Effect of mannitol on cerebral blood flow and cerebral perfusion pressure in human head injury

Transcription

1 J Neurosurg 63:43-48, 1985 Effect of manntol on cerebral blood flow and cerebral perfuson pressure n human head njury A. DAVD MENDELOW, PH.D., F.R.C.S., GRAHAM M. TEASDALE, M.R.C.P., F.R.C.S., THOMAS RUSSELL, B.Sc., F.R.C.S., JOHN FLOOD, F.R.C.S., JAMES PATTERSON, B.Sc., PH.D., AND GORDON D. MURRAY, M.A., PH.D. Department of Neurosurgery, nsttute of Neurologcal Scences, Southern General Hosptal, Glasgow, Scotland Patents wth severe head njury frequently have evdence of elevated ntracranal pressure (CP) and schemc neuronal damage at autopsy. Manntol has been used clncally to reduce CP wth varyng success, and t s possble that t s more effectve n some types of head njury than n others. The am of the present study was to determne the effect of manntol on CP, cerebral perfuson pressure (CPP), and cerebral blood flow () n patents wth severe head njury, and to dscover f these effects dffered n dfferent types of njury. Measurements of CPP, CP, and were made n 55 patents wth severe head njury. n general, the restng level of was hgher n patents wth dffuse njury (mean 50.2 ml/100 gm/mn) than n those wth focal njury (mean 39.8 ml/100 gm/mn). Manntol consstently reduced CP and ncreased CPP and by 10 to 20 mnutes after nfuson. The lowest flows (31.8 ml/100 gm/mn) were recorded from the most damaged hemspheres of patents wth focal njures and elevated CP. The baselne levels of flow dd not correlate wth CP, CPP, Glasgow Coma Scale score, or outcome. Only four of the 55 patents had a of less than 20 ml/100 gm/mn n ether or both hemspheres. The few low 's n ths and other studes may reflect the steady-state condtons under whch measurements are made n ntensve care unts, and that these patents have entered a phase of reperfuson. KEY WORDS 9 head njury 9 ntracranal pressure manntol 9 Glasgow Coma Scale 9 cerebral blood flow 9 cerebral perfuson pressure SCHEMC bran damage s found n the majorty of head-njured patents who de. 6 For ths reason, management of severe head njures has often attempted to mprove cerebral blood flow (), for example by ncreasng the cerebral perfuson pressure (CPP). Nevertheless, there have been few clncal reports of changes n n response to such maneuvers, 13 partcularly wth reference to dfferent types of njury. Manntol s used wdely, n varyng regmens, n the management of severe head njury, ~,~l,t4,j5 and there s a large body of evdence that ndcates that t can reduce ntracranal pressure (CP) n such patents. 8A6 On the other hand, reported effects of manntol on mean systemc blood pressure are controversal, wth some work suggestng that the drug may produce hypotenson 4 wth some resultant reducton n CPP. Furthermore, a large mult-center study of head-njured patents has ndcated that no beneft s derved from the general use of manntol n unselected groups of patents wth head njury. ~~ t s lkely that the effects of any agent dffer n dfferent stes wthn the damaged bran, as well as n dfferent types of head njury. Prevous studes have ndcated that manntol can ncrease n severely njured patents n the acute phase of head njury, but the changes have usually been reported n only one hemsphere, and dfferent types of njures have not been compared. 2,2~ A consstent relatonshp between changes n CPP and has not therefore emerged, although ths aspect has been well studed expermentally. ~2'18 The ams of the present study were to document the effects of a bolus of manntol on and CPP n head-njured patents, and to ascertan whether the responses were smlar n dfferent dagnostc categores, and n the two hemspheres. Clncal Materal and Methods A total of 55 patents (mean age 37 years) are ncluded n ths study. All had survved for more than 6 hours after head njury, and had been admtted to the J. Neurosurg. / Volume 63/July,

2 A. D. Mendelow, et al. TABLE 1 Mean related to 1CP n patents wth d[(~tse and f~cal njures'* Parameter Low CP (_< 20 mm Hg) Hgh CP (_> 21 mm Hg) focal njures (ml/100 gm/mn) 43.2 _ _+ 3.5 no. of cases dffuse njures (ml/100 gn/ran) _+ 8.7 no. of cases 16 6 * Values are means _+ slandard error of the means. = cerebral blood flow; CP = ntracranal pressure. ntensve care unt of the nsttute of Neurologcal Scences n Glasgow. At the tme of measurement 73% were n coma. All had undergone computerzed tomography scannng, and CP montorng had been nsttuted. Ther was measured wthn 72 hours of njury or operaton. Patents were dvded nto those wth focal and those wth dffuse njures, accordng to the followng crtera. A leson was regarded as focal f the patent had an ntracerebral hematoma of greater than 2.5 cm n dameter, or a subdural hematoma more than 1 cm thck or producng a mdlne shft of more than l cm. ntracranal Pressure Measurement Ventrcular flud pressure or subdural pressure was measured by a flud-flled catheter connected to a Statham P23 or P50 pressure transducer connected to a Gould pen recorder for contnuous recordng.* Measurement of Cerebral Blood Flow Blateral smultaneous measurements were made from two large sodum odde crystal scntllaton detectors (50 mm n dameter) arranged n parallel and amed n an anteroposteror drecton from the frontal regon above the frontal snus. The xenon-133 (~33Xe) ntravenous method was used, 24 wth subtracton of the end-expratory ~33Xe curve from the bran clearance curves to correct for recrculaton. End-expratory ~33Xe concentratons were measured by samplng gas obtaned from the endotracheal tube or va a tghtly fttng face mask. An ext tube and a room fan were used to elmnate xenon gas from the patent area. A bolus dose of 10 mc of ~33Xe was gven ntravenously, and clearance curves were montored for 10 mnutes. Restng hemspherc was measured before the admnstraton of manntol. n general, global s expressed as the mean value for the two hemspheres. Where ndcated n the text and tables, the two sdes were recorded separately n ths study: n focal njures they * Statham pressure transducer manufactured by Statham Laboratores, nc., Halo Rey, Puerto Rco; and Gould pen recorder manufactured by Gould, nc., 3631 Perkns Avenue, Cleveland, Oho. FG. 1. Dstrbuton of global cerebral blood flow () values as a percentage of all the values n each group. The dffuse-njury group comprsed 22 patents and the focalnjury group 33. were expressed as the more and the less damaged hemsphere (the dstncton made from radologcal and operatve fndngs), and n dffuse njures as left and rght. Level of Conscousness and Outcome The level of conscousness at the tme of measurement was recorded usng the Glasgow Coma Scale, 23 and outcome at 6 months s expressed usng the Glasgow Outcome Scale. 9 Measurement of Physologcal Varables Arteral blood gases were measured on a Cornng t75 blood gas analyzer. End-expratory carbon doxde was measured on a Goddart capnograph.t Mean systemc blood pressure (MBP) was recorded wth a sphygmomanometer cuff or by an arteral lne connected to a Statham P50 pressure transducer connected to a Gould pen recorder for contnuous recordng. The CPP was calculated as the dfference between MBP and CP at the tme of each measurement. Admnstraton of Manntol A bolus of 20% manntol (0.25 to 0.5 gm/kg) was gven ntravenously over 10 to 15 mnutes. Measurement of was ntated 10 to 20 mnutes after the manntol nfuson was completed, and MBP and CP were recorded at the tme of the '33Xe njecton. Statstcs Restng flow values and CP and CPP measurements were avalable n 55 patents. Full documentaton of CP,, and CPP after completon of the manntol nfuson was avalable n 41 patents. All values are Goddart capnograph manufactured by nstrumentaton Assocates, 17 West 60th Street, New York, New York. 44 J. Neurosurg. / Volume 63 ~July, 1985

3 Effect of manntol on hemodynamcs n head njury (mllloog/mln) Focal njures 00~ Focal njures 80, 80, u,o2 20- o= 20" t CP(mmHg) CPP(mmH9) 100- (roll 100g/m~) loo- Dffuse njures (mj/loog/m~) Dffuse njures 80. D 80- o 60" == D " o ~ CP(mmHg) CPP(mmH~) FG. 2. Restng cerebral blood flow () n patents wth dffuse and focal njures dd not correlate well wth ether ntracranal pressure (CP) or cerebral perfuson pressure (CPP). expressed as means + standard errors of the mean. Comparsons were made wth Student's pared or unpared t-tests and dfferences were consdered sgnfcant when p < Results Of the 55 patents, 33 (60%) had focal njures and, of these, nne (27 %) were studed whle undergong CP montorng to ad n decdng whether surgcal removal of a hematoma was requred. Restng Cerebral Blood Flow The mean for all 55 patents was ml/ 100 gm/mn. The 33 patents wth focal njures had a mean flow of 39.8 _+ 2.7 ml/100 gm/mn and the 22 wth dffuse njures had a mean flow of 50.2 _+ 4.1 ml/ 100 gm/mn. The mean was sgnfcantly hgher n the dffuse-njury group than n the focal-njury group, and the dstrbuton of flows ndcates the preponderance of lower values n patents wth focal njury (Fg. 1). Patents were further dvded nto groups wth low and hgh CP, based on the pressure values on the day of measurement. There were 33 patents wth an CP of less than 20 mm Hg (low-cp group), and 22 patents had pressures above ths level. Although mean was hgher n the low-cp group, no sgnfcant dfference was found between the mean values of the hgh- and low-cp groups taken as a whole. Ths dfference was less evdent n the dffuse-njury group, and was greatest n patents wth focal njures, where hgh CP was assocated wth the lowest mean (36.1 _+ 3.5 ml/100 gm/mn) (Table 1). ndeed, the lowest mean was recorded n the most damaged hemsphere of patents wth focal njures and hgh CP (31.8 _+ 3.2 ml/100 gm/mn). n general, however, the restng dd not correlate well wth ether the ntal CP or the CPP (Fg. 2). n only four patents was below 20 ml/100 gm/ ran recorded. n one patent wth a dffuse njury there was blateral reducton n flow to 15 and 18 ml/100 J. Neurosurg. / Volume 63 ~July,

4 A. D. Mendelow, et al. TABLE 2 Mean, CP, and CPP n patents bejore and after manntol nfuson * Parameter Control Manntolf (ml/100 gm/mn) _+ 3.5 CP (mm Hg) 21.9 _ _+ 1.9 CPP (mm Hg) _+ 2.5 * Values are means standard error of the means for 41 patents. = cerebral blood flow; CP = ntracranal pressure; and CPP = cerebral perfuson pressure. t Each value showed a sgnfcant dfference between control and manntol values (one-sded pared t-test). TABLE 3 Mean cerebral blood flow () before and ader manntol nf~son n palents wth f~cal and dffuse njures* No. of Patent Group Cases Control Manntol global dffuse njures focal njures leson present _ leson absent hemspherc focal more damaged hemsphere less damaged hemsphere _ 5. dffuse rt hemsphere t hemsphere * Values are means + standard error of the means (ml/100 gn/ ran). The patents wth focal njury are subdvded dependng on whether the leson was stll present or had been removed, and dependng on whch hemsphere had been affected. gm/mn n the left and rght hemspheres, respectvely. One patent wth a focal njury from a left-sded ntracerebral hematoma, whch had not been evacuated, had flows of 1 1 and 12 ml/100 gm/mn, respectvely. n another patent, a fght-sded subdural hematoma, whch had been evacuated, was assocated wth a of 9 ml/100 gm/mn; the flow n the other hemsphere n ths patent was 24 ml/100 gm/mn. The fourth patent had a left-sded focal leson, and flows of 17 and 18 ml/100 gm/mn were recorded from the left and fght sdes, respectvely. Although there was a sgnfcant sde-to-sde dfference n patents wth dffuse njury, t was quanttatvely small and s of uncertan bologcal mportance. Of greater mportance s the fndng that all the mean values n the dffuse-njury group were at a hyperemc level. Effect of Manntol Manntol consstently reduced CP and ncreased MBP. Ths produced a sgnfcant ncrease n CPP and (Table 2). The ncrease n wth manntol nfuson was slghtly greater n patents wth dffuse njures (Table 3) and n the undamaged hemspheres TABLE 4 Change n followng manntol nf~son n patents wth very hgh CP or low CPP * ntal CP ntal CPP Status (mm Hg) (mm Hg) <_40 >_41 <50 >_51 ncrease n decrease or no change n 14 0 l 13 * = cerebral blood flow; CP = ntracranal pressure; CPP = cerebral perfuson pressure. of patents wth focal njures. Ths ncrease was also greater when a focal njury resulted from a hematoma that was stll present than after t had been removed, although ths was not sgnfcant. Manntol nfuson produced an ncrease n n all patents wth a very hgh level of CP (_ 41 mm Hg), and consstently resulted n an ncrease n when CPP was 50 mm Hg or less (Table 4). n patents wth dffuse njury, there was a greater ncrease n n the fght than n the left hemsphere (Table 3), and the hghest flows were recorded after manntol n the fght hemsphere of dffusely njured patents wth hgh CP ( ml/100 gm/mn). n these studes, there was no correlaton between the Glasgow Coma Scale score and, ether n dffuse or focal njures (Fg. 3). Smlarly, the outcome at 6 months was unrelated to or the type of njury. Dscusson These studes have documented levels n the two hemspheres of patents wth ether a dffuse or a focal head njury, and related these to CP, CPP, and the effect of manntol. n general, patents wth dffuse bran njury had hgher levels of than dd those wth focal njury. The lowest restng values were recorded from the most damaged hemspheres of patents wth a focal njury and hgh CP. However, restng was not related to ntal CP, CPP, or Glasgow Coma Scale score, and follow-up studes have revealed that t s not related to outcome ether. Manntol consstently ncreased, and ths ncrease was assocated wth a correspondng ncrease n CPP and reducton n CP. Very few schemc flow levels were recorded n our seres; four of the 55 patents had of less than 20 ml/100 gm/mn. Ths may be because, at the tme of blood flow measurements, patents had been stablzed n an ntensve care unt. These observatons correspond wth those of Overgaard, et al., 2~ who also reported a low ncdence of schemc flow values (< 20 ml/100 gm/mn) n stable head-njured patents: only 1% of regons of patents n better outcome categores and 15% of the regons of those who ded or remaned vegetatve had schemc levels. The few schemc flows observed were most often seen n the early hours after njury. Our results are also consstent wth those of 46 J. Neurosurg. / Volume 63 /July, 1985

5 Effect of manntol on hemodynamcs n head njury O0- (mll 000/~n ) Focal njures 100- (raft OOo/m,n} Focal njures J 60* % " l t Coma~m 100. (mu loog/m~) DffUSe njures 100- (n~/1oog/~n> O~ffuse ndes J m B~ B B t L f Outcome Scale Coma Sum FG. 3. Restng cerebral blood flow () n patents wth dffuse and focal njures compared wth Glasgow Coma Scale (rght, 3-15) and Glasgow Outcome Scale (left, 1-5). Obrst, et al., 19 who observed a hgh ncdence of hyperema n ther patents wth acute head njury, and recorded flows of less than 20 ml/100 gm/mn n only 14% of ther cases. They also showed that all these patents had a reduced cerebral metabolc rate for oxygen (CMRO2). ndeed, they further demonstrated couplng between and CMRO2 for patents n ther "reduced-flow" group, whch ncluded patents wth flows of up to 33 ml/100 gm/mn; the patents wth ntermedate levels of flow (20 to 33 ml/100 gm/mn) havng hgher levels of CMRO2. Enevoldsen, et al., 5 lkewse commented on the low ncdence of schema, and a hgh frequency of hyperema. Our fndng that the lowest levels of were n the damaged hemspheres of focally njured patents suggests that hematomas (classfed as focal njures n ths study) are assocated wth schemc bran damage. Ths s n accordance wth human autopsy studes 6 and recent expermental work, ~7 whch has revealed profound regonal schema wthn mnutes of the start of ntracranal hemorrhage. t may be that, to record the real extent of areas of such profound schema n man, a focal cross-sectonal technque for measurement of s requred. 22 Prevous reports that characterze patterns n patents wth dfferent types of head njury have ndcated that dffuse njury s assocated wth hyperema more frequently than focal njury. 19 The sgnfcantly hgher densty measurements on computerzed tomography reported n patents wth dffuse swellng suggests that ths hyperema may be the result of ncreased cerebral blood volume, 3 but whether changes n volume alone account for the changes n Hounsfeld number s n doubt. The mechansm for the ncrease n that we observed after manntol admnstraton s uncertan. t may reflect some loss of autoregulaton, so that elevaton of the CPP leads to a passve elevaton of. Ths s suggested from our data whch showed that manntol consstently ncreased n patents whose CPP was below 60 mm Hg, the lower threshold for autoregulaton. Nevertheless, t s well known that manntol mproves n schema 25 wthout profoundly alterng CPP. An alternatve explanaton for the effect of manntol may le n ts osmotc effects or n ts effects on blood vscosty. The fact that ncreased n all patents wth very hgh CP ndcates that the osmotc effect may be very mportant n these cases. J. Neurosurg. / Volume 63 ~July,

6 A. D. Mendelow, et al. t should be stressed that n our studes the effects were short-term, and may dffer consderably from the long-term effects of manntol or ts contnued use. Manntol acts over tme to reduce the crculatng blood volume and produce hypotenson. 4 Ths may explan why manntol faled to mprove the outcome n a large group of patents wth head njury reported by Jennett, et al. 1o ts resusctatve effects on head-njured patents n the acute phase may have to be measured separately from the ultmate outcome. Furthermore, newer technques for the long-term admnstraton of manntol 7 may produce a more stable control of CP. Wth these technques, the dosage of manntol s constantly revsed by computer montorng of the CP. t seems, therefore, that there s a place for the evaluaton of both the acute effects of manntol and ts use wth servo-asssted nfuson pumps. f the man cause of bran damage n head njury s schemc, early restoraton of the CPP offers the most lkely opportunty for therapeutc advance. These hemodynamc effects, however, may not necessarly apply to the more stable resusctated patent n the ntensve care ward, unless an ntercurrent reducton n CPP develops secondarly. Ths study demonstrates that manntol s most lkely to be of value n patents wth focal njures, n those wth very hgh CP, and n those n whom the CPP s at or below the lower lmt of autoregulaton. Acknowledgment Our thanks go to Ms. S. Halley for preparng the manuscrpt. References 1. Becker DP, Mller JD, Ward JD, et al: The outcome from severe head njury wth early dagnoss and ntensve management. J Neurosurg 47: , Bruce DA, Langftt TW, Mller JD, et al: Regonal cerebral blood flow, ntracranal pressure, and bran metabolsm n comatose patents. J Neurosurg 38: , Bruce DA, Schut L, Bruno LA, et al: Outcome followng severe head njures n chldren. J Neurosurg 48: , Cot6 C J, Greenhow DE, Marshall BE: The hypotensve response to rapd ntravenous admnstraton of hypertonc solutons n man and n the rabbt. Anaesthesology 50:30-35, Enevoldsen EM, Cold G, Jensen FT, et al: Dynamc changes n regonal, ntraventrcular pressure, CSF ph and lactate levels durng the acute phase of head njury. J Neurosurg 44: , Graham D, Adams JH, Doyle D: schaemc bran damage n fatal non-mssle head njures. J Neurol Sc 39: , wata K, Yuasa H, Sugyama T, et al: Automatc CP controller: a new devce, n sh S, Naga H, Brock M (eds): ntracrana Pressure V. Berln/Hedelberg/New York: Sprnger-Verlag, 1983, pp James HE, Langftt TW, Kumar VS, et al: Treatment of ntracranal hypertenson. Analyss of 105 consecutve, contnuous recordngs of ntracranal pressure. Acta Neurochr 36: , Jennett B, Bond M: Assessment of outcome after severe bran damage. Lancet 1: , Jennett B, Teasdale G, Fry J, et al: Treatment for severe head njury. J Neurol Neurosurg Psychatry 43: , Johnston H, Johnston JA, Jennett B: ntracranal-pressure changes followng head njury. Lancet 2: , Kassell NF, Baumann KW, Htchon PW, et al: The effects of hgh dose manntol on cerebral blood flow n dogs wth normal ntracranal pressure. Stroke 13:59-6 l, Langftt TW, Obrst WD: Cerebral blood flow and metabolsm after ntracranal trauma. Prog Neuro Surg 10: 14-48, Marshall LF, Smth RW, Rauscher LA, et al: Manntol dose requrements n bran-njured patents. J Neurosurg 48: , Marshall LF, Smth RW, Shapro HM: The outcome wth aggressve treatment n severe head njures. Part. The sgnfcance of ntracranal pressure montorng. J New rosurg 50:20-25, McGraw CP, Howard G: Effect of manntol on ncreased ntracranal pressure. Neurosurgery 13: l, Mendelow AD, Bullock R, Teasdale GM, et al: ntracranal haemorrhage nduced at arteral pressure n the rat. Part 2: Short term changes n local cerebral blood flow measured by autoradography. Neurol Res 6: , Muzelaar JP, We EP, Kontos HP, et al: Manntol causes compensatory cerebral vasoconstrcton and vasodlataton n response to blood vscosty changes. J Neurosurg 59: , Obrst WD, Langftt TW, Jagg JL, et al: Cerebral blood flow and metabolsm n comatose patents wth acute head njury. Relatonshp to ntracranal hypertenson. J Neurosurg 61: , Overgaard J, Mosdal C, Tweed WA: Cerebral crculaton after head njury. Part 3: Does reduced regonal cerebral blood flow determne recovery of bran functon after blunt head njury? J Neurosurg 55:63-74, Overgaard J, Tweed WA: Cerebral crculaton after head njury. Part 1: Cerebral blood flow and ts regulaton after closed head njury wth emphass on clncal correlatons. J Neurosurg 41: l, Phelps ME, Mazzotta JC, Huang SC: Study of cerebral functon wth postron computed tomography. J Cereb Blood Flow Metab 2: , Teasdale G, Jennett B: Assessment of coma and mpared conscousness. A practcal scale. Lancet 2:81-84, Wyper D, Pckard JD, Acar U: Montorng cerebral blood flow durng ntracranal operatons: an ntravenous njecton method. Neurol Res 1:31-37, Yoshmoto T, Sakamoto T, Watanabe T, et al: Expermental cerebral nfarcton. Part 3: Protectve effect of manntol n thalamc nfarcton n dogs. Stroke 9: , 1978 Manuscrpt receved October 4, Ths study was supported by the Medcal Research Councl. Address reprnt requests to: A. Davd Mendelow, F.R.C.S., Department of Neurosurgery, Southern General Hosptal, Glasgow G51 4TF, Scotland. 48 J. Neurosurg. / Volume 63/July, 1985