I

F

Evidence for endothelial cell activationlinjuryin heatstroke,

Abderrezak Bouchama, MD, FCCP; Muhammad M. Hammarni, MD, PhD, FACP; Afrozul Haq, PhD;JDbn Jackson, MD; Sultan Al-Sedairy, PhD

Qbjectfves: We tested the hypothesis that heatstroke is associ‘ sled wih erdotheflal cell acllvatloainjury arid examined th.e os

sbWity that the markers of endothelial cell activatioMnjury may beassociated vlth its severity and complications such as dissemi—nated Intravascular coagulation1lung njury, and renal dysfunction.

Pesign: Prospective analyses.Setting: Heatstroke Center in Mnkkah. SaudI Arabia,

F Paienls: Twenty-two adult patients with healstroe.Interventions: The plasma concentration of endotheiln, circur lating intercellular adhesion molecule-I (ICAM-I), and von

Wiflebrand factor-antigen values were measured, respectIvely, byradioimmunoassay, enzyme-linked immunosarbent assay, androcket eiectroimmunoassay, in heatstroke patients on admission(precooiing) and after complete cooling (postcoolng), and In tannormal control patients.

Measurements and Main flasuils: Precooilng heatstroke patients (rectal temperaturs 40.9 ±1.1 [so] ‘C) had increased circWatng cencentrations of endotheiin c-1CAM-1, and von Wiflebrand

actor-aritigen in 100%. 80%, and 77% of patients to 126.4: 11.2mcVL, 523.1 ± 154.4 nglmL, and 3.85 ± 2.3 U/mL, respectively(cont’oi values: 13.7 ± 4.2 pmoifl. [p c .001]; 247.4 s 68.2 ngirnL [p<.001;; and <1.5 U!mL, respecflveiy). There was a sIgnificant (r’

[ .68, p <DI) correiation between circuistlng CAM-i and endotheilt

concentrations. Plasma endothelin concentration correlated negatively with temperature (r = .35, p< .05). Mean endotheiln Corcentration was s:m:iar in patients with or without renal dysfuncUon.and mean von Wlilebrand factor-antigen concentration was simiar!n patients with or without iun injury or thss.minated intravascuar coagulation. There were no significant cQueiatlons between

circulating iCAM-I endothelin, or von WThebrnd factor-antigenconcentration and the Simplified Acute PhysIology care. Aftercoaling, mean clrcuialing CAM-I and endothelin concentrationsdecreased significantly to 400 ± 109 nglmL and 93 ± 38.5 prnoi/L,respectively, whereas the mean von Wiliebrand factor-antigen concentratton increased to 5.55 2.18 U/niL (p .05).___Conciusions.Our finoings-of increased-circulating concentrations of circulating 1CAM-1 endothelin, and von Wli(ebrand factorantigen are consistent with the hypothesis that heatstroke Is associated with endotheflal ceU activationllnjury. Whether the endothehalcell acdvallooimnjury is impilcated in the pathophysloiogy of thisdisorder merits further studies. tCrit Care Mcd 19%; 24:1173—1178)

K!y WD€os: intercellular adhesion molecules; endotiielin; vonWiiiiebrand factor; heatstroke; endotheflurn; organ faflure;hyperthermia: dissemnated intravascular coagulation; ung injury; renal failure; craicai illness; temperature

Heatstroke is characterizedby hypertherrnia and neurologic abnormalities oc

- curring after exposure toa high ambient temperature (1. 2).Despite recent advances in oling andmonitoring the mortality and morbidity rates from heatstroke remain high(1, 2). This failure to improve outcomeis due, in part, to the act that theunderlying pathoohysiology has not

From be Departments ol Medicine (Drs.Bc chania and Hamniami), Pathology (Dr. Jackscri), and Biological and Medical Research (Drs.Haq and Al-Sedairy), King Faisal Specialist Hospitaland Research Centre, Rlyadh. Saudi Arabia.

Supporied, in part, by granl 90009 from KingFajsar Specialist Hospital and Resesrcn Centre,

Address re$sests ton reprints to: AbderrezakEotrtafl. ,.S, De3azvnec ci Meine MED 4),

kfr Faisa Specias: csc a 3n Resoarn Cene. P.O. Ex 3354, R.yad ‘1211, Sat.. Araba.

Copyrglt© fl98 by W’lans & Wrkws

been fully established, and thus, specific treatment is not available (1-4).

There is considorable evidence tosuggest that endothelial cell damageoccurs in heatstroke patients (5. Gi.Necropsies have disciosed: a) necrosis and/or hemorrhage into various organs, namely, lung, brain, kithiey,liver, and gut; b) widespread microthrombi in the microcircujation ofthese organs; and c) ultrastructuralevidence of endothelial cell damage.Further, disseminated intravascularcoagulation, acute respiratory distresssyndrome (ARDS), and multiple organ dysfunction (1,2, 7,8) can complicate heatstroke.

We (4, 9) have previously shownthat heatstroke is associated withendotoxemia and increased concentrations of tumor necrosis facttr (TNTa. interleukin (IL)-1, IL-6, andinterferonic The infusion Df TNT-a

and/or IL-i in animals has been shownto result in pathophysiologic 2nd morphologic changes that closely resemblethose changes of heatstroke (10, 11).Further, recentin vitro studies (10—13)have demonstrated that endotoñn andproinftarnmatory cytoidnes can activate the vascular endothelium. resulting in increased adhesiveness of leukocvtes to the endochelium and in therelease of vasoconstrictor Feg,,

endothelin) and procoagulant peptides(e.g., von Willebrand factor-antigen).thereby promoting vasoconstnctiDnand thrombosis, respectively.

In this study, we examined whetherthe plasma concentrations of endothehal cell activation/injury markers,circulating intercellular adhesionmoLecule-i (TeAM-i), endothelin, andvon Willebrand factor-antigen areincreased in heatstroke and, if so, weexamined their relationship with some

are.

—

ur

her•fty

se

It’d

Care Mec iggs Vo. 24. No.7 1173

of the pathologic manifestations ofheatstroke such as disseminated intravascular coagu1ation, lung injury,and renal dysfunction, as well as heatstroke seventy.

MATERIALS AND METHODS

Patients and Clinical Data. Afterapproval by the Institutional ReviewBoard of King Faisal Specialist Hospital and Research Centre. Riyadh.Saudi Arabia, which waived the needfor informed consent, the study wasconducted at the Heatstroke Center ofKing Faisa Hospita. 3fakkah, SaudiArabia, during the 1990 pilgrimageseaso. Twenty-two consecutive patients with classic heatstroke, dingnosed by a rectal temperature of4OIC and associated with neurologic abnormalities (delirium, convulsions, or coma) and a history of exposure to a hot environment, wereincluded in the study. Blood pressure,heart rate, and restiratcry rates wererecorded at the time of hospital admission. Temperature was recordedcontinuously by a four-channel recorder from thermometers placed onthe skin and in the rectum. The indexof severity of heatstroke was calculated using the Simplified Acute Physiology Score (14). Cooling of the patients wa achieved by evaporation (4)as reported previously.

In the first 13 patients (group 1).we measured plasma endothelin,ICAM- 1, and creatinine concentrations. In the next nine patients (group2), Von Wiflebrand factor-antigen concentration a coagulation profile (Iibrinogen and D-dirner concentration,prothrombin and partial thromboplastin times), arterial blood gases, andchest radiograph ‘Vera obtained.

An arterial blood sample was drawnanaerobically and sent for blood gasanalysis (AEL III. Radiometer,Copenhagen, Denmark,. Arterial bloodgas values were corrected for body temperature. D-dirner concentration wasdetermined by a latex agglutinationslide test (Diag,iostica Stago,Asnieressur-Seine, France).

Patients were classified as havinglung injury, disseminated intravascular coagulation, or renal dysfunctionby the following criteria: lung injury,PaojFio. of <300, with or without infiltrates on chest radiograph; disseminated intravascular coagulation,

1174

Iplatelet count <150,000 x 10 cells/Land D-dimer concentration of >0.5 pg/mL; renal dysfunction, plasma creatinine concentration or >1.6 mg/dL(>141.4 prnol/L).

Collection and Analysis of Samplesfor ICAM- 1, Endothelin, and vonWillebrand Factor-Antigen. The timefrom onset of symptoms to arrival atthe Heatstroke Center is not preciselyknown for each patient. However, RESULTSblood samples were obtained from allpatients immediately on hospital ad- Cliniral and Biochemical Data nmission, before any parenteral treat- Heatstrok& Patients. The clinical and .

mont or cooling (procooling), and at biohemica data obtained at the time0800 hrs the day af±er cooling was of hospit& drni5sion are given incompieted (postcooiing). The mean Tables 1, 2, and 3 and &‘-e similar totime between precooling and post- those data previously reported (4, 7).cooling blood coUectic’n was 18.4 his Three patients decreased their tern-range 13 to 22). A blood sample was peruture to <40.l’C before any COOi

drawn by venipuncture into sterile ing. The patients were divided intoheparinized tubes, centrifuged at 3000 two groups according to whether cirrpm for 10 mins, and aliquots of culating ICAM-! and endothelin(groupplasma were stored at 70C until as- 1, patients 1 ts 13). or von Willebrand .4saved. ICAM-1 values were measured factor-antigen group 2, patients 14 toby an enzyme-linked imthunosorbent 22) values were measureiassay 351 inidiarsiferns, Plasma Corwenrraton of ICAM-2Ti&nna Austria). The sensitivit)- ofthe and Endotheli’ in Heatstroke Pativzts.assay was -0.5 ng/ruL ofplasrna. intra- At the time of hospital admission, cirand inter-assay coefficients of varia- cuating lOAM-i and endothetin contion were both <15%. Ten plasma centrations were significantly in-samples from healthy individuals were creased in eight (80) of ten, and nincluded in the assay 247.4 ± 68.2 ng/ 13 (1009k) of 13 patients, compared

with normal control values (p < .001)(Fig. 1). Mean plasma concentrationsof [CAM-i and endothelin were 523.1± 154.4 nglmt and 126.4 ± 11.2 pmollI respectively. Figure 2 shows the

significant correlation found betweenprecooling plasma concentrations of

circulating lOAM-i and endothelin Cr1

= .68, p < .01); and the significantnegative correlation between temperature and endothelin concentration (r’

= .35,p < .05). Six of 13 patients (Table

2) had evidence of renal dysfunction(mean creatinine concentration of 2.1

= 0.44 mg/dL 1S5.6 = 35.9 urnoVLl)- -

There was no significant difference in

the mean endothelin concentration in

patients with or without renal CY

function (112.6 ± 54.3 vs. 138.1 30

pmol/L). No significant correlation was

found between precooling plasma cOn -

centration of circulating lOAM-i OF

endothelin arid severity of heatstroke. -

Postcooiing, the mean plasma c0fl -

centratjos of lOAM-I and endothehfldecreased significantly to 400 t 109

nglmL (p <.01) and 93 ± 38.5 pmQ

(p < .05), respectively, compared with rprecooling values. The correlatiOfli

Crit Care Med 1996 VoL 24, No. I

1’

statistical package (StatgraphicsSTSC, Rockville, MD). All values areexpressed as mean ± so. Paired (pro.cooling and postcooling) and unpaireddata were compared using Student’st-test. Linear regression analysis wasused to determine correlation coefficients. Differences were considered significant at a p < .05,

mU.Eudothelin-like immunoreactivity

was measured using endothelin 1-21specific 2I) assay (16) (AmershamInternational p3c, Amersham, UK) after extraction on Amprep 02 columnaccording to the protocol recommendedby Amersham. The sensitivity of theassay was 0.2 femtomolltube; intraassay and inter-assay coefficients ofvariation were each <3%, and crossreactivities with endothelin-1,endothelin-2, endothelin-3, or bigendothelin were 100%. 144%, 52%, and0, respectively. Ten plasma samplesfrom healthy individuals were includedin the assay (13.7 ± 4.2 ,mot’L).

von Willebrand factor-antigen wasquantitated by rocket ejectroimmunoassay (Helena Factor VIII RelatedAntigen rocket ElectroimmunoassayMethod, Beaumont, TX) (17) according to the manufacrare?s recommendation. Normal plasma values providei by the rnanufacftrer for vonWi [1€ brand factor-antigen conc e ntrafinn are 0.5 to 1.5 U/mL.

Statist6cal Analysis. Data were analyzed with the use of a standard

Rectal Systolic Respiratory GiasgcwAge Temperature Bi Preis. Rate Coma

patient yr/gender) (C) mm Hg) breaths/mm) Score SAPS Outcome

1 4SIDvl 39.7 100 28 13 18 Survived2 55/)1 39.5 110 32 14 8 Survirtd3 551)1 39.9 130 32 14 7 Survivd4 50/F 42,8 110 48 3 20 Survived5 26/)1 40.1 160 34 Seizures 10 Survived6 65/F 41.9 170 50 13 6 Sur,ved7 27ZM 40.1 130 32 14 .5 Survved8 2&F 40.6 HO 38 14 17 Srvived9 39iM 42.3 50 52 3 27 Died

0 72 I 14 150 21 12 7 Survived11 55’)I 434 70 3 3 Died12 38/F 42.7 60 36 3 17 Survived13 441)1 42.7 170 50 Seizures 22 Survived14 26/)1 40.5 100 36 13 5 Survived15 25/M 40.1 130 40 12 7 Survived16 6WM 42.2 SO 44 3 20 Died17 34Th! 40.3 120 32 14 9 Survived18 55/I’I 40.1 130 32 14 7 Survived19 26/31 40.1 130 26 12 6 Sun’iveñ20 601 3 135 45 Seizuns 20 Survived21 36M 40.1 110 38 &izures 10 Survived22 3M 40.2 149 32 14 la Sjrvived

Press., preur:SAPS,SimçlifleaMute?hysioVgyScore

TableS. LaOoratury data from patients’ plasma on admission

Crestinine Creatine Glucose PC1 Ca DilirubiningidL Kinase mg’dL mg/dL mg/dL Na K mgidL AST A? Amylase

‘t. imoL) (Ut) (mmoVLJ mmolIL, mmol!L) (mmol/L) (mmol/LJ (pmol/Li nh (U/L) 11/LI

I 2.26 2UO >lOCO 254(14:’ I2NA 9915’ 148 5.1 0,4i7: 112 15.3 ‘42 1-14 i01) 130 318 (18 2.1 (0.7) 8.1 (2.1) 144 2.9 0.6 11W 28 126 823 0.83(73) 81 144(8) 1.6’0.5) 9.02.6) 145 3.7 2.1(36) 62 138 el4 1.90 jIGS; 2090 159 9) 4.1 (1.3, SI 2.1;- 129 3-0 2.4:41; C9 75 1665 125 111) >1O 207 12 97 ‘2.4 138 3.3 1.5 64 77 726 1.12 (99) 73 102 (6) 2,8 (0.9) 9.0 (26) 144 5.4 0.4 (7) 44 95 1557 1.32 117) 153 204 (1i 22 (0.7) 8.8 (2.2) 242 3.8 2.3 (3Q 30 73 988 1,60 (141) >1000 119 (7) 2.9 (0.9) 8.8 (2.2) 149 5.5 0.5 (9) 104 63 L799 286 (253) >1000 311 (17) 1.9 (0.6) 9.8 (2.1) 146 5.0 0.8 (14) 137 181 U76

10 0.97 (86) 57 181 (10) 2.5 (0.8) 8.7 (2.2) 143 3.7 1.0 (17) 96 79 20011 2,30 (203) 485 153 (8) 1.0 (0.3) 9.1 (2.3) 143 3.6 1.5 (26) 120 65 204

2 1.30 (115) 124 196 (11) 3.8 (1.2 9.4 (2.4 138 4.4 0.6 (10) 48 70 1451 L83U62; 1027 194(1:; 0.SiO.3) S.52.1) 3S 3.4 0814, 55 57 1041 :.:91O6 lBS 116(6) 2.50.8) 8.42.1) 141 3.5 0.59) 3 55 20215 1.18 104) 856 113 (6) 2.1 (07) 7.4 (1.9) 115 3.7 1.0 (17) 18 65 10316 2.15 (190) >1000 195 (108:. 240.& &6 ‘.2.2) I40 5.3 0.6 (10J lb 70 25117 1.25(110; 116 108(6) i.90,6 9.1(2.3) 145 3.1 2.5143) 27 115 124lB 0.56 71, 81 159 I9 1.7 tO.6) 8.4 (2.1) 145 3.7 2.1 (36) 62 135 8119 0.96 (85) 32 93 (5) 2.8 (1.0) 8.3 (2.1) 138 3.8 0.8 (14) 89 136 11620 1.65 (145) >1000 284 (16) 2.2 0.7) 9.0 (26) 138 3.8 0.9 (15) 123 - 85 12421 1.23 (109) >1000 97 (5) 2.0 (0.7) 8.8 (2.2) 149 3.1 1.2 (21) 32 53 8422 1.17 (103) 346 111 (6) 2.7 (0.8) 8.1 (2.1) 136 4.6 05 (9) 54 52 146

Pt., patient; P04, phosphate; Ca, calcium; Na. sodium; K. potassium; AST, aspartate aminotransferase; AP, alkaline phosphatose.

between plasma concentrations Df

!CA),1-1 and endothelin was not staltstjcajly signiflcant.

Plasma von Willebrand Factor-Antigen Concentration in HeatstrokePatients. Figure 3 shows that precod

significantly different from the precooling concentration (p > .05i.

Tables 3 ai,d 4 show that of thenine patients, two patients had evidence of disseminated intravascularcoagulation (patients 17 and 22), and

7 le 1. Demographic and clinical :harazterislics cfheatatroke patients Gfl admission

S

.1]F,

\Villebrand factor-antigen was increased in seven (77%) of nine patientsto a mean of 3.85 ± 2.3 U/mL (normalrange 0.5 to 1.5). Postcooiing, the meanplasma concentration ofvon Willebrandfactor-antigen increased to 5.55 ± 2.18

ing plasma concentration of von U/mL; however, this increase was no three patients had evidence of acute

C Care Med 1996 Vol. 24. No. 7 1175

7001BOO

soo-J

Z 400

oo’-

oI

I”Nm;Co.’ c I

175 —

1501

—.

100-i a.

C75j

a.e

25-,

—

No.inj Httlrofr. N..tsha.C40bt1 Pnco,:Irg ostDo’Ing

Figure 1. Plasma circulating intercellularadhesion molecule-i (ICAM’!) and endoth&in concentrations in nonnal controls andheatstroke patients me- and posttco!ing.The solid circles and uprticcl bars indicatemean SD values.

‘75—

150

251

175’’

I5OH

I ‘H100

75—

5O

Table 3. Arte,ial Mtod as values hat2tnce patients ona3flhISiO;,

O Therupy pH Pncc, Pao. 14C0.Pt. L’min) Units torrkPa: corr(kPaJ mmol’t)

I 5 691 29 39) 90 (11,9)2 5 7.46 32 :43) 4-S (6.4) 243 2 T46 29 3.9) (11,5: 214 Room air 7.35 27 (aS) 97 12.9 135 1 7.59 19 2.6) 85 (11.3) 136 4 7.33 38 &1) 74 (9,9)7 Room air 7.49 29 (3.7) 57 (7.6) 218 3 7.19 27 3.6) 101 (135) 109 3 7.15 43 3.7) 122 (16,8) 13

10 2 7.45 28 3.7) 58 (7.7) 19Ii 3 7.41 21 (2.8) - 114 (15.2) 1212 5 7.46 18 (2,4) 69 (11.9) 1313 Room air 7.43 28 (3.7) 107 (14.3) 1814 Room air 7.53 25 (3.3) 54 (7.2) 2115 Room air 7.51 29 (3.9) 68 (9.1) fl16 Room air 7.32 31 (4. L) 62 (8,3) 1517 5 7.41 35 110 14,0) 2118 Roam air 7.46 39) 66 (115: 2119 Rooni air 7.40 37 (45J 10 (13.9 2220 5 7.32 25 33 60 (10.1, 1221 Room air 7.18 21 (28) 107 (14.3) 722 5 7.45 25 (3.5) 57 7.6) 18

-J

C

a10C

c,

20 300 400 500 600 700

ICAM-l (nghnL)

‘40 41 42 43 44

Temperature 0

S

-I

t

Pt., paent; UCO,, bicarbonate.

lung injury (patients 14, 20 and 22\There was no significant difference inthe mean plasma von Willebrand factor-antigen concentration in patientswith or without disseminated intravascular coagulation (2.56 ± 0.33 vs.3.45 ± 2.7 U/mL) or lung injury (3.71 ±

3.6 vs. 302 ± 1.8 U/mL). The plasma0-dinter concentration was(0.66 = 0.28 ugImL vs. 1.25 = 0.88 ugimL) in patients with er without lunginjury. ?asma von Willebrand factor-antigen concentration correlated Bignificantly with platel& count (r2 = .49,p < .0::. but not with fThrinogen canentration (r3 .37. p > .05 or theseverity of heatstroke (r2 = .22, p >

.05).

DiSCUSSION

This study confirms and extendsthe clinical and pathological observations suggestive of endothelial cell activationJinjury in heatstroke by demonstrating marked increases in theplasma concentrations of three markers ofendothelial cell activationfimjurv,namely, von Wiflebrand factor-antigen,ICAM-1, and endothelin in 77%, 80%,and 100% respectively, of heatstrokepatients. These markers were selectedbecause of their potential role in the

1176

Hstttrck. H..15r0k0Pr.tcoh Pcstcocn

Figure 2. Correlation between precnolingplasma circulating intercellular adhesionmolecule-i (lOAM-I) and endothelin concentration (r1 = .68, p c .01), and correlationbetween plasma endothetin concentrationand temperature r2 = p .05) in heatstroke patients on admission (precooling).

Hentidrok. H.at*IreK.Pr.ccolFng

Figure 3. Plasma von Willebrand factor-antigen concentration (VWF-Ag) in nineheatstroke patients pre- and postcooling. ,The solid circles and veflical bar, indicatemean ± so values. The normal range i indicated by the dashed lines.

formation of thrombi. in inflammation,and in the regulation of vascular tone(13, 18, 19)

Increased concentration of vonWillebrand factor-antigen was reported previously (20—22 in a valiety

Chi Care Med 1996 Vol. 24, No. 7 ;t

•1

r

Pa:ele: Court PT Ftrinogen D. DinerPt (x !Ge]!sL sat’ scc .L.gfllL

14 147 12 35 2G9 <3.55 MO 14 60 3-81 <0.516 2& 11 31 N/A N/A17 :2 21 ±25 >2<4S 1 13 31 N/A >2<1t9 135 13 55 N/A <0520 250 12 22 N/A N/A2’ 204 12 29 1.83 >1<222 118 15 39 N/A ‘0.5<1

ur,naIrune 150—430 11—14.4 26—39 15—i <0.5

Pt., patient; Pr, prothombtn time; PV, partial thromboplastin time.

0 diseases associated with endothe- in contrast to a previous study (22),hail cell injury, such as acute myocar- we found that the circulating plasmadial infarction (20), vasctiHtis (21), and concentration of von Willebrand facacute lung injury t22), Ehis study is tor-antigen “as similar in patients;r first study to demonstrate an in- with or without disseminated intra

• ease of von Willebrand factor-anti- vascular coagulation or lung lujury.gsTi concentration in heatstroke. Cut- However, our small patient sampletured endothejial cells reiease von precludes a meaningful statisticalViebrand factor-antigen constftu- interpretation.tively and after stimuiation with von Wil!ebrand factor-antigen isthromhinEhTtftiliidocoxin, or known to facilitate the adherence ofcytokines (23) Increased concentra- ptateletF to the subendothe]iun, olintin13 of endotoxin and cytokines in jured endothelial cells (13, 18). In thisheatstroke patients (3, 4, 9) nay thus study, we found a strong positive asso

p nplain the increased concentration of ciation between von Willebrand facn Willebrand factor-antigen ob- tor-antigen concentration and platelet

- ned in this study. Alternatively, the count. The mechanism underlying thisincrease of von Willebrand factor-an- association is not clear and deservestigen concentration may be nonspe- further investigation.cific and may represent an acute phase Exposure to a high ambient tern-reaction; however, this concept seems perature ‘eads to adaptative renal andunlikely because of the lack of sigtiii- splanchnic vasoconstriction that shifts

• cant correlatiDa between the concen- blood flow from the iociy core to thetration of von Wiltebrand factor-anti- periphery, thus helping to prevent ang.n and another acute phase reactant, increase in core temperature C2, 23,. Arinogen (20). hemodynamic study (2) demonstrated

Our data concur with those End- that when heatstroke develops, thereings of other investigators (1 2, 8) in is an ir,crease in cardiac output and ashowing that coagulation abnormali- decrease in systemic vascular resist-ties and hypoxemia with or without ante. The mechanism(s) for the reducovert lung injury are common in heat- tion of renal and splanchnic blood flowstroke. A previous report (24) Bug- and subsequently hyperdynamic cirgested that high concentrations of cir- culation is not well established, alculating 0-dimer may be either a though activation of the sympatheticmarker or a mediator of the microvas- and renin-angiotensin systems, andcular injury observed in ARDS. This increases of catecholamine cancentra

ggestion is supported by the find- tions have all been implicated (2, 25)..gs nt El Kassimi et at. (8) who re- There is growing evidence to suggest

ported a strong association between that endothelial cells play a key roleARDS and disseminated intravascu- in reguahng the regional Nood flowlay coagulation in heatstroke patients, in both physiologic and pathologicIn this study, however, we found no states by producing and reeasingSignificant relationship between the endotholium-derived contractingconcentration of circulating D-dimer (endothelin) and relaxing (nitric oxand the presence of lung injury. Also. ide) factors (26). This specuation is

and pathological observa

tions suggesttve of endothe

11(11 cell actiu.1tion / injury in

- hPatstroke by drnonstrat

ng marked inciases in th

plasm a r?nn: n / rations of

three ,na,’ke,s of endothehal

ce/I at ti VU tuJn / I ti jit iv.

suppt.rted by the findings of Hall etal. i 7), who demonstrated an enhanced production of nitric oxidewithin the spinochnic circulation in aheatstroke rat model. We observedthat a the endothelin concenuationis eight-fold higher in heatstroke patients than in normal controls; b)endothelin concentration correlatesinversely with the degree of hyper-’thermia; and c) endothelin concentration decreases significantly after cooling. These observations, along withthe findings of Hall et at. (27), suggestthat vabcu[ar endothejium is involvedin the cardiovascular changes observeddurirg heatstro:e. The relationshipbetween endothelin and temperatureis not clear, but theoretically, higherendoth€lin concentrations may beassociated with splanchnic vas000n-stricdan, thereby shifting blood flowto the skin ur.d causing greater elitniW.tlQn of heat and a lower body temperature. On the other hand, decreasedendothelin production andlor increasednitric oxide production may result insplanchnic vasodilation, vascular collapse, and the syndrome ofheatstroke,These speculaUons merit furtherstudy.

Although the pathophysiologic roleof endothelin is unclear, it has beensuggested that increased endothelinconcentrations may be implicated inthe decreased glornerular filtrationrate of acute renal failure (28). In thepresent study, we found no significant correlation between plasmaendothelin and creatinine concen

ible 4. Coagulation variables ofheatstroke patient on admission in group 2 m his study con

firms and cx-

tends the clinical

Ct Care Med l9€ ‘4. 24, 7 ‘177

tra U uns, suggesting U, at emlt,thelmay not play a rousutive role in therenal impairment of heatstroke.

Recently, it was shown (29) thatleukocyte adhesion is important ingranuloevte extruvasation at sites ofinfiammadon and other immunologicresponses involving cell to cell interaction. Intercellular adhesion owlecule-! (IC.AM-1, CD54), a member ofthe immunoglobulin super-family thatis expressed on the cell surface of endothelial cells as well as leulcocvtes.mediates cell-to-cell adhesion by binding to two leukocyte integrins, LFA-1(CD11/CDIS) and MAC-i 1CD11/CD1S) (26). A circulating form ofICAM-i (ICAM-1) has been shown toretain the ability to bind specificallyto LFA-1 (15). Further, a rapidly increasing number of studies (30, 31)have shown that c.ICAM-1 concentration is increased in various diseasestates and may correlate with theirseverity. Both forms of [CAM-i areinducible by cytulcines such as TNF-a,IL. 1 and interforon-y (15). We (4, 9)

tetentlrdeiithtaWdjjjtiased concentrations of TNF-a. IL-i, and interferon-’y in heatstroke patients. In thisstudy, we found that the circulatingICAM-i concentration is increasedtwo-fold in heatstroke patients. However, the circulating ICA.1-1 concentration did not correlate with the severity at the disease, as assessed bythe degree oflyperthermia or the Simplified Acute Physiology Store.

We found significant positive torrelatiin between circulating SCAM-i andendothelin concentrations. This finding suggests that, similarly withendothelin, the source of circulatingICAM-1 in heatstroke patients may beactivated/injured endothelial cells. Alternatively, the association betweencirculating lOAM-i and endothelinconcentration may be caasative, Recently, endothelin-1 was shown (32) tostimulate neutrophil adhesion to endothelial cells by regulating the expression of adhesion molecules on thesurface of neutrophi]s. Thus, increasedendothelin concentration may have induced the expression of ICA1vI-1.

In conclusion, we have shown thatcirculating concentrations of ICAM-1,endothelin, and you Wiflebrand factor-antgen arc significantly increasedin heatstroke patients, suggestingendothelial cell activation/injury.Whether or not these markers canmediate certain aspects of the1178

p atli ophysii I gy uf heatstroke meritsfurther study.

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Cl Care Med 1996 Vol. 24, No. 7 S