Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

BackgroundFree hemoglobin (fHb) may induce vasoconstriction by scavenging nitric oxide. It may increase in older blood units due to storage lesions. This study evaluated whether old red blood cell transfusion increases plasma fHb in sepsis and how the microvascular response may be affected.MethodsThis is a secondary analysis of a randomized study. Twenty adult septic patients received either fresh or old (<10 or >15 days storage, respectively) RBC transfusions. fHb was measured in RBC units and in the plasma before and 1 hour after transfusion. Simultaneously, the sublingual microcirculation was assessed with sidestream-dark field imaging. The perfused boundary region was calculated as an index of glycocalyx damage. Tissue oxygen saturation (StO2) and Hb index (THI) were measured with near-infrared spectroscopy and a vascular occlusion test was performed.ResultsSimilar fHb levels were found in the supernatant of fresh and old RBC units. Despite this, plasma fHb increased in the old RBC group after transfusion (from 0.125 [0.098–0.219] mg/mL to 0.238 [0.163–0.369] mg/mL, p = 0.006). The sublingual microcirculation was unaltered in both groups, while THI increased. The change in plasma fHb was inversely correlated with the changes in total vessel density (r = -0.57 [95% confidence interval -0.82, -0.16], p = 0.008), De Backer score (r = -0.63 [95% confidence interval -0.84, -0.25], p = 0.003) and THI (r = -0.72 [95% confidence interval -0.88, -0.39], p = 0.0003).ConclusionsOld RBC transfusion was associated with an increase in plasma fHb in septic patients. Increasing plasma fHb levels were associated with decreased microvascular density.Trial RegistrationClinicalTrials.gov NCT01584999

BackgroundUntil now, the prognostic value of microcirculatory alterations in critically ill patients has been mainly evaluated in highly selected subgroups. Aim of this study is to monitor the microcirculation daily in mixed group of Intensive Care Unit (ICU)-patients and to establish the association between (the evolution of) microcirculatory alterations and outcome.MethodsThis is a prospective longitudinal observational single-centre study in adult patients admitted to a 12-bed ICU in an Italian teaching hospital. Sublingual microcirculation was evaluated daily, from admission to discharge/death, using Sidestream Dark Field imaging. Videos were analysed offline to assess flow and density variables. Laboratory and clinical data were recorded simultaneously. A priori, a Microvascular Flow Index (MFI) < 2.6 was defined as abnormal. A binary logistic regression analysis was performed to evaluate the association between microcirculatory variables and outcomes; a Kaplan–Meier survival curve was built. Outcomes were ICU and 90-day mortality.ResultsA total of 97 patients were included. An abnormal MFI was present on day 1 in 20.6%, and in 55.7% of cases during ICU admission. Patients with a baseline MFI < 2.6 had higher ICU, in-hospital and 90-day mortality (45 vs. 15.6%, p = 0.012; 55 vs. 28.6%, p = 0.035; 55 vs. 26%, p = 0.017, respectively). An independent association between baseline MFI < 2.6 and outcome was confirmed in a binary logistic analysis (odds ratio 4.594 [1.340–15.754], p = 0.015). A heart rate (HR) ≥ 90 bpm was an adjunctive predictor of mortality. However, a model with stepwise inclusion of mean arterial pressure < 65 mmHg, HR ≥ 90 bpm, lactate > 2 mmol/L and MFI < 2.6 did not detect significant differences in ICU mortality. In case an abnormal MFI was present on day 1, ICU mortality was significantly higher in comparison with patients with an abnormal MFI after day 1 (38 vs. 6%, p = 0.001), indicating a time-dependent significant difference in prognostic value.ConclusionsIn a general ICU population, an abnormal microcirculation at baseline is an independent predictor for mortality. In this setting, additional routine daily microcirculatory monitoring did not reveal extra prognostic information. Further research is needed to integrate microcirculatory monitoring in a set of commonly available hemodynamic variables.Trial registration NCT 02649088, www.clinicaltrials.gov. Date of registration: 23 December 2015, retrospectively registeredElectronic supplementary materialThe online version of this article (10.1186/s13613-018-0411-9) contains supplementary material, which is available to authorized users.

Analysis of the microcirculation is currently performed offline, is time consuming and operator dependent. The aim of this study was to assess the ability and efficiency of the automatic analysis software CytoCamTools 1.7.12 (CC) to measure microvascular parameters in comparison with Automated Vascular Analysis (AVA) software 3.2. 22 patients admitted to the cardiothoracic intensive care unit following cardiac surgery were prospectively enrolled. Sublingual microcirculatory videos were analysed using AVA and CC software. The total vessel density (TVD) for small vessels, perfused vessel density (PVD) and proportion of perfused vessels (PPV) were calculated. Blood flow was assessed using the microvascular flow index (MFI) for AVA software and the averaged perfused speed indicator (APSI) for the CC software. The duration of the analysis was also recorded. Eighty-four videos from 22 patients were analysed. The bias between TVD-CC and TVD-AVA was 2.20 mm/mm (95 % CI 1.37-3.03) with limits of agreement (LOA) of -4.39 (95 % CI -5.66 to -3.16) and 8.79 (95 % CI 7.50-10.01) mm/mm. The percentage error (PE) for TVD was ±32.2 %. TVD was positively correlated between CC and AVA (r = 0.74, p < 0.001). The bias between PVD-CC and PVD-AVA was 6.54 mm/mm (95 % CI 5.60-7.48) with LOA of -4.25 (95 % CI -8.48 to -0.02) and 17.34 (95 % CI 13.11-21.57) mm/mm. The PE for PVD was ±61.2 %. PVD was positively correlated between CC and AVA (r = 0.66, p < 0.001). The median PPV-AVA was significantly higher than the median PPV-CC [97.39 % (95.25, 100 %) vs. 81.65 % (61.97, 88.99), p < 0.0001]. MFI categories cannot estimate or predict APSI values (p = 0.45). The time required for the analysis was shorter with CC than with AVA system [2'42″ (2'12″, 3'31″) vs. 16'12″ (13'38″, 17'57″), p < 0.001]. TVD is comparable between the two softwares, although faster with CC software. The values for PVD and PPV are not interchangeable given the different approach to assess microcirculatory flow.