Shock index as predictor of massive transfusion and mortality in patients with trauma: a systematic review and meta-analysis.

BACKGROUND: Management of bleeding trauma patients is still a difficult challenge. Massive transfusion (MT) requires resources to ensure the safety and timely delivery of blood products. Early prediction of MT need may be useful to shorten the time process of blood product preparation. The primary aim of this study was to assess the accuracy of shock index to predict the need for MT in adult patients with trauma. For the same population, we also assessed the accuracy of SI to predict mortality. METHODS: This systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. We performed a systematic search on MEDLINE, Scopus, and Web of Science from inception to March 2022. Studies were included if they reported MT or mortality with SI recorded at arrival in the field or the emergency department. The risk of bias was assessed using the QUADAS-2. RESULTS: Thirty-five studies were included in the systematic review and meta-analysis, for a total of 670,728 patients. For MT the overall sensibility was 0.68 [0.57; 0.76], the overall specificity was 0.84 [0.79; 0.88] and the AUC was 0.85 [0.81; 0.88]. Positive and Negative Likelihood Ratio (LR+; LR-) were 4.24 [3.18-5.65] and 0.39 [0.29-0.52], respectively. For mortality the overall sensibility was 0.358 [0.238; 0.498] the overall specificity 0.742 [0.656; 0.813] and the AUC 0.553 (confidence region for sensitivity given specificity: [0.4014; 0.6759]; confidence region for specificity given sensitivity: [0.4799; 0.6332]). LR+ and LR- were 1.39 [1.36-1.42] and 0.87 [0.85-0.89], respectively. CONCLUSIONS: Our study demonstrated that SI may have a limited role as the sole tool to predict the need for MT in adult trauma patients. SI is not accurate to predict mortality but may have a role to identify patients with a low risk of mortality.

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.

Oxygen in the critically ill: friend or foe?

PURPOSE OF REVIEW: To examine the potential harmful effects of hyperoxia and summarize the results of most recent clinical studies evaluating oxygen therapy in critically ill patients. RECENT FINDINGS: Excessive oxygen supplementation may have detrimental pulmonary and systemic effects because of enhanced oxidative stress and inflammation. Hyperoxia-induced lung injury includes altered surfactant protein composition, reduced mucociliary clearance and histological damage, resulting in atelectasis, reduced lung compliance and increased risk of infections. Hyperoxemia causes vasoconstriction, reduction in coronary blood flow and cardiac output and may alter microvascular perfusion. Observational studies showed a close relationship between hyperoxemia and increased mortality in several subsets of critically ill patients. In absence of hypoxemia, the routine use of oxygen therapy in patients with myocardial infarction, stroke, traumatic brain injury, cardiac arrest and sepsis, showed no benefit but rather it seems to be harmful. In patients admitted to intensive care unit, a conservative oxygen therapy aimed to maintain arterial oxygenation within physiological range has been proved to be well tolerated and may improve outcome. SUMMARY: Liberal O2 use and unnecessary hyperoxia may be detrimental in critically ill patients. The current evidence supports the use of a conservative strategy in O2 therapy to avoid patient exposure to unnecessary hyperoxemia.

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.

Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial.

Importance: Despite suggestions of potential harm from unnecessary oxygen therapy, critically ill patients spend substantial periods in a hyperoxemic state. A strategy of controlled arterial oxygenation is thus rational but has not been validated in clinical practice. Objective: To assess whether a conservative protocol for oxygen supplementation could improve outcomes in patients admitted to intensive care units (ICUs). Design, Setting, and Patients: Oxygen-ICU was a single-center, open-label, randomized clinical trial conducted from March 2010 to October 2012 that included all adults admitted with an expected length of stay of 72 hours or longer to the medical-surgical ICU of Modena University Hospital, Italy. The originally planned sample size was 660 patients, but the study was stopped early due to difficulties in enrollment after inclusion of 480 patients. Interventions: Patients were randomly assigned to receive oxygen therapy to maintain Pao2 between 70 and 100 mm Hg or arterial oxyhemoglobin saturation (Spo2) between 94% and 98% (conservative group) or, according to standard ICU practice, to allow Pao2 values up to 150 mm Hg or Spo2 values between 97% and 100% (conventional control group). Main Outcomes and Measures: The primary outcome was ICU mortality. Secondary outcomes included occurrence of new organ failure and infection 48 hours or more after ICU admission. Results: A total of 434 patients (median age, 64 years; 188 [43.3%] women) received conventional (n = 218) or conservative (n = 216) oxygen therapy and were included in the modified intent-to-treat analysis. Daily time-weighted Pao2 averages during the ICU stay were significantly higher (P < .001) in the conventional group (median Pao2, 102 mm Hg [interquartile range, 88-116]) vs the conservative group (median Pao2, 87 mm Hg [interquartile range, 79-97]). Twenty-five patients in the conservative oxygen therapy group (11.6%) and 44 in the conventional oxygen therapy group (20.2%) died during their ICU stay (absolute risk reduction [ARR], 0.086 [95% CI, 0.017-0.150]; relative risk [RR], 0.57 [95% CI, 0.37-0.90]; P = .01). Occurrences were lower in the conservative oxygen therapy group for new shock episode (ARR, 0.068 [95% CI, 0.020-0.120]; RR, 0.35 [95% CI, 0.16-0.75]; P = .006) or liver failure (ARR, 0.046 [95% CI, 0.008-0.088]; RR, 0.29 [95% CI, 0.10-0.82]; P = .02) and new bloodstream infection (ARR, 0.05 [95% CI, 0.00-0.09]; RR, 0.50 [95% CI, 0.25-0.998; P = .049). Conclusions and Relevance: Among critically ill patients with an ICU length of stay of 72 hours or longer, a conservative protocol for oxygen therapy vs conventional therapy resulted in lower ICU mortality. These preliminary findings were based on unplanned early termination of the trial, and a larger multicenter trial is needed to evaluate the potential benefit of this approach. Trial Registration: clinicaltrials.gov Identifier: NCT01319643.

The role of cardiac dysfunction in multiorgan dysfunction.

PURPOSE OF REVIEW: The aim of this review was to examine the main determinants of cardiac dysfunction in critically ill patients, as well as how a reduction in cardiac performance influences other organ function. RECENT FINDINGS: Cardiac dysfunction is a frequent complication in critically ill patients and contributes to organ hypoperfusion and poor outcome. Pathophysiological determinants may include a primary ischaemia/reperfusion injury of the heart, effects of systemic inflammatory and adrenergic responses of the body to a variety of acute insults, as well as cardiovascular effects of commonly applied intensive respiratory or haemodynamic treatments. A strict connection exists between cardiac and other organ function, mediated by haemodynamic, humoral, and immune mechanisms. Heart, lungs, kidneys, and other splanchnic organs such as gut and liver influence each other function in a bidirectional way: this organ crosstalk must be regarded as a key aspect in multiorgan dysfunction. SUMMARY: The heart should never be regarded as an isolated organ. When dealing with cardiac dysfunction, clinicians must consider the underlying pathophysiology, potential myocardial depressant effects of intensive treatments, and the complex interaction with other organ function.

Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma.

Berberine (BBR) is a natural isoquinoline alkaloid with proven antiangiogenic and anticancer activities. We recently demonstrated that BBR and its synthetic derivative 13-(4-chlorophenylethyl)berberine iodide, NAX014, exert antiproliferative activity against HER2-overexpressing breast cancer cells, inducing apoptosis, modulating the expression of cell cycle checkpoint molecules involved in cell senescence, and reducing both HER2 expression and phosphorylation on tumor cells. In this study, we examined the anticancer properties of BBR and NAX014 in a transgenic mouse model which spontaneously develops HER2-positive mammary tumors. Repeated intraperitoneal injections of a safety dose (2.5mg/kg) of NAX014 delayed the development of tumors, reducing both the number and size of tumor masses. In vivo sidestream dark field videomicroscopy revealed a significant lower vessel density in mammary tumors from NAX014-treated mice in comparison with the control group. Immunohistochemical evaluation using CD34 antibody confirmed the reduced vessel density in NAX014 group. Statistically significant increase of senescence associated ß-galactosidase and p16 expression, and reduced expression of heparanase were observed in tumors from NAX014-treated mice than in tumors from control animals. Finally, NAX014 treatment decreased the level of perforine and granzyme mRNA in mammary tumors. Berberine did not show any statistically significant modulation in comparison with control mice. The results of the present study indicate that NAX014 is more effective than BBR in exerting anticancer activity delaying the development of mammary tumors in mice transgenic for the HER-2/neu oncogene. The antitumor efficacy of NAX014 is mainly related to its effect on tumor vascular network and on induction of tumor cell senescence.

Sidestream dark field videomicroscopy for in vivo evaluation of vascularization and perfusion of mammary tumours in HER2/neu transgenic mice.

Angiogenesis plays a key role in tumour growth and the formation of metastases. Angiogenesis inhibitors and antivascular agents may prove useful in the treatment of breast cancer. A comprehensive characterization of the vasculature and perfusion of mammary tumours is a prerequisite for developing new specific drugs. We used sidestream dark field videomicroscopy to evaluate in vivo the vascular network of spontaneous mammary tumours in HER2/neu transgenic mice. The tumour masses showed higher vessel density compared with the healthy mammary gland (median (interquartile range) total vessel density 16.8 (13.4-20.5) vs 9.1 (8.1-10.9) mm/mm(2), respectively; P < 0.001). Tumor vessel density was reduced in mice treated with the anti-angiogenesis agent berberine, 12.1 (10.6-13.1) mm/mm(2). Sidestream dark field imaging is a versatile technique that may be useful for understanding the role of angiogenesis in the progression of breast cancer and its relationship with outcome. It may represent a valuable tool for dynamic monitoring of the effects of new anti-angiogenesis therapies.

Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis.

INTRODUCTION: The safety of arterial hyperoxia is under increasing scrutiny. We performed a systematic review of the literature to determine whether any association exists between arterial hyperoxia and mortality in critically ill patient subsets. METHODS: Medline, Thomson Reuters Web of Science and Scopus databases were searched from inception to June 2014. Observational or interventional studies evaluating the relationship between hyperoxia (defined as a supranormal arterial O2 tension) and mortality in adult intensive care unit (ICU) patients were included. Studies primarily involving patients with exacerbations of chronic pulmonary disease, acute lung injury and perioperative administration were excluded. Adjusted odds ratio (OR) of patients exposed versus those not exposed to hyperoxia were extracted, if available. Alternatively, unadjusted outcome data were recorded. Data on patients, study characteristics and the criteria used for defining hyperoxia exposure were also extracted. Random-effects models were used for quantitative synthesis of the data, with a primary outcome of hospital mortality. RESULTS: In total 17 studies (16 observational, 1 prospective before-after) were identified in different patient categories: mechanically ventilated ICU (number of studies (k) = 4, number of participants (n) = 189,143), post-cardiac arrest (k = 6, n = 19,144), stroke (k = 2, n = 5,537), and traumatic brain injury (k = 5, n = 7,488). Different criteria were used to define hyperoxia in terms of PaO2 value (first, highest, worst, mean), time of assessment and predetermined cutoffs. Data from studies on ICU patients were not pooled because of extreme heterogeneity (inconsistency (I(2)) 96.73%). Hyperoxia was associated with increased mortality in post-cardiac arrest patients (OR = 1.42 (1.04 to 1.92) I(2) 67.73%) stroke (OR = 1.23 (1.06 to 1.43) I(2) 0%) and traumatic brain injury (OR = 1.41 (1.03 to 1.94) I(2) 64.54%). However, these results are limited by significant heterogeneity between studies. CONCLUSIONS: Hyperoxia may be associated with increased mortality in patients with stroke, traumatic brain injury and those resuscitated from cardiac arrest. However, these results are limited by the high heterogeneity of the included studies.

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.

Anesthetic management of patients with sepsis/septic shock.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, while septic shock is a subset of sepsis with persistent hypotension requiring vasopressors to maintain a mean arterial pressure (MAP) of ≥65 mmHg and having a serum lactate level of >2 mmol/L, despite adequate volume resuscitation. Sepsis and septic shock are medical emergencies and time-dependent diseases with a high mortality rate for which early identification, early antibiotic therapy, and early source control are paramount for patient outcomes. The patient may require surgical intervention or an invasive procedure aiming to control the source of infection, and the anesthesiologist has a pivotal role in all phases of patient management. During the preoperative assessment, patients should be aware of all possible organ dysfunctions, and the severity of the disease combined with the patient's physiological reserve should be carefully assessed. All possible efforts should be made to optimize conditions before surgery, especially from a hemodynamic point of view. Anesthetic agents may worsen the hemodynamics of shock patients, and the anesthesiologist must know the properties of each anesthetic agent. All possible efforts should be made to maintain organ perfusion supporting hemodynamics with fluids, vasoactive agents, and inotropes if required.

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.