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).

Background The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. Methods We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient’s age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. Results The median age in the sample of 7487 consecutive patients was 84 years (IQR 81–87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). Conclusion Knowledge about a patient’s frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2)

SUMMARY1. Two preparations, a segment of rat ileum and the vagally innerved guinea-pig auricles, have been used in an analysis of the responses to vagal or to electrical field stimulation.2. The responses to parasympathetic stimulation were depressed by atropine and by tetrodotoxin, and potentiated by eserine.3. Supramaximal stimulation (10-20 Hz) resulted in increased release of acetylcholine and histamine, both in rat ileum and guinea-pig auricles.4. The release of histamine after parasympathetic stimulation did not exhibit tachyphylaxis, and it was not reproduced by non-parasympathetic stimuli.5. In both preparations, atropine produced a significant, dose-related reduction of histamine measured in the bath fluid after stimulation, while eserine increased histamine output.6. A significant diminution of mast cell granules metachromasia was observed in guinea-pig auricles and in rat intestine after parasympathetic stimulation.7. The possibility is discussed that acetylcholine released by parasympathetic stimulation would in turn evoke the secretion of histamine from tissue mast cells.

The content of acetylcholine and histamine in the effluent of isolated, vagally innerved guinea-pig auricles was determined. Spontaneous or stimulation-induced overflow of acetylcholine was detected only in the presence of acetylcholinesterase inhibitors. The histamine overflow was measurable also in the absence of inhibition of cholinesterase, and neatly increased during vagal stimulation. The vagally evoked histamine overflow was blocked by atropine and potentiated by eserine. The stimulation-induced histamine overflow in the effluent is discussed, presumably assuming that acetylcholine may release histamine from cardiac histamine stores.

The effect of electrical field stimulation on mediator release from the isolated rat ileum was evaluated by recording the muscle responses and by measuring acetylcholine and histamine appearing in the perfusion fluid. In the presence of cholinesterase inhibitors, supramaximal field stimulation (10 Hz) resulted in twitch responses accompanied by an increased release of acetylcholine. The resting output of histamine was measurable also in the absence of inhibition of cholinesterases, and neatly increased during electrical stimulation. Atropine produced a dose-related decrease in the release of histamine from electrically stimulated muscle, while eserine extends the time-course of the contractile response and of the histamine release as well. The results are discussed in the context of the role ascribed to acetylcholine as a physiological modulator of histamine release.

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Following publication of the original article [1] the authors identified that the collaborators of the TOCIVID-19 investigators, Italy were only available in the supplementary file. The original article has been updated so that the collaborators are correctly acknowledged.For clarity, all collaborators are listed in this correction article.

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