P ŘÍ L O H A K DI Z E R T A Č NÍ P R Á CI
V y b r a n é p u bli k a c e s I F k t é m at u di ze rt a č ní p r á c e v pl n é m t e xt u
2 0 2 1
K U R Z O V Á, Ali c e; H E S S, L a disl a v; S LÍ V A, Jiří; M Á L E K, Jiří: Ca n c ha n ges i n s ki n i m p e d a n c e b e us e d t o m o nit or s e dati o n aft er mi d a z ol a m a n d d uri n g r ec o ver y fr o m a n est hesi a ?.
P h ysi ol o gi c al R es e arc h , 2 0 2 1, 7 0 ( 2): 2 6 5-2 7 2. D OI: 1 0. 3 3 5 4 9/ p h ysi olr es. 9 3 4 6 2 1 . I F: 2. 1 3 9/ 2 0 2 1; K vartil: Q 4 /2 0 2 1 ( P h ysi ol o gy)
2 0 1 9
K U R Z O V Á, Ali c e; M Á L E K, Jiří; H E S S, La disl a v; J A Č E K, Marti n; S LÍ V A, Jiří: N o n -tr a diti o n al a d mi nistr ati o n of r e mif e nt a nil i n a n e x peri me nt al s etti n g.
P h ysi ol o gi c al R es e arc h , 2 0 1 9, 6 8 ( S u p pl. 1): S 9 7-S 1 0 3. D OI: 1 0. 3 3 5 4 9/ p h ysi olr es. 9 3 4 3 3 0 . I F: 1. 6 5 5/ 2 0 1 9; K vartil: Q 4 /2 0 1 9 ( P h ysi ol o gy)
2 0 1 6
H E S S, L a disl a v; V O T A V A, M arti n; M Á L E K, Jiří; S LÍ V A, Jiří; K U R Z O V Á, Ali ce: S e dati ve eff e cts of i ntr a n as al o x yt o ci n i n r a b bits a n d r h es us m o n ke ys.
P h ysi ol o gi c al R es e arc h , 2 0 1 6, 6 5 ( S u p pl. 4): S 4 7 3-S 4 8 0. D OI: 1 0. 3 3 5 4 9/ p h ysi olr es. 9 3 3 5 1 3 .
I F: 1. 4 6 1/ 2 0 1 6; K vartil: Q 4 /2 0 1 6 ( P h ysi ol o gy)
P H Y SI O L O GI C A L R E S E A R C H • I S S N 1 8 0 2-9 9 7 3
( o nli n e) 2 0 2 1 I nstit ut e of P h ysi ol o g y of t h e C zec h Ac a d e m y of S ci e n c es, Pr a g u e, C zec h R e p u bli c Fa x + 4 2 0 2 4 1 0 6 2 1 6 4, e -m ail: p h ysr es @ f g u.c as.c z, w w w. bi o m e d. cas.c z/ p h ysi olr es
P h ysi ol. R es. 7 0: 2 6 5 -2 7 2 , 2 0 2 1 htt ps:// d oi. or g/ 1 0. 3 3 5 4 9/ p h ysi olr es. 9 3 4 6 2 1
C a n C h a n g es i n S ki n I m p e d a n c e B e Us e d to M o nit o r S e d ati o n Aft e r Mi d a z ol a m a n d D u ri n g R e c o v e r y F r o m A n est h esi a ?
Ali c e K U R Z O V Á
1, L a disl a v H E S S
2, Ji ří S LÍ V A
3, Ji ří M Á L E K
11
D e p art m e nt of A n est h esi ol o g y a n d Criti c al C ar e M e di ci n e, T hir d F a c ult y of M e di ci n e, C h arl es U ni v ersit y i n Pr a g u e, a n d U ni v ersit y H os pit al Kr al o vs k e Vi n o hr a d y, Pr a g u e, C z e c h R e p u bli c,
2
I nstit ut e f or Cli ni c al a n d E x p eri m e nt al M e di ci n e, La b or at or y of E x p eri m ent al A n est h esi ol o g y, Pr a g u e, C z e c h R e p u bli c,
3D e p art m e nt of P h ar m a c ol o g y, T hir d F a c ult y of M e di ci n e, C h arl es U ni v ersit y i n Pr a g u e, C z e c h R e p u bli c
R e c ei v e d N o v e m b er 1 2 , 2 0 2 0 Ac c e pt e d J a n u ar y 4, 2 02 1
E p u b A h e a d of Pri nt M ar c h 8 , 2 02 1
S u m m ar y
It h a s b e e n s u g g e st e d t h at s y m p at h eti c a cti vit y, m e a s ur e d a s c h a n g e s i n el e ctri c al s ki n i m p e d a n c e ( SI), c a n b e u s e d t o a s s es s t h e a d e q u a c y of g e n er al a n e st h esi a. O ur pr o s p e cti v e st u d y i n v e sti g at e d if m e a s ur e m e nt s of s ki n i m p e d a n c e c a n d et er mi n e l e v el s of s e d ati o n i n d u c e d b y mi d a z ol a m. T w e nt y-s e v e n p ati e nt s s c h e d ul e d f or art hr o s c o p y r e q uiri n g g e n er al a n e st h e si a w er e s er v e d a s t h eir o w n c o ntr ol. T h e s e w er e bli n d e d t o t h e or d er of i nj e cti o n s b y t elli n g t h e m t h at t h e y will b e r a n d o ml y a d mi ni st er e d a pl a c e b o ( s ali n e) or s e d ati v e a g e nt. A D M 3 9 0 0 m ulti m et er w a s u s e d f or SI m e a s ur e m e nt s. T h e d e gr e e of s e d ati o n w a s m e a s ur e d u si n g t h e m o difi e d O b s er v er’ s A s s e s s m e nt of A l ert n e s s a n d S e d ati o n ( m O A A S) s c al e. R e sti n g SI v al u e s w er e n ot e d, a n d all p arti ci p a nt s w er e t h e n a d mi ni st er e d t h e pl a c e b o f oll o w e d 5 mi n l at er b y mi d a z ol a m 2 m g i. v. Fi v e mi n aft er t h at, p ati e nt s w er e a d mi ni st er e d st a n d ar d g e n er al a n e st h e si a wit h pr o p of ol , o x y g e n, nitr o u s o xi d e 6 0 %, a n d i s ofl ur a n e 1 M A C vi a a l ar y n g e al m a s k, a n d s uf e nt a nil 5 – 1 0 µ g. SI si g nifi c a ntl y i n cr e a s e d aft er a d mi ni str ati o n of mi d a z ol a m a n d i n d u cti o n of a n e st h e si a. T h er e w er e n o si g nifi c a nt diff er e n c e s b et w e e n pr e -a d mi ni str ati o n ( ba s eli n e) a n d pl a c e b o a n d e n d of s ur g er y a n d e n d of a n e st h e si a wit h cl o s e d e y e s. T h er e w er e hi g hl y si g nifi c a nt diff er e n c e s ( p < 0. 0 0 1) b et w e e n pr e-a d mi ni str ati o n v s. mi d a z ol a m, pl a c e b o v s. mi d a z ol a m, pr e -a d mi ni str ati o n v s. i n d u cti o n of a n e st h e si a.
W e f o u n d sl i g ht c orr el ati o n b et w e e n m O A A S a n d SI. T h er e w er e n o si g nifi c a nt c h a n g e s b et w e e n t h e e n d of s ur g er y a n d t h e e n d of a n e st h e si a wit h cl o s e d e y e s, b ut SI si g nifi c a ntl y d e cr e a s e d ( p < 0. 0 1) aft er e y e s o p e n e d.
K e y w or d s
A n e st h e si a • Mi d a z ol a m • S ki n i m p e d a n c e • S e d ati o n
C orr e s p o n di n g a ut h or
Jiri Sli v a, D pt. of P h ar m a c ol o g y, C h arl e s U ni v er sit y, R u s k á 8 7, 1 0 0 0 0 Pr a g u e, C z e c h R e p u bli c. E -m ail: Jiri. Sli v a @lf 3. c u ni. c z
I nt r o d u cti o n
S e d ati o n is fr e q u e ntl y us e d f or a v ari et y of pr o c e d ur es p erf or me d o utsi d e t h e o p er ati n g r o o ms b y n o n -a n est h etists. Us u all y, a n xi ol ysis is pr ef er a bl e t o s e d ati o n si n c e s e d ati o n ma y i nt erfer e wit h r e c o v er y aft er s h ort pr o c e d ur es a n d ma y bri n g t h e ris k of i n a d v ert e nt d e e p s e d ati o n wit h l oss of air wa y p at e n c y. U nf ort u n at el y, alt h o u g h a n xi ol yti c s e d ati v es ar e wi d el y us e d i n cli ni c al pr a cti c e, t h e met h o d ol o g y f or ass essi n g t h e tr e at m e nt effe ct of t h es e c o m p o u n ds h as n ot b e e n well d e v el o p e d.
Ps yc h ol o gi c al t ests li k e t h e H a milt o n A n xi et y R ati n g S c al e ( H A R S), t h e W a n g A n xi et y R ati n g S c al e ( W A R S), or t h e Z u n g S elf -R ati n g A n xi et y S c al e ( S A S) h a v e b e e n us e d t o ass ess c h a n g es i n a n xi et y, b ut t h e y wer e d e v el o p e d t o me as ur e t h e eff e ct of l o n g -t er m t h er a p y a n d ar e r at h er c u m b ers o me a n d diffi c ult t o us e i n r o uti n e cli ni c al pr a cti c e.
T ests s u c h as t h e R a ms a y s e d ati o n s c al e ( R S S), t h e Ri c h m o n d A git ati o n– S e d ati o n S c al e ( R A S S), a n d t h e O bs er v er’s Ass ess m e nt of Al ert n ess a n d S e d ati o n ( O A A S) s c al e ar e c o m m o nl y us e d i n p eri o p er ati v e
2 6 6
K ur z o v á et al. V ol. 7 0cli ni c al s etti n gs, b ut t h e y f o c us mai nl y o n t h e l e v el of s e d ati o n a n d n ot t h e l e v el of a n xi ol ysis. T h er e ar e f e w m et h o ds a v ail a bl e f or ass essi n g t h e o ns et a n d i nt e nsit y of s e d ati o n. A bis p e ctr al i n d e x ( BI S) m o nit or is c o m m o nl y us e d as a n o bj e cti v e me as ur e of t h e “al ert ” st at e, alt h o u g h m ai nl y d uri n g g e n er al a n est h esi a. A l ar g e m et a -a n al ysis c o n cl u d e d t h at its us e f or s e d ati o n was l ar g el y u nr eli a bl e ( S h ett y et al. 2 0 1 8, Z h a n g et al. 2 0 1 9) .
T h er e h a v e b e e n s e v er al st u di es d e m o nstr ati n g a c orr el ati o n b et we e n t h e l e v el of a n xi et y a n d c h a n g es i n s ki n i m p e d a n c e. C ha n g es of s ki n i m p e d a n c e wer e first us e d i n cri mi n ol o g y i n 1 8 9 7. I n 1 9 2 1 A u g ust Lars o n c o m bi n e d c h a n g es i n SI wit h c h a n g es i n h e art r at e, r es pir at or y r at e, a n d bl o o d pr ess ur e t o cr e at e a d e vi c e f or us e b y l a w e nf or c e m e nt ( M ars h 2 0 1 9, Wi d a c ki 2 0 1 5).
T his met h o d h as b e e n v ali d at e d ma n y ti m es, a n d t h es e d e vi c es , p ol y gr a p hs, ar e still us e d as “li e d et e ct ors. ” M or e r e c e ntl y, s e v er al st u di es h a v e d e m o nstr at e d a c orr el ati o n b et we e n c h a n g es i n s ki n i m p e d a n c e a n d t h e d e gr e e of s e d ati o n, t h e bis p e ctr al i n d e x, r e a cti o n t o sti m ul ati o n, p ai n, a n d m ot or a cti vit y ( C o we n et al. 2 0 1 5, Gj erst a d et al. 2 0 0 7, Wi nt er h alt er et al. 2 0 0 8, 2 0 0 9, 2 0 1 0) . A c h a n g e i n s ki n i m p e d a n c e is a c o m pl e x r es p o ns e t o s y m p at h eti c n er v o us s yst e m ( S N S) a cti vit y a n d d e p e n ds o n e m oti o n al st at es li k e f e ar, a n xi et y, a n d p ai n. S N S a cti vit y c a n b e me as ur e d usi n g s e cr eti o ns fr o m e c cri n e s we at gl a n ds. V ari o us dr u gs li k e s e d ati v es, o pi oi ds, a n d a n est h eti cs a ct t hr o u g h c e ntr al me c h a nis ms t h at d e pr ess
S N S a cti vit y, w hi c h is t h e n f oll o we d b y c h a n g es i n s ki n i m p e d a n c e ( Gj erst a d et al. 2 0 0 7, Wi nt er h alt er et al.
2 0 1 0) .
T h e pr es e nt d o u bl e -bli n d st u d y was d esi g n e d t o r efi n e t h e met h o d ol o g y f or e v al u ati n g t h e eff e ct of s e d ati v e a n d a n xiol yti c a g e nts b y ass essi n g dr u g -r el at e d S N S -me di at e d c h a n g es i n SI.
T h e pri mar y ai m of o ur st u d y was t o d et er mi n e if s ki n i m p e d a n c e c a n b e us e d as a n o bj e cti v e m e as ur e me nt of t h e l e v el of s e d ati o n c o m p ar e d t o t h e, m or e or l ess, s u bj e cti v e O A A S. T h e O A A S w as c h os e n b e c a us e t h e s c ori n g s yst e m was i niti all y i ntr o d u c e d t o ass ess s e d ati o n wit h b e n z o di a z e pi n es, w hi c h wer e us e d ( mi d a z ol a m) i n o ur st u d y. T h e O A A S c at e g ori es wer e r es p o nsi v e n ess, s p e e c h, f a ci al e x pr essi o n a n d e y e a p p e ar a n c e, a n d e a c h of t h e c at e g ori es was s c or e d o n 5 di me nsi o ns. T h e O A A S s c al e was f o u n d t o h a v e hi g h dis cri mi n at or y p o wer f or t h e diff er e nt l e v els of s e d ati o n ( C h er ni k et al. 1 9 9 0) , b ut m a y v ar y b et we e n ass ess ors.
M o difi e d O A A S ( m O A A S) ( N o n a k a et al. 2 0 1 8) was us e d i n o ur st u d y b e c a us e of b ett er r efl e cti o n of c h a n g es d uri n g d e e p l e v el of s e d ati o n a n d a n est h es i a ( T a bl e 1).
Mi d a z ol a m was us e d i n o ur tri al b e c a us e it is t h e m ost c o m m o nl y us e d dr u g t o r e d u c e a n xi et y b ef or e a n est h esi a a n d s ur g er y.
A s e c o n d ar y st u d y g o al was t o i n v esti g at e if s ki n i m p e d a n c e c a n h el p t o d et er mi n e t h e l e v el of o ns et a n d r e c o v er y fr o m g e n er al a n est h esi a.
T a bl e 1. M o difi e d O b s er v er' s A ss e s s m e nt of Al ert n e s s/ S e d ati o n S c al e ( m O A A S). A v ail a bl e vi a li c e n s e: C C B Y -N C -N D
S c o r es D es c ri pti o n
5 F ull y a wa k e. R es p o n ds r e a dil y t o n a m e s p o k e n i n n or mal t o n e 4 Dr o ws y. Let h ar gi c r es p o n ds t o n a me s p o k e n i n n or mal t o n e
3 E yes cl os e d. R es p o n ds o nl y aft er n a me is c all e d l o u dl y a n d/ or r e p e at e dl y 2 R es p o n ds o nl y aft er mil d pr o d di n g or s h a ki n g
1 D o es n ot r es p o n d t o mil d pr o d di n g or s h a ki n g 0 D o es n ot r es p o n d t o d e e p sti m ul us
M et h o ds
T h e st u d y was a p pr o v e d b y t h e Et hi cs C o m mitt e e of t h e U ni v ersit y H os pit al Kr al o vs k e Vi n o hr a d y a n d is r e gist er e d at Cli ni c al Tri als. g o v as N C T 0 3 7 9 1 4 2 4.
S u bj e cts
T h e st u d y was p erf or me d o n a d ult p ati e nts s c h e d ul e d f or k n e e art hr os c o p y u n d er g e n er al a n est h esi a.
C o ns e nt was o bt ai n e d t h e d a y b ef or e s ur g er y d uri n g t h e pr e -a n est h eti c visit. E x cl usi o n crit eri a wer e a pr e vi o us hist or y of t a ki n g dr u gs aff e cti n g m e nt al f u n cti o ns, hist or y of m e nt al ill n ess, a n i m pl a nt e d el e ctri c al d e vi c e, all er g y t o b e n z o di a z e pi n es, m y ast h e ni a gr a vis, a n A m eri c a n S o ci et y of A n est h esi ol o gists ( A S A) cl assifi c ati o n of A S A 3 or hi g h er. All p ati e nts c o ns e nt e d t o n ot us e a n y m e di c ati o n f or s e d ati o n or a n xi et y, o pi oi d a n al g esi cs, et h a n ol, a n d/ or illi cit dr u gs wit hi n 2 4 h o urs b ef or e
2 0 2 1 S ki n I m p e d a n c e D uri n g A n est h esi a
2 6 7
s ur g er y. P ati e nts wer e i nstr u ct e d t h at t h e y w o ul d b e a d mi nist er e d, i n r a n d o m or d er, a s e d ati v e a g e nt or pl a c e b o, a n d w o ul d b e o bs er v e d f or t h eir l e v el of s e d ati o n.
M e as ur e m e nts
Aft er arri v al at t h e o p er ati n g t h e at er a n d v e ni p u n ct ur e, t w o st a n d ar d A g Cl E C G el e ctr o d es ( M e di c o El e ctr o d es I nt er n ati o n al lt d.) si z e 2 7 m m x 3 5 m m wer e att a c h e d t o t h e p al m si d e of t h e s e c o n d a n d t hir d fi n g er of t h e n o n-d o mi n a nt h a n d. A D M 3 9 0 0 M ulti m et er ( M ast e c h) was us e d t o me as ur e SI. T h e d e vi c e was c o ntr oll e d a n d a p pr o v e d f or us e o n h u m a ns b y t h e D e p art m e nt of M e di c al Bi o p h ysi cs a n d Inf or mati cs of t h e T hir d F a c ult y of M e di ci n e of C h arl es U ni v ersit y.
As d es cri b e d a b o v e, t h e m o difi e d O A A S ( m O A A S) s c al e was us e d as a st a n d ar d t o ol t o me as ur e s e d ati o n l e v els. It was a d mi nist er e d at t h e s a m e ti mes as t h e SI m e as ur e m e nts wer e t a k e n. T h e p erso n pr o vi di n g t h e m O A A S ass ess m e nt was als o bli n d e d t o t h e or d er of mi d a z ol a m a n d pl a c e b o i nj e cti o n, a n d o nl y t h e a n est h esi ol o gist a d mi nist eri n g t h e i nj e cti o ns k n e w t h e or d er of dr u gs.
D at a r e c or di n g: P arti ci p a nts wer e gi v e n 1 0 mi n t o a c cli mat e t o t h e t est sit u ati o n. T h e r esti n g SI v al u e f or e a c h p ati e nt was n ot e d. D es pit e t h e i nstr u cti o ns t o t h e c o ntr ar y, all p ati e nts wer e a d mi nist er e d t h e pl a c e b o first, f oll o we d 5 mi n l at er b y mi d a z ol a m 2 m g i. v., s o t h e y c o ul d s er v e as t h eir o w n c o ntr ols. Aft er a n ot h er 5 mi n , p ati e nts wer e a d mi nist er e d st a n d ar d g e n er al a n est h esi a wit h pr o p of ol, o x y g e n, nitr o us o xi d e 6 0 %, a n d is ofl ur a n e 1 M A C ( a dj ust e d t o t h e a g e a n d B MI of t h e p ati e nt) vi a a l ar y n g e al m as k, a n d s uf e nt a nil 5 – 1 0 µ g as n e e d e d.
M o nit ori n g was r o uti n e f or t his t y p e of s ur g er y (i. e., E C G, n o n -i n v asi v e bl o o d pr ess ur e, c a p n o gr a p h y, a n d p uls e o xi m etr y). SI a n d O A A S wer e r e c or d e d at t h e e n d of t h e s ur g er y (i. e., aft er st o p pi n g t h e v ol atil e a n a est h eti c a g e nt), t h e n wit h z er o e x h al e d is ofl ur a n e (i. e., t h e e n d of a n est h esi a wit h e yes cl os e d) a n d t h e e n d of a n est h esi a wit h t h e p ati e nt’s e yes o p e n a n d v er b all y e n g a g e d.
St atisti c al a n al ysis
SI v al u es b ef or e pl a c e b o a d mi nistr ati o n ( b as eli n e), 5 mi n aft er pl a c e b o, 5 mi n aft er mi d a z ol a m, 5 mi n aft er i n d u cti o n, at t h e e n d of t h e s ur g er y, z er o e x h al e d is ofl ur a n e aft er a n est h esi a wit h cl os e d e yes, a n d aft er e y es o p e n e d wer e r e c or d e d. C h a n g es i n SI v al u es c o m p ar e d t o b as eli n e d at a w er e us e d f or a n al ys es usi n g a o n e -wa y A N O V A wit h t h e p ost -h o c T u k e y's t est. T h es e r el ati v e c h a n g es all o we d us t o c o m p ar e t h e c o urs e of
c h a n g es i n d e p e n d e ntl y of t h e a bs ol ut e v al u es. P e ars o n's c orr el ati o n c o effi ci e nts wer e us e d t o a n al y z e t h e r el ati o ns hi p b et we e n m O A A S a n d SI v al u es. P-v al u es
< 0. 0 5 wer e c o nsi d er e d st atisti c all y si g nifi c a nt.
R es ults
All 3 0 p ati e nts eli gi bl e f or t h e st u d y c o ns e nt e d, b ut b e c a us e of t w o p ost p o n e d s ur g eri es, o nl y 2 8 p ati e nts wer e a n al y z e d. T h er e wer e 1 4 me n a n d 1 4 w o me n. T h e m e a n a g e was 3 9. 8 ye ars (st a n d ar d d e vi ati o n ( S D) was 9. 3 y), t h e m e a n B MI was 2 6. 2 k g/ m2 ( S D= 4. 4 k g/ m2), a n d t h e m e a n d ur ati o n of s ur g er y was 2 5. 5 mi n.
( S D= 1 6. 5 mi n).
Pri m ar y o ut c o m e m e as ur es
SI si g nifi c a ntl y i n cr e as e d aft er a d mi nistr ati o n of mi d a z ol a m a n d i n d u cti o n of a n est h esi a, alt h o u g h t h e i nt er-i n di vi d u al b as eli n e s ki n i m p e d a n c e v al u es diff er e d gr e atl y fr o m p ati e nt t o p ati e nt. F or t his r e as o n, p er c e nt c h a n g es fr o m b as eli n e wer e us e d i nst e a d of a bs ol ut e v al u es. T h er e wer e n o si g nifi c a nt diff er e n c es b et we e n pr e -a d mi nistr ati o n vs. pl a c e b o a n d e n d of s ur g er y vs. e n d of a n est h esi a wit h cl os e d e yes. Hi g hl y si g nifi c a nt diff er e n c es wer e s e e n b et we e n t h e first t w o a n d t h e l ast m e as ur e d p oi nts (i. e., 5 mi n aft er pl a c e b o a n d 5 mi n aft er mi d a z ol a m, a n d e n d aft er a n est h esi a wit h e y es o p e n) a n d t h e f o urt h a n d fift h m e as ur e d p oi nts (i. e., at t h e e n d of s ur g er y vs. z er o e x h al e d is ofl ur a n e, e n d of a n est h esi a wit h cl os e d e yes) – p < 0. 0 0 1 f or all c o m p aris o ns.
A d diti o n al si g nifi c a nt diff er e n c es i n v ol v e d c o m p aris o n b et we e n m e as ur e me nts at 5 mi n aft er i n d u cti o n a n d 5 mi n aft er pl a c e b o ( p = 0. 0 2), a n d at t h e e n d of s ur g er y ( p= 0. 0 0 3) a n d at z er o e x h al e d is ofl ur a n e, e n d of a n est h esi a wit h e y es cl os e d ( p = 0. 0 1) ( Fi g. 1). T h er e was a sli g ht c orr el ati o n b et we e n t h e m O A A S a n d SI. T h e m O A A S d e cr e as e d fr o m a p pr o xi mat el y 5. 0 b ef or e t h e a d mi nistr ati o n of mi d a z ol a m t o 4. 2 aft er mi d a z ol a m a d mi nistr ati o n. C orr el ati o ns b et we e n r el ati v e s ki n i m p e d a n c e a n d m O A A S ar e s h o w n i n Fi g. 2. T her e was s o me g e n d er diff er e n c e i n t h e r el ati v e c h a n g es i n s ki n i m p e d a n c e. E x c e pt of C E ( p < 0. 0 5), all of t h e m wer e st atisti c all y n o n-si g nifi c a nt ( Fi g. 3).
S e c o n d ar y o ut c o m e m e as ur es
T h er e wer e n o si g nifi c a nt c h a n g es b et we e n t h e e n d of s ur g er y a n d t h e e n d of a n est h esi a wit h e y es cl os e d, b ut SI si g nifi c a ntl y d e cr e as e d ( p < 0. 0 1) aft er e yes o p e n e d.
2 6 8
K ur z o v á et al. V ol. 7 0Fi g. 1. R el ati v e c h a n g e s i n s ki n i m p e d a n c e fr o m b a s e li n e (i. e., pri or t o pl a c e b o a d mi ni str ati o n). L e g e n d: p l a c e b o - 5 mi n aft er pl a c e b o, M D Z - 5 mi n aft er mi d a z ol a m, G A - 5 mi n aft er i n d u cti o n, E O S - at t h e e n d of s ur g er y, C E - z er o e x h al e d i s ofl ur a n e, e n d of a n e st h e si a wit h e y e s cl o s e d, O E - e n d of a n e st h e si a, e y e s o p e n. B ar s r e pr e s e nt m e a n s wit h w hi s k er s s h o w i n g ± st a n d ar d err or s of m e a n s ( * * * p < 0. 0 0 1 v s. pl a c e b o, M D Z, a n d O E; * * p = 0. 0 0 3 v s. E O S; + + + p = 0. 0 1 v s. C E;
+ + p = 0. 0 2 v s. pl a c e b o)
Fi g. 2. C orr el ati o n s b et w e e n r el ati v e s ki n i m p e d a n c e a n d m O A A S. B ar s r e pr e s e nt m e a n s wit h w hi s k er s s h o wi n g ± st a n d ar d err or s of m e a n s
Fi g. 3. G e n d er diff er e n c e s r el ati v e t o c h a n g e s i n s ki n i m p e d a n c e. B ar s r e pr e s e nt m e a n s wit h w hi s k er s s h o wi n g ± st a n d ar d err or s of m e a n s (+ p =0. 0 5)
Dis c ussi o n
Ass ess m e nts of t h e d e pt h of s e d ati o n ar e us u all y d e p e n d e nt o n v er b al or m ot or r es p o ns es t o v ari o us sti m ul ati o ns a n d ar e d e p e n d e nt o n t h e s u bj e cti v e s kills of t h e ass ess or. T h e us e of sti m uli c a n p ot e nti all y r es ult i n p ati e nt r es p o ns es t h at disr u pt t h e pr o c e d ur e f or w hi c h t h e p ati e nt is s e d at e d. V ari o us o bj e cti v e met h o ds h a v e b e e n tri e d t o ass ess t h e l e v el of a n xi ol ysis a n d li g ht s e d ati o n.
T h e g o al is t o fi n d a n o bj e cti v e m e as ur e of t h e l e v el of c o ns ci o us n ess, w hi c h, if v ali d, w o ul d i m pr o v e t h e q u alit y of c o ns ci o us s e d ati o n ( C his h ol m et al. 2 0 0 6) . I d e al m o nit ori n g of s e d ati o n l e v els w o ul d h a v e s e v er al p ot e nti al a d v a nt a g es o v er o bs er v ati o n al cli ni c al s e d ati o n s c ori n g s yst e ms: it w o ul d b e o bj e cti v e, q u a ntit ati v e, e as y t o us e, fr e e of o bs er v er bi as, e c o n o mi c al, a n d n o n- i n v asi v e. O bj e cti v e m o nit ori n g us u all y us es E E G-b as e d m e as ur e me nts, w hi c h wer e d e v el o p e d mai nl y t o a v oi d
2 0 2 1 S ki n I m p e d a n c e D uri n g A n est h esi a
2 6 9
al ert n ess d uri n g g e n er al a n est h esi a. T h er e ar e s o me w or ks c o m p ari n g s u bj e cti v e a n d o bj e cti v e met h o ds li k e t h e bis p e ctr al i n d e x ( BI S) m o nit or or t h e P ati e nt St at e A n al y z er; h o we v er, f or t h e ar e a of cli ni c al i nt er est, i. e., mil d s e d ati o n, t h e y ar e n ot s uffi ci e ntl y s e nsiti v e ( C his h ol m et al. 2 0 0 6) . V er y si mil ar r es ults wer e o bt ai n e d b y H a b erl a n d et al. ( 2 0 1 1), w h o us e d BI S t o ass ess l e v els of s e d ati o n i n c hil dr e n ( H a b erl a n d et al.
2 0 1 1) . C orr el ati o ns b et w e e n BI S a n d cli ni c al o bs er v ati o ns wer e st atisti c all y si g nifi c a nt, b ut o nl y m o d er at el y s o. T h er e wer e s e v er al c hil dr e n o bs er v e d t o b e i n d e e p s e d ati o n w hil e t h e BI S m o nit or s h o we d al ert n ess. R es ults of t h e C o c hr a n e r e vi e w ( S h ett y et al.
2 0 1 8) als o f o u n d t h at BI S me as ur e m e nt s h a d littl e v al u e r el ati v e t o I C U s e d at e d p at e nts. R e c e ntl y, t w o m o nit ors f or me as ur e m e nt p ai n, d e pt h of a n al g esi a a n d a n est h esi a usi n g r el ati v e c h a n g es of SI as a p art of gl o b al c al c ul at e d s c al e e. g. N O L i n d e x ( P M D-2 0 0 T M, M e d as e ns e, R a m at G a n, Isr a el) a n d N F S C i n d e x ( S ki n C o n d u ct a n c e Al g esi met er, M e d St or m i n n o v ati o ns, Osl o, N or wa y) h as i ntr o d u c e d t o cli ni c al pr a cti c e, b ut t h e y ar e i nt e n d e d f or m o nit ori n g of r e a cti o n t o p ai n sti m ul ati o n d uri n g s ur g er y ( R o g o y o v a n d V a n e k 2 0 2 0).
O ur r es ults s h o we d t h at s ki n i m p e d a n c e c o ul d b e us e d t o m e as ur e l e v els of a n xi et y a n d s e d ati o n. C h a n g es i n s ki n i m p e d a n c e c a n pr o vi d e c o m pl e x i nf or m ati o n r e g ar di n g a n xi et y or f e ar a n d d e pr ess e d l e v els of c o ns ci o us n ess.
S y m p at h eti c a cti v ati o n b y c orti c al a n d s u b c orti c al ar e as i n t h e br ai n pr o d u c e c h a n g es i n s we at gl a n d a cti vit y, w hi c h ar e e x cl usi v el y i n n er v at e d b y t h e S N S ( Gj erst a d 2 0 1 2). T h er e is a dir e ct c orr el ati o n b et we e n e c cri n e s we at gl a n d a cti vit y a n d s ki n i m p e d a n c e ( Wi nt er h alt er et al. 2 0 0 8) . T h er e is als o a dire ct c orr el ati o n b et we e n t h e dis c h ar g e r at e d uri n g s y m p at h eti c n er v e sti m ul ati o n a n d t h e a m plit u d e of si m ult a n e o usl y m e as ur e d s ki n i m p e d a n c e c h a n g es ( B a c h 2 0 1 4). T h er e h a v e b e e n s e v er al att e m pts t o us e s ki n i m p e d a n c e t o ass ess s p e cifi c p arts of t his c o m pl e x st at e, b ut t h e r es ults wer e i n c o nsist e nt. M e as ur e m e nts of s ki n i m p e d a n c e or c o n d u ct a n c e h a v e als o b e e n us e d t o ass ess p ai n i nt e nsit y or t h e q u alit y of a n al g esi a. St or m et al. r e c o m m e n d e d usi n g s ki n c o n d u ct a n c e, i nst e a d of h e art r at e, bl o o d pr ess ur e, a n d el e ctr o e n c e p h al o gr a p hs ( E E G), as a m or e s e nsiti v e t o ol f or me as uri n g p ai n p er c e pti o n si n c e it is i n d e p e n d e nt of a n est h esi a l e v el a n d m us cl e r el a x ati o n ( St or m 2 0 0 8). C z a pli k et al. tri e d usi n g c h a n g es i n s ki n c o n d u ct a n c e as a wa y t o t ar g et a c ut e p ai n t h er a p y i n t h e p ost -a n est h esi a c ar e u nit; h o w e v er, t h e y fail e d t o fi n d a n y
l o n g-t er m c orr el ati o n b et we e n t h e n u meri c p ai n r ati n g s c al e a n d t h e n u m b er of fl u ct u ati o n i n s ki n c o n d u ct a n c e ( N F S C) ( C z a pli k et al. 2 0 1 2) . T h e y c o n cl u d e d t h at t h er e ar e ma n y ot h er f a ct ors affe cti n g SI r es ults, e. g., a n xi et y, l e v el of s e d ati o n, dis ori e nt ati o n, s hi v eri n g, et c., a n d t h at t his m et h o d w or ks b est f or s e d at e d p ati e nts. Si mil ar r es ults wer e s e e n i n ot h er st u di es. Le d o ws ki et al.
d e m o nstr at e d a hi g h c orr el ati o n b et we e n N F S C a n d p ai n r ati n gs, alt h o u g h wit h s e v er al li mit ati o ns, m ai nl y t h e f a ct t h at m a n y dr u gs us e d f or s e d ati o n a n d a n est h esi a ma y i nfl u e n c e t h e r es ult ( Le d o ws ki et al. 2 0 0 7) . I n a l at er st u d y fr o m 2 0 1 0, Le d o ws ki et al. f ail e d t o fi n d a n y c orr el ati o n b et we e n str ess h or m o n es l e v els a n d s ki n c o n d u ct a n c e ( Le d o ws ki et al. 2 0 1 0) . M or e r e c e ntl y, V al k e n b ur g et al. ( 2 0 1 2) dr e w si mil ar c o n cl usi o ns wit h i nfa nts, a n d G ü nt h er et al. f o u n d t h e s a m e wit h I C U a d ult p ati e nts ( G u nt h er et al. 2 0 1 3) . T h e l att er c o n cl u d e d t h at N F S C mi g ht b e m or e i nfl u e n c e d b y a n xi et y a n d str ess t h a n b y p ai n i nt e nsit y. T h es e fi n di n gs s u p p ort o ur o pi ni o n t h at fa ct ors r es p o nsi bl e f or s ki n i m p e d a n c e c h a n g es ar e c o m pl e x, a n d SI is pr o b a bl y b est s uit e d f or o bj e cti v e ass ess m e nt of a n xi et y a n d s e d ati o n l e v el. T h e i nt er pr et ati o n of t h e diff er e n c es b et we e n m e n a n d w o m e n ( Fi g. 3) is diffi c ult. W e c a n o nl y s p e c ul at e t h at it is a r es ult of diff er e nt s y m p at h eti c n er v e r e g ul ati o n ( Hi n oj os a-La b or d e et al. 1 9 9 9, Kitt n ar 2 0 2 0, U e n o et al.
2 0 0 3) . G e n d er diff er e n c es w er e d es cri b e d als o i n p ai n p er c e pti o n a n d t h e r e as o ns ar e pr o b a bl y m ultif a ct ori al ( R o k yt a a n d Y a ma m ot o v a 2 0 1 3).
S e v er al st u di es m e as ur e d s ki n i m p e d a n c e d uri n g a n est h esi a a n d c o m p ar e d it t o E C G m et h o ds.
Wi nt er h alt er et al. d e m o nstr at e d t h at s ki n i m p e d a n c e c orr el at e d t o t h e d e pt h of s e d ati o n d uri n g t ar g et e d - c o ntr oll e d i nf usi o n of pr o p of ol a n d was c orr el at e d wit h b ot h BI S a n d m O A A S v al u es i n 2 2 p ati e nts a n d 8 h e alt h y v ol u nt e ers. I n a s e c o n d st u d y, Wi nt er h alt er et al.
m e as ur e d s ki n i m p e d a n c e c h a n g es d uri n g a n est h esi a i n d u cti o n wit h f e nt a n yl a n d et o mi d at e a n d c o m p ar e d t h e r es ults wit h BI S v al u es. I n s pit e of usi n g diff er e nt dr u gs a n d a sli g htl y diff er e nt pr ot o c ol (i. e., c o n c e ntr ati n g m ai nl y o n t h e i n d u cti o n of a n est h esi a), t h eir r es ults c orr es p o n d wit h o ur fi n di n gs ( Wi nt er h alt er et al. 2 0 0 9, Wi nt er h alt er et al. 2 0 1 0) .
W e di d n ot c o nfir m t h e us ef ul n ess of s ki n i m p e d a n c e m e as ur e m e nts f or ass essi n g d e pt h a n d e mer g e n c e fr o m a est h esi a; h o we v er, Gj erst a d et al.
( Gj erst a d et al. 2 0 0 7) f o u n d a c orr el ati o n b et we e n N F S C a n d R es p o ns e E ntr o p y ( R E), w hi c h m e as ur es el e ctr o m y o gr a p hi c a n d el e ctr o e n c e p h al o gr a p hi c a cti vit y
2 7 0
K ur z o v á et al. V ol. 7 0fr o m el e ctr o d es pl a c e d o n t h e f or e h e a d. H o we v er, i n t his st u d y, c h a n g es i n s ki n i m p e d a n c e d uri n g e mer g e n c e fr o m a n est h esi a wer e sl o wer t h a n R E c h a n g es. I n o n e of t h eir 2 0 p ati e nts, t h e N F S C was u n c h a n g e d 1 mi n aft er e xt u b ati o n.
Li mit ati o ns
O ur st u d y h as s e v er al li mit ati o ns. T h e first is a st u d y d esi g n i n w hi c h t h e s a me p ati e nts wer e us e d f or b ot h pl a c e b o a n d a cti v e tr e at me nt. H o we v er, t h e v ari a bilit y i n a bs ol ut e v al u es of s ki n i m p e d a n c e m a d e it t h e o nl y m et h o d s uit a bl e f or t esti n g t h e differ e n c e b et we e n t h e pl a c e b o a n d a cti v e tr e at m e nt. T h e s e c o n d li mit ati o n i n v ol v e d t h e i nt er pr et ati o n of v al u es. A hi g h l e v el of i nt er-i n di vi d u al v ari a bilit y pr e v e nts t h e us e of a bs ol ut e v al u es, a n d t h e p er c e nt a g e c h a n g e o v er ti m e h a d t o b e us e d. I n t h e c o nt e xt of t h e c o m p ar a bilit y of s ki n i m p e d a n c e me as ur e m e nts, r el ati v e c h a n g es fr o m a n i n di vi d u al p ati e nt´s b as eli n e v al u e h a d t o b e us e d.
A n ot h er iss u e, w hi c h was m e nti o n e d b y s e v er al ot h er a ut h ors, i n v ol v e d mi n or differ e n c es li n k e d t o t h e el e ctr o d es, e. g., c h a n g es i n h y dr ati o n u n d er el e ctr o d es, a n a bs e n c e of s we at gl a n d a cti vit y, a n d s we at a c c u m ul ati o n u n d er el e ctr o d es d uri n g h e a v y p ers pir ati o n. F or t h e p ur p os e of o ur st u d y, t h e a d mi nistr ati o n of atr o pi n e a n d
ot h er dr u gs us e d d uri n g t h e mai nt e n a n c e of a n est h esi a a n d e mer g e n c e fr o m a n est h esi a wit h t h e or eti c al e x c e pti o n of s m all d os e of s uf e nt a nil i n all p ati e nts wer e n ot r el e v a nt t o t h e o ut c o mes, as t h e y wer e n ot us e d.
C o n cl usi o ns
C h a n g es of s ki n i m p e d a n c e c a n b e us e d as a si m pl e a n d e c o n o mi c al met h o d t o me as ur e t h e o ns et of a n xi ol ysis a n d s e d ati o n i n d u c e d b y mi d a z ol a m;
a d diti o n all y, SI c orr el at e d wit h m O A A S s c or es.
H o we v er, u ntil t his us e of SI will b e m or e a n d d e e pl y st u di e d, we c a n n ot r e c o m m e n d it f or t h e ass ess m e nt of t h e d e pt h of a n est h esi a a n d f or pr e di cti n g e m er g e n c e fr o m a n est h esi a.
C o nfli ct of I nt e r est
T h er e is n o c o nfli ct of i nt er est.
A c k n o wl e d g e me nts
T h e a ut h ors wis h t o a c k n o wl e d g e Pr of. J o z ef R osi n a, M D, P h. D., M B A fr o m t h e D e p art me nt of M e di c al Bi o p h ysi cs a n d I nf or mati cs of t h e T hir d M e di c al F a c ult y of C h arl es U ni v ersit y f or his t e c h ni c al h el p. T his w or k was s u p p ort e d b y P R O G R E S S Q 3 5.
R ef e r e n c es
B A C H D R: S y m p at h eti c n er v e a cti vit y c a n b e esti m at e d fr o m s ki n c o n d u ct a n c e r es p o ns es - a c o m m e nt o n H e n d ers o n et al. ( 2 0 1 2). N e ur oi ma g e. 8 4: 1 2 2 -1 2 3, 2 0 1 4. htt ps:// d oi. or g/ 1 0. 1 0 1 6/j. n e ur oi ma g e. 2 0 1 3. 0 8. 0 3 0
C H E R NI K D A, GI L LI N G S D, L AI N E H, H E N D L E R J, SI L V E R J M, D A VI D S O N A B, S C H W A M E M, SI E G E L J L:
V ali dit y a n d r eli a bilit y of t h e O bs er v er's Ass ess m e nt of Al ert n ess/ S e d ati o n S c al e: st u d y wit h i ntr a v e n o us mi d a z ol a m. J Cli n Ps yc h o p h ar m a c ol 1 0: 2 4 4 -2 5 1, 1 9 9 0. htt ps:// d oi. or g/ 1 0. 1 0 9 7/ 0 0 0 0 4 7 1 4 -1 9 9 0 0 8 0 0 0 -0 0 0 0 3 C HI S H O L M CJ, Z U RI C A J, MI R O N O V D, S CI A C C A R R, O R N S T EI N E, H E Y E R EJ: C o m p aris o n of
el e ctr o p h ysi ol o gi c m o nit ors wit h cli ni c al ass ess m e nt of l e v el of s e d ati o n. M a y o Cli n Pr o c 8 1: 4 6 -5 2, 2 0 0 6.
htt ps:// d oi. or g/ 1 0. 4 0 6 5/ 8 1. 1. 4 6
C O W E N R, S T A SI O W S K A M K, L A Y C O C K H, B A N T E L C: Ass essi n g p ai n o bj e cti v el y: t h e us e of p h ysi ol o gi c al m ar k ers. A n a est h esi a 7 0: 8 2 8 -8 4 7, 2 0 1 5. htt ps:// d oi. or g/ 1 0. 1 1 1 1/ a n a e. 1 3 0 1 8
C Z A P LI K M, H U B N E R C, K O N Y M, K A LI CI A K J, K E Z Z E F, L E O N H A R D T S, R O S S AI N T R: Ac ut e p ai n t h er a p y i n p ost a n est h esi a c ar e u nit dir e ct e d b y s ki n c o n d u ct a n c e: a r a n d o mi z e d c o ntr oll e d tri al. P L o S O n e 7:
e 4 1 7 5 8 -2 0 1 2. htt ps:// d oi. or g/ 1 0. 1 3 7 1/j o ur n al. p o n e. 0 0 4 1 7 5 8
GJ E R S T A D A C, S T O R M H, H A G E N R, H UI K U M, Q VI G S T A D E, R A E D E R J: C o m p aris o n of s ki n c o n d u ct a n c e wit h e ntr o p y d uri n g i nt u b ati o n, t et a ni c sti m ul ati o n a n d e m er g e n c e fr o m g e n er al a n a est h esi a. Act a A n a est h esi ol S c a n d 5 1: 8 -1 5, 2 0 0 7. htt ps:// d oi. or g/ 1 0. 1 1 1 1/j. 1 3 9 9 -6 5 7 6. 2 0 0 6. 0 1 1 8 9. x
GJ E R S T A D A C: Is s ki n c o n d u ct a n c e a pr e di ct or of ar o us al, n o xi o us sti m uli a n d p ai n i n t h e s e d at e d a n d a n a est h eti z e d p ati e nt ? S eri es of diss ert ati o ns s u b mitt e d t o t h e F a c ul t y of M e di ci n e, U ni v ersit y of Osl o n. 1 2 4 9, I S B N 9 7 8-8 2 - 8 2 6 4 -1 7 7 -7 2 0 1 2.
2 0 2 1 S ki n I m p e d a n c e D uri n g A n est h esi a
2 7 1
G U N T H E R A C, B O T T AI M, S C H A N D L A R, S T O R M H, R O S SI P, S A C K E Y P V: P al mar s ki n c o n d u ct a n c e v ari a bilit y a n d t h e r el ati o n t o sti m ul ati o n, p ai n a n d t h e m ot or a cti vit y ass ess m e nt s c al e i n i n t e nsi v e c ar e u nit p ati e nts. Crit C ar e 1 7: R 5 1 -2 0 1 3. htt ps:// d oi. or g/ 1 0. 1 1 8 6/ c c 1 2 5 7 1
H A B E R L A N D C M, B A K E R S, LI U H: Bis p e ctr al i n d e x m o nit ori n g of s e d ati o n d e pt h i n p e di atri c d e nt al p ati e nts.
A n est h Pr o g 5 8: 6 6 -7 2, 2 0 1 1. htt ps:// d oi. or g/ 1 0. 2 3 4 4/ 0 0 0 3 -3 0 0 6 -5 8. 2. 6 6
HI N OJ O S A -L A B O R D E C, C H A P A I, L A N G E D, H A Y W O O D J R: G e n d er diff er e n c es i n s y m p at h eti c n er v o us s yst e m r e g ul ati o n. Cli n E x p P h ar ma c ol P h ysi ol 2 6: 1 2 2 -1 2 6, 1 9 9 9. htt ps:// d oi. or g/ 1 0. 1 0 4 6/j. 1 4 4 0 -1 6 8 1. 1 9 9 9. 0 2 9 9 5. x KI T T N A R O: S el e ct e d s e x r el at e d differ e n c es i n p at h o p h ysi ol o g y of c ar di o v as c ul ar s yst e m. P h ysi ol R es 6 9: 2 1 -3 1,
2 0 2 0. htt ps:// d oi. or g/ 1 0. 3 3 5 4 9/ p h ysi olr es. 9 3 4 0 6 8
L E D O W S KI T, B R O MI L O W J, W U J, P A E C H MJ, S T O R M H, S C H U G S A: T h e ass ess m e nt of p ost o p er ati v e p ai n b y m o nit ori n g s ki n c o n d u ct a n c e: r es ults of a pr os p e cti v e st u d y. A n a est h esi a 6 2: 9 8 9 -9 9 3, 2 0 0 7.
htt ps:// d oi. or g/ 1 0. 1 1 1 1/j. 1 3 6 5 -2 0 4 4. 2 0 0 7. 0 5 1 9 1. x
L E D O W S KI T, P A S C O E E, A N G B, S C H M A R B E C K T, C L A R K E M W, F U L L E R C, K A P O O R V: M o nit ori n g of i ntr a-o p er ati v e n o ci c e pti o n: s ki n c o n d u ct a n c e a n d s ur gi c al str ess i n d e x v ers us str ess h or m o n e pl as m a l e v els.
A n a est h esi a 6 5: 1 0 0 1 -1 0 0 6, 2 0 1 0. htt ps:// d oi. or g/ 1 0. 1 1 1 1/j. 1 3 6 5 -2 0 4 4. 2 0 1 0. 0 6 4 8 0. x
M A R S H A: A Bri ef Hi st or y of t h e Li e D et e ct or. htt ps://s p e ctr u m.i e e e. or g/t e c h -hist or y/ h er oi c -fail ur es/ a-bri ef -hist or y - of -t h e-li e-d et e ct or. Ac c e ss e d 3 1/ 1 0/ 2 0 2 0. 2 0 1 9.
N O N A K A T, I N A M O RI M, MI Y A S HI T A T, I N O H Y, K A N O S HI M A K, HI G U R A S HI T, O H K U B O H, II D A H, F UJI T A K, K U S A K A B E A, G O T O H T, N A K AJI M A A: C a n s e d ati o n usi n g a c o m bi n ati o n of pr o p of ol a n d d e x me d et o mi di n e e n h a n c e t h e s atisf a cti o n of t h e e n d os c o pist i n e n d os c o pi c s u b m u c os al diss e cti o n ? E n d os c I nt O p e n 6: E 3 -E 1 0, 2 0 1 8. htt ps:// d oi. or g/ 1 0. 1 0 5 5/s -0 0 4 3 -1 2 2 2 2 8
R O G O Y O V V, V A N E K T: T h e i m p ort a n c e a n d o pti o ns of p eri o p er ati v e e v al u ati o n of n o ci c e pti o n (i n C z e c h). A n est I nt e n zi v M e d 3 1: 2 2 5-2 3 2, 2 0 2 0.
R O K Y T A R, Y A M A M O T O V A A: S e x diff er e n c es i n p ai n p er c e pti o n a n d i nt er pr et ati o n. Act N er v S u p er R e di vi v a 5 5:
1 2 5 -1 3 4, 2 0 1 3.
S H E T T Y R M, B E L LI NI A, WIJ A Y A TI L A K E D S, H A MI L T O N M A, J AI N R, K A R A N T H S, N A M A C HI V A Y A M A: BI S m o nit ori n g v ers us cli ni c al ass ess m e nt f or s e d ati o n i n me c h a ni c all y v e ntil at e d a d ults i n t h e i nt e nsi v e c ar e u nit a n d its i m p a ct o n cli ni c al o ut c o m es a n d r es o ur c e utili z ati o n. C o c hr a n e D at a b as e S yst R e v 2:
C D 0 1 1 2 4 0 -2 0 1 8.
S T O R M H: C h a n g es i n s ki n c o n d u ct a n c e as a t o ol t o m o nit or n o ci c e pti v e sti m ul ati o n a n d p ai n. C urr O pi n A n a est h esi ol 2 1: 7 9 6 -8 0 4, 2 0 0 8. htt ps:// d oi. or g/ 1 0. 1 0 9 7/ A C O. 0 b 0 1 3 e 3 2 8 3 1 8 3f e 4
U E N O T, T R E M B L A Y J, K U N E S J, ZI C H A J, D O B E S O V A Z, P A U S O V A Z, D E N G A Y, S U N Y, J A C O B HJ, H A M E T P: G e n d er -s p e cifi c g e n eti c d et er mi n a nts of bl o o d pr ess ur e a n d or g a n wei g ht: p h ar m a c o g e n eti c a p pr o a c h. P h ysi ol R es 5 2: 6 8 9 -7 0 0, 2 0 0 3.
V A L K E N B U R G AJ, NI E H O F S P, V A N D M, V E R H A A R EJ, TI B B O E L D: S ki n c o n d u ct a n c e p e a ks c o ul d r es ult fr o m c h a n g es i n vit al p ar a m et ers u nr el at e d t o p ai n. P e di atr R es 7 1: 3 7 5 -3 7 9, 2 0 1 2.
htt ps:// d oi. or g/ 1 0. 1 0 3 8/ pr. 2 0 1 1. 7 2
WI D A C KI J: Dis c o v er ers of t h e G al v a ni c S ki n R es p o ns e. E ur P ol y gr a p h 9: 2 0 9 -2 2 0, 2 0 1 5. htt ps:// d oi. or g/ 1 0. 1 5 1 5/ e p - 2 0 1 5 -0 0 0 8
WI N T E R H A L T E R M, M U N T E S, G E R H A R D M, D A N Z EI S E N O, J U T T N E R T, M O N A C A E, H O Y L, R A H E - M E Y E R N, KI E N B A U M P: Pr os p e cti v e st u d y c o m p ari n g s ki n i m p e d a n c e wit h E E G p ar a met ers d uri n g t h e i n d u cti o n of a n a est h esi a wit h fe nt a n yl a n d et o mi d at e. E ur J M e d R es 1 5: 4 7-5 3, 2 0 1 0.
htt ps:// d oi. or g/ 1 0. 1 1 8 6/ 2 0 4 7 -7 8 3 X -1 5 - 2-4 7
WI N T E R H A L T E R M, M U N T E S, T A S C H E N B R E C K E R P, H E C K E R H, W EI L B A C H C, O S T H A U S A W, G R O S S M, PI E P E N B R O C K S, R A H E -M E Y E R N: S ki n i m p e d a n c e c orr el at es t o s e d ati o n gr a d e, pl as ma pr o p of ol c o n c e ntr ati o ns a n d bis p e ctr al i n d e x d uri n g a t ar g et -c o ntr oll e d i nf usi o n of pr o p of ol. E ur J A n a est h esi ol 2 6:
5 8 9 -5 9 6, 2 0 0 9. htt ps:// d oi. or g/ 1 0. 1 0 9 7/ EJ A. 0 b 0 1 3 e 3 2 8 3 2 9 b 1 4 9
WI N T E R H A L T E R M, S C HI L L E R J, M U N T E S, B U N D M, H O Y L, W EI L B A C H C, PI E P E N B R O C K S, R A H E - M E Y E R N: Pr os p e cti v e i n v esti g ati o n i nt o t h e i nfl u e n c e of v ari o us str ess ors o n s ki n i m p e d a n c e. J Cli n M o nit C o m p ut 2 2: 6 7 -7 4, 2 0 0 8. htt ps:// d oi. or g/ 1 0. 1 0 0 7/s 1 0 8 7 7 -0 0 7 -9 1 0 7 - 7
2 7 2
K ur z o v á et al. V ol. 7 0Z H A N G H, L U Y, W A N G L, L V J, M A Y, W A N G W, LI G, LI Y: Bis p e ctr al i n d e x m o nit ori n g of s e d ati o n d e pt h d uri n g e n d os c o p y: a m et a -a n al ysis wit h tri al s e q u e nti al a n al ysis of r a n d o mi z e d c o ntr oll e d tri als . Mi n er v a A n est esi ol 8 5: 4 1 2 -4 3 2, 2 0 1 9. htt ps:// d oi. or g/ 1 0. 2 3 7 3 6/ S 0 3 7 5 -9 3 9 3. 1 8. 1 3 2 2 7 - 5
P H Y SI O L O GI C A L R E S E A R C H • I S S N 0 8 6 2 -8 4 0 8
( pri nt)• I S S N 1 8 0 2 -9 9 7 3
( o nli n e) 2 0 1 9 I nstit ut e of P h ysi ol o g y of t h e C zec h Ac a d e m y of S ci e n c es, Pr a g u e, C zec h R e p u bli c Fa x + 4 2 0 2 4 1 0 6 2 1 6 4, e-m ail: p h ysr es @ f g u.c as.c z, w w w. bi o m e d. cas.c z/ p h ysi olr es
P h ysi ol. R es. 6 8 ( S u p pl. 1): S 9 7 - S1 0 3 , 2 0 1 9 htt ps:// d oi. or g/ 1 0. 3 3 5 4 9/ p h ysi olr es. 9 3 4 3 3 0
N o n- Tr a diti o n al A d mi nist r ati o n of R e mif e nt a nil i n a n E x p e ri m e nt al S etti n g
A. K U R Z O V Á
1, J. M Á L E K
1, L. H E S S
2, M. J A Č E K
3, J. S LÍ V A
41
D e p art m e nt of A n est h esi ol o g y a n d R es us cit ati o n, T hir d F a c ult y of M e di ci n e, F a c ult y H os pit al Kr ál o vs k é Vi n o hr a d y, Pr a g u e, C z e c h R e p u bli c,
2D e p art m e nt of La b or at or y of E x p eri m e nt al A n est h esi ol o g y, I nstit ut e f or Cli ni c al a n d E x p eri m e nt al M e di ci n e, Pr a g u e, C z e c h R e p u bli c,
3
D e p art m e nt of H y gi e n e, T hir d F a c ult y of M e di ci n e, C h arl es U ni v ersit y, Pr a g u e, C z e c h R e p u bli c,
4
D e p art m e nt of P h ar m a c ol o g y, T hir d F a c ult y of M e di ci n e, C h arl es U ni v ersit y, Pr a g u e, C z e c h R e p u bli c
R e c ei v e d S e pt e m b er 3, 2 0 1 9 Ac c e pt e d S e pt e m b er 1 6 , 2 0 1 9
S u m m ar y
R e mif e nt a nil i s ultr a s h ort -a cti n g o pi oi d wit h a u ni q u e p h ar m a c o ki n eti c pr ofil e. It i s u s e d e x cl u si v el y i ntr a v e n o u sl y.
W hil e c o n si d eri n g it s r a pi d o n s et of a cti o n a n d ot h er p h ar m a c o ki n eti c pr o p erti e s, w e d e ci d e d t o a s s e s s it s eff e ct s f oll o wi n g a d mi ni str ati o n vi a n o n -tr a diti o n al r o ut es. R a b bits ( n= 1 0 p er e a c h gr o u p) w er e r a n d o mi z e d i nt o f o ur gr o u p s: r e mif e nt a nil 1 μ g/ k g a n d 3 μ g/ k g I M, 5. 0 a n d 1 0. 0 μ g/ k g c o nj u n cti v all y, a n d 1 0 μ g/ k g a n d 2 5. 0 μ g/ k g i ntr a n a s all y. S e d ati n g eff e ct s w er e a s s e s s e d vi a a l os s of t h e ri g hti n g r efl e x. S e c o n d ar y, m e a n art eri al bl o o d pr e s s ur e, art eri al o x y g e n s at ur ati o n of h e m o gl o bi n, a n d p ul s e r at e w a s m o nit or e d i n all r a b bit s. N o n -tr a diti o n al r o ut e s of a d mi ni str ati o n w er e s h o w n t o pr o vi d e a r a pi d o n s et of a cti o n a s w ell a s f a st r e c o v er y. I m p ort a ntl y, t h e a d mi ni str ati o n of r e mif e nt a nil di d n ot r e s ult i n a n y d et eri or ati o n of c ar di o v a s c ul ar f u n cti o n s.
K e y w or d s
R e mif e nt a nil • O pi oi d s • R a b bit s • P ai n • N o n -tr a diti o n al a d mi ni str ati o n • C o nj u n cti v al a d mi ni str ati o n • N a s al a d mi ni str ati o n
C orr e s p o n di n g a ut h or
J. Slí v a, D e p art m e nt of P h ar m a c ol o g y, T hir d F a c ult y of M e di ci n e, C h arl e s U ni v er sit y, R u s k á 8 7, 1 0 0 0 0 Pr a g u e 1 0, C z e c h R e p u bli c.
E- m ail: Jiri. Sli v a @lf 3. c u ni. c z
I nt r o d u cti o n
I n s ur g er y, t h e o pi oi ds c o nti n u e t o pl a y a c e ntr al r ol e i n e v er y f a c et of m o d er n pr a cti c e a n d tr e at me nt of s e v er e a c ut e p ai n. F o r o pi oi ds s u c h as fe nt a n yl a n d its d eri v ati v es, t h e a bilit y t o d et er mi n e a well -t ol er at e d a n d effe cti v e d os e is li mit e d b y v ari a bilit y i n b ot h p h ar ma c o ki n eti cs a n d p h ar m a c o d y n a mi cs. O n t h e ot h er h a n d, alt h o u g h r e mif e nt a nil is a t y pi c al m u -o pi oi d r e c e pt or a g o nist wit h p h ar m a c o d y n a mi c pr o p erti es li k e t h os e of f e nt a n yl a n d its d eri v ati v es, met a b olis m b y n o n -s p e cifi c est er as es gi v es r e mif e nt a nil a u ni q u e p h ar ma c o ki n eti c pr ofil e. T h e cli ni c al a d v a nt a g e of t his dr u g li es i n its e xtr e m el y r a pi d cl e ar a n c e, a n d t h er ef or e offs et of effe ct, w hi c h is i n d e p e n d e nt of e x cr et or y or g a ns.
Ot h er o pi oi ds u n d er g o a “ m ulti c o m p art m e nt ” dis p ositi o n, i. e. t h e y ar e r a pi dl y distri b ut e d t hr o u g h o ut t h e b o d y a n d ar e s u bs e q u e ntl y i n a cti v at e d b y sl o wer h e p ati c bi otr a nsf or m ati o n. B ot h t h es e pr o c ess es d et er mi n e t h e cl e ar a n c e of tr a diti o n al o pi oi ds, b ut t h eir r el ati v e c o ntri b uti o ns ma y b e diff er e nt d e p e n di n g o n t h e d os e us e d a n d t h e r o ut e of a d mi nistr ati o n ( H u g h es et al.
1 9 9 2). I n di vi d u al p ati e nts m a y als o h a v e mar k e dl y differ e nt distri b uti o n v ol u m es a n d r at es of m et a b oli c cl e ar a n c e. T h es e diff er e n c es m e a n t h at t h e p e a k o pi oi d c o n c e ntr ati o n aft er a b ol us c a n n ot b e pr e di ct e d wit h c ert ai nt y. O nl y a s mall p orti o n of t his p h ar ma c o ki n eti c v ari a bilit y c a n b e mi ni mi z e d b y a dj usti n g f or f a ct ors s u c h as a g e, g e n d er, wei g ht, a n d dr u g i nt er a cti o ns, a n d t h es e
S 9 8
K ur z o v á et al. V ol. 6 8d at a ar e n ot a v ail a bl e f or m ost o pi oi ds. E v e n if t h e pl as ma c o n c e ntr ati o n wer e k n o w n pr e cis el y, it w o ul d still b e diffi c ult t o pr e di ct o pi oi d se nsiti vit y f or a n y i n di vi d u al p ati e nt. T his is i m p ort a nt b e c a us e a n o pi oi d -s e nsiti v e p ati e nt will e x p eri e n c e n ot o nl y a gr e at er i nt e nsit y of eff e ct, b ut als o a l o n g er effe ct d ur ati o n, a n d t h e c o n c e ntr ati o n m ust b e l o wer f or a n or mal r e c o v er y r at e t o o c c ur).
W e a nti ci p at e l o wer o pi oi d r e q uir e me nts i n el d erl y or d e bilit at e d p ati e nts a n d i n t h os e w h o h a v e r e c ei v e d ot h er d e pr ess a nt dr u gs; i n cr e as e d r e q uir e me nts mi g ht b e e x p e ct e d i n o pi oi d -t ol er a nt i n di vi d u als or t h os e u n d er g oi n g e xtr e mel y p ai nf ul pr o c e d ur es. U nf ort u n at el y, t h er e is a l ar g e a m o u nt of i nt er p ati e nt v ari a bilit y d u e t o fa ct ors t h at c a n n ot b e e asil y i d e ntifi e d; a m pl e d at a s h o ws t h at i n di vi d u al p ati e nts c a n h a v e a t hr e e- t o fi v ef ol d r a n g e of s e nsiti vit y t o a gi v e n c o n c e ntr ati o n of o pi oi d ( A us e ms et al. 1 9 8 6). A d mi nist eri n g a 9 9 % eff e cti v e d os e t o e v er y p ati e nt will pr o d u c e e x c essi v e effe cts i n m a n y p ati e nts a n d is o b vi o usl y n ot a n o pti o n i n m ost cir c u mst a n c es.
I n c as es of s e v er e a c ut e p ai n, a c hi e vi n g a d e q u at e a n al g esi a wit h a n a c c e pt a bl e s p e e d of r e c o v er y d e p e n ds o n h o w well t h e o pi oi d is titr at e d. A n o v er d os e wit h a n y o pi oi d c a n b e a pr o bl e m. T h e pri mar y a d v a nt a g e of r e mife nt a nil is a r e d u cti o n i n p h ar ma c o ki n eti c v ari a bilit y ( Gl ass et al. 1 9 9 8). T h e dr u g is eli mi n at e d b y e n z y m ati c h y dr ol ysis wit h r e distri b uti o n r el e g at e d t o a mi n or r ol e.
R e mife nt a nil is met a b oli z e d b y n o n -s p e cifi c est er as es, a n e n or m o usl y a cti v e gr o u p of e n z y m es f o u n d i n bl o o d a n d tiss u es t hr o u g h o ut t h e b o d y. M ost of t his h y dr ol ysis pr o b a bl y o c c urs i n s k el et al m us cl e, a n d t ot al r e mife nt a nil cl e ar a n c e is 3 0 -5 0 % of t h e c ar di a c o ut p ut. M or e o v er, t his m et a b olis m is n ot s u bj e ct t o t h e s a m e s orts of g e n eti c v ari a bilit y a n d dr u g i nt er a cti o ns as t h at s e e n wit h s p e cifi c est er as es li k e pl as m a c h oli n est er as e ( W est m or el a n d et al.
1 9 9 3).
T h e cl e ar a n c e is pr e di ct a bl e b e c a us e it is u n affe ct e d b y s o ma n y ot h er v ari a bl es ( e. g. b ol us v ers us i nf usi o n, h e p ati c or r e n al f u n cti o n, g e n d er, dr u g i nt er a cti o n, et c.). T h e f e w f a ct ors t h at h a v e b e e n d e m o nstr at e d t o alt er r e mif e nt a nil cl e ar a n c e ( e. g. a g e) a n d distri b uti o n v ol u me ( wei g ht) d o n ot pr o d u c e gr e at c h a n g es i n t h e d ur ati o n of a cti o n. T his me a ns t h at, c o m p ar e d wit h ot h er o pi oi ds, a n i nf usi o n of r e mife nt a nil will pr o d u c e m or e c o nsist e nt st e a d y-st at e bl o o d c o n c e ntr ati o ns, a n d t h e r at e of dis a p p e ar a n c e will b e m or e u nif or m wit hi n a gi v e n p ati e nt p o p ul ati o n.
T h er e is still p h ar ma c o d y n a mi c v ari a bilit y wit h r e mife nt a nil, a n d t h e e n d p oi nt f or titr ati o n is n o diff er e nt
t h a n th at wit h ot h er o pi oi ds. U nli k e ol d er o pi oi ds, h o we v er, a c c ur at e d osi n g of r e mif e nt a nil is n ot q uit e as criti c al b e c a us e r a pi d r e c o v er y is eff e cti v el y d os e - i n d e p e n d e nt ( R os o w et al. 1 9 9 9). I n t h e or y, r e mif e nt a nil c o ul d b e us e d i n a n y cli ni c al sit u ati o n c alli n g f or a p ot e nt o pi oi d a n al g esi c, e. g. r e mif e nt a nil c a n b e a d mi nist er e d i n d os es t h at w o ul d b e i m pr a cti c al or h a z ar d o us wit h ot h er f e nt a n yl d eri v ati v es b e c a us e of its r a pi d offs et.
I n a d diti o n, r e mif e nt a nil c a n b e us e d at hi g h er a n al g esi c d os es wit h o ut c o n c er n f or r esi d u al o pi oi d effe cts, m ai nl y r es pir at or y d e pr essi o n. T h e pri n ci p al pr o bl e m wit h utili zi n g its u ni q u e c h ar a ct eristi cs i n a n e mer g e n c y sit u ati o n is t h at u nli k e ot h er o pi oi ds, r e mif e nt a nil is li mit e d t o i ntr a v e n o us a d mi nistr ati o n o nl y.
N o n -tr a diti o n al r o ut es of a d mi nistr ati o n of r e mif e nt a nil a n d ot h er o pi oi ds
N as al a d mi nistr ati o n of o pi oi ds is br o a dl y us e d f or a c ut e s e v er e p ai n w h e n a r a pi d o ns et is n e e d e d, e. g. tr e at m e nt of br e a kt hr o u g h p ai n i n o n c ol o gi c p ati e nts.
Bi o a v ail a bilit y of n as al a d mi nistr ati o n of dr u gs is i nfl u e n c e d b y ma n y f a ct ors, e. g. si z e of t h e m ol e c ul e, li pi d s ol u bilit y, p H of t h e s ol v e nt a n d p K a of t h e dr u g, its c o n c e ntr ati o n, v ol u m e, distri b uti o n of s ol uti o n, a n d r o ut e/ met h o d of a d mi nistr ati o n, e. g. s pr a ys h a v e hi g h er bi o a v ail a bilit y t h a n n as al dr o ps. T h er e is p u blis h e d d at a t o s u g g est t h at t h er e is dir e ct c o m m u ni c ati o n b et we e n t h e n as al c a vit y a n d br ai n vi a p eri n e ur al s p a c e. Dr u gs ar e a bs or b e d t hr o u g h t h e olfa ct or y ar e a dir e ctl y i nt o t h e s u b ar a c h n oi d s p a c e ( S ut er-Zi m m er ma n n 2 0 0 8 , H ess et al.
2 0 1 6). T h e a d v a nt a g e of n as al a d mi nistr ati o n of o pi oi ds i n h u m a ns is n o n -i n v asi v e n ess, hi g h c o m pli a n c e e v e n i n c hil dr e n, a n d g o o d bi o a v ail a bilit y. T his r o ut e is alr e a d y a v ail a bl e f or fe nt a n yl cli ni c al us e (e. g. I N S T A N Y L N yc o me d), a n d t h e r o ut e h as b e e n st u di e d f or s ufe nt a nil ( H e n d ers o n et al. 1 9 8 8 , K arl et al. 1 9 9 2 , Ni els e n et al.
2 0 1 4 , Hr o n o v a et al. 2 0 1 6) a n d alf e nt a nil ( Br e n c hl e y a n d R a ml a k h a n 2 0 0 6). T h er e h as o nl y b e e n o n e tri al usi n g t h e n as al r o ut e wit h r e mif e nt a nil i n h u m a ns, i. e. a d os e of 4 μ g/ k g was gi v e n n as all y t o f a cilit at e i nt u b ati o n i n c hil dr e n ( V er g h es e et al. 2 0 0 8). N as al a d mi nistr ati o n of r e mif e nt a nil was als o t est e d i n a ni m als i n a pil ot st u d y b y t h e a ut h ors of t his pr oj e ct ( H ess et al. 2 0 1 2 a). T h e r es ults wer e pr o misi n g, i. e. t h e o ns et was r a pi d, d ur ati o n was l o n g er t h a n aft er I V i nj e cti o n, a n d si d e eff e cts wer e l ess pr o mi n e nt. M or e o v er, t h e s p e cifi c o pi oi d a nti d ot e, n al o x o n e, is als o eff e cti v e w h e n gi v e n i ntr a n as all y ( K ell y et al. 2 0 0 5) a n d h as b e e n a p pr o v e d i n t h e U nit e d St at es b y t h e F D A f or us e i n h er oi n o v er d os es.
2 0 1 9 N o n - Tr a diti o n al Re mif e nt a nil
S 9 9
I ntr a m us c ul ar a d mi nistr ati o n is t h e st a n d ar d r o ut e of a d mi nistr ati o n of m a n y i nj e ct a bl e f or ms of dr u gs. T h e o ns et of eff e ct c a n b e a c c el er at e d b y t h e a d mi nistr ati o n i nt o t h e d elt oi d m us cl e i nst e a d of t h e gl ut e us m us cl e ( R e y n ol ds et al. 1 9 9 6 , R e y n ol ds et al.
1 9 9 7 , H ess et al. 2 0 1 2 b) as well as wit h t h e a d diti o n of h yal ur o ni d as e ( H ess et al. 2 0 1 0). T h er e ar e n o p u blis h e d r es ults c o n c er ni n g t h e i ntr a m us c ul ar a d mi nistr ati o n of r e mif e nt a nil, alt h o u g h its effi c a c y i n a ni m als h as b e e n d e m o nstr at e d ( u n p u blis h e d p ers o n al e x p eri e n c es).
C o nj u n cti v al a d mi nistr ati o n is r ar el y us e d i n h u m a n m e di ci n e d es pit e c as e r e p orts of life-t hr e at e ni n g i nt o xi c ati o n b y t h e a c ci d e nt al a d mi nistr ati o n of p ot e nt o pi oi ds t o t h e e y e ( Ri vi er e a n d P a pi c h 2 0 0 3). It is well k n o w n t h at s o m e o p ht h al mi c dr u gs ar e e asil y a bs or b e d i nt o t h e s yst e mi c cir c ul ati o n. T h er e is a r e p ort of t h e effi c a c y of o c ul ar a d mi nistr ati o n of n al o x o n e i n h u m a ns ass o ci at e d wit h h er oi n a b us e ( D u n c alf et al. 1 9 7 5 , G h o ds e et al. 1 9 9 5). I n a ni m al e x p eri me nts, s uf e nt a nil ( F ar ns w ort h et al. 1 9 9 8, M al e k et al. 2 0 1 1), b u pr e n or p hi n e ( M al e k et al. 2 0 1 2), a n d fe nt a n yl ( Z öll n er et al. 2 0 0 8) h a v e b e e n t est e d, a n d r e mif e nt a nil was t est e d i n o ur pil ot st u d y ( M al e k et al. 2 0 1 2).
T h e ai m of t his st u d y was t o e x pl or e t h e fe asi bilit y a n d s af et y of a d mi nist eri n g r e mif e nt a nil usi n g n as al, c o nj u n cti v al, a n d i ntr a m us c ul ar r o ut es of a d mi nistr ati o n. O ur h y p ot h esis was t h at r e mife nt a nil a d mi nist er e d b y t h es e r o ut es 1) w o ul d b e a bs or b e d r a pi dl y, 2) w o ul d b e p h ar m a c ol o gi c all y a cti v e, 3) w o ul d h a v e a r a pi d o ns et a n d r a pi d r e c o v er y, a n d 4) i n t h e c as e of c o nj u n cti v al a d mi nistr ati o n, w o ul d b e n o n -i nj uri o us t o r a b bit c o nj u n cti v a. T h e s e c o n d ai m of t his e x p eri m e nt al st u d y was t o ass ess t h e d os e -effe ct r el ati o n wit h r es p e ct t o pl as ma c o n c e ntr ati o ns r el ati v e t o t h e r o ut e of a d mi nistr ati o n of r e mif e nt a nil (i. e. n as al, c o nj u n cti v al, a n d i ntr a m us c ul ar). T o o ur b est k n o wl e d g e, n o s u c h s eri es of e x p eri me nts usi n g t h es e r o ut es of a d mi nistr ati o n h a v e b e e n d o n e e x c e pt f or pr e vi o us pil ot st u di es ( H ess et al. 2 0 1 2 c, M al e k et al. 2 0 1 2).
M et h o ds
E x p eri m e nt al a ni m als
W e us e d N e w Ze al a n d W hit e r a b bits wei g hi n g 2. 5 -4. 5 k g of b ot h s e x es. T e n a ni mals wer e us e d f or e a c h t est. R a b bits wer e br e d i n i n di vi d u al c a g es at a t e m p er at ur e of 2 0 -2 2 ° C a n d air h u mi dit y of 4 0 -6 5 %.
T h e y wer e fe d a st a n d ar d di et wit h u nli mit e d a c c ess t o wat er. T h e e x p eri m e nts wer e a p pr o v e d b y t h e Et hi cs
C o m mitt e e f or Ani m al Ex p eri me nts of t h e C z e c h Mi nistr y of P u bli c H e alt h a n d I K E M.
O bt ai ni n g d at a
C ar di or es pir at or y p ar a met ers ( h e m o gl o bi n o x y g e n s at ur ati o n ( S p O2), p uls e, a n d bl o o d pr ess ur e) wer e m e as ur e d aft er 1 5 mi n of a c cli m ati z ati o n t o t h e l a b or at or y e n vir o n m e nt. T h e pr o b e f or p uls e o xi m etr y was a p pli e d t o a n ar e a of s h a v e d s ki n o n t h e b a c k of t h e n e c k of t h e a ni m als, a n d n o n -i n v asi v e bl o o d pr ess ur e ( NI B P) was m e as ur e d o n t h e t h or a ci c e xtr e mit y usi n g a M e m o pri nt m o nit or ( M e d v et, G er m a n y) at 5 mi n i nt er v als. T h e first m e as ur e m e nts wer e p erf or me d b ef or e a d mi nistr ati o n of r e mif e nt a nil a n d c o nti n u e d at 1 mi n i nt er v als, e x c e pt f or NI B P f or 2 0 mi n. T h e first si g ns of s e d ati o n i n cl u d e d d e cr e as e d vi briss a e m o v e m e nts, d e cr e as e d m us cl e t o n e, a n d a c h a n g e i n b o d y p ositi o n.
T h e a ni mals’ r e a cti o n t o t a p pi n g o n its f or e h e a d was ass ess e d, a n d i m m o bili z ati o n ti me was m e as ur e d as t h e a p p e ar a n c e of t h e l oss of t h e ri g hti n g r efl e x. T h e o ns et of t h e l oss of ri g hti n g r efl e x was t est e d b y pl a ci n g t h e a ni m al i n a pr o n e p ositi o n at 1 mi n i nt er v als a n d o bs er vi n g t h e r efl e x r es p o ns e.
E x p eri m e nts
W e t est e d t w o d os es of i ntr a m us c ul ar r e mife nt a nil, 1. 0 µ g/ k g a n d 3. 0 µ g/ k g, i nj e cti o ns of r e mife nt a nil wer e i nt o t h e m us c ul us s e mit e n di n os us.
N as al a n d c o nj u n cti v al d os es of r e mif e nt a nil wer e 1 0. 0 µ g/ k g a n d 2 5. 0 µ g/ k g, a n d 5. 0 µ g/ k g a n d 1 0. 0 µ g/ k g, r es p e cti v el y. All d os es wer e c h os e n wit h res p e ct t o o ur pil ot e x p eri me nts a n d lit er at ur e d at a. N as al a n d c o nj u n cti v al a d mi nistr ati o ns wer e d o n e usi n g c a n n ul a wit h a s p h eri c al ti p t o a v oi d i nj ur y. Si g ns of e y e irrit ati o n wer e m e as ur e d usi n g t h e m o difi e d st at e r e g ul ati o n C S N E N I S O 1 0 9 9 3 -1 0 a n d ma cr o -p h ot os wer e t a k e n.
D os e -eff e ct r el ati o ns hi ps wer e t est e d a n d c o m p ar e d f or e a c h gr o u p of a ni m als (i. e. t h e o ns et of s e d ati o n a n d i m m o bili z ati o n, l oss of t h e ri g hti n g r efl e x, a n d c ar di or es pir at or y p ar a met ers, w hi c h wer e t a k e n at b as eli n e a n d 1, 1 0, a n d 2 0 mi n aft er a d mi nistr ati o n). T h e d os e r a n g es us e d i n t his e x p eri me nt wer e pr e vi o usl y t est e d i n pil ot e x p eri m e nts.
Pl as m a c o n c e ntr ati o n a n al ys es
I n s el e ct e d a ni m als, pl as ma l e v els of r e mife nt a nil wer e m e as ur e d at t w o i nt er v als: i m m e di at el y aft er t h e l oss of t h e ri g hti n g r efl e x a n d 1 0 mi n aft er.
Bl o o d s a m pl es wer e dr a w n fr o m t h e v e n a a uri c ul aris i nt o
S 1 0 0
K ur z o v á et al. V ol. 6 8pl asti c t u b es c o nt ai ni n g citr at e b uff er wit h a p H = 4. 2, w hi c h pr e v e nt e d s p o nt a n e o us h y dr ol ysis of r e mif e nt a nil at a b asi c p H or b y n o n -s p e cifi c pl as ma est er as es. Aft er c e ntrif u g ati o n f or 5 mi n at 3, 7 5 0 g, bl o o d pl as ma was o bt ai n e d a n d i m m e di at el y fr o z e n usi n g li q ui d nitr o g e n a n d st or e d i n a fr e e z er at -2 0 ° C. Li q ui d -li q ui d e xtr a cti o n ( L L E) or s oli d-p h as e e xtr a cti o n ( S P E) was us e d f or s a m pl e pr e p ar ati o n (J a c e k et al. 2 0 1 3, K a b b aj a n d V ari n 2 0 0 3). A n al ysis of s a m pl es was p erf or me d o n a g as c hr o mat o gr a p h wit h a nitr o g e n -p h os p h or o us d et e ct or ( N P D), w hi c h is m or e s el e cti v e a n d s e nsiti v e f or nitr o g e n -c o nt ai ni n g c o m p o u n ds t h a n t h e c o m m o n fl a m e i o ni z ati o n d et e ct or ( FI D).
St atisti c al a n al ysis
T h e S h a pir o -Wil k W st atisti cs was us e d t o t est n or malit y. A N O V A wit h r e p e at e d me as ur es was us e d f or a n al ysis wit hi n gr o u ps a n d b et we e n gr o u ps f or d at a wit h a n or mal distri b uti o n. F or d at a, w hi c h aft er tr a nsf or mati o n (l o g arit h m, s q u ar e r o ot) di d n ot h a v e a n or mal distri b uti o n, n o n -p ar a metri c m et h o ds, i. e. t h e Fri e d ma n a n al ysis a n d Kr us k al -W allis a n al ysis, wer e us e d. B o nferr o ni c orr e cti o ns wer e us e d f or m ulti pl e c o m p aris o ns. All t ests wer e t w o-si d e d, a n d a P < 0. 0 5 was ass u me d t o b e st atisti c all y si g nifi c a nt.
R es ults
L oss of ri g hti n g r efl e x
T h e a d mi nistr ati o n of r e mife nt a nil at d os es of 3. 0 µ g/ k g IM, 1 0. 0 µ g/ k g a n d 2 5. 0 µ g/ k g n as all y a n d 5. 0 µ g/ k g a n d 1 0. 0 µ g/ k g c o nj u n cti v all y r es ult e d i n a l oss of t h e ri g hti n g r efl e x ( m e a n ± S D) b y 1 4 3. 0 ± 8 4. 7 s, 1 6 5. 0 ± 9 2. 9 s, 1 1 1. 5 ± 3 8. 6 s, 1 2 3. 6 ± 6 5. 8 s, a n d 1 8 7. 0 ± 1 1 0. 2 s, r es p e cti v el y ( Fi g. 1). At t h e l o west I M d os e ( 1. 0 µ g/ k g), t h er e w as virt u all y n o l oss of t h e r efl e x. T h e effe ct s u bsi d e d i n h alf of t h e e x p eri m e nt al a ni m als wit hi n 2 0 mi n of t h e a p pli c ati o n. T his d at a was n ot e v al u at e d st atisti c all y.
P uls e r at e
T h e t w o -wa y r e p e at e d A N O V A s h o we d n o si g nifi c a nt effe ct b et we e n t h e si x tr e at m e nts o n t h e p uls e r at e ( Fi g. 2).
P uls e r at e
T h e t w o -wa y r e p e at e d A N O V A s h o we d n o si g nifi c a nt effe ct b et we e n t h e si x tr e at m e nts o n t h e p uls e r at e ( Fi g. 2).
Art eri al bl o o d pr ess ur e
T h e t w o -wa y r e p e at e d A N O V A s h o we d n o si g nifi c a nt eff e ct b et we e n t h e six tr e at me nts o n t h e s yst oli c, di ast oli c, or me a n art eri al bl o o d pr ess ur e ( Fi g. 3).
Fi g. 1. R a b bit wit h l o s s of t h e ri g hti n g r efl e x.
Fi g. 2. P ul s e r at e.
Fi g. 3. M e a n art eri al bl o o d pr e s s ur e.
