Clinical trial NCT04397172: Intensive Care Associated Complications and Outcome of Acute Respiratory Distress Syndrome Due to COVID-19
Official title: Characterization of ARDS, Critical Illness Myopathy and Their Long-term Consequences in Patients With Covid-19 Disease: Effects of Inflammation, Mitochondrial Dysfunction and Plasma Concentrations of Various Sedative Drugs
Study type: OBSERVATIONAL
Overall status: TERMINATED
Conditions: COVID
Corona Virus Infection
Sars-CoV2
Keywords: Corona
SARS-CoV2
ARDS
PICS
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2020-05-21
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The present study aims to prospectively evaluate the incidence and severity of CIM in patients with ARDS due to SARS-CoV-2.

The investigators therefore conduct a study including patients with ARDS admitted to the intensive care unit (ICU) due to the novel COVID-19 disease (SARS-CoV-2). The investigators plan to analyze 50 full data sets of ICU patients (regarding primary endpoint), out of which about 30-50% will be expected to develop CIM. There is no alternative group of patients with whom this study could be conducted.

Brief summary: COVID-19 patients with a severely symptomatic progression with development of an Acute respiratory distress syndrome (ARDS) due to SARS-CoV-2 need prolonged intensive care treatment involving pharmacological immobilization, sedation and mechanical ventilation, leaving them at a very high risk for developing Critical illness myopathy (CIM). CIM is associated with increased mortality and significant consequences for recovery and the ability to return to normal daily life. Up to date, there are no studies investigating the mid- or long-term course of the novel COVID-19 disease. The present study therefore aims to evaluate the clinical outcome of patients with ARDS due to SARS-CoV-2 with special attention to the development of CIM and its underlying causes. To provide the possibility of early diagnosis of CIM, critically ill patients will be regularly screened for muscle membrane alterations using (Muscle velocity recovery cycles) MRVC measurements.

The primary endpoint is the incidence of CIM in patients with ARDS due to SARS-CoV-2, diagnosed according to the current diagnostic criteria.

Detailed description: COVID-19 patients with a severely symptomatic progression with development of an ARDS due to SARS-CoV-2 need prolonged intensive care treatment involving pharmacological immobilization, sedation and mechanical ventilation, leaving them at a very high risk for developing CIM. CIM is associated with increased mortality and significant consequences for recovery and the ability to return to normal daily life. Up to date, there are no studies investigating the mid- or long-term course of the novel COVID-19 disease. The present study therefore aims to evaluate the clinical outcome of patients with ARDS due to SARS-CoV-2 with special attention to the development of CIM and its underlying causes. To provide the possibility of early diagnosis of CIM, critically ill patients will be regularly screened for muscle membrane alterations using MRVC measurements.

Objective:

The primary objective of this project is to prospectively evaluate the incidence and severity of CIM in patients with ARDS due to SARS-CoV-2.

The secondary objectives of this project include:

1. To assess the quality of life of patients with and without CIM after ARDS due to SARS-CoV-2.
2. To monitor changes in muscle excitability parameters in critically ill patients with ARDS due to SARS-CoV-2 in relation to a later confirmed diagnosis of CIM according to the current standards.
3. To explore underlying pathophysiological processes for CIM (mitochondrial dysfunction, medication e.g. Neuromuscular blocking agents (NMBA), sedative drugs, and metabolic (amino acids, inflammatory parameters)).

Method:

After enrolment in the study, patients will be examined for the first time within 24 hours after admission to the ICU, and follow-up visits will be performed at day 2, 5 and 10 or upon termination of therapy with NMBA, respectively. The endpoint will be at the clinical follow-up appointment.

Eligibility criteria: Inclusion Criteria:

* Informed consent as documented by a surrogate assessment by an independent physician
* Adult ICU Patients with ARDS due to SARS-CoV-2 requiring mechanical ventilation

Exclusion Criteria:

* Age \<18 years and \> 80 years
* Pregnancy and breast feeding
* The presence of pre-existing:

  * Known (at time of inclusion) Polyneuropathy,
  * Known (at time of inclusion) Guillain-Barré syndrome,
  * Known (at time of inclusion) Acute or chronic spinal cord lesion,
  * Known (at time of inclusion) Myasthenia gravis, or
  * Known (at time of inclusion) Myopathy

Primary outcomes:
measure: Short Form (36) Health Survey (SF-36)
timeFrame: 3 months
Secondary outcomes:
measure: Mortality
timeFrame: 90 days
measure: Modified Rankin Scale (mRS)
timeFrame: 90 days
measure: Duration of mechanical ventilation in days
timeFrame: 3 months
measure: Barthel Index
timeFrame: 3 months
measure: Beck's Depression Inventory II (BDI-II)
timeFrame: 3 months
measure: Essener Questionnaire for Coping with a Disease (EFK)
timeFrame: 3 months
measure: Number of patients with Critical Illness Myopathy
timeFrame: day 10
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: Inselspital Bern
Study officials:
affiliation: Universitätsklinik für Neurochirurgie und Neurologie
name: Werner Z'Graggen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Belgnaoui SM, Paz S, Hiscott J. Orchestrating the interferon antiviral response through the mitochondrial antiviral signaling (MAVS) adapter. Curr Opin Immunol. 2011 Oct;23(5):564-72. doi: 10.1016/j.coi.2011.08.001. Epub 2011 Aug 22.
citation: Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30.
citation: Dinglas VD, Aronson Friedman L, Colantuoni E, Mendez-Tellez PA, Shanholtz CB, Ciesla ND, Pronovost PJ, Needham DM. Muscle Weakness and 5-Year Survival in Acute Respiratory Distress Syndrome Survivors. Crit Care Med. 2017 Mar;45(3):446-453. doi: 10.1097/CCM.0000000000002208.
citation: De Jonghe B, Sharshar T, Lefaucheur JP, Authier FJ, Durand-Zaleski I, Boussarsar M, Cerf C, Renaud E, Mesrati F, Carlet J, Raphael JC, Outin H, Bastuji-Garin S; Groupe de Reflexion et d'Etude des Neuromyopathies en Reanimation. Paresis acquired in the intensive care unit: a prospective multicenter study. JAMA. 2002 Dec 11;288(22):2859-67. doi: 10.1001/jama.288.22.2859.
citation: de Letter MA, Schmitz PI, Visser LH, Verheul FA, Schellens RL, Op de Coul DA, van der Meche FG. Risk factors for the development of polyneuropathy and myopathy in critically ill patients. Crit Care Med. 2001 Dec;29(12):2281-6. doi: 10.1097/00003246-200112000-00008.
citation: Griffiths J, Hatch RA, Bishop J, Morgan K, Jenkinson C, Cuthbertson BH, Brett SJ. An exploration of social and economic outcome and associated health-related quality of life after critical illness in general intensive care unit survivors: a 12-month follow-up study. Crit Care. 2013 May 28;17(3):R100. doi: 10.1186/cc12745.
citation: Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D, Slutsky AS, Cheung AM; Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011 Apr 7;364(14):1293-304. doi: 10.1056/NEJMoa1011802.
citation: James MA. Use of the Medical Research Council muscle strength grading system in the upper extremity. J Hand Surg Am. 2007 Feb;32(2):154-6. doi: 10.1016/j.jhsa.2006.11.008. No abstract available.
citation: Lacomis D. Electrophysiology of neuromuscular disorders in critical illness. Muscle Nerve. 2013 Mar;47(3):452-63. doi: 10.1002/mus.23615. Epub 2013 Feb 6.
citation: Latronico N, Bolton CF. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011 Oct;10(10):931-41. doi: 10.1016/S1474-4422(11)70178-8.
citation: Liu Y, Yan LM, Wan L, Xiang TX, Le A, Liu JM, Peiris M, Poon LLM, Zhang W. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis. 2020 Jun;20(6):656-657. doi: 10.1016/S1473-3099(20)30232-2. Epub 2020 Mar 19. No abstract available.
citation: Shi CS, Qi HY, Boularan C, Huang NN, Abu-Asab M, Shelhamer JH, Kehrl JH. SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome. J Immunol. 2014 Sep 15;193(6):3080-9. doi: 10.4049/jimmunol.1303196. Epub 2014 Aug 18.
citation: Weber-Carstens S, Deja M, Koch S, Spranger J, Bubser F, Wernecke KD, Spies CD, Spuler S, Keh D. Risk factors in critical illness myopathy during the early course of critical illness: a prospective observational study. Crit Care. 2010;14(3):R119. doi: 10.1186/cc9074. Epub 2010 Jun 18.
citation: Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr;8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X. Epub 2020 Feb 18. No abstract available.
citation: Z'Graggen WJ, Brander L, Tuchscherer D, Scheidegger O, Takala J, Bostock H. Muscle membrane dysfunction in critical illness myopathy assessed by velocity recovery cycles. Clin Neurophysiol. 2011 Apr;122(4):834-41. doi: 10.1016/j.clinph.2010.09.024. Epub 2010 Nov 1.