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Preliminary report on the use of hydroxyethyl starch solution in man
on the Use of Starch Solution in W A L T E R F. B A L L I N G E R , I1, M.D., G O R D O N F. M U R R A Y , M.D., and E D W A R D E. M O R S E , M.D., The Johns Hopkins Univetwity School of Medicine
Starch has been k n o w n for s o m e time to exert a colloid effect w h e n administered intravenously. However, ordinary starch solutions are physically unstable due to associative forces between long linear chains. Moreover, rapid e n z y m a t i c destruction occurs u p o n contact with blood serum. In 1959, the use o f physically stable branched or " w a x y " p o l y m e r s o f starch and the introduction of h y d r o x y e t h y l a t i o n to resist e n z y m a t i c hydrolysis initiated re-examination of starch as a plasma expander. T h e resulting p r o d u c t , h y d r o x y e t h y l starch (HES), is inexpensively m a n u f a c t u r e d with reproducible characteristics, a distinct advantage o v e r the cost and variability of fi'actionated dextran. In addition, H E S has the same viscosity in solution as dextran and has displayed excellent physical stability. In terms o f stockpiling for national defense, p r e s e n t r e p l a c e m e n t o f unstable dextran represents a significant expenditure. T h e r e are also theoretical considerations, based on the similarity of H ES to normal b o d y glycogen, that indicate that it may have a lower incidence of side effects than dextran in clinical use. Previous studies by us d e m o n s t r a t e d that t h e administration o f a 6% solution of H E S in saline to dogs subjected to hemorrhagic s h o c k was a s effective in restoring arterial blood pressure and maintaining survival as clinical dextran solution? A s a result of these encouraging studies, prelin~inary clinical investigations a r e being c o n d d upon patients o f T h e J o h n s H o p k i n s Hospital. T h e current report, therefore, presents the results following initial trials of H E S in man. From |he Departments of Surgery and Medicine, The Johns Hopkins Universily School of Medicine. Baltimore, Maryland. Supported by U.S, Army contract DA 49-193-MD-2574. Submitted for publication October 29, 1965. i~0
MATERIALS AND METHODS In the first portion o f this study, the persistence of H ES in blood and its excretion in the urine was investigated. T w o healthy, adult volunteers served as subjects. O n e thousand ml. o f a 6% solution o f H E S in normal saline was given intravenously over a period of 60 minutes to each subject w h o remained recumbent during this time, Vital signs were monitored and careful observation t2~r side effects was made. D e t e r m i n a t i o n s o f hematocrit, hemoglobin, electrolytes, s e r u m e x p a n d e r and protein concentration, and urinary e x p a n d e r c o n c e n t r a t i o n were made before, immediately after a~d at I, 4, 10 and 24 hours following infusion. T h e total v o l u m e of blood withdrawn for sampling was about 160 ml. during the 24 h o u r study period. T h e original plasma volume was d e t e r m i n e d using C r '~ tagged red cells: the succeeding v o l u m e s from the changes in hemoglobin and hematocrit, and fi'om tile changes in serum protein concentration, ~ Plasma protein concentrations were m e a s u r e d with lhe biuret technique. Total p l a s m a c a r b o h y d r a t e concentration was measured in duplicate by the a n t h r o n e t e c h n i q u e s ~ using trichloracetic acid filtrates of plasma, Urine total c a r b o h y d r a t e concentrations were m e a s u r e d with the a n t h r o n e technique after dilution o f urine with 0,9% NaCI. Hematocrit, hemoglobin, plasma glucose and s e r u m electrolytes were m e a s u r e d by standard procedures. N o glucosuria was observed, T h e difference b e t w e e n total carboh y d r a t e concentration and the glucose concentration was taken to indicate the c o n c e n t r a t i o n of H E S ih plasma and urine, T h e s e c o n d portion o f the study was performed in order to d e t e r m i n e the effect of the infusion o f I000 ml. of 6% H E S in saline upon the coagulation m e c h a n i s m of the s a m e two JSR -- Vol. VI, No. 4 - April 1966
JSR - ,Vol. VI,INo,-~4 ~:April 1966
vblunteer subjects. Theq, ollowing coagulatioa studies Were .perfdl]ne~t just prior to ~ and immediately follov~ing the;~infusiort~fibrinogen: (tyrosine), thrombin time,:oprd~thrombih time, residhal proth?Omlsl~n tir ~ plasiir~ timel :wh61~'~blood C0~'ilt, clot retraciibh: and ':£:F0r the'ithird' ipOrtfdn : 15 patients~were infused Accident:, Room of:The. JohnsHoPkinS Hospital(. All~ were sufferirig, fi'om trauma or a &sease wh~cl~ wou|d normMly bgexpected to, produce a deficit in blood volume, No formal selection procedure was dev:ised tbr"th~se preliminary observations. Patients: .::~~ f e included at the dism'etion of the membd~?df the surgical house staff after exptanafigfi)of the purposes of the investigation and? after. H ES was made available in this' area, The diagnoses ~incltided traumatic hen'/orrh~e, crush injury, peritonitis and gastrointestinal hemorrhage. The patients received either 500 or 1000 ml. of the HES solution* infused via a large bore plastic cannula inserted into an appropriate vein. Arterial btood pressure was carefully recorded before, during and following the infusion. Depending upon the condition of the patient, the infusion of starch was fotlowed either by no further intravenous therapy or by the subsequent administration of plasma or whNe blood, The latter agents were administered, only ~ when it became obvious that continued losses of fluid or brood were occurring, Several. patients required emergency operations and were transferred to the operating room with the HES infusion continuing. ,RESULTS The intravaScular pe~,'sistence of H E S a s a percentage of the mass infused is recorded in "Fable 1, In this case, retention of the starch expander is similar to that'observed f o r clinical dextran "~, and ~is gr~z,4er at 24 .hours (starch 50 to 60%, dextran 30%). The c,iamulatire urinary excretion 0f HES is als0 recorded in Table 1~ These preliminary measurements indicate a significantly 10wer rate of excretion than the following dextran infusions,?
* L o t No. $2681A, kim:Ily supplied by Dr. Marlin Robei'ts, Don Baxter Co., Glendale; California.
HYDROXYETHY.E
STARCH SOLUTION--
I81"
nogen occmTed in Fable:2; The t0w~r neth0di~iS/150 m~ii iim~, pro!hr0mbin tin timewas:noted; ~idual prothromNn Cipiegt:i:Theri~ was no change m me levels o t factors. V Or VII; The platelet, c0um.did, not decrease and* clot ~ retraction was not impaired. The bleeding time :increase~l slightly in one reci~ient. The measikJrements were~all within'the limits of normal with the'2!borderline iexception Of fibrinogenl Determ~nati0ns Of t h e blood group and type revealed no difference ~ter m f u s m n . D,'ect m~d indirect Coombs tests remainednegative; In Table 3:.the wtal s~gns, hemoglobin, hemab ocrit, p£0tein arid e*iectroly,!e d~termlnatlons are dei~led~:and indicate no SigN~cant derangement through~t the~experimems. The 15 pat!ents receiving 6% H ES can be divided into three groups acCordingto their: arterial blood pressure u p o n arrival in the Accident Room. There were 8 patient s Wilh a systolic arterial blood, pressure below 90.mm. H g, All the usual clinical criteriawere present and the causefor the acute volume defic!t was immediately .apparent :(e.g,, :external h e m o r , rhage, peritonitis), An intermediate group was composed of 4 patients, the systolic: arterial blood pressure ranging between 8 0, and. 100 ram. Hg on admission. The pu!se rate was o,ver t00 in all t h e s e patients: Several appeared pale and were thought to be in profound Shock before the blood pressures were obtained. . The final gr0up;of 3 patients ~c0nsisted o f individuals with iNuries, which oftenproduce Shdck if su~eiently severe. An example W, asa alpene:: trating: stab wound of the abd0men or. chest in whichit was not immediatelyapparentwhether a major vesse! had been divided, In :a!!:0f these patients, . t h e initial :systolic ::arterial blood: pressure was over ] 00 ~ d tlie: pulse ~ t e less than 100. •All /patients'..with hypolension :~responded rapidly to:the administration .Of 6 % HES/~ n saline, This.. response w a s Observed,. clinically: by a rise in arterial blood pressure, in:all Cases to 90 ram. Hg:oii. a b 0 v G and by:g?fall jn:ipuise rate, I n several instances, in, palimltS'inlwhdm a Foley catheter:was ~inserted, gutput of urine began witN n !5 minuted o f the admhiisn,atibh o f t h e : s t a r c h solution, The. paiiehts):,ih the thh-d .i:gi'oup i- ,with i n o r m a l blood : i~i,essi]res: exhibited, n O chan.~e in •:: preS~Ure.,:ifoil0wing
182
BALL!NGER
ET AL.
JSR -
Table I.
VoL Vl, No, 4 -
April 1966
ttydroxyetbyl Starch PersiStence Studies PlaSma I)et~rminations
Recipient A Ti me After Infusion
Tothl CIIO
Glucose
Starch
10 minutes 60 minutes 4 hours I0 hours 24 hours
12t4.5 mg. % 1148.0 1130.0 960.0 -931.0
[16 mg. % 103 118 113 I13
1099 mg. % 1045 1012 847 818
100 90 82 64 63
1494.0 1400.0 1310,0 1255.0 1057.0
108 125 120 !25 103
1386 1275 1 I90 1140 954
100 87 67 72 50
% Retention
Recipient B 10 r~inutes 60 minut$s 4 hours 10 hours 24 htiurs
Urine Determinations Time A fter Infus ion
Mg, %
Vol,
Mg. Excreted
Cumulative %
10 minutes A: B:
120
545
136
590
654 802
5.0 6,5
60 minutes A: B~
376 555
120~ 80
45{ 444
9.0 10.0
4 hours
A: 13:
114 333
155 150
177 499
10.5 14~5
10 hours
A:
24 85
440 425
96 361
11.5 17.5
24 hours
A: B:
43 42
160 175
58 3/3
12.0 20,0
Temp.
Vital s i g n s C ontr o I l5 30 45 60
B
p
~
Pt. A
Pt. B
Pt. A
98.6
98,0
164/I08 Infusion 142/90 150/II0 140/110 145/105 Infusion 140/90 140/85
minutes
minutes minutes minutes
15 minutes 30 minutes
~
98.0
98.2 ~
Pulse
•
Pt. B I34/78 Start 120/80 122/90 115/80 120/80 Off 120/85 120/80
Pt. A
Pt. B
68
58
64 64 64 64
64 64 64 64
55 64
68 64
Hematocrit, ftemoglobin and Protein Determinations Patient A:
Hct. %
Hgh. Gm. %
Protein Gm. %
Control 10 minutes I h our 4 hours 10 hours 24 hours
43.5 40,0 40.5 41,5 43.0 43.0
14. O0 12.75 13.35 13,25 i3.60 13,90
6,4 5,5 5.6 6.3 6,6 6,3
51.0 49.5 49,5 53.0 50,0 53,0
16,65 15,20 15,50 17,30 15,90 I7.00
6,3 5.1 5,5 6.1 6,0 6.8
Patient B: Control. I0 minutes I hour 4 hours I0 hours 24 hours
JSR -- Vet, Vl, No. 4 -- April 1966
Table
2..
HYDROXYETHYL
SOLUTFION.
L83
Studies o/CoagulatiOn Before and,After HES Infusion : A Pre
Fibrinog~bn (tyreMne) Thrombin t line Prothromhin time Residual prothrombin time Partial thromboplastin time ~}'hole h Iood clotting time Plat e l e t . c o unt Clot retraction Bleeding time
STARCH
A Post
BPre
233 rag. % i57.mg. % 14 s e c o n d s . 20 s e c o n d s 15 seconds (100%) 17, seconds (80%). 63 s e c o n d s 58' s e c o n d s 80 s e c o n d s ~120.seeonds 13 minutes 16 minutes " 361,000 358,000 •
85% 2 minutes
94% 9 minutes
17a mg. % t4.5 s e c o n d s . 18 seconds (80%) 93 Seconds I10 s e c o n d s 16 minutes. 308,000 72% " 2 minutes
B Post~ 1~5 rag. % 22 s e c o n d s " 20 seconds (65N) 173 s e c o n d s . .125 s e c o n d s • :! 8 mimites 291;000
88% 4. mintltes
Table 3. Electrolyte Determinations (mEq,/L.) Pt. A
Pt..B
100
22,3
26.0.
104
i01
26:8
4.4
104
105
22.0 24.10
4.2
4.0
103
101
20.8
23.o
145
4.4
4.0
104
i03
• 8.o
2S.o
152
3.7•
3.7
105
.104
• 25.a
:28:8
Pt. A
Pt, B
Pt. A.
Pt. B
;Pt, A
Control
149
145
4,4
4.0
104
]O minutes 60 minutes 4 hours 10 hours 24 hours
157
t49
4,4
4.4
t50
159
4.7
t52
'159
155 t47
Time Alter Infusion
COz
C1
K
Na
administration of starch and in two of these p a t i e n t s c e n t r a l venous pressure was moni-tored and no essential alteration w a s n o t e d , The intermediate group responded by.a slight elevation in pressure, all of ttaese patients having a systolic arterial blood pressure over 110-mm, Hg following the Conclusion of t h e adminislration of starch solution, In none of the 15-patients Was an u n t o w a r d . reaction to .the administration of H E S o b s e r v e d clinically nor .was t h e r e gross e v i d e n c e of any Change in the coagulation mechanism, either during the infusion o r later, w h e t h e r a major procedure Was carried out or not, CONCLUSIONS T h e s e preliminary studies .indicate..that 6% H ES solution in salirie is well •tolerated in man when. administered intravenously in amounts up to 1000 n i l . Arterial b l o o d p r e s s u r e is rapidly restored and maintained unless blood o r p l a s m a losses conthme, .The clinical response i s c o m P a r a b l e to that observed following the infusion of dextran, N o clinical e v i d e n c e
• Pt. B
24.6
•
of. untoward reaction, t o 6 % HES- Solution-.in saline was observed. " , .., • Investigations in t w o h e a l t h y .volunteers indicate: that. starch is .retained ;longer than d e x t r a n , and t h a t t h e u r i n a r y - excretion.":Js s o m e w h a t slower: .There w a s a slight d e c r e a s e in fibrinogen in the blood in these two .volun2. teers, F u r t h e r in vitro and:in r i v e Studies o f the. coagulation m e c h a n i s m :.are u n d e r . w a y as~ well as a continuing study o f t h e r e s p o n s e . o f patients in shock to the infusion o f l i E S , .: R E F E R E N C E S
1•, BaIlinger, W..F., I t , Solanke, T[F~i and Thonlpson,. W, .L: The effect of hydroxyethyl starch upon survival of dogs subjemed m hemorrhagic~shock. Surg. GYneC..& Obstet., [22i33, 1966. 2, Me~catf, W,: The.intrinsic method- f0r, serial plasma. . volume determinadoris. J.. Lab, &. Clin. iMed., :58:704,. 1961. 3. Metcalf, i W,, Rousselot;, L: M . , H a r m 0 n , J,' M,, and. Gilbei'tson, F. E.; The determinants of'. |he efficacy of. various expanders in. plasma- Vofume-.expansion arid, :mainlenance in 'normal subjects. Surg. Forum, 4:7:14,: t 954, 4. Watlenius, G . : Renal Clearance tip Dextran as a Measu r e o f Gtomerular Pel:ineabi!~ty. Uppsala,.Almgristland. ) Wiksellsi 1954.
Starch has been k n o w n for s o m e time to exert a colloid effect w h e n administered intravenously. However, ordinary starch solutions are physically unstable due to associative forces between long linear chains. Moreover, rapid e n z y m a t i c destruction occurs u p o n contact with blood serum. In 1959, the use o f physically stable branched or " w a x y " p o l y m e r s o f starch and the introduction of h y d r o x y e t h y l a t i o n to resist e n z y m a t i c hydrolysis initiated re-examination of starch as a plasma expander. T h e resulting p r o d u c t , h y d r o x y e t h y l starch (HES), is inexpensively m a n u f a c t u r e d with reproducible characteristics, a distinct advantage o v e r the cost and variability of fi'actionated dextran. In addition, H E S has the same viscosity in solution as dextran and has displayed excellent physical stability. In terms o f stockpiling for national defense, p r e s e n t r e p l a c e m e n t o f unstable dextran represents a significant expenditure. T h e r e are also theoretical considerations, based on the similarity of H ES to normal b o d y glycogen, that indicate that it may have a lower incidence of side effects than dextran in clinical use. Previous studies by us d e m o n s t r a t e d that t h e administration o f a 6% solution of H E S in saline to dogs subjected to hemorrhagic s h o c k was a s effective in restoring arterial blood pressure and maintaining survival as clinical dextran solution? A s a result of these encouraging studies, prelin~inary clinical investigations a r e being c o n d d upon patients o f T h e J o h n s H o p k i n s Hospital. T h e current report, therefore, presents the results following initial trials of H E S in man. From |he Departments of Surgery and Medicine, The Johns Hopkins Universily School of Medicine. Baltimore, Maryland. Supported by U.S, Army contract DA 49-193-MD-2574. Submitted for publication October 29, 1965. i~0
MATERIALS AND METHODS In the first portion o f this study, the persistence of H ES in blood and its excretion in the urine was investigated. T w o healthy, adult volunteers served as subjects. O n e thousand ml. o f a 6% solution o f H E S in normal saline was given intravenously over a period of 60 minutes to each subject w h o remained recumbent during this time, Vital signs were monitored and careful observation t2~r side effects was made. D e t e r m i n a t i o n s o f hematocrit, hemoglobin, electrolytes, s e r u m e x p a n d e r and protein concentration, and urinary e x p a n d e r c o n c e n t r a t i o n were made before, immediately after a~d at I, 4, 10 and 24 hours following infusion. T h e total v o l u m e of blood withdrawn for sampling was about 160 ml. during the 24 h o u r study period. T h e original plasma volume was d e t e r m i n e d using C r '~ tagged red cells: the succeeding v o l u m e s from the changes in hemoglobin and hematocrit, and fi'om tile changes in serum protein concentration, ~ Plasma protein concentrations were m e a s u r e d with lhe biuret technique. Total p l a s m a c a r b o h y d r a t e concentration was measured in duplicate by the a n t h r o n e t e c h n i q u e s ~ using trichloracetic acid filtrates of plasma, Urine total c a r b o h y d r a t e concentrations were m e a s u r e d with the a n t h r o n e technique after dilution o f urine with 0,9% NaCI. Hematocrit, hemoglobin, plasma glucose and s e r u m electrolytes were m e a s u r e d by standard procedures. N o glucosuria was observed, T h e difference b e t w e e n total carboh y d r a t e concentration and the glucose concentration was taken to indicate the c o n c e n t r a t i o n of H E S ih plasma and urine, T h e s e c o n d portion o f the study was performed in order to d e t e r m i n e the effect of the infusion o f I000 ml. of 6% H E S in saline upon the coagulation m e c h a n i s m of the s a m e two JSR -- Vol. VI, No. 4 - April 1966
JSR - ,Vol. VI,INo,-~4 ~:April 1966
vblunteer subjects. Theq, ollowing coagulatioa studies Were .perfdl]ne~t just prior to ~ and immediately follov~ing the;~infusiort~fibrinogen: (tyrosine), thrombin time,:oprd~thrombih time, residhal proth?Omlsl~n tir ~ plasiir~ timel :wh61~'~blood C0~'ilt, clot retraciibh: and ':£:F0r the'ithird' ipOrtfdn : 15 patients~were infused Accident:, Room of:The. JohnsHoPkinS Hospital(. All~ were sufferirig, fi'om trauma or a &sease wh~cl~ wou|d normMly bgexpected to, produce a deficit in blood volume, No formal selection procedure was dev:ised tbr"th~se preliminary observations. Patients: .::~~ f e included at the dism'etion of the membd~?df the surgical house staff after exptanafigfi)of the purposes of the investigation and? after. H ES was made available in this' area, The diagnoses ~incltided traumatic hen'/orrh~e, crush injury, peritonitis and gastrointestinal hemorrhage. The patients received either 500 or 1000 ml. of the HES solution* infused via a large bore plastic cannula inserted into an appropriate vein. Arterial btood pressure was carefully recorded before, during and following the infusion. Depending upon the condition of the patient, the infusion of starch was fotlowed either by no further intravenous therapy or by the subsequent administration of plasma or whNe blood, The latter agents were administered, only ~ when it became obvious that continued losses of fluid or brood were occurring, Several. patients required emergency operations and were transferred to the operating room with the HES infusion continuing. ,RESULTS The intravaScular pe~,'sistence of H E S a s a percentage of the mass infused is recorded in "Fable 1, In this case, retention of the starch expander is similar to that'observed f o r clinical dextran "~, and ~is gr~z,4er at 24 .hours (starch 50 to 60%, dextran 30%). The c,iamulatire urinary excretion 0f HES is als0 recorded in Table 1~ These preliminary measurements indicate a significantly 10wer rate of excretion than the following dextran infusions,?
* L o t No. $2681A, kim:Ily supplied by Dr. Marlin Robei'ts, Don Baxter Co., Glendale; California.
HYDROXYETHY.E
STARCH SOLUTION--
I81"
nogen occmTed in Fable:2; The t0w~r neth0di~iS/150 m~ii iim~, pro!hr0mbin tin timewas:noted; ~idual prothromNn Cipiegt:i:Theri~ was no change m me levels o t factors. V Or VII; The platelet, c0um.did, not decrease and* clot ~ retraction was not impaired. The bleeding time :increase~l slightly in one reci~ient. The measikJrements were~all within'the limits of normal with the'2!borderline iexception Of fibrinogenl Determ~nati0ns Of t h e blood group and type revealed no difference ~ter m f u s m n . D,'ect m~d indirect Coombs tests remainednegative; In Table 3:.the wtal s~gns, hemoglobin, hemab ocrit, p£0tein arid e*iectroly,!e d~termlnatlons are dei~led~:and indicate no SigN~cant derangement through~t the~experimems. The 15 pat!ents receiving 6% H ES can be divided into three groups acCordingto their: arterial blood pressure u p o n arrival in the Accident Room. There were 8 patient s Wilh a systolic arterial blood, pressure below 90.mm. H g, All the usual clinical criteriawere present and the causefor the acute volume defic!t was immediately .apparent :(e.g,, :external h e m o r , rhage, peritonitis), An intermediate group was composed of 4 patients, the systolic: arterial blood pressure ranging between 8 0, and. 100 ram. Hg on admission. The pu!se rate was o,ver t00 in all t h e s e patients: Several appeared pale and were thought to be in profound Shock before the blood pressures were obtained. . The final gr0up;of 3 patients ~c0nsisted o f individuals with iNuries, which oftenproduce Shdck if su~eiently severe. An example W, asa alpene:: trating: stab wound of the abd0men or. chest in whichit was not immediatelyapparentwhether a major vesse! had been divided, In :a!!:0f these patients, . t h e initial :systolic ::arterial blood: pressure was over ] 00 ~ d tlie: pulse ~ t e less than 100. •All /patients'..with hypolension :~responded rapidly to:the administration .Of 6 % HES/~ n saline, This.. response w a s Observed,. clinically: by a rise in arterial blood pressure, in:all Cases to 90 ram. Hg:oii. a b 0 v G and by:g?fall jn:ipuise rate, I n several instances, in, palimltS'inlwhdm a Foley catheter:was ~inserted, gutput of urine began witN n !5 minuted o f the admhiisn,atibh o f t h e : s t a r c h solution, The. paiiehts):,ih the thh-d .i:gi'oup i- ,with i n o r m a l blood : i~i,essi]res: exhibited, n O chan.~e in •:: preS~Ure.,:ifoil0wing
182
BALL!NGER
ET AL.
JSR -
Table I.
VoL Vl, No, 4 -
April 1966
ttydroxyetbyl Starch PersiStence Studies PlaSma I)et~rminations
Recipient A Ti me After Infusion
Tothl CIIO
Glucose
Starch
10 minutes 60 minutes 4 hours I0 hours 24 hours
12t4.5 mg. % 1148.0 1130.0 960.0 -931.0
[16 mg. % 103 118 113 I13
1099 mg. % 1045 1012 847 818
100 90 82 64 63
1494.0 1400.0 1310,0 1255.0 1057.0
108 125 120 !25 103
1386 1275 1 I90 1140 954
100 87 67 72 50
% Retention
Recipient B 10 r~inutes 60 minut$s 4 hours 10 hours 24 htiurs
Urine Determinations Time A fter Infus ion
Mg, %
Vol,
Mg. Excreted
Cumulative %
10 minutes A: B:
120
545
136
590
654 802
5.0 6,5
60 minutes A: B~
376 555
120~ 80
45{ 444
9.0 10.0
4 hours
A: 13:
114 333
155 150
177 499
10.5 14~5
10 hours
A:
24 85
440 425
96 361
11.5 17.5
24 hours
A: B:
43 42
160 175
58 3/3
12.0 20,0
Temp.
Vital s i g n s C ontr o I l5 30 45 60
B
p
~
Pt. A
Pt. B
Pt. A
98.6
98,0
164/I08 Infusion 142/90 150/II0 140/110 145/105 Infusion 140/90 140/85
minutes
minutes minutes minutes
15 minutes 30 minutes
~
98.0
98.2 ~
Pulse
•
Pt. B I34/78 Start 120/80 122/90 115/80 120/80 Off 120/85 120/80
Pt. A
Pt. B
68
58
64 64 64 64
64 64 64 64
55 64
68 64
Hematocrit, ftemoglobin and Protein Determinations Patient A:
Hct. %
Hgh. Gm. %
Protein Gm. %
Control 10 minutes I h our 4 hours 10 hours 24 hours
43.5 40,0 40.5 41,5 43.0 43.0
14. O0 12.75 13.35 13,25 i3.60 13,90
6,4 5,5 5.6 6.3 6,6 6,3
51.0 49.5 49,5 53.0 50,0 53,0
16,65 15,20 15,50 17,30 15,90 I7.00
6,3 5.1 5,5 6.1 6,0 6.8
Patient B: Control. I0 minutes I hour 4 hours I0 hours 24 hours
JSR -- Vet, Vl, No. 4 -- April 1966
Table
2..
HYDROXYETHYL
SOLUTFION.
L83
Studies o/CoagulatiOn Before and,After HES Infusion : A Pre
Fibrinog~bn (tyreMne) Thrombin t line Prothromhin time Residual prothrombin time Partial thromboplastin time ~}'hole h Iood clotting time Plat e l e t . c o unt Clot retraction Bleeding time
STARCH
A Post
BPre
233 rag. % i57.mg. % 14 s e c o n d s . 20 s e c o n d s 15 seconds (100%) 17, seconds (80%). 63 s e c o n d s 58' s e c o n d s 80 s e c o n d s ~120.seeonds 13 minutes 16 minutes " 361,000 358,000 •
85% 2 minutes
94% 9 minutes
17a mg. % t4.5 s e c o n d s . 18 seconds (80%) 93 Seconds I10 s e c o n d s 16 minutes. 308,000 72% " 2 minutes
B Post~ 1~5 rag. % 22 s e c o n d s " 20 seconds (65N) 173 s e c o n d s . .125 s e c o n d s • :! 8 mimites 291;000
88% 4. mintltes
Table 3. Electrolyte Determinations (mEq,/L.) Pt. A
Pt..B
100
22,3
26.0.
104
i01
26:8
4.4
104
105
22.0 24.10
4.2
4.0
103
101
20.8
23.o
145
4.4
4.0
104
i03
• 8.o
2S.o
152
3.7•
3.7
105
.104
• 25.a
:28:8
Pt. A
Pt, B
Pt. A.
Pt. B
;Pt, A
Control
149
145
4,4
4.0
104
]O minutes 60 minutes 4 hours 10 hours 24 hours
157
t49
4,4
4.4
t50
159
4.7
t52
'159
155 t47
Time Alter Infusion
COz
C1
K
Na
administration of starch and in two of these p a t i e n t s c e n t r a l venous pressure was moni-tored and no essential alteration w a s n o t e d , The intermediate group responded by.a slight elevation in pressure, all of ttaese patients having a systolic arterial blood pressure over 110-mm, Hg following the Conclusion of t h e adminislration of starch solution, In none of the 15-patients Was an u n t o w a r d . reaction to .the administration of H E S o b s e r v e d clinically nor .was t h e r e gross e v i d e n c e of any Change in the coagulation mechanism, either during the infusion o r later, w h e t h e r a major procedure Was carried out or not, CONCLUSIONS T h e s e preliminary studies .indicate..that 6% H ES solution in salirie is well •tolerated in man when. administered intravenously in amounts up to 1000 n i l . Arterial b l o o d p r e s s u r e is rapidly restored and maintained unless blood o r p l a s m a losses conthme, .The clinical response i s c o m P a r a b l e to that observed following the infusion of dextran, N o clinical e v i d e n c e
• Pt. B
24.6
•
of. untoward reaction, t o 6 % HES- Solution-.in saline was observed. " , .., • Investigations in t w o h e a l t h y .volunteers indicate: that. starch is .retained ;longer than d e x t r a n , and t h a t t h e u r i n a r y - excretion.":Js s o m e w h a t slower: .There w a s a slight d e c r e a s e in fibrinogen in the blood in these two .volun2. teers, F u r t h e r in vitro and:in r i v e Studies o f the. coagulation m e c h a n i s m :.are u n d e r . w a y as~ well as a continuing study o f t h e r e s p o n s e . o f patients in shock to the infusion o f l i E S , .: R E F E R E N C E S
1•, BaIlinger, W..F., I t , Solanke, T[F~i and Thonlpson,. W, .L: The effect of hydroxyethyl starch upon survival of dogs subjemed m hemorrhagic~shock. Surg. GYneC..& Obstet., [22i33, 1966. 2, Me~catf, W,: The.intrinsic method- f0r, serial plasma. . volume determinadoris. J.. Lab, &. Clin. iMed., :58:704,. 1961. 3. Metcalf, i W,, Rousselot;, L: M . , H a r m 0 n , J,' M,, and. Gilbei'tson, F. E.; The determinants of'. |he efficacy of. various expanders in. plasma- Vofume-.expansion arid, :mainlenance in 'normal subjects. Surg. Forum, 4:7:14,: t 954, 4. Watlenius, G . : Renal Clearance tip Dextran as a Measu r e o f Gtomerular Pel:ineabi!~ty. Uppsala,.Almgristland. ) Wiksellsi 1954.