Delayed cerebral ischemia is a major complication

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1 5 Effect of Fludrocortisone Acette in Ptients With Subrchnoid Hemorrhge Djo Hsn, MD, Ken W. Lindsy, FRCS, Eelco F.M. Wijdicks, MD, Gordon D. Murry, PhD, Pul J.A.M. Brouwers, MD, Willem H. Bkker, PhD, Jn vn Gijn, MD, nd Mrinus Vermeulen, MD In this study with rndomized controls, we dministered fludrocortisone cette to of ptients with subrchnoid hemorrhge in n ttempt to prevent excessive ntriuresis nd plsm volume depletion. Fludrocortisone significntly reduced the frequency of negtive sodium blnce during the first dys (from to, p=.). A negtive sodium blnce ws significntly correlted with decresed plsm volume during both the first dys (p=.) nd during the entire -dy study period (p=.). Although fludrocortisone tretment tended to diminish the decrese in plsm volume, the difference ws not significnt (/;=.). More ptients in the control group developed cerebrl ischemi ( vs. ) nd, consequently, more control ptients were treted with plsm volume expnders ( vs. 5), which my hve msked the effects of fludrocortisone on plsm volume. Fludrocortisone therefore reduces ntriuresis nd remins of possible therpeutic benefit in the prevention of delyed cerebrl ischemi fter neurysml subrchnoid hemorrhge. (Stroke ;:5-) Downloded from by on December 5, Delyed cerebrl ischemi is mjor compliction occurring fter neurysml subrchnoid hemorrhge. - 5 One possible cusl fctor is decrese in plsm volume, - ssocited with excessive ntriuresis - nd hypontremi. - In ptients with hypontremi fter subrchnoid hemorrhge, fluid restriction leds to n incresed risk of cerebrl infrction. Severl uthors hve reported prtil or complete reversl of signs nd symptoms of cerebrl ischemi fter plsm volume expnsion, with or without induced rteril hypertension. - 5 Mintennce of n dequte intrvsculr volume is therefore importnt in ptients with subrchnoid hemorrhge. In smll nonrndomized study, the minerlocorticoid fludrocortisone cette ' ppered to prevent plsm volume depletion in the first dys fter the hemorrhge. The im of our study ws to investigte the effect of fludrocortisone cette on sodium blnce, fluid bl- From the Deprtments of Neurology (D.H., M.V.) nd Nucler Medicine (W.H.B.), University Hospitl Dijkzigt, Rotterdm nd the University Deprtment of Neurology, Utrecht (P.J.A.M.B., E.F.M.W., J.v.G.), the Netherlnds, the Deprtment of Neurosurgery, The Royl Free Hospitl, London, Englnd (K.W.L.), nd the Deprtment of Surgery, University of Glsgow, Glsgow, Scotlnd (G.D.M.). Address for correspondence: Djo Hsn, Deprtment of Neurology, University Hospitl Dijkzigt Rotterdm, Dr Molewterplein, 5 GD Rotterdm, The Netherlnds. Received Februry, ; ccepted My 5,. nce, nd plsm volume in rndomized tril of ptients with subrchnoid hemorrhge. Subjects nd Methods The tril commenced in Jnury nd ended in My. Three centers prticipted: the Deprtment of Neurosurgery, Royl Free Hospitl, London; the Deprtment of Neurology, University Hospitl Rotterdm; nd the Deprtment of Neurology, University Hospitl, Utrecht. The ethics committee t ech center pproved the study. Ptients with signs nd symptoms of subrchnoid hemorrhge nd with confirmtory evidence on the initil computed tomogrm - or in the cerebrospinl fluid were eligible. Resons for exclusion were lpse of > hours since the presenting hemorrhge; ge of > yers; previous tretment with diuretics or corticosteroids; presence of endocrine, renl, or crdic disese; or computed tomogrphic evidence of cuse for the subrchnoid hemorrhge other thn neurysm. > If deth ppered imminent, entry ws delyed. The mount of cisternl blood on the initil computed tomogrm ws grded seprtely for ech of the cisterns on scle of to (mximum score points) s previously described. - Similrly, intrventriculr blood ws grded seprtely for ech of the four ventricles on scle of to (mximum score points). - Four-vessel ngiogrphy nd neurysm surgery were performed depend-

2 Downloded from by on December 5, ing on the ptient's clinicl condition. Surgery ws plnned between Dys nd in London nd on Dy in Rotterdm nd Utrecht. The level of consciousness ws ssessed t entry by mens of the -point Glsgow Com Scle. Eligible ptients were rndomized fter informed consent ws obtined. Rndomiztion ws strtified per center, ccording to rndom number tbles by mens of seled-envelope technique. Tretment with fludrocortisone cette ws lwys strted < hours fter the hemorrhge. The drug ws dministered intrvenously or orlly, /xg/dy in two doses, for mximum durtion of dys. Tretment ws discontinued if signs of hert filure developed. Anticogulnts, pltelet ggregtion inhibitors, nd diuretics were prohibited during the study period. Antihypertensive drugs were given only if the ptient ws receiving this tretment before dmission. Corticosteroid tretment ws strted (in those who were eligible for neurysm surgery) hours before the opertion. All ptients received trnexmic cid intrvenously for the first dys fter dmission, in six doses of g/dy. During the first dys, fluid intke ws mintined t I/dy either orlly or intrvenously (isotonic sline). For every degree of body temperture bove C, n dditionl 5 ml/dy fluid ws dministered. When signs of cerebrl ischemi developed, extr fluid in the form of dextrn, polygelin (in London), or lbumin (in Rotterdm nd Utrecht) ws given. Serum electrolytes, blood ure nitrogen, serum cretinine, nd routine blood hemtologic vlues were mesured dily. Plsm volume ws mesured during the first hours fter dmission nd ws gin on Dys nd. Plsm volume ws determined by the isotope dilution technique. A totl dose of kbq of 5 mg rdioiodinted humn serum lbumin (iodine-5 in London nd iodine- in Rotterdm nd Utrecht) in isotonic sline ws injected intrvenously. Blood ws smpled before injection nd t given times fter injection (in London t,,, nd minutes; in Rotterdm nd Utrecht t nd minutes). Isotope ctivity ws nlyzed with Gmmtrc (Trcor Anlytic, Elk Grove Villge, Illinois). We expressed the results s totl plsm volume nd clculted the percentge chnge between the second (Dy ) nd the first mesurements nd between the third (Dy ) nd the first mesurements. Becuse bed rest lone my cuse certin decrese in plsm volume fter week, we considered only drop in plsm volumes of > relevnt, nd we referred only to this s "decresed plsm volume." Hsn et l Fludrocortisone After SAH 5 Sodium blnce ws clculted dily for the first dys or until surgery for the neurysm by subtrcting sodium excretion from sodium intke. Ptients who were well enough to et were plced on specilly prepred low-sodium diet s well s on intrvenous fluids to minimize errors in sodium intke clcultions. Sodium excretion ws mesured in -hour urine smples. Fluid blnce ws clculted dily by subtrcting totl urine production from totl fluid intke. Cumultive sodium nd fluid blnces were nlyzed for the first dys nd for the entire -dy study period. Clinicl deteriortion occurring within dys or until neurysm surgery ws investigted by clinicl exmintion nd, where possible, by repeted computed tomogrphy. Cerebrl events were defined s probble delyed cerebrl ischemi (grdul development of focl neurologic signs, with or without deteriortion in the level of consciousness, without confirmtion by computed tomogrphy or utopsy) nd definite delyed cerebrl ischemi (grdul or sudden deteriortion in the level of consciousness, or the development of focl signs, or both, with computed tomogrphic or utopsy confirmtion of cerebrl infrction). Outcome ws ssessed ccording to the 5-point Glsgow Outcome Scle. The fourfold tbles were nlyzed with Fisher's exct probbility test. Results Ninety-one ptients were rndomized; (treted) ptients received fludrocortisone nd 5 (control ptients) did not. Except for slightly higher proportion of treted ptients with little cisternl blood (score -) on the initil computed tomogrm entry chrcteristics were well mtched between the groups (Tble ). Antibiotic tretment ws dministered in one of the treted ptients nd in four of the 5 control ptients. No other drug tht might ffect renl function ws dministered. We mesured plsm volume in ptients on Dy, in ptients on Dy, nd in ptients on Dy, which enbled us to clculte plsm volume chnges in ptients for the first dys nd in ptients for the entire -dy study period. In the remining ptients, mesurements were omitted becuse of erly deth, neurysm surgery, the finding of cuse for subrchnoid hemorrhge other thn neurysm, or technicl problems. Fluid blnce nd sodium blnce were clculted for the first dys in nd ptients, respectively, nd for the entire -dy study period in nd ptients, respectively. This included ll ptients with complete mesurement of plsm volume. Cumultive sodium blnce nd decresed plsm volume could be correlted in ptients for the first dys nd in ptients for the entire -dy study period; we were ble to compre cumultive sodium blnce nd fluid blnce in ptients for the first dys nd in ptients for the entire -dy study period. Fluid intke nd sodium intke were well mtched in the groups. Men dily fluid intke in the treted group ws, ml during the first dys nd,5 ml during the entire -dy study period; in the control group these vlues were, nd, ml, respectively. Men dily sodium intke in the treted group ws mmol during the first dys nd

3 5 Stroke Vol, No, September TABLE. Comprison of Entry Chrcteristics of Control nd Fludrocortisone-Treted Ptients With Aneurysml Subrchnoid Hemorrhge Downloded from by on December 5, Chrcteristic Sex Mle Femle Age (men yr) Hours to entry < 5- - Loss of consciousness History of hypertension Glsgow Com Scle score < - Evidence of neurysm Not investigted No neurysm Aneurysm Site of ruptured neurysm* Anterior cerebrl rtery Crotid rtery Middle cerebrl rtery Posterior circultion Unknown Cisternl blood Not scored Intrventriculr blood * of those with evidence of neurysm. Controls (rc=5) 5 mmol during the entire -dy study period. In the control group these vlues were nd mmol, respectively. Fludrocortisone tretment significntly reduced the incidence of negtive cumultive sodium blnce during the first dys (p=.) nd during the entire -dy study period (/>=., Tble ). There ws no effect of fludrocortisone tretment on cumultive fluid blnce. A negtive cumultive sodium blnce during the first dys ws correlted with decresed plsm volume ( vs.,/>=.) nd with negtive cumultive fluid blnce ( vs., /?=., Tble ). During the entire -dy study period, Treted (n=) negtive sodium blnce correlted significntly with decresed plsm volume (/?=.) but not with negtive fluid blnce (/?=., Tble ). Despite the reltions between fludrocortisone tretment nd sodium blnce nd between sodium blnce nd plsm volume, the direct reltion between fludrocortisone tretment nd plsm volume ws not significnt (p=.5 nd />=., respectively, for the first dys nd for the entire -dy study period; Tble, Figure ). Of the ptients treted with fludrocortisone, only seven (5) received plsm volume expnders, compred with () of the 5 control ptients. Plsm volume expnders were dminis-

4 Hsn et l Fludrocortisone After SAH 5 TABLE. Comprison of Control nd Fludrocortisone-Treted Ptients With Aneurysml Subrchnoid Hemorrhge Negtive cumultive sodium blnce First dys Entire -dy period Negtive cumultive fluid blnce First dys Entire -dy period Decresed plsm volume (>) Dy Dy Cerebrl ischemi 5 5 *tp<.5,., respectively, different from control by Fisher's exct probbility test. 5 Control n * t 5 Treted n Downloded from by on December 5, tered to (5) of the ptients with probble or definite cerebrl ischemi nd to four () of the ptients without cerebrl ischemi. The incidence of cerebrl ischemi ws lower in the treted group, but the difference ws not significnt. Of the treted ptients, () developed delyed cerebrl ischemi (seven definite nd three probble) compred with of 5 control ptients (, seven definite nd seven probble, p=.; Tble ). This trend ws seen in ech center. Outcome ws similr in the two groups; independent outcome ws chieved in () of the treted ptients nd in () of the 5 control ptients (p=.). Fludrocortisone tretment ws discontinued in two ptients becuse of pulmonry edem, but in the control group pulmonry edem lso occurred in two ptients. No other side effects developed except hypoklemi. The effect of fludrocortisone tretment on blood pressure ws investigted by compring men blood pressure on Dys,, nd in ptients dmitted in Rotterdm ( of ll ptients). No differences in men blood pressure between the groups were found. Discussion Our study confirms tht ptients with subrchnoid hemorrhge my hve excessive ntriuresis, s lmost hlf of our ptients in whom it ws ssessed hd negtive sodium blnce during the first dys fter dmission. This excessive ntriuresis cnnot be explined by high sodium intke before dmission followed by low intke fter dmission since the men dily sodium intke in our ptients mtched tht in the verge North Americn nd Western Europen popultion (- mmol). 5 The relese of ntriuretic fctor fter subrchnoid hemorrhge is more likely explntion for this sodium loss. - A negtive sodium blnce ws correlted significntly with negtive fluid blnce during the first dys nd with decresed plsm volume during both the first dys nd the entire -dy study period. It is therefore resonble to ssume tht ny mens of preventing the development of negtive sodium blnce would help mintin plsm volume. Fludrocortisone tretment significntly reduced the occurrence of negtive sodium blnce, during both the first dys nd the entire -dy study period. Although the results did suggest tht plsm volume depletion ws reduced by fludrocortisone tretment, the difference ws not significnt. The effect of fludrocortisone in preventing plsm volume depletion my hve been msked by the dministrtion of plsm volume expnders. These were dministered when the clinicins in chrge TABLE. Correltion of Cumultive Sodium Blnce With Plsm Volume nd Fluid Blnce After Aneurysml Subrchnoid Hemorrhge Cumultive sodium blnce Negtive Positive n n Decresed plsm volume (>) Dy Dy Negtive fluid blnce First dys Entire -dy period * *t/><.,.5, respectively, different from positive cumultive sodium blnce by Fisher's exct probbility test. * t

5 Downloded from by on December 5, Stroke Vol, No, September plsm volume chnge {) o- s sn- F - F F - F FIGURE. Sctterplot of percentge plsm volume chnge (difference between plsm volume mesured on Dy or Dy nd tht on Dy divided by plsm volume mesured on Dy ) by tretment with (+) or without ( ) fludrocortisone. i L dy six A- " dy twelve j B i.! -* i " suspected tht cerebrl ischemi ws developing, nd fewer treted ptients received plsm volume expnders thn control ptients. A decrese in plsm volume my led to n increse in hemtocrit, n increse in blood viscosity, nd impired cerebrl blood flow, especilly in the microcircultion. Inhibition of sodium excretion is directed t preventing such decrese in plsm volume in the hope tht the risk of cerebrl ischemi cn be minimized. The design of our study did not im t demonstrting reduced incidence of cerebrl ischemi. To show such benefit would hve required mny more ptients in ech group. Despite this, it is of interest tht the proportion of ptients with cerebrl ischemi ws lower in the fludrocortisone-treted group nd tht this trend ws observed not only between the two groups in the study s whole, but lso between the two subgroups in ech of the three prticipting centers. In conclusion, we hve confirmed the reltion between ntriuresis nd decrese in plsm volume in reltively lrge number of ptients. Fludrocortisone significntly reduced sodium excretion nd therefore remins of possible therpeutic benefit in ptients with subrchnoid hemorrhge. Acknowledgments We re grteful to Mrs. Betty Mst, Mrs. Jill Brown, Mrs. Jopie Hensen, Mrs. Agnes de Lnge, * the Deprtment of Medicl Physics of the Royl Free Hospitl, London, nd to the Deprtment of Nucler Medicine of the University Hospitl, Utrecht, for their invluble help throughout this study. References l. Adms HP, Kssell NF, Torner JC, Hley EC: Predicting cerebrl ischemi fter neurysml subrchnoid hemorrhge: Influences of clinicl condition, computed tomogrphy results, nd ntifibrinolytic therpy. A report of the Coopertive Aneurysm Study. Neurology ;:5-5. Hijdr A, vn Gijn J, Stefnko S, vn Dongen KJ, Vermeulen M, vn Crevel H: Delyed cerebrl ischemi fter neurysml subrchnoid hemorrhge. Clinicontomic correltions. Neurology ;:-. Hijdr A, Brkmn R, vn Gijn J, Vermeulen M, vn Crevel H: Aneurysml subrchnoid hemorrhge: Complictions nd outcome in hospitl popultion. Stroke ; :-. Hijdr A, vn Gijn J, Ngelkerke NJD, Vermeulen M, vn Crevel H: Prediction of delyed cerebrl ischemi, rebleeding, nd outcome fter neurysml subrchnoid hemorrhge. Stroke ;: Vermeulen M, Lindsy KW, Murry GD, Cheh F, Hijdr A, Muizelr JP, Schnnong M, Tesdle GM, vn Crevel H, vn Gijn J: Antifibrinolytic tretment in subrchnoid hemorrhge. N Engl J Med ;:-. Wijdicks EFM, Vermeulen M, Ten Hf JA, Hijdr A, Bkker WH, vn Gijn J: Volume depletion nd ntriuresis in ptients with ruptured intrcrnil neurysm. Ann Neurol 5;:-. Wijdicks EFM, Vermeulen M, vn Brummelen P, vn Gijn J: The effect of fludrocortisone cette on plsm volume nd ntriuresis in neurysml subrchnoid hemorrhge. Clin Neurol Neurosurg ;:-. Wijdicks EFM, Vermeulen M, vn Brummelen P, Den Boer NC, vn Gijn J: Digoxin-like immunorective substnce in ptients with neurysml subrchnoid hemorrhge. BrMed J ;:-. Fler C, Gill GB, Burn J: Hypontremi: Mechnisms nd mngement. Lncet ;:-. vn Gijn J, Hijdr A, Wijdicks EFM, Vermeulen M, vn Crevel H: Acute hydrocephlus fter neurysml subrchnoid hemorrhge. J Neurosurg 5;:55-. Wijdicks EFM, Vermeulen M, Hijdr A, vn Gijn J: Hypontremi nd cerebrl infrction in ptients with ruptured intrcrnil neurysms. Is fluid restriction hrmful? Ann Neurol 5;:-. Wijdicks EFM, vn Dongen KJ, vn Gijn J, Hijdr A, Vermeulen M: Enlrgement of the third ventricle nd hypontremi in neurysml subrchnoid hemorrhge. / Neurol Neurosurg Psychitry ;5:5-5. Finn SS, Stephensen SA, Miller CA, Drobnich L, Hunt WE: Observtions on the periopertive mngement of neurysml subrchnoid hemorrhge. / Neurosurg ;5:-. Kssell N, Peerless S, Durwrd Q, Beck DW, Drke CG, Adms HP: Tretment of ischemic deficits from vsospsm with intrvsculr volume expnsion nd induced rteril hypertension. Neurosurgery ;ll:- 5. Kosnik EJ, Hunt WE: Postopertive hypertension in the mngement of ptients with intrcrnil rteril neurysms. J Neurosurg ;5:-5. Liddle GW: Adrenl cortex, in Beeson PB, McDermott W, Wyngrden JB (eds): Cecil Textbook of Medicine, ed 5. Phildelphi, WB Sunders Co,, p. Von Vogt W, Fischer I, Ebenroth S, Appel S, Kjiedel M, Lucker PW, Rennekmp H: Zur phrmkokinetik von Fludrohydrocortison. Arzneimittelforschung ;: -

6 Hsn et l Fludrocortisone After SAH. vn Gijn J, vn Dongen KJ: Computed tomogrphy in the dignosis of subrchnoid hemorrhge nd ruptured neurysm. Clin Neurol Neurosurg ;:ll-. vn Gijn J, vn Dongen KJ, Vermeulen M, Hijdr A: Perimesencephlic hemorrhge. A nonneurysml nd benign form of subrchnoid hemorrhge. Neurology 5;5:-. Tesdle GM, Jennett B: Assessment of com nd impired consciousness. A prcticl scle. Lncet ;:-. Slcinsky P, Hope J, McLen C, Clement-Jones V, Sykes J, Price J, Lowry PJ: A new simple method which llows theoreticl incorportion of rdio-iodine into proteins nd peptides without dmge (bstrct). J Endocrinol ;:P. Glss HI: Stndrd techniques for the mesurement of red-cell nd plsm volume. BrJHemtol ;5:-. Greenlef JE, Bernuer EM, Young HL, Morse JT, Stley RW, Juhos LT, vn Beumont W: Fluid nd electrolyte shifts during bedrest with isometric nd isotonic exercise. / Appl Physlol ;:5-. Jennett B, Bond M: Assessment of outcome fter severe brin dmge. A prcticl scle. Lncet 5;l:- 5. Felig P: Nutritionl mintennce nd diet therpy in cute nd chronic diseses, in Beeson PB, McDermott W, Wyngrden JB (eds): Cecil Textbook of Medicine, ed 5. Phildelphi, WB Sunders Co,, p KEY WORDS ntriuresis plsm volume subrchnoid hemorrhge Downloded from by on December 5,