 1250 labile blood products. Half of these labile blood products were transfused within 3 h of admission and consumed by 26 patients requiring massive transfusion (≥4 red blood cells [RBC] within 1 h). Among these, the median delay from patient's admission to labile blood products prescription was -11 min (-34 to -1); from admission to delivery of labile blood products was 1 min (-20 to 16); and from admission to first transfusion was 20 min (7-37) for RBC, 26 min (13-38) for plasma, and 72 min (51-103) for platelet concentrates. The anticipated prescription of labile blood products and the use of massive transfusion packs and lyophilized plasma units were associated with earlier achievement of high transfusion ratios. CONCLUSION: This study provides detailed data on the transfusion timelines and composition, from prescription to initial transfusion. Transfusion anticipation, use of preconditioned transfusion packs including platelets, and lyophilized plasma allow rapid and high-ratio transfusion practices in severe trauma patients.

Renal Microcirculation and Function in a Pig Model of Hemorrhagic Shock Resuscitation with Norepinephrine.

Rationale: Norepinephrine (NE) is commonly used in combination with fluid during resuscitation of hemorrhagic shock, but its impact on kidney microcirculation, oxygenation, and function is still unknown in this setting. Objectives: During hemorrhagic shock resuscitation, does a combination of fluid and NE affect kidney oxygenation tension, kidney microcirculatory perfusion, and 48-hour kidney function, as compared with fluid alone? Methods: Hemorrhagic shock was induced in 24 pigs, and 8 pigs were included as a sham group. Resuscitation of hemorrhagic shock was performed, using a closed-loop device, either by fluid alone (0.9% NaCl; fluid group) or associated with the administration of NE at two doses (moderate dose: mean rate of 0.64 µg ⋅ kg-1 ⋅ min-1; high dose: mean rate of 1.57 µg ⋅ kg-1 ⋅ min-1) to obtain a target systolic arterial pressure of 80 to 90 mm Hg. Resuscitation was followed by transfusion of the withdrawn blood. Measurements and Main Results: The amount of fluid required to reach the target systolic arterial pressure was lower in the NE groups than in the fluid group, with subsequently less hemodilution. NE restored kidney microcirculation, oxygenation, and function in a manner comparable to that achieved with fluid resuscitation alone. There were no histologic differences between animals resuscitated with fluid and those resuscitated with NE. Conclusions: In pigs with hemorrhagic shock, resuscitation with a combination of NE and fluid restored kidney microcirculation and oxygenation, as well as renal function, in a manner comparable to fluid resuscitation alone and without differences between the two NE doses. NE administration led to a fluid volume-sparing effect with subsequently less hemodilution.

Relationship between creatine kinase and liver enzymes in war wounded with rhabdomyolysis.

BACKGROUND: Rhabdomyolysis is a frequent complication in war wounded. Its complex pathophysiology suggests that it not only affects kidneys but also other organs such as the liver. The aim of this study was to evaluate the relationship between creatine kinase (CK) and liver enzymes in war wounded with rhabdomyolysis. METHODS: War wounded admitted to the intensive care unit of Percy Military Hospital between 2009 and 2017 with a rhabdomyolysis (CK peak >1,000 U/L) were included. They were divided in two groups: mild (CK peak <10,000 U/L) and severe rhabdomyolysis (CK peak ≥10,000 U/L). Demographic characteristics, peaks in transaminases, alkaline phosphatase (ALP), bilirubin, and CK were recorded. Mann Whitney-U test and, Fisher's exact test were used as appropriate. A Pearson's correlation test was used to determine the correlation between CK and liver enzymes after a log-normal transformation of the data. RESULTS: Fifty-one patients were included (31 in the mild and 20 in the severe rhabdomyolysis group). Patients in the severe rhabdomyolysis group were more likely victims of explosions (85% vs 39%, p = 0.003). The transaminases peak was significantly higher in the severe rhabdomyolysis group (median AST peak 398 (270-944) vs 91 (63-157) U/L, p <0.0001, and median ALT peak 106 (77-235) vs 45 (34-71) U/L, p<0.0001). Bilirubin and ALP were higher in the severe rhabdomyolysis group (39 (25-49) vs 14(11-23) U/L, p = 0.0031 and 84 (55-170) vs 52 (39-85) U/L, p = 0.0063, respectively). We found a significant positive linear correlation between CK and ALT (r = 0.73, p<0.0001), AST (r = 0.89, p<0.0001), ALP (r = 0.41, p = 0.0035), and bilirubin (r = 0.37, p = 0.0083). CONCLUSION: We found a statistically significant positive correlation between CK and liver enzymes in rhabdomyolysis war wounded, indicating that hepatic damage occurs when rhabdomyolysis is severe and associated with elevated bilirubin and ALP. Further studies are needed to confirm this phenomenon and elucidate the pathophysiological mechanism. LEVEL OF EVIDENCE: IV STUDY TYPE: Diagnostic.

Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock.

Severe trauma is the principal cause of death among young people worldwide. Hemorrhagic shock is the leading cause of death after severe trauma. Traumatic hemorrhagic shock (THS) is a complex phenomenon associating an absolute hypovolemia secondary to a sudden and significant extravascular blood loss, tissue injury, and, eventually, hypoxemia. These phenomena are responsible of secondary injuries such as coagulopathy, endotheliopathy, microcirculation failure, inflammation, and immune activation. Collectively, these dysfunctions lead to secondary organ failures and multi-organ failure (MOF). The development of MOF after severe trauma is one of the leading causes of morbidity and mortality, where immunological dysfunction plays a central role. Damage-associated molecular patterns induce an early and exaggerated activation of innate immunity and a suppression of adaptive immunity. Severe complications are associated with a prolonged and dysregulated immune-inflammatory state. The current challenge in the management of THS patients is preventing organ injury, which currently has no etiological treatment available. Modulating the immune response is a potential therapeutic strategy for preventing the complications of THS. Mesenchymal stromal cells (MSCs) are multipotent cells found in a large number of adult tissues and used in clinical practice as therapeutic agents for immunomodulation and tissue repair. There is growing evidence that their efficiency is mainly attributed to the secretion of a wide range of bioactive molecules and extracellular vesicles (EVs). Indeed, different experimental studies revealed that MSC-derived EVs (MSC-EVs) could modulate local and systemic deleterious immune response. Therefore, these new cell-free therapeutic products, easily stored and available immediately, represent a tremendous opportunity in the emergency context of shock. In this review, the pathophysiological environment of THS and, in particular, the crosstalk between the immune system and organ function are described. The potential therapeutic benefits of MSCs or their EVs in treating THS are discussed based on the current knowledge. Understanding the key mechanisms of immune deregulation leading to organ damage is a crucial element in order to optimize the preparation of EVs and potentiate their therapeutic effect.

COVID-19-Associated Pneumonia: Radiobiological Insights.

The evolution of SARS-CoV-2 pneumonia to acute respiratory distress syndrome is linked to a virus-induced "cytokine storm", associated with systemic inflammation, coagulopathies, endothelial damage, thrombo-inflammation, immune system deregulation and disruption of angiotensin converting enzyme signaling pathways. To date, the most promising therapeutic approaches in COVID-19 pandemic are linked to the development of vaccines. However, the fight against COVID-19 pandemic in the short and mid-term cannot only rely on vaccines strategies, in particular given the growing proportion of more contagious and more lethal variants among exposed population (the English, South African and Brazilian variants). As long as collective immunity is still not acquired, some patients will have severe forms of the disease. Therapeutic perspectives also rely on the implementation of strategies for the prevention of secondary complications resulting from vascular endothelial damage and from immune system deregulation, which contributes to acute respiratory distress and potentially to long term irreversible tissue damage. While the anti-inflammatory effects of low dose irradiation have been exploited for a long time in the clinics, few recent physiopathological and experimental data suggested the possibility to modulate the inflammatory storm related to COVID-19 pulmonary infection by exposing patients to ionizing radiation at very low doses. Despite level of evidence is only preliminary, these preclinical findings open therapeutic perspectives and are discussed in this article.

Performance of closed-loop resuscitation in a pig model of haemorrhagic shock with fluid alone or in combination with norepinephrine, a pilot study.

We evaluated the performance of a new device to control the administration of fluid alone or co-administration of fluid and norepinephrine in a pig model of haemorrhagic shock in two sets of experiments. In the first one, resuscitation was guided using continuous arterial pressure measurements (three groups: resuscitation with fluid by a physician, CL resuscitation with fluid, and CL resuscitation with fluid and norepinephrine). In the second one, resuscitation was guided using discontinuous arterial pressure measurements (three groups: CL resuscitation with fluid alone, CL resuscitation with fluid and moderate dose norepinephrine, and CL resuscitation with fluid and a high dose of norepinephrine). Pigs were resuscitated for 1 h. In the first set of experiments, proportion of time spent in the target area of 78-88 mmHg of systolic arterial pressure was not statistically different between the three groups: manual, 71.2% (39.1-80.1); CL with fluid, 87.8% (68.3-97.4); and CL with fluid and norepinephrine, 78.1% (59.2-83.6), p = 0.151. In the second set of experiments, performance of CL resuscitation with fluid or with combination of fluid and high or moderate dose of norepinephrine was not significantly different (p = 0.543 for time in target). Pigs resuscitated with norepinephrine required less fluid and had less haemodilution than pigs resuscitated with fluid alone. Performance of CL resuscitation using continuous arterial pressure measurement was not significantly different than optimised manual treatment by a dedicated physician. Performance of CL resuscitation was reduced with discontinuous arterial pressure measurements in comparison with continuous arterial pressure measurements.

Prioritisation of ICU treatments for critically ill patients in a COVID-19 pandemic with scarce resources.

BACKGROUND: Relying on capacity increases and patient transfers to deal with the huge and continuous inflow of COVID-19 critically ill patients is a strategy limited by finite human and logistical resources. RATIONALE: Prioritising both critical care initiation and continuation is paramount to save the greatest number of lives. It enables to allocate scarce resources in priority to those with the highest probability of benefiting from them. It is fully ethical provided it relies on objective and widely shared criteria, thus preventing arbitrary decisions and guaranteeing equity. Prioritisation seeks to fairly allocate treatments, maximise saved lives, gain indirect life benefits from prioritising exposed healthcare and similar workers, give priority to those most penalised as a last resort, and apply similar prioritisation schemes to all patients. PRIORITISATION STRATEGY: Prioritisation schemes and their criteria are adjusted to the level of resource scarcity: strain (level A) or saturation (level B). Prioritisation yields a four level priority for initiation or continuation of critical care: P1-high priority, P2-intermediate priority, P3-not needed, P4-not appropriate. Prioritisation schemes take into account the patient's wishes, clinical frailty, pre-existing chronic condition, along with severity and evolution of acute condition. Initial priority level must be reassessed, at least after 48h once missing decision elements are available, at the typical turning point in the disease's natural history (ICU days 7 to 10 for COVID-19), and each time resource scarcity levels change. For treatments to be withheld or withdrawn, a collegial decision-making process and information of patient and/or next of kin are paramount. PERSPECTIVE: Prioritisation strategy is bound to evolve with new knowledge and with changes within the epidemiological situation.

Performance of closed-loop resuscitation of haemorrhagic shock with fluid alone or in combination with norepinephrine: an experimental study.

BACKGROUND: Closed-loop resuscitation can improve personalization of care, decrease workload and bring expert knowledge in isolated areas. We have developed a new device to control the administration of fluid or simultaneous co-administration of fluid and norepinephrine using arterial pressure. METHOD: We evaluated the performance of our prototype in a rodent model of haemorrhagic shock. After haemorrhagic shock, rats were randomized to five experimental groups: three were resuscitated with fluid and two with co-administration of fluid and norepinephrine. Among groups resuscitated with fluid, one was resuscitated by a physician and two were resuscitated according to two different closed-loop algorithms. Among groups resuscitated with fluid and norepinephrine, one was resuscitated by a physician and the other one by the closed-loop device. The precision of arterial pressure during the resuscitation period was assessed using rising time, time passed in the target area and performance error calculations. RESULTS: Groups resuscitated with fluid had similar performances and passed as much time in the target area of 80-90 mmHg as the manual group [manual: 76.8% (67.9-78.2), closed-loop: 64.6% (45.7-72.9) and 80.9% (59.1-85.3)]. Rats resuscitated with fluid and norepinephrine using closed-loop passed similar time in target area than manual group [closed-loop: 74.4% (58.4-84.5) vs. manual: 60.1% (46.1-72.4)] but had shorter rising time to reach target area [160 s (106-187) vs. 434 s (254-1081)] than those resuscitated by a physician. Rats resuscitated with co-administration of fluid and norepinephrine required less fluid and had less hemodilution than rats resuscitated with fluid alone. Lactate decrease was similar between groups resuscitated with fluid alone and fluid with norepinephrine. CONCLUSIONS: This study assessed extensively the performances of several algorithms for closed-loop resuscitation of haemorrhagic shock with fluid alone and with co-administration of fluid and norepinephrine. The performance of the closed-loop algorithms tested was similar to physician-guided treatment with considerable saving of work for the caregiver. Arterial pressure closed-loop guided algorithms can be extended to combined administration of fluid and norepinephrine.

Acute kidney injury in trauma patients.

PURPOSE OF REVIEW: To review epidemiology and pathophysiology of acute kidney injury (AKI) in trauma patients and propose strategies that aim at preventing AKI after trauma. RECENT FINDINGS: AKI in trauma patients has been reported to be as frequent as 50% with an association to a prolonged length of stay and a raise in mortality. Among the specific risk factors encountered in trauma patients, hemorrhagic shock, rhabdomyolysis severity, age, and comorbidities are independently associated with AKI occurrence. Resuscitation with balanced solutes seems to have beneficial effects on renal outcome compared with NaCl 0.9%, particularly in the context of rhabdomyolysis. However, randomized clinical studies are needed to confirm this signal. Abdominal compartment syndrome (ACS) is rare but has to be diagnosed to initiate a dedicated therapy. SUMMARY: The high incidence of AKI in trauma patients should lead to early identification of those at risk of AKI to establish a resuscitation strategy that aims at preventing AKI.

Full-field OCT technique for high speed event-based optical flow and particle tracking.

This article introduces a method to extract the speed and density of microparticles in real time at several kHz using an asynchronous event-based camera mounted on a full-field optical coherence tomography (FF-OCT) setup. These cameras detect significant amplitude changes, allowing scene-driven acquisitions. They are composed of an array of autonomously operating pixels. Events are triggered when an illuminance change at the pixel level is significant at 1µs time precision. The event-driven FF-OCT algorithm relies on a time-based optical flow computation to operate directly on incoming events and updates the estimation of velocity, direction and density while reducing both computation and data load. We show that for fast moving microparticles in a range of 0.4 - 6.5mm/s, the method performs faster and more efficiently than existing techniques in real time. The target application of this work is to evaluate erythrocyte dynamics at the microvascular level in vivo with a high temporal resolution.

Intestinal microcirculation and mucosal oxygenation during hemorrhagic shock and resuscitation at different inspired oxygen concentrations.

BACKGROUND: Hypotensive resuscitation is the standard of care of hemorrhagic shock resuscitation. The optimal level of arterial pressure is debated and there is a lack of data on relationships between arterial pressure, microcirculation and tissue oxygenation. We investigated the relationship between mean arterial pressure, intestinal microcirculation and mucosal oxygen tension during hemorrhagic shock and resuscitation at different inspired oxygen fraction concentration. METHODS: The study was divided into two phases: 32 mice were progressively exsanguinated and then transfused in mean arterial pressure (MAP)-titrated steps of 10 mm Hg. Mice were randomized to four experimental groups: a control group in which sham mice underwent a laparotomy and three interventional groups with a common phase of exsanguination followed by progressive resuscitation at three different inspired oxygen concentrations (FIO2) (15%, 30%, and 100%). Intestinal mucosal oxygenation (intestinal PO2) and microcirculatory parameters were recorded at each 10 mm Hg MAP step. RESULTS: During exsanguination, intestinal PO2 decreased linearly with MAP levels. Microcirculatory parameters decreased nonlinearly with MAP levels while they had a linear relationship with intestinal PO2. Intestinal mucosal hypoxia (PO2 ≤ 20 mm Hg) began at a MAP of 60 mm Hg and MAP < 60 mm Hg was associated with a high percentage of animal with intestinal hypoxia (≥32%). Combination of MAP and microcirculatory parameters was superior to MAP alone at predicting mucosal oxygenation. Inversely, during resuscitation with FIO2 = 30%, the microcirculatory parameters increased linearly with MAP levels while they had a nonlinear relationship with intestinal PO2. Hypoxia (FIO2 = 15%) was poorly tolerated. In hyperoxic group (FIO2 = 100%) intestinal PO2 became significantly higher than baseline values as soon as 50 mm Hg MAP. CONCLUSION: During hemorrhagic shock, intestinal PO2 decreased linearly with MAP levels and microcirculatory parameters. Associating MAP and microcirculatory parameters allowed a better prediction of intestinal PO2 than MAP alone. A MAP < 60 mm Hg was associated with a high percentage of animal with intestinal hypoxia. Normoxic resuscitation (FIO2 = 30%) was sufficient to restore intestinal PO2.

Haemodynamic coherence in haemorrhagic shock.

In case of haemorrhage, a combination of low volume fluid resuscitation and permissive hypotension is used to avoid the adverse effects of early aggressive fluid resuscitation. During this phase, occult microvascular hypoperfusion can possibly develop over time. After controlling the bleeding, it is expected that optimization of macrocirculation will result in an improvement in microcirculation. However, this is the case only without alterations in microcirculation regulation. Haemodynamic coherence must be maintained to expect the restoration of microcirculation through systemic haemodynamic-driven resuscitation. However, haemorrhagic shock, reperfusion, traumatic injury and inflammation can damage microcirculation and thus lead to a loss of haemodynamic coherence. In these cases, a systemic haemodynamic-driven resuscitation would not be effective in restoring microcirculation and tissue oxygenation. A real-time technique enabling microcirculation monitoring can create an opportunity for microcirculatory haemodynamic-driven resuscitation to become the gold standard in the future.