Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia

 

by Chel Hee Lee, Mohammad M. Banoei, Mariam Ansari, Matthew P. Cheng, Francois Lamontagne, Donald Griesdale, David E. Lasry, Koray Demir, Vinay Dhingra, Karen C. Tran, Terry Lee, Kevin Burns, David Sweet, John Marshall, Arthur Slutsky, Srinivas Murthy…

 

Critical Care volume 28, Article number: 63 (2024) Published: 27 February 2024

 

Rationale

Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair.

Objective

To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis.

Methods

We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC–MS/MS and DI-MS/MS analytical platforms.

Results

Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms.

Conclusion

Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.

 

Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial

 

by Chevret Sylvie, Bouadma Lila, Dupuis Claire, Burdet Charles and Timsit Jean-François 

 

Annals of Intensive Care volume 13, Article number: 75 (2023)

 

Background

The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching very important difference in the effect-size. In the COVIDICUS trial, no evidence of additional benefit of high-dose dexamethasone (DXM20) was found. We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care 6 mg dose of DXM (DXMSoC).

Methods

We performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXMSoc or DXM20 in the COVIDICUS trial. The outcome was the 60 day mortality rate of DXM20 over DXMSoC, with treatment effect measured on the hazard ratio (HR) estimated from Cox model. Bayesian analyses allowed to compute the posterior probability of a more than trivial benefit (HR < 0.95), and that of a potential harm (HR > 1.05). Bayesian measures of interaction then quantified the probability of interaction (Pr Interact) that the HR of death differed across the subsets by 20%. Primary analyses used noninformative priors, centred on HR = 1.00. Sensitivity analyses used sceptical and enthusiastic priors, based on null (HR = 1.00) or benefit (HR = 0.95) effects.

Results

Overall, the posterior probability of a more than trivial benefit and potential harm was 29.0 and 51.1%, respectively. There was some evidence of treatment by subset interaction (i) according to age (Pr Interact, 84%), with a 86.5% probability of benefit in patients aged below 70 compared to 22% in those aged above 70; (ii) according to the time since symptoms onset (Pr Interact, 99%), with a 99.9% probability of a more than trivial benefit when lower than 7 days compared to a < 0.1% probability when delayed by 7 days or more; and (iii) according to use of remdesivir (Pr Interact, 91%), with a 90.1% probability of benefit in patients receiving remdesivir compared to 19.1% in those who did not.

Conclusions

In this exploratory post hoc Bayesian analysis, compared with standard-of-care DXM, high-dose DXM may benefit patients aged less than 70 years with severe ARF that occurred less than 7 days after symptoms onset. The use of remdesivir may also favour the benefit of DXM20. Further analysis is needed to confirm these findings.

Letter: High-dose intravenous vitamin C may help in cytokine storm in severe SARS-CoV-2 infection

 

Letter: High-dose intravenous vitamin C may help in cytokine storm in severe SARS-CoV-2 infection

 

by Adriana Françozo de Melo and Mauricio Homem-de-Mello 

 

Critical Care volume 24, Article number: 500 (2020) 

 

The complete mechanism of action of the SARS-CoV-2 remains unclear. The severity of the disease is probably linked to the “cytokine storm” that leads to the acute respiratory distress syndrome. Cytokine storm is an overwhelming increase of several inflammatory markers at once, and it is a cause of severity in some conditions such as sepsis, acute pancreatitis, and multiple sclerosis, among others.

These conditions, characterized by a variety of inflammatory etiologies, have the common prognostic of hemodynamic abnormalities, multiple organs failure, and high mortality rates. Treatment of cytokine storm associated syndromes usually focuses in this environment: intensive care of hemodynamic parameters, uphold of damaged organs, and supervision of coagulopathy. The main cause of the cytokine induction, however, must yet be treated and is the main reason why in bacterial sepsis antibiotics are used.

High doses of intravenous vitamin C, higher than 6 g per day (however, even 15 g/day, or more, are reported), have demonstrated efficacy in treatment of sepsis and acute pancreatitis [1, 2]. To the best of our knowledge, oral formulations cannot exert the same effects.

In parenteral administration of high doses, vitamin C may decrease several inflammatory parameters (cytokines, cellular response, and homeostatic control), already observed in human and animal models. As adverse effect, ascorbic acid may cause oxalate accumulation in the kidneys that can be prevented with the concomitant use of thiamine.

Recovery Trial [3] recently finished its dexamethasone arm in severe COVID-19 patients and has shown decrease in mortality among patients that requires mechanical ventilation and support of oxygen. We are convinced about a possible synergistic effect of vitamin C and this corticosteroid.

Recently, Dr. Carr commented [4] about a new clinical trial in development in China, using intravenous vitamin C in high dose. This trial, registered by Dr. Peng (Wuhan University), is now closed, since new severe cases became rare in Wuhan. (Confirmed by Dr. Peng by e-mail, even if in clinicaltrials.gov the status of the trial is yet as “recruiting”).

Dr. Hernández and colleagues proposed a protocol including vitamin C in high dose to be used in COVID-19 patients [5]. However, the manuscript is in Spanish, decreasing the accessibility of the information.

The protocol using intravenous high dosage of vitamin C, thiamine and a glucocorticoid (as dexamethasone) seems to be useful, not expensive, with low risk of severe adverse effects. The aim is providing further discussion about the recovery of complicated cases of cytokine storm associated to the SARS-CoV-2.

Prone positioning under VV-ECMO in SARS-CoV-2-induced acute respiratory distress syndrome

Link to article: Prone positioning under VV-ECMO in SARS-CoV-2-induced acute respiratory distress syndrome

by Bruno Garcia, Nicolas Cousin, Claire Bourel, Mercé Jourdain, Julien Poissy and Thibault Duburcq

Critical Care volume 24, Article number: 428 (2020) 14 July 2020

Background 

Infection due to severe acute respiratory coronavirus 2 (SARS-CoV-2) may lead to an atypical acute respiratory distress syndrome (ARDS) [1], requiring in the most severe cases veno-venous extracorporeal membrane oxygenation (VV-ECMO). The management of persistent severe hypoxemia under VV-ECMO requires a multi-step clinical approach including prone positioning (PP), which could improve oxygenation [2].

Methods

We performed a retrospective study of patients with SARS-CoV-2-induced ARDS submitted to PP during VV-ECMO. We aimed to describe mechanical ventilation parameters and gas exchanges before and after PP. We assess the safety of PP and compare patients with PP under ECMO (prone ECMO group) to those maintained in the supine position (supine ECMO group). Patients were treated in accordance with the recommendation guidelines on ARDS [3]. During VV-ECMO, PP was considered in case of severe hypoxemia (PaO2/FiO2 ratio below 80 mmHg) despite FDO2 and FiO2 both at 100% and in case of extensive lung consolidation (ECL) on chest imaging (> 50% of lung volume).

Results

We enrolled 208 COVID-19 patients. Among the 125 patients with ARDS, 25 (20%) required VV-ECMO, and 14 (56%) were placed at least once in PP for a total of 24 procedures with a median duration of 16 (15–17) h. The delay from ECMO implantation therapy to PP was 1.5 days [1,2,3]. The resultant changes in ventilator/ECMO settings and blood gas analysis before and after PP are displayed in Table 1. The median PaO2/FiO2 ratio improvement after PP was 28% [2–36]. High responders (increase PaO2/FiO2 ratio > 20%) were 62.5%, moderate-responders (increase PaO2/FiO2 < 20%) were 16.7%, and non-responders (decrease PaO2/FiO2) were 20.8%. We did not observe any major safety concerns but only pressure sores after 6 procedures, three minor hemorrhages at the injection cannula, and three moderate drops in VV-ECMO flow requiring fluid resuscitation. Pre-ECMO characteristics, ventilator/ECMO settings, and outcomes are exposed in Table 2. Patients in the prone ECMO group were less likely to be weaned from ECMO, and 28-day mortality rate was significantly higher.

Discussion

We report that during VV-ECMO, PP improved oxygenation without a change in respiratory system compliance and PaCO2 at constant levels of minute ventilation and sweep gas flow. This does not suggest lung recruitment by PP but rather an optimization of ventilation and perfusion matching. Three explanations could be advanced for the mortality rate in the prone ECMO group (78.6%). First, prone ECMO patients may be more severe than supine ECMO patients. As described by Gattinoni et al., worsening patients progress from type 1 to type 2 (higher percentage of non-aerated tissue) [1], which is associated with a higher mortality rate [4]. Prone ECMO patients had much more consolidations, obviously because ECL was the main indication to be prone (n = 10/14). Furthermore, prone ECMO patients need a higher respiratory rate for a higher sweep gas flow suggesting that they may be exposed to a higher mechanical power, and they possibly had also a higher dead space. Second, postmortem biopsies, performed in 6 patients with ECL in the prone ECMO group, found a fibrin exudative presence both in the alveolar spaces and bronchioles followed by a fibroblastic phase [5] and raise the question of the use of corticosteroids (only one patient in the prone ECMO group). Third, as already described by Zeng et al. [6], more than half (8/11) of the patients died from septic shock and multiple organ failure, for which ECMO may be useless.

Conclusion

Prone positioning under VV-ECMO improves oxygenation in SARS-CoV-2-induced ARDS without compromising the safety of the patients. The high mortality rate in prone ECMO patients may be explained by the greater illness severity and the lack of an immunomodulatory therapy such as corticosteroids.

Letter: Advanced respiratory monitoring in COVID-19 patients: use less PEEP!

Letter: Advanced respiratory monitoring in COVID-19 patients: use less PEEP!

by Lisanne Roesthuis, Maarten van den Berg and Hans van der Hoeven

Critical Care volume 24, Article number: 230 (2020) Published: 15 May 2020

In the majority of coronavirus disease 2019 (COVID-19) patients, respiratory mechanics is different from the “normal” acute respiratory distress syndrome (ARDS) patient. Plateau pressures and driving pressures are often low and respiratory system compliance relatively normal compared to the ARDS patient [1]. Many physicians use high positive end-expiratory pressure (PEEP) for patients with COVID-19 although the potential for recruitment is often low [1, 2]. We fear that the high compliance of the respiratory system in combination with high PEEP will lead to hyperinflation, high dead space, and potentially right ventricular failure.

We have used the following strategy for COVID-19 patients (N = 70): after intubation, immediately prone positioning for at least 3 days, using the lowest possible PEEP to obtain adequate oxygenation with FiO2 of 50%. We assessed the effects of different PEEP levels on respiratory mechanics and ventilation-perfusion mismatching.

Prolonged prone position ventilation for SARS-CoV-2 patients is feasible and effective

Prolonged prone position ventilation for SARS-CoV-2 patients is feasible and effective

by Andrea Carsetti, Agnese Damia Paciarini, Benedetto Marini, Simona Pantanetti, Erica Adrario and Abele Donati

Critical Care volume 24, Article number: 225 (2020) Published: 15 May 2020

Recently, novel coronavirus 2019 (nCOV-19) is spreading all around the world causing severe acute respiratory syndrome (SARS-CoV-2) requiring mechanical ventilation in about 5% of infected people [1, 2]. Prone position ventilation is an established method to improve oxygenation in severe acute respiratory distress syndrome (ARDS), and its application was able to reduce mortality rate [3]. Although the severity of critically ill patients with SARS-CoV-2 may require pronation [4], the huge number of patients requiring intensive care unit (ICU) admission may create management problems due to the limited number of healthcare workers compared to the number of patients. Often, sustained oxygenation improvement can only be achieved after several cycles of pronation, with a work overload for healthcare staff. To face these problems, we implemented a pronation protocol that allows to extend the time for the prone position beyond 16 h, aiming to reduce the number of pronation cycles per patient. Thus, the aim of this report was to assess the feasibility and efficacy of prone position ventilation beyond the usual 16 h...

Our recommendations for acute management of COVID-19

Our recommendations for acute management of COVID-19

by Francesco Mojoli, Silvia Mongodi, Anita Orlando, Eric Arisi, Marco Pozzi, Luca Civardi, Guido Tavazzi, Fausto Baldanti, Raffaele Bruno and Giorgio Antonio Iotti

Critical Care volume 24, Article number: 207 (2020) Published: 08 May 2020

The 2019 coronavirus disease (COVID-19) epidemic is currently spreading worldwide; in particular, Italy and our region (Lombardy) have been facing the largest European outbreak since February 21st [1]. We here share our practical clinical management suggestions, derived from the direct experience of the first 200 patients with acute respiratory failure, of which 75 were finally admitted to intensive care unit (ICU) to undergo mechanical ventilation…

Letter: Liver injury in critically ill patients with COVID-19: a case series

Letter: Liver injury in critically ill patients with COVID-19: a case series

by Filipe S. Cardoso, Rui Pereira and Nuno Germano 

Critical Care volume 24, Article number: 190 (2020) Published: 05 May 2020

Almost all reports on liver injury in patients with 2019 coronavirus disease (COVID-19) found blood liver tests to be frequently abnormal, especially in patients with more severe disease, but with substantial heterogeneity [1]. Moreover, blood liver tests’ abnormalities were frequently thought to be of doubtful clinical value.

Most studies have described blood liver tests in a single time point, usually at inclusion [2, 3]. Therefore, we used our case series of the first 20 consecutive patients with COVID-19 admitted to the intensive care unit (ICU) at Curry Cabral Hospital in Lisbon, Portugal, from March 10, 2020, onwards, to describe the temporal evolution of blood liver tests.

Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia

Soluble urokinase plasminogen activator receptor (suPAR) as an early predictor of severe respiratory failure in patients with COVID-19 pneumonia

by Nikoletta Rovina, Karolina Akinosoglou, Jesper Eugen-Olsen, Salim Hayek, Jochen Reiser and Evangelos J. Giamarellos-Bourboulis

Critical Care volume 24, Article number: 187 (2020) Published: 30 April 2020

As of April 1, 2020, 885,689 cases of infections by the novel coronavirus SARS-CoV-2 (COVID-19) have been recorded worldwide; 44,217 of them have died (https://www.worldometers.info/coronavirus). At the beginning of the illness, patients may experience low-degree fever or flu-like symptoms, but suddenly, severe respiratory failure (SRF) emerges [1]. Increased circulating levels of D-dimers [1, 2] suggest endothelial activation. Urokinase plasminogen activator receptor (uPAR) that is bound on the endothelium may be cleaved early during the disease course leading to an increase of its soluble counterpart, namely suPAR [3]. If this holds true, then suPAR may be used as an early predictor of the risk of SRF…

Shining a light on the evidence for hydroxychloroquine in SARS-CoV-2

Shining a light on the evidence for hydroxychloroquine in SARS-CoV-2

by Nicholas E. Ingraham, David Boulware, Matthew A. Sparks, Timothy Schacker, Bradley Benson, Jeffrey A. Sparks, Thomas Murray, John Connett, Jeffrey G. Chipman, Anthony Charles and Christopher J. Tignanelli

Critical Care volume 24, Article number: 182 (2020) Published: 28 April 2020

The 2020 COVID-19 pandemic has stunned the world, financial markets, and healthcare systems. Researchers are rushing to identify effective treatments while maintaining rigorous adherence to the scientific method. Clinicians are doing their best to provide evidence-based care in a setting of very little good evidence. To date, no effective treatments exist for COVID-19 management. Unfortunately, traditional and social media coupled with world leader commentary have led some to believe hydroxychloroquine offers a bona fide cure and even prevention. The purpose of this commentary is to review the medical literature related to hydroxychloroquine building on knowledge over the past 17 years since the 2003 SARS-CoV epidemic.

Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation

Facing COVID-19 in the ICU: vascular dysfunction, thrombosis, and dysregulated inflammation

Daniel E. Leisman, Clifford S. Deutschman & Matthieu Legrand 

Intensive Care Medicine (2020)Cite this article Published: 28 April 2020

 Current management guidelines for COVID-19 reflect the assumption that critically ill patients infected with SARS-CoV-2 develop acute respiratory distress syndrome (ARDS). However, emerging data and clinical reports increasingly suggest an alternative view that severe COVID-19 reflects a confluence of vascular dysfunction, thrombosis, and dysregulated inflammation…

SARS-CoV-2 viral load in sputum correlates with risk of COVID-19 progression

SARS-CoV-2 viral load in sputum correlates with risk of COVID-19 progression

by Xia Yu, Shanshan Sun, Yu Shi, Hao Wang, Ruihong Zhao and Jifang Sheng / 25d//keep unread//hide

Critical Care volume 24, Article number: 170 (2020) Published: 23 April 2020

The pandemic of coronavirus diseases 2019 (COVID-19) imposes a heavy burden on medical resources [1]. Whether there is correlation between viral load and disease severity has not been clarified. In the study, we retrospectively collected the virological data, as well as demographic, epidemiological clinical information of 92 patients with confirmed COVID-19 in a single hospital in Zhejiang Province, China. We compared the baseline viral loads between severe patients and those mild to moderate at admission and also between those developing severe disease during hospitalization and those not…

Therapeutic strategies for critically ill patients with COVID-19

Therapeutic strategies for critically ill patients with COVID-19

by Lei Li, Ranran Li, Zhixiong Wu, Xianghong Yang, Mingyan Zhao, Jiao Liu and Dechang Chen 

Annals of Intensive Care volume 10, Article number: 45 (2020)

Published: 20 April 2020

Abstract

Since the 2019 novel coronavirus disease (COVID-19) outbreak originated from Wuhan, Hubei Province, China, at the end of 2019, it has become a clinical threat to the general population worldwide. Among people infected with the novel coronavirus (2019-nCoV), the intensive management of the critically ill patients in intensive care unit (ICU) needs substantial medical resource. In the present article, we have summarized the promising drugs, adjunctive agents, respiratory supportive strategies, as well as circulation management, multiple organ function monitoring and appropriate nutritional strategies for the treatment of COVID-19 in the ICU based on the previous experience of treating other viral infections and influenza. These treatments are referable before the vaccine and specific drugs are available for COVID-19.

Letter: Critically ill SARS-CoV-2-infected patients are not stratified as sepsis by the qSOFA

Letter: Critically ill SARS-CoV-2-infected patients are not stratified as sepsis by the qSOFA

by Marion Ferreira, Timothee Blin, Nived Collercandy, Piotr Szychowiak, Pierre-François Dequin, Youenn Jouan and Antoine Guillon

Annals of Intensive Care , volume 10, Article number: 43 (2020) 

Published: 19 April 2020

The SEPSIS-3 definitions had facilitated earlier recognition of patients at risk of developing sepsis for timely management [1]. The quickSOFA (qSOFA) has emerged as a bedside clinical score to clinically categorize a septic patient. In out-of-hospital, emergency department, or general hospital ward settings, adult patients with suspected infection are likely to have poor outcomes typical of sepsis if they have at least 2 of the qSOFA criteria: respiratory rate ≥ 22/min, altered mentation, or systolic blood pressure ≤ 100 mmHg [1]. This definition has been subsequently validated in the emergency department for patients with suspected infection: for qSOFA ≤ 1 the mortality rate was 3% (95% CI 2–5%) vs 24% (95% CI 18–30%) for patients with a qSOFA ≥ 2 [2]. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes coronavirus disease 2019 (Covid-19) is a game changer. Mass ICU care and ventilatory support are needed to treat patients with Covid-19. Prompt and accurate clinical identification of SARS-CoV-2-infected patients at risk to have poor outcomes is an utmost priority. The aim of the study was to examine if the 2-point qSOFA threshold is an appropriate bedside clinical score for Covid-19 patients…