key: cord-0329578-7pxvzrq8 authors: Tornero, C.; Pastor, E.; Garzando, M. d. M.; Orduna, J.; Forner, M. J.; Bocigas, I.; Cedeno, D.; Vallejo, R.; Staats, P.; Liebler, E. title: Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I) date: 2021-09-27 journal: nan DOI: 10.1101/2021.09.24.21264045 sha: b800e9051e17e929973706bc55e4ea6b7abba667 doc_id: 329578 cord_uid: 7pxvzrq8 Background: Severe coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various pro-inflammatory cytokines. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 (ClinicalTrials.gov identifier: NCT04368156). Methods: Participants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-minute doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events. Results: Of the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n=47; SoC, n=50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (ie, all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study. Conclusions: nVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential to be used earlier in the course of COVID-19 and possibly mitigate some of the symptoms associated with post-acute COVID-19 syndrome is warranted. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint P S , a n d E J L p a r t i c i p a t e d i n t h e a n a l y s i s a n d i n t e r p r e t a t i o n o f t h e d a t a . A l l a u t h o r s c o n t r i b u t e d t o m a n u s c r i p t r e v i s i o n , r e a d , a n d a p p r o v e d t h e s u b m i t t e d v e r s i o n a n d a g r e e t o b e a c c o u n t a b l e f o a t n o n -i n v a s i v e v a g u s n e r v e s t i m u l a t i o n ( n V N S ) c o u l d i n h i b i t t h e i n f l a m m a t o r y s i g n a l i n g p r o c e s s i n d i c a t i v e o f C O V I D -1 9 p r o g r e s s i o n a n d t e s t e d t h i s h y p o t h e s i s i n t h e f i r s t p r o s p e c t i v e r a n d o m i z e d c o n t r o l l e d s t u d y o f n V N S t h e r a p y i n p a t i e n t s w i t h C O V I D -1 9 . T h e i n f l a m m a t o r y b i o m a r k e r s C -r e a c t i v e p r o t e i n a n d p r o c a l c i t o n i n s h o w e d s i g n i f i c a n t l y g r e a t e r r e d u c t i o n s f r o m b a s e l i n e w i t h n V N S t h e r a p y t h a n w i t h t h e s t a n d a r d o f c a r e . n V N S i s e a s i l y d e p l o y a b l e t r e a t m e n t m o d a l i t y w i t h a w e l l -e s t a b l i s h e d s a f e t y a n d t o l e r a b i l i t y p r o f i l e a n d h a s m u l t i p l e m e c h a n i s m s o f a c t i o n t h a t m a y b e r e l e v a n t t o C O V I D -1 9 . T h e p o t e n t i a l b e n e f i t s o f i t s u s e i n t h i s c a p a c i t y s h o u l d b e f u r t h e r s t u d i e d . . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint A B S T R A C T B a c k g r o u n d : S e v e r e c o r o n a v i r u s d i s e a s e 2 0 1 9 ( C O V I D -1 9 ) i s c h a r a c t e r i z e d , i n p a r t , b y a n e x c e s s i v e i n f l a m m a t o r y r e s p o n s e . E v i d e n c e f r o m a n i m a l a n d h u m a n s t u d i e s s u g g e s t s t h a t v a g u s n e r v e s t i m u l a t i o n c a n l e a d t o r e d u c e d l e v e l s o f v a r i o u s p r o -i n f l a m m a t o r y c y t o k i n e s . W e c o n d u c t e d a p r o s p e c t i v e r a n d o m i z e d c o n t r o l l e d s t u d y ( S A V I O R -I ) t o a s s e s s t h e f e a s i b i l i T h e n V N S g r o u p r e c e i v e d 2 c o n s e c u t i v e 2 m i n u t e d o s e s o f n V N S 3 t i m e s d a i l y a s p r o p h y l a x i s . E f f i c a c y a n d s a f e t y w e r e e v a l u a t e d v i a t h e i n c i d e n c e o f s p e c i f i c c l i n i c a l e v e n t s , i n f l a m m a t o r y b i o m a r k e r l e v e l s , a n d t h e o c c u r r e n c e o f a d v e r s e e v e n t s . R e s u l t s : O f t h e 1 1 0 p a r t i c i p a n t s w h o w e r e e n r o l l e d a n d r a n d o m l y a s s i g n e d , 9 7 ( n V N S , n = 4 7 ; S o C , n = 5 0 ) h a d s u f f i c i e n t a v a i l a b l e d a t a a n d c o m p r i s e d t h e e v a l u a b l e p o p u l a t i o n . C -r e a c t i v e p r o t e i n ( C R P ) l e v e l s d e c r e a s e d f r o m b a s e l i n e t o a s i g n i f i c a n t l y g r e a t e r d e g r e e i n t h e n V N S g r o u p t h a n i n t h e S o C g r o u p a t d a y 5 a n d o v e r a l l ( i e , a l l p o s t b a s e l i n e d a t a p o i n t s c o l l e c t e d t h r o u g h d a y 5 , c o m b i n e d ) . P r o c a l c i t o n i n l e v e l a l s o s h o w e d s i g n i f i c a n t l y g r e a t e r d e c r e a s e s f r o m b a s e l i n e t o d a y 5 i n t h e n V N S g r o u p t h a n i n t h e S o C g r o u p . D -d i m e r l e v e l s w e r e d e c r e a s e d f r o m b a s e l i n e f o r t h e n V N S g r o u p a n d i n c r e a s e d f r o m b a s e l i n e f o r t h e S o C g r o u p a t d a y 5 a n d o v e r a l l , a l t h o u g h t h e d i f f e r e n c e b e t w e e n t h e t r e a t m e n t g r o u p s d i d n o t r e a c h s t a t i s t i c a l s i g n i f i c a n c e . N o s i g n i f i c a n t t r e a t m e n t d i f f e r e n c e s w e r e s e e n f o r c l i n i c a l r e s p i r a t o r y o u t c o m e s o r a n y o f t h e o t h e r . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint b i o c h e m i c a l m a r k e r s e v a l u a t e d . N o s e r i o u s n V N S -r e l a t e d a d v e r s e e v e n t s o c c u r r e d d u r i n g t h e s t u d y . C o n c l u s i o n s : n V N S t h e r a p y l e d t o s i g n i f i c a n t r e d u c t i o n s i n l e v e l s o f i n f l a m m a t o r y m a r k e r s , s p e c i f i c a l l y C R P a n d p r o c a l c i t o n i n . B e c a u s e n V N S h a s m u l t i p l e m e c h a n i s m s o f a c t i o n t h a t m a y b e r e l e v a n t t o C O V I D -1 9 , a d d i t i o n a l r e s e a r c h i n t o i t s p o t e n t i a l t o b e u s e d e a r l i e r i n t h e c o u r s . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted September 27, 2021. ; https://doi.org/10.1101/2021.09.24.21264045 doi: medRxiv preprint w h e r e t h e v a g u s n e r v e i s l o c a t e d ( i e , b e t w e e n t h e t r a c h e a a n d t h e s t e r n o c l e i d o m a s t o i d m u s c l e , a b o v e t h e p a l p a b l e c a r o t i d p u l s e ) . F o r p r o p h y l a c t i c t r e a t m e n t , p a r t i c i p a n t s o r h o s . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint h i g h e r i n t h e S o C g r o u p t h a n i n t h e n V N S g r o u p , b u t b a s e l i n e c h a r a c t e r i s t i c s w e r e o t h e r w i s e s i m i l a r b e t w e e n t h e g r o u p s ( T a b l e 3 ) . N o o t h e r s i g n i f i c a n t d i f f e r e n c e s w e r e d e t e c t e d b e t w e e ) . . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint t o b e p r e d i c t i v e o f t h r o m b o t i c c o m p l i c a t i o n s , c r i t i c a l i l l n e s s , a n d / o r d e a t h d u r i n g h o s p i t a l i z a t i o n f o r C O V I D -1 9 ( 3 0 ) . T o g e t h e r , r e s u l t s f r o m s e v e r a l r e c e n t s t u d i e s s u g g e s t t h a t e l e v a t i o n s i i n c o n s i s t e n c y i n t h e t i m i n g o f s u c h m e a s u r e m e n t s . I n h i n d s i g h t , w e r e c o g n i z e t h a t m e a s u r e m e n t o f o x y g e n s a t u r a t i o n i m m e d i a t e l y b e f o r e a n d i m m e d i a t e l y a f t e r n V N S a p p l i c a t i o p o i n t s . D e s p i t e t h e s e o b s t a c l e s , n V N S t h e r a p y w a s a s s o c i a t e d w i t h s i g n i f i c a n t l y g r e a t e r i m p r o v e m e n t s ( v s t h e S o C a l o n e ) i n l e v e l s o f t h e i n f l a m m a t o r y b i o m a r k e r s C R P a n d p r o c a l c i t o n i n . T h e e f f e c t s o f n V N S t h e r a p y i n p a t i e n t s w i t h C O V I D -1 9 a r e b e i n g f u r t h e r i n v e s t i g a t e d i n a n o t h e r o n g o i n g c l i n i c a l t r i a l ( S A V I O R -I I , C l i n i c a l T r i a l s . g o v I d e n t i f i e r : N C T 0 4 3 8 2 3 9 1 ) . . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint A C K N O W L E D G M E N T S S t a t i s t i c a l a n a l y s e s w e r e p e r f o r m e d b y C a n d a c e M c C l u r e , P h D , o f N o r t h A m e r i c a n S c i e n c e A s s o c i a t e s , I n c . T h e a u t h o r s a c k n o w l e d g e C h r i s C z u r a , P h D , o f C o n v e r g e n t M e d i c a l T e c h n o l o g i e s , I n c . , f o r r e v i e w o f t h e m a n u s c r i p t a n d N u r i a B a r g u e s M a r t i n o f I N C L I V A I n s t i t u t o d e I n v e s t i g a c i รณ n S a n i t a r i a f o r s t u d y s u p p o r t , s t a t i s t i c a l a s s i s t a n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention Managing the supportive care needs of those affected by COVID-19 Rapid progression to acute respiratory distress syndrome: review of current understanding of critical illness from COVID-19 infection US Food and Drug Administration . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.