Handbook of Neurosurgery 8th Edition-4

Neurophysiology and Regional Brain Syndrom es 99 5. pure w ord blin dn ess: AKA alexia w ith out agraph ia (rare) due to lesion in parieto-occipital lobe 3 th at in terrupts con n ect ion s bet w een left an gular gyrus an d both occipital lobes. Patien ts can w rite, but are un able to read w h at th ey’ve w rit ten , an d frequen tly seem un con cern ed about th is. Often accom pan ied by loss of abilit y to n am e colors. Readin g an d n am in g n um bers usually preserved 3.2.3 Fost er Kennedy syndrom e Nam ed after n eurologist Robert Foster Ken n edy. Usually from olfactor y groove or m edial th ird sph e- n oid w in g tum or (usually m en in giom a). Now rare due to early detect ion by CT or MRI. Classic t riad: 1. ipsilateral an osm ia 2. ipsila tera l cen tral scotom a (w ith opt ic a t rophy due pressure on optic n er ve) 3. cont ra la tera l papilledem a (from elevated ICP) Occasion ally ipsilateral proptosis w ill also occur due to orbital invasion by tum or. 3.2.4 Brain st em and relat ed syndrom es Weber’s syndrom e Cr. N. III palsy w ith con tralateral h em iparesis; also see Lacun ar st rokes (p. 1267). Th ird n er ve palsies from paren chym al lesion s m ay be relatively pupil sparin g. Benedikt’s syndrom e Sim ilar to Weber’s, plus red n ucleus lesion . Cr. N. III palsy w ith con tralateral h em iparesis except arm w h ich h as hyperkin esia, ataxia, an d a coarse in ten tion trem or. Lesion : m idbrain tegm en tum involv- in g red n ucleus, brach ium conjun ct ivum , an d fascicles of III. Millard-Gubler syndrom e Facial (VII) & abducens (VI) palsy + con tralateral h em iplegia (cort icospin al tract) from lesion in base of pon s (usually isch em ic in farct, occasion ally tum or). 3.2.5 Parinaud’s syndrom e Definit ion AKA dorsal m idbrain syn drom e, AKA pretectal syn drom e. As origin ally described, a supran uclear paralysis of vert ical gaze resultin g from dam age to th e m esen ceph alon .13 Th ere are a n um ber of som ew h at var yin g descript ion s, h ow ever m ost in clude: ● supran uclear upw ard gaze palsy (i.e. upgaze palsy a ect in g both volun tar y saccadic an d pursuit m ovem en ts, w ith preser vation of vestibulo-ocular or oculoceph alic (doll’s eyes) reflexes in m ost cases). Horizon tal eye m ovem ents are spared ● lid retract ion (Collier’s sign ): NB: upgaze palsy + lid retract ion produces th e “settin g sun sign ” ● convergen ce palsy ● accom m odation palsy ● less com m on association s: pseudoabducen s palsy (AKA th alam ic esotropia), see-saw nystagm us, fixed pupils, dissociated ligh t-n ear respon se (pseudo-Argyll Robertson ), convergen ce spasm , nys- tagm us retractorius, in tern uclear oph th alm oplegia (INO) Skew deviation m ay be a un ilateral varian t of Parin aud’s syn drom e. Syn drom e of th e Sylvian aqueduct: Parin aud’s syn drom e (PS) com bined w ith dow n gaze palsy. Di erent ial diagnosis Et io lo gie s 1. m asses pressin g directly on quadrigem in al plate (e.g. pin eal region tum ors) 2. elevated ICP: secon dar y to com pression of m esen ceph alic tect um by dilated suprapin eal recess, e.g. in hydroceph alus

100 Anatom y and Physiology 3. stroke or hem orrhage in upper brainstem 4. m ultiple sclerosis (MS) 5. occasionally seen w ith toxoplasm osis Con dition s a ect in g ocular m otilit y th at could m im ic th e upgaze palsy of PS: 1. Guillain -Barré syn drom e 3 2. m yasth en ia gravis 3. botulism 4. hypothyroidism 5. th ere m ay be a gradual ben ign loss of upgaze w ith sen escen ce 3.3 Jugular foram en syndrom es 3.3.1 Applied anat om y Th e jugular foram en (JF) is on e of a pair of open in gs bet w een th e lateral par t of th e occipital bon e an d th e pet rous par t of th e tem poral bon e. Th e foram en is usually divided in 2 by a bony spin e from th e pet rous tem poral bon e th at attach es via a fibrous bridge (w h ich is bony in 26%) to th e jugular process of th e occipital bon e.14 Th e righ t JF is usually larger th an th e left.14,15 Th e carot id ridge sepa- rates th e JF from th e n earby carotid can al. Con ten ts of jugular foram en (JF): Cr. N. IX, X, XI, petrosal sin us, sigm oid sin us, som e m en in geal bran ch es from th e ascen din g ph ar yn geal an d occipital art eries.16 Nearby: Cr. N. XII passes th rough th e hypoglossal can al just above th e occipital con dyle. Th e caro- tid artery w ith the sym pathetic plexus enters the carotid canal. Com part m en talizat ion of th e jugular foram en rem ain s con troversial. As m any as 4 foram in a h ave been described over th e years. Alth ough it h ad been recogn ized previously, an early 2-com par tm en t description w as publish ed in 1967 by Hovelacque.17 In th is, th e bony spin e (± its fibrous septum ) divide th e foram en in to: ● pars vascularis: th e larger posterolateral com par tm en t con tain in g th e vagal n er ve (an d bran ch in g Arn old’s n er ve), spin al accessory n er ve an d th e in tern al jugular vein ● pars n er vosa: th e sm aller an terom edial com part m en t con tain in g th e glossoph aryn geal n er ve (an d bran ch in g Jacobson’s n er ve), in ferior petrosal sin us an d m en in geal bran ch of th e ascendin g ph a- ryngeal artery A publication in 1997 described these 3 com partm ents18: ● Sigm oid: large posterolateral com part m en t con tain in g sigm oid sin us ● Pet rosal: sm aller an terom edial com part m en t con tain in g petrosal sin us ● In trajugular or n eural: CN 9, 10 an d 11 3.3.2 Clinical syndrom es General inform at ion A n um ber of eponym ous syndrom es w ith som e conflicting findings in the literature have been described. See Table 3.2 for a sum m ar y an d Fig. 3.2 for a sch em atic diagram of deficits in various JF syn drom es. Vernet’s syndrom e: CN IX, X & XI palsy AKA syn drom e of th e jugular foram en . Usually due to in tracran ial lesion . Etiologies in clude: jugular foram en t um ors, ICA dissect ion s, m ycotic an eur ysm s of th e extern al carotid, th rom bosis of th e jugular vein , follow in g carotid en darterectomy. Sym ptom s: un ilateral paralysis of th e palate, vocal cords, stern ocleidom astoid, trapezius, w ith loss of taste in th e posterior 1/3 ton gue, an esthesia of th e soft palate, lar yn x an d ph ar yn x. Collet -Sicard syndrom e Palsies of CN IX, X, XI & XII w ith out sym path etic involvem en t. More likely w ith lesion outside skull. If caused by an in tracran ial lesion , it w ould h ave to be of such a large size th at it w ould usually pro- duce brain stem com pression → long tract findings.

Neurophysiology and Regional Brain Syndrom es 101 Table 3.2 Cranial nerve dysfunction in jugular foram en syndromes Ne r ve Result of lesion Syndrom e Vernet Collet Villaret Tapia Jackson Schm idt Sicard IX loss of taste and sensation in posterior X X X 3 third of tongue X paralysis of vocal cords & palate, XXX X X X anesthesia of pharynx & larynx XI weak trapezius & SCM XX X ± X X XII tongue paralysis & atrophy XX X X sym pathetics Horner’s syndrome X± Key: X indicates dysfunction / deficit (lesion) of that nerve; ± indicates involvem ent m ay or may not occur SS XI X IX IPS jugular Fig. 3.2 Schematic diagram of the fo ra m e n jugular foram en (coronal section {Classical through left jugular foram en viewed fmo raag nm ue nm from the front). Includes the classic 2 Ta xo n o m y compartment model and the 3 com- partm ent classification of Katsuta et {3 Compart- al.18 Jugular foram en syndromes are illustrated: a solid line through a ment Model nerve indicates a deficit, dashed line indicates ± involvement. Ve rn e t IJV Schm idt XII to pharynx Co lle t - hypoglossal Sicard to larynx canal Jackson Ta p ia sym p at h e t ics (on carotid) Villaret Etiologies in clude: con dylar an d Je erson’s fract ures, in tern al carotid dissect ion , prim ar y an d m etastatic t um ors, Lym e disease an d fibrom uscular dysplasia. Sym ptom s: un ilateral paralysis of th e palate, vocal cords, stern ocleidom astoid, t rapezius, tongue, loss of taste in posterior 1/3 tongue, an esth esia of soft palate, lar yn x an d ph ar yn x.

102 Anatom y and Physiology Villaret’s syndrom e : CN IX, X, XI & XII palsy + sym pat het ic dysfunct ion AKA posterior retropharyngeal syndrom e, AKA the nervous syndrom e of the posterior retroparotid space). Collet-Sicard syndrom e with sympathetic involvem ent. Usually due to retropharyngeal leasions. Etiologies in clude: parotid t um ors, m etastases, extern al carotid an eur ysm an d osteom yelitis of the skull base. Sym ptom s: as w ith Collet-Sicard + Horn er’s syn drom e. 3 Tapia syndrom e : CN X & XII palsy (± XI) AKA Matador’s disease (first described in a bullfigh ter by An ton io Garcia Tapia). Som e auth ors describe an in tracran ial an d extracran ial form .19 Etiologies in clude: oral in t ubation (m ajorit y of cases prior to 2013), m etastases, rarely associated w ith carotid or vertebral artery dissections. Sym ptom s: h oarsen ess of voice, dysph agia secon dar y to in coordin at ion of tongue an d food bolus propulsion , un ilateral atrophy an d paralysis of th e tongue, ± paralysis of stern ocleidom astoid & t ra- pezius, sparin g th e soft palate. (Hughlings) Jackson’s syndrom e: CN X, XI & XII palsy First described in 1864 w ith un ilateral paralysis of th e soft palate, lar yn x, stern ocleidom astoid, t ra- pezius an d tongue. Schm idt syndrom e : CN X & XI AKA vago-spin al syn drom e. Sch m idt first described th is in 1892. Un ilateral vocal cord an d paralysis of stern ocleidom astoid, soft palate, lar yn x an d t rapezius. Re fe r e n ce s [10] Tolterod in e for Overact ive Blad der. Med Letter. 1998; 40:101–102 [1] Neuw elt EA, Barn ett PA, McCorm ick CI, Fren kel EP, et al. Osm otic Blood-Brain Barrier Modification : [11] Tam sulosin for Ben ign Prostatic Hyp erp lasia. Med Mon oclon al An tibody, Album in , an d Meth ot rexate Letter. 1997; 39 Deliver y to Cerebrospin al Fluid an d Brain. Neuro- surger y. 1985; 17:419–423 [12] Adam s RD, Victor M. Prin cip les of Neu rology. 2n d ed. New York: McGraw -Hill; 1981 [2] Neuw elt EA, Maravilla KR, Fren kel EP, et al. Use of En h an ced Com puterized Tom ograph y to Evaluate [13] Pearce JM. Parin au d's syn drom e. J Neu rol Neurosurg Osm otic Blood-Brain Barrier Disruption . Neurosur- Psych iat r y. 2005; 76 gery. 1980; 6:49–56 [14] Rh oton AL, Jr, Bu za R. Microsu rgical an atom y of th e [3] Marcus JC. Flexor Plan tar Resp on ses in Ch ildren jugular foram en. J Neurosurg. 1975; 42:541–550 W ith Upper Motor Neuron Lesion s. Arch Neurol. 1992; 49:1198–1199 [15] Osunw oke EA, Oladip o GS, Gw u in eream a IU, Ngao- kere JO. Morph om etric an alysis of th e foram en [4] Doh rm an n GJ, Now ack W J. Th e Upgoin g Great Toe: Optim al Meth od of Elicitation . Lan cet. 1973; 1:339– m agn u m an d jugular foram en in ad u lt sku lls in 341 sou th ern Nigerian p op ulation . Am J Sci In d ust Res. 2012; 3:446–448 [5] Hou ten JK, Noce LA. Clin ical correlat ion s of cervical [16] Svien HJ, Baker HL, Rivers MH. Ju gular Foram en m yelopathy an d the Ho m an n sign . J Neurosurg Syn drom e and Allied Syn drom es. Neurology. 1963; Spin e. 2008; 9:237–242 13:797–809 [17] Hovelacqu e A. Osteologie. Paris, Fran ce: G. Doin an d [6] Glaser JA, Cu re JK, Bailey KL, Morrow DL. Cer vical Cie; 1967; 2 spin al cord com pression an d th e Ho m an n sign . [18] Katsu ta T, Rh oton AL, Jr, Matsush im a T. Th e ju gular Iowa Orthop J. 2001; 21:49–52 foram en : m icrosurgical an atom y and operative approach es. Neurosurger y. 1997; 41:149–201; dis- [7] MacDiarm id SA. Th e ABCs of Neu rogen ic Bladd er cussion 201-2 for th e Neurosurgeon . Con tem p Neu rosu rg. 1999; 21:1–8 [19] Krasn ian ski M, Neud ecker S, Sch luter A, Krau se U, W interholler M. Cen tral Tapia's syn drom e (\"m ata- [8] You m an s JR. Neu rological Su rgery. Ph ilad elph ia dor's disease\") caused by m etastatic hem angiosar- 1982 com a. Neurology. 2003; 61:868–869 [9] Wein AJ, Walsh PC, Ret ik AB, Vau gh an ED, Wein AJ. In: Neurom uscular Dysfu n ction of th e Low er Uri- n ar y Tract an d Its Treatm en t . Cam pbell's Urology. 7th ed. Ph ilad elp h ia: W .B. Sau n d ers; 1998:953– 1006

Part II 4 Neuroanesthesia 104 5 Sodium General and Neurology 110 Hom eostasis and 126 Osm olalit y 6 General 132 Neurocritical Care 144 7 Sedatives, 153 Pa ra lyt ics, 174 An a lg e sics 8 Endocrinology 194 9 Hem atology 10 Neurology for Ne u r o su r g e o n s 11 Neurovascular Disorders and Ne u ro t o xico lo g y II

104 General and Neurology 4 Neuroanest hesia 4.1 General inform at ion Table 4.1 sh ow s th e Am erican Society of An esth esiologists (ASA) gradin g system to estim ate an es- th etic risk for various con dition s. For issues related to in tracran ial pressure (ICP), cerebral perfusion pressure (CPP), in tracran ial 4 con stituen ts, etc., see ICP prin ciples (p. 856). For cerebral blood flow (CBF) an d cerebral m etabolic rate of oxygen con sum ption (CMRO2), see CBF an d oxygen utilization (p.1264). Param eters of prim ary relevance to neurological surgery that can be m odulated by th e a n e st h esiolo gist : 1. blood pressure: on e of th e factors th at determ in es CPP as w ell as spin al cord perfusion . May n eed to be m an ipulated (e.g. reduced w h en w orking on an an eurysm , or in creased to en h an ce collateral circulation durin g cross clam ping). Measurem en t by arterial lin e is m ost accurate an d depen din g on th e patien t’s presentation an d th e plan n ed procedure, often sh ould be placed pri- or to in duct ion of an esth esia. For in tracran ial procedures, th e ar terial lin e sh ould be calibrated at th e extern al auditor y m eatus to m ost closely reflect in tracran ial blood pressure 2. jugular ven ous pressure: on e of th e factors th at in fluen ces ICP 3. ar te rial CO2 te n sion (PaCO2): CO2 is t h e m ost p ot en t cerebral vasod ilator. Hyp er ven t ilat ion red u ces PaCO2 (h yp ocap n ea) w h ich d ecreases CBV bu t also CBF. Goal is gen e rally en d t id al CO2 (ETCO2) of 25–30 m m Hg w it h a correlat in g PaCO2 of 30–35. Use w it h care for ste reo- tactic procedures to m in im ize shift of int racranial con ten ts w h en using th is m eth od to con- t rol ICP4 4. arterial O2 ten sion 5. hem atocrit: in neurosurgery it is critical to balance oxygen carr ying capacity (decreased by ane- m ia) again st im proved blood rh eology (im paired by elevated Hct ) 6. patien t tem perature: m ild hypotherm ia provides som e protect ion again st isch em ia by reducing th e cerebral m etabolic rate of oxygen (CMRO2) by ≈ 7%for each 1° C drop 7. blood glucose level: hyperglycem ia exacerbates isch em ic deficits5 8. CMRO2: reduced w ith cer tain n euro-protect ive agen ts an d by hypotherm ia w h ich h elps protect against isch em ic injur y 9. in cases w h ere a lum bar drain or a ven tr icular drain h as been placed: CSF out put 10. elevation of th e h ead of th e pat ien t: low erin g th e h ead in creases arterial blood flow, but also in creases ICP by im pairin g ven ous outflow 11. in travascular volum e: hypovolem ia can im pair blood flow in n eurovascular cases. In surgery in th e pron e position , excessive fluids m ay con tribute to facial edem a w h ich is on e of th e risk fac- tors for PION (p. 1056) 12. position in g injuries: during th e procedure, th e patien t’s position m ay ch ange an d be un n ot iced due to drapin g. Careful an d frequen t exam in ation of th e patien t’s position m ay preven t injuries associated w ith prolonged m alposition in g 13. post operative n ausea an d vom it in g (PONV): m ay adversely a ect ICP an d m ay n egatively im pact recen t cer vical surgical procedures. Avoidan ce of an esth etic agen ts kn ow n to cause PONV or pretreatm en t to preven t PONV m ay be pruden t 4.2 Drugs used in neuroanest hesia 4.2.1 Inhalat ional agent s General inform at ion Most reduce cerebral m etabolism (except nitrous oxide) by suppressing neuronal activity. Th ese age n t s d ist u rb ce r eb r al au t or e gu lat ion an d cau se ce r eb r al va sod ilat at ion w h ich in cr e ase s ce r eb r al blood volu m e (CBV) an d can in cr e ase ICP. W it h ad m in ist r at ion > 2 h rs t h ey in cr e ase CSF volu m e w h ich can a lso p ot e n t ia lly con t r ib u t e t o in cr e ase d ICP. Most age n t s in cr e ase t h e CO2 r e act ivit y of ce r eb r al blood ve ssels. Th ese age n t s a ect in t r a- op e r at ive EP m onitoring (p . 107).

Neuroanesthesia 105 Drug info : Nit rous oxide 4 A potent vasodilator that markedly increases CBF and m inim ally increases cerebral metabolism. Con- tributes to post-op N/V. Nit rous oxide, pneum ocephalus and air em bolism : The solubilit y of nitrous oxide (N2O) is ≈ 34 times that of nitrogen.6 When N2O com es out of solution in an airtight space it can increase the pres- sure which m ay convert pneumocephalus to “tension pneumocephalus.” It m ay also aggravate air embolism. Thus caution must be used especially in the sit ting position where significant post-op pneum ocephalus and air embolism are common. The risk of tension pneumocephalus may be reduced by filling the cavit y with fluid in conjunction with turning o N2O about 10 minutes prior to completion of dural closure. See Pneumocephalus (p. 887). Halogenat ed agent s Agen ts in prim ar y usage today are sh ow n below. All suppress EEG activit y an d m ay provide som e degree of cerebral protect ion. Drug info : Isoflurane (Forane®) Can produce isoelectric EEG without m etabolic toxicit y. Im proves neurologic outcome in cases of incomplete global ischem ia (although in experim ental studies on rats, the am ount of tissue injury was greater than with thiopental7). Drug info : Desflurane (Suprane®) A cerebral vasodilator, increases CBF and ICP. Decreases CMRO2 which tends to cause a compensatory va so co n st rict io n . Drug info : Sevoflurane (Ult ane®) Mildly increases CBP and ICP, and reduces CMRO2. Mild negative inotrope, cardiac output not as well maintained as with isoflurane or desflurane. 4.2.2 Int ravenous anest het ic agent s Agent s generally used for induct ion 1. propofol: exact m ech an ism of action un kn ow n . Sh ort h alf–life w ith n o act ive m etabolites. May be used for in duct ion an d as a con tin uous in fusion durin g total in traven ous an esth esia (TIVA). Causes dose depen den t decrease in m ean arterial blood pressure (MAP) an d ICP. See also in for- m ation oth er th an use in in duct ion (p. 106). Is m ore rapidly cleared th an , an d h as largely replaced, thiopental 2. barbiturates: produce sign ifican t reduct ion in CMRO2 an d scaven ge free radicals am ong oth er e ect s (p. 1202). Produce dose-depen den t EEG suppression w h ich can be taken all th e w ay to iso- elect ric. Min im ally a ect EPs. Most are an ticonvulsan t, but m eth oh exital (Brevital®) (p. 132) can low er th e seizure th reshold. Myocardial suppression an d periph eral vasodilatat ion from barbitu- rates m ay cause hypoten sion an d com prom ise CPP, especially in hypovolem ic pat ien ts sodium th iopen tal (Pen toth al®): th e m ost com m on agen t. Rapid on set, sh ort acting. Min im al e ect on ICP, CBF an d CMRO2 3. etom idate (Am idate®): a carboxylated im idazole derivative. An esth etic an d am n estic, but n o an algesic properties. Som etim es produces m yoclon ic act ivit y w h ich m ay be con fused w ith seiz- ures. Im pairs ren al fun ct ion an d sh ould be avoided in patien ts w ith kn ow n ren al disease. May

106 General and Neurology produce adren al in su cien cy. See Miscellan eous drugs in n euroan esth esia (p. 106) for in form a- tion other than use in induction. 4. ketam in e: NMDA receptor an tagon ist. Produces a dissociative an esth esia. Main tain s cardiac out- put. May sligh tly in crease both h eart rate an d blood pressure. ICP in creases in parallel w ith in creased cardiac out put. Narcot ics in anest hesia Nonsynthet ic narcotics 4 Narcotics in crease CSF absorpt ion an d m in im ally reduce cerebral m etabolism . Th ey slow th e EEG but w ill not produce an isoelect ric t racin g. All n arcotics cause dose-depen den t respirator y depression w h ich can result in hypercarbia an d con com itan t in creased ICP in n on -ven tilated pat ien ts. Often also contribute to post-op N/V Morph in e: does n ot sign ifican tly cross th e BBB. Disadvan tages in n euro patien ts: 1. causes histam ine release w hich a) m ay produce hypoten sion b) m ay cau se cerebrovascu lar vasod ilation → in creased ICP8 (p 1593) c) th e above togeth er m ay com prom ise CPP 2. in ren al or h epatic in su cien cy, th e m etabolite m orph in e-6-glucuron ide can accum ulate w h ich m ay cause con fusion Synthetic narcot ics Th ese do not cause h istam in e release, un like m orph in e an d m eperidin e. Rem ifen tan il (Ultiva®); see also detailed in form ation (p. 133): reduces CMRO2, CBV an d ICP. Large doses m ay be n eurotoxic to lim bic system an d associated areas. May be used for aw ake cra- niotom y (p.1432). Fen tanyl: crosses th e BBB. Reduces CMRO2, CBV an d ICP. May be given as bolus an d/or as a con tin - uous in fusion . Sufen tan il: m ore poten t th en fen tanyl. Does n ot in crease CBF. Raises ICP (m ay be due to hypo- ven tilation – w h ich can occur w ith any n arcotic) an d is th us often n ot appropriate for n eurosurgical cases. Expen sive. 4.2.3 Miscellaneous drugs in neuroanest hesia Ben zod iazep in es. Th ese drugs are GABA agon ists an d decrease CMRO2. Th ey also provide an ti- convulsan t action an d produce am n esia. See also agen ts an d reversal (p. 205). Etom id at e (p. 105) . Used prim arily for in duct ion (p. 105). ● a cerebrovasocon strictor w h ich th erefore: reduces CBF an d ICP; reduces CMRO2 but n o lon ger pro- m oted as a cerebral protectan t based on experim en tal studies9 an d a drop in pBtO2 w ith tem po- rar y MCA clipp ing10 ● does not suppress brainstem activity ● suppresses adren ocort ical fun ction cort isol product ion . Th is usually occurs w ith prolonged adm in istration , but can occur even after single dose for in duct ion an d m ay persist up to 8 h rs (n o adverse outcom es from sh ort-term suppression h ave been reported) ● in creases activit y of seizure foci w h ich m ay be used for m appin g foci durin g seizure surger y but m ay also induce seizures Prop ofol. A sedative hypn otic. Useful for in duct ion (p. 105). Reduces cerebral m etabolism , CBF and ICP. Has been described for cerebral protect ion (p.1203) an d for sedation (p. 133). Sh ort h alf–life perm its rapid aw aken in g w h ich m ay be useful for aw ake cran iotom y (p. 1434). Not an algesic. Lid ocain e. Given IV, suppresses lar yn geal reflexes w h ich m ay h elp blun t ICP elevation s th at n or- m ally follow en dotrach eal in tubation or suct ion in g. An t iconvulsan t at low doses, m ay provoke seiz- ures at h igh con cen tration s. Esm olol. Selective beta-1 adren ergic an tagon ist, blun ts th e sym path et ic respon se to lar yn goscopy and in tubation . Less sedating th an equipoten t doses of lidocain e or fen tanyl used for th e sam e pur- pose. Half life: 9 m in utes. See also dosin g, etc. (p.127)

Neuroanesthesia 107 Dexm ed et om id in e (Preced ex®). Alph a 2 adren ergic receptor agon ist, used for con trol of hyper- 4 ten sion post operat ively, as w ell as for its sedatin g qualit ies durin g aw ake cran iotom y eith er alon e or in conjun ct ion w ith propofol (p.105). Also used to h elp patien ts tolerate en dotracheal t ube w ith out sedatives/n arcotics to facilitate extubation . 4.2.4 Paralyt ics for int ubat ion Paralyt ics (n eu rom u scu lar blockin g agen t s (NMBA)): ad m in istered t o facilit ate t rach eal in t u ba- t ion an d to im p rove su rgical con d it ion s w h en in d icated . Ad m in ist rat ion of p aralyt ics id eally sh ou ld alw ays be gu id ed by n eu rom u scu lar t w itch m on itor in g. Also see Sed at ives & p aralyt ics (p. 132). In ad d it ion to p aralyt ics, all con sciou s p at ien t s sh ou ld also receive a sed at ive to blu n t aw aren ess. Paralytics sh ould n ot be given un t il it h as been determ in ed th at patien t can be ven tilated m an - ually, un less t reatin g lar yn gospasm (m ay be tested w ith th iopen tal). Use w ith caution in n on -fixated patien ts w ith un stable C-spin e. Due to lon g action , pan curon ium (Pavulon ®) is n ot in dicated as th e prim ar y paralyt ic for in tuba- t ion , but m ay be useful on ce patien t is in t ubated or in low dose as an adjun ct to succinylch olin e. Drug info : Succinylcholine (Anect ine®) The only depolarizing agent. May be used to secure airway for em ergency intubation, but due to possible side e ect s (p. 135), should not be used acut ely following injury or in adolescent s or children (a short acting nondepolarizing blocker is preferred). May transiently increase ICP. Prior dosing with 10% of the ED95 dose of a non-depolarizing m uscle relaxant reduces m uscle fa scicu la t io n s. Intubating dose: 1–1.5 mg/kg (supplied as 20 m g/m l → 3.5–5 cc for a 70 kg patient), onset 60– 90 sec, duration 3–10 min, may repeat same dose × 1. Drug info : Rocuronium (Zem uron®) Intermediate acting, am inosteroid, non-depolarizing muscle relaxant. The only nondepolarizing neu- rom uscular blocking agent approved for rapid sequence intubation. Duration of action and onset are dose dependent. (p. 135). Drug info : Vecuronium (Norcuron®) See details (p. 136). Aminosteroid with activit y sim ilar to that of rocuronium , however, does not cause histamine release and is not approved for rapid sequence intubation. . Drug info : Cisat racurium (Nim bex®) See details (p. 136). Metabolized by Ho man degradation (tem perature dependent), intermediate acting, no signifi- cant increases in histamine. 4.3 Anest het ic requirem ent s for int ra-operat ive evoked pot ent ial m onit oring For details of in t ra-operative evoked poten tial (EP) m on itoring itself, see In t ra-op erat ive evoked poten tials (p.239).

108 General and Neurology All volatile an esth etics produce dose-depen den t reduct ion in SSEP peak am plitu de an d an in crease in peak laten cy. Adding n it rous oxide in creases th is sen sitivity to an esth etic agen ts. An esth esia issues related to in tra-operative evoked poten tial (EPs) m on itorin g: 1. in duct ion : m in im ize pen toth al dose (produces ≈ 30 m in utes of suppression of EPs), or use eto- m idate (w h ich in creases both SSEP am plitu de an d laten cy11) 2. total in t raven ous an esth esia (TIVA) is ideal (i.e. n o in h alat ional agen ts) 3. n itrous/n arcot ic tech n ique is a distan t secon d ch oice 4. if in halational anesth etic agents are required: a) use < 1 MAC (m axim al alveolar con cen tration ), ideally < 0.5 MAC 4 b) avoid older agen ts such as Haloth an e 5. n on depolarizing m uscle relaxan ts h ave litt le e ect on EP (in m on keys12) 6. propofol h as a m ild e ect on EP: total an esthesia w ith propofol causes less EP depression th an in h alation al agen ts at th e sam e depth of an esth esia13 7. ben zodiazepin es h ave a m ild-to-m oderate depressan t e ect on EPs 8. con tin uous in fusion of an esth etic drugs is preferred over in term itten t boluses 9. SSEPs can be a ected by hyper- or hypo-th erm ia, an d ch anges in BP 10. hypocapn ia (dow n to en d tidal CO2 = 21) causes m in im al reduct ion in peak laten cies14 11. an t iepilept ic drugs: ph enytoin , carbam azipin e an d ph en obarbital do n ot a ect SSEP15 4.4 Malignant hypert herm ia 4.4.1 General inform at ion Malign an t hyper th erm ia (MH) is a hyperm etabolic state of skeletal m uscle due to idiopath ic block of Ca + + re-en tr y in to sarcoplasm ic reticulum . Tran sm itted by a m ultifactorial gen et ic predisposition . Total body O2 con sum ption in creases × 2–3. In ciden ce: 1 in 15,000 an esth etic adm in istration s in peds. 1 in 40,000 adults. 50% h ad previous an esth esia w ith out MH. Frequen tly associated w ith adm in istration of h alogen ated in h alation al agen ts an d th e use of succinylch olin e (fulm in an t form : m uscle rigidit y alm ost im m ediately after suc- cinylch olin e, m ay involve m asseters → di cult y in tubatin g). In it ial attack an d recrudescen ce m ay also occur post-op. 30%m ortalit y.16 4.4.2 Present at ion 1. earliest possible sign : increa se in en d-tidal pCO2 2. tachycardia (early) an d oth er arrhyth m ias 3. w ith progression: a) coagulation disorder (DIC) (bleedin g from surgical w oun d an d body orifices) b) ABG: in creasing m etabolic acidosis & decreasing pO2 c) pulm onary edem a d) elevated body tem perat ure (m ay reach ≥ 44° C (113° F) at rate of 1° C/5-m in ) (n orm al pat ien ts becom e hypoth erm ic w ith gen eral an esthesia) e) lim b m uscle rigidit y (com m on , but late) f) rh abdom yolysis → elevated CPK & m yoglobin (late) 4. term inal: a) hypotension b) bradycardia c) cardiac arrest 4.4.3 Treat m ent 1. elim in ate o en din g agen ts (stop th e operation , D/C in h alation an esth esia an d ch ange t ubin g on an esth esia m ach in e) 2. dan trolen e sodium (Dan trium ®) 2.5 m g/kg IV usually e ect ive, in fuse un til sym ptom s subside, up to 10 m g/kg 3. hyper ven tilation w ith 100%O2 4. surface an d cavit y cooling: IV, in w oun d, per NG, PR 5. bicarbon ate 1–2 m Eq/kg for acidosis 6. IV in sulin an d glucose (low ers K+, glucose acts as en ergy substrate) 7. procain am ide for arrhyth m ias 8. diuresis: volum e loading + osm otic diuretics

Neuroanesthesia 109 4.4.4 Prevent ion 4 1. identification of patients at risk: a) on ly reliable test: 4 cm viable m uscle biopsy for in -vitro tests at a few region al test cen ters (abnorm al contracture to ca eine or halothane) b) fam ily h istor y: any relative w ith syn drom e puts pat ien t at risk c) related traits: 50%of MH patien ts h ave h eavy m usculature, Duch en n e t ype m uscular dyst ro- phy, or scoliosis d) patients w ho exhibit m asseter spasm in response to succinylcholine 2. in patien ts at risk: avoid succinylch olin e (n on depolarizing blockers preferred if paralysis essen - t ial), m ay safely h ave n on -h alogen ated an esth etics (n arcotics, barbiturates, ben zodiazepin es, dro- peridol, n itrous…) 3. prophylact ic oral dan trolen e: 4–8 m g/kg/day for 1–2 days (last dose given 2 h rs before an esth e- sia) is usually e ect ive Re fe r e n ce s ad verse e ects of etom idate in th e settin g of focal cerebral isch em ia in rats. An esth An alg. 2005; [1] Sch n eider AJ. Assessm en t of Risk Factors an d Surgi- 100:841–6, table of contents cal Ou tcom e. Su rg Clin N Am . 1983; 63:1113–1126 [10] Ho m an W E, Ch arbel FT, Ed elm an G, Misra M, Au s- [2] Vacan t i CJ, Van Houten RJ, Hill RC. A Statist ical An al- m an JI. Com parison of th e e ect of etom idate and ysis of th e Relation sh ip of Physical Stat us to Post- desflurane on brain tissue gases and pH during pro- operative Mortalit y in 68,388 Cases. An esth An alg lon ged m id dle cerebral arter y occlu sion . An esth esi- Cu rr Res. 1970; 49:564–566 ology. 1998; 88:1188–1194 [11] Koh t A, Sch utz W , Sch m idt G, Sch ram m J, Watan abe [3] Mar x GF, Mateo CV, Orkin LR. Com p uter An alysis of E. E ects of etom idate, m idazolam , an d thiopen tal Postan esth etic Death s. An esth esiology. 1973; on m ed ian n er ve som atosen sor y evoked p oten t ials 39:54–58 an d th e add itive e ects of fentan yl an d n it rous oxide. An esth An alg. 1988; 67:435–441 [4] Benveniste R, Germ an o IM. Evaluat ion of factors [12] Sloan TB. Nondepolarizing n eurom uscular blockade predict in g accu rate resect ion of h igh -grad e gliom as does n ot alter sen sor y evoked poten t ials. J Clin by u sin g fram eless im age-gu id ed stereotactic gu id - an ce. Neu rosu rg Focus. 2003; 14 Monit. 1994; 10:4–10 [13] Liu EH, Won g HK, Chia CP, Lim HJ, Chen ZY, Lee TL. [5] Mar tin A, Rojas S, Ch am orro A, Falcon C, Bargallo N, Plan as AM. W h y does acute h yperglycem ia w orsen E ects of isofluran e and propofol on cort ical som a- th e ou tcom e of tran sien t focal cerebral isch em ia? tosen sor y evoked poten tials du rin g com p arable Role of cort icosteroids, in flam m ation , an d protein depth of anaesthesia as guided by bispectral index. O-glycosylation . Stroke. 2006; 37:1288–1295 Br J An aesth . 2005; 94:193–197 [14] Sch u bert A, Dru m m on d JC. Th e e ect of acute hypo- [6] Raggio JF, Fleisch er AS, Su n g YF, et al. Exp an din g capn ia on h u m an m edian n er ve som atosen sor y Pn eu m oceph alus d ue to Nitrou s Oxide An esth esia: evoked responses. An esth An alg. 1986; 65:240–244 Case Repor t . Neu rosurger y. 1979; 4:261–263 [15] Borah NC, Math esh w ari MC. E ect of an t iepileptic drugs on short-latency som atosensory evoked [7] Dru m m on d JC, Cole DJ, Patel PM, Reyn old s LW . poten tials. Acta Neu rol Scand. 1985; 71:331–333 Focal Cerebral Isch em ia durin g An esthesia w ith Eto- m idate, Isofluoran e, or Th iopental: A Com parison of [16] Nelson TE, Flew ellen EH. Th e Malign an t Hyperth er- th e Exten t of Cerebral Inju r y. Neurosurger y. 1995; m ia Syn drom e. N En gl J Med . 1983; 309:416–418 37:742–749 [8] Sh ap iro HM, Miller RD. In : Neu rosu rgical An esth e- sia and In t racran ial Hyperten sion . An esth esia. 2n d ed. New York: Church ill Livingston e; 1986:1563– 1620 [9] Dru m m on d JC, McKay LD, Cole DJ, Patel PM. Th e role of nit ric oxide syn thase in h ibition in th e

110 General and Neurology 5 Sodium Hom eost asis and Osm olalit y 5.1 Serum osm olalit y and sodium concent rat ion Clin ical sign ifican ce of various serum osm olarit y values is sh ow n in Table 5.1. Seru m osm olalit y. May be estim ated usin g Eq (5.1). Osm o larit y ðm Osm ⁄ LÞ ¼ 2 Â ÈÂNaþ Ã ÂKþ ÃÉ þ ½BUN þ ½glucose ð5:1Þ þ 2:8 18 5 (w ith [Na+] in m Eq/L or m m ol/L, an d glucose an d BUN in m g/dl). NB: term s in square brackets [] represen t th e serum con cen tration s (in m Eq/L for elect rolytes). Sod iu m con ten t . In th e diet: usually expressed in gram s Na+ (n ot NaCl), a low sodium diet is con - sidered 2 gm of Na+ per day or less. 1 teaspoon of table salt (NaCl) h as 2.3 gm of Na+. 1 m g NaCl h as 17 m Eq Na+. 1 m g Na+ h as 43 m Eq Na+. Norm al salin e h as 0.9 gm of NaCl/100 m l. 3%NaCl h as 3 gm NaCl/100 m l. 5.2 Hyponat rem ia 5.2.1 General inform at ion Key concept s ● definition: serum [Na+] < 135 m Eq/L. Common etiologies: ○ SIADH: hypotonic hyponatremia (e ective serum osmol < 275 mOsm/L) with inappropriately high urinary conentration (urine osmol > 100 mOsm /L) and euvolemia or hypervolem ia ○ cerebral salt wasting (CSW): similar to SIADH but with extracellular fluid volume depletion due to renal sodium loss (urinary [Na}> 20 m Eq/L) ● minimum W/U: serum [Na+], serum osmolalit y, urine osmolalit y, clinical assessment of volume status. If volume status is high or low: urinary [Na+] TSH (to R/O hypothyroidism) ● treatment: based on acuit y, severity, symptom s & etiology; see SIADH (p. 115) or CSW (p. 118) as a p p ro p ria t e ● risk of overly rapid correction: osmotic demyelination (including central pontine myelinolysis) Classificat ion . [Na+] < 135 m Eq/L= m ild, < 130 = m oderate, < 125 = severe hypon atrem ia. Hyp on at r em ia in n eu rosu rgical p at ien t s. Ch iefly seen in : ● syn drom e of in appropriate an t idiuretic h orm on e secretion (p.114), SIADH (p. 114): dilution al hypon atrem ia w ith n orm al or eleva ted intra va scula r volume. Th e m ost com m on t ype of Table 5.1 Clinical correlates of serum osm olalit y Value (m Osm /L) Com m ent 282–295 n o rm al <240 or >321 panic values > 320 risk of renal failure > 384 produces stupor > 400 risk of generalized seizures > 420 usually fatal

Sodium Hom eostasis and Osm olality 111 hypon atrem ia.1 Usually treated w ith fluid restrict ion. May be associated w ith n um erous in tracra- n ial abn orm alit ies ( Table 5.2) an d follow in g t ran ssph en oidal surgery ● cerebral salt w ast in g (CSW): in appropriate n atriuresis w ith volume deplet ion. Treated w ith volume repla cement (opposite to SIADH) an d sodium; sym ptom s from derangem en ts due to CSW m ay be exacerbated by fluid restrict ion (p.118).2 Etiology of 6%of cases of hypon atrem ia follow in g an eur- ysm al SAH3 Table 5.2 Etiologies of SIADa 5 Malignant tum ors 1. especially bronchogenic sm all-cell Ca 2. tumors of GI or GU tract 3. lymphomas 4. Ewing’s sarcom a CNS disorders 1. infection: a) encephalitis b) m eningitis: especially in peds c) TB m eningitis d) AIDS e) brain abscess 2. head trauma: 4.6% prevalence 3. increased ICP: hydrocephalus, SDH… 4. SAH 5. brain tum ors 6. cavernous sinus thrombosis 7. post craniotomy, especially following surgery for pituitary tum ors, craniopharyngiom as, hypothalamic t um ors 8. MS 9. Guillain-Barré 10. Shy-Drager 11. delirium trem ens (DTs) Pulm onary disorders 1. infection: pneum onia (bacterial & viral), abscess, TB, aspergillosis 2. asthma 3. respiratory failure associated with positive pressure respiration Dru g s 1. drugs that release ADH or potentiate it a) chlorpropram ide (Diabinese®): increases renal sensitivit y to ADH b) carbam azepine (Tegretol®), even more comm on with oxcarbazepine c) HCTZ d) SSRIs, TCAs e) clofibrate f) vincristine g) antipsychotics h) NSAIDs i) MDMA (“ecstasy”) 2. ADH analogues a) DDAVP b) oxytocin: ADH cross activit y, m ay also be contam inated with ADH Endocrine disturbances 1. adrenal insufficiency 2. hypothyroidism Misce lla n e o u s 1. anem ia 2. stress, severe pain, nausea or hypotension (all can stimulate ADH release), postoperative state 3. acute interm it tent porphyria (AIP) aexcerpted and m odified9,1

112 General and Neurology Ot h er et iologies of h yp on at rem ia: ● ren al failure ● volum e overload (e.g. as in congest ive h eart failure) ● p seu d oh yp on at rem ia: osm ot ically act ive solu tes (e.g. glu cose, m an n itol, m arked h yp erlip id e- m ia, or hyp erp rotein em ia (w h ich can occu r in m ult ip le m yelom a)4) d raw w ater from cells an d also red u ce th e w ater fract ion of p lasm a an d p rod u ce ar t ifact u ally low sod iu m valu es (an ar t i- fact of in direct lab tech n iqu es). For ever y 100 m g/d l in crease of glu cose, seru m [Na] d ecreases by 1.6–2.4 m Eq/L. It is n ecessar y to m easu re ser u m osm olalit y to ru le-ou t pseu dohypon at rem ia ● postoperative hypon at rem ia: a rare con dition usually described in youn g, oth erw ise h ealthy w om en un dergoing elect ive surger y5 an d m ay be related to adm in istration of even on ly m ildly hypoton ic fluids (som etim es in m odest am oun ts)6 an d th e act ion s of ADH (w h ich m ay be 5 increased due to stress, pain or m edications) 5.2.2 Evaluat ion of hyponat rem ia Fig. 5.1 sh ow s an algorith m for evaluating th e etiology of hypon atrem ia7 w h ich drives t reatm en t decision s. Work-up requires assessm en t of: 1. serum sodium : m ust be < 135 m Eq/L to qualify as hypon at rem ia 2. th e e ective serum osm olality(AKA ton icit y) is sh ow n in Eq (5.2) e ffe ct ive serum osmolality ¼ m e asure d osmolality À ½BUN ðmg⁄ dlÞ ð5:2Þ 2:8 an d sh ould be used w h en th e blood urea n itrogen (BUN) level is elevated (for a n orm al [BUN] of 7– 18 m g/dl, just subtract 5 from th e m easured osm olality). Values < 275 m Osm /kg in dicate hypoton ic hypon atrem ia 1. urin e osm olalit y: values > 100 m Osm /kg are in appropriately h igh if serum ton icit y is < 275 m Osm /kg 2. volum e status: di eren tiates SIADH from CSW a) clin ical assessm ent: better for hyper volem ia (edem a, upw ard t ren d in patien t w eigh ts) but is in sen sitive in iden tifyin g extracellular fluid depletion as an etiology of hypon at rem ia8 (look for dr y m ucous m em bran es, loss of skin turgor, or th ostatic hypoten sion ) b) n orm al salin e in fusion test used in un cert ain cases. If baselin e urin e osm olalit y is < 500 m Osm /kg, it is usually safe to in fuse 2 L of 0.9%salin e over 24–48 h ours. Correct ion of th e hypon atrem ia suggests extracellular fluid volum e depletion w as th e cause c) cent ral ven ous pressure (CVP) m ay be used: CVP < 5–6 cm H2O suggests hypovolem ia in patien ts w ith n orm al cardiac fun ct ion3,7 3. ch eck urin ar y [Na+] if volum e status is h igh or low 4. determ in e durat ion of hypon at rem ia: a) duration docum en ted as < 48 h ours is con sidered acute b) hypon atrem ia of > 48 h ours duration or of un kn ow n duration is ch ron ic c) hypon atrem ia th at occurs outside th e h ospital is usually ch ronic an d asym ptom atic except in m arathon ers and MDMA (“ecstasy”) drug users 5.2.3 Sym pt om s Due to slow com pen sator y m ech anism s in th e brain , a gradual declin e in serum sodium is better tolerated th an a rapid drop. Sym ptom s of m ild ([Na] < 130 m Eq/L) or gradual hypon atrem ia in clude: an orexia, h eadach e, di cult y con cen tratin g, irritabilit y, dysgeusia an d m uscle w eakn ess. Severe hypon atrem ia (< 125 m Eq/L) or a rapid drop (> 0.5 m Eq/h r) can cause n eurom uscular excitabilit y, cerebral edem a, m uscle t w itch in g an d cram ps, n ausea/vom it in g, con fusion , seizures, respirator y arrest an d possibly perm an en t n eurologic injur y, com a or death . 5.2.4 Syndrom e of inappropriat e ant idiuresis (SIAD) Th is term covers excess w ater reten tion in th e face of hypon at rem ia, in cludin g cases due to in appro- priate ADH secretion (SIADH) as w ell as oth ers w ith out in creased circulatin g levels of ADH (e.g.

Sodium Hom eostasis and Osm olality 113 Hyponatrem ia (Serum [Na+] < 135 m Eq/L) Iso t o n ic 275-290 Effe ct ive > 290 Hyp e rt o n ic hyponatrem ia m Osm / kg serum osmo- m Osm / kg hyponatrem ia Et io lo g ie s la lit y* (AKA • paraproteinemia pseudohyponatrem ia) • hypertriglyceridem ia < 275 m Osm /kg Et io lo g ie s Water intoxication Hypotonic hyponatrem ia Et io lo g ie s • hyperglycemia • mannitol therapy 5 • psychogenic polydipsia < 100 Urine m Osm / kg o sm o la lit y > 100 m Osm / kg Inappropriately con- centrated urine De cre a se d Volum e In cre a se d status† Norm al > 20 Urinary Et io lo g ie s > 20 § < 10 m Eq/L so d iu m • SIADH§ m Eq/L m Eq/L • K+ loss Urinary • endocrinopathies so d iu m < 10 m Eq / L Re n a l Ext ra re n a l Renal failure Edem atous solute loss solute loss states Et io lo g ie s Et io lo g ie s Et io lo g ie s • CSW • GI tract • CHF • diuretics • skin • cirrhosis • Addison disease Fig. 5.1 Evaluation of the etiology of hyponatremia (adapted7) * e ective serum osmolalit y = measured osm olalit y – [BUN]/2.8 (Eq (5.2)) † volum e status is usually assessed clinically, but this may be insensitive to volume depletion § SIADH may be associated with euvolemia or hypervolem ia h eigh ten ed respon se to ADH, cer tain drugs…). A par t ial list of etiologies is sh ow n in Table 5.2 (see referen ces1,9 for details). Th e diagn ost ic criteria of SIAD is sh ow n in Table 5.3. It is critical to mea sure ser um osmola lit y to rule-out pseudohypon at rem ia (p.112), an art ifact of in direct lab tech n iques.

114 General and Neurology Table 5.3 Diagnostic criteria for SIAD1 Essent ial feat ures ● decreased effective serum osm olalit ya (< 275 m Osm /kg of water) ● simulatneous urine osm olalit y > 100 mOsm/kg of water ● clinical euvolemia a) no clinical signs of extracellular (EC) volum e orthostatic hypotension (orthostasis, tachycardia, decreased skin turgor, dry m ucous mem branes…) b) no clinical signs of excess EC volum e (edema, ascites…) ● urinary [Na] > 40 m Eq/L with norm al dietary Na intake ● norm al thyroid and adrenal function ● no recent diuretic use 5 Supplem ental features ● plasm a [uric acid] < 4 mg/dl ● [BUN] < 10 mg/dl ● fractional Na excretion > 1%; fractional urea excretion > 55% ● NS infusion test: failure to correct hyponatremia with IV infusion of 2 L 0.9% saline over 24–48 hrs ● bcorrection of hyponatrem ia with fluid restriction ● abnormal result on water load testc: a) < 80% excretion of 20 m l of water/kg body weight over 5 hours, or b) inadequate urinary dilution (< 100 m Osm /kg of water) ● elevated plasm a [ADH] with hyponatrem ia and euvolemia aeffective osm olalit y (AKA tonicit y) = (measured osmolalit y) – [BUN]/2.8 with [BUN] measured in mg/dl bthis test is used in uncertain cases (corrects volum e depletion), and is usually safe when baseline urine osm olalit y is < 500 m Osm /L cwater load test & [ADH] levels are rarely recomm ended; see text for details (p. 115) 5.2.5 Syndrom e of inappropriat e ant idiuret ic horm one secret ion (SIADH) General inform at ion Key concept s ● definition: release of ADH in the absence of physiologic (osm otic) stimuli ● results in hyponatrem ia with hypervolem ia (occasionally with euvolemia) with inappropriately high urine osmolalit y (> 100 mOsm/L) ● may be seen with certain malignancies and m any intracranial abnorm alities ● critical to distinguish from cerebral salt wasting which produces hypovolem ia ● treatment: initial guidelines in brief, see details (p. 115) ○ avoid rapid correction or overcorrection to reduce risk of osm otic demyelination (p. 115). Check serum [Na+] q 2–4 hours and do not exceed 1 mEq/Lper hour, or 8 mEq/Lin 24 hrs or 18 mEq/L in 48 hrs ○ severe ([Na+] < 125 mEq/ Lof < 48 hrs duration or with severe sym ptoms (coma, Sz): start 3%sal- ine at 1–2 ml/kg body weight/hr + furosemide 20 m g IV qd ○ severe ([Na+] < 125 mEq/ Lof duration > 48 hours or unknown without severe sym ptoms: normal saline infusion @ 100 m l/hr + furosemide 20 mg IV qd ○ chronic or unknown duration and asym ptom atic: fluid restriction ( Table 5.4) with dietary salt and protein, and, if necessary, adjuvant drugs (dem eclocycline, conivaptan…) SIADH, AKA Sch w art z-Bartter syn drom e, w as first described w ith bron ch ogen ic can cer w h ich is on e cause of SIAD. SIADH is th e release of an t idiuret ic h orm on e (ADH), AKA argin in e vasopressin (AVP) (p. 151), in th e absen ce of physiologic (osm otic) st im uli. Result: elevated urin e osm olality, an d expan sion of th e extracellular fluid volum e leading to a dilution al hypon atrem ia w h ich can produce fluid overload (hyper volem ia), but SIADH m ay also occur w ith euvolem ia. For un clear reason s, ede- m a does not occur. Th e hypon atrem ia of SIADH m ust be di eren tiated from th at due to cerebral salt w ast in g (CSW ) due to di erences in treatm ent recom m endation s (p.118). Etiologies: Table 5.2.

Sodium Hom eostasis and Osm olality 115 Table 5.4 Fluid restriction recommendations1 Solute rat ioa Recom m ended fluid intake > 1 < 500 m l/d 1 500–700 m l/d <1 < 1 L/d aso lu t e ra t io d e fin e d as: urinary ½Na þ urinary ½K plasm a ½Na Diagnosis of SIADH 5 In gen eral, 3 diagn ostic criteria are: hypon at rem ia, in appropriately con cen trated urin e, an d n o evi- den ce of ren al or adren al dysfun ct ion . In m ore detail: 1. low serum sodium (hypon atrem ia): usually < 134 m Eq/L 2. low e ect ive serum osm olality: < 275 m Osm /L 3. h igh urin ar y sodium (salt w ast in g): at least > 18 m Eq/L, often 50–150. Note: th ere h as n ot been an adequate explanation of th e h igh urin ar y sodium in SIADH 4. h igh ratio of urin e:serum osm olalit y: often 1.5–2.5:1, but m ay be 1:1 5. n orm al ren al fun ction (ch eck BUN & creatin in e): BUN com m on ly < 10 6. n orm al adren al fun ct ion (n o hypoten sion , n o hyperkalem ia) 7. no hypothyroidism 8. n o sign s of dehydrat ion or overhydration (in m any patien ts w ith acute brain disease, th ere is sig- n ifican t hypovolem ia often due to CSW (p.118) an d as th is is a st im ulus for ADH secretion , th e ADH release m ay be “appropriate”10). In un cert ain cases, th e n orm al salin e in fusion test (p. 112) may be used. If furth er test ing is required, th e follow in g are opt ion s, but are rarely recom m en ded: 1. m easure serum or urin ar y levels of ADH. Rarely in dicated sin ce urin e osm olality > 100 m Osm /kg is usually su cien t to in dicate excessive ADH.1 ADH is n orm ally un detectable in etiologies of hypon atrem ia oth er th an SIADH 2. w ater-load test: con sidered to be th e defin itive test.11 Th e patien t is asked to con sum e a w ater load of 20 m l/kg up to 1500 m l. In th e absen ce of adren al or ren al in su cien cy, th e failure to excrete 65%of th e w ater load in 4 h rs or 80%in 5 h rs indicates SIAD. CONTRAINDICATIONS: th is test is dangerous if th e start in g serum [Na+] is ≤ 124 m Eq/L or if th e patien t h as sym ptom s of hypon atrem ia Sym pt om s of SIADH Sym ptom s of SIADH are th ose of hypon atrem ia (p. 112) an d possibly fluid overload. If m ild, or if descen t of [Na+] is gradual, it m ay be tolerated. [Na+] < 120–125 m Eq/L is alm ost alw ays sym ptom atic. Th ese pat ien ts often h ave a paradoxical (in appropriate) th irst. Treat m ent of hyponat rem ia w it h SIADH Man agem en t is based on th e severit y an d durat ion of hypon at rem ia, an d th e presen ce of sym ptom s. Tw o caveats: 1. be sure th at hypon at rem ia is n ot due to CSW (p. 118) before restrict in g fluids 2. avoid too rapid correction an d avoid correct in g to norm al or supranorm al (overcorrection ) sodium to reduce the risk of osm otic dem yelination syndrom e Osm ot ic dem yelination syndrom e A com plication associated w ith som e cases of treatm ent for hyponatrem ia. While excessively slow correc- tion of acute hyponatrem ia is associated w ith increased m orbidity and m ortality,12 som e cases of inordin- ately rapid treatm ent have been associated w ith osm otic demyelination syndrom e (w hich includes central pontine myelinolysis (CPM) a rare disorder of pontine w hite m atter13 ( Fig. 5.2) and extrapontine myelinolysis ( Fig. 5.3), as well as other areas of cerebral w hite m atter). First described in alcoholics,14 producing insidious flaccid quadriplegia, m ental status changes, and cranial nerve abnorm alities w ith a pseudobulbar palsy appearance. In one review,15 no patient developed CPM w hen treated slowly as

116 General and Neurology Fig. 5.2 Central pontine myelinolysis (arrowhead). Axial FLAIR MRI 5 Fig. 5.3 Osm otic demyelination of pons (black arrowhead) & thalamus (white arrowhead). Coronal T2WI MRI outlined below. And yet, the rate of correction correlates poorly w ith CPM; it m ay be that the m agnitude is another critical variable.16 Features com m on to patients w ho develop CPM are15: ● delay in th e diagn osis of hypon at rem ia w ith resultan t respirator y arrest or seizure w ith probable hypoxem ic even t ● rapid correct ion to n orm o- or hyper-n at rem ia (> 135 m Eq/L) w ith in 48 h ours of in itiat in g th erapy ● in crease of serum sodium by > 25 m Eq/L w ith in 48 h ours of in itiation of th erapy ● over-correcting serum sodium in patients w ith hepatic encephalopathy ● NB: m any patien ts developin g CPM w ere vict im s of ch ron ic debilitatin g disease, m aln ourish m en t, or alcoh olism an d n ever h ad hypon atrem ia. Many h ad an episode of hypoxia/an oxia17 ● presen ce of hypon atrem ia > 24 h rs prior to treatm en t16 Th e on ly defin itive t reatm en t is t reatm en t of th e un derlying cause ● if caused by an em ia: usually respon ds to tran sfusion ● if caused by m align an cy, m ay respon d to an tin eoplastic th erapy ● m ost drug related cases respond rapidly to discontinuation of the o ending drug Treatm ent algorithm s Fig. 5.4 depicts an algorith m for select ing th e correct SIADH t reatm en t protocol. Aggressive t r eat m en t p rotocol. In dication s (also refer to Fig. 5.4): 1. severe hypon atrem ia (serum [Na+] < 125 m Eq/L)

Sodium Hom eostasis and Osm olality 117 Start Mild to Moderate Se ve re ([Na+] = 125-135 m Eq/L) Degree of ([Na+] < 125 m Eq/L) Hyponatrem ia 5 Symptom s? no Ro u t in e (asym p - Treatm ent yes tom atic) (see text) Interm ediate none ≥ 48 hours Treatm ent Symptom s or unknown Du ra t io n (see text) m oderate or n o n sp e cific (H/ A, se ve re < 48 (com a, hours le t h a rg y) se izu re s) Aggressive Treatm ent (see text) Fig. 5.4 Treatment protocol selection for hyponatremia in SIADH 2. AND eith er a) duration know n to be < 48 hours b) or severe sym ptom s (com a, seizures) Treatm en t ● tran sfer pat ien t to ICU ● interven tion s ○ 3%salin e: start in fusion 1–2 m l/kg body w eigh t per h our (in fusion rate m ay be doubled to 2– 4 m l/kg/h r for lim ited periods in patien ts w ith com a or seizures1) ○ an d furosem ide (Lasix®) 20 m g IV q d (furosem ide accelerates th e in crease in [Na+] an d pre- ven ts volum e overload w ith subsequen t in crease in atrial n atriuretic factor an d resultan t uri- n ar y dum ping of th e extra Na+ bein g adm in istered) ● m onitoring and adjustm ents ○ ch eck serum [Na+] ever y 2–3 h ours an d adjust in fusion rate of 3%salin e – goal: raise serum sodium by 1–2 m Eq/L/h r18 (use low er en d of ran ge for hypon at rem ia > 48 hours duration or unknow n duration) – lim its: do n ot exceed 8–10 m Eq/L in 24 h rs an d 18–25 m Eq/L in 48 h rs1 (use low er en d of th ese ran ges for hypon atrem ia > 48 h ours duration or un kn ow n duration) ○ m easure K+ lost in urin e an d replace accordingly

118 General and Neurology ○ if sym ptom s of osm otic dem yelin ation occur (early sym ptom s are leth argy an d a ect ive ch anges, usually after in itial im provem en t): deficits m ay im prove by stopping treatm en t an d m odestly relow erin g th e serum sodium e.g. w ith DDAVP19,20 In t er m ed iate t reat m en t p rotocol. In dication s (also refer to Fig. 5.4): 1. sym ptom atic n on severe hypon atrem ia (serum [Na+] = 125–135 m Eq/L), or 2. severe hypon atrem ia (serum [Na+] < 125 m Eq/L), AND a) duration > 48 h ours or un kn ow n AND b) on ly m oderate sym ptom s or n on specific sym ptom s (e.g. H/A, or leth argy) Treatm en t 1. interven tions 5 a) 0.9%salin e (n orm al salin e) in fusion b) an d furosem ide (Lasix®) 20 m g IV q d c) con sider con ivaptan for refractor y cases 2. m on itorin g: ch eck serum [Na+] ever y 4 h ours an d adjust in fusion rate of n orm al salin e 3. goals: [Na+] in crease of 0.5–2 m Eq/L/h r 4. lim its: do not exceed 8–10 m Eq/L in 24 h rs an d 18–25 m Eq/L in 48 h rs1 Rou t in e t reat m en t p rotocol an d m ain ten an ce t h erap y. In dication s (also refer to Fig. 5.4): 1. asym ptom atic n on severe hypon atrem ia (serum [Na+] = 125–135 m Eq/L), or 2. severe hypon atrem ia (serum [Na+] < 125 m Eq/L) AND a) duration > 48 h ours or un kn ow n AND b) asym ptom atic Treatm en t 1. interven tions a) fluid restriction Table 5.4 for adults, for peds: 1 L/m 2/day) w h ile en couraging use of dietar y salt an d protein . Caution restricting fluids in hypon at rem ia follow in g SAH (p.1166). b) for refractor y cases, con sider ● dem eclocycline: a tetracycline antibiotic that partially antagonizes the e ects of ADH on the renal tubules.21,22,23 E ects are variable, and nephrotoxicity m ay occu r. 300–600 m g PO BID ● con ivaptan (Vaprisol®): a n onpeptide an tagon ist of V1A & V2 vasopressin receptors. FDA approved for euvolem ic an d hypervolem ic m oderate-to-severe hypon atrem ia in h ospital- ized pat ien ts (NB: severe sym ptom s of seizures, com a, delirium … w arran ts aggressive treat m en t w ith hyperton ic salin e1). Use in th e n euro-ICU h as been described for t reatin g elevated ICP w h en serum [Na] is not respon din g to t radition al m eth ods24 (o -label use – use w ith caution ). loading dose 20 m g IV over 30 m in utes, follow ed by in fusion s of 20 m g over 24 h ours × 3 days. If serum [Na+] are n ot rising as desired, th e in fusion m ay be in creased to th e m axim al dose of 40 m g over 24 h ours. Use is approved for up to 4 days total. Caution re drug in teract ion s ● lithium : not ver y e ect ive an d m any side e ects. Not recom m en ded 5.2.6 Cerebral salt w ast ing Cerebral salt w astin g (CSW ): ren al loss of sodium as a result of in tracran ial disease, producin g hypo- n atrem ia an d a decrease in extracellular fluid volum e.11 CAUTION: pat ien ts w ith an eur ysm al SAH m ay h ave CSW w ith hypon atrem ia w h ich m im ics SIADH, how ever th ere is usually also hypovolem ia in CSW . In th is settin g, flu id restrict ion m ay exacerbate vasospasm in d u ced isch em ia.11,25,26,27 Th e m ech an ism w h ereby th e kidn eys fail to con ser ve sodium in CSW is n ot kn ow n , an d m ay be eith er a result of an as yet un iden tified n atriuretic factor or direct n eural con trol m ech an ism s (see Hypon atrem ia follow in g SAH (p.1166)). Laboratory tests (serum and urinary electrolytes and osm olalities) m ay be identical w ith SIADH and CSW.28 Furtherm ore, hypovolem ia in CSW may stim ulate ADH release. To di erentiate: CVP, PCWP, and plasm a volum e (a nuclear m edicine study) are low in hypovolem ia (i.e. CSW). Table 5.5 compares som e features of CSW and SIADH, the two m ost important di erences being extracellular volum e and salt bal- ance. An elevated serum [K+] with hyponatrem ia is incom patible with the diagnosis of SIADH. Treat m en t of CSW ● Goals: ○ volum e replacem ent ○ positive salt balance

Sodium Hom eostasis and Osm olality 119 Table 5.5 Comparison of CSW and SIADH11 CSW SIADH Param eter Plasm a volum e ↓ (< 35 m l/kg) ↑ or WNL Salt balance n e g a t ive variable Signs & sym ptom s of dehydration present absent Weight ↓ ↑ or no Δ PCWP ↓ (< 8 m m Hg) ↑ or WNL CVP ↓ (< 6 m m Hg) ↑ or WNL 5 Orthostatic hypotension +± Hem atocrit ↑ ↓ or no Δ Serum osm olalit y ↑ or WNLa ↓ Ratio of serum [BUN]:[creatinine] ↑ WNL Serum [protein] ↑ WNL Urinary [Na+] ↑↑ ↑ Serum [K+] ↑ or no Δ ↓ or no Δ Serum [uric acid] WNL ↓ Abbreviations: ↓ = decreased, ↑ = increased, ↑ ↑ = significantly increased, WNL= within normal limits, no Δ = no change, [] = concentration, + = present, ± = may or m ay not be present aIn realit y, serum osm olalit y is usually ↓ in CSW ○ avoid excessively rapid correct ion of hypon atrem ia or overcorrect ion w h ich m ay be associated w ith osm ot ic dem yelin ation (p. 115) as w ith SIADH (p. 115). ● In terven tion s ○ Hydrate patien t w ith 0.9%NS at 100–125 m l/h r. For severe cases, 3%salin e at 25–50 cc/h r is occasion ally required. ○ Do n ot give furosem ide. ○ Salt m ay also be sim ultan eously replaced orally. ○ Blood products m ay be n eeded if an em ia is presen t . ○ Medications a) Fludrocort ison e acetate acts directly on th e ren al t ubule to in crease sodium absorption . Ben - efits of giving 0.2 m g IV or PO q d in CSW h ave been reported,29 but sign ifican t com plicat ion s of pulm on ar y edem a, hypokalem ia an d HTN m ay occur. b) Urea: an altern ative t reat m en t usin g urea m ay be applicable to th e hypon at rem ia of eith er SIADH or CSW , an d th erefore m ay be used before th e cause h as been ascertain ed: urea (Ure- aph il®) 0.5 gram s/kg (dissolve 40 gm in 100–150 m l NS) IV over 30–60 m in s q 8 h rs.30 Use NS + 20 m Eq KCl/L at 2 m l/kg/h r as th e m ain IV un til th e hypon atrem ia is corrected (un like m an n itol, urea does n ot in crease ADH secretion ). Th ey supplem en ted w ith colloids (viz. 250 m l of 5%album in IV q 8–12 h rs x 72 h rs). 5.3 Hypernat rem ia 5.3.1 General inform at ion Defin ition : serum sodium > 150 m Eq/L. In n eurosurgical patien ts, th is is m ost often seen in th e set- t in g of diabetes in sipidus (DI). Sin ce n orm al total body w ater (TBW ) is ≈ 60% of th e patien t’s n orm al body w eigh t , th e pat ien t’s curren t TBW m ay be estim ated by Eq (5.3).

120 General and Neurology ÂNaþ Ã ÃÂ TBWnorm 140m Eq=LÂ Â0N:6aþÂÃcuusrrueantl body wt ðkg Þ TBWcurrent ¼ nÂoNrmaaþl current al ¼ ð5:3Þ Th e free w ater deficit to be replaced is given by Eq (5.4). Correct ion m ust be m ade slow ly to avoid exacerbating cerebral edem a. One ha lf th e water deficit is replaced over 24 h ours, an d th e rem ain der is given over 1–2 addition al days. Judicious replacem en t of deficien t ADH in cases of true DI m ust also be m ade. 5 free wa t e r deficit ¼ Â0N:6aþÂÃcuuÂsrNrueaantlþ body wt ðkgÞ À TBWcurrent ¼ ÀÃ 140mEq=L Â 0:6 Â usual body wt ðkgÞ ð5:4Þ current 5.3.2 Diabet es insipidus General inform at ion Key concept s ● due to low levels of ADH (or, rarely, renal insensitivit y to ADH) ● high output of dilute urine (< 200 m Osm ol/Lor SG < 1.003) with normal or high serum osmolalit y and high serum sodium ● often accom panied by craving for water, especially ice-water ● danger of severe dehydration if not m anaged carefully Diabetes in sipidus (DI) is due to in su cien t ADH act ivity at th e kidn eys, an d results in th e excessive ren al loss of w ater an d elect rolytes. DI m ay be produced by t w o di eren t etiologies: ● cent ral or n eurogen ic DI: subn orm al levels of ADH caused by hypothalam ic-pituitar y axis dys- fun ct ion . Th is is th e t ype m ost often seen by n eurosurgeon s ● “n eph rogen ic DI”: due to relative resistan ce of th e kidn ey to n orm al or supra-n orm al levels of ADH. Seen w ith som e drugs (drugs: l) Etiologies of DI31: 1. (n eurogen ic AKA cen tral) diabetes in sipidus a) fam ilial (autosom al dom in an t) b) idiopathic c) postt raum atic (brain injur y, in cludin g surgery) d) t um or: cran ioph ar yn giom a, m etastasis, lym ph om a… e) gran ulom a: n eurosarcoidosis, h ist iocytosis f) in fect ious: m en in gitis, en cephalit is g) autoim m un e h ) vascular: an eur ysm , Sh eeh an’s syn drom e (rarely causes DI) 2. n eph rogen ic diabetes in sipidus a) fam ilial (X-lin ked recessive) b) hypokalem ia c) hypercalcem ia d) Sjögren’s syn drom e e) drugs: lithium , dem eclocyclin e, colch icin e… f) ch ronic ren al disease: pyelon eph ritis, am yloidosis, sickle cell disease, polycystic kidn ey dis- ease, sarcoidosis Cent ral DI 85% of ADH secretor y capacit y m ust be lost before clin ical DI en sues. Ch aracterist ic features: h igh urin e out put (polyuria) w ith low urin e osm olality, an d (in th e con scious patien t) cravin g for w ater (polydipsia), especially ice-w ater.

Sodium Hom eostasis and Osm olality 121 Di eren tial diagn osis of DI: 5 1. (n eurogen ic) diabetes in sipidus (true DI) 2. n eph rogen ic diabetes in sipidus 3. psychogen ic a) idiopathic: from reset tin g of th e osm ostat b) psych ogen ic polydipsia (excess free water in take) 4. osm ot ic diuresis: e.g. follow in g m an n itol, or w ith ren al glucose spillin g 5. diuretic use: furosem ide, hydroch loroth iazide… Cent ral DI m ay be seen in th e follow in g situation s: 1. follow in g tran ssph en oidal surger y or rem oval of cran ioph ar yn giom a: (usually tran sien t, th ere- fore avoid lon g-act in g agen ts un til it can be determ in ed if lon g-term replacem en t is required). Injur y to th e posterior pituitar y or stalk usually causes on e of th ree pattern s of DI32: a) t ran sien t DI: supra-n orm al urin e output (UO) an d polydipsia w h ich t ypically n orm alizes ≈ 12–36 hrs post-op b) “prolonged” DI: UO stays supra-n orm al for prolonged period (m ay be m on th s) or even per- m an en tly: on ly about on e–th ird of th ese pat ien ts w ill n ot return to n ear-n orm al at on e year post-op c) “triph asic respon se”: least com m on ● ph ase 1: injur y to pituitar y reduces ADH levels for 4–5 days → DI (polyuria/polydipsia) ● ph ase 2: cell death liberates ADH for th e n ext 4–5 days → t ran sien t n orm alization or even SIADH-like w ater reten tion ( NB: th ere is a dan ger of in adver tently con tin uin g vasopres- sin th erapy beyon d th e in itial DI ph ase in to th is ph ase causin g sign ifican t h em odilution ) ● ph ase 3: reduced or absen t ADH secretion → eith er t ran sien t DI (as in “A” above) or a “pro- lon ged” DI (as in “B” above) 2. central h ern iation (p. 303): sh earin g of pit uitar y stalk m ay occur 3. brain death : hypoth alam ic product ion of ADH ceases 4. w ith certain tum ors: a) pituitar y aden om as: DI is rare even w ith ver y large m acroaden om as. DI m ay occur w ith pituitary apoplexy (p.720) b) cran ioph ar yn giom a: DI usually on ly occurs postoperatively sin ce dam age to pituitar y or low - er stalk does n ot preven t product ion an d release of ADH by hypoth alam ic n uclei c) suprasellar germ cell tum ors d) rarely w ith a colloid cyst e) hypoth alam ic t um ors: Lan gerh an s cell h ist iocytosis 5. m ass lesion s pressin g on hypoth alam us: e.g. a-com m an eur ysm 6. follow in g h ead injur y: prim arily w ith basal (clival) skull fract ures (p.884) 7. w ith encephalitis or m eningitis 8. drug induced: a) eth an ol an d ph enytoin can in h ibit ADH release b) exogen ous steroids m ay seem to “brin g out” DI because th ey m ay correct adren al in su - cien cy (below ) an d th ey in h ibit ADH release 9. granulom atous diseases a) Wegen er’s gran ulom atosis (p.199): a vasculit is b) n eurosarcoidosis involvin g th e hypoth alam us (p. 189) 10. in flam m ator y: autoim m un e hypophysit is (p. 1373) 33 or lym ph ocytic in fun dibulon eurohypo- physitis34 (distinct conditions) Dia g n o sis Th e follow in g are usually adequate to m ake th e diagn osis of DI, especially in th e appropriate clin ical se t t in g: 1. dilute urin e: a) urin e osm olalit y < 200 m Osm /L (usually 50–150) or specific gravit y (SG) < 1.003 (m ay be 1.001 to 1.005). (Note th at n orm ally, urin e osm olality averages bet w een 500–800 m Osm /L; extrem e ran ge: 50–1400.) b) or th e in abilit y to con cen trate urin e to > 300 m Osm /L in th e presen ce of clinical dehydration c) NB: large doses of m an n itol as m ay be used in h ead t raum a can m ask th is by producin g a m ore con cen trated urin e 2. urin e output (UO) > 250 cc/h r (peds: > 3 cc/kg/h r) 3. norm al or above-norm al serum sodium

122 General and Neurology ©2001 Ma rk S Gre e nbe rg, M.D. All rights re s e rve d. Una uthorize d us e is prohibite d. 1400 1200urine os mola lity (mOs m/L) 5 1000 800 P OLYDIP S IA 600 NORMAL 400 200 DIABETES INS IP IDUS 0 276 280 284 288 292 296 serum osmolality (mOsm/L) Fig. 5.5 Interpretation of simultaneous serum vs. urine osm olalit y (Provided by Arnold M. Moses, M.D., used with perm ission) 4. n orm al adren al fun ct ion : DI can n ot occur in prim ar y adren al in su cien cy because a m in im um of m in eralocort icoid activit y is n eeded for th e kidn ey to m ake free w ater, th us steroids m ay “brin g out” un derlyin g DI by correcting adren al in su cien cy In un certain cases, plot urin e an d sim ultan eous serum osm olality on th e graph in Fig. 5.5. 1. low serum osm olalit y: usually in dicates psych ogen ic polydipsia (path ological drin kin g of w ater) 2. if th e poin t falls in th e “n orm al” ran ge, a super vised w ater deprivation test is n eeded to determ in e if th e patien t can con cen trate th eir urin e w ith dehydrat ion (caution : see below ) 3. h igh serum osm olalit y: ● diagn osis of DI is establish ed an d n o fur th er test in g to establish th e diagn osis is required ● furth er test ing is on ly n eeded to di eren tiate cent ral from n eph rogen ic DI, if desired to di er- en tiate cen tral from n eph rogen ic DI, give aqueous Pitressin ® 5 U SQ ● in cen t ral DI th e urin e osm olalit y sh ould double w ith in 1–2 h ours 4. plotting m ore th an on e data poin t m ay h elp as som e patien ts tend to “vacillate” aroun d th e bor- der zones Water deprivation test If st ill un clear, th e diagnosis of DI is con firm ed by a w ater deprivation test ( CAUTION: perform on ly un der close supervision as rapid an d poten tially fatal dehydration m ay en sue in DI). Th is test is rarely n ecessar y if serum osm olality > 298 m Osm /L. (Note th at in com pen sated DI, serum osm olality is m ore likely to be low er an d to overlap w ith n orm al.35)

Sodium Hom eostasis and Osm olality 123 Table 5.6 Highest urinary osmolalit y after Pitressin in water deprivation test Δ in urinary Osm Int erpret at ion < 5% increase norm al 6–67% increase partial ADH deficiency > 67% increase severe ADH deficiency ● Stop IVs an d m ake th e patien t NPO 5 ● Mon itoring: ○ check urine osm olality q h r ○ ch eck patien t w eigh t q 1 h r ● con tin ue th e test un t il on e of th e follow in g occurs: ○ n orm al respon se occurs: urin e out put decreases, an d urin e osm olalit y rises to 600–850 m Osm / L ○ 6–8 hours lapse ○ urin e osm olalit y plateaus (i.e. ch anges < 30 m Osm in 3 con secutive h ours) ○ patien t loses 3%of body w eigh t ● if th e patien t fails to dem on strate th e n orm al respon se, th en : ○ give exogen ous ADH (5 U aqueous Pitressin ® SQ), w h ich n orm ally in creases urin e osm olalit y to > 300 m Osm /L ○ check urine osm olality 30 and 60 m inutes later ○ com pare h igh est urin e osm olalit y after Pitressin ® to th e osm olalit y just before Pitressin ® according to Table 5.6 Treat m ent of DI In con sciou s am bu lator y p at ien t If DI is m ild, an d th e patien t’s n atural th irst m ech an ism is in tact , in struct patien t to drin k only w h en th irst y an d th ey usually “keep up” w ith losses an d w ill n ot becom e overhydrated. If severe, th e patien t m ay n ot be able to m ain tain adequate in take of fluid or tolerate th e frequen t t rips to bath room . In th ese cases, treatm en t t ypically involves a vasopressin an alogue. See below for a syn opsis of vasopressin an alogues. Typically start w ith eith er: 1. desm opressin (DDAVP®) a) PO: 0.1 m g PO BID, adjust up or dow n PRN urin e out put (t ypical dosage ran ge: 0.1–0.8 m g/d in divided doses) b) n asal spray: 2.5 m cg (0.025 m l) by n asal in su ation BID, t itrate up to 20 m cg BID as n eeded (th e n asal spray m ay be used for doses th at are m ultiples of 10 m cg) OR 2. ADH en h an cin g m edication s (w orks prim arily in ch ron ic partial ADH deficien cy. Will n ot w ork in total absen ce of ADH) ● clofibrate (Atrom id S®) 500 m g PO QID ● ch lorpropram ide: in creases ren al sen sitivit y to ADH ● hydroch loroth iazide: th iazide diuretics m ay act by depletin g Na+ w h ich in creases reabsorpt ion in proxim al tubules an d sh ift in g fluid aw ay from distal t ubules w h ich is w h ere ADH w orks. : e.g. Dyazide® 1 PO q d (m ay in crease up to 2 per day PRN) In con sciou s am bu lator y p at ien t w it h im p aired t h irst m ech an ism s If th irst m ech an ism s are not in tact in con scious am bulator y patien t, th ey run th e risk of dehydra- tion or fluid overload. For th ese patien ts: 1. h ave patien t follow UO an d daily w eigh ts, balan ce fluid in take an d output using an tidiuretic m edicat ion as n eeded to keep UO reason able 2. ch eck serial labs (approxim ately q w eekly) in cludin g serum sodium , BUN In n on -am bu lat or y, com at ose/st u p orou s, or brain -d ead p at ien t; see also Medical Man agem en t of th e Poten tial Organ Don or (p. 313) 1. follow I’s & O’s q 1 h r, w ith urin e specific gravit y (SG) q 4 h rs an d w hen ever urin e out put (UO) > 250 m l/hr 2. labs: serum elect rolytes w ith osm olalit y q 6 hrs

124 General and Neurology Table 5.7 Available preparations of vasopressin analogues Generic nam e Trade nam e Ro u t e Co n ce n t ra t io n Availabilit y Ma n u fa ct u re r d e sm o p re ssin DDAVP® SQ, IM, IV 4 m cg/ml 1 & 10 ml Ave n t is d e sm o p re ssin DDAVP® Nasal nasal spray 100 m cg/m l, 50 doses per Ave n t is Spray each spray de- b o t t le livers 10 mcg d e sm o p re ssin DDAVP® PO 0.1 & 0.2 mg Ave n t is Ta b le t s arginine vasopressin aqueous SQ, IM 20 U/ml 0.5 and 1 ml Parke-Davis 5 Pitressin® (50 mcg/m l) Table 5.8 Mean tim e of hypertonic urinea (relative to plasma)b Generic nam e Ro u t e Do se Mean durat ion of act ionc desm opressin SQ, IM, IV 0.5 mcg 8 hrs desm opressind SQ, IM, IV 1.0 mcg 12 hrs desm opressin SQ, IM, IV 2.0 mcg 16 hrs desm opressin SQ, IM, IV 4.0 mcg 20 hrs desm opressin in t ra n a sa l 10 mcg (0.1 ml) 12 hrs desm opressin in t ra n a sa l 15 mcg (0.15 ml) 16 hrs desm opressin in t ra n a sa l 20 mcg (0.2 ml) 20 hrs arginine vasopressin SQ, IM 5 U (12.5 m cg) 4 hrs (range: 4–8) aprovided by Arnold M. Moses, M.D., used with permission bonset of antidiuretic action of these preparations is 30–45 m inutes following administration (except pituitary powder in oil which takes 2–4 hrs to start working) ctimes m ay vary from patient to patient, but are usually consistent in any individual dNote: 1 m cg BID of desmopressin is as effective as 4 mcg q d, but would obviously be less expensive 3. IV fluid m an agem en t: BASE IV: D5 1/2 NS + 20 m Eq KCl/L at appropriate rate (75–100 m l/h r) PLUS: replace UO above base IV rate m l for m l w ith 1/2 NS NB: for post-op patien ts, if th e patien t received sign ifican t in traoperative fluids, th en th ey m ay h ave an a ppropria te post-op diuresis, in th is case use 1/2 NS to replace on ly ≈ 2/3 of UO th at exceeds th e basal IV rate 4. if un able to keep up w ith fluid loss w ith IV (or NG) replacem en t (usually w ith UO > 300 m l/h r), th en EITHER ● 5 U argin in e vasopressin (aqueous Pitressin ®) IVP/IM/SQ q 4–6 h rs (avoid tan n ate oil suspen - sion due to erratic absorption an d variable duration ) OR ● vasopressin IV drip: start at 0.2 U/m in & t it rate (m ax: 0.9 U/m in ) OR ● desm opressin inject ion SQ/IV t it rated to UO, usual adult dose: 0.5–1 m l (2–4 m cg) daily in 2 divided doses Vasopressin an alogu es Table 5.8 sh ow s dosin g form s an d durat ion of action of vasopressin Table 5.6, Table 5.7 an d a n a lo gu es.

Sodium Hom eostasis and Osm olality 125 Pitressin ® is aqueous solution of 8-arginine vasopressin and should be used w ith caution in patien ts w ith vascular disease (especially coron ary arteries). Caution – soun dalikes: som et im es pitocin is con fused w ith pit ressin because of sim ilarities of th e n am e. DDAVP (1-deam in o-8-D-argin in e vasopressin ) AKA desm opressin . More poten t an d lon ger acting than vasopressin. Re fe r e n ce s excessive correct ion of hypon atrem ia. Clin Neph rol. 5 1999; 51:383–386 [1] Ellison DH, Berl T. Clin ical p ract ice. Th e syn drom e [20] Oya S, Tsutsum i K, Ueki K, Kirino T. Reinduct ion of of in ap p ropriate an tidiu resis. N En gl J Med . 2007; hypon atrem ia to treat central pon tin e m yelin olysis. 356:2064–2072 Neu rology. 2001; 57:1931–1932 [2] Dirin ger M, Lad en son PW , Borel C, et al. Sod iu m [21] De Troyer A, Dem an et JC. Correct ion of An tid iuresis an d Water Regu lation in a Patien t W ith Cerebral Salt Wastin g. Arch Neurol. 1989; 46:928–930 by Dem eclocyclin e. N En gl J Med. 1975; 293:915– 918 [3] Sh erlock M, O'Su llivan E, Agh a A, Behan LA, Raw luk [22] Perks W H, Mohr P, Liversedge LA. Dem eclocyclin e D, Bren n an P, Torm ey W , Th om p son CJ. Th e in ci- in In ap propriate ADH Syn d rom e. Lan cet. 1976; 2 den ce an d path ophysiology of h ypon atraem ia after [23] Forrest JN, Cox M, Hon g C, et al. Superiorit y of su barach n oid h aem orrh age. Clin En docrin ol (Oxf). Dem eclocyclin e over Lith ium in th e Treatm en t of 2006; 64:250–254 Ch ron ic Syn drom e of In approp riate Secretion of An tid iu retic Horm on e. N En gl J Med. 1978; [4] Weisberg LS. Pseud oh yp on atrem ia: a reapp raisal. 298:173–177 Am J Med. 1989; 86:315–318 [24] Wright W L, Asbur y W H, Gilm ore JL, Sam uels OB. Con ivap tan for h ypon at rem ia in th e n eurocritical [5] Arie AI. Hypon atrem ia, Con vulsion s, Respiratory care u n it. Neu rocrit Care. 2009; 11:6–13 Arrest an d Perm an en t Brain Dam age After Elective [25] Maroon JC, Nelson PB. Hypovolem ia in Patients w ith Surgery in Healthy Wom en . N En gl J Med. 1986; Subarach n oid Hem orrh age: Th erapeut ic Im plica- 314:1529–1535 t ion s. Neurosurger y. 1979; 4:223–226 [26] W ijdicks EFM, Verm eulen M, Hijdra A, et al. Hypo- [6] Steele A, Gow rish an kar M, Abrah am son S, et al. n atrem ia an d Cerebral In farct ion in Patients w ith Postop erat ive Hypon atrem ia desp ite Near-Isoton ic Ru p tu red In tracran ial Aneurysm s: Is Fluid Restric- Saline Infusion : A Ph en om en on of Desalin ation. t ion Harm ful? An n Neu rol. 1985; 17:137–140 Ann Intern Med. 1997; 126:20–25 [27] W ijd icks EFM, Verm eulen M, ten Haaf JA, et al. Vol- um e Dep letion an d Natriuresis in Patien ts w ith a [7] Powers CJ, Fried m an AH. Diagn osis an d m an age- Ru p tu red In tracran ial An eur ysm . An n Neurol. 1985; m ent of hyponatrem ia in neurosurgical patients. 18:211–216 Con tem p Neu rosurg. 2007; 29:1–5 [28] Nelson PB, Seif SM, Maroon JC, et al. Hypon atrem ia [8] Ch u n g HM, Klu ge R, Sch rier RW , An derson RJ. Clin i- in Intracranial Disease. Perhaps Not th e Syndrom e cal assessm en t of extracellular fluid volum e in of In appropriate Secretion of An tidiuretic Horm one hypon atrem ia. Am J Med . 1987; 83:905–908 (SIADH). J Neurosurg. 1981; 55:938–941 [9] Lester MC, Nelson PB. Neurological Aspects of Vaso- [29] Hasan D, Lin d say KW , W ijd icks EFM, et al. E ect of pressin Release an d th e Syn drom e of In ap propriate Flud rocort ison e Acetate in Patien ts w ith Subarach - Secretion of An tid iu retic Horm on e. Neurosurgery. n oid Hem orrh age. Stroke. 1989; 20:1156–1161 1981; 8:725–740 [30] Reeder RF, Harbaugh RE. Adm in istration of In t rave- [10] Kröll M, Juh ler M, Lin d h olm J. Hypon atrem ia in n ous Urea an d Norm al Salin e for th e Treatm en t of Acu te Brain Disease. J In t Med . 1992; 232:291–297 Hypon atrem ia in Neurosurgical Patien ts. J Neuro- surg. 1989; 70:201–206 [11] Harrigan MR. Cerebral Salt Wastin g Syn d rom e: A Review. Neu rosu rgery. 1996; 38:152–160 [31] Th ibon n ier M, Barrow DL, Selm an W. In : An tid iu ret- ic Horm on e: Regulation , Disorders, an d Clin ical [12] Ayu s JC, Kroth apalli RK, Arie AI. Ch an gin g Con - Evaluation . Neuroen docrinology. Balt im ore: W il- cepts on Treatm en t of Severe Sym ptom at ic Hypon a- liam s an d Wilkin s; 1992:19–30 trem ia: Rap id Correct ion an d Possible Relat ion to Cen tral Pon tin e Myelin olysis. Am J Med . 1985; [32] Verbalis JG, Robin son AG, Moses AM. Postoperat ive 78:879–902 an d Post-Traum atic Diabetes In sip id u s. Fron t Horm Res. 1985; 13:247–265 [13] Fraser CL, Arie AI. Sym ptom atic Hyp on atrem ia: Man agem en t an d Relat ion to Cen tral Pon tin e Myeli- [33] Abe T, Matsu m oto K, San n o N, Osam u ra Y. Lym ph o- nolysis. Sem Neurol. 1984; 4:445–452 cytic Hypophysitis: Case Report . Neurosurgery. 1995; 36:1016–1019 [14] Adam s RD, Victor M, Man call EL. Cen tral Pon tin e Myelin olysis: A Hith er to Undescribed Disease [34] Im u ra H, Nakao K, Sh im atsu A, et al. Lym p h ocyt ic Occurrin g in Alcoh olic an d Maln ourish ed Patien ts. Arch Neu rol Psych iatr. 1959; 81:154–172 In fu n dibulon eurohypoph ysit is as a Cause of Cen tral Diabetes In sip id u s. N En gl J Med . 1993; 329:683– [15] Ayu s JC, Kroth apalli RK, Arie AI. Treatm en t of 689 Sym ptom at ic Hypon atrem ia an d Its Relation to [35] Miller M, Dalakos T, Moses AM, et al. Recogn ition of Brain Dam age. N En gl J Med . 1987; 317:1190–1195 par t ial d efects in an tid iuretic h orm on e secretion . An n In tern Med . 1970; 73:721–729 [16] Berl T. Treatin g Hypon atrem ia: W h at is All th e Con - troversy Abou t? An n In tern Med. 1990; 113:417– 419 [17] Arie AI. Hyp on at rem ia Associated w ith Perm an en t Brain Dam age. Adv In tern Med . 1987; 32:325–344 [18] Adrogue HJ, Mad ias NE. Hypon atrem ia. N En gl J Med. 2000; 342:1581–1589 [19] Soup art A, Ngassa M, Decau x G. Th erap eutic relow - erin g of th e seru m sodium in a patien t after

126 General and Neurology 6 General Neurocrit ical Care 6.1 Parent eral agent s for hypert ension Drug info : Nicardipine (Cardene®) Calcium channel blocker (CCB) that may be given IV. Does not require arterial line, does not raise ICP. Does not reduce heart rate, but may be used in conjunction with e.g. labetalol or esmolol if that is desired. Side e ect s: H/A 15%, nausea 5%, hypotension 5%, reflex tachycardia 3.5%. start at 5 mg/hr IV (o label: 10 mg/hr may be used in situations where urgent reduction is needed). Increase by 2.5 mg/hr every 5–15 minutes up to a maximum of 15 mg/hr. Decrease to 6 3 mg/hr once control is achieved. Ampules contain 25 mg and must be diluted before ad m in ist rat io n . Drug info : Nit roglycerin (NTG) Raises ICP (less than with nitroprusside due to preferential venous action1). Vasodilator, venous > arte- rial (large coronaries > small). Result: decreases LV filling pressure (pre-load). Does not cause “coro- nary steal” (cf nitroprusside). 10–20 mcg/m in IV drip (increase by 5–10 mcg/m in q 5–10 min). For angina pectoris: 0.4 m g SL q 5 min × 3 doses, check BP before each dose. Drug info : Labet alol (Norm odyne®, Trandat e®) Blocks α1 selective, β non-selective (potency < propranolol). ICP reduces or no change.2 Pulse rate: decreases or no change. Cardiac output does not change. Does not exacerbate coronary ischemia. May be used in controlled CHF, but not in overt CHF. Contraindicated in asthma. Renal failure: sam e dose. Side e ect s: fatigue, dizziness, orthostatic hypotension. Int ravenous (IV) Onset 5 m ins, peak 10 mins, duration 3–6 hrs. IV: patient supine; check BP q 5 min; give each dose slow IVP (over 2 min) q 10 minutes until desired BP achieved; dose sequence: 20, 40, 80, 80, then 80 m g (300 mg total). Once controlled, use ≈ same total dose IVP q 8 hrs. IVdrip (alternative): add 40 ml (200 m g) to 160 ml of IVF (result: 1 mg/ml); run at 2 ml/min (2 mg/min) until desired BP (usual e ective dose = 50–200 mg) or until 300 mg given; then titrate rate (bradycardia limits dose, increase slowly since e ect takes 10–20 minutes). Oral (PO) Undergoes first pass liver degradation, therefore requires higher doses PO. PO onset: 2 hrs, peak: 4 hrs. PO: to convert IV → PO, start with 200 mg PO BID. To start with PO, give 100 mg BID, and increase 100 mg/dose q 2 day; m ax. = 2400 mg/day. Drug info : Enalaprilat (Vasot ec®) An angiotensin-converting enzym e (ACE) inhibitor. The active metabolite of the orally adm inistered drug enalapril (see below). Acts within ≈ 15 m ins of administration. Side e ect s: hyperkalemia occurs in ≈ 1%. Do not use during pregnancy. IV: start with 1.25 mg slow IV over 5 m ins, may increase up to 5 mg q 6 hrs PRN.

General Neurocritical Care 127 Drug info : Esm olol (Brevibloc®) 6 Cardioselective short-acting beta blocker.3 Being investigated for hypertensive emergencies. Metabo- lized by RBC esterase. Elim ination half-life: 9 mins. Therapeutic response (> 20%decrease in heart rate, HR< 100, or conversion to sinus rhythm) in 72%. Side e ect s: dose related hypotension (in 20–50%), generally resolves within 30 m ins of D/C. Bronchospasm less likely than other beta blockers. Avoid in CHF. 500 mcg/kg loading dose over 1 min, follow with 4 min infusion starting with 50 mcg/kg/m in. Repeat loading dose and increment infusion rate by 50 mcg/kg/min q 5 mins. Rarely > 100 mcg/kg/ min required. Doses > 200 mcg/kg/m in add little. Drug info : Fenoldopam (Corlopam ®) Vasodilator. Onset of action < 5 m inutes, duration 30 mins. IV infusion (no bolus doses): start with 0.1–0.3 mcg/kg/m in, titrate by 0.1 mcg/kg/m in q 15 min up to a maxim um of 1.6 mcg/kg/m in. Drug info : Propranolol (Inderal®) Main use IV is to counteract tachycardia with vasodilators (usually doesn’t lower BP acutely when used alone), but esmolol and labetalol are more comm only used for this. IV: load with 1–10 mg slow IVP, follow with 3 m g/hr. PO: 80–640 mg q d in divided doses. 6.2 Hypot ension (shock) 6.2.1 Classificat ion 1. hypovolem ic: first sign usually tachycardia. > 20–40%of blood volum e loss m ust occur before per- fusion of vital organ s is im paired. In cludes: a) hem orrhage (external or internal) b) bow el obstruct ion (w ith th ird spacing) 2. septic: m ost often due to gram n egative sepsis 3. cardiogen ic: in cludes MI, cardiom yopathy, dysrhyth m ias (in cludin g A-fib) 4. n eurogen ic: e.g. paralysis due to spin al cord injur y. Blood pools in ven ous capacitan ce vessels 5. m iscellan eous a) anaphylaxis b) in sulin reaction 6.2.2 Cardiovascular agent s for shock Plasm a expan ders. In cludes: 1. cr ystalloids: n orm al salin e h as less ten den cy to prom ote cerebral edem a th an oth ers; see IV flu- ids (p. 870), un der con trol of elevated ICP 2. colloids: e.g. h etastarch (Hespan ®). CAUTION: repeated adm in istration over a period of days m ay prolong PT/PTT an d clott in g t im es an d m ay in crease th e risk of rebleedin g in an eur ysm al SAH (p. 1167).4 3. blood products: expen sive. Risk of t ran sm issible diseases or t ran sfusion react ion

128 General and Neurology Drug info : Dopam ine See Table 6.1 for a sum mary of the e ects of dopamine (DA) at various dosages. DA is primarily a vasoconstrictor (β1 e ects usually overridden by α-activit y). 25%of dopam ine given is rapidly con- verted to norepinephrine (NE). At doses > 10 mcg/kg/min one is essentially giving NE. May cause sig- nificant hyperglycemia at high doses. Start with 2–5 mcg/kg/m in and titrate. Table 6.1 Dopam ine dosage Effe ct Re su lt Do se (m cg/kg/m in) 0.5–2.0 (sometimes up to 5) dopam inergic renal, mesenteric, coronary, & cere- bral vasodilatation, (+) inotrope 6 2–10 β1 positive inotrope > 10 α, β & dopam inergic releases nor-epi (vasoconstrictor) Drug info : Dobut am ine (Dobut rex®) Vasodilates by β1 (prim ary) and by increased CO from (+) inotropy (β2); result: lit tle or no fall in BP, less tachycardia than DA. No alpha release nor vasoconstriction. May be used synergistically with nitroprusside. Tachyphylaxis after ≈ 72 hrs. Pulse increases > 10%may exacerbate myocardial ische- mia, more common at doses > 20 mcg/kg/m in. Optim al use requires hemodynamic monitoring. Pos- sible platelet function inhibition. usual range 2.5–10 mcg/kg/m in; rarely doses up to 40 used (to prepare: put 50 mg in 250 ml D5 W to yield 200 mcg/m l). Drug info : Am rinone (Inocor®) Nonadrenergic cardiotonic. Phosphodiesterase inhibitor, e ects similar to dobutamine (including exacerbation of myocardial ischem ia). 2%incidence of thrombocytopenia. 0.75 mg/kg initially over 2–3 min, then drip 5–10 m cg/kg/min. Drug info : Phenylephrine (Neo-Synephrine®) Pure alpha sympathom im etic. Useful in hypotension associated with tachycardia (atrial tachyarrhyth- mias). Elevates BP by increasing SVR via vasoconstriction, causes reflex increase in parasympathetic tone (with resultant slowing of pulse). Lack of β action means non-inotropic, no cardiac acceleration, and no relaxation of bronchial smooth muscle. Cardiac output and renal blood flow may decrease. Avoid in spinal cord injuries (p. 950). pressor range: 100–180 mcg/m in; m aintenance: 40–60 m cg/min. To prepare: put 40 m g (4 amps) in 500 ml D5 W to yield 80 mcg/m l; a rate of 8 ml/hr = 10 m cg/min. Drug info : Norepinephrine Prim arily vasoconstrictor (? counterproductive in cerebral vasospasm, ? decreases CBF). β-agonist at low doses. Increases pulmonary vascular resistance.

General Neurocritical Care 129 Drug info : Epinephrine (adrenalin globally) 6 0.5–1.0 m g of 1:10,000 solution IVP; may repeat q 5 minutes (may bolus per ET tube). Drip: start at 1.0 m cg/min, titrate up to 8 m cg/min (to prepare: put 1 m g in 100 ml NS or D5W). Drug info : Isoprot erenol (Isuprel®) Positive chronotropic and inotropic, → increased cardiac O2 consumption, arrhythmias, vasodilatation (by β1 action) skeletal muscle > cerebral vessels. Drug info : Levophed Direct β stim ulation (positive inotropic and chronotropic). start drip at 8–12 m cg/min; m aintenance 2–4 mcg/min (0.5–1.0 ml/m in) (to prepare: put 2 m g in 500 ml NS or D5 W to yield 4 mcg/cc). 6.3 Acid inhibit ors 6.3.1 St ress ulcers in neurosurgery See referen ce.5 Th e risk of developin g st ress ulcers (SU) AKA Cush in g’s ulcers is h igh in crit ically ill patien ts w ith CNS path ology. Th ese lesion s are AKA Cush in g’s ulcers due to Cush in g’s classic t reatise.6 17%of SUs produce clin ically sign ifican t h em orrh age. CNS risk factors in clude in tracran ial path ology: brain injur y (especially Glasgow Com a scale score < 9), brain t um ors, in t racerebral h em orrh age, SIADH, CNS in fect ion , isch em ic stroke, as w ell as spin al cord injur y. Th e odds are in creased w ith th e coexis- ten ce of extra-CNS risk factors in cludin g: lon g-term use of steroids (usually > 3 w eeks), burn s > 25% of body surface area, hypoten sion , respirator y failure, coagulopath ies, ren al or h epatic failure an d se p sis. Th e path ogen esis of SUs is in com pletely un derstood, but probably results from an im balan ce of destruct ive factors (acid, pepsin & bile) relative to protect ive factors (m ucosal blood flow, m ucus- bicarbon ate layer, en doth elial cell replen ish m ent & protaglan din s).5 CNS path ology, especially th at involving the diencephalon or brain stem , can lead to reduction of vagal output w hich leads to hypersecretion of gast ric acid an d pepsin . Th ere is a peak in acid and pepsin product ion 3–5 days after CNS injur y. 6.3.2 Prophylaxis for st ress ulcers Th ere is st ron g eviden ce th at reduct ion of gast ric acid (w h eth er by an tacids or agen ts th at in h ibit acid secretion ) reduces th e in ciden ce of GI bleedin g from st ress ulcers in critically ill pat ien ts. Elevat- in g gast ric pH > 4.5 also in act ivates pepsin . Oth er th erapies th at don’t involve alteration s of pH th at m ay be e ect ive in clude sucralfate (see below ) an d en teral n utr it ion (con troversial).5 Titrated an tacids or sucralfate appear to be superior to H2 an tagon ists in reducing th e in ciden ce of SUs. Routin e prophylaxis w h en steroids are used is n ot w arran ted un less on e of th e follow in g risk fac- tors are presen t: prior PUD, con curren t use of NSAIDs, h epatic or ren al failure, m aln ourish m en t , or prolonged steroid therapy > 3 weeks. 6.3.3 Possible increased pneum onia and m ort alit y from alt ering gast ric pH W h ereas brin gin g gastric pH to a m ore n eut ral level reduces th e risk of SUs, pH > 4 perm its bacterial colon ization of th e n orm ally sterile stom ach . Th is m ay in crease th e risk of pn eum on ia from aspira- t ion , an d th ere is a suggest ion th at m ortalit y m ay also be in creased.7 Sucralfate m ay be as e ect ive

130 General and Neurology in reducing bleedin g, but m ay be associated w ith low er rates of pn eum on ia an d m ortalit y. Th ere is in su cien t data to determ in e th e n et result of sucralfate com pared to n o t reatm en t.7 6.3.4 Hist am ine2 (H2) ant agonist s Drug info : Ranit idine (Zant ac®) Adult age ≤ 65 yrs: 150 mg PO BID, or 50 mg IVPB q 8 hrs. For age > 65 with norm al renal function: 50 m g IV q 12 hrs. IV drip (provides a m ore consistently higher pH without peaks and troughs; som e cont roversy that this m ay increase gastric bacterial concent ration with increased risk of aspiration pneum onia has not been borne out ): 6.25 m g/ hr (e.g. inject 150 m g into 42 m l of IVF yielding 3.125 m g/m l, run at 2 m l/hr). 6 Drug info : Fam ot idine (Pepcid®) Adult: 20 m g PO q hs for maintenance; 40 m g PO q hs for active ulcer therapy; IV: 20 mg q 12 hrs (for hypersecretory conditions, 20 mg IVPB q 6 hrs).8 Supplied: 20 & 40 mg tablets, 40 mg/5 m l sus- pension, and 20 & 40 mg orally disintegrating tablets as Pepcid RPD. Available OTC in 10 mg tablets as Pepcid AC. Available IV. Drug info : Nizat idine (Axid®) 300 mg PO q d or 150 mg PO BID. Supplied: 150 & 300 mg pulvules. Available OTC in 75 mg tablets as Axid AR. 6.3.5 Gast ric acid secret ion inhibit ors (prot on pum p inhibit ors) Th ese agen ts reduce gastric acid by specific in h ibition of th e fin al step in acid secretion by gastric parietal cells (by in h ibitin g th e (H+, K+)-ATPase en zym e system on th e cell surface, th e so-called “acid pum p”). Th ey block acid secretion regardless of th e st im ulus (Zollinger-Ellison syn drom e, hypergas- t rin em ia…). Full recover y of acid secretion upon discon tin uat ion m ay n ot occur for w eeks. Not in dicated for lon g-term treatm en t as th e t roph ic e ects of th e resultan t elevated levels of gastrin m ay lead to gastric carcinoid tum ors. Drug info : Om eprazole (Prilosec®) Inhibition of some hepatic P-450 enzymes results in reduced clearance of warfarin and phenytoin. Decreases the e ectiveness of prednisone. Adult: for peptic ulcers and gastro-esophageal reflux disease (GERD) 20–40 m g PO daily. For Zol- linger-Ellison syndrom e: 20 m g PO q d to 120 mg PO TID (dose adjusted to keep basal acid output < 60 mEq/hr). Side e ect s: N/V, H/A, diarrhea, abdominal pain or rash in 1–5%of patients. Supplied: 10, 20 & 40 m g delayed-release capsules. Available OTC in 20.6 mg tablets as Prilosec OTC.

General Neurocritical Care 131 Drug info : Lansoprazole (Prevacid®) 6 Found not to have an a ect on a number of other drugs metabolized by cytochrome P-450 including: phenytoin, warfarin and prednisone. Adult: 15 m g (for duodenal ulcer, GERD, or maintenance therapy) or 30 m g (for gastric ulcer or erosive esophagitis) PO q d, short-term treatm ent × 4 wks. Supplied: 15 & 30 mg delayed-release capsules. Drug info : Pant oprazole (Prot onix®) PO: 40 mg PO q d for up to 8 wks. IV: 40 mg IV q d × 7–10 d. Supplied: PO: 40 m g delayed-release capsules. 6.3.6 Miscellaneous Drug info : Sucralfat e (Carafat e®) Minimally absorbed from GI tract. Acts by coating ulcerated areas of mucosa, does not inhibit acid secretion. This m ay actually result in a lower incidence of pneumonia and mortalit y than agents that a ect gastric pH (see above). 1 gm PO QID on an empty stomach. Do not give antacids within one half-hour of sucralfate. Re fe r e n ce s [5] Lu W Y, Rh on ey DH, Bolin g W B, et al. A Review of Stress Ulcer Prophylaxis in th e Neurosurgical In ten - [1] Cott rell JE, Patel K, Tu rn d orf H, et al. ICP Ch an ges sive Care Unit. Neu rosu rger y. 1997; 41:416–426 In duced by Sodium Nitropru sside in Patients w ith In tracran ial Mass Lesion s. J Neurosurg. 1978; [6] Cu sh in g H. Pept ic Ulcers an d th e In terbrain . Su rg 48:329–331 Gyn ecol Obstet. 1932; 55:1–34 [2] Orlow ski JP, Sh iesley D, Vid t DG, Barn ett GH, et al. [7] Cook DJ, Reeve BK, Guyat t GH, et al. Stress Ulcer Labetalol to Con t rol Blood Pressure After Cerebro- Prop hylaxis in Crit ically Ill Patien ts: Resolvin g Dis- vascular Surgery. Crit Care Med. 1988; 16:765–768 cordan t Meta-An alyses. JAMA. 1996; 275:308–314 [3] Esm olol - A Sh ort -Act in g IV Beta Blocker. Med Let- [8] Fam otid in e (Pep cid). Med Letter. 1987; 29:17–18 ter. 1987; 29:57–58 [4] Trum ble ER, Muizelaar JP, Myseros JS. Coagu lop ath y w ith th e Use of Hetastarch in th e Treatm en t of Vas- ospasm . J Neurosurg. 1995; 82:44–47

132 General and Neurology 7 Sedat ives, Paralyt ics, Analgesics 7.1 Sedat ives and paralyt ics 7.1.1 Richm ond agit at ion-sedat ion scale (RASS) A validated scale1,2 th at uses positive n um bers for agitation an d n egative n um bers for sedation as sh ow n in Table 7.1. Useful for quan t itating th e desired level of sedat ion w h en t itrating sedatives for agitated patien ts. Procedure for perform ing RASS assessm en t: 1. on obser vation, patien t is alert, restless or agitated: score 0 to + 4 2. if pat ien t is n ot aler t , state patien t’s n am e an d verbally in st ruct to open eyes an d look at speaker: score –1 to –3 3. if n o respon se to verbal stim ulus, physically st im ulate by sh aking sh oulder an d/or stern al rub: score –4 or –5 7 7.1.2 Conscious sedat ion Use of th ese agen ts requires abilit y to provide im m ediate em ergen cy ven tilator y support (in cluding in tubation ). Agen ts in clude: 1. m idazolam (Versed®) (p.870) w ith fen tanyl 2. fen tanyl 3. pen tobarbital (Nem butal®): a barbiturate. for 70 kg adult: 100 m g slow IVP Drug info : Met hohexit al (Brevit al®) More potent and shorter acting than thiopental (useful e.g. for percutaneous rhizotom y where pa- tient needs to be sedated and awakened repeatedly). Lasts 5–7 m in. Similar cautions with the added problem that methohexital may induce seizures. May no longer be available in the U.S. Adult: 1 gm %solution (add 50 ml diluent to 500 mg to yield 10 m g/ml), 2 m l test dose, then 5– 12 m l IVP at rate of 1 m l/5 secs, then 2 to 4 ml q 4–7 m in PRN. Table 7.1 Richm ond agitation-sedation scale Sco r e Te r m De scrip t io n overly combative, violent, imm ediate danger to staff + 4 com bative pulls or rem oves tubes or catheters; aggressive frequent non-purposeful m ovements, fights ventilator Ag it a t io n +3 very agitated anxious, but movem ents not aggressive /vigorous +2 a g it a t e d + 1 restless 0 alert & calm drowsy not fully alert, but has –1 sustained awakening (eye- opening/contact) to voice –2 light sedation (≥ 10 seconds) verbal stimulation physical stim ulation Se d a t io n –3 m oderate sedation briefly awakens with eye –4 deep sedation contact to voice (< 10 seconds) –5 unarousable m ovement or eye opening to voice (no eye contact) no response to voice, but m ovement or eye-opening to physical stim ulation no response to voice or pjysical stimulation

Sedatives, Paralytics, Analgesics 133 7.1.3 Sedat ion Gen erally requires in tubation an d m ech an ical ven tilator y support in th e ICU. Doses are gen erally low er th an th ose used by an esth esiologists for gen eral an esthesia. Drug info : Thiopent al (Pent ot hal®) 7 A short acting barbiturate. 1st dose causes unconsciousness in 20–30 secs (circulation tim e), depth increases up to 40 secs, duration = 5 mins (terminated by redistribution), consciousness returns over 20–30 mins. Side e ect s: dose related respiratory depression, irritation if extravasated, intra-arterial injection → necrosis, agitation if injected slowly, an antianalgesic, m yocardial depressant, hypotension in hypo- volem ic patients. Adult: initial concentration should not exceed 2.5%, give 50 mg test dose moderately rapid IVP, then if tolerated give 100–200 mg IVP over 20–30 secs (500 mg m ay be required in large patient). Drug info : Rem ifent anil (Ult iva®) Ultrashort acting micro-opioid receptor agonist. Potency similar to fentanyl. Rapidly crosses BBB. Onset: < 1 m in. O set: 3–10 mins. Lowers ICP. Metabolism : non-hepatic hydrolysis by nonspecific blood and tissue esterases, no accum ulation. Synergy with thiopental, propofol, isoflurane, midazo- lam requires reducing doses of these agents by up to 75%. Side e ect s: bradycardia, hypotension (these side e ects m ay be blunted by pretreatm ent with anticholinergics), N/V, muscle rigidit y, pruri- tis (aspecially facial) dose dependent respiratory depression at doses > 0.05 mcg/kg/min. Adult: avoid bolus doses. Start with drip of 0.05 m cg/kg/min. Titrate in 0.025 mcg/kg/min incre- ments tp a maxim um of 0.1–0.2 m cg/kg/min. Add a sedative if adequate sedation not achieved at maxim um dose. Wean infusion in 25%decrements over 10 m inues after extubation. Supplied: vials of 1, 2 or 5 mg powder to be reconstituted to 1 mg/ml solution. Drug info : Fent anyl (Sublim aze®) Narcotic, potency ≈ 100 × morphine. High lipid solubilit y → rapid onset. O set (sm all doses): 20– 30 mins. Unlike morphine and m eperidine, does not cause histamine release. Lowers ICP. Side e ect s: dose dependent respiratory depression, large doses given rapidly may cause chest wall rigidit y. Repeated dosing may cause accumulation. Diminished sensitivit y to CO2 stim ulation, may persist lon- ger than the depression of respiratory rate (up to 4 hours). Adult: 25–100 m cg (0.5–2 m l) IVP, repeat PRN. Supplied: 50 mcg/ml; requires refrigeration. Drug info : Propofol (Diprivan®) A sedative hypnotic. Also useful in high doses during aneurysm surgery as a neuroprotectant (p. 1203). Protection seems to be less than with barbiturates. O set time increases after ≈ 12 hours of use. for sedation: start at 5–10 m cg/kg/min. Increase by 5–10 mcg/kg/min q 5–10 minutes PRN desired sedation (up to a max of 50 mcg/kg/min). Side e ect s: include Propofol Infusion Syndrom e: hyperkalem ia, hepatomegaly, lipemia, m etabol- ic acidosis, myocardial failure, rhabdom yolosis, renal failure and som etimes death.3 First identified in children, but m ay occur at any age. NB: metabolic acidosis of unknown etiology in a patient on propo- fol is propofol infusion syndrome until proven otherwise. Use with caution at doses > 50 m cg/kg/min or at any dose for > 48 hrs. Also note that the lipid carrier provides 1.1 kCal/m l and hypertriglyceride- m ia m ay occur. Supplied: 500 mg suspended in a 50 ml bottle of fat em ulsion. The bot tle and tubing must be changed every 12 hours since it contains no bacteriostatic agent.

134 General and Neurology Drug info : Precedex® (Dexm edet om idine) An alpha-2 adrenoceptor agonist. Acts in locus ceruleur and dorsal root ganglia. Has both sedative and analgesic properties and dramatically reduce the risk of respiratory depression and the am ount of narcotic analgesics required. Reduces shivering. : usual loading dose is 1 mcg/kg IV over 10 minutes (loading dose not needed if patient already sedated with other agents), followed by continuous IV infusion of 0.2–1.0 mcg/kg/hr titrated to desired e ect, not to exceed 24 hours (for short sedation or use as a “transition” drug). Side e ects: clinically significant bradycardia and sinus arrest have occurred in young, healthy volunteers with increased vagal tone (anticholinergics such as atropine 0.2 m g IV or glycopyrrolate 0.2 m g IV may help). Use with caution in patients with advanced heart block, baseline bradycardia, using other drugs that lower heartrate, and hypovolemia. Supplied: 2 m l vials of 100 mcg/ml to be diluted in 48 ml NS for a final concentration of 4 mcg/m l for IV use. 7 7.2 Paralyt ics (neurom uscular blocking agent s) 7.2.1 General inform at ion CAUTION: requires ven tilation (in t ubation or Am bu-bag/m ask). Rem in der: paralyzed patien ts m ay st ill be con scious an d th erefore able to feel pain , th e sim ultan eous use of sedation is th us required for con scious patien ts. Early routin e use in h ead-injured patien ts low ers ICP (e.g. from suct ion in g4) an d m ortalit y, but does n ot im prove overall outcom e.5 Neurom uscular blockin g agen ts (NMBAs) are classified clin ically by tim e to on set an d durat ion of paralysis as sh ow n in Table 7.2. Addition al in form ation for som e agen ts follow s th e table alon g w ith som e con sideration s for n eurosurgical patien ts. Table 7.2 Onset and duration of muscle relaxants Clinical class Agent Tr a d e On se t Du r a - Spont aneous Com m ent name (m in) t ion r e co ve r y (®) (m in) (m in) Ult ra -sh o rt succinylcho- An e ct in e 1 5–10 20 shortest onset and dura- line tion; plasm a cholinesterase dependent; many side ef- fe ct s Short rocuronium Zem uron 1–1.5 20–35 40–60 close to succinylcholine in onset in large doses; some vagolytic action in children Interm ediate vecuronium Norcuron 3–5 20–35 40–60 m inimal cardiovascular side effects (bradycardia reported); no histamine release cisatracurium Nimbex 1.5–2 40–60 60–80 no histam ine release at recommended doses

Sedatives, Paralytics, Analgesics 135 7.2.2 Ult ra-short act ing paralyt ics 7 Drug info : Succinylcholine (Anect ine®) The only depolarizing ganglionic blocker (the rest are com petitive blockers). Rapidly inactivated by plasma pseudocholinesterases. A single dose produces fasciculations then paralysis. Onset: 1 min. Duration of action: 5–10 m in. Indicat ions Due to significant side e ects (see below), use is now limited primarily to the following indications. Adults: generally recommended only for emergency intubations where the airway is not controlled. In children: only when intubation is needed with a full stomach, or if laryngospasm occurs during at tempted intubation using other agents. Side e ect s CAUTIONS: usually increases serum K+ by 0.5 mEq/ L(on rare occasion causes severe hyperkalemia ([K+] up to 12 m Eq/ L) in patients with neuronal or muscular pathology, causing cardiac complications which cannot be blocked), therefore contraindicated in acute phase of injury following major burns, m ultiple traum a or extensive denervation of skeletal m uscle or upper m otor neuron injury. Do not use for routine intubations in adolescents and children (may cause cardiac arrest even in apparently healthy youngsters, many of whom have undiagnosed myopathies). Linked to m alignant hyperther- m ia (p. 108). May cause dysrhythmias, especially sinus bradycardia (treat with atropine). May get autonomic sti- m ulation from ACh-like action → HTN, and brady- or tachycardia (especially in peds with repeated doses). The fasciculations may increase ICP, intragastric pressure, and intraocular pressure (contraindi- cated in penetrating eye injury, especially to anterior chamber; OK in glaucoma). Precurarization with a “prim ing dose” of a nondepolarizing blocker (usually ≈ 10%of the intubat- ing dose, e.g. pancuronium 0.5–1 mg IV 3–5 m inutes prior to succinylcholine) in patients with ele- vated ICP or increased intraocular pressure (to ameliorate further pressure increases during fasciculation phase) and in patients who have eaten recently (controversial6). Phase II block (sim ilar to nondepolarizing blocker) may develop with excessive doses or in patients with abnormal p se u d o ch o lin e st e ra se. Do s in g Adult: 0.6–1.1 mg/kg (2–3 m l/70 kg) IVP (err on high side to allow tim e for procedure & to avoid multi-dosing complications), may repeat this dose × 1. Peds (CAUTION: Not recom mended for routine use, see above) Children: 1.1 mg/kg. Infants (< 1 mos): 2 m g/kg. Supplied: 20 mg/ml concentration. 7.2.3 Short act ing paralyt ics Drug info : Rocuronium (Zem uron®) In large doses, has speed of onset that approaches succinylcholine. However, in these doses, paralysis usually lasts ≈ 1–2 hrs. Expensive. Adult: initial dose 0.6–1 mg/kg. May be used as infusion of 10–12 mcg/kg/min.

136 General and Neurology 7.2.4 Int erm ediat e act ing paralyt ics Drug info : Vecuronium (Norcuron®) Nondepolarizing (com petitive) NMBA. Adequate paralysis for intubation within 2.5–3 minutes of administration. About one–third m ore potent than pancuronium, shorter duration of action (lasts ≈ 30 minutes after initial dose). Unlike pancuronium , very lit tle vagal (i.e. cardiovascular) e ects. No CNS active metabolites. Does not a ect ICP or CPP. Hepatically metabolized. Due to active metabo- lites, paralysis has been reported to take 6 hrs to 7 days to recede following discontinuation of the drug after ≥ 2 days use in patients with renal failure.7 Must be m ixed to use. Do s in g Supplied: 10 mg freeze-dried cakes requiring reconstitution. Use within 24 hrs of m ixing. Adult and children > 10 years age: 0.1 m g/kg (for m ost adults use 8–10 mg as initial dose). May repeat q 1 hr PRN. Infusion: 1–2 mcg/kg/m in. Pediatric: children (1–10 yrs) require slightly higher dose and more frequent dosing than adult. 7 Infants (7 weeks – 1 yr): slightly more sensitive on a mg/kg basis than adults, takes ≈ 1.5 × longer to recover. Use in neonates and continuous infusion in children is insu ciently studied. Drug info : Cisat racurium (Nim bex®) Nondepolarizing (com petitive) blocker. This isom er of atracurium does not release histamine unlike its parent compound (see below). Provides about 1 hour of paralysis. Also undergoes Hofm ann degra- dation, with laudanosine as one of its m etabolites. Adult and children > 12 years age: 0.15 or 0.2 mg/kg as part of propofol/nitrous oxide/oxygen induction-intubation technique produces muscle paralysis adequate for intubation within 2 or 1.5 m inutes, respectively. Infusion: 1–3 mcg/kg/min. Pediatric: children (2–12 yrs): 0.1 m g/kg given over 5–10 seconds during inhalational or opioid a n e st h e sia . 7.2.5 Reversal of com pet it ive m uscle blockade Reversal is usually n ot attem pted un til patien t h as at least 1 t w itch to a t rain of 4 stim ulus, oth erw ise reversal m ay be in com plete if patien t is profoun dly blocked an d blockade m ay reoccur as th e rever- sal w ears o (a respon se of 1/4 in dicates 90%m uscle blockade) ● n eostigm in e (Prostigm in ®): 2.5 m g (m in im um ) to 5 m g (m axim um ) IV (start low, n o e cacy from > 5 m g an d can produce severe w eakn ess especially if th e m axim um dose is exceeded in the absence of neurom uscular blockade) ● PLUS (to preven t bradycardia…), ○ EITHER 0.5 m g atropin e for each m g of n eostigm in e ○ OR 0.2 m g glycopyrrolate (Robin ul®) for each m g of n eostigm in e 7.3 Analgesics 7.3.1 General inform at ion For a discussion of t ypes of pain an d pain procedures (p.476). Th ree t ypes of pain m edicat ion 1. n on -opioid pain m edication (see below ) a) n on steroidal an ti-in flam m ator y drugs: aspirin , ibuprofen … b) acetam inophen 2. opioids (p.138) a) agonists b) partial agonists c) m ixed agonist/antagonists

Sedatives, Paralytics, Analgesics 137 3. drugs th at are n ot st rictly an algesics, but w h ich act as adjuvan ts (p.143) w h en added to any of 7 th e above: tricyclic an tidepressan ts, an ticonvulsan ts, ca ein e, hydroxyzin e, corticosteroids (p . 1 4 3 ) 7.3.2 Guiding principles Th e key to good pain con trol is th e early use of adequate levels of e ect ive an algesics. For can cer pain , sch eduled dosin g is superior to PRN dosin g, an d “rescue” m edication sh ould be available.8 Non - opioid an algesics sh ould be con tin ued as m ore poten t m edication s an d invasive tech n iques are u t ilize d . 7.3.3 Analgesics for som e specific t ypes of pain Visceral or dea erent at ion pain May som etim es be e ectively treated w ith tricyclic antidepressants (p.477). Tr yptoph an m ay be e ect ive (p. 143). Carbam azepin e (Tegretol®) m ay be useful for paroxysm al, lan cin atin g pain . Pain from m et ast at ic bone disease Steroids, aspirin , or NSAIDs are especially h elpfu l, probably by reducin g prostaglan din m ediated sen - sit ization of A-delta an d C fibers, an d th erefore m ay be preferred to APAP. 7.3.4 Nonopioid analgesics Acet am inophen Table 7.3 Acetam inophen dosing Do sa g e Me d ica t io n ace t a m in o p h e n adult dose: 650 or 1000 mg PO/PR q 4–6 hrs, not to exceed (APAP) 4000 mg/daya (Tylenol®) pediatric dose: infants: 10–15 m g/kg PO/PR q 4–6 hrs children: 1 grain/yr age (= 65 m g/yr up to 650 m g) PO/PR q 4–6 hrs not to exceed 15 m g/kg q 4 hrs ahepatic toxicit y from APAP: usually with doses ≥ 10 gm /day, rare at doses < 4000 m g. However, m ay occur at lower doses (even at high therapeutic doses) in alcoholics, fasting patients, and those taking cytochrome P-450 enzym e-inducing drugs Nonst eroidal ant i-inflam m at ory drugs (NSAIDs) Th e an t i-in flam m ator y propert ies of NSAIDs is prim arily due to in h ibition of th e en zym e cyclooxy- gen ase (COX) w h ich part icipates in th e syn th esis of prostaglan din s an d th rom boxan es.9 Ch aracterist ics of n on select ive n on steroidal an t i-in flam m ator y drugs: 1. all are given orally except ketorolac t rom eth am in e (Toradol®) (see below ) 2. no dependence develops 3. additive e ect im proves th e pain relief w ith opioid an algesics 4. NSAIDs (an d APAP) dem on strate a ceiling e ect: a m axim um dose above w h ich n o furth er an al- gesia is obtain ed. For aspirin an d APAP, th is is usually betw een 650–1300 m g, an d is often h igh er for oth er NSAIDs w h ich m ay also h ave a lon ger duration of action 5. risk of GI upset is com m on , m ore serious risks of h epatotoxicit y,10 or GI ulceration , h em orrh age, or perforation are less com m on 6. takin g m edicat ion w ith m eals or an tacids h as n ot been proven e ect ive in reducin g GI side e ect s. Misoprostol (Cytotec®), a prostaglan din , m ay be e ect ive in m it igat in g NSAID-in duced gast ric erosion or peptic ulcer. Con t rain dicated in pregn an cy. 200 m cg PO QID w ith food as lon g as patien t is on NSAIDs. If n ot tolerated, use 100 m cg. CAUTION: an abortifacien t. Sh ould n ot be given to pregn an t w om en or w om en of ch ildbearing poten tial 7. m ost reversibly in h ibit platelet fun ct ion an d prolong bleedin g tim e (n on acetlyated salicylates h ave less an tiplatelet action , e.g. salsalate, t risalicylate, n abum etom e). Aspirin , un like all oth er

138 General and Neurology NSAIDS, ir reversibly bin ds to cyclooxygen ase an d th us in h ibits platelet fun ct ion for th e 8–10 day life of th e platelet 8. all cause sodium an d w ater reten tion an d carr y th e risk of NSAID-in duced n eph rotoxicit y11 (by reducing syn th esis of ren al vasodilator prostaglan din s → reduced ren al blood flow w h ich can → ren al in su cien cy, in terstitial n eph rit is, n eph rotic syn drom e, hyperkalem ia) 9. n on -aspirin NSAIDs in crease th e risk of h eart attack or stroke12 Drug info : Ket orolac t rom et ham ine (Toradol®) The only parenteral NSAID approved for use in pain control in the U.S. Analgesic e ect is more potent than anti-inflam matory e ect. Half-life ≈ 6 hrs. May be useful to control pain in the following sit u a t io n s: 1. where the avoidance of sedation or respiratory depression is critical 2. when constipation cannot be tolerated 3. for patients who are nauseated by narcotics 4. where narcotic dependency is a serious concern 7 5. when epidural morphine has been used and further analgesia is needed without risk of respiratory depression (agonist t ype narcotics are contraindicated) 6. cautions: a) not indicated for use > 72 hrs (complications have been reported prim arily with prolonged use of the oral form) b) use with caution in postoperative patients since (as with m ost NSAIDs) bleeding tim e is pro- longed by platelet function inhibition (risk of GI or op-site hemorrhage is small, but is increased in patients > 75 yrs old, when used > 5 days, and when used in higher doses13) c) even though IM dosing circumvents the GI system , gastric mucosal irritation and erosions m ay occur as with all NSAIDs (avoid use with PUD) d) as with all NSAIDs, use with caution in patients at risk for renal side e ects Parenteral:For single dose adm inistration: 30 mg IV or 60 m g IM in healthy adult. For multiple dos- ing: 30 mg IV or IM q 6 hrs PRN. Maximum dosage: 120 mg/day. Parenteral use should not exceed 5 days (3 days may be a better guideline). For patient weight < 50 kg, age > 65 yrs, or reduced renal function (creatinine clearance < 50 ml/ min), all of the above dosages are halved (max daily dose: 60 mg). Creatinine clearance can be esti- mated using the Cockcroft-Gault equation14 shown in Eq (7.1), with normal values ≥ 60 ml/m in. Cre a t in in e cle aran ce ðm l⁄ minÞ ¼ ½140 À ageðyearsÞ iÂninideeðaml wg⁄tðdklgÞÞÂ ð0:85 for fem alesÞ ð7:1Þ 72 Â serum creat PO: Indicated only as a continuation of IVor IM therapy, not for routine use as an NSAID. Switching from IM to PO: start with 10 m g PO q 4–6 hrs (combined PO and IM dose should be ≤ 120 mg on the day of transition). Supplied: 10 m g tablets. 7.3.5 Opioid analgesics General inform at ion Narcotics are m ost com m on ly used for m oderate to severe acute pain or can cer pain (som e exper ts characterize cancer pain as recurrent acute pain and not chron ic pain). Ch aracterist ics of n arcotics: 1. n o ceilin g e ect (p. 137): i.e. in creasin g dosage in creases th e e ect iven ess (alth ough w ith w eak opioids for m oderate pain , side e ect s m ay lim it dosages to relatively low levels8) 2. w ith ch ron ic use, toleran ce develops (physical an d psych ological) 3. overdose possible (p.207), w ith th e poten tial for respirator y depression w ith all, an d seizures w ith som e

Sedatives, Paralytics, Analgesics 139 Table 7.4 Nonsteroidal anti-inflamm atory drugs (NSAIDs)a Generic nam e Proprietary Typical adult oral doseb Ta b s/ ca p s Daily m axi- (®) mum dose availabilit y (m g) (m g)c aspirind (m a ny) 500–1000 m g PO q 4–6 hrs (ceiling 325, 500 4000 dose ≈ 1 gm) diclofenac Vo lt a re n , start at 25 m g QID; additional dose q hs 25, 50, 75 200 Ca t a fla m PRN; increase up to 50 mg TID or QID, or 75 mg BID etodolac for acute pain: 200–400 m g q 6–8 hrs 200, 300 caps, 1200 400 tabs fenoprofen Nalfon 200 m g q 4–6 hrs; for rheumatoid 200, 300, 600 3200 arthritis 300–600 m g TID-QID flurbiprofen 50 m g TID-QID or 100 mg TID 50, 100 300 ke t o p ro fe n im m ediate start at 75 mg TID or 50 m g QID, 25, 50, 75 300 7 release ↑ to 150–300 mg daily DIV TID-QID e xt e n d e d 150 mg q d ERc 150 release ketorolac see below see below ib u p ro fe n e Mo t rin 400–800 m g QID (ceiling dose: 300, 400, 600, 3200 800 mg) 800 in d o m e t h acin 25 mg TID, ↑ by 25 m g total per day 25, 50, SR 75 150–200 PRN m eclofenam ate 50 mg q 4–6 hrs; ↑ to 100 m g QID if 50, 100 400 needed m efenam ic Po n st e l 500 m g initial; then 250 m g q 6 hrs 250 nabumetomef Relafen 1000–2000 mg/d given in 1 or 2 doses 500, 750 2000 naproxen Naprosyn 500 m g, then 250 m g q 6–8 hrs 250, 375, 500 <1250 naproxen sodium Anaprox 550 m g, followed by 275 mg q 6–8 hrs 275, DS = 550 1375 oxaprozin Daypro 1200 m g q d (1st day m ay take 1800) 600 1800 piroxicam Feldene 10–20 mg q d (steady state takes 7–12 10, 20 d) sulindac 200 m g BID; ↓ to 150 BID when pain 150, 200 400 controlled sa lsa la t e 3000 m g divided BID-TID (e.g. 500 mg 500, 750 2-tabs TID) t o lm et in 400 m g TID (bioavailability is reduced 200, DS = 400, 1800 by food) 600 aNSAIDs increase the risk of cardiovascular thrombotic events (heart at tack or stroke)12 bwhen dosage ranges are given, use the smallest effective dose cabbreviations: DS = double strength; SR= slow release; ER= extended release; DOC = drug of choice daspirin: has unique effectiveness in pain from bone m etastases eibuprofen: is available as a suspension (PediaProfen®) 100 mg/m l; dose for children 6 mos to 12 yrs age is 5–10 m g/kg with a m aximum of 40 m g/kg/day (not FDA approved for children because of possible Reye’s syn d ro m e ) funlike most NSAIDs, nabum etom e does not interfere with platelet function

140 General and Neurology Mild t o m oderat e pain Table 7.5 Weak opioids for m ild to m oderate pain Medicat ion Do sa g e codeine usual adult dose: 30–60 m g IM/PO q 3 hrs PRN; use with caution in nursing mothersa and children (30 mg PO is equivalent to 300 m g aspirin) pediatric dose: 0.5–1 m g/kg/dose q 4–6 hrs PO or IV PRN p e n t a zo cin e pentazocine is a mixed agonist-antagonist Talwin® → 12.5 m g pentazocine, 325 m g ASA. : 2 PO TID-QID PRN with naloxone → 50 m g pentazocine, 0.5 m g naloxone. : 1–2 PO q 3–4 hrs PRN up to 12 tabs/day tram adol (Ultram ®) (see below) 7 a1–28% of wom en are ultrafast m etabolizers of codeine and the resultant m orphine may be passed on to the infant via the breast m ilk Som e useful m edicat ion s are sh ow n in Table 7.5. Codein e an d congen er pen tazocin e, are usually n o m ore e ect ive th at ASA or APAP an d are usu- ally com bined w ith th ese drugs. Drug info : Tram adol (Ult ram ®) An oral opioid agonist that binds to µ-opioid receptors, and is also a centrally acting analgesic that inhibits reuptake of norepinephrine and serotonin. For acute pain, 100 mg is com parable to codeine 60 m g with ASA or APAP.15,16 There has been no report of respiratory depression when oral dosing recommendations are followed. Seizures and opioid-like dependence have been reported.16 50 to 100 mg PO q 4–6 hrs PRN pain up to a maxim um of 400 mg/day (or 300 mg/d for older patients). For m oderately severe acute pain, an initial dose of 100 m g followed by 50 mg doses m ay su ce. Supplied: 50 mg tabs. Moderat e t o severe pain Table 7.6 Opioids for moderate to severe pain Medicat ion Do sa g e hydrocodone (Vicodin®, Lorcet®, Lortab®…): 5 mg hydrocodone + 500 mg acetam inophen; (Vicodin ES®, Lortab 7.5/500®): 7.5 m g hydrocodone + 500 m g APAP; 1 tab PO q 6 hrs PRN (may increase up to 2 tabs PO q 3–4 hrs not to exceed 8 pills/24 hrs). (Lorcet® Plus, Lorcet® 10/650): 7.5 or 10 m g hydrocodone (respectively) + 650 m g APAP; 1 tab PO q 6 hrs PRN (not to exceed 6 tabs in 24 hrs). (Lortab® 10/500: 10 mg. hydrocodone + 500 m g APAP); : 1–2 PO q 4 hrs PRN up to 6 tabs/day. (Norco®): 10 m g hydrocodone + 325 m g APAP scored tabs; : 1 PO q 4 hrs PRN up to 6 tabs/day. oxycodone Supplied : usually available in com bination as: aspirin 325 mg with oxycodone 5 m g (Percodan®) or acetam inophen (APAP) (Tylox® = APAP 500 m g + oxycodone 5 m g) (Percocet® = oxycodone/APAP in 2.5/325, 5/325, 7.5/500, 10/650) dose: 1 PO q 3–4 hrs PRN (m ay increase up to 2 PO q 3 hrsa)

Sedatives, Paralytics, Analgesics 141 Table 7.6 continued Do sa g e Me d ica t io n Supplied :also available alone as OxyIR® 5 mg, OxyFast® oral solution of 20 m g/ ml, or in controlled-release tablets as OxyContin® 10, 20, 40, 80b & 160 b mg (which last 12 hours, achieving steady state in 24–36 hours). Adult: OxyContin® tablet s are taken whole and are not to be divided, chewed or crushed. It is intended for m anagem ent of m oderate to severe pain when continuous around-the-clock analgesic is needed for an extended period of tim e and is not intended for use as a PRN analgesic. For opiate naive patients, start with 10 m g PO q 12 hrs. For patients on narcotic m edications, a conversion table is provided below for som e m edications. Titrate dose every 1–2 days, increasing dose by 25–50% q 12 hrs. Conversion t able for st arting OxyCont in® Preparation currently Dose Suggested starting dose of being used OxyCo n t in ® oxycodone com bina- 1–5 pills/day 10–20 mg PO q 12 hrs 7 tion pills (Tylox, Per- 6–9 pills/day 20–30 mg PO q 12 hrs codan…) or Lortab, 10–12 pills/day 30–40 mg PO q 12 hrs Vicodin or Tylenol #3 IV PCA m orphine determine total multiply total MSO4 dose in 24 hrs × MSO4 dose 1.3 for total OxyContin dose in 24 hrs used per 24 hrs hydrom orphone Dilaudid®: (see Table 7.7) m orphine used in low doses (see Table 7.7) anot to exceed 4000 mg of acetam inophen/24 hrs (see footnote to Table 7.3) bfor use only in opioid-tolerant patients Severe pain Table 7.7 Equianalgesic doses for SEVERE pain, AGONISTopioids (parenteral route is referenced to 10 mg IM m o rp h in e ) Drug nam e: Ro u t e Do se Peak Durat ion Com m ent s g e n e r ic (m g) (hrs) (hrs) (propriet ary®) m o rp h in e IM 10 0.5–1 4–6 respiratory depression PO 20–60a 1.5–2 4–7 long acting PO form s: MS Contin®, Avinza® (see below) codeine (not rec- IM 130 3–5 these high doses cause unacceptable ommended at PO 200 side effect s these doses) methadoneb IM 10 0.5–1 4–6 long half-lifeb (Dolophine®) PO 20 1.5–2 4–7 o xyco d o n e IM 15 (e.g. Tylox®c) PO 30 1 3–4 combination (Tylox®) or liquid (OxyCo n t in ®) PO 30–40 12 OxyContin, see Table 7.6 o xym o rp h o n e IM 1 3–5 available as suppository PR 10 hydrom orphone IM 1.5 0.5–1 3–4 (Dila u d id ®)

142 General and Neurology Table 7.7 continued Drug nam e: Ro u t e Do se Peak Durat ion Com m ent s g e n e r ic (m g) (hrs) (hrs) (propriet ary®) PO 7.5 1.5–2 3–4 supplied: 1, 2, 3, & 4 m g tabs fe n t a nyl IV 0.1 1–2 not recom mended for acute pain (Su b lim a ze ®) control, esp. in narcotic naive pts. t ran sd e rm al transdermal e 12–24 72 patches of 25, 50, 75, 100 or 125 m cg/hr (use lowest effective) fentanyl patch (Du ra g e sic®)d aIM:PO potency ratio for m orphine is 1:6 for single doses, but changes to 1:2–3 with chronic dosing bdue to long half-life, repeated dosing can lead to accumulation and CNS depression (m ust reduce dose after ≈ 3 days, even though the analgesic half-life does not change), especially in the elderly or debilitated patient. Use should be lim ited to physicians with experience using these drugs cmay not be practical for use in severe pain since 1 Tylox® contains only 5 m g oxycodone (the acetam inophen lim its the dosage), m ay use OxyContin® for higher doses of oxycodone 7 d should not be used as routine post-op analgesic (risk of respiratory depression). Apply 1 patch to upper torso, replace q 72 hrs PRN. econversion from total daily parenteral m orphine as follows: 8–27 mg MSO4/day → Duragesic 25 m cg/hr 28–37 m g MSO4/day → Duragesic 50 m cg/hr 38–52 m g MSO4/day → Duragesic 75 m cg/hr 53–67 m g MSO4/day → Duragesic 100 m cg/hr 68–82 m g MSO4/day → Duragesic 125 m cg/hr Table 7.8 Equianalgesic doses for SEVERE pain, AGONIST/ANTAGONISTopioids (referenced to 10 m g IM m o rp h in e ) Drug nam e: generic (propriet ary®) Rout e Dose Peak Durat ion Com m ents (m g) (hrs) (hrs) b u p re n o rp h in e IM 0.4 partial agonist (Buprenex®) SL 0.3 Mixed agonist /ant agonist a b u t orp h an o l IM 2 0.5–1 4–6 nalbuphine IM 10 1 3–6 no sigma receptor o ccu p a t io n b IV 140 0.5 2–5 m cg/kg p e n t a zo cin e IMb 20–40 0.5–1 4–6 (Talwin®c) POb 180 1.5–2 4–7 (start @ 50) aall can precipitate withdrawal sym ptom s in patients physically dependent on agonists bmost agonist/antagonist drugs occupy sigma receptors (Stadol > Nubain), which m ay cause hallucinations cTalwin injectable (for IM use) contains only pentazocine. Talwin® Com pound tablets contain ASA, therefore for high PO doses, use Talwin Nx which contains no ASA ( Table 7.5)

Sedatives, Paralytics, Analgesics 143 Drug info : Avinza® (ext ended release m orphine) Once daily oral morphine form ulation using a spherical oral drug absorption system (SODAS) (numer- ous ammonio-methacrylate copolymer beads, ≈ 1 mm dia.). Potential for overdosage and/or abuse. : Dosage is titrated based on patient’s opioid tolerance and degree of pain. Taken as 1 capsule p. o. q d. Not to be taken “PRN.” Not for post-op pain. CAUTION: To prevent potentially fatal doses of morphine, capsules are to be swallowed whole, and are not to be chewed, crushed or dissolved. How- ever, the contents of the capsule (the beads) m ay be sprinkled on apple-sauce for those unable to swallow the capsules, but the beads are not to be chewed or crushed. Side e ects:Due to the poten- tially nephrotoxic e ect of fum aric acid used in SODAS, the m aximum dose of Avinza is 1600 m g/d. Doses ≥ 60 mg are for opioid tolerant patients only. Supplied:30, 60, 90 & 120 mg capsules. 7.3.6 Adjuvant pain m edicat ions 7 Th e follow in g m ay h ave e cacy in en h an cin g th e e ect iven ess of opioid an algesics (an d th ereby m ay reduce the required dose). Tricyclic an tidepressan ts: Tr yptoph an : an am in o acid an d a precursor of seroton in , m ay w ork by in creasing seroton in levels. Requires h igh doses an d h as hypn otic e ects, th erefore 1.5–2 gm given usually q h s. Must give daily MVI as ch ron ic tr yptoph an th erapy depletes vitam in B6. An tih istam in es: h istam in es play a role in n ociception . An tih istam in es, w h ich are also an xiolyt ic, an t iem etic, an d m ildly hypn otic, are e ect ive as an algesics or as adjuvan ts. Hydroxyzin e (Atarax®, Vistaril®): start w ith 50 m g PO q AM an d 100 m g PO q h s. May in crease up to ≈ 200 m g daily. An ticonvulsan t-class drugs: carbam azepin e, clon azepam , ph enytoin , gabapen tin or pregabalin ten d to be m ore e ect ive in n europath ic pain , e.g. from diabetic n europathy, t rigem in al n euralgia, post-h erpetic n euralgia, glossoph ar yn geal n euralgia, an d n euralgias due to n er ve injur y or in filtra- t ion w ith can cer.16 See in dex for en tries. Phenothiazines: some cause m ild reduction in nociception. Most are tranquilizing and antiem etic. Best know n for this use is fluphenazine (Prolixin®), usually given with a tricyclic antidepressant for neuro- pathic pain, Diabetic n europathy, Treatm en t (p.545). Phenothiazines m ay reduce the seizure threshold. Cort icosteroids: in addit ion to th e reduct ion of toxic e ect s of radiation or ch em oth erapy, th ey m ay poten tiate n arcotic an algesics. Th ere are also a n um ber of n on specific ben eficial e ect s: in creased appetite, sen se of w ell being, an tiem etic. Side e ects m ay lim it usefuln ess (p. 146). Ca ein e: alth ough it possesses n o in trin sic an algesic properties, doses of 65–200 m g en h an ce th e an algesic e ect of APAP, ASA or ibuprofen in for pain in cludin g: H/A, oral surger y pain an d post- partum pain . Re fe r e n ce s Adm inistration of Vecuron ium . N Engl J Med. 1992; 327:524–528 [1] Sessler CN, Gosn ell MS, Grap MJ, Brop hy GM, O'Neal [8] Marsh all KA. Man aging Can cer Pain : Basic Prin ci- PV, Kean e KA, Tesoro EP, Elsw ick RK. Th e Rich m on d ples an d Invasive Treatm en t . Mayo Clin Proc. 1996; Agitation -Sedation Scale: validity an d reliabilit y in 71:472–477 ad ult in ten sive care u n it p atien ts. Am J Resp ir Crit [9] Celecoxib for Arth rit is. Med Letter. 1999; 41:11–12 Care Med . 2002; 166:1338–1344 [10] Helfgot t SM, San d berg-Cook J, Zakim D, Nestler J. Diclofen ac-Associated Hepatotoxicit y. JAMA. 1990; [2] Ely EW , Trum an B, Sh in tan i A, Th om ason JW , 264:2660–2662 W h eeler AP, Gordon S, Fran cis J, Spero T, Gautam S, Margolin R, Sessler CN, Ditt us RS, Bernard GR. [11] Hen rich W L. An algesic Nep h ropathy. Am J Med Sci. Mon itorin g sed ation status over t im e in ICU 1988; 295:561–568 patien ts: reliability an d valid it y of th e Rich m on d Agitation -Sedation Scale (RASS). JAMA. 2003; [12] U.S. Food an d Drug Adm in istration (FDA). FDA Dru g 289:2983–2991 Safet y Com m u n ication : FDA st ren gth en s w arn in g th at non-aspirin n on steroidal an ti-in flam m atory [3] Kang TM. Propofol infusion synd rom e in critically ill dru gs (NSAIDs) can cau se h eart attacks or strokes. patients. Ann Ph arm acoth er. 2002; 36:1453–1456 2015 [4] Werba A, Wein stabi C, Petricek W , et al. Vecu ron iu m [13] Strom BL, Berlin JA, Kin m an JL, et al. Paren teral Preven ts Increases in Intracran ial Pressu re Du ring Ketorolac an d Risk of Gastroin test in al and Operative Rou tine Trach eobron chial Su ction ing in Neu rosurgi- Site Bleedin g. JAMA. 1996; 275:376–382 cal Patien ts. Anaesthetist. 1991; 40:328–331 [14] Cockcroft DW, Gault MH. Pred iction of creatin in e [5] Hsian g JK, Ch esn u t RM, Crisp CD, et al. Early, Rou- t in e Paralysis for In tracran ial Pressu re Con t rol in clearan ce from serum creatin in e. Neph ron . 1976; Severe Head In jury: Is It Necessary? Crit Care Med. 16:31–41 1994; 22:1471–1476 [15] Tram ad ol - A n ew oral an algesic. Med Letter. 1995; 37:59–60 [6] Oh lin ger MJ, Rh on ey DH. Neurom u scular Blockin g [16] Drugs for Pain . Med Letter. 1998; 40:79–84 Agen ts in th e Neurosurgical In ten sive Care Unit . Surg Neurol. 1998; 49:217–221 [7] Segred o V, Caldw ell JE, Matth ay MA, et al. Persisten t Paralysis in Critically Ill Patien ts After Lon g-Term

144 General and Neurology 8 Endocrinology 8.1 Cort icost eroids 8.1.1 General inform at ion Un der n orm al, basal con dition s, th e zon a fasciculata of th e adren al cortex secretes 15–25 m g/day of cort isol (hydrocort ison e is th e n am e for th e iden tical ph arm aceutical com poun d for adm in istration ), an d 1.5–4 m g/day of cort icosteron e. Cort isol h as a h alf-life of ≈ 90 m in utes. Th e release of cort isol by th e adren al glan ds is stim ulated by adren ocort icotroph ic h orm on e (ACTH) from th e pit uitary w h ich in turn is st im ulated by cort icot ropin releasing h orm on e (CRH) from th e hypoth alam us. 8.1.2 Replacem ent t herapy In prim ar y adren ocort ical in su cien cy (Addison’s disease), both glucocor ticoids an d m in eralocor ti- coids m ust be replaced. In secon dar y adren al in su cien cy caused by deficien t corticotropin (ACTH) release by th e pituitar y, m in eralocort icoid secretion is usually n orm al an d on ly glucocorticoids n eed to be replaced. Table 8.1 sh ow s equivalen t daily cort icosteroid doses for replacem en t th erapy. Physiologic replacem en t (in th e absen ce of stress) can be accom plish ed w ith eith er: 8 1. hydrocortison e: 20 m g PO q AM an d 10 m g PO q PM 2. or predn ison e: 5 m g PO q AM an d 2.5 m g PO q PM Cort isol an d cort ison e are useful for ch ronic prim ar y adren ocor tical in su cien cy or for Addison ian crisis. Because of m in eralocort icoid act ivit y, use for ch ron ic th erapy of oth er con dition s (e.g. hypopi- t uitarism ) m ay result in salt an d fluid reten tion , hyper ten sion an d hypokalem ia. 8.1.3 Hypot halam ic-pit uit ary-adrenal axis suppression General inform at ion Ch ron ic steroid adm in istration suppresses th e hypothalam ic-pituitar y-adren al (HPA) axis, an d even - t ually causes adren al atrophy. W h en th e HPA is suppressed, if exogen ous steroids are abru ptly Table 8.1 Equivalent corticosteroid dosesa St eroid: generic Equiv dose Rout e Do sin g Mineralocort i- Oral dosing (propriet ary) (m g) coid pot ency form s cortisone acetate 25 PO, IM 2/3 in AM, 2 + tabs: 5, 10 & 25 mg 1/3 in PM h yd ro co r t iso n e 20 PO 2/3 in AM, 2 + tabs: 5, 10 & AKA cort isol 1/3 in PM 20 mg (Cort ef®) (So lu -Co r t e f®) IV, IMb p re d n iso n e 5 PO only divided 1+ tabs: 1, 2.5, 5, BID-TID 10, 20, 50 mgc m ethylprednisolone 4 PO, IV, IM 0 Tabsd: 2, 4, 8, 16, 24, 32 mg dexam ethasone 0.75 PO, IV divided 0 scored tabs: 0.25, 0.5, 0.75, BID-QID 1.5, 4, 6 mg adoses given are daily doses. Steroids listed are used prim arily as glucocorticoids: equivalent glucocorticoid PO or IV dose is given; IM m ay differ bIM route recommended only for em ergencies where IV access cannot be rapidly obtained cSterapred Uni-Pak® contains 21 tabs of 5 m gs prednisone and tapers dosage from 30 to 5 mgs over 6 days; “DS” contains 10 m g tabs and tapers from 60 m g to 10 m g over 6 days; “DS 12-Day” contains 48 10 m g tabs and tapers from 60 m g to 20 m g over 12 days dMedrol Dosepak® contains 21 tabs of 4 mgs m ethylprednisolone and tapers dosage from 24 mg/d to 4 m g/d over 6 days

Endocrinology 145 stopped or if acute illness develops (w h ich increases the steroid requirem ents), sym ptom s of adre- 8 n ocor tical in su cien cy (AI) m ay en sue Table 8.2. Severe cases of AI m ay progress to Addison ian crisis (p.147). Recover y of adren al cortex lags beh in d th e pit uitar y, so basal ACTH levels in crease before cort isol levels do. HPA su p p r ession d ep en d s on t h e sp e cific glu cocor t icoid u sed , t h e r ou t e, fr e qu en cy, t im e, an d d u rat ion of t r e at m en t . Su p p r ession is u n likely w it h < 4 0 m g p re d n ison e (or equ ivalen t ) giv- en in t h e m or n in g for less t h an ≈ 7 d ays, or w it h eve r y- ot h er -d ay t h e rapy of < 40 m g for ≈ 5 w eeks.1 Som e ad ren al at rop h y m ay occu r afte r 3 –4 d ays of h igh d ose st e roid s, an d som e a xis sup p ression w ill alm ost cer tain ly occu r after 2 w eeks of 40–60 m g hyd rocortison e (or equ iva- le n t ) d aily. Aft e r a m on t h or m or e of ste r oid s, t h e HPA a xis m ay be d ep r essed for as lon g as one year. Measuring m orning plasm a hydrocortison e can evaluate the degree of recovery of basal adreno- cort ical fun ction , but does not assess adequacy of stress respon se. St eroid w it hdraw al See referen ce.1 In addition to th e above dan gers of hypocort isolism in th e presen ce of HPA suppression , too rapid a taper m ay cause a flare-up of th e un derlyin g con dition for w h ich steroids w ere prescribed. W h en th e risk of HPA suppression is low (as is th e case w ith sh ort courses of steroids for less th an ≈ 5–7 days2 gen erally prescribed for m ost n eurosurgical in dicat ion s) abrupt discon tin uation usually carr ies a low risk of AI. For up to ≈ 2 w eeks of use, steroids are usually safely w ith draw n by tapering over 1–2 w eeks. For lon ger t reatm en t , or w h en w ith draw al problem s develop, use th e follow in g con- ser va tive ta per: 1. m ake sm all decrem en ts (equivalen t to 2.5–5 m g predn ison e) ever y 3–7 d. Patien t m ay experien ce m ild w ith draw al sym ptom s of3: a) fatigue b) an orexia c) nausea d) orth ostatic dizzin ess 2. “backtrack” (i.e. in crease th e dose an d resum e a m ore gradual taper) if any of th e follow in g occur: a) exacerbation of th e un derlying con dition for w h ich steroids w ere used b) evidence of steroid w ith draw al sym ptom s ( Table 8.2) c) in tercurren t in fect ion or n eed for surger y; see St ress doses (p. 146) 3. on ce “physiologic” doses of glucocorticoid h ave been reach ed (about 20 m g hydrocort ison e/day or equivalen t ( Table 8.1): a) th e patien t is sw itch ed to 20 m g hydrocort ison e PO q AM (do n ot use lon g acting p r e p a r a t ion s) b) after ≈ 2–4 w eeks, a m orn in g cort isol level is ch ecked (prior to th e AM hydrocor tison e dose), an d th e hydrocortison e is tapered by 2.5 m g w eekly un til 10 m g/d is reach ed (low er lim its of p h ysio lo gic) c) th en , ever y 2–4 w eeks, th e AM cort isol level is draw n (prior to AM dose) un til th e 8 AM cort i- sol is > 10 m cg/100 m l, in dicat in g return of baselin e adren al fun ct ion d) w h en th is return of baselin e adren al fun ction occurs: ● daily steroids are stopped, but stress doses m ust still be given w h en needed (see below ) ● m on t h ly cosyn t rop in st im u lat ion (p. 735) test s are p erfor m ed u n t il n or m al. Th e n eed for st ress d oses of steroid s ce ases w h en a p osit ive t est is obtain ed . Th e r isk for ad ren al in su cien cy p ersist ≈ 2 years after cessat ion of ch ron ic steroid s (especially th e first year) Table 8.2 Symptoms of adrenal insu ciency (AI) ● fatigue ● weakness ● arthralgia ● anorexia ● nausea ● hypotension ● orthostatic dizziness ● hypoglycemia ● dyspnea ● Addisonian crisis (p. 147) (if severe; with risk of death)

146 General and Neurology St eroid st ress doses Durin g physiologic “st ress” th e n orm al adren al glan d produces ≈ 250–300 m g hydrocor tison e/day. With chronic glucocorticoid therapy (either at present, or w ithin last 1–2 yrs), suppression of the n orm al “stress-respon se” n ecessitates supplem en tal doses. In patien ts w ith a suppressed HPA axis: ● for m ild illn ess (e.g. UTI, com m on cold), sin gle den tal extract ion : double th e daily dose (if o ste- roids, give 40 m g hydrocortison e BID) ● for m oderate stress (e.g. flu), m in or surger y un der local an esth esia (en doscopy, m ultiple den tal extract ion s…): give 50 m g hydrocor tison e BID ● for m ajor illn ess (pn eum on ia, system ic in fect ion s, h igh fever), severe traum a, or em ergen cy sur- ger y un der gen eral an esthesia: give 100 m g hydrocort ison e IV q 6–8 h rs for 3–4 days un t il th e stress is resolved ● for elective surger y, see Table 8.3 for guidelin es 8.1.4 St eroid side e ect s Alth ough deleterious side e ects of steroids are m ore com m on w ith prolonged adm in istration ,4 som e can occur even w ith sh ort treat m en t courses. Som e evidence suggests th at low -dose glucocor- t icoids (≤ 10 m g/d of predn isolon e or predn ison e equivalen t) for rh eum atoid arth rit is does n ot in crease osteoporotic fract ures, blood pressure, cardiovascular disease, or peptic ulcers,5 but w eigh t 8 gain an d skin ch anges are com m on . Possible side e ects in clude3,6: ● cardiovascular and renal ○ hypertension ○ sodium an d w ater retention ○ hypokalem ic alkalosis ● CNS ○ progressive m ultifocal leukoen ceph alopathy (PML) (p. 331) ○ m en tal agitat ion or “steroid psych osis” ○ spinal cord com pression from spin al epidural lipom atosis (p.1408): rare ○ pseudotum or cerebri, Idiopath ic in tracran ial hyperten sion (IIH) (p. 766) ● endocrine ○ caution : because of grow th suppressan t e ect in ch ildren , daily glucocort icoid dosing over pro- lon ged periods sh ould be reserved for th e m ost urgen t in dication s ○ secon dary am en orrh ea ○ suppression of hypothalam ic-pituitar y-adren al axis: reduces en dogen ous steroid production → risk of adren al insu cien cy w ith steroid w ith draw al (see above) ○ Cush in goid features w ith prolonged usage (iatrogen ic Cush in g’s syn drom e): obesit y, hyperten - sion, hirsutism … ● GI: risk in creased on ly w ith steroid th erapy > 3 w eeks duration an d regim en s of predn ison e > 400– 1000 m g/d or dexamethasone > 40 m g/d7 ○ gast rit is an d steroid ulcers: in ciden ce low ered w ith th e use of an tacids an d/or H2 an tagon ists (e.g. cim etidin e, ran it idin e…) ○ pancreatitis Table 8.3 Steroid stress doses for elective surgery On day of surgery, 50 m g cort isone acet at e IM, followed by 200 m g hydrocort isone IV infused over 24 hrs Post -op day Hydrocort isone (m g) 8 AM 4 PM 10 PM 1 50 50 50 2 50 25 25 3 40 20 20 4 30 20 10 5 25 20 5 6 25 15 – 7 20 10 –

Endocrinology 147 ○ in testin al or sigm oid diverticular perforation 8: in ciden ce ≈ 0.7%. Sin ce steroids m ay m ask sign s 8 of periton itis, th is sh ould be con sidered in patien ts on steroids w ith abdom in al discom fort , especially in th e elderly an d th ose w ith a h istory of diverticular disease. Abdom in al x-ray usu- ally sh ow s free in traperiton eal air ● inh ibition of fibroblasts ○ im paired w ound healing or w ound breakdow n ○ subcutaneous tissue atrophy ● m etabolic ○ glucose in toleran ce (diabetes) an d dist urban ce of n itrogen m etabolism ○ hyperosm olar nonketotic com a ○ hyperlipidem ia ○ ten d to in crease BUN as a result of protein catabolism ● ophthalm ologic ○ posterior subcapsular cataracts ○ glaucom a ● m usculoskeletal ○ avascular n ecrosis (AVN) of th e h ip or oth er bon es: usually w ith prolonged adm in istration →cush ingoid h abit us an d in creased m arrow fat w ith in th e bon e9 (predn ison e 60 m g/d for sev- eral m on th s is probably th e m in im um n ecessar y dose, w h ereas 20 m g/d for several m on th s w ill probably not produce AVN10). Many cases blam ed on steroids m ay in stead be due to alcoh ol use, cigarette sm oking,11 liver disease, un derlyin g vascular in flam m ation … ○ osteoporosis: m ay predispose to vertebral com pression fract ures w h ich occur in 30–50%of patien ts on prolonged glucocor ticoids. Steroid in duced bon e loss m ay be reversed w ith cyclical adm in istration of etidron ate12 in 4 cycles of 400 m g/d 14 days follow ed by 76 days of oral calcium supplem en ts of 500 m g/d (n ot proven to reduced rate of VB fract ures) ○ m uscle w eakness (steroid m yopathy): often w orse in proxim al m uscles ● in fect ious ○ im m un osuppression : w ith possible superin fect ion , especially fun gal, parasitic ○ possible reactivation of TB, ch icken pox ● hem atologic ○ hypercoagulopathy from in h ibition of tissue plasm in ogen activator ○ steroids cause dem argin at ion of w h ite blood cells, w h ich m ay artifactually elevate th e W BC coun t even in th e absen ce of in fect ion ● m iscellaneous ○ h iccups: m ay respon d to ch lorprom azin e (Th orazin e®) 25–50 m g PO TID-QID 2–3 days (if sym ptom s persist, give 25–50 m g IM) ○ steroids readily cross th e placen ta, an d fetal adren al hypoplasia m ay occur w ith th e adm in istra- tion of large doses during pregnancy 8.1.5 Hypocort isolism General inform at ion AKA adren al in su cien cy. Assessm en t: 8 A.M. serum cortisol level is th e best w ay to test for hypocort isolism . Each lab sh ould provide a low er lim it of n orm al for th eir lab, w h ich m ay be broken dow n furth er by age an d ge n d e r. Addisonian crisis General inform ation AKA adren al crisis. An adren al in su cien cy em ergency. Sym ptom s: m en tal status ch anges (con fusion , lethargy, or agitation ), m uscle w eakn ess. Sign s: postural hypoten sion or sh ock, hyperth erm ia (as h igh as 105° F, 45.6 C) La b s Hypon atrem ia, hyperkalem ia, hypoglycem ia. Treatm ent of Addisonian crisis If possible, draw serum for cort isol determ in ation (do n ot w ait for th ese results to in stit ute th erapy). Give fluids su cien t for dehydration an d sh ock.

148 General and Neurology For “glu cocor t icoid em er gen cy” ● hydrocort ison e sodium succin ate (Solu-Cortef®): 100 m g IV STAT an d th en 50 m g IV q 6 h rs AND ● cort ison e acetate 75–100 m g IM STAT, an d th en 50–75 m g IM q 6 h rs For “m in eralocor t icoid em ergen cy” Usually n ot n ecessary in secon dar y adren al in su cien cy (e.g. pan hypopituitarism ) ● desoxycort icosteron e acetate (Doca®): 5 m g IM BID OR ● fludrocort ison e (Florin ef®): 0.05- 0.2 m g PO q d m ethylpredn isolon e is NOT recom m en ded for em ergen cy treat m en t . 8.2 Hypot hyroidism 8.2.1 General inform at ion Ch ron ic prim ar y hypothyroidism m ay result in (n on -path ologic) en largem en t of th e pit uitar y glan d. Plasm a TSH determ in ation w ill dist in guish prim ar y hypothyroidism (h igh TSH) from secon dar y 8 hypothyroidism (low TSH). Woun d h ealing an d cardiac fun ction m ay be com prom ised, an d surger y un der gen eral an esth esia sh ould be postpon ed if possible un t il thyroid levels are n orm alized. E ects of an esth esia m ay be m arkedly prolonged, an d dosages sh ould be adjusted accordin gly. 8.2.2 Thyroid replacem ent Caut ion in pat ient s w it h adrenal insu ciency Prim ar y hypothyroidism m ay be associated w ith im m un ologic destruction of adren al cortex (Sch m idt syn drom e). Secon dary hypothyroidism m ay be associated w ith an d m ay m ask reduced adren al fun ction . Thyroid replacem en t w ith out adren al replacem en t in patien ts w ith adren al insu ciency (as m ay occur in pan hypopituitarism ) m ay precipitate adrenal crisis (thus give ≈ 300– 400 m g hydrocor t ison e IV over 24 h rs in addit ion to thyroid replacem en t). 8.2.3 Rout ine t hyroid replacem ent dosing Drug info : Levot hyroxine (Synt hroid®) Almost pure T4 (contains no T3 as most T3 is produced peripherally from T4). Dose required to prevent myxedem a com a (not to achieve euthyroidism): ● Maintenance: 0.05 mg po q d ● when patient has been hypothyroid: start at 0.05 mg po q d and increase by 0.025 m g every 2–3 weeks For euthyroidism (approximate dose, follow levels and clinical evaluation): ● for most adults < 60 years age: 0.18 mg/day ● for elderly patients: 0.12 mg/day Drug info : Desiccat ed t hyroid (e.g. Arm our t hyroid®) Typical dose: 60 m g (1 grain) to 300 mg daily. Thyroid replacem ent in m yxedem a com a Myxedem a com a is an em ergency of hypothyroidism an d carries 50%m ortality. Sym ptom s: altered m en tal status or un respon siven ess.