Sublingual microcirculation in patients with SARS-CoV-2 undergoing veno-venous extracorporeal membrane oxygenation.

Veno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) is a rescue treatment for severe acute respiratory failure refractory to conventional ventilation. We examined the alterations of sublingual microcirculation in patients with SARS-CoV-2 during VV-ECMO treatment and assessed the relationship between microvascular parameters and ventilation, hemodynamics, and laboratory tests. Nine patients were included in the study and the following microcirculatory parameters were estimated: TVD 16.81 (14.46-18.6) mm/mm2; PVD 15.3 (14.09-17.96) mm/mm2; PPV 94.85% (93.82%-97.79%); MFI 2.5 (2.5-2.92); HI 0.4 (0.18-0.4). TVD and PVD were inversely related to D-dimer levels (rho = -0.667, p = 0.05 and rho = -0.733, p = 0.025 respectively), aspartate aminotransferase (AST) (rho = -0.886, p = 0.019 and rho = -0.886, p = 0.019 respectively) and alanine aminotransferase (ALT) (rho = -0.829, p = 0.042 and rho = -0.829, p = 0.042 respectively). Our results showed an altered sublingual microcirculation in patients receiving VV-ECMO for severe SARS-CoV-2 and suggest a potential contribution of endothelia dysfunction to determine microvascular alteration.

Changes in Cytokines, Haemodynamics and Microcirculation in Patients with Sepsis/Septic Shock Undergoing Continuous Renal Replacement Therapy and Blood Purification with CytoSorb.

BACKGROUND: Extracorporeal blood purification therapies have been proposed as a strategy to remove inflammatory mediators during sepsis, thus improving outcome. OBJECTIVES: We aimed to evaluate changes in cytokines, haemodynamics and microcirculation during blood purification with Cytosorb adsorber in septic patients. METHODS: Prospective observational study on critically ill adult patients with sepsis/septic shock underwent renal replacement therapy (RRT) for acute renal failure and haemoadsorption with Cytosorb as adjunctive therapy for 24 h. Measurements were taken at baseline, after 6 and 24 h: haemodynamic parameters, arterial and central venous blood gases, plasma levels of tumour necrosis factor alpha, interleukin (IL) 1-beta, IL-6, IL-8 and IL-10. The sublingual microcirculation was assessed with sidestream dark field videomicroscopy to evaluate the perfused vessel density (PVD) and microvascular flow quality. Tissue oxygenation and microvascular reactivity were assessed with thenar near infrared spectroscopy (NIRS) with a vascular occlusion test. RESULTS: Nine patients; plasma levels of IL-8 decreased at 24 h (p < 0.05 versus 6 h); no significant variation was found for other cytokines. Haemodynamic remained stable throughout the observation. Microvascular perfusion improved over time, with an increase in PVDs at 6 and 24 h (from 13.9 [13.3-16.4] to 15.7 [15-17.3] and 17 [14.8-18.6] mm/mm2 respectively, p = 0.003) and total vessel densities at 24 h (14.9 [13.9-16.9] vs. 17.9 [15.3-20], p = 0.0015). No significant variation was detected in NIRS-derived parameters. The Sequential Organ Failure Assessment score decreased from 12 ± 3 to 10 ± 1 at 24 h (p = 0.039). CONCLUSIONS: In septic patients undergoing RRT, haemoadsorption with Cytosorb seems to determine a decreasing in plasma levels of IL-8, although levels of other cytokines did not vary significantly, and an improvement of microcirculation despite no significant variation in macro-haemodynamics.

Tissue oxygen saturation changes and postoperative complications in cardiac surgery: a prospective observational study.

BACKGROUND: Cardiac surgery with extracorporeal circulation (ECC) can induce microvascular dysfunction and tissue hypoperfusion. We hypothesized that the alterations in near-infrared spectroscopy (NIRS)-derived parameters would be associated with post-operative complications in cardiac surgery patients. METHODS: Prospective observational study performed at two University Hospitals. Ninety patients undergoing cardiac surgery with ECC were enrolled. The NIRS sensor was applied on the thenar eminence. A vascular occlusion test (VOT, 3-min ischemia) was performed at baseline (t0), at Intensive Care Unit (ICU) admission (t1), 3 (t2) and 6 (t3) hours later. Baseline tissue oxygen saturation (StO2), oxygen extraction rate and microvascular reactivity indices were calculated. RESULTS: In the first hours after cardiac surgery, StO2 tended to increase (86% [80-89] at T3 versus 82% [79-86] at T0, p = ns), while both tissue oxygen extraction and microvascular reactivity tended to decrease, as indicated by increasing occlusion slope (- 8.1%/min [- 11.2 to - 7] at T3 versus - 11.2%/min [- 13.9 to - 7.9] at T0, p = ns) and decreasing recovery slope (1.9%/sec [1.1-2.9] at T3 versus 3.1%/sec [2.3-3.9] at T0, p = ns). No substantial differences were found in NIRS-derived variables and their changes over time between patients with complications and those without complications. CONCLUSIONS: Peripheral tissue oxygen extraction and microvascular reactivity were reduced during the first hours after cardiac surgery. NIRS-derived parameters were not able to predict complications in this population of cardiac surgery patients.

Changes in the sublingual microcirculation following aortic surgery under balanced or total intravenous anaesthesia: a prospective observational study.

BACKGROUND: In vascular surgery with aortic cross-clamping, ischemia/reperfusion injury induces systemic haemodynamic and microcirculatory disturbances. Different anaesthetic regimens may have a varying impact on tissue perfusion. The aim of this study was to explore changes in microvascular perfusion in patients undergoing elective open abdominal aortic aneurysm repair under balanced or total intravenous anaesthesia. METHODS: Prospective observational study. Patients undergoing elective open infrarenal abdominal aortic aneurysm repair received balanced (desflurane + remifentanil, n = 20) or total intravenous anaesthesia (TIVA, propofol + remifentanil using target-controlled infusion, n = 20) according to the clinician's decision. A goal-directed haemodynamic management was applied in all patients. Measurements were obtained before anaesthesia induction (baseline) and at end-surgery and included haemodynamics, arterial/venous blood gases, sublingual microvascular flow and density (incident dark field illumination imaging), peripheral muscle tissue oxygenation and microcirculatory reactivity (thenar near infrared spectroscopy with a vascular occlusion test). RESULTS: The two groups did not differ for baseline characteristics, mean aortic-clamping time and requirement of vasoactive agents during surgery. Changes in mean arterial pressure, systemic vascular resistance index, haemoglobin and blood lactate levels were similar between the two groups, while the cardiac index increased at end-surgery in patients undergoing balanced anaesthesia. The sublingual microcirculation was globally unaltered in the TIVA group at end-surgery, while patients undergoing balanced anaesthesia showed an increase in the total and perfused small vessel densities (from 16.6 ± 4.2 to 19.1 ± 5.4 mm/mm2, p < 0.05). Changes in microvascular density were negatively correlated with changes in the systemic vascular resistance index. The area of reactive hyperaemia during the VOT increased in the balanced anaesthesia group (from 14.8 ± 8.1 to 25.6 ± 14.8%*min, p < 0.05). At end-surgery, the tissue haemoglobin index in the TIVA group was lower than that in the balanced anaesthesia group. CONCLUSIONS: In patients undergoing elective open abdominal aortic aneurysm repair with a goal-directed hemodynamic management, indices of sublingual or peripheral microvascular perfusion/oxygenation were globally preserved with both balanced anaesthesia and TIVA. Patients undergoing balanced anaesthesia showed microvascular recruitment at end-surgery. TRIAL REGISTRATION: NCT03510793 , https://www.clinicaltrials.gov, date of registration April 27th 2018, retrospectively registered.

Effects of short-term hyperoxia on erythropoietin levels and microcirculation in critically Ill patients: a prospective observational pilot study.

BACKGROUND: The normobaric oxygen paradox states that a short exposure to normobaric hyperoxia followed by rapid return to normoxia creates a condition of 'relative hypoxia' which stimulates erythropoietin (EPO) production. Alterations in glutathione and reactive oxygen species (ROS) may be involved in this process. We tested the effects of short-term hyperoxia on EPO levels and the microcirculation in critically ill patients. METHODS: In this prospective, observational study, 20 hemodynamically stable, mechanically ventilated patients with inspired oxygen concentration (FiO2) ≤0.5 and PaO2/FiO2 ≥ 200 mmHg underwent a 2-hour exposure to hyperoxia (FiO2 1.0). A further 20 patients acted as controls. Serum EPO was measured at baseline, 24 h and 48 h. Serum glutathione (antioxidant) and ROS levels were assessed at baseline (t0), after 2 h of hyperoxia (t1) and 2 h after returning to their baseline FiO2 (t2). The microvascular response to hyperoxia was assessed using sublingual sidestream dark field videomicroscopy and thenar near-infrared spectroscopy with a vascular occlusion test. RESULTS: EPO increased within 48 h in patients exposed to hyperoxia from 16.1 [7.4-20.2] to 22.9 [14.1-37.2] IU/L (p = 0.022). Serum ROS transiently increased at t1, and glutathione increased at t2. Early reductions in microvascular density and perfusion were seen during hyperoxia (perfused small vessel density: 85% [95% confidence interval 79-90] of baseline). The response after 2 h of hyperoxia exposure was heterogeneous. Microvascular perfusion/density normalized upon returning to baseline FiO2. CONCLUSIONS: A two-hour exposure to hyperoxia in critically ill patients was associated with a slight increase in EPO levels within 48 h. Adequately controlled studies are needed to confirm the effect of short-term hyperoxia on erythropoiesis. TRIAL REGISTRATION: ClinicalTrials.gov ( www.clinicaltrials.gov ), NCT02481843 , registered 15th June 2015, retrospectively registered.

Impact of microcirculatory video quality on the evaluation of sublingual microcirculation in critically ill patients.

We aimed to assess the impact of image quality on microcirculatory evaluation with sidestream dark-field (SDF) videomicroscopy in critically ill patients and explore factors associated with low video quality. This was a retrospective analysis of a single-centre prospective observational study. Videos of the sublingual microcirculation were recorded using SDF videomicroscopy in 100 adult patients within 12 h from admittance to the intensive care unit and every 24 h until discharge/death. Parameters of vessel density and perfusion were calculated offline for small vessels. For all videos, a quality score (-12 = unacceptable, 1 = suboptimal, 2 = optimal) was assigned for brightness, focus, content, stability, pressure and duration. Videos with a total score ≤8 were deemed as unacceptable. A total of 2455 videos (853 triplets) was analysed. Quality was acceptable in 56 % of videos. Lower quality was associated with worse microvascular density and perfusion. Unreliable triplets (≥1 unacceptable or missing video, 65 % of total) showed lower vessel density, worse perfusion and higher flow heterogeneity as compared to reliable triplets (p < 0.001). Quality was higher among triplets collected by an extensively-experienced investigator or in patients receiving sedation or mechanical ventilation. Perfused vessel density was higher in patients with Glasgow Coma Scale (GCS) ≤8 (18.9 ± 4.5 vs. 17.0 ± 3.9 mm/mm2 in those with GCS >8, p < 0.001) or requiring mechanical ventilation (18.0 ± 4.5 vs. 17.2 ± 3.8 mm/mm2 in not mechanically ventilated patients, p = 0.059). We concluded that SDF video quality depends on both the operator's experience and patient's cooperation. Low-quality videos may produce spurious data, leading to an overestimation of microvascular alterations.

Near-infrared spectroscopy for assessing tissue oxygenation and microvascular reactivity in critically ill patients: a prospective observational study.

BACKGROUND: Impaired microcirculatory perfusion and tissue oxygenation during critical illness are associated with adverse outcome. The aim of this study was to detect alterations in tissue oxygenation or microvascular reactivity and their ability to predict outcome in critically ill patients using thenar near-infrared spectroscopy (NIRS) with a vascular occlusion test (VOT). METHODS: Prospective observational study in critically ill adults admitted to a 12-bed intensive care unit (ICU) of a University Hospital. NIRS with a VOT (using a 40 % tissue oxygen saturation (StO2) target) was applied daily until discharge from the ICU or death. A group of healthy volunteers were evaluated in a single session. During occlusion, StO2 downslope was measured separately for the first (downslope 1) and last part (downslope 2) of the desaturation curve. The difference between downslope 2 and 1 was calculated (delta-downslope). The upslope and area of the hyperaemic phase (receive operating characteristic (ROC) area under the curve (AUC) of StO2) were calculated, reflecting microvascular reactivity. Outcomes were ICU and 90-day mortality. RESULTS: Patients (n = 89) had altered downslopes and upslopes compared to healthy volunteers (n = 27). Mean delta-downslope was higher in ICU non-survivors (2.8 (0.4, 3.8) %/minute versus 0.4 (-0.8, 1.8) in survivors, p = 0.004) and discriminated 90-day mortality (ROC AUC 0.72 (95 % confidence interval 0.59, 0.84)). ICU non-survivors had lower mean upslope (141 (75, 193) %/minute versus 185 (143, 217) in survivors, p = 0.016) and AUC StO2 (7.9 (4.3, 12.6) versus 14.5 (11.2, 21.3), p = 0.001). Upslope and AUC StO2 on admission were significant although weak predictors of 90-day mortality (ROC AUC = 0.68 (0.54, 0.82) and 0.70 (0.58, 0.82), respectively). AUC StO2 ≤ 6.65 (1st quartile) on admission was independently associated with higher 90-day mortality (hazard ratio 7.964 (95 % CI 2.211, 28.686)). The lowest upslope in the ICU was independently associated with survival after ICU discharge (odds ratio 0.970 (95 % CI 0.945, 0.996)). CONCLUSIONS: In critically ill patients, NIRS with a VOT enables identification of alterations in tissue oxygen extraction capacity and microvascular reactivity that can predict mortality. TRIAL REGISTRATION: NCT02649088, www.clinicaltrials.gov , date of registration 23rd December 2015, retrospectively registered.

Microcirculatory effects of the transfusion of leukodepleted or non-leukodepleted red blood cells in patients with sepsis: a pilot study.

INTRODUCTION: Microvascular alterations impair tissue oxygenation during sepsis. A red blood cell (RBC) transfusion increases oxygen (O2) delivery but rarely improves tissue O2 uptake in patients with sepsis. Possible causes include RBC alterations due to prolonged storage or residual leukocyte-derived inflammatory mediators. The aim of this study was to compare the effects of two types of transfused RBCs on microcirculation in patients with sepsis. METHODS: In a prospective randomized trial, 20 patients with sepsis were divided into two separate groups and received either non-leukodepleted (n = 10) or leukodepleted (n = 10) RBC transfusions. Microvascular density and perfusion were assessed with sidestream dark field (SDF) imaging sublingually, before and 1 hour after transfusions. Thenar tissue O2 saturation (StO2) and tissue hemoglobin index (THI) were determined with near-infrared spectroscopy, and a vascular occlusion test was performed. The microcirculatory perfused boundary region was assessed in SDF images as an index of glycocalyx damage, and glycocalyx compounds (syndecan-1, hyaluronan, and heparan sulfate) were measured in the serum. RESULTS: No differences were observed in microvascular parameters at baseline and after transfusion between the groups, except for the proportion of perfused vessels (PPV) and blood flow velocity, which were higher after transfusion in the leukodepleted group. Microvascular flow index in small vessels (MFI) and blood flow velocity exhibited different responses to transfusion between the two groups (P = 0.03 and P = 0.04, respectively), with a positive effect of leukodepleted RBCs. When within-group changes were examined, microcirculatory improvement was observed only in patients who received leukodepleted RBC transfusion as suggested by the increase in De Backer score (P = 0.02), perfused vessel density (P = 0.04), PPV (P = 0.01), and MFI (P = 0.04). Blood flow velocity decreased in the non-leukodepleted group (P = 0.03). THI and StO2 upslope increased in both groups. StO2 and StO2 downslope increased in patients who received non-leukodepleted RBC transfusions. Syndecan-1 increased after the transfusion of non-leukodepleted RBCs (P = 0.03). CONCLUSIONS: This study does not show a clear superiority of leukodepleted over non-leukodepleted RBC transfusions on microvascular perfusion in patients with sepsis, although it suggests a more favorable effect of leukodepleted RBCs on microcirculatory convective flow. Further studies are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01584999.

Alteration of the sublingual microvascular glycocalyx in critically ill patients.

Glycocalyx degradation may contribute to microvascular dysfunction and tissue hypoperfusion during systemic inflammation and sepsis. In this observational study we evaluated the alteration of the sublingual microvascular glycocalyx in 16 healthy volunteers and 50 critically ill patients. Sidestream Dark Field images of the sublingual microcirculation were automatically analyzed by dedicated software. The Perfused Boundary Region (PBR) was calculated as the dimensions of the permeable part of the glycocalyx allowing the penetration of circulating red blood cells, providing an index of glycocalyx damage. The PBR was increased in ICU patients compared to healthy controls (2.7 [2.59-2.88] vs. 2.46 [2.37-2.59]µm, p<0.0001) and tended to be higher in the 32 septic patients compared to non-septics (2.77 [2.62-2.93] vs. 2.67 [2.55-2.75]µm, p=0.05), suggesting more severe glycocalyx alterations. A PBR of 2.76 showed the best discriminative ability towards the presence of sepsis (sensitivity: 50%, specificity: 83%; area under the receiver operating characteristic curve: 0.67, 95% CI 0.52-0.82, p=0.05). A weak positive correlation was found between PBR and heart rate (r=0.3, p=0.03). In 17 septic patients, a correlation was found between PBR and number of rolling leukocytes in post-capillary venules (RL/venule) (r=0.55, p=0.02), confirming that glycocalyx shedding enhances leukocyte-endothelium interaction.

The aPC treatment improves microcirculation in severe sepsis/septic shock syndrome.

BACKGROUND: The role of recombinant activated protein C (aPC) during sepsis is still controversial. It showed anti-inflammatory effect and improved the microvascular perfusion in experimental models of septic shock. The present study was aimed at testing the hypothesis that recombinant aPC therapy improves the microcirculation during severe sepsis. METHODS: Prospective observational study on patients admitted in a 12-beds intensive care unit of a university hospital from July 2010 to December 2011, with severe sepsis and at least two sepsis-induced organ failures occurring within 48 hours from the onset of sepsis, who received an infusion of aPC (24 mcg/kg/h for 96 hours) (aPC group). Patients with contraindications to aPC administration were also monitored (no-aPC group).At baseline (before starting aPC infusion, T0), after 24 hours (T1a), 48 hours (T1b), 72 hours (T1c) and 6 hours after the end of aPC infusion (T2), general clinical and hemodynamic parameters were collected and the sublingual microcirculation was evaluated with sidestream dark-field imaging. Total vessel density (TVD), perfused vessel density (PVD), De Backer score, microvascular flow index (MFIs), the proportion of perfused vessels (PPV) and the flow heterogeneity index (HI) were calculated for small vessels. The perfused boundary region (PBR) was measured as an index of glycocalyx damage. Variables were compared between time points and groups using non parametric or parametric statistical tests, as appropriate. RESULTS: In the 13 aPC patients mean arterial pressure (MAP), base excess, lactate, PaO2/FiO2 and the Sequential Organ Failure Assessment (SOFA) score significantly improved over time, while CI and ITBVI did not change. MFIs, TVD, PVD, PPV significantly increased over time and the HI decreased (p < 0.05 in all cases), while the PBR did not change. No-aPC patients (n = 9) did not show any change in the microcirculation over time. A positive correlation was found between MFIs and MAP. TVD, PVD and De Backer score negatively correlated with norepinephrine dose, and the SOFA score negatively correlated with MFIs, TVD and PVD. CONCLUSIONS: aPC significantly improves the microcirculation in patients with severe sepsis/septic shock. TRIAL REGISTRATION: NCT01806428.

Microcirculation-guided resuscitation in sepsis: the next frontier?

Microcirculatory dysfunction plays a key role in the pathogenesis of tissue dysoxia and organ failure in sepsis. Sublingual videomicroscopy techniques enable the real-time non-invasive assessment of microvascular blood flow. Alterations in sublingual microvascular perfusion were detected during sepsis and are associated with poor outcome. More importantly, sublingual videomicroscopy allowed to explore the effects of commonly applied resuscitative treatments in septic shock, such as fluids, vasopressors and inotropes, and showed that the optimization of macro-hemodynamic parameters may not be accompanied by an improvement in microvascular perfusion. This loss of "hemodynamic coherence," i.e., the concordance between the response of the macrocirculation and the microcirculation, advocates for the integration of microvascular monitoring in the management of septic patients. Nonetheless, important barriers remain for a widespread use of sublingual videomicroscopy in the clinical practice. In this review, we discuss the actual limitations of this technique and future developments that may allow an easier and faster evaluation of the microcirculation at the bedside, and propose a role for sublingual microvascular monitoring in guiding and titrating resuscitative therapies in sepsis.

Too much tolerance for hyperoxemia in mechanically ventilated patients with SARS-CoV-2 pneumonia? Report from an Italian intensive care unit.

Background: In COVID-19 patients requiring mechanical ventilation, the administration of high oxygen (O2) doses for prolonged time periods may be necessary. Although life-saving in most cases, O2 may exert deleterious effects if administered in excessive concentrations. We aimed to describe the prevalence of hyperoxemia and excessive O2 administration in mechanically ventilated patients with SARS-CoV-2 pneumonia and determine whether hyperoxemia is associated with mortality in the Intensive Care Unit (ICU) or the onset of ventilator-associated pneumonia (VAP). Materials and methods: Retrospective single-center study on adult patients with SARS-CoV-2 pneumonia requiring invasive mechanical ventilation for ≥48 h. Patients undergoing extracorporeal respiratory support were excluded. We calculated the excess O2 administered based on the ideal arterial O2 tension (PaO2) target of 55-80 mmHg. We defined hyperoxemia as PaO2 > 100 mmHg and hyperoxia + hyperoxemia as an inspired O2 fraction (FiO2) > 60% + PaO2 > 100 mmHg. Risk factors for ICU-mortality and VAP were assessed through multivariate analyses. Results: One hundred thirty-four patients were included. For each day of mechanical ventilation, each patient received a median excess O2 of 1,121 [829-1,449] L. Hyperoxemia was found in 38 [27-55]% of arterial blood gases, hyperoxia + hyperoxemia in 11 [5-18]% of cases. The FiO2 was not reduced in 69 [62-76]% of cases of hyperoxemia. Adjustments were made more frequently with higher PaO2 or initial FiO2 levels. ICU-mortality was 32%. VAP was diagnosed in 48.5% of patients. Hyperoxemia (OR 1.300 95% CI [1.097-1.542]), time of exposure to hyperoxemia (OR 2.758 [1.406-5.411]), hyperoxia + hyperoxemia (OR 1.144 [1.008-1.298]), and daily excess O2 (OR 1.003 [1.001-1.005]) were associated with higher risk for ICU-mortality, independently of age, Sequential Organ failure Assessment score at ICU-admission and mean PaO2/FiO2. Hyperoxemia (OR 1.033 [1.006-1.061]), time of exposure to hyperoxemia (OR 1.108 [1.018-1.206]), hyperoxia + hyperoxemia (OR 1.038 [1.003-1.075]), and daily excess O2 (OR 1.001 [1.000-1.001]) were identified as risk factors for VAP, independently of body mass index, blood transfusions, days of neuromuscular blocking agents (before VAP), prolonged prone positioning and mean PaO2/FiO2 before VAP. Conclusion: Excess O2 administration and hyperoxemia were common in mechanically ventilated patients with SARS-CoV-2 pneumonia. The exposure to hyperoxemia may be associated with ICU-mortality and greater risk for VAP.

Antibiotic Treatment of Acinetobacter baumannii Superinfection in Patients With SARS-CoV-2 Infection Admitted to Intensive Care Unit: An Observational Retrospective Study.

Introduction: In COVID-19 patients on mechanical ventilation, VAP from Acinetobacter baumannii remains a crucial risk factor for death. Antibiotic resistance represents an important problem in treating this infection. This study aims to describe the evolution of the superinfection from PDR Acinetobacter baumannii in patients with acute respiratory failure from SARS-CoV-2 infection admitted to ICU and compare the impact of two different antibiotic strategies on microbiological negativization. Methods: Single-center observational retrospective study, including patients admitted to our ICU from March 2020 to May 2021 for acute respiratory failure from SARS-CoV-2 infection who developed PDR Acinetobacter baumannii superinfection. Clinical data at ICU admission were collected, as well as the timing of isolation of Acinetobacter baumannii, its resistance profile, the site of infection, and the antibiotic therapy. Results: Of the 32 patients enrolled, 10 patients (31.2%) were treated with the combination of high-dose ampicillin/sulbactam, high-dose tigecycline, intravenous and inhaled colistin (Protocol), the other 22 (68.8%) were treated with the combination of two antibiotics (Control). Of the 10 patients in the Protocol group, 8 patients (80%) received also fosfomycin. All patients (100%) in the Protocol group had microbiological negativization, while in the Control group microbiological negativization was observed in 8 (36.4%) patients, p < 0.01. Conclusion: Our report shows microbiological negativization in all patients treated with the combination therapy of nebulized and intravenous colistin, high-dose tigecycline, and high-dose ampicillin/sulbactam. This combination of antibiotics seems to be a useful alternative when other treatments are not available or fail.

Effects of Normoxia, Hyperoxia, and Mild Hypoxia on Macro-Hemodynamics and the Skeletal Muscle Microcirculation in Anesthetised Rats.

Objectives: Excessive oxygen (O2) administration may have a negative impact on tissue perfusion by inducing vasoconstriction and oxidative stress. We aimed to evaluate the effects of different inhaled oxygen fractions (FiO2) on macro-hemodynamics and microvascular perfusion in a rat model. Methods: Isoflurane-anesthetised spontaneously breathing male Wistar rats were equipped with arterial (carotid artery) and venous (jugular vein) catheters and tracheotomy, and randomized into three groups: normoxia (FiO2 21%, n = 6), hyperoxia (FiO2 100%, n = 6) and mild hypoxia (FiO2 15%, n = 6). Euvolemia was maintained by infusing Lactate Ringer solution at 10 ml/kg/h. At hourly intervals for 4 h we collected measurements of: mean arterial pressure (MAP); stroke volume index (SVI), heart rate (HR), respiratory rate (by means of echocardiography); arterial and venous blood gases; microvascular density, and flow quality (by means of sidestream dark field videomicroscopy on the hindlimb skeletal muscle). Results: MAP and systemic vascular resistance index increased with hyperoxia and decreased with mild hypoxia (p < 0.001 in both cases, two-way analysis of variance). Hyperoxia induced a reduction in SVI, while this was increased in mild hypoxia (p = 0.002). The HR increased under hyperoxia (p < 0.05 vs. normoxia at 3 h). Cardiax index, as well as systemic O2 delivery, did not significantly vary in the three groups (p = 0.546 and p = 0.691, respectively). At 4 h, microvascular vessel surface (i.e., the percentage of tissue surface occupied by vessels) decreased by 29 ± 4% in the hyperoxia group and increased by 19 ± 7 % in mild hypoxia group (p < 0.001). Total vessel density and perfused vessel density showed similar tendencies (p = 0.003 and p = 0.005, respectively). Parameters of flow quality (microvascular flow index, percentage of perfused vessels, and flow heterogeneity index) remained stable and similar in the three groups. Conclusions: Hyperoxia induces vasoconstriction and reduction in skeletal muscle microvascular density, while mild hypoxia has an opposite effect.

Mid-Regional Proadrenomedullin (MR-proADM) and Microcirculation in Monitoring Organ Dysfunction of Critical Care Patients With Infection: A Prospective Observational Pilot Study.

Introduction: Microvascular alterations are involved in the development of organ injury in critical care patients. Mid-regional proadrenomedullin (MR-proADM) may predict organ damage and its evolution. The main objective of this study was to assess the correlation between MR-proADM and microvascular flow index (MFI) in a small cohort of 20 adult critical care patients diagnosed with infection, sepsis, or septic shock. Further objectives were to evaluate the correlation between the clearance of MR-proADM and the variables of microcirculation and between MR-proADM and the Sequential Organ Failure Assessment (SOFA) score. Materials and Methods: This is a prospective observational pilot study. Inclusion criteria: consecutive adult patients admitted to intensive care unit (ICU) for or with infection-related illness. Daily measurement of MR-proADM and calculation of the SOFA score from admission in ICU to day 5. Repeated evaluations of sublingual microcirculation, collection of clinical data, and laboratory tests. Results: Primary outcome: MR-proADM was not significantly correlated to the MFI at admission in ICU. A clearance of MR-proADM of 20% or more in the first 24 h was related to the improvement of the MFIs and MFIt [percentual variation of the MFIs + 12.35 (6.01-14.59)% vs. +2.23 (-4.45-6.01)%, p = 0.005; MFIt +9.09 (4.53-16.26)% vs. -1.43 (-4.36-3.12)%, p = 0.002]. Conclusion: This study did not support a direct correlation of MR-proADM with the MFI at admission in ICU; however, it showed a good correlation between the clearance of MR-proADM, MFI, and other microvascular variables. This study also supported the prognostic value of the marker. Adequately powered studies should be performed to confirm the findings.

Variation in the Outcome of Norepinephrine-Dependent Septic Patients After the Institution of a Patient-Tailored Therapy Protocol in an Italian Intensive Care Unit: Retrospective Observational Study.

Objective: To evaluate the outcome of patients with septic shock after the institution of a patient tailored therapy protocol in our Intensive Care Unit (ICU). Methods: Single-center retrospective observational study including 100 consecutive septic patients (≥ 16 years) requiring norepinephrine infusion, admitted to our ICU between 2018 and 2019 after the institution of a patient-tailored therapy protocol, compared with a historical control group of 100 patients admitted between 2010 and 2013 (historical controls). The patient-tailored therapy protocol included the use of IgM-enriched immunoglobulins for patients with low plasma IgM levels, blood purification strategies for patients with high plasma levels of cytokines or endotoxin, albumin correction and modulation of vasoactive agents. Clinical and therapeutic parameters were noted at the time of initiation of norepinephrine infusion and for the 1st 24 h. The primary outcome was ICU mortality. Results: ICU-mortality was lower in the patient-tailored therapy cohort as compared to historical controls (32 vs. 57%, p < 0.001). Patient-tailored therapy was associated with a lower risk of ICU-mortality even after adjusting for the main clinical severity indices (adjusted odds ratio 0.331 [95% confidence interval 0.166-0.658], p = 0.002). After propensity score matching, 48 patients in historical control group and 48 patients in the patient-tailored therapy cohort with similar general characteristics were selected. ICU-mortality was lower in the patient-tailored therapy matched subgroup as compared to historical controls (40 vs. 60%, p = 0.037). Conclusions: An individualized therapeutic approach in septic patients may be associated with a survival benefit. However, the use of an historical control group of patients admitted between 2010 and 2013 may introduce substantial bias. Further adequately designed studies are needed to demonstrate the impact of patient-tailored therapy on outcome.

Lipid metabolic signatures deviate in sepsis survivors compared to non-survivors.

Sepsis remains a major cause of death despite advances in medical care. Metabolic deregulation is an important component of the survival process. Metabolomic analysis allows profiling of critical metabolic functions with the potential to classify patient outcome. Our prospective longitudinal characterization of 33 septic and non-septic critically ill patients showed that deviations, independent of direction, in plasma levels of lipid metabolites were associated with sepsis mortality. We identified a coupling of metabolic signatures between liver and plasma of a rat sepsis model that allowed us to apply a human kinetic model of mitochondrial beta-oxidation to reveal differing enzyme concentrations for medium/short-chain hydroxyacyl-CoA dehydrogenase (elevated in survivors) and crotonase (elevated in non-survivors). These data suggest a need to monitor cellular energy metabolism beyond the available biomarkers. A loss of metabolic adaptation appears to be reflected by an inability to maintain cellular (fatty acid) metabolism within a "corridor of safety".

Relationship between norepinephrine dose, tachycardia and outcome in septic shock: A multicentre evaluation.

PURPOSE: Septic shock is associated with massive release of endogenous catecholamines. Adrenergic agents may exacerbate catecholamine toxicity and contribute to poor outcomes. We sought to determine whether an association existed between tachycardia and mortality in septic shock patients requiring norepinephrine for more than 6 h despite adequate volume resuscitation. MATERIALS AND METHODS: Multicentre retrospective observational study on 730 adult patients in septic shock consecutively admitted to eight European ICUs between 2011 and 2013. Three timepoints were selected: T1 (first hour of infusion of norepinephrine), Tpeak (time of highest dose during the first 24 h of treatment), and T24 (24-h post-T1). Binary logistic regression models were constructed for the three time-points. RESULTS: Overall ICU mortality was 38.4%. Mortality was higher in those requiring high-dose (≥0.3 mcg/kg/min) versus low-dose (<0.3 mcg/kg/min) norepinephrine at T1 (53.4% vs 30.6%; p < 0.001) and T24 (61.4% vs 20.4%; p < 0.0001). Patients requiring high-dose with concurrent tachycardia had higher mortality at T1; in the low-dose group tachycardia was not associated with mortality. Resolving tachycardia (from T1 to T24) was associated with lower mortality compared to patients where tachycardia persisted (27.8% vs 46.4%; p = 0.001). CONCLUSIONS: Use of high-dose norepinephrine and concurrent tachycardia are associated with poor outcomes in septic shock.

Association between sublingual microcirculation, tissue perfusion and organ failure in major trauma: A subgroup analysis of a prospective observational study.

INTRODUCTION: Previous studies described impaired microvascular perfusion and tissue oxygenation as reliable predictors of Multiple Organ Failure in major trauma. However, this relationship has been incompletely investigated. The objective of this analysis is to further evaluate the association between organ dysfunction and microcirculation after trauma. MATERIALS AND METHODS: This is a retrospective subgroup analysis on 28 trauma patients enrolled for the Microcirculation DAIly MONitoring in critically ill patients study (NCT 02649088). Patients were divided in two groups according with their Sequential Organ Failure Assessment (SOFA) score at day 4. At admission and every 24 hours, the sublingual microcirculation was evaluated with Sidestream Darkfield Imaging (SDF) and peripheral tissue perfusion was assessed with Near Infrared Spectroscopy (NIRS) and Vascular Occlusion Test (VOT). Simultaneously, hemodynamic, clinical/laboratory parameters and main organ supports were collected. RESULTS: Median SOFA score at Day 4 was 6.5. Accordingly, patients were divided in two groups: D4-SOFA ≤6.5 and D4-SOFA >6.5. The Length of Stay in Intensive Care was significantly higher in patients with D4-SOFA>6.5 compared to D4-SOFA≤6.5 (p = 0.013). Total Vessel Density of small vessels was significantly lower in patients with high D4-SOFA score at Day 1 (p = 0.002) and Day 2 (p = 0.006) after admission; the Perfused Vessel Density was lower in patients with high D4-SOFA score at Day 1 (p = 0.007) and Day 2 (p = 0.033). At Day 1, NIRS monitoring with VOT showed significantly faster tissue oxygen saturation downslope (p = 0.018) and slower upslope (p = 0.04) in patients with high D4-SOFA. DISCUSSION: In our cohort of major traumas, sublingual microcirculation and peripheral microvascular reactivity were significantly more impaired early after trauma in those patients who developed more severe organ dysfunctions. Our data would support the hypothesis that restoration of macrocirculation can be dissociated from restoration of peripheral and tissue perfusion, and that microvascular alterations can be associated with organ failure.

Airway pressure release ventilation during acute hypoxemic respiratory failure: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Airway pressure release ventilation (APRV) has been considered a tempting mode of ventilation during acute respiratory failure within the concept of open lung ventilation. We performed a systematic review and meta-analysis to verify whether adult patients with hypoxemic respiratory failure have a higher number of ventilator-free days at day 28 when ventilated in APRV compared to conventional ventilation strategy. Secondary outcomes were difference in PaO2/FiO2 at day 3, ICU length of stay (LOS), ICU and hospital mortality, mean arterial pressure (MAP), risk of barotrauma and level of sedation. We searched MEDLINE, Scopus and Cochrane Central Register of Controlled Trials database until December 2018. RESULTS: We considered five RCTs for the analysis enrolling a total of 330 patients. For ventilatory-free day at day 28, the overall mean difference (MD) between APRV and conventional ventilation was 6.04 days (95%CI 2.12, 9.96, p = 0.003; I2 = 65%, p = 0.02). Patients treated with APRV had a lower ICU LOS than patients treated with conventional ventilation (MD 3.94 days [95%CI 1.44, 6.45, p = 0.002; I2 = 37%, p = 0.19]) and a lower hospital mortality (RD 0.16 [95%CI 0.02, 0.29, p = 0.03; I2 = 0, p = 0.5]). PaO2/FiO2 at day 3 was not different between the two groups (MD 40.48 mmHg [95%CI - 25.78, 106.73, p = 0.23; I2 = 92%, p < 0.001]). MAP was significantly higher during APRV (MD 5 mmHg [95%CI 1.43, 8.58, p = 0.006; I2 = 0%, p = 0.92]). Then, there was no difference regarding the onset of pneumothorax under the two ventilation strategies (RR 1.94 [95%CI 0.54, 6.94, p = 0.31; I2 = 0%, p = 0.74]). ICU mortality and sedation level were not included into quantitative analysis. CONCLUSION: This study showed a higher number of ventilator-free days at 28 day and a lower hospital mortality in acute hypoxemic patients treated with APRV than conventional ventilation, without any negative hemodynamic impact or higher risk of barotrauma. However, these results need to be interpreted with caution because of the low-quality evidence supporting them and the moderate heterogeneity found. Other well-designed RCTs need to be conducted to confirm our findings.