Cyclosporine A prevents cardiac arrest-induced acute respiratory failure: a post-hoc analysis of the CYRUS trial

Kreitmann, Louis; Argaud, Laurent; Ovize, Michel; Cour, Martin

doi:10.1007/s00134-020-06043-0

Cited by 6 publications

(5 citation statements)

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“…In experimental models of sepsis and/or inflammationinduced acute lung injury, CsA has been consistently reported to improve lung function via mitochondrial processes, including PTP inhibition [7,8]. Even though no clinical trial has been specifically designed to investigate the potential benefits of CsA in ARF, we reported, in a post hoc analysis of the CsA in cardiac arrest resuscitation (CYRUS) trial, that CsA may dramatically limit the severity of post-cardiac arrest ARF, corroborating the abovementioned pre-clinical findings [9,10]. Encouragingly, we also observed, in a predefined ancillary study of the CYRUS trial, significantly higher total and CD4+ lymphocyte counts at 24 h after cardiac arrest in patients treated with CsA than in controls [11].…”

supporting

confidence: 82%

“…Encouragingly, we also observed, in a predefined ancillary study of the CYRUS trial, significantly higher total and CD4+ lymphocyte counts at 24 h after cardiac arrest in patients treated with CsA than in controls [11]. Importantly, no safety concerns, including an increase in nosocomial infections, were reported in trials (in which thousands of patients were included) that have tested short-term off-label CsA use, as it would be the case for COVID-19 [3,[9][10][11][12][13]]. Yet, the toxicity of CsA cannot be excluded at concentrations that may be required to inhibit SARS-CoV-2 [3][4][5][6].…”

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confidence: 52%

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Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure?

2020

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Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented number of hypoxemic pneumoniae since the first cases were diagnosed in China in December 2019. In only a few weeks, tens of thousands of patients have died of acute respiratory failure (ARF) in Europe and then in North America, according to Johns Hopkins University and Medicine Coronavirus Resource Center (https://coronavirus.jhu.edu). Numerous promising antiviral therapies against SARS-CoV-2 are being investigated with the hope of preventing both interindividual transmission and severe complications of the disease [1]. COVID-19-induced ARF is thought to be related to both direct viral pathogenicity and dysregulated inflammatory host response. Unfortunately, current treatment remains only supportive and symptomatic [2]. Therefore, there is an urgent need for effective drugs targeting this life-threatening complication, in particular, for patients developing acute respiratory distress syndrome. The best candidate drug should (1) prevent hyperinflammation-induced lung injury; (2) inactivate viral replication; (3) be widely available; (4) be safe, including when administered with other antivirals; and (5) be affordable. We speculate that cyclosporine A (CsA) might fulfill all these criteria. CsA has been used for decades to prevent organ rejection and to treat T cell-associated autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, or interstitial lung disease [3, 4]. CsA exerts its immunosuppressive and anti-inflammatory effects by

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confidence: 82%

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confidence: 52%

Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure?

2020

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“…The use of antibiotics in the patients of our study was likely related to long stay in hospital and to endotracheal intubation and no to corticosteroids or CsA administration. The low-dose and short-term schedule of CsA used in our study is unlikely to cause serious secondary effects on kidney, liver or immunity, as shown in several clinical trials using low dose and short course of CsA, which have not reported serious adverse events [41][42][43], compared to the nephrotoxicity observed in transplanted patients with a prolonged use of CsA (reviewed in [44]).…”

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confidence: 54%

Cyclosporine A plus low‐dose steroid treatment in COVID‐19 improves clinical outcomes in patients with moderate to severe disease: A pilot study

et al. 2021

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Background COVID‐19 pandemic causes high global morbidity and mortality, and better medical treatments to reduce mortality are needed. Objective To determine the added benefit of Cyclosporine‐A (CsA), to low‐dose steroid treatment, in patients with COVID‐19. Methods Open‐label, non‐randomized pilot study of patients with confirmed infection of SARS‐CoV2, hospitalized from April to May 2020 at a single center in Puebla, Mexico. Comparative treatment with steroids or CsA plus steroids. Pneumonia severity was assessed by clinical, laboratory, and lung tomography. The death rate was evaluated at 28 days. Results 209 adult patients were studied, 105 received CsA plus steroids (age 55.3 ±13.3; 69% men), and 104 steroids alone (age 54.06 ±13.8; 61% men). All patients received clarithromycin, enoxaparin, and methylprednisolone or prednisone up to 10 days. Patient´s death was associated with hypertension (RR=3.5) and diabetes (RR=2.3). Mortality was 22 and 35% for CsA and control groups (p=0.02), respectively, for all patients, and 24 and 48.5% for patients with moderate to severe disease (p=0.001). Higher cumulative clinical improvement was seen for the CsA group (Nelson Aalen curve, p=0.001, log‐rank test) in moderate to severe patients. The Cox proportional hazard analysis showed the highest HR improvement value of 2.15 (1.39‐3.34, 95%CI, p=0.0005) for CsA treatment in moderate to severe patients, and HR = 1.95 (1.35‐2.83, 95%CI, p=0.0003) for all patients. Conclusion CsA used as an adjuvant to steroid treatment for COVID‐19 patients showed to improve outcomes and reduce mortality, mainly in those with moderate to severe disease. Further investigation through controlled clinical trials is warranted.

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“…These organelles synthesize ATP, and regulate cell calcium homeostasis and cell death (28). We and others have previously highlighted the key role of mPTP opening (a mega-canal located in the inner membrane of mitochondria) in the pathophysiology of the post-CA syndrome (19–22, 29, 30). Indeed, under stress conditions (e.g., burst of reactive oxygen species and calcium overload), mPTP opening drives the uncoupling of the respiratory chain, mitochondrial matrix swelling, and efflux proapoptotic factors (28).…”

Section: Discussionmentioning

confidence: 99%

Molar Sodium Lactate Attenuates the Severity of Postcardiac Arrest Syndrome: A Preclinical Study

Stevic

Argaud

Loufouat

et al. 2021

Critical Care Medicine

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To determine whether continuous IV infusion of molar sodium lactate would limit cardiac arrest-induced neurologic injury and cardiovascular failure.DESIGN: Randomized blinded study (animal model). SETTING: University animal research facility.SUBJECTS: Twenty-four adult male "New Zealand White" rabbits. INTERVENTIONS:Anesthetized rabbits underwent 12.5 minutes of asphyxial cardiac arrest and were randomized to receive either normal saline (control group, n = 12) or molar sodium lactate (molar sodium lactate group, n = 12) at a rate of 5 mL/kg/hr during the whole 120-minute reperfusion period. MEASUREMENTS AND MAIN RESULTS:Pupillary reactivity (primary outcome), levels of S100β protein, in vitro brain mitochondria functions, cardiovascular function, and fluid balance were assessed. Molar sodium lactate reduced brain injury, with a higher proportion of animals exhibiting pupillary reactivity to light (83% vs 25% in the CTRL group, p = 0.01) and lower S100β protein levels (189 ± 42 vs 412 ± 63 pg/mL, p < 0.01) at the end of the protocol. Molar sodium lactate significantly prevented cardiac arrest-induced decrease in oxidative phosphorylation and mitochondrial calcium-retention capacity compared with controls. At 120 minutes of reperfusion, survival did not significantly differ between the groups (10/12, 83% in the molar sodium lactate group vs nine of 12, 75% in the control group; p > 0.99), but hemodynamics were significantly improved in the molar sodium lactate group compared with the control group (higher mean arterial pressure [49 ± 2 vs 29 ± 3 mm Hg; p < 0.05], higher cardiac output [108 ± 4 vs 58 ± 9 mL/min; p < 0.05], higher left ventricle surface shortening fraction [38% ± 3% vs 19% ± 3%; p < 0.05], and lower left ventricular end-diastolic pressure [3 ± 1 vs 8 ± 2 mm Hg; p < 0.01]). While fluid intake was similar in both groups, fluid balance was higher in control animals (11 ± 1 mL/kg) than that in molar sodium lactate-treated rabbits (1 ± 3 mL/kg; p < 0.01) due to lower diuresis. CONCLUSIONS: Molar sodium lactate was effective in limiting the severity of the postcardiac arrest syndrome. This preclinical study opens up new perspectives for the treatment of cardiac arrest.

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Cyclosporine A prevents cardiac arrest-induced acute respiratory failure: a post-hoc analysis of the CYRUS trial

Cited by 6 publications

References 6 publications

Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure?

Cyclosporine A: a valid candidate to treat COVID-19 patients with acute respiratory failure?

Cyclosporine A plus low‐dose steroid treatment in COVID‐19 improves clinical outcomes in patients with moderate to severe disease: A pilot study

Molar Sodium Lactate Attenuates the Severity of Postcardiac Arrest Syndrome: A Preclinical Study

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