Effects of sevoflurane on lung alveolar epithelial wound healing and survival in a sterile in vitro model of acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a serious lung condition that often leads to hospitalization in intensive care units and a high mortality rate. Sevoflurane is a volatile anesthetic with growing interest for sedation in ventilated patients with ARDS. It has been shown to have potential lung-protective effects, such as reduced inflammation and lung edema, or improved arterial oxygenation. In this study, we investigated the effects of sevoflurane on lung injury in cultured human carcinoma-derived lung alveolar epithelial (A549) cells. We found that sevoflurane was associated with improved wound healing after exposure to inflammatory cytokines, with preserved cell proliferation but no effect on cell migration properties. Sevoflurane exposure was also associated with enhanced cell viability and active autophagy in A549 cells exposed to cytokines. These findings suggest that sevoflurane may have beneficial effects on lung epithelial injury by promoting alveolar epithelial wound healing and by influencing the survival and proliferation of A549 epithelial cells in vitro. Further research is needed to confirm these findings and to investigate the key cellular mechanisms explaining sevoflurane's potential effects on lung epithelial injury.

Inhaled Sedation with Volatile Anesthetics for Mechanically Ventilated Patients in Intensive Care Units: A Narrative Review.

Inhaled sedation was recently approved in Europe as an alternative to intravenous sedative drugs for intensive care unit (ICU) sedation. The aim of this narrative review was to summarize the available data from the literature published between 2005 and 2023 in terms of the efficacy, safety, and potential clinical benefits of inhaled sedation for ICU mechanically ventilated patients. The results indicated that inhaled sedation reduces the time to extubation and weaning from mechanical ventilation and reduces opioid and muscle relaxant consumption, thereby possibly enhancing recovery. Several researchers have reported its potential cardio-protective, anti-inflammatory or bronchodilator properties, alongside its minimal metabolism by the liver and kidney. The reflection devices used with inhaled sedation may increase the instrumental dead space volume and could lead to hypercapnia if the ventilator settings are not optimal and the end tidal carbon dioxide is not monitored. The risk of air pollution can be prevented by the adequate scavenging of the expired gases. Minimizing atmospheric pollution can be achieved through the judicious use of the inhalation sedation for selected groups of ICU patients, where the benefits are maximized compared to intravenous sedation. Very rarely, inhaled sedation can induce malignant hyperthermia, which prompts urgent diagnosis and treatment by the ICU staff. Overall, there is growing evidence to support the benefits of inhaled sedation as an alternative for intravenous sedation in ICU mechanically ventilated patients. The indication and management of any side effects should be clearly set and protocolized by each ICU. More randomized controlled trials (RCTs) are still required to investigate whether inhaled sedation should be prioritized over the current practice of intravenous sedation.

Impact of Macintosh blade size on endotracheal intubation success in intensive care units: a retrospective multicenter observational MacSize-ICU study.

PURPOSE: To investigate the impact of Macintosh blade size used during direct laryngoscopy (DL) on first-attempt intubation success of orotracheal intubation in French intensive care units (ICUs). We hypothesized that success rate would be higher with Macintosh blade size No3 than with No4. METHODS: Multicenter retrospective observational study based on data from prospective trials conducted in 48 French ICUs of university, and general and private hospitals. After each intubation using Macintosh DL, patients' and operators' characteristics, Macintosh blade size, results of first DL and alternative techniques used, as well as the need of a second operator were collected. Complications rates associated with intubation were investigated. Primary outcome was success rate of first DL using Macintosh blade. RESULTS: A total of 2139 intubations were collected, 629 with a Macintosh blade No3 and 1510 with a No4. Incidence of first-pass intubation after first DL was significantly higher with Macintosh blade No3 (79.5 vs 73.3%, p = 0.0025), despite equivalent Cormack-Lehane scores (p = 0.48). Complications rates were equivalent between groups. Multivariate analysis concluded to a significant impact of Macintosh blade size on first DL success in favor of blade No3 (OR 1.44 [95% CI 1.14-1.84]; p = 0.0025) without any significant center effect on the primary outcome (p = 0.18). Propensity scores and adjustment analyses concluded to equivalent results. CONCLUSION: In the present study, Macintosh blade No3 was associated with improved first-passed DL in French ICUs. However, study design requires the conduct of a nationwide prospective multicenter randomized trial in different settings to confirm these results.

Association between proteinuria trajectories and outcomes in critically ill patients with sepsis or shock.

BACKGROUND: Proteinuria results from kidney damage and can be a predictor of illness severity and mortality in the intensive care unit (ICU). However, the optimal timing of proteinuria measurements and the reference values remain undetermined. Our objective was to identify the patterns of proteinuria change associated with mortality in ICU patients with sepsis or shock. METHODS: This monocentric retrospective cohort study performed from April 2010 to April 2018 involved all ICU patients with sepsis or shock and at least two measurements of proteinuria from a 24h-urine collection during the first 10 days of ICU stay, the first of which was made within 48h after ICU admission. We identified proteinuria trajectories by a semi-parametric mixture model and analysed the association between the trajectories and the mortality at day 28 by Cox proportional-hazards model. RESULTS: A total of 3,344 measurements of proteinuria from 659 patients were analysed. Four proteinuria trajectories were identified. Trajectories 1, 2, 3 and 4 comprised 127, 421, 60 and 51 patients, and were characterized by a first proteinuria of 1.14 [0.66-1.55], 0.52 [0.26-0.91], 2.92 [2.38-3.84] and 2.58 [1.75-3.32] g/24h (p<0.001) and a mortality of 24.4%, 38%, 20% and 43% (p = 0.002), respectively. Trajectories 3 and 4 had a high first proteinuria (>2g/24h). Only, the proteinuria of trajectory 4 increased within 3 days following the first measurement and was associated with increased mortality at day 28 (hazard ratio: 2.36 95%CI [1.07-5.19], p = 0.03), regardless of acute renal failure. The factors associated with trajectory 4 were cancer (relative risk: 8.91 95%CI [2.09-38.02], p = 0.003) and use of inotropic drugs (relative risk: 0.17 95%CI [0.04-0.69], p = 0.01). CONCLUSION: This exploratory study of ICU patients with sepsis or shock identified four proteinuria trajectories with distinct patterns of proteinuria change over time and mortality rates. These results provide novel insights into renal pathophysiology and may be helpful to investigate subphenotypes of kidney injury among ICU patients in future studies.

One-year patient outcomes based on lung morphology in acute respiratory distress syndrome: secondary analysis of LIVE trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) has different phenotypes and distinct short-term outcomes. Patients with non-focal ARDS have a higher short-term mortality than focal ones. The aim of this study was to assess the impact of the morphological phenotypes of ARDS on long-term outcomes. METHODS: This was a secondary analysis of the LIVE study, a prospective, randomised control trial, assessing the usefulness of a personalised ventilator setting according to lung morphology in moderate-to-severe ARDS. ARDS was classified as focal (consolidations only in the infero-posterior part of the lungs) or non-focal. Outcomes were assessed using mortality and functional scores for quality of life at the 1-year follow-up. RESULTS: A total of 124 focal ARDS and 236 non-focal ARDS cases were included. The 1-year mortality was higher for non-focal ARDS than for focal ARDS (37% vs. 24%, p = 0.012). Non-focal ARDS (hazard ratio, 3.44; 95% confidence interval, 1.80-6.59; p < 0.001), age, McCabe score, haematological cancers, SAPS II, and renal replacement therapy were independently associated with 1-year mortality. This difference was driven by mortality during the first 90 days (28 vs. 16%, p = 0.010) but not between 90 days and 1 year (7 vs. 6%, p = 0.591), at which point only the McCabe score was independently associated with mortality. Morphological phenotypes had no impact on patient-reported outcomes. CONCLUSION: Lung morphologies reflect the acute phase of ARDS and its short-term impact but not long-term outcomes, which seem only influenced by comorbidities. TRIAL REGISTRATION: NCT02149589; May 29, 2014.

The receptor for advanced glycation end-products enhances lung epithelial wound repair: An in vitro study.

Re-epithelialization of the alveolar surface is a key process of lung alveolar epithelial barrier repair after acute lung injury. The receptor for advanced glycation end-products (RAGE) pathway plays key roles in lung homeostasis, and its involvement in wound repair has been already reported in human bronchial epithelial cells. However, its effects on lung alveolar epithelial repair after injury remain unknown. We investigated whether RAGE stimulation with its ligands high-mobility group box 1 protein (HMGB1) or advanced glycation end-products (AGEs), alone or associated with RAGE inhibition using RAGE antagonist peptide, affects in vitro wound healing in human alveolar epithelial A549 cells. We further asked whether these effects could be associated with changes in cell proliferation and migration. We found that treatment of A549 cells with HMGB1 or AGEs promotes RAGE-dependent wound healing after a scratch assay. In addition, both RAGE ligands increased cell proliferation in a RAGE-dependent manner. Treatment with HMGB1 increased migration of alveolar epithelial cells at 12 h, independently of RAGE, whereas AGEs stimulated migration as measured 48 h after injury in a RAGE-dependent manner. Taken together, these results suggest that RAGE pathway is involved in lung alveolar epithelial wound repair, possibly through enhanced cell migration and proliferation.

Advanced Glycation End Products and Receptor (RAGE) Promote Wound Healing of Human Corneal Epithelial Cells.

Purpose: We used a human corneal epithelial cell (HCE) line to determine the involvement of the advanced glycation end products (AGEs) / receptor for AGEs (RAGE) couple in corneal epithelium wound healing. Methods: After wounding, HCE cells were exposed to two major RAGE ligands (HMGB1 and AGEs), and wound healing was evaluated using the in vitro scratch assay. Following wound healing, the HCE cells were used to study the influence of the RAGE ligands on HCE proliferation, invasion, and migration. Activation of the nuclear factor (NF)-κB signaling pathway by the AGEs/RAGE couple was tested using a luciferase reporter assay. Functional transcriptional regulation by this pathway was confirmed by quantification of expression of the connexin 43 target gene. For each experiment, specific RAGE involvement was confirmed by small interfering RNA treatments. Results: AGEs treatment at a dose of 100 µg/mL significantly improved the wound healing process in a RAGE-dependent manner by promoting cell migration, whereas HMGB1 had no effect. No significant influence of the AGEs/RAGE couple was observed on cell proliferation and invasion. However, this treatment induced an early activation of the NF-κB pathway and positively regulated the expression of the target gene, connexin 43, at both the mRNA and protein levels. Conclusions: Our results demonstrate that the RAGE pathway is activated by AGEs treatment and is involved in the promotion of corneal epithelial wound healing. This positive action is observed only during the early stages of wound healing, as illustrated by the quick activation of the NF-κB pathway and induction of connexin 43 expression.

Pathological Implications of Receptor for Advanced Glycation End-Product (AGER) Gene Polymorphism.

The receptor for advanced glycation end-products (RAGE) is a cell surface transmembrane multiligand receptor, encoded by the AGER gene. RAGE presents many transcripts, is expressed mainly in the lung, and involves multiple pathways (such as NFκB, Akt, p38, and MAP kinases) that initiate and perpetuate an unfavorable proinflammatory state. Due to these numerous functional activities, RAGE is implicated in multiple diseases. AGER is a highly polymorphic gene, with polymorphisms or SNP (single-nucleotide polymorphism) that could be responsible or co-responsible for disease development. This review was designed to shed light on the pathological implications of AGER polymorphisms. Five polymorphisms are described: rs2070600, rs1800624, rs1800625, rs184003, and a 63 bp deletion. The rs2070600 SNP may be associated with the development of human autoimmune disease, diabetes complications, cancer, and lung diseases such as chronic obstructive pulmonary disease and acute respiratory distress syndrome. The rs1800624 SNP involves AGER gene regulation and may be related to reduced risk of heart disease, cancer, Crohn's disease, and type 1 diabetes complications. The rs1800625 SNP may be associated with the development of diabetic retinopathy, cancer, and lupus but may be protective against cardiovascular risk. The rs184003 SNP seems related to coronary artery disease, breast cancer, and diabetes. The 63 bp deletion may be associated with reduced survival from heart diseases during diabetic nephropathy. Here, these potential associations between AGER polymorphisms and the development of diseases are discussed, as there have been conflicting findings on the pathological impact of AGER SNPs in the literature. These contradictory results might be explained by distinct AGER SNP frequencies depending on ethnicity.

Method validation of a set of 12 GEM® Premier™ 4000 blood gas analyzers for point-of-care testing in a university teaching hospital.

BACKGROUND: Blood gas analyzers are o0.ften integrated into point-of-care testing provisions. International standards (ISO 22870 and 15189) as adapted to French COFRAC regulations make accreditation of point-ofta-care testintag obligatory. We installed and assessed 12 GEM PREMIER 4000 analyzers for pH, pCO2, pO2, Na+, K+, Cl-, Ca2+, lactate, hemoglobin and oxyhemoglobin (O2Hb) at Clermont-Ferrand Hospital. These instruments were distributed across 11 care sites in the hospital. METHODS: Precision was studied at two control levels for each parameter. Comparisons between GEM analyzers were performed (on 30 samples) for pH, pCO2, pO2, Na+, K+, Cl-, Ca2+, lactate, hemoglobin and O2Hb; and between GEM analyzers and the central laboratory for Na+, K+, Cl-, Ca2+ and hemoglobin (on 30-50 samples). Uncertainty in measurement (UM) was evaluated with an approach using reproducibility and accuracy data. RESULTS: The coefficients of variation (CVs) were in line with recommendations, except for the repeatability CV for pO2. All CVs were below 4%. All comparisons complied with recommendations. Uncertainties of measurement were also validated. CONCLUSION: Our results met standard requirements and the 12 analyzers were assessed as suitable for point-of-care testing in services of academic medical centers, as exemplified at Clermont-Ferrand hospital.

RAGE inhibition reduces acute lung injury in mice.

The receptor for advanced glycation end-products (RAGE) is involved in inflammatory response during acute respiratory distress syndrome (ARDS). Growing body of evidence support strategies of RAGE inhibition in experimental lung injury, but its modalities and effects remain underinvestigated. Anesthetised C57BL/6JRj mice were divided in four groups; three of them underwent orotracheal instillation of acid and were treated with anti-RAGE monoclonal antibody (mAb) or recombinant soluble RAGE (sRAGE), acting as a decoy receptor. The fourth group served as a control. Lung injury was assessed by the analysis of blood gases, alveolar permeability, histology, AFC, and cytokines. Lung expression and distribution epithelial channels ENaC, Na,K-ATPase, and aquaporin (AQP)-5 were assessed. Treatment with either anti-RAGE mAb or sRAGE improved lung injury, arterial oxygenation and decreased alveolar inflammation in acid-injured animals. Anti-RAGE therapies were associated with restored AFC and increased lung expression of AQP-5 in alveolar cell. Blocking RAGE had potential therapeutic effects in a translational mouse model of ARDS, possibly through a decrease in alveolar type 1 epithelial cell injury as shown by restored AFC and lung AQP-5 expression. Further mechanistic studies are warranted to describe intracellular pathways that may control such effects of RAGE on lung epithelial injury and repair.

Rationale, study design and analysis plan of the lung imaging morphology for ventilator settings in acute respiratory distress syndrome study (LIVE study): Study protocol for a randomised controlled trial.

Different acute respiratory distress syndrome (ARDS) phenotypes may explain controversial results in clinical trials. Lung-morphology is one of the ARDS-phenotypes and physiological studies suggest different responses in terms of positive-end-expiratory-pressure (PEEP) and recruitment-manoeuvres (RM) according to loss of aeration. To evaluate whether tailored ventilator regimens may impact ARDS outcomes, our group has designed a randomised-clinical-trial of ventilator settings according to lung morphology in moderate-to-severe ARDS (LIVE study). METHOD: Patients will be enrolled within the first 12hours of ARDS onset. In both groups, volume-controlled ventilation with low tidal-volumes (Vt) will be used to target a plateau pressure≤30 cmH2O. In the control group, the PEEP level and inspired fraction of oxygen (FiO2) will be set using the ARDSNet table; a Vt of 6 mL/kg of predicted body weight (PBW) will be set and prone position (PP) will be applied. In the intervention arm, the ventilator will be set according to lung morphology (focal/non-focal) that will be assessed according to CT-scan±chest x-ray+lung echography. For focal ARDS patients, a Vt of 8 mL/kg PBW will be used along with low PEEP and PP. For non-focal ARDS patients, a Vt of 6 mL/kg PBW will be used with RM and PEEP to reach a plateau pressure≤30 cmH2O. The primary outcome is all-cause 90-day mortality and the secondary outcomes are: in-hospital mortality, mortality at day 28, 60, 180 and 365; ventilator-free days at day 30, quality of life at one year; ventilator-associated pneumonia rate; barotrauma; ICU and hospital length of stay. This RCT is registered on Clinicaltrials.gov under identifier NCT02149589.

Modulation by Polymyxin-B Hemoperfusion of Inflammatory Response Related to Severe Peritonitis.

Conflicting results have been reported on the influence of Polymyxin-B hemoperfusion treatment on systemic inflammation markers. The aim of the study was to assess in a randomized control trial the influence on plasma cytokine concentrations of Polymyxin-B hemoperfusion in septic shock due to peritonitis. A panel of 10 pro- or anti-inflammatory cytokines was measured in 213 patients with peritonitis-induced septic shock enrolled in the randomized trial ABDOMIX testing the impact of 2 Polymyxin-B hemoperfusion sessions with standard treatment. Gram-negative bacteria were identified in 69% of patients. In the overall population, baseline plasma cytokine concentrations were not different between the two groups. Circulating tumor necrosis factor-α, interleukin (IL)-1ß, IL-10, IL-6, and IL-1RA decreased significantly over time in both groups (P <0.0001 for all in controls, and P = 0.0002, 0.003, and <0.0001 in patients treated with Polymyxin-B hemoperfusion). IL-17A decreased significantly in patients treated with Polymyxin B hemoperfusion (P = 0.045) but not in controls. At the end of the second Polymyxin-B hemoperfusion session or at corresponding time in controls, plasma levels of cytokines did not differ between the two groups. Similar results were found in the subgroup of patients with gram-negative peritonitis who completed two Polymyxin-B hemoperfusion sessions. These results do not support a significant influence of Polymyxin-B hemoperfusion on circulating cytokines assessed except for IL-17A which clinical significance remains to be elucidated.

Association between intraoperative ventilator settings and plasma levels of soluble receptor for advanced glycation end-products in patients without pre-existing lung injury.

BACKGROUND AND OBJECTIVE: The soluble form of the receptor for advanced glycation end-products (sRAGE) is elevated and correlated with severity in patients with acute respiratory distress syndrome (ARDS). The impact of ventilator settings on plasma levels of sRAGE, in patients with or without pre-existing lung injury, remains under-investigated to date. Our objective was to assess the effects of a lung-protective ventilation strategy (combining low tidal volume, positive end-expiratory pressure and recruitment maneuvers), as compared with a non-protective approach (with high tidal volume and zero end-expiratory pressure), on plasma levels of sRAGE in patients without lung injury undergoing major abdominal surgery. METHODS: Plasma samples were obtained from 95 patients enrolled in a large randomized controlled trial of lung-protective ventilation for major abdominal surgery. Plasma levels of sRAGE were measured in duplicate with an enzyme-linked immunoassay on day 1, immediately after surgery, and on postoperative days 1, 3 and 7. RESULTS: Early postoperative plasma levels of sRAGE were significantly lower in the lung-protective ventilation group (n = 47) than in the non-protective ventilation group (n = 48) (mean (standard deviation), 1782 (836) vs 2171 (1678) pg/mL, respectively, P = 0.03). Intraoperative changes in plasma sRAGE were associated with postoperative hypoxemia and ARDS. CONCLUSIONS: A lung-protective ventilation strategy decreased plasma sRAGE in patients without lung injury undergoing major abdominal surgery compared with the patients with non-protective ventilation. This intraoperative decrease could reflect a lesser degree of epithelial injury.

Epidural analgesia in the intensive care unit: An observational series of 121 patients.

BACKGROUND: Epidural analgesia (EA) has been more investigated during the perioperative period than in the intensive care unit (ICU) setting. Recent studies support beneficial effects for EA beyond analgesia itself. However, data on feasibility and safety are still lacking in the ICU. Our goal was to assess the feasibility and practice of EA in ICU patients. METHODS: Multicentre observational study in 3 ICUs over a 10-month period. Goals were to report the incidence of EA-related complications and EA duration. All ICU patients receiving EA were included, whether EA was initiated in the ICU or elsewhere, e.g. in the operating room. Demographics, clinical and biological data were prospectively recorded. Epidural catheter tips were sent to the microbiology laboratory for culture. RESULTS: One hundred and twenty-one patients were included (mean age 60 years), with mean SOFA and median SAPS II scores of 3.2 and 32, respectively. Reasons for EA initiation included trauma (14%), postoperative pain management after major surgery (42%), and pancreatitis (31%). No EA-related neurologic complication was recorded, and one case of epidural abscess is discussed. No other EA-related infectious complications were observed. Median duration of EA was 11 days. Reasons for EA discontinuation included efficient analgesia without EA (60%) and accidental catheter removal (17%). 22% of epidural catheter cultures were positive for skin flora bacteria. CONCLUSION: EA seems feasible in the ICU. Its apparent safety should be further validated in larger cohorts, but these preliminary results may stimulate more interest in the assessment of potential benefits associated with EA in the ICU setting.

Early use of polymyxin B hemoperfusion in patients with septic shock due to peritonitis: a multicenter randomized control trial.

PURPOSE: To test whether the polymyxin B hemoperfusion (PMX HP) fiber column reduces mortality and organ failure in peritonitis-induced septic shock (SS) from abdominal infections. METHOD: Prospective, multicenter, randomized controlled trial in 18 French intensive care units from October 2010 to March 2013, enrolling 243 patients with SS within 12 h after emergency surgery for peritonitis related to organ perforation. The PMX HP group received conventional therapy plus two sessions of PMX HP. Primary outcome was mortality on day 28; secondary outcomes were mortality on day 90 and a reduction in the severity of organ failures based on Sequential Organ Failure Assessment (SOFA) scores. PRIMARY OUTCOME: day 28 mortality in the PMX HP group (n = 119) was 27.7 versus 19.5% in the conventional group (n = 113), p = 0.14 (OR 1.5872, 95% CI 0.8583-2.935). Secondary endpoints: mortality rate at day 90 was 33.6% in PMX-HP versus 24% in conventional groups, p = 0.10 (OR 1.6128, 95% CI 0.9067-2.8685); reduction in SOFA score from day 0 to day 7 was -5 (-11 to 6) in PMX-HP versus -5 (-11 to 9), p = 0.78. Comparable results were observed in the predefined subgroups (presence of comorbidity; adequacy of surgery, <2 sessions of hemoperfusion) and for SOFA reduction from day 0 to day 3. CONCLUSION: This multicenter randomized controlled study demonstrated a non-significant increase in mortality and no improvement in organ failure with PMX HP treatment compared to conventional treatment of peritonitis-induced SS.

Low Molecular Weight Heparin Induced Skin Necrosis without Platelet Fall Revealing Immunoallergic Heparin Induced Thrombocytopenia.

Low molecular weight heparins (LMWH) are commonly used in the ICU setting for thromboprophylaxis as well as curative decoagulation as required during renal replacement therapy (RRT). A rare adverse event revealing immunoallergic LMWH induced thrombopenia (HIT) is skin necrosis at injection sites. We report the case of a patient presenting with skin necrosis witnessing an HIT after RRT, without thrombocytopenia. The mechanism remains unclear. Anti-PF4/heparin antibodies, functional tests (HIPA and/or SRA), and skin biopsy are of great help to evaluate differential diagnosis with a low pretest probability 4T's score.

Central venous O2 saturation and venous-to-arterial CO2 difference as complementary tools for goal-directed therapy during high-risk surgery.

INTRODUCTION: Central venous oxygen saturation (ScvO2) is a useful therapeutic target in septic shock and high-risk surgery. We tested the hypothesis that central venous-to-arterial carbon dioxide difference (P(cv-a)CO2), a global index of tissue perfusion, could be used as a complementary tool to ScvO2 for goal-directed fluid therapy (GDT) to identify persistent low flow after optimization of preload has been achieved by fluid loading during high-risk surgery. METHODS: This is a secondary analysis of results obtained in a study involving 70 adult patients (ASA I to III), undergoing major abdominal surgery, and treated with an individualized goal-directed fluid replacement therapy. All patients were managed to maintain a respiratory variation in peak aortic flow velocity below 13%. Cardiac index (CI), oxygen delivery index (DO2i), ScvO2, P(cv-a)CO2 and postoperative complications were recorded blindly for all patients. RESULTS: A total of 34% of patients developed postoperative complications. At baseline, there was no difference in demographic or haemodynamic variables between patients who developed complications and those who did not. In patients with complications, during surgery, both mean ScvO2 (78 ± 4 versus 81 ± 4%, P = 0.017) and minimal ScvO2 (minScvO2) (67 ± 6 versus 72 ± 6%, P = 0.0017) were lower than in patients without complications, despite perfusion of similar volumes of fluids and comparable CI and DO2i values. The optimal ScvO2 cut-off value was 70.6% and minScvO2 < 70% was independently associated with the development of postoperative complications (OR = 4.2 (95% CI: 1.1 to 14.4), P = 0.025). P(cv-a)CO2 was larger in patients with complications (7.8 ± 2 versus 5.6 ± 2 mmHg, P < 10-6). In patients with complications and ScvO2 ≥ 71%, P(cv-a)CO2 was also significantly larger (7.7 ± 2 versus 5.5 ± 2 mmHg, P < 10-6) than in patients without complications. The area under the receiver operating characteristic (ROC) curve was 0.785 (95% CI: 0.74 to 0.83) for discrimination of patients with ScvO2 ≥ 71% who did and did not develop complications, with 5 mmHg as the most predictive threshold value. CONCLUSIONS: ScvO2 reflects important changes in O2 delivery in relation to O2 needs during the perioperative period. A P(cv-a)CO2 < 5 mmHg might serve as a complementary target to ScvO2 during GDT to identify persistent inadequacy of the circulatory response in face of metabolic requirements when an ScvO2 ≥ 71% is achieved. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00852449.