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Is the Cerebral Intra-Arterial Heparin Flushing (IAHF), Beneficial for the Treatment of Ischemic Stroke? BAOJ Neurology

Authors:
Machfoed
Machfoed
Machfoed

Abstract

Since 2012 until now, in Indonesia, there has been an interventional medical procedure that is called brain washing. Without preceded by an in-depth study, this procedure has been applied to the community. The purpose of this procedure is to treat, both acute and chronic ischemic stroke.
Is the Cerebral Intra-Arterial Heparin Flushing (IAHF), Benecial for the Treatment of
Ischemic Stroke?
Moh Hasan Machfoed, et al., BAOJ Neuro 2016 2: 1
2: 013
BAOJ Neuro, an openaccess journal Volume 2; Issue 1; 013
Moh Hasan Machfoed1*, Achmad Firdaus Sani1, Amiruddin Aliah2, Abdul Muis2, Susi Aulina2, Andi Kurnia Bintang2, Ashari Bahar2, Jumraini2,
Mohammad Kurniawan3, Fenny L Yudiarto4 and Fritz Sumantri Usman5
1Department of Neurology, Medical Faculty of Airlangga University, Dr Soetomo Hospital, Surabaya, Indonesia.
2Department of Neurology, Medical Faculty of Hasanuddin University, Dr Wahidin Soediro Husodo Hospital, Makassar, Indonesia.
3Department of Neurology Medical Faculty of University of Indonesia, Dr Cipto Mangoenkusumo Hospital, Jakarta, Indonesia.
4Department of Neurology, Medical Faculty of Diponegoro University, Dr. Kariadi Hospital, Semarang, Indonesia.
5Department of Neurology, Fatmawa Hospital, Jakarta, Indonesia.
BAOJ Neurology
*Corresponding author: Moh Hasan Machfoed, Department of Neu-
rology, Medical Faculty of Airlangga University, Dr Soetomo Hospital,
Surabaya, Indonesia, E-mail: mh.machfoed@gmail.com
Sub Date: May 26, 2016, Acc Date: June 8, 2016, Pub Date: June 8,
2016.
Citaon: Moh Hasan Machfoed, Achmad Firdaus Sani, Amiruddin Aliah,
Abdul Muis, Susi Aulina (2016) Is the Cerebral Intra-Arterial Heparin
Flushing (IAHF), Benecial for the Treatment of Ischemic Stroke?. BAOJ
Neuro 2: 013.
Copyright: © 2016 Moh Hasan Machfoed, et al. This is an open-access
arcle distributed under the terms of the Creave Commons Aribuon
License, which permits unrestricted use, distribuon, and reproducon
in any medium, provided the original author and source are credited.
Review
Abstract
Since 2012 until now, in Indonesia, there has been an interventional
medical procedure that is called brain washing. Without preceded
by an in-depth study, this procedure has been applied to the
community. e purpose of this procedure is to treat, both acute
and chronic ischemic stroke.
In 2013, the American Heart Association (AHA)/American Stroke
Association (ASA), published a Guideline for the Early Management
of Patients with Acute Ischemic Stroke. e managements consist
of the use of recombinant tissue plasminogen activator (rtPA),
endovascular treatment, including intra-arterial brinolysis,
mechanical clot retrieval, acute angioplasty and stenting.
Unlike acute ischemic stroke, until now, no guidelines have been
provided about the management of chronic ischemic stroke that
approved universally. Many studies were conducted in various
ways, but no evidence based studies have been approved yet.
Among them are the uses of medical rehabilitation, stem cells and
others.
e purpose of this article is to review the brain washing procedure,
in accordance with the applied scientic principles and is based on
the standard literatures and guidelines.
Keywords: IAHF; CBF; Ischemic Stroke
Introduction
Stroke is a major cause of mortality and disability worldwide [1].
According to the data of Riskesdas, stroke is the rst rank of death
in Indonesia [2].
Ischemic stroke is caused by a reduction in blood ow to the brain.
Based on the AHA consensus 2013, ischemic stroke is dened as an
episode of neurological dysfunction caused by cerebral infarction
[3]. e disease accounts for 87% of all acute stroke occurrences.
Hence, in the past decade, various studies have been done to
improve the understanding of the pathophysiology, diagnosis, and
therapy of ischemic stroke [4].
Brain washing procedure carried out in Indonesia since 2012 up to
now, is intended as an alternative therapy for treating both acute
and chronic ischemic stroke. e method used in brainwashing is
DSA with IAHF. is procedure is welcomed especially by stroke
patients who experienced residual symptoms and gave burdens to
their families. ey consider this is a new way to treat the disabilities
of stroke patients.
Intra Arterial Heparin Flushing in Cerebral DSA
e journey of angiography of the brain was started in 1927 by Egaz
Moniz, a neurologist from Portugal. is procedure was called as
a Cerebral Arteriography. He performed an injection of contrast
through an internal carotid artery and pictured the contrast that
lled the blood vessel. At the same year, he published his worked in
Review Neurologie journal. Further development, noted the eorts
of neurointervention to nd the right kind of contrast to produce
an optimize picture. e DSA introduced in 1979 by Charles
Mistretta, was a method To view the arterial system through the
injection of intra-arterial contrast that is captured by the x-ray.
Because the feature of the bones had been suppressed, by this
method, the clinicians were more attention to focus on the imagery
of the blood vessels (Usman et al., 2014).
Diagnostic angiography procedures have been done at an early
stage neurointervention. is cerebral DSA becomes a gold stan-
dard as a diagnostic procedure in viewing the picture of the cere-
bral vessels, especially for detect brain/spinal aneurysm or vascular
Citaon: Moh Hasan Machfoed, Achmad Firdaus Sani, Amiruddin Aliah, Abdul Muis, Susi Aulina (2016) Is the Cerebral Intra-Arterial
Heparin Flushing (IAHF), Benecial for the Treatment of Ischemic Stroke?. BAOJ Neuro 2: 013.
Page 2 of 9
BAOJ Neuro, an openaccess journal Volume 2; Issue 1; 013
malformation (Usman et al., 2012). e use of DSA has several ad-
vantages in terms of the following: (1) physical description; (2) de-
tection, accuracy and sensitivity; (3) diagnostic decision makes [5].
In every procedure of cerebral DSA, heparin is used to reduce the
formation of thrombotic coating on the outer surface of the catheter,
clot formation in the catheter, and prevents thromboembolic
complications [6]. A bolus of 40-60 IU/kg of heparin was
administered at the beginning of the procedure, and heparinized
saline solution was used for intermittent ushing of the catheter
(Usman et al, 2012).
In the past ten years, a number of studies about the risk of cerebral
DSA, have shown that the proportion of neurological complications
that occur during the procedure has been 0.05%-2.9%. While the
proportion of non-neurological complications has been 0.05%-
14.7%. e mortality risk has been around 0.05%-0.08% (Usman
et al 2012).
IAAF is a modication of angiography using DSA. Heparin ushing
is done with a catheter guide. e use of heparin either as a bolus or
diluted with saline as the uid ushing of catheters, has long been
known in the procedures of interventional radiology [6].
e occurrence of thrombus formation at the entry site of the
catheter is around 0.4-2.3% e complication that comes in a
thromboembolic formation at angiography does not occur at the
site of entry only, but also at the catheter and the guide wire being
used [7]. Catheter with a specic material such as polyurethane is
less thrombogenic than that of other materials (polyethylene, vinyl
chloride, selastic). Regardless the material used, the catheter must
be soaked with heparin ushing before the angiography [8].
e usage of systemic heparinization can be eective with
combination of intra-arterial direct injection through the catheter
in the beginning of the procedure (3000 U bolus) with intermittent
ushing, using a dilute solution of heparinized saline (5000 U/500
cc saline) [9].
Nowadays, the usage of heparin at the transfemoral cerebral
angiography is given in a variety of dose. Heparin can be given
through either trans-arterial sheath in a continuous ushing (4000
U/L) or through combination of intravenous heparin (100U/
kg) or at maximum dose of 2000U [10]. A larger dose of more
than 6000U/L is given as continuous ushing at the sheath and
intermittent ushing during procedure [11].
Heparin used in interventional procedures like DSA, aims to
reduce the formation of thrombotic coating on the outer surface
of the catheter, clot formation in the catheter, and prevents
thromboembolic complications [6].
Biological Mechanisms of Heparin
Heparin is extraordinary because of its variability. Since it was rst
introduced in 1916 [12], a long-lasting debate has ran regarding its
structure and anticoagulant properties [13, 14]. Chemically, it is a
collection of fragments, each with dierent molecular weights and
dierent modes of action. e most important action of heparin is
its interference in the coagulation cascade [14].
Generally, heparin acts on dierent levels of the coagulation
cascade. Its properties can be dened as anti-inammatory
[15, 16] anticoagulative, antithrombotic, pro-brinolytic, anti-
aggregative, anti-proliferative and anti-ischemic [17, 18]. Recently,
a clear change in the main use of heparin, as well as low-molecular
weight heparins has been advocated representing a shi from
treatment and prophylaxis of deep vein thrombosis to prophylaxis
of thromboembolic disease following vascular, cardiovascular or
orthopedic surgery, treatment of unstable angina and prevention
of acute myocardial infarction [18].
Fig 1: Biological Mechanisms of Heparin
e anticoagulation eect of heparin occurs with the help of a
plasmatic cofactor that is antithrombin (AT). Heparin binds to
AT and forms a stable covalent heparin-AT complexes (H/AT
complexes). e H/AT complexes will activate (the symbol of →)
AT becomes activated AT. en, the activated AT will inactivate
(the symbol of –I) thrombin (factor IIa), activated factor IX (IXa)
and activated factor X (Xa). Finally, inactivated thrombin will
inhibit the change of brinogen into brin that ultimately led to
the brin degradation products.
e anticoagulation eect of heparin occurs with the help of a
plasmatic cofactor. Heparin itself does not have any anticoagulation
properties. e cofactor is antithrombin (AT). Heparin binds
to antithrombin through the unique pentasaccharide sequence
present in its molecule, and forms stable covalent AT-heparin
complexes (AT/H complexes). en, the complexes inactivate both
thrombin (factor IIa) and activated factor X (Xa) at approximately
the same level. Similarly, activated factor IX (IXa) is inhibited by
the AT/H complex. To trigger inhibition of thrombin by the AT/H
complex, not only the pentasaccharide terminal is required, but
additionally the heparin molecule ought to be big enough to create
a bridge between thrombin and antithrombin [19].
As mentioned, antithrombin is a major cofactor of heparin;
however it is not the only one. A high concentration of heparin
potentiates thrombin inhibition in an antithrombin-independent
manner, through another cofactor, known as heparin cofactor II
(HCII). is catalysis is also molecular weight-dependent, as it
requires heparin to carry at least 24 saccharide units [20]. In vivo,
heparin binds to platelets and then, depending on the conditions,
can accelerate or inhibit platelet aggregation. Generally, high
molecular weight heparin with low anity to factor Xa aects
Citaon: Moh Hasan Machfoed, Achmad Firdaus Sani, Amiruddin Aliah, Abdul Muis, Susi Aulina (2016) Is the Cerebral Intra-Arterial
Heparin Flushing (IAHF), Benecial for the Treatment of Ischemic Stroke?. BAOJ Neuro 2: 013.
Page 3 of 9
BAOJ Neuro, an openaccess journal Volume 2; Issue 1; 013
the platelets more than low molecular weight heparins with high
anity to factor Xa.
Heparin increases coagulation times in humans [21]. Moreover, it
increases the vessel wall permeability. e interaction of heparin
with platelets and vascular endothelial cells can contribute
to heparin-induced bleeding in a manner, independent of its
previously described anticoagulant properties. Generally, heparin
disturbs homeostasis through inhibition of coagulation enzymes.
is eect is facilitated by plasma cofactors and through inhibition
of platelets [18].
Heparin is thought to enhance thrombolytic by inhibiting TAFI
(thrombin activatable brinolysis inhibitor), a carboxypeptidase
that inhibits brinolysis. A study of Colucci showed that heparin
is unable to stimulate brinolysis through a TAFI-dependent
mechanism, most likely because of its ineciency in inhibiting
thrombin generation on the clot surface [22].
The Use of Heparin in Clinical Pracces
e main eect of heparin lies in its anticoagulant activity. Heparin
is involved in dierent pathways of the coagulation cascade with
anticoagulant, antithrombotic, probrinolytic, anti-aggregative, as
well as anti-inammatory eects. Moreover, there is a little doubt
about their anti-proliferative and anti-ischemic activity [23].
e American College of Chest Physicians (ACCP), recommended
the use of heparin in the following indications:
1. Prophylaxis of deep vein thrombosis in general surgery,
gynecology and urology, in middle-and high-risk patients,
in total hip replacement and hip arthroplasty, as well as in
neurosurgery.
2. Prophylaxis of VTE in acute myocardial infarction or acute
stroke, and in high-risk patients with multiple disorders
3. Treatment of deep vein thrombosis.
4. Early treatment of an acute myocardial infarction (AMI) using
thrombolytic or in patients at risk of embolization; in AMI
treatment, a combination of heparin with acetyl salicylic acid
(ASA) is recommended.
5. Early treatment of an unstable angina pectoris; Uncomplicated
percutaneous coronary angioplasty (PCA).
6. Treatment of cardio embolic disease aecting large vessels,
especially in connection with risk of VTE.
7. Peripheral vascular reconstructive surgery.
8. Cardio version in patients suering from atrial brillation,
during cardiopulmonary bypass, during intra-arterial balloon
contra-pulsation and hemodialysis.
9. Treatment of cerebral sinus venosus thrombosis.
10. Treatment of aseptic thrombotic endocarditis and embolization.
11. Prophylaxis of patients with disseminated carcinoma and asep-
tic valvular proliferation.
12. Selected cases of disseminated intravascular coagulopathy.
13. Prophylaxis of pediatric patients following Blalock-Taussig
shunt or following Fontan procedure.
14. Prophylaxis in pregnant and post-parturition women with a
history of deep vein thrombosis - replacement of coumarin de-
rivatives, at least till 13 week of gravidity and again in the 3rd
trimester
15. Recommended especially in thrombophilic women with re-
peated abortions, preeclampsia, placental disorders and/or in-
trauterine growth deformity of the fetus.
16. Anticoagulation of blood collected for laboratory analysis and
of catheters and cannulas during regular patient care of several
clinical conditions mentioned above, there is no statement
mentioning that heparin can be used as treatment of acute and
chronic ischemic stroke [24].
Pathophysiological Cascades of Ischemic Stroke
Ischemic stroke may manifest in the form of thrombotic stroke
(large vessel and small vessel types); embolic stroke (with/without
known cardiac and/or arterial factor); systemic hypo perfusion
(Watershed or Border Zone stroke); or venous thrombosis [25].
Irrespective of the cause, compromised vascular supply to the
brain is the primary event in majority (85–90%) of acute stroke.
Low respiratory reserve and complete dependence on aerobic
metabolism make brain tissue particularly vulnerable to eects
of ischemia. A spectrum of severity is generally observed in the
aected region of the brain, owing to the presence of collateral
circulation. us, part of the brain parenchyma (core) undergoes
immediate death, while others may only be partially injured with
potential to recover (penumbra) [25].
Cerebrovascular tissue undergoing ischemia has two layers: (1)
inner core of severe ischemia with blood ow below 10–25%,
displaying necrosis of both neuronal as well as supporting glial
elements; and (2) outer layer of less severe ischemia (penumbra),
supplied by collaterals, and contain cells which can be retrieved by
timely therapeutic intervention.
Following an ischemic event, the centre of the core is perfused
at 10–12 ml/100 g/min or less, while the ischemic area around it
(surrounded by the penumbra) is critically hypoperfused at less
than 18–20 ml/100 g/min and is at risk of dying within hours. In
contrast, the penumbra is perfused at less likely at approximately
60 ml/100 g/min and is less likely to die [26]. e optimal reported
CBF thresholds varied widely, from 14.1 to 35.0 and from 4.8 to 8.4
mL/100 g per minute for penumbra and infarct core, respectively.
Neurons in the penumbra are mostly dysfunctional, but may
recover if reperfused in time [27].
In the area of reduced blood supply, adenosine triphosphate (ATP)
consumption continues despite insucient synthesis, causing total
ATP levels to drop and lactate acidosis to develop with concomitant
loss of ionic homeostasis in neurons. Once this initial step has
taken place, an ischemic cascade follows involving a multimodal
and multicell series of downstream mechanisms [28].
Ischemic stroke can occur due to the obstruction of clot. In the area
Citaon: Moh Hasan Machfoed, Achmad Firdaus Sani, Amiruddin Aliah, Abdul Muis, Susi Aulina (2016) Is the Cerebral Intra-Arterial
Heparin Flushing (IAHF), Benecial for the Treatment of Ischemic Stroke?. BAOJ Neuro 2: 013.
Page 4 of 9
BAOJ Neuro, an openaccess journal Volume 2; Issue 1; 013
of reduced blood supply, there is a decline in energy production
that causes the decrease of ATP level, and followed by lactate
acidosis and ionic homeostasis disruption. Lactate acidosis causes
ion pump failure and ionic imbalance.
e imbalance of ion causes calcium inux into neuronal cells.
e high level of calcium ions within the cells led to the activation
of proteases, degradation of membranes and cause damage to
the mitochondria. Damage to mitochondria causes an increased
production of oxygen free radicals that can damage the nucleus and
cytoskeleton. Ultimately, these multimodal cascades will result in a
complex mix of neuronal death comprising of necrosis, apoptosis,
and autophagy.
Severe cerebral ischemia leads to a loss of e energy stores resulting
in ionic imbalance and neurotransmitter release and inhibition of
reuptake. It is especially the case for glutamate, the main excitotoxic
neurotransmitter. Glutamate binds to ion tropic N-Methyl-
D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptors promoting a major
inux of calcium. is calcium overload triggers phospholipases
and proteases that degrade essential membranes and proteins. e
broken cell’s membrane, it becomes more permeable, and more
ions and harmful chemicals ow into the cell. Mitochondria break
down, releasing toxins and apoptotic factors into the cell. e
caspase-dependent apoptosis cascade is initiated, causing cells to
commit suicide.” In addition, the glutamate receptors promote an
excessive sodium and water inux with concomitant cell swelling,
edema and shrinking of extracellular space. Massive calcium inux
activates a catabolic process mediated by proteases, lipases, and
nucleases [29].
High calcium, sodium, and adenosine diphosphate (ADP) levels
in ischemic cells stimulate excessive mitochondrial oxygen radical
production within other sources of free radicals production such
as prostaglandin synthesis and degradation of hypoxanthine. ese
reactive oxygen species (ROS) directly damage lipids, proteins,
nucleic acid, and carbohydrates [30].
Downstream of free radicals, other neuronal death mechanisms
will also be induced involving, e.g. mitochondrial transition pore
formation [31], the lipoxygenase cascade [32], the activation of poly
ADP-ribose polymerase (PARP) [33] and amplied ionic imbalance
via secondary recruitment of calcium-permeable transient
receptor potential ion (TRPM) channels [34]. Furthermore, ROS
and reactive nitrogen species also has the potential of modifying
endogenous functions of proteins, which may be neuroprotective
[35]. Ultimately, these multimodal cascades will result in a
complex mix of neuronal death comprising necrosis, apoptosis,
and autophagy [36], Fig 2.
e post-stroke angiogenesis is the key step for recovery aer
ischemia and provide the critical neurovascular substrates for
neuronal remodeling aer stroke. In the process of angiogenesis,
loss of vascular integrity and degradation of cell matrix are crucial
initiating steps. Matrix metalloproteinase (MMPs) degrade the
extracellular matrix and prepare the stage for growth factors and
guidance molecules [37].
is forms the basis of current protocols which favor early
pharmacologic intervention for re-canalization of occluded vessel.
It will not only salvage neuronal and glial cells from penumbra,
but also glial cells from the central ischemic core zone, thereby
markedly limiting the size of infracted tissue [38].
Fig 2: Pathophysiological Cascades of Ischemic Stroke
Citaon: Moh Hasan Machfoed, Achmad Firdaus Sani, Amiruddin Aliah, Abdul Muis, Susi Aulina (2016) Is the Cerebral Intra-Arterial
Heparin Flushing (IAHF), Benecial for the Treatment of Ischemic Stroke?. BAOJ Neuro 2: 013.
Page 5 of 9
BAOJ Neuro, an openaccess journal Volume 2; Issue 1; 013
CBF in Ischemic Stroke
CBF is the blood supply to the brain tissue, which plays a role
in providing oxygen and nutrients. When the blood supply is
interrupted, there will be a disruption of brain function that would
cause morbidity and mortality (Detre et al., 2012).
Under normal conditions, the CBF is regulated by auto regulation
mechanism of the brain. e CBF is maintained in the range of 60
to 100mL/100g/ min, with a central perfusion pressure (CPP) in
the range of 60 to 160 mmHg. Auto regulation ability will disappear
when blood pressure is less/more than 60 to 160 mmHg. In this
condition, CBF became dependent on mean arterial pressure
(MAP) [39].
A decrease in CBF will be compensated by an increase in oxygen
extraction. When CBF drops below a certain value, the ability to
increase oxygen extraction will be lost. is leads to functional,
biochemical, and structural changes, which ultimately results in
irreversible neuronal cell death [27]. e brain has a high demand
for oxygen and glucose to energy production. is high metabolic
demand causes the brain to be vulnerable to the decline of CBF [40].
CBF disruption either focal or global, results in limited fulllment
of the substrate, causing changes in brain activity that led to the
failure of energy production [41]. Animal studies indicated that
some time aer ischemia, the concentration of glucose, glycogen,
adenosine triphosphate (ATP) and phosphocreatinine (PCr)
decrease rapidly, and almost completely disappear within 10-12
minutes of ischemia [40].
Protein synthesis is inhibited at CBF less than 50ml/100g/min and
obstacles complete at the level of CBF below 35ml/100g/min. e
use of sugar and energy metabolism increases at this level, but it
experiences a sharp decline if CBF level below 25ml/100g/min. In
this circumstance occurs an anaerobic glycolysis and edema [40].
Damage due to induced sodium ions, causes an increase in cytosolic
calcium, ATP depletion, and the release of glutamate. Glutamate is a
neurotransmitter that activates destroyed enzymes like lipase, pro-
tease, and nuclease causing neuronal tissue breakdown. Free radi-
cal formation also increases in the initial period aer ischemia [40].
A decrease in CBF below 16-18 ml/100g/min results in a decrease
of the electrical activity of either spontaneous or spark. At this
level, the function of electrical neuronal lost (electrical failure)
[42]. When CBF decreases into 10-12ml/100g/min, an anoxic
depolarization will happen. is depolarization will be followed
by ion hemostasis disorders, changes in intra and extracellular
electrolyte composition, decreased ATP and malfunction of
membrane (membrane failure). e failure of membrane function
causes the decreased of extracellular sodium, chloride and calcium
as well as a decrease of potassium eux to the extracellular and
resulting in an increase in intracellular calcium by up to 25% [40, 42].
Ischemic stroke is caused by a reduction in blood ow to the brain.
Hence, the decrease in CBF has received an eective answer:
accelerated reperfusion via thrombolytic using rt-PA is associated
with an improved clinical outcome. is achievement is now
routinely transferred to practice. is ease of translation is due to
the fact that the underlying conceptual model is simple: an arterial
occlusion decreases CBF. So an eective treatment should increase
CBF [43].
Restoring CBF is an obvious and primary goal. But ischemia–
reperfusion itself can also set o numerous cascades of secondary
injury. Reactive radicals will be generated, blood–brain barrier
integrity may be compromised, and multimodal neuronal death
processes composed of programmed necrosis, apoptosis, and
autophagy may still continue unabated [43].
Treatment of Acute Ischemic Stroke
In 2013, the American Heart Association (AHA)/American
Stroke Association (ASA) published a Guideline for the Early
Management of Patients with Acute Ischemic Stroke. e purpose
of the paper was to present an overview of the current evidence
and management recommendations for evaluation and treatment
of adults with acute ischemic stroke, within the rst 48 hours from
stroke onset. e goal of these guidelines is to limit the morbidity
and mortality associated with stroke. e guideline discusses early
stroke evaluation and general medical care, as well as ischemic
stroke, specic interventions such as reperfusion strategies, and
general physiological optimization for cerebral resuscitation [44].
Intravenous administration of rtPA (IV rtPA) remains the only
FDA approved pharmacological therapy for treatment of patients
with acute ischemic stroke [45]. Its use is associated with improved
outcomes for a broad spectrum of patients who can be treated
within 3 hours of the last known well time before symptom onset
and a mildly more selective spectrum of patients who can be
treated between 3 and 4.5 hours of the last known well time. Most
importantly, earlier treatment is more likely to result in a favorable
outcome. Patients within 3 hours of onset with major strokes
(NIHSS score >22) have a very poor prognosis, but some positive
treatment eect with IV rtPA remains. Treatment with intravenous
rtPA is associated with increased rates of intracranial hemorrhage,
which may be fatal [46].
A number of techniques and devices are under study in several
trials. Although several devices have resulted in recanalization
with acceptable safety, direct comparative data between the devices
are not available. e combination of pharmacological brinolysis
and mechanical thrombectomy appears to have the highest rate
of recanalization without any dierence in rate of intracranial
hemorrhage. Consistently, recanalization rates in trials exceed
rates of the best clinical outcomes, which suggest the importance
of patient selection independent of the technical eectiveness of
thrombectomy devices. As with the intra-arterial administration of
brinolytics, the use of these devices will be limited to those CSCs
that have the resources and physician expertise to perform these
procedures safely [46]. Lastly, as with intravenous brinolysis, time
is brain for all forms of endovascular reperfusion, and all eorts must
be made to reduce time to reperfusion, because the likelihood of
favorable outcome is directly linked to the time to reperfusion [47].
e International Stroke Trial (IST) tested subcutaneously
administered unfractionated heparin (UFH) in doses of 5000
or 25 000 U/d started within 48 hours of stroke (International
Citaon: Moh Hasan Machfoed, Achmad Firdaus Sani, Amiruddin Aliah, Abdul Muis, Susi Aulina (2016) Is the Cerebral Intra-Arterial
Heparin Flushing (IAHF), Benecial for the Treatment of Ischemic Stroke?. BAOJ Neuro 2: 013.
Page 6 of 9
BAOJ Neuro, an openaccess journal Volume 2; Issue 1; 013
Stroke Trial Collaborative Group, 1997). Dual randomization
meant that approximately half of the patients receiving heparin
were also prescribed aspirin. Neither monitoring of the level of
anticoagulation nor adjustment of dosages in response to levels
of anticoagulation was performed. In addition, some patients
did not have a brain imaging study before entry into the trial,
and thus, some patients with hemorrhagic stroke may have been
enrolled. Although heparin was eective in lowering the risk of
early recurrent stroke, an increased rate of bleeding complications
negated this benet. A subgroup analysis did not nd a benet
from heparin in lowering the risk of recurrent stroke among those
patients with atrial brillation [48]. Other studies of anticoagulation
similarly failed to show denitive benet. A Swedish study failed to
demonstrate a benet from heparin for treatment of patients with
progressing stroke [49].
Eriksson examined “Discarding Heparins as Treatment for Progres-
sive Stroke in Sweden 2001 to 2008”. e conclusion of the study
stated that there is no immediate, stepwise eect of new scientic
information and national guidelines on clinical practice concern-
ing heparin as treatment for progressive ischemic stroke [50].
Chung studied trends in the intravenous heparin use during a
6-year time period and the potential inuence of clinical guidelines
in national language on intravenous heparin for the treatment of
acute ischemic stroke administration in Korea. e conclusions
showed that the use of intravenous heparin for acute ischemic
stroke treatment has decreased in Korea, and this change may
be attributable to the spread and successful implementation of
regional clinical practice guidelines [51].
Treatment of Chronic Ischemic Stroke
Up to now, have been no studies or guidelines that are universally
agree concerning the treatment of chronic ischemic stroke. Several
fragmented studies mentioned that a particular method can
improve the clinical condition of patients with chronic ischemic
stroke [52]. Among them are the uses of medical rehabilitation,
stem cells and others.
Approximately one third of heparins molecular weight is
represented by a unique pentasaccharide that is necessary for
binding to antithrombin, accelerating thrombin and activated
factor X inhibition [53]. An additional anticoagulant activity of
heparin goes through heparin cofactor II activation, which is less
potent and generally requires higher systemic concentrations of
heparin. e remainder of the heparin molecule does not possess
any anticoagulant properties.
Stroke treatments need to promote neuroplasticity to improve
motor function. Physical exercise is considered as a major
candidate for ultimately promoting neural plasticity and could be
used for dierent purposes in human. First, acute exercise could
be used as a diagnostic tool to understand new neural mechanisms
underlying stroke physiopathology. Secondly, it is well established
that physical exercise training is advised as an eective rehabilitation
tool. Indeed, it reduces inammatory processes and apoptotic
marker expression, promotes brain angiogenesis and expression
of some growth factors, and improves the activation of aected
muscles during exercise. Nevertheless, exercise training might also
aggravate sensor motor decits and brain injury depending on the
chosen exercise parameters. For the last few years, physical training
has been combined with pharmacological treatments to accentuate
and/or accelerate benecial neural and motor eects. Finally,
physical exercise might also be considered as a major nonpharma-
cological preventive strategy that provides neuroprotective eects
reducing adverse eects of brain ischemia [52].
Previous data suggest that the amount and aerobic intensity of step-
ping training may improve walking post stroke. Recent animal and
human studies suggest that training in challenging and variable
contexts can also improve locomotors function. Such practice may
elicit substantial stepping errors, although alterations in locomotors
strategies to correct these errors could lead to improved walking
ability. e study of Holleran et al suggests that stepping training at
high aerobic intensities in variable contexts was tolerated by partic-
ipants post stroke, with signicant locomotors improvements [54].
e regenerative potential of brain has led to emerging therapies
that can cure clinico-motor decits aer neurological diseases. Bone
marrow mononuclear cell therapy is a great hope to mankind as
these cells are feasible, multipotent and aid in neurofunctional gains
in stroke patients. Bhasin evaluated safety, feasibility and ecacy
of autologous mononuclear (MNC) stem cell transplantation in
patients with chronic ischemic stroke (CIS) using clinical scores
and functional imaging (fMRI and DTI). e result showed that
there was an increased number of cluster activation of Brodmann
areas BA 4, BA 6 post stem cell infusion compared to controls
indicating neural plasticity. Cell therapy is safe and feasible which
may facilitate restoration of function in CIS [55].
Cell therapy is emerging as a viable therapy to restore neurological
function aer stroke. Many types of stem/progenitor cells from
dierent sources have been explored for their feasibility and
ecacy for the treatment of stroke. Transplanted cells not only
have the potential to replace the lost circuitry, but also produce
growth and tropic factors, or stimulate the release of such factors
from host brain cells, thereby enhancing endogenous brain repair
processes. Although stem/progenitor cells have shown a promising
role in ischemic stroke in experimental studies as well as initial
clinical pilot studies, cellular therapy is still at an early stage in
humans. Many critical issues need to be addressed including the
therapeutic time window, cell type selection, delivery route, and
in vivo monitoring of their migration pattern. Liau concluded that
cell therapies can be used as a neurorestorative regimen in the
management of chronic ischemic stroke [56].
Ancoagulants Treatment in Ischemic Stroke
Here are the recommendations of the AHA/ASA Guidelines for the
Early Management of Patients with Acute Ischemic Stroke:
1. At present, the usefulness of argatroban or other thrombin
inhibitors for treatment of patients with acute ischemic stroke is
not well established.
2. e usefulness of urgent anticoagulation in patients with severe
Citaon: Moh Hasan Machfoed, Achmad Firdaus Sani, Amiruddin Aliah, Abdul Muis, Susi Aulina (2016) Is the Cerebral Intra-Arterial
Heparin Flushing (IAHF), Benecial for the Treatment of Ischemic Stroke?. BAOJ Neuro 2: 013.
Page 7 of 9
BAOJ Neuro, an openaccess journal Volume 2; Issue 1; 013
stenosis of an internal carotid artery ipsilateral to an ischemic
stroke is not well established.
3. Urgent anticoagulation, with the goal of preventing early
recurrent stroke, halting neurological worsening, or improving
outcomes aer acute ischemic stroke, is not recommended for
treatment of patients with acute ischemic stroke.
4. Urgent anticoagulation for the management of noncerebrovascular
conditions is not recommended for patients with moderate-to-
severe strokes because of an increased risk of serious intracranial
hemorrhagic complications.
5. Initiation of anticoagulant therapy within 24 hours of treatment
with intravenous rtPA is not recommended [44].
Summary
Intra Arterial Heparin Flushing in Cerebral DSA
In every procedure of cerebral DSA, heparin is used to reduce the
formation of thrombotic coating, and prevents thromboembolic
complications. Without being followed by other procedures,
such as stenting or coiling, then the act of cerebral DSA is only a
diagnostic not therapeutic procedure. No references mentioning
that the cerebral angiography with heparin can be used for the
management of ischemic stroke either acute or chronic [6, 7, 8, 9,
11, 57].
Biological Mechanisms of Heparin
ere is a change in the main use of heparin, from treatment
and prophylaxis of deep vein thrombosis to prophylaxis of
thromboembolic disease following vascular, cardiovascular or
orthopedic surgery, treatment of unstable angina and prevention
of acute myocardial infarction. Heparin was not able to destroy the
clot that occurs in acute and chronic ischemic stroke [18].
Treatment of Ischemic Stroke
e AHA/ASA guidelines (2013), recommended that rtPA can be
used in the treatment of acute ischemic stroke. Heparin was not
benecial in lowering the risk of recurrent stroke among those
patients with atrial brillation. Heparin failed for treatment of
patients with progressing stroke. ere was no immediate, stepwise
eect of new scientic information and national guidelines on
clinical practice concerning heparin as treatment for progressive
ischemic stroke. e use of heparin for acute ischemic stroke
treatment has decreased in Korea, and this change may be
attributable to the successful implementation of regional clinical
practice guidelines [44, 48, 49, 50, 51]. ere were no studies
supporting that heparin was useful for the treatment of acute and
chronic ischemic stroke [52, 54, 55, 56].
Conclusion
From all discussion above, it is concluded that IAHF in brain
washing procedure is not in accordance with the applied scientic
principles and does not have any literatures and guidelines that
support the benets of heparin in acute and chronic ischemic
stroke.
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Despite the global impact and advances in understanding the pathophysiology of cerebrovascular diseases, the term "stroke" is not consistently defined in clinical practice, in clinical research, or in assessments of the public health. The classic definition is mainly clinical and does not account for advances in science and technology. The Stroke Council of the American Heart Association/American Stroke Association convened a writing group to develop an expert consensus document for an updated definition of stroke for the 21st century. Central nervous system infarction is defined as brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury. Central nervous system infarction occurs over a clinical spectrum: Ischemic stroke specifically refers to central nervous system infarction accompanied by overt symptoms, while silent infarction by definition causes no known symptoms. Stroke also broadly includes intracerebral hemorrhage and subarachnoid hemorrhage. The updated definition of stroke incorporates clinical and tissue criteria and can be incorporated into practice, research, and assessments of the public health.
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Previous data suggest that the amount and aerobic intensity of stepping training may improve walking poststroke. Recent animal and human studies suggest that training in challenging and variable contexts can also improve locomotor function. Such practice may elicit substantial stepping errors, although alterations in locomotor strategies to correct these errors could lead to improved walking ability. This unblinded pilot study was designed to evaluate the feasibility and preliminary efficacy of providing stepping practice in variable, challenging contexts (tasks and environments) at high aerobic intensities in participants >6 months and 1-6 months post-stroke. A total of 25 participants (gait speeds <0.9 m/s with no more than moderate assistance) participated in ≤40 training sessions (duration of 1 hour) within 10 weeks. Stepping training in variable, challenging contexts was performed at 70% to 80% heart rate reserve, with feasibility measures of total steps/session, ability to achieve targeted intensities, patient tolerance, dropouts, and adverse events. Gait speed, symmetry, and 6-minute walk were measured every 4 to 5 weeks or 20 sessions, with a 3-month follow-up (F/U). In all, 22 participants completed ≥4 training weeks, averaging 2887 ± 780 steps/session over 36 ± 5.8 sessions. Self-selected (0.38 ± 0.27 to 0.66 ± 0.35 m/s) and fastest speed (0.51 ± 0.40 to 0.99 ± 0.58 m/s), paretic single-limb stance (20% ± 5.9% to 25% ± 6.4%), and 6-minute walk (141 ± 99 to 260 ± 146 m) improved significantly at posttraining. This preliminary study suggests that stepping training at high aerobic intensities in variable contexts was tolerated by participants poststroke, with significant locomotor improvements. Future studies should delineate the relative contributions of amount, intensity, and variability of stepping training to maximize outcomes.