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Angiotensin II infusion and markers of organ function in invasively ventilated COVID-19 patients
Alberto Zangrillo , Sergio Colombo, Anna Mara Scandroglio, Evgeny Fominskiy , Marina Pieri , Maria Grazia Calabrò , Paolo Federico Beccaria, Nicola Pasculli, Francesca Guzzo, Maria Rosa Calvi , Antonella Cipriani, Chiara Sartini, Pasquale Nardelli , Alessandro Ortalda, Gaetano Lombardi , Marianna Sartorelli, Giacomo Monti , Andrea Assanelli, Moreno Tresoldi , Lorenzo Dagna , Stefano Franchini, Ary Serpa Neto, Rinaldo Bellomo , Giovanni Landoni
Crit Care Resusc 2021; 23 (2): 215-224
- Alberto Zangrillo 1, 2
- Sergio Colombo 1
- Anna Mara Scandroglio 1
- Evgeny Fominskiy 1
- Marina Pieri 1
- Maria Grazia Calabrò 1
- Paolo Federico Beccaria 1
- Nicola Pasculli 1
- Francesca Guzzo 1
- Maria Rosa Calvi 1
- Antonella Cipriani 1
- Chiara Sartini 1
- Pasquale Nardelli 1
- Alessandro Ortalda 1
- Gaetano Lombardi 1
- Marianna Sartorelli 1
- Giacomo Monti 1
- Andrea Assanelli 3
- Moreno Tresoldi 4
- Lorenzo Dagna 2, 5
- Stefano Franchini 6
- Ary Serpa Neto 7, 8
- Rinaldo Bellomo 7, 9, 10
- Giovanni Landoni 1, 2
OBJECTIVE: The use of angiotensin II in invasively ventilated patients with coronavirus disease 2019 (COVID-19) is controversial. Its effect on organ function is unknown.
DESIGN: Prospective observational study.
SETTING: Intensive care unit (ICU) of a tertiary academic hospital in Milan, Italy.
PARTICIPANTS: Adult patients receiving mechanical ventilation due to COVID-19.
INTERVENTIONS: Use angiotensin II either as rescue vasopressor agent or as low dose vasopressor support.
MAIN OUTCOME MEASURES: Patients treated before angiotensin II was available or treated in an adjacent COVID-19 ICU served as controls. For data analysis, we applied Bayesian modelling as appropriate. We assessed the effects of angiotensin II on organ function.
RESULTS: We compared 46 patients receiving angiotensin II therapy with 53 controls. Compared with controls, angiotensin II increased the mean arterial pressure (median difference, 9.05 mmHg; 95% CI, 1.87–16.22; P = 0.013) and the Pao2
CONCLUSIONS: In ventilated patients with COVID-19, angiotensin II therapy increased blood pressure and Pao2
/Fio2 ratios, decreased the OR of liver dysfunction, and appeared to decrease the risk of RRT use in patients with abnormal baseline serum creatinine. However, all of these findings are hypothesis-generating only.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04318366.
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- mean arterial pressure and norepinephrine dose for the cardiovascular system;
- Pao2/Fio2 ratio for the respiratory system;
- urinary output, serum creatinine, and use of RRT for the renal system;
- C-reactive protein level for the inflammatory arm of the immune system;
- lactate for the metabolic system;
- elevated liver enzymes for the hepatic system;
- platelets for the coagulation and bone marrow system; and
- clinical thromboembolic complications for the coagulation system.
- Additional exploratory analyses included the following clinical outcomes:
- the composite of failure to be discharged alive from the ICU at day 28 or death;
- hospital mortality at day 28;
- duration of mechanical ventilation at day 28; and
- hospital length of stay at day 28.
Primary and key secondary outcomes were explored and assessed using a Bayesian perspective. The analysis of key outcomes was done using a Bayesian model considering a Bernoulli distribution or using a Bayesian Cox proportional hazard model, as appropriate. All models were developed using a Markov Chain Monte Carlo simulation with four chains, and considered a burn-in of 1000 iterations, with sampling from a further 10 000 iterations for each chain. To monitor convergence, trace plots and the Gelman–Rubin convergence diagnostic (Rhat) were used for all parameters. As is conventional for such analyses, results are presented as hazard ratio (HR) or OR with 95% credible interval (CrI) and as the probability of minimum clinical benefit. All models were adjusted by key prognostic variables at baseline (age, presence of diabetes, and oxygen saturation measured by pulse oximetry [Spo2]).
Hospital length of stay and duration of ventilation were assessed under the frequentist approach using subdistribution HR derived from a Fine–Gray competing risk model, with death before the event treated as competing risk and presented in cumulative incidence plots.
It was expected that the effect of angiotensin II would be influenced by the presence of renal dysfunction. Therefore, in the present study, we assessed the different effect of the drug in the subgroup of patients with abnormal serum creatinine at admission (defined as creatinine > 1.10 mg/dL in females and > 1.20 mg/dL in males). To explore the potential heterogeneity of treatment effect among these subgroups, a Bayesian binomial model was applied and the posterior distribution was sampled using Markov Chain Monte Carlo simulations. Results are displayed through the probability distribution of HR or OR for the subgroups, and as the probability of a higher benefit in a specific subgroup. Since no previous information about the impact of angiotensin II on COVID-19 is available, all analyses used non-informative flat priors, to have the posteriors completely dominated by the likelihood (reflecting the data).
Due to the nature of the study, and since the sample size was small and the number of events was low, all analyses should be considered exploratory and hypothesis-generating only. All analyses were conducted in R v.3.6.3 (R Foundation). 14
The median time from symptoms to hospital admission and ICU admission was 7.0 (IQR, 4.0–10.0 days) and 10.0 days (IQR, 7.0–14.0 days) respectively (Online Appendix, S1 table). At hospital admission, fever was present in 56.4% of patients, median Spo2 was 92% (IQR, 84–96%), and median respiratory rate was 30 breaths per minute (IQR, 25–36 breaths per minute). All characteristics were similar among the groups (Table 1 and Online Appendix, S1 table).