Muscle relaxants in the ICU

Servizio di Anestesia e Rianimazione Ospedale di Faenza(RA)

Miorilassanti in terapia intensiva

by C.Melloni

Quando?Perchè? Quali?


Topics� Indicazioni� patol.di impiego� utilizzo effettivo in lett.� Problemi;

» paz,» effetti collat,» laudanosina,» passaggio barriera ematoencef.….

� patol attribuite ai miorilass;casistiche� tachifilassi:up and down reg:

» animali---uomo(Dodson)� studi di confronto:casistiche � indicaz e linee guida


Indicazioni all’impiego dei miorilassanti in TI

� Adattamento al supporto ventilatorio meccanico» aumento della compliance della parete toracica (in presenza

di elevate pressioni di insuffll.(.ARDS….)(Ma Conti ****….» riduzione del lavoro muscolare resp» riduzione del VO2» prevenzione dei movimenti incoordinati con riduzione delle

pressioni di picco e del rischio di barotrauma;» mantenimento ipercapnia permissiva per il miglioramento

degli scambi gassosi


Conti G,Vilardi V,Rocco M et al.Paralysis has no effect on chest wall and respiratory system mechanics of mechanically ventilated ,sedated patients.Intens. Care Med 21;808-812:1995.

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Elastrespsyst

Elastcw

elast l resistcw

maxtot

resistsyst

minrwesp

restsyst

D RRS sedaz,apneica

sedaz+ paralisi


Indicazioni all’impiego dei miorilassanti in TI:II

� prevenzione del brivido(ustioni,ipotermia,postop..)

� prevenzione movimenti incoordinati e pericolosi in corso di procedure speciali:RX,TAC,RMN;ECMO…

� prevenzione tosse,reazione alle aspirazioni ecc nei paz con ICP aumentata(**)

� facilitazione di manovre anestesiologiche e/ o chirurgiche(tracheostomia)

� facilitazione della terapia in malattie particolari;tetano,stato epilettico,stato asmatico,avvelenamento da stricnina

� mantenimento della immobilità dopo interventi particolari,inserimento di protesi vascolari….


Gosch M, Spiss CK. The level of neuromuscular block needed to supress diaphragmatic movement during tracheal suction

in patients with raised intracranial pressure: a study with vecuronium and atracurium. Anaesthesia 1993; 48:301-303.

01020

304050607080

mmHg

ICP CPP

ICP increases,CPP abs. values

SEDAZSedaz+nmb


Patologie di applicazione dei miorilassanti in TI

� Traumi cranici� Insufficienze resp di varie eziologie….� Tetano� stato epilettico� stato di male asmatico� avvelenamento da stricnina


Utilizzo di nmb in ICU

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%MurrayDastaKlessig


Loper KA,Butler S,Nessly M.Paralyzed with pain:the need for education.Pain 1989;37:315-16

� Cosa pensano( e sanno di farmacologia ….) medici e infermiere in ICU:

� 50-70% pensano che il pancuronium sia un ansiolitico� 80% pensano che il diazepam abbia proprietà

analgesiche…….


Problemi dei miorilassanti in TIProblemi dei miorilassanti in TI

Cinetica e dinamica studiata in genere in anestesia,inacuto

Cinetica e dinamica studiata in genere in anestesia,inacuto

che cosa accade per somministrazionecronica?che cosa accade per somministrazionecronica?

estrapolazone delle raccomandazioni..........estrapolazone delle raccomandazioni..........

informazione limitatainformazione limitatapochi studipochi studi

necessità di studi pk/pd in ambiente TI....necessità di studi pk/pd in ambiente TI....

mancata definizione delle necessitàmancata definizione delle necessità

quanto rilasciamento?quanto rilasciamento?

per quanto tempo?per quanto tempo?


Differenze nella somministrazione dei nmb : ICU vs chirurgia

� Infusione continua� mancanza del monitoraggio� alterazioni pd e pk nei pazienti� disfunzioni di organi(MOF)� alterazioni elettrolitiche…� stato ipercatabolico� anormalità acido-basiche� multiterapia,interazioni farmacologiche


Effetti neurologici dei miorilassanti in TI

� Laudanosina….

� Passaggio barriera ematoencefalica???


Interazioni farmacologiche dei miorilassanti

� Potenziamento» (anest.alogenati)» anest locali

» antibiotici(..micine…,polipeptidi(polimixin b),cilindamic,tetrac…

» antiaritmici:Mg,procainamide,chinidina…

» bloccanti canali del Ca» bloccanti beta adrenergici» chemioterapici(ciclofosfam

ide)» dantrolene

» diuretici

» litio» ciclosporina

� Antagonismo» fenitoina» carbamazepina

» teofillina

» simpatomimetici

» corticosteroidi


Condizioni potenzianti i miorilassanti in TI

� Disturbi elettrolitici:– ipocalcemia– ipokaliemia

– ipermagnesemia

� ipotermia� acidosi resp� miastenia� sindr neopl

» Eaton-Lambert

� distrofie muscolari� sindromi miotoniche� sclerosi multipla� neurofibromatosi� porfiria acuta intermittente� SLA� poliomielite


Condizioni antagonizzanti i miorilassanti in TI

� Ipercalcemia� endotossinemia,sepsi� ustioni maggiori� politraumi� insuff epatica con ascite� sindr.da denervazione� emiplegia� neuropatie periferiche� diabete


Effetti potenziali avversi dei miorilassanti in TI

� Paz svegli e paralizzati…….� Aumentato rischio per i paz in caso di accidentale

deconnessione dal resp� interaz.autonomiche e cardiovasc� cumulatività� rischio cutaneo?� Rischio di danno ai nervi periferici� rischio (specifico ?) di paraplegia,quadriplegia….� Costi…� tossicità per il SNC?


Ci sono prove che l’impiego dei miorilassanti in TI comprometta l’outcome?

� Beck,TP.Advances in the management of the status epilepticus.Crit Care med.21;991-4,1993.» Neuromuscular complications prolong the

lenght of stay(twice) and have a higher mortality”

» ma non riguarda l’uso dei miorilassanti,bensì le complicanze neuromuscolari ….


Kushimo OT, Darowski MJ, Morris P, et al. Dose requirements of atracurium in paediatric intensive care

patients. Br J Anaesth 1991; 67:781-3.

� 12 children� infusion of atracurium to facilitate mechanical

ventilation � mean duration of infusion was 98 h (range 36–284 h) � an increasing dose requirement was observed in all

patients: mean infusion rate was 1.60 (SEM 0.08) mg kg-1 h-1, and in seven patients a mean infusion rate of 1.72 (0.15) mg kg-1 h-1 was observed at 72 h.

� Cessation of neuromuscular block occurred promptly (23.7 (3.1) min ,range 10–35 min).


Mean infusion rates of atracurium i n the study by Kushimo OT et al.


Tobias J. The Increased cis-atracurium requirements during prolonged administration

to a child . Can J Anaesth 1997 / 44: 1 / 82-84

� To report increased infusion requirements of cis-atracurium during prolonged infusion (6 weeks) to provide nm blockade in a child during prolonged mechanical ventilation:a considerable increase over 6 weeks was noted.

� 7 month old infant required prolonged mechanical ventilation and nm blockade following an episode of MOF from pseudomembranous colitis. The infusion of cis-atracurium was adjusted according to the tof response obtained with a peripheral nerve stimulator using standard tof monitoring. Initial infusion requirements were 2.8 mg×kg-1 min-1 on day #1 increased to 22.3 mg×kg-1 min-1 on day #40.

� Conclusion: Increased infusion requirements were necessary during the prolonged administration of cis-atracurium to a critically ill infant. Titration of the dose based on monitoring with a peripheral nerve stimulator is recommended.


Bambino di 7 mesi,10 kg,MOF.

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cisatracurium infusion requirements

day 1510152025303540

g/kg/min

Monitoraggio TOF,mant a 1-2 twitch


Tobias JD. Continuous infusion of rocuronium in a paediatric intensive care unit. Can J

Anaesth 1996; 43:353-7.� To evaluate prospectively the efficacy and dose requirements of

rocuronium administered by continuous infusion for neuromuscular blockade in a paediatric ICU population.

� METHODS: Nm function was monitored by TOF stimulation of the ulnar or peroneal nerve. Rocuronium was administered as a bolus dose (0.6 mg.kg-1) followed by a continuous infusion starting at 0.6 mg.kg-1.hr-1. The infusion was increased or decreased by 0.1 mg.kg-1.hr-1 to maintain one visible twitch of the TOF. All patients also received a benzodiazepine or a barbiturate infusion.

� RESULTS: The study population included 20 patients (12 boys, eight girls) ranging in age from two months to 16 yr and in weight from 3.6 to 64 kg. The duration of the rocuronium infusion varied from 26 to 172 hr for a total of 1492 hr in the 20 patients.


Dosaggi di Rocuronium nello studio di Tobias

� Obbiettivo:mantenere il I twitch del TOF» giorno 1:

» da 0.3 to 0.8 mg/kg/hr (0.76 ± 0.3 mg/ kg/ hr). » Per tutta la degenza:da 0.3 a 2.2 mg/ kg/h (media 0.95 ±

0.4 mg/ kg/ hr). � dosaggi: � 0.5 to 0.8 mg /kg/ hr in 45 dei 64 gg.paz (70%) � 0.3 to 1.0 mg/kg/hr in 58 dei 64 gg.paz (90%). � Tachifilassi (per i paz con terapia > 3 gg)

» 0.65 mg/ kg/ hr( g. 1)» 0.84 mg/kg/hr (g.3) (P = 0.07)

» nei 5 paz che hanno richiesto il farmaco per almeno 5 gg,le richieste sono aum. da 0.67 mg/kg/hr il g. 1 a 1.2 mg/kg/hr il g 5 (P < 0.05).

� Dopo sospensione della infus di rocu,il ritorno spontaneo della funz nm ha richiesto(TOF e tetano sostenuto a 50 Hz) 24 - 44 min (31 ± 12 min)

� no paralisi prolungata


Miorilassanti in PICU:note sui dosaggi

� Tobias» increase in pancuronium requirements (0.056 vs 0.14 mg ×

kg-1 × hr-1, P < 0.05) in seven of 25 patients receiving anticonvulsants including barbiturates, phenytoin, and carbamazepine.

» Both of our previous studies, have demonstrated eight- to 10-fold variations in the doses required to maintain one twitch of the train-of-four.


tachifilassi

� Conservazione inappropriata di certi nmb

� alterazioni nel legame plasmatico� alterazione nel volume di distribuzione� alterazione nella temperatura o

equilibrio acido-base…� variabilità isomerica� proliferazione dei recettori nAch

extragiunzionali


Up and down regulation

Upregulationaum dei recettorisensibile agli agonistiresist agli antagonisti

Esposizione cronica a DTCaum dei nAchRsensib all’ACH(Scc….)resist alla DTCaum dose DTC per lo stesso rilasciamento...


Up and down regulation

� Upregulation� aum recettori� aum.sensib.agonisti� dim sensib antag

� Downregulation� diminuz recettori� dim sensib agonisti� aum sensib antag

Inibizione cronica Stimolazione cronica


Proliferazione dei recettori nAch

� Immaturità� non localizzati alla placca nm,ma

migrano a tutta la superficie di membrana

� emivita breve� attività ionica più sostenuta� maggiore sensibilità ai depolarizzanti� resistenza ai non depolarizzanti


Kim C,Hirose M. Martyn JAJd-Tubocurarine Accentuates the Burn-induced Upregulation of Nicotinic Acetylcholine Receptors at the Muscle Membrane Anesthesiology 83:309-

315, 1995

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ust finta+fisiol

ust+fisiol ust+inf dtc

Numero degli AchR nei musc gastrocnemi di ratto dopo ustione e infus di dtc(f moli/mg di

proteina)

gastrcnemio sngastrocnemio dx


Kim C,Hirose MM,Martin JAJ. d-Tubocurarine Accentuates the Burn-induced Upregulation of Nicotinic Acetylcholine

Receptors at the Muscle Membrane . Anesthesiology 83:309-315, 1995

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nAchr

fint ustione confisiolustione con fisiol

ustione con DTC

Muscolo gastrocnemio di ratto;alfa bungarotossina.


Yanez P,Martin JAJ.Prolonged d-tubocurarine infusion and/or immobilization causes upregulation of acetylcholine

receptors and hiperkalemia to succinylcholine.Anesthesiology 84;384-391:1996.

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AchR numbers in gastrocnemius following immobilization and or dtc infusion

num.AchR


Condizioni che portano alla proliferazione dei recettori nAch

� Sindr di G-B� ictus� polio� trauma midollo spinale� ustioni� trauma muscolare (severo)� immobilizzazione forzata� (tutte le condizioni che portano a perdita della

funzione nervosa)


Dodson BA, Kelly BJ, Braswell LM, Cohen NH. Changes in acetylcholine receptor number in muscle from critically ill patients

receiving muscle relaxants: an investigation of the molecular mechanism

of prolonged paralysis. Crit Care Med 1995; 23:815-21. � The purpose of this study was to examine possible

pathophysiologic causes for this paralysis by measuring muscle-type, nicotinic acetylcholine receptor number in necropsy muscle specimens from patients who had received muscle relaxants to facilitate mechanical ventilation before death

� . DESIGN: Prospective laboratory study of human muscle collected at autopsy.

� SETTING: Medical and surgical ICUs at a university hospital and a research laboratory.

� PATIENTS: 14 critically ill patients, with a variety of diagnoses, all of whom required mechanical ventilatory support before their deaths in the ICU and who underwent post mortem examination.


Dodson et al :II

� Patients were arbitrarily divided into 3 groups, according to their total vecuronium dose and number of days mechanically ventilated before death. 3 patients were in the control group (defined as dying within 72 hrs of initiation of ventilatory support and receiving a total dose of < 5 mg of vecuronium).

� 6 patients were in the low-dose group (defined as requiring ventilatory support for > 3 days before death and receiving a total vecuronium dose of < or = 200 mg).

� 5 patients were in the high-dose group (defined as requiring ventilatory support for > 3 days before death and receiving a total vecuronium dose of > 200 mg).


Dodson et al :III

� MEASUREMENTS AND MAIN RESULTS: Nicotinic acetylcholine receptor numbers as measured by specific 125I-alpha-bungarotoxin binding to human rectus abdominis muscle obtained at autopsy were determined. In general, receptor number reflected the clinical requirements for the muscle relaxants of each patient. Patients who had increasing requirements for muscle relaxants before death had increases in receptor number, as compared with control values.


Conclusioni di Dodson

� increased density of acetylcholine receptors in muscle from patients who have received prolonged infusions of neuromuscular blocking agents suggesting that prolonged neuromuscular blockade, like partial or complete deafferentation injury, leads to proliferation of acetylcholine receptors.


conclusioni

� I lavori di Yanez,Kim,Dodson,Martin tutti dimostrano che la infusione continua di DTC,anche a dosi subparalizzanti,induce un aumento dei RAch

� questi Recettori sono ulteriormente aumentati dalla immobilità e dall’ustione


Il monitoraggio del blocco nm.in ICU


Hansen-Flaschen JH, Brazinsky S, Basile C, et al. Use of sedating drugs and neuromuscular blocking agents in

patients requiring mechanical ventilation for respiratory failure. JAMA 1991; 266:2870-6

� ICU con formazione degli specializzandi in pneumologia….

� Farmaci nmb usati “occasionalmente” ,cioè < 20% degli insuff resp

� frequenza:» panc 47%76 iv intermitt.21 iv cont)

» vecu 22%(45-34)» atrac 17%(5-14 )» stimo.perif usati solo nel 21% delle ICU


Carenze nella somministrazione dei miorilassanti in TI

� Mancanza del monitoraggio� insufficienza del

monitoraggio(occasionale,intervalli lunghi…?

� Dosi elevate� dosi a orari fissi


Circolo vizioso dei miorilassanti in TI.

Insuff.monitoraggio

Iperdosaggio (rel o ass)

Paralisi prolungate


Complicanze riportate in letteratura dopo somministrazione prolungata di miorilassanti

in TI.

� tachifilassi

� Paralisi prolungata con paresi periferica � atrofia muscolare da disuso� tetraplegia� areflessia

� Eziologia� la malattia di base(MOF…)� somministrazione concomitante di altri

farmaci(corticosteroidi!!)� alterazioni della pk.cinetica� alterazioni della normale funzione nm.( "pharmacologic

denervation" )� sovradosaggio assoluto o relativo(Kupfer)


Giostra E, Magistris MR, Pizzolato G, et al. Neuromuscular disorder in intensive care unit patients treated with pancuronium bromide:

occurrence in a cluster group of seven patients and two sporadic cases, with electrophysiologic and histologic examination. Chest 1994; 106:210-

20. � sindr tetraparetica + paralisi peronea

con aum del CK,senza segni di sepsi o MOF,specie epatica e/o renale

� 9 paz in 2 anni:1.55% di tutti i paz intubati e ventilati

� sedaz con midaz,curarizz con panc,8 paz trattati con corticosteroidi.

� Durata del deficit neurol 4-52 sett.


Giostra et al. Neuromuscular disorder in intensive care unit patients treated with pancuronium bromide: occurrence in a cluster group of seven patients and two sporadic cases, with electrophysiologic and

histologic examination. Chest 1994; 106:210-20.

� L’aumento delle CPK appare legato alla somministrazione di panc(3179+-2514)

� durata dei sintomi neurol legata alla somministraz di corticosteroidi

� Studi elettrofisiologici:» sensory nerve action potential ;norm o dim» conduction velocities;dim» compound muscle action potentials; amplitude dim» fibrillation potentials and sharp positive waves in all(attività

spontanea)


Segredo V, Caldwell JE, Mathay MA, et al. Persistent paralysis in critically ill patients after long-term

administration of vecuronium. N Engl J Med 1992; 327:524-8.

� Pz studiati al termine della somministrazione di vecu

� 7 paz con blocco nm persistente vs 9 normali:

� variabili discriminanti:» sesso femminile

» mg plasmatico ↑» pH arter. ↓» 3 desacetil vecu ↑» insuff renale


Case reports of prolonged paralysisAUT JOUR.,

YNMB DOSE DUR RIPR

Gooch CCM1991

Vecu/panc/Metoc

600/419/610

7/10/3 1

Vecu 315 6 2

Vecu/panc/metoc

87/90/406

4/12/12 1

Subramony

CCM,1991

Vecu 7700 20 4


Case reports of prolonged paralysisAut Jour.,

YNmb Dose Dur ripr

Gooch CCM,1991

Vecu 2780 25 3

Vecu 408 10 5

Vecu/panc

115/210

3 ?

Vecu 112 2 1-2

Panc 941 8 2

Vecu 2069 9 1


Tousignant C, Bevan D, Eisen A, Fenwick J, Tweedale M.Acute quadriparesis in an

asthmatic treated with atracurium CAN J ANAESTH 1995 / 42: 3 / pp224-7.

� An 18-yr-old male asthmatic was paralyzed with atracurium for a period of seven days to facilitate mechanical pulmonary ventilation. After withdrawal of the muscle relaxant, tof nm monitoring demonstrated rapid recovery of normal function. Three days later he developed acute quadriparesis without respiratory compromise. Electrophysiological studies showed normal conduction velocities, low compound muscle action potential amplitudes and evidence of denervation.


Tousignant et al.Acute quadriparesis in an asthmatic treated with atracurium CAN J ANAESTH 1995 / 42: 3 / pp224-7.

� Electrophysiological studies were performed at 15 and 21 days after admission. The first examination revealed normal motor and sensory nerve conduction velocities with small compound muscle action potentials in the arms and legs. There was no evidence of a transmission defect either to slow or fast stimulation rates. Needle electromyography (EMG) studies showed early evidence of denervation with membrane irritability and occasional fibrillations, particularly in the tibialis anterior. The second electrophysiological examination was similar to the first with moderate denervation, fibrillation and positive sharp waves in both anterior and posterior compartments of the legs in a fairly symmetrical fashion. By the 18th day after admission, he had regained considerable arm function with good strength but lower limbs remained weak. He did not exhibit any deep tendon reflexes. He returned to Japan before a muscle biopsy could be performed.


Tousignant C, Bevan D, Eisen A, Fenwick J, Tweedale M.Acute quadriparesis in an asthmatic treated with atracurium CAN J ANAESTH 1995 / 42: 3 / pp224-7.

� 164 h e 7230 mg di atrac � altri farmaci: midaz,fent,metiprednisolone,teofillina,salbutamolo,

eritromicina,cefixozime,� VIII giorno: apre occhi e muove arti a comando:� IX giorno; irrequieto;si siede e sporge le gambe � X giorno trachea estubata e ripete i movimenti:ma nel pomeriggio fatica

a sollevare il collo � XI :debolissimo :quadriplegico eccetto alcune dita e movimenti del

piede,senza deficit sensoriali o bulbari.


Diagnosi differenziale fra critical illness polyneuropathy e neuromuscular dysfunction in ICU

patients

� CIP» deficit sensitivo e

motorio» associaz con MOF e

sepsi

» outcome poor

» istologia….

� NMDICU» deficit motorio» non associata a MOF

e sepsi

» outcome good

» istologia miopatica,con livelli di degenerazione variabili e necrosi focale


Sindr.postparalitica ,dopo miorilassanti...

� storia� es obb.e lab.� Biopsia musc� Biopsia nerv.� EMG� NCS� decorso

� Uso di nmb

� deboleza diffusa,risparmio della sensibilità,aum CPK

� degeneraz filamenti spessiEM;perdita focale ATPasi MO:+ tardi necrosi

� CMAP piccoli:SNAP norm;Atrofia di tipo II

� favorevole in genere,ma mal.di base….

Abbreviaz:CMAP:compound action potental;SNAP:Sensory action potential:Ncs:nerve conduction study:Me microsc.elettron.MO;microsc.ottico


Critical illness polyneuropathy

� storia� es obb.e lab.� Biopsia musc� Biopsia nerv.� EMG� NCS� decorso

� Sepsi,anziani,severam.amalati,iperglicemia

� interessamento sensitivo e motorio.nn.cranici preservati

� degeneraz.assonale

� consistente con polineuropatia distale assonale sensorimotoria:

» CMAP bassi,potenz da fibrillaz,onde pos ampie;velocità conservata.

� protratto e spesso sfavorevle


Miopatia da steroidi

� storia

� es obb.e lab.

� Biopsia musc� Biopsia nerv.� EMG� NCS� decorso

� Processo acuto o cronico,+ comune nei musc prossimali,uso di steroidi,nmb,aminoglicosidi,ciclosporin….

� sequele sistemiche degli steroidi;modificaz cutanee,diabete,PA elevata,ecc….Associaz con rabdomiolisi

� atrofia fibre musc tipo II

� norm;nei casi più severi modificaz.ievem.miopatiche

� tendenzialm.favorevole

Esiste un modello animale:aum.espress dei rec.steroidei


Sindrome decondizionante

� storia� es obb.e lab.� Biopsia musc� Biopsia nern.� EMG� NCS� decorso

� Immobilità,ipercatabolismo

� debolezza diffusa,perdita massa muscolare

� atrfia fibre tipo II

� norm

� dipende dalla patol di base


Guillain Barrè


� Infez.virale,polineuropatia ascendente

� debolezza motoria diffusa;labilità autonomica

� non indicata

� compatibile con polineuropatia demielinizz. Sensorimotoria

� favorevole,infuenz.dalla plasmaferesi


Miastenia grave


� Variabile

� affaticabilità musc.� Non indicata

� risposta in decremento alla stimolaz ripetitiva:

� Potenz.delle Unità motorie variabili

� dipende dalla aggressività della malattia


Rabdomiolisi acuta


� Crush sindr.,overdose da farmaci,overdose da tossine

� CPK aum:mioglobinuria

� necrosi diffusa delle fibre musc.

� Attività spontanea con modificazioni miopatiche

� favorevole,ma mal.di base...


Mielinolisi pontina centrale


� Alterazioni rapide degli elettroliti

� locked in sindr.

� Non indic

� norm

� sfavorevole


Disfunz nm e malattie critiche

� Associaz nota


Eziologia e caratteristiche della debolezza muscolare dopomal.critiche

Eziologia e caratteristiche della debolezza muscolare dopomal.critiche

rianimazione?rianimazione?

interessamento motorio esensitivo

interessamento motorio esensitivo

CIPCIP

debolezza diffusadebolezza diffusa

sindr.postnmbsindr.postnmb

miopatia dasteroidi(prossimali..però)miopatia dasteroidi(prossimali..però)

sindr decondiz.sindr decondiz.

Guillain BarrèGuillain Barrè

miasteniamiastenia

liquorliquor

CIP:norm.CIP:norm.

G/B;abnormG/B;abnorm


Altri problemi di diagnosi differenziale in TI:I

� Guillain-Barrè» poliradicoloneurite» dissociaz albumino-

citologica

» blocco di conduzione nervosa

� Miasthenia gravis


Altri problemi di diagnosi differenziale in TI:II

� Miopatia da steroidi» associata alla

somministrazione di steroidi

» coinvolgim,.della musc prossimale

» non c’è attività spontanea

� Neuropatia assonica» attività abbondante

spontanea,ma a 2-3 settimane dall’evento

» i potenziali di denervazione durano mesi

» riprese lente


Altri problemi di diagnosi differenziale in TI:III

� Miosite» segni istol di

infiammazione….


Problemi di diagnosi differenziale in ICUProblemi di diagnosi differenziale in ICUchiamare i neurologi........chiamare i neurologi........

clinicaclinica liquorliquorblocchicond.nerv.blocchicond.nerv. istolistol

Critical illness polyneuropathyCritical illness polyneuropathy MOF,sepsiMOF,sepsi nono sisi nono

Sindr.catabolica mopaticaSindr.catabolica mopatica ut supraut supra nono nono sisi

Guillain BarrèGuillain Barrè ezioleziol dissoc.alb-citoldissoc.alb-citolnono nono

Miasthenia gravisMiasthenia gravis tipicatipica nono tipici dastim.nerv.ripetitivatipici dastim.nerv.ripetitiva

nono

Sindrome neuromuscolarepostmiorilassantiSindrome neuromuscolarepostmiorilassanti

nmb,corticosternmb,corticosternono variabvariab deg.focale.necrosideg.focale.necrosi

Miopatie da steroidiMiopatie da steroidi steroidisteroidi nono nono nono


Effetti centrali dei miorilassanti

� Negli animali(ratti,infus diretta nel CSF):debolezza,irritaz corticale,convulsioni…(AA.76;1304-1309: 1993).

� I nmb possono superare la barriera ematoencefalica se:» la barriera diviene meno selettiva….» i dosaggi sono elevati» vengono iniettati direttamente...


Studi comparativi in ICU


Khuenl-Brady KS, Reitstätter B, Schlager A, et al. Long-term administration of pancuronium and pipecuronium in the

intensive care unit. Anesth Analg 1994; 78:1082-6.

� Ricerca della dose ottimale di panc o pipec

� TI;trauma cranico,politrauma � 60 paz.(30 vs 30)� sedazione e analgesia continue� aperto� monitoraggio nm con neurostimolatore.


Metodiche di somministrazione Khuenl-Brady KS, Reitstätter B, Schlager A, et al. Long-term administration of pancuronium and pipecuronium in the

intensive care unit. Anesth Analg 1994; 78:1082-6.

� Bolo iniziale ev di panc o pipec 8 mg� monitoraggio nm con TOF ogni 30 min� valutaz visiva e tattile da

studenti,addestrati� somministraz successive a comparsa di

I-II twitches.


Khuenl-Brady KS, Reitstätter B, Schlager A, et al. Long-term administration of pancuronium and pipecuronium in the intensive care unit. Anesth Analg 1994; 78:1082-6.


Prielipp RC, Coursin DB, Scuderi PE, et al. Comparison of the infusion requirements and recovery profiles of vecuronium

and cisatracurium 51W89 in intensive care unit patients. Anesth Analg 1995; 81:3-12

0

50

100150

200

250

300

350

400

dur inf(h) cons tof 0.70min) ritardi

Monit.con I del tof visibile

vecuroniumcisatrac

0,92,6

Micr/kg/h

Multicenter,randomized,double blind


Magorian T, Wood P, Caldwell J, et al. The pharmacokinetics and neuromuscular effects of rocuronium bromide in patients

with liver disease. Anesth Analg 1995; 80:754-9.

� Control» vol.comp

centr(lt):5.96» vol.distr(lt):16.4» hl(min):75

� Liver disease

» 7.87» 23,4» 111


Eliminazione del rocuronium

0

10

20

30

40

50

60

70

80

%

urine feci

anim minanim maxuomo minuomo maxuom max 0.9

Dati di archivio Organon Teknika


Eliminazione del rocuronium

0

5

10

15

20

25

30

35

%

urine bile feci

<24 h<48 h<7 gg

Proost JH,Eriksson LI,Mirakhur RK,Roest G,Wierda JMKHUrinary,biliary and faecal excretion of rocuronium in humans.BJA 85;717-23:2000


Proost JH,Eriksson LI,Mirakhur RK,Roest G,Wierda JMKHUrinary,biliary and faecal excretion of rocuronium in humans.

BJA 85;717-23:2000

� L’analisi farmacocinetica del rocu contenuto nel drenaggio biliare a T rivela un decremento biesponenziale con t 1/2 di 2.3 e 16 hr rispettivamente ;la I emivita coincide con quella plasmatica,la II è molto più lunga e diventerà apparente nel caso di somministrazioni prolungate; infatti la mean terminal hl dopo somministraz di 1-2 gg era di 6-24 h in paz con MOF.(vedi ref.bibl).La emivita terminale più lunga dopo somministraz prolungate dimostra che il VDSS è molto più ampio di quello osservato in studi dopo dosi singole……

� Sparr HJ,Wierda JMKH,Proost JKH,Keller C,Khueny-Brady K.Pharmacodynamics and pharmcokinetics of rocuronium in intensive care patients.BJA 1997;78:267-73.

� Kern H,Daugherty M,Sneyd JR,Proost JH,Spies C,Kox W.Pharmacokinetics of the long term use of rocuronium in ICU patients with multiple organ failure.(MOF)Anaesth.Intensivther.Notfallmed.1998;33 suppl 3:s432.


Sparr HJ,Wierda JMKH,Proost JKH,Keller C,Khueny-Brady K.Pharmacodynamics and pharmacokinetics of rocuronium

in intensive care patients.BJA 1997;78:267-73

� patients in the bolus and infusion groups, respectively. Median total dose requirements, recovery times and pharmacokinetics of rocuronium in 32 intensive care patients.

� initial dose of 50 mg, rocuronium was administered as maintenance doses of 25 mg whenever two responses to train-of-four (TOF) stimulation reappeared (bolus group; n=27) or by continuous infusion to maintain one response in the TOF (infusion group; n=5).

� Median requirements for rocuronium were 27.4 (range 14.5–68.3) mg h-

1 and 43.7 (30.9–50.3) mg h-1 in duration of rocuronium administration was 29.0 (12.4–95.5) h and 63.4 (24.0–140.3) h, respectively. Median time from administration of the last bolus dose and end of infusion to recovery of the fourth twitch in the TOF was 100 (45–300) min and 60 (15–155) min, respectively. Arterial blood samples were obtained for up to 10 h after cessation of rocuronium administration, and concentrations of the parent compound and its putative metabolites were measured using high pressure liquid chromatography (HPLC). The plasma concentration profile (n=12) was described adequately by a two-compartment model. Mean plasma clearance (CI), steady-state distribution volume (Vss), mean residence time (MRT) and elimination half-life (T1/2b) were 3.16 (SD 1.15) ml kg-1 min-1, 769 (334) ml kg-1, 262 (120) min and 337 (163) min, respectively. Recovery times, Vss, MRT, and T1/2b differed from previously published data obtained after rocuronium infusion of moderate duration in surgical patients.


Variabili farmacocinetiche medie del

rocuronium;confronto fra pazienti ICU e chirurgici.


Riprese della funzione nm dopo rocuronium;confronto fra pazienti ICU e chirurgici.


Tavola comparativa sulle proprietà deinmb utili in TI

Tavola comparativa sulle proprietà deinmb utili in TI

cumulativitàcumulativitàindipendenzad'organoindipendenzad'organo metaboliti attivimetaboliti attivi

effettiemodinamicieffettiemodinamici

atracuriumatracurium nono sisi laudlaud sisi

cisatracuriumcisatracurium nono sisi laudlaud (si)(si)

pancuroniumpancuronium sisi no,reneno,rene si,3 OH pancsi,3 OH panc sisi

pipecuroniumpipecuronium sisi no,feg.reneno,feg.rene si,3 desac.pipsi,3 desac.pip nono

doxacuriumdoxacurium (no)(no) (si)(si) nono nono

vecuroniumvecuronium sisi no,fegato,reneno,fegato,rene si,3,17,3-17desac.vecsi,3,17,3-17desac.vec

nono

rocuroniumrocuronium (si)(si) no,epato-biliareno,epato-biliare nono nono


Raccomandazioni finali

� Utilizzare un nmb solo quando necessario...

� Scegliere un nmb organo-indipendente� monitorizza la risposta nm :

» obbiettivamente ( TOF a intervalli appropriati al farmaco)

» clinicamente

� non utilizzare blocchi profondi� evitare farmaci potenzianti il blocco nm.


Linee guida per l’impiego dei miorilassanti in TI

� Disponibilità di monitoraggio (quantitativo) delle funzione nm;

� utilizzo del monitoraggio ad intervalli appropriati� pazienti sedati per evitare psicosi da risveglio� i pazienti devono ricevere un supporto ventilatorio

adeguato� il personale(infermieristico??) deve essere istruito

nella farmacologia e nel significato dell’impiego dei miorilassanti


Fine

Dedica cura alla fine come all’inizio


Mc Govern I,Cunliffe A,Goldhill DR.Assessment of neuromuscular function in intensive care patients and

volunteers,BJA 84:688P;2000

0

10

20

30

40

50

60

volont ICU<7gg ICU>7gg

F 10/30MRR30;

F 10/30:ratio of force generated at supramax stimulation at 10 Hz vs 30 Hz.MRR30%:max relax rate of the muscle following stim.at 30 Hz


Murray MJ,Strickland RA,Weiler C. The use of neuromuscular blocking drugs in the intensive care unit:a US

perspective.Intens Care Med. 1993;19:s40-44.

� Uso di nmb» :0-15%(neonati)(1-2 paz/mese)» pazienti più gravi(Apache II 24.4 vs 11.4)» insuff resp;9%(sul 21%) del totale» panc 27%,vecu 56%,atrac 17%

» < 1g:78%» >1-3 sett 22%» 1 paz/anno ammesso alla unità di ventilazione cronica

per somministrazione pregressa di nmb.


Klessig HT, Geiger HJ, Murray MJ, et al. A national survey on the practice patterns of anesthesiologist intensivists in the use

of muscle relaxants. Crit Care Med 1992; 20:1341-5. � risposta a questionario scritto � 185/339 anestesisti in possesso del certificato di competenza in

Critical care(USA)� ICU med/chir con in media 19 letti (6-64)

� 10 paz adulti /mese e 19 bambini/mese in media con necessità di nmb

� farmaci:vecu 52% ;panc 28%,metub 5,atrac 3 � monitoraggio;

» giudizio clinico 55%» 34% neurostim perif;

» 11% no monit� se questi intensivisti usano poco il monitoraggio,figuratevi gli

altri….


Dasta JF,Fuhrmann TM,McCandles C. Patterns of prescribing and administering drugs for agitation and pain in patients in a

surgical intensive care unit.CCM 1994;22:974-980

� TI chirurgica� sett 1992-genn ‘93� 221 paz;30 medici prescrittori e 200 nurse trascrittori� 1.9 ±1.4 farmaci/paz� vecu 3.2%(sempre con morf e/o BDZ)


Hogue CW Jr, Ward JM, Itani MS, et al. Tolerance and upregulation of acetylcholine receptors follows chronic

infusions of d-tubocurarine. J Appl Physiol 1992; 72:1326-31

� This study confirms that chronic doses of dTC cause tolerance to its effects and proliferation of nAChR even in the absence of immobilization. The absence of nAChR changes in the diaphragm may be due to the higher margin of safety of the diaphragm for muscle relaxants than for peripheral muscles. Intensive Care Unit patients receiving chronic infusions of dTC to facilitate mechanical ventilation will require increased doses with time.


Martyn JAJ, White DA, Gronert GA, et al. Up and down regulation of skeletal muscle acetylcholine receptors. Effects on

neuromuscular blockers. Anesthesiology 1992; 76:822-43.


Livelli plasmatici di laudanosinaEastwood,NB,Boyd AH,Parker cir,Hunter,JM.Pharmacokinetics of 1r-cis1’rcis atracurium besylate(51W89)and

plasma laudanosine concentrations in health and chronic renal failure ,BJA 1995,75.431-5.Fahey MR,Rupp SM,Canfell C,Mier RD,Sharma M,Castagnoli K,Hennis PJ.Effect of renal failure on laudanosine

excretion in man.BJA 1995;57:1049-51)

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

sani insuff ren

atraccis


Dosi di laudanosina(µg/ml):subepilettogene….

0

0,2

0,4

0,6

0,8

1

1,2

atrac 2 ED95 laudanos cis 4 ED95

Fahey 1984Chapple 1987Lien 1996


Dosi di laudanosina(µg/ml):epilettogene:da Shi WZ, Fahey

MR, Fisher DM, Miller RD: Modification of central nervous system effects of laudanosine by inhalational anaesthetics. BrJ Anaesth 1989; 63:598 600‑

….Rapporto eccitazione SNC/concentrazione

plasmatica di laudanosina

0

2

4

6

8

10

12

14

conc

.pla

sm

no anestenfl 2%haloth 1%isof 1,6%enfl 2% + ipocapniaN2O 70%haloth 1%+N2O70%haloth 0,7%


Concentrazioni di laudanosina dalla letteratura

0

1

2

3

4

5

6

microgr/ml

normali insuff renale

Fahey 1984Ward 1985Ward 1986Yate(1985)

0,7-1.9 mg/kg/hr per 40-139 hr,ICU

↓

↓


Problemi della laudanosina

� Metabolismo:» 70% biliare» 30% renale

� metabolizzazione epatica?:tetraidropapaverina?

� Rapporto CSF/plasma:0.3-0.6(Fahey 1985)

� Hennis( 1985):segni di risveglio dopo bolo di 2 mg/kg(cani in anestesia alotanica):

� Miller (1985): Mac dell’alotano aumentato del 30% nei conigli a conc tra 0.4-0.8 µg/ml


Prielipp RC, Coursin DB, Scuderi PE, et al. Dose response, safety, and recovery profile of a new neuromuscular blocking drug, 51W89, in ICU patients [abstract] Anesthesiology 1994;

81(3A):A258.


Prielipp RC, Coursin DB, Scuderi PE, et al. Comparison of the infusion requirements and recovery profiles of vecuronium

and cisatracurium 51W89 in intensive care unit patients. Anesth Analg 1995; 81:3-12

� . We compared the dose-response and recovery pharmacodynamics of a new intermediate-acting NMB drug, cisatracurium besylate, to the intermediate-acting NMB drug, vecuronium (VEC), in a prospective, randomized, double-blind, multicenter study in critically ill adults. After informed consent, 58 mechanically ventilated ICU patients from five medical centers were randomized to receive either cisatracurium or VEC. Fifty-four of the 58 patients received NMB drugs before entering this study but demonstrated at least partial recovery (> or = one twitch) in the train-of-four (TOF) response before initiation of the NMB study drug.


Prielipp RC et al.:II

� NMB drug infusion was titrated by peripheral nerve stimulation to maintain at least one twitch in the TOF response. NMB drugs were infused for 1-5 days. After discontinuation of NMB drug infusion, recovery of neuromuscular transmission was monitored with an accelerometer. NMB drug infusion for 28 cisatracurium patients averaged 2.6 +/- 0.2 (mean +/- SEM) micrograms.kg-1.min-1 with a mean duration of 80 +/- 7 h. After discontinuing cisatracurium administration, recovery to 70% TOF ratio averaged 68 +/- 13 min. The mean infusion rate for 30 VEC patients was 0.9 +/- 0.1 micrograms.kg-1.min-1 with a mean duration of 66 +/- 12 h. Neuromuscular recovery after VEC averaged 387 +/- 163 min, which was significantly longer (P = 0.02) than that after cisatracurium. Prolonged recovery of neuromuscular function after discontinuation of NMB drug infusion (identified by the primary investigator at each medical center) was reported in two cisatracurium patients and 13 VEC patients (P = 0.002), and occurred despite the routine use of neuromuscular twitch monitoring. Seven VEC and one cisatracurium patients died during the infusion of study drug or within 48 h after discontinuation of the NMB drug infusion. In summary, we found recovery of neuromuscular function after discontinuation of NMB drug infusion in ICU patients is significantly faster with cisatracurium than with VEC. In addition, routine neuromuscular monitoring was not sufficient to eliminate prolonged recovery and myopathy in ICU patients.


Fung, D L, White, D. A., M.D.†; Gronert, G. A., M.D.*; Disbrow, E., M.A.‡

The Changing Pharmacodynamics of Metocurine Identify the Onset and Offset of Canine Gastrocnemius Anesthesiology

83:134-140, 1995� Immobilization of skeletal muscle results in disuse atrophy and

resistance to nondepolarizing muscle relaxants. We studied the pharmacodynamics of metocurine (MTC) to identify the development and recovery of disuse-related resistance to MTC.

� Methods: Nineteen dogs underwent cast immobilization of a hind limb for as long as 3 weeks. Before, during, and after casting, dogs were intermittently anesthetized with thiamylal-N2O-fentanyl. The blood concentration of MTC and the corresponding degree of paralysis after a

brief infusion were recorded and were used to characterize the pharmacokinetics and pharmacodynamics of MTC.

� Results: Pharmacodynamic study of the response to MTC demonstrated resistance by the 4th day of casting. The effect-site concentration associated with 50% paralysis of twitch increased after 3 weeks from approximately 250 to 750 ng/ml. After cast removal, resistance persisted for 2 more weeks. Six weeks after cast removal, the effect-site concentration associated with 50% paralysis of twitch was normal in every dog.

� Conclusions: Within the context of this study of immobilization disuse atrophy, pharmacokinetic and pharmacodynamic characterization of antagonist responses can be used to infer muscle disuse-related changes in acetylcholine receptors.


Magorian T, Wood P, Caldwell J, et al. The pharmacokinetics and neuromuscular effects of rocuronium bromide in patients

with liver disease. Anesth Analg 1995; 80:754-9.� To determine the effect of liver disease on the pharmacokinetics of

rocuronium,� 0.6 mg/kg (twice the ED95) to 10 patients with liver disease and

compared these results to values in 10 healthy surgical patients.� Anesthesia was induced with thiopental and maintained with isoflurane

(0.9%-1.1% end-tidal concentration) and nitrous oxide (60%).� Venous blood samples were obtained for 6 h after rocuronium injection

and plasma concentrations were measured using gas chromatography� Pharmacokinetic differences between groups were determined using a

population-based pharmacokinetic analysis (NONMEM).


Magorian ET AL:II

� Hepatic impairment did not alter the plasma clearance of rocuronium (217 +/- 21.8 mL/min, mean +/- SE, for both groups), but did increase the volume of the central compartment (5.96 +/- 1.01 L for controls, 7.87 +/- 1.33 L for patients with liver disease) and volume of distribution at steady state (16.4 L for controls, 23.4 L for patients with liver disease). In turn, elimination half-life was longer in patients with liver disease (111 min) compared to controls (75.4 min). The authors conclude that liver disease alters the pharmacokinetics of rocuronium by increasing its volume of distribution. The longer elimination half-life might result in a longer duration of action of rocuronium in patients with liver disease, particularly after prolonged administration.


� 8: Elliot JM, Bion JF. The use of neuromuscular blocking drugs in the intensive care practice. Acta Anaesthesiologica Scandinavica 1995; 39:70-82.

� 9: Watling SM, Dasta JF. Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: a review of the literature. Critical Care Medicine 1994; 22:884-893.

� 10: Meyer KC, Prielipp RC, Grossmann JE, Coursin DB. Prolonged weakness after infusion of atracurium in two intensive care unit patients. Anesthesia and Analgesia 1994; 78:722-724.

� 11: Agoston S, Seyr M, Khuenl-Brady KS, Henning RH. Use of neuromuscular blocking agents in the intensive care unit. Anesthesiology Clinics of North America 1993; 11:345-359.

� 12: Viby-Mogensen J. Monitoring neuromuscular function in the intensive care unit. Intensive Care Medicine 1993; 19 (Suppl. 2):74-79.

Health & Medicine

Muscle relaxants in the ICU