SIMPLE AND SAFE HEPARIN REGIMEN
FOR ACUTE ISCHAEMIA
P. R. M. BITTENCOURT * S. PADILHA *
S. MAZER **
T h e role of acute a n t i c o a g u l a t i o n in ischaemic c e r e b r o v a s c u l a r disease is complex. It is well established w i t h respect t o p r e v e n t i n g further embolization in cardiogenic cerebral e m b o l i s m4 , 8 , 1 1
. W h e n t h e r e is occlusive disease of t h e s u p r a - a o r t i c or intra-cranial vessels p r o d u c i n g thromboembolism of t h e brain, and specially in cases in which s u r g e r y is n o t recommended, t h e risk/benefit ratio is not well defined. N o controlled s t u d i e s of t h e efficacy or of t h e r a t e of complications of acute a n t i c o a g u l a t i o n in c e r e b r o - v a s c u l a r disease have been r e p o r t e d since t h e a d v e n t of computerized axial t o m o g r a p h y . T h e earlier studies became obsolete since it became clear t h a t t h i s method d e t e c t s ischaemic a n d h a e m o r r h a g i c infarction a s well a s h e m a t o m a s , avoiding use of a n t i c o a g u l a n t s in h a e m o r r h a g i c d i s e a s e1 2
. Although aspirin h a s been d e m o n s t r a t e d to be efficient in t h e prevention of recurrence of t r a n s i e n t ischaemic a t t a c k s 5, 8
, t h e physician a d m i t t i n g a patient with the recent onset of a s t a b l e or a fluctuating vascular neurological deficit will be in difficulty to decide on t h e utilization of anticoagulation. T r a n s i e n t ischaemic a t t a c k s of recent onset, for example, m a y be followed by a completed s t r o k e , t h e g r e a t e s t risk o c c u r r i n g in the first w e e k1 0
. T h e time between admission a n d t h e completion of t h e full w o r k up needed by such p a t i e n t s , which includes c a r d i a c a n d v a s c u l a r investigations not immediately available a t all hospitals, is usually of t h e o r d e r of d a y s r a t h e r than hours. On t h e other hand computerized axial t o m o g r a p h y is becoming very common all over t h e world a n d m a y be carried out soon after t h e patient is admitted, w i t h o u t a n y w o r s e n i n g of p r o g n o s i s .
In this study w e have evaluated t h e risk of complications of a simple method of administration of heparin to p a t i e n t s with acute ischaemic c e r e b r o -vascular disease, specifically with respect to a g e a n d arterial hypertension, which have been t radi t i ona lly considered to be c o n t r a - i n d i c a t i o n s for a n t i c o a g u l a n t use. Heparin regimen — T h e clearence of heparin from t h e blood s t r e a m is exponential a n d d o s e - d e p e n d e n t . T h e half-life a t d o s a g e s of 100 IU per kilogram is a r o u n d 152 minutes 7. It t h u s follows t h a t intermittent regimens in which 5000 IU a r e given at i n t e r v a l s of 4 or 6 h o u r s will p r o d u c e a very high blood level for between one a n d t w o h o u r s , w h e n the coagulation time is infinite
a n d the risk is very high 7. In fact it h a s been d e m o n s t r a t e d t h a t the frequency
of serious bleeding d u r i n g intermittent administration is a b o v e 1 0 %
1 3. In
con-tinuous infusion the p e a k s in blood level are avoided, d e c r e a s i n g s e r i o u s bleeding
to a b o u t 1 %
13. Deykin reviewed a n u m b e r of s t u d i e s on the complications
and efficacy of heparin r e g i m e n s
2. In a prospective s t u d y carried out by his
g r o u p 72 p a t i e n t s w e r e given intermittent i n t r a v e n o u s injection r e g u l a t e d by
activated p a r t i a l t h r o m b o p l a s t i n time ( A P T T ) ; 68 p a t i e n t s w e r e given
inter-mittent i n t r a v e n o u s injection with fixed d o s e s ; a further g r o u p of 69 p a t i e n t s
were given intravenous infusion with the dose r e g u l a t e d by A P T T . T h e mean
heparin dose w a s 3 1 7 0 0 I U in the first g r o u p , 3 5 6 0 0 I U in the second g r o u p
a n d 2 4 5 0 0 I U in the third g r o u p . Recurrences occurred in one case in each
g r o u p . Major bleeding complications o c c u r r e d in 6 p a t i e n t s in the first g r o u p ,
7 in the second and one patient in the third g r o u p . M e a s u r i n g the efficacy of
anti-coagulation by the recurrence r a t e t h e r e is no difference in the t h r e e
regimens. Considering the number of bleeding complications as evidence of
p e a k s of intermittent anticoagulation c o n t i n u o u s infusion is the better regimen.
It should be emphasized t h a t t h e r e is a g r e a t difference of dose between the
three regimens, and t h a t the lesser n u m b e r of complications with continuous
infusion m a y also be related to the dose utilized, which w a s % of the two
other regimens. Since infusion p u m p s a r e not generally avaiable in general
hospitals in less developed countries w e decided to use a safe and simple
a p p r o a c h , i.e., to give intravenously a total dose of 20000 IU daily, divided in
doses of 2500 IU every three h o u r s .
P A T I E N T S A N D METHODS
selective catheterization of supra-aortic branches or other t e s t s were done as necessary Blood pressure w a s monitored every three hours. An effort w a s made to control blood pressure progressively over a period of a few hours after initiation of heparin.
The anticoagulation r e g i m e n w a s 2500 I U given intravenously every three hours until the clinical picture w a s defined. I n case thromboembolic phenomena persisted the dose w a s raised to 5000 I U every 4 hours. If no surgically correctable source of emboli w a s detected, and the patient w a s thought to have made an improvement on heparin, he w a s put on coumarin anticoagulants.
R E S U L T S
A total of 27 males and 23 females entered the study. Their age w a s 57 ± 14 (mean ± standard deviation) years w i t h a range of 23 to 83 years. Their clinical presentations were recurrent severe transient ischaemic attacks in 11 cases and recent or progressive cerebral infarction in 39. T h e presumed d i a g n o s i s were cardiogenic embolism in 22 c a s e s ; carotid occlusive disease in 8 c a s e s ; carotid plaques (proved by angiography) in three c a s e s ; fat embolism in one case and intra-cranial thromboembolic disease in 16 cases. The cerebral arterial zones involved as determined clinically or b y computerized tomography w e r e t h e left m i d d l e cerebral in 21 cases; the right middle cerebral in 12; the posterior cerebrals (right -f left) in 4; the basilar territory in 5 and multiple arterial zones in 8 cases. Of the 22 patients w i t h embolization of cardiac origin there w a s one w i t h complete atrial-ventricular block, one w i t h isolated atrial fibrillation and one with isolated ventricular premature contractions. There were t w o patients w i t h atrial fibrillation and cardiomegaly; t w o patients w i t h atrial fibrillation, ventricular premature contractions and cardiomegaly; t w o patients w i t h cardiomegaly and mixed premature contractions; and 8 patients w i t h cardiomegaly only. There w a s one patient with mitral stenosis w i t h ectopic beats, and another patient with aortic insufficiency and stenosis. One patient had Chagas' d i s e a s e and a further patient had an aneurism of the left ventricle. Thirty of the patients had computerized tomography before starting heparin and 17 after. In t w o patients computerized axial tomography w a s not carried out because of an early death, and in one because a technical problem delayed the exam until the patient had had arteriography and surgical excision of a carotid plaque. Of the 6 patients w h o had angiography carotid plaques were demonstrated in three. One patient had aortography and ventriculography w i t h the demonstration of a ruptured tendinous chord which w a s corrected surgically. T w o patients had coronary and ventricular s t u d i e s but were considered inoperable. T w o patients had ecocardiograms which were non-contributory. Three patients had holter monitoring of electrocardiogram w h i c h showed arrythmias. One patient had a lumbar puncture which showed a clear cerebro-spinal fluid. The initial blood pressure w a s below 160/95 in 33 patients, below 180/100 in 10 patients, below 190/130 in 3, and above 190/131 in 4 cases.
origin had the severity and number of episodes decreased by this regimen, but they only ceased completely after t h e dosage w a s increased to 30000 I U daily. One patient with cerebral fat embolism had a deep venous thrombosis in the left lower limb of traumatic origin while on the 20000 I U daily regimen.
There were no bleeding complications. Of 48 patients who survived until a definite clinical situation w a s achieved, 35 w e r e t h o u g h t to be improved by heparin and were started on coumarin anticoagulants. Of these, 21 were of the cardiogenic embolism group.
COMMENTS
Full immediate a n t i c o a g u l a t i o n in cardiogenic cerebral embolism h a s been
d e m o n s t r a t e d to be safe if a h a e m o r r h a g i c component is excluded by
compu-terized axial t o m o g r a p h y 9. T h e p r e s e n t s t u d y s u p p o r t s such findings since
t h e r e w e r e no complications in 22 p a t i e n t s w i t h cardiogenic cerebral embolism.
With respect to the efficacy of t h e regimen these r e s u l t s confirm previous
findings 2,13 t h a t close m o n i t o r i n g of c o a g u l a t i o n t e s t s m a y not be critical,
since in the t w o cases in w h o m further cardiogenic embolization w a s diagnosed
clinically r a i s i n g of the dose of h e p a r i n w a s efficient in t e r m i n a t i n g the episodes.
T h e efficacy of the regimen a d v o c a t e d here, i.e., 20000 IU daily divided
in three hourly i n t r a v e n o u s injections is more difficult to evaluate in the
r e m a i n i n g 28 patients with cerebral ischaemia due to s u p r a - a o r t i c or intra-cranial
thrombo-embolic phenomena, because the r a t e of re-embolization or the course
of the neurological deficit is less predictable. T h e risk of n o n - c a r d i a c r e c u r r e n t
t r a n s i e n t ischaemic a t t a c k s developing into completed s t r o k e s is highest in the
first week 10. None of the p a t i e n t s w i t h t r a n s i e n t ischaemic a t t a c k s in this
study developed a completed s t r o k e while on heparin. In fact the only v a s c u l a r
event in non-cardiogenic embolism w a s deep v e n o u s t h r o m b o s i s in a severely
fractured lower limb. At any r a t e t h e regimen p r o p o s e d here did not produce
major bleeding complications a s r e p o r t e d in p r e v i o u s studies 3,6,14
a n d clotting m o n i t o r i n g a r e available routinely to the l a r g e n u m b e r s of such
p a t i e n t s admitted to general hospitals.
SUMMARY
T h e risk/benefit ratio of acute anticoagulation in ischaemic cerebro-vascular
disease is not clearly established. A simple a n d safe intermittent i n t r a v e n o u s
heparin regimen (20000 IU daily) w a s used prospectively in 50 p a t i e n t s of
57 ± 14 (m ± s d ) y e a r s of a g e w h o s e blood p r e s s u r e s r a n g e d from normal
to severe hypertension. T w e n t y - t w o p a t i e n t s h a d cardiogenic embolism and the
remaining h a d r e c u r r e n t severe t r a n s i e n t ischaemic a t t a c k s of recent onset or
progressive cerebral infarcts. T i m e of e x p o s u r e to heparin w a s 6.4 ± 4 ( m ± s d )
d a y s . T w o p a t i e n t s had r e c u r r e n c e s of cerebral thromboembolism and none
had bleeding complications. T h i s is a safe a n d efficient method of a n t i c o a g u
-lation for p a t i e n t s with cerebral ischaemia w h e n continuous infusion of heparin
or close monitoring of clotting times a r e not used routinely.
RESUMO
Regime simples e seguro de heparina para isquemia aguda.
A r e l a ç ã o entre risco e benefício de a n t i c o a g u l a ç ã o imediata em doença
c e r e b r o v a s c u l a r isquêmica é discutível. Um r e g i m e simples e s e g u r o de a d m i
-n i s t r a ç ã o e -n d o v e -n o s a de h e p a r i -n a (20000 I U / d i a ) foi utilizado prospectivame-nte
em 50 pacientes d e 57 ± 14 (média ± desvio p a d r ã o ) a n o s de idade cujas p r e s
-sões a r t e r i a i s v a r i a r a m de n o r m a i s a h i p e r t e n s ã o severa. Vinte e dois d o s
pacientes sofreram embolia cerebral cardiogênica e o r e s t a n t e a t a q u e s
isquê-micos t r a n s i t ó r i o s de início recente ou infartos c e r e b r a i s p r o g r e s s i v o s . O tempo
de exposição à h e p a r i n a foi de 6,4 ± 4 (média ± desvio p a d r ã o ) dias. Dois
pacientes tiveram recorrência de t r o m b o e m b o l i s m o cerebral e nenhum teve
complicações h e m o r r á g i c a s . Este p a r e c e ser um método s e g u r o e eficiente de a n t i
-c o a g u l a ç ã o p a r a pa-cientes -com isquemia -cerebral a g u d a , q u a n d o infusão -contínua
de h e p a r i n a ou monitorização de t e s t e s de c o a g u l a ç ã o frequente n ã o s ã o u s a d o s
rotineiramente.
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