Dissertation on
“SERUM MAGNESIUM AND POTASSIUM LEVELS AT ADMISSION AS PROGNOSTIC MARKERS IN
ACUTE CEREBROVASCULAR ACCIDENTS”
Submitted in partial fulfillment for the Degree of
M.D GENERAL MEDICINE BRANCH – I
THE TAMIL NADU DR.M.G.R MEDICAL UNIVERSITY CHENNAI
INSTITUE OF INTERNAL MEDICINE
MADRAS MEDICAL COLLEGE CHENNAI – 600003
APRIL 2018
CERTIFICATE
This is to certify that the dissertation titled “SERUM MAGNESIUM AND POTASSIUM LEVELS AT ADMISSION AS PROGNOSTIC MARKERS IN ACUTE CEREBROVASCULAR ACCIDENTS” is the bonafide original work done by DR. LAVANYA .K, post graduate student, Institute of Internal medicine, Madras medical college, Chennai-3, in partial fulfillment of the University Rules and Regulations for the award of MD Branch -1 General Medicine, under our guidance and supervision, during the academic year 2015-2018.
Prof. Dr.S.MAYILVAHANAN M.D., Director & Professor,
Institute of Internal Medicine, Madras Medical College &
RGGGH, Chennai – 600003.
Prof. Dr.K.S.CHENTHIL M.D., Professor of Medicine,
Institute of Internal Medicine, Madras Medical College &
RGGGH, Chennai – 600003.
Prof. Dr. NARAYANA BABU, M.D.
DEAN,
Madras Medical College & Rajiv Gandhi Government General Hospital, Chennai 600 003.
DECLARATION
I, Dr. LAVANYA .K, solemnly declare that dissertation titled
“SERUM MAGNESIUM AND POTASSIUM LEVELS AT ADMISSION AS PROGNOSTIC MARKERS IN ACUTE CEREBROVASCULAR ACCIDENTS” is a bonafide work done by me at Madras Medical College and Rajiv Gandhi Government General Hospital, Chennai-3 during February 2017 to July 2017 under the guidance and supervision of my unit chief Prof. Dr.K.S.CHENTHIL M.D, Professor of Medicine, Madras Medical College and Rajiv Gandhi Government General Hospital, Chennai.
This dissertation is submitted to Tamilnadu Dr. M.G.R Medical University, towards partial fulfillment of requirement for the award of M.D.
DEGREE IN GENERAL MEDICINE BRANCH-I.
Place: Chennai -03 Dr. LAVANYA .K
Date: MD General Medicine,
Post Graduate,
Institute of Internal Medicine, Madras Medical College, Chennai – 03
ACKNOWLEDGEMENT
I owe my thanks to Dean, Madras Medical College and Rajiv Gandhi Govt General Hospital, Chennai-3. Prof. Dr. R.NARAYANA BABU, M.D., for allowing me to avail the facilities needed for my dissertation work.
I am grateful to beloved mentor Prof. Dr.S.MAYILVAHANAN M.D., Director and Professor, Institute of Internal Medicine, Madras Medical College and Rajiv Gandhi Government General Hospital, Chennai-03 for permitting me to do the study and for his encouragement.
With extreme gratitude, I express my indebtedness to my beloved Chief and teacher Prof. K.S.CHENTHIL M.D, for his motivation, advice and valuable criticism, which enabled me to complete this work. I am extremely thankful to my Assistant Professor Dr.B.PRIYADHARSHINI, M.D., DCH. and Dr.BIJIN OLIVER JOHN, M.D., for their guidance and encouragement.
I am also thankful to all my unit colleagues and other post graduates in our institute for helping me in this study and my sincere thanks to all the patients and their families who were co-operative during the course of this study.
CONTENTS
S.
NO. TITLE PAGE
NO.
1. AIMS & OBJECTIVES 1
2. INTRODUCTION 2
3. REVIEW OF LITERATURE 5
4. MATERIALS & METHODS 64 5. OBSERVATIONS & RESULTS 67
6. DISCUSSION 91
7. LIMITATIONS 93
8. CONCLUSION 94
9. BIBLIOGRAPHY 95
10. ANNEXURES
ABBREVIATIONS
PROFORMA
ETHICAL COMMITTEE
PLAGIARISM SCREENSHOT
INFORMATION SHEET
CONSENT FORM
MASTER CHART
Aims & Objectives
1
AIM OF THE STUDY
1. To study the prognostic impact of serum magnesium and potassium levels at admission on intrahospital outcome in patients with acute cerebrovascular accidents.
2. To study the correlation of serum magnesium and potassium levels with risk factors of stroke such as age, sex, diabetes, hypertension, dyslipidemia and coronary artery disease.
Introduction
2
INTRODUCTION
This study aims to determine the relationship between serum magnesium and potassium levels with the intrahospital outcome in patients with acute cerebrovascular accidents.
In acute cerebrovascular accidents,there occurs rapid loss of brain potassium and magnesium levels with rapid uptake of sodium and calcium channels, the lower the concentration of magnesium and potassium the greater the magnitude of cerebral arterial contraction.
Interruption of cerebral blood flow will lead on to ischemic cell death causing ATP depletion and ischemic depolarisation leading to excessive calcium entry which causes vasospasm.
Interruption of cerebral blood flow causes release of excitatory glutamate through NMDA receptors which causes influx of calcium and sodium leading onto production of free radicals and initiation of inflammatory response.
3
Magnesium exerts neuroprotection in the following ways:
1. it is nature’s physiologic calcium blocker antagonises calcium mediated metabolic process.
2. it decreases the release of excitatory neurotransmitter 3. it increases the release of inhibitory neurotransmitter 4. it relaxes vascular smooth muscle
5. it decreases platelet aggregation.
Potassium exerts its action in the following ways:
1. it improves endothelial function with vasodilatation 2. it increases vascular nitric oxide
3. it decreases vascular intercellular calcium and sodium .
4. alteration in DNA synthesis and proliferation in cerebral vascular smooth muscles.
5. decreases the vascular neointimal formation and lowers thrombosis risk
6. reduces the production of free radicals.
Chronic low levels of magnesium and other electrolytes are atherogenic and thrombogenic and disrupts the arterial and cardiac integrity and so is associated with hypertension , diabetes, CAD ,CVA etc
4
There is developing research in the role of magnesium and other electrolytes like potassium in the prevention and treatment of diseases like CVA,CAD, DM and HT.
The present study was done to evaluate the prognostic impact of serum magnesium and potassium levels on the intrahospital outcome of CVA patients and to evaluate the correlation between serum magnesium and potassium levels with, hypertension ,DM ,dyslipidemia and CAD.
Review of literature
5
REVIEW OF LITERATURE
CEREBROVASULAR ACCIDENTS DEFINITION:
WHO clinically defines stroke as “the rapid development of clinical signs and symptoms of a focal neurological disturbance lasting more than 24 hours or leading to death with no apparent cause other than vascular origin”.(1)
EPIDEMIOLOGY OF STROKE
Stroke is a global health problem.It is the second commonest cause of death and fourth leading cause of disability worldwide .Approximately 20 million people each year will suffer from stroke and of these 5 million will not survive. In developed countries,stroke is the leading cause for disability ,second leading cause of dementia and third leading cause of death.Stroke is also a predisposing factor for epilepsy, falls and depression in developed countries and is a leading cause of functional impairments with 20% of survivors requiring institutional care after 3 months and 15% - 30 % being permanently disabled .Stroke is no longer a disease of the developed world, low and middle income countries account for 85.5% of total stroke deaths worldwide and the disability adjusted life years in these countries was approximately seven times that in high income countries.1
6
MORBIDITY AND MORTALITY ASSOCIATED WITH STROKE:1 Global Stroke Estimates:
400 – 800 strokes per 100,000
5.7 million deaths
16 million new acute strokes every year
28,500,000 DALYs(disability adjusted life years)
28-30 day case fatality ranges from 17%-35%
Stroke Morbidity and Mortality in India:
Prevalence 90- 222 per100,000
102,620 million deaths
1.44-1.64 million cases of new acute strokes every year
7
6,398,000 DALYs
12% of strokes occur in the population ages >40 years
28-30 day case fatality ranges from 18-41%
STROKE –RISK FACTORS
NON MODIFIABLE RISK FACTORS
A. Age - elderly are more at risk. After 55 years, risk doubles for every decade.4
B. Sex –male are at more risk than female except at extremes of age C. Heriditary/Genetic factors
D. Race - Afro Carrribeans> Asians > Europeans
MODIFABLE RISK FACTORS
A. Hypertension - the most important risk factor.
B. Diabetes mellitus - it increases stroke incidence by 1.8 to 3.5 times.Hyperglycemia and insulin resistance are very important risk factors.5
C. Hyperlipidaemia
D. Cigarette smoking - risk doubling is seen in heaviest of smokers. 6 E. Excessive alcohol intake
F. Obesity G. Heart disease
AF(Atrial fibrillation)
8 CCF(Congestive cardiac failure) Infective endocarditis
H. Oestrogen containing drugs (OCP, Hormone replacement therapy)
As cerebrovascular accidents are one of the most leading cause of mortality and morbidity in our country there is a need to access the risk factors , management and efficacy of treatment. It is for this purpose that the Modified Rankin scale (mRS), National Institute of Health Stroke scale (NIHSS) and the Barthel Index was developed.
MODIFIED RANKIN SCALE:
The Rankin scale is named after the Scottish physician John Rankin who made this scale in view to access the disability of the patient with specific reference to the mobility of the patient .Initially this scale was made to access the patient who suffered from stroke to access the global disability of these patients was later to be used in clinical trial and the name Modified Rankin Scale (mRS).
The Modified Rankin scale was used initially in a study in Great Britain for patients suffering from TIA. After this the scale has gained popularity and now is widely used to assess the functional outcomes of patients who suffer from stroke.
9 Advantages of mRS scale:
1. It is easy to perform
2. It takes about five minutes to perform
3. It has close correlation with other stroke scale like the NIHSS scale and theBI
4. The volume of infarct correlates well with the imaging findings of patients with CVA
5. It has six point score which correlates well with the outcome of patients.
6. As in the case of NIHSS there are various mobile phone apps, DVDs, online certificate courses for learning the scale.
Limitations of the MRS scale:
1. As there are only six point score it is less probable to change than other stroke scales
2. The specificity of the scale is less
3. Inter observer variability is high with respect to this scale
4. Detailed training in scripted interviews is required to improve the reliability and the consistency of the scale.
10 National Institute of Health Stroke Scale
As to all scaling system NIHSS scale has its strengths and its limitations. It incorporates a 15 item scale which are part of the basic neurological examination, where it pays specific attention to those aspects that are more affected by stroke. The 15 item scale examines ones language, speech , motor function, consciousness, eye movements, cerebellar function, neglect, visual fields, neglect and so forth. The scoring system of NIHSS scale is from 0-42, with 0 being no stroke and 42 being very severe stroke.
A score greater than 21 in itself is considered as severe stroke. To assess
11
level of consciousness there is a standard approach on scaling these patients who are not able to respond to oral commands.
The history of NIHSS scale starts as far as 1980 where it was used as a consistent tool for research purposes for reporting neurological deficits in patients with acute stroke. This was used in trials of intervention in stroke as in case of thrombolysis and in case where neuroprotective agents were used.
The scale was derived from previous scales that were existent in Canada and other parts of Europe. And at present it is one of the most widely used scaling system in acute stroke in clinical trials as well as in management of cases in wards.
On the basis of this a modified NIHSS scale was made with the purpose that it would be much faster to perform and it has a 11 point scoring system. But since NIHSS in itself took only 6 minutes to complete the importance of the NIHSS has reduced and is not in use even in trials and in management of cases in ward.
12 Advantages of NIHSS scale:
1. It is easy to perform.
2. It is not time consuming , taking about 6 min to perform the whole test.
3. There are no instruments that are required.
4. It has been proven with various clinical studies of its efficacy.
5. It helps to assess the clinical improvement or deterioration of the patient, a change of score even by 2 is significant.
6. There is no major changes even when it is used by trained non-medical personal.
7. It can even be used by non-neurologist.
8. Its validity even holds when used via telemedicine.
9. There are training apps even online, dvd,and mobile phones which can be used to high degree of accuracy.
10. There is clinical correlation that is obtained with NIHSS and the ones obtained by imaging in the form of CT brain or MRI brain.
11. It has great predictive ability in not only assessing acute stroke but also the hospital stays and the morbidity of patients over a period of 90 days.
12. With respect to the other scaling system like the mRS and the BI, this system has greater sensitivity and specificity even when the sample size is small.
13 Limitations of NIHSS scale :
1. It is more biased to the dominant hemisphere, with non-dominant hemisphere validity being less.
2. A lower core in NIHSS does not mean the patient has less disability as discussed before. A score of 1 in NIHSS means the patient as mild stroke, but this might be a visual field defect which hampers his quality of life to a great extent.
3. Posterior territory stroke has less validity with respect to other stroke like anterior circulatory stroke.
4. NIHSS scale gives less importance to cranial nerve examination.
5. With respect to quantifying the volume of infarct size , it is noted that for the same score the right sided non dominant stroke has greater volume with respect to the left sided dominant stroke. Indirectly implying the fact that there is a bias of this scale towards the dominant hemisphere.
14
15 BARTHEL INDEX
The history of the Barthel index starts as early as the 1960s, and was developed for a simple index to assess the improvement in patients in rehabilitation and how independent they are in their day to day activities and to plan discharges in patients with stroke admitted in rehabilitation centres.
The scale was pioneered by Mahoney and Dorothea Barthel. In the following years the scale has been accepted as a good scale even for assessing the geriatric population . The BI is the most commonly used scale to assess functional improvement in the rehabilitation setting and the second most used index in patients suffering from acute stroke to assess their functional disability after the mRS scale. The scale uses mainly activities of daily living and uses a 10 tasks , and the tasks are graded to a score of zero to hundred. This scale tests the independence of the patient suffering from stroke during the acute phase and also during the rehabilitation phase of these patient. The higher the score in the BI it indicates the patient is recovering and has greater independence to his activities of daily living. So a patient with a score of 50 is less independent when compared to a patient with a score of 80, and a score of greater than 80 is taken as one who can be discharged and sent home as he can manage his activities of daily living.
16 Advantages of Barthel Index:
1. It is well validated.
2. Good prognostic tool .
3. Predicts recovery of patients.
4. Duration of rehabilitation required.
5. Correlates well with other indexes mentioned earlier.
6. Inter observer variability is good in this scale.
Limitations of Barthel Index:
1. The cognitive impairment’s and impairments due to speech are not calculated.
2. Stroke mortality is not well represented.
3. The floor and ceiling effect of the BI, indicates that a patient with severe morbidity following discharge may be high on a scale and a patient who has improved significantly in the ICU setting will still score low and hence the response to the clinical change in patients is low, it is due to this fact that the BI is more widely used in the rehabilitation centre than in intensive care management.
17
The BI is one of the earliest scale made to assess the independence of patients following which emerged much more complex indices to assess the activity of daily living, of noteworthy to mention are E-ADL, Lawton I-ADL, Nottingham Extended ADL and so forth.
BLOOD SUPPLY OF BRAIN
Brain is supplied by
Internal carotid artery
Vertebral artery
18 Internal carotid arteries :
They arise from common carotid arteries and enter middle cranial fossa through the carotid canal which opens in the side of foramen lacerum.
It turns upwards to reach the side of body of sphenoid bone.It then turns forward in the cavernous sinus to reach the medial aspect of anterior clinoid process and lies lateral to optic chiasma. Its course follows a series of bends (carotid siphon).
BRANCHES
1. Hypophyseal arteries 2. Ophthalmic artery
3. Anterior choroidal artery 4. Anterior cerebral artery
5. Posterior communicating artery 6. Middle cerebral artery
Ophthalmic artery is first branch from internal carotid artery, which supplies eye and other structures in the orbit.
Posterior communicating artery is the next branch, and it runs back to join the posterior cerebral artery, and supplying optic chiasma, optic tract, hypothalamus, midbrain, thalamus.
19
Anterior choroidal artery - which arises from distal region and it supplies the internal capsule, basal ganglia, thalamus, lateral geniculate body, optic tract, midbrain, proximal optic radiation.
Middle cerebral artery- it enters sylvian fissure, before it enters it gives deep cerebral branches (Lenticulostriate branches). The middle cerebral artery, in the sylvian fissure, divides into superior & inferior division and supplies the lateral part of the cerebral cortex. The lenticulostriate branches supply the, internal capsule (posterior limb), putamen and outer globus pallidus.
Anterior cerebral artery –it passes medially above the optic nerve and then passes in to the great longitudinal fissure between the frontal lobe where it joins the corresponding vessels of the opposite side by anterior communicating artery. It follows the curvature of corpus callosum and ramifies over medial surface of frontal and parietal lobe and supply them.
Also supply a narrow lateral band of frontal and parietal cortices.The territory supplied by it includes motor sensory cortices for the lower limb.
VERTEBRAL ARTERY :
Vertebral artery arises from the first part of subclavian artery, then ascends through the transverse foramina of upper six cervical vertebrae, then it join with the vertebral artery of the other side to form basilar artery.
20
Its branches includes – anterior spinal artery, posterior spinal artery, PICA (posterior inferior cerebellar artery), small penetrating branches to medulla. PICA supplies inferior vermis, inferior and posterior surfaces of the cerebellum, brainstem.
Basilar artery ascends to the pons and in the inter-peduncular cistern and it divides into posterior cerebral artery. The other branches of it are
Labyrinthine artery
AICA (anterior inferior cerebellar artery) which supply the rostral cerebellum, brainstem, inner ear
the superior cerebellar artery ,supplying the brainstem, cerebellar hemisphere(superior part) ,vermis, dentate nucleus
Posterior Cerebral Artery.
The posterior cerebral artery, which winds around the midbrain near the occulomotor nerve. It supplies temporal lobe (inferior part), occipital lobe. Its deep branches supply mainly midbrain, thalamus, hypothalamus, and geniculate bodies ( thalamostriate branches).
CIRCLE OF WILLIS
It is an arterial anastomosis in the interpeduncular fossa, formed anteriorly by two ACA (anterior cerebral artery), which is connected by anterior communicating artery anteriorly, posteriorly by two PCA (posterior
21
cerebral artery), communicating with anterior circulation by the posterior communicating artery.
COLLATERAL BLOOD SUPPLY IN THE BRAIN
Usually the anterior two-third of the cerebral circulation is by the internal carotid artery and the posterior one – third is by vertebral artery. In blood vessels occlusion, collateral develop distal to the site of occlusion.
collateral development depends on the vessels occluded, and also whether other artery are free of disease or not.
Venous drainage of the brain 1. Superficial cerebral veins 2. Deep cerebral veins
22
Both these veins drains into the dural venous sinuses. It further drains into the internal jugular vein. The cerebral veins are valveless and they are thin walled, & the blood flow in these veins are in the same direction as that of nearby arteries.3
23 CLASSIFICATION OF STROKE
BASED ON PATHOGENESIS:
A) Ischemic stroke B) Hemorrhagic stroke
C)Stroke of undetermined origin
24 A) ISCHEMIC STROKE
a) Thrombosis
Large vessels disease
lacunar stroke (small Vessels) Dehydration
b) Embolic Occlusion i. Cardio –embolic
a. Myocardial infarction (MI) b. Mural thrombus
c . Atrial fibrillation (AF) ii. Dilated cardiomyopathy (DCM)
c) Valvular lesions
i. Prosthetic valves ii. Mitral stenosis
iii. Bacterial Endocarditis iv. Atria septal aneurysm v. Spontaneous ECHO contrast vi. Paradoxical embolus:
Patent Foramen ovale, Atrial septal defect (ASD)
25 d) Artery to Artery
Aortic arch
Carotid artery bifurcation Arterial dissection
e) Cardiogenic
i Marantic Endocarditis ii. Libman sacks Endocarditis iii. Intracardiac mass
iv. Mitral valve calcification v. Atrial myxoma
f) Vasculitis
i. Primary CNS vasculitis ii. Systemic Vasculitis –
1.Wegener’sGranulomatosis 2.Polyarteritisnodasa (PAN) 3.Takayasu arteritis
4. Giant cell arteritis
g) Meningitis
(TB, syphilis, bacterial, fungal, Bacterial, Zoster)
26 h) Hypercoagulable disorders
Antiphospholipid Antibody Syndrome Protein C,S deficiency
Antithrombi III deficiency Prothrombin v G20210 mutation Systemic lupus erythematosis(SLE)
Thrombotic thrombocytopenic Purpura (TTP) Disseminated Intravascular Coagulation (DIC) Systemic Malignancy
Inflammatory bowel disease (IBD) OralContraceptive pills(OCP) Homocysteinemia.
Dysproteinemias i) Eclampsia
j) Drugs –cocaine, Amphetamine
27 B) HEMORRHAGIC STROKE
1. hypertension
2. rupture of cerebral aneurysm 3. head trauma
4. blooddyscrasias
5. drug induced ( anticoagulation therapy or thrombolytic therapy) 6. bleeding in the brain tumors
7. miscellaneous cause
28
C) STROKE OF UNDETERMINED ORIGIN 1. leukariosis
2. aortic arch syndrome 3. Fibromuscular dysplasia 4. Binswanger’s disease 5. moyamoya disease
CLINICAL CLASSIFICATION 2 (1) Based on arterial territory involved
(a) Anterior circulation stroke:
It may be
- Anterior cerebral artery (ACA) syndrome - Middle cerebral artery (MCA) syndrome (b) Posterior circulation stroke:
It may be
- Vertebro basilar artery syndrome - Posterior cerebral artery syndrome (2) Based on clinical manifestations: 2
(a) completed stroke:
It is rapid onset of stroke, with persistent neurological deficit But does not progress beyond 96 hours.
29 (b) Evolving stroke :
In this type, there is stuttering or gradual development of deficit
(c) Reversible ischemic neurological deficit :
There will be neurological deficit but there will be complete recovery within one week.
(d) Transient ischemic attack (TIA):
TIA refers to focal neurological deficit which completely recovers within 24 hours.
30
PATHOGENESIS OF DIFFERENT TYPES OF STROKE:
PATHOPHYSIOLOGY OF STROKE CEREBRAL AUTOREGULATION
Cerebral blood flow normally depends on the amount of resistance of cerebral blood vessels, which depends on their circumference. Cerebral blood vessels dilatation leads to increased amount of cerebral blood flow, while constriction has opposite effect. Cerebral blood flow was also determined by the cerebral perfusion pressure. 7
Cerebral autoregulation is the maintenance of constant blood flow inspite of changes in the perfusion pressure of brain. There are three mechanism which are thought to responsible for cerebral autoregulation.
They are
metabolic
myogenic
neurogenic
Metabolic regulation is by the balance between the demand and oxygen supply through cerebral blood flow and it acts through vasoactive substance. It acts through negative feedback system.
Myogenic regulation –the transmural blood pressure are detected by smooth muscle in the arteriole and they are adjusted to keep constant blood flow.
31
Neurogenic regulation is by sympathetic innervations which controls the resistance in arterioles. Parasympathetic fibers which release nitric oxide also plays role.
Cerebral blood flow is maintained by cerebral autoregulation within a range of 60 to 150 mmHg of MAP (mean arterial Pressure). The limits may vary but beyond this range of mean arterial pressure, the brain will be unable to compensate for the perfusion pressure changes, and hence cerebral blood flow increases or decreases passively according to the corresponding changes in pressure, resulting in the risk of ischemia when there is low pressures and edema occurs at high pressures.
CEREBRAL AUTOREGULATION DURING STROKE :
Cerebral autoregulation will get impaired in some diseases including ischemic stroke. When perfusion pressure of brain decreased there will be compensatory cerebral vascular dilatation leading to increased flow. When the autoregulation fails, when it falls below the compensatory ability of the brain then there will be decrease in the cerebral blood flow. Initially, there will be increase in the extraction fraction of the oxygen so that there will be maintenance in the level of oxygen supply to the brain. When there is continuous fall in the cerebral blood flow, other mechanisms come into play. 8
32
In hypertensive patient, cerebral autoregulation occurs at higher arterial pressures. So on suddenly reducing the blood pressure to normal levels in ischemic stroke would exacerbate the derangement of autoregulation which would lead to further decrease in cerebral blood flow.
So it is safe to modestly decrease blood pressure in patient with acute ischemic stroke. There are no data on controlled trial to indicate decreasing blood pressure is beneficial in acute ischemic stroke. In patient with acute ischemic stroke, blood pressure should be decreased when there is malignant hypertension, concomitant myocardial ischemia, blood pressure
>185/110mmhg and there is anticipation of thrombolytic therapy.
EFFECT OF DECREASED CEREBRAL BLOOD FLOW ON VITAL BRAIN FUNCTIONS AND CONSEQUENCES OF REDUCTION IN BLOOD FLOW DURING STROKE
The human brain is more sensitive to ischemia even on short durations. Among the cardiac output, 20% is received by the brain. The human brain has no own energy stores, so it completely depend on the blood flow for their delivery. Hence even brief deprivation in flow leads to death of the brain tissue affected. Reduction of cerebral blood flow results in a deprivation of oxygen and glucose during stroke.9
In ischemic stroke .when the blood vessel is affected, the area which is supplied by the vessel, that is immediately surrounding the vessel get
33
involved earlier. In this area if there is prolonged ischemia then there will be death of the cells by necrosis. This area which underwent necrosis is known as cerebral infarct. The peripheral area which receives blood flow-nutrients and oxygen through collaterals, will not die immediately and it can be revived by restoration of blood flow by timed intervention.10This area surrounding the dead cells is known as Ischemic penumbra
The possible sequence of events in cerebral ischemia are14 1.Depletion of ATP
2.Sodium, potassium, calcium ionic concentration changes 3.Acidosis due to increased amount of lactic acid
4.Oxygen free radicals
CEREBRAL EDEMA
Cerebral edema in stroke can cause numerous secondary damages in brain-increasing intracranial pressure which leads to decreased cerebral blood flow and other is mass effect which causes herniation which may be life threatening .In stroke two types of edema can occur.
1. Cytotoxic edema 2. Vasogenic edema
34 CYTOTOXIC EDEMA
During the attack of stroke, there will be failure of energy dependent pumping system of sodium and calcium, which will lead to accumulation of water inside the cells resulting in cerebral edema 11,12,13. Cytotoxic edema implies large volume of dying or dead cells implies poor outcome.
VASOGENIC EDEMA
The blood brain barrier breakdown occurs, resulting in leakage of osmotically active substance from intravascular to interstitial space which results in increased extracellular fluid volume. It does not necessarily implies neuronal injury and this extravascular fluid can be mobilized and removed.
35
About 10% of ischemic stroke is massive because of this cerebral edema which may be severe to produce increased intracranial tension and herniation.
ISCHEMIC CASCADE IN THE PATHOGENESIS OF STROKE After occlusion of the intracranial cerebral vessels, a series of time dependant neurochemical events takes place called the ischemic cascade which results in energy failure.
36 ISCHEMIC CASCADE
The neuropathogenic processes involved in this ischemic insult include, 1. The glutamate, an excitatory amino acid (EAA) is the most excessive
excitatory neurotransmitter in the brain stored in the presynaptic vesicles. When it is released, it binds to the post synaptic glutamate NMDA (N- methyl D-aspartate) receptor. 14
2. Once the reduction of cerebral blood flow commences, there is abundant release of excitatory neurotransmitters, especially glutamate and causes excess activation of the NMDA receptor.
3. Activation of these receptors leads to the influx of the calcium and the sodium ions through the ligand and voltage gated channels.
4. The intracellular enzyme systems which are dependent on calcium are activated and leads to the induction of
i. free radical production15
ii. membrane lipid breakdown proteolysis
iii. initiation of an inflammatory response which stimulates apoptosis
5. All of this contribute to compromise of the metabolic functions, expansion of the infarct volume and the development of neurotoxicity over a time scale of days or even weeks.
6. The leucocyte and platelet activation cause direct micro vascular damage and worsen ischemia.16
37 IMAGING STUDIES
CT SCAN
It helps in differentiation of infarct and hemorrhages. Infarct is seen as hypodense lesion whereas hemorrhage is seen as hyperdense area.
Hypodense marking of involved vein, grey enhancement, post contrast enhancement of the involved vein suggest cortical venous thrombosis.
MERITS
- helps in differentiating infarct and hemorrhages and hence line of management can be decided.
- highly sensitive in detecting SAH.
DEMERITS
- In acute setting it may not detect infarct in the first 24 hours - it may miss cortical surface small infarct.
- It will not detect lesion in posterior fossa due to artifact.
MRI SCAN
- It is more sensitive for early brain infarction.
- it is considered superior to ct scan for detecting posterior fossa and cortical infarction.
- MR Angiogram helps in detecting stenosis of intracranial vessels
38
TREATMENT OF ACUTE ISCHEMIC STROKE MEDICAL SUPPORT
Blood pressure should be lowered
- when BP >185/110mmHg,thrombolytic therapy anticipated.
- malignant hypertension
- concomitant myocardial ischemia
Serum glucose should be maintained and kept below180mg/dl, if needed by insulin infusion.
Fever will be detrimental, should be lowered by surface cooling and antipyretics.
For cerebral edema, iv mannitol, water restriction can be tried. But hypovolemia should be avoided.
INTRAVENOUS THROMBOLYSIS INDICATIONS
Clinical diagnosis of stroke
Time between symptoms and drug administration <4.5hrs Age >=18yrs
No hemorrhage in CT and edema <1/3 of MCA Territory
39 ANTITHROMBOTIC TREATMENT PLATLET INHIBITION
Aspirin is the only agent which was effectively proven for acute ischemic stroke. Clopidogrel is under trial for preventing stroke following TIA. It can be given to patients who show resistance to aspirin.
ANTICOAGULATION
Anticoagulation has no benefit for atherothrombotic stroke and also it increases risk of hemorrhage .It is useful in cortical venous thrombosis and in patient with atrial fibrillation.
ANTIEDEMA MEASURES FOR MASSIVE ISCHEMIC AND
HEMORRHAGIC STROKE NEUROPROTECTION
STROKE CENTRES AND REHABILITATION - Physical, occupational, speech therapy
40
THE NEED FOR NEUROPROTECTION:
WINDOW OF OPPORTUNITY:
In humans, following a cerebrovascular accident , the neurological insult produced spreads from the central core of the infarct or hemorrhage.
The excitotoxic injury continues beyond 48 hours to produce the maximal size of the infarct, and the local cerebral perfusion and the autoregulation are disturbed for the first hours. In most of the cases, within three to four days, the collateral vessels develop and reperfuse the damaged areas and the regional blood flow abnormalities tend to resolve. The PET (Positron Emission Tomography) imaging, which can distinguish ischemia from an infarct, cannot identify the areas of ischemia which will recover or transform into an infarct. It was found that blood flow was reduced locally in 100% of patients within 9 hours of the insult and it was reduced to 30%
within 4 days. Following stroke, this ischemic but viable tissue was found for upto 48 hours. Because the hemorrhagic complications are high when reperfusion is done at later stages, the time window for thrombolysis is relatively short. So there is a rationale for need of initiating neuroprotective measures to prevent the continuing cerebral ischemia and to salvage the viable ischemic tissue during the time the cerebral autoregulation is deranged and the collateral circulation is developing (ie,3 to 4 days after the onset of stroke) when patient comes beyond the critical time allocated for thrombolysis.
41 NEUROPROTECTION:
The main treatment strategies for therapeutic intervention in ischemic stroke are aspirin and thrombolysis. The concept of neuroprotection emerged only recently and is considered as an alternative additional intervention because of its relative safety, evidence of efficacy in animal models and potential to administer in the pre-hospital setting. Thousands of experimental papers and more than 500 articles have been published on neuroprotection to emphasize its potential utility.
BASIC CONCEPTS OF NEUROPROTECTION:
Neuroprotection19 in stroke refers to the therapeutic interventions applied in single or in combination which will counteract, block, or slow the sequence of the injurious biochemical and molecular events that take place in the cascade of the irreversible ischemic brain injury. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof of evidence that high grade protection of brain is an achievable goal.
A number of possible approaches have been suggested, considering the pathophysiological processes of neuroprotection. Excitotoxicity can be attenuated by
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1. Decreasing the release of the excitatory neurotransmitters (especially glutamate) 17 or increasing its reuptake or its breakdown
2. Reducing their toxicity by blocking or down-regulating post-synaptic NMDA receptors
3. The release of inhibitory amino acids or the neurotransmitters like gammaaminobutyric acid (GABA) can be stimulated.
4. By blocking the voltage-sensitive channels, the calcium influx is reduced by promoting its extrusion or sequestration there reducing the toxicity of excess intracellular calcium.
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5. Modifying the other ‘downstream’ intracellular processes, such as the various nitric oxide-dependent pathways.
6. Other ways for neuronal salvage include the reduction of cerebral oedema, correcting acidosis and scavenging free radicals.
CLASSIFICATION OF NEUROPROTECTIVE AGENTS19 1. Modulators of Excitatory Amino Acids
2. Modulators of Calcium Influx 3. Metabolic Activators
4. Anti-edema Agents
5. Inhibitors of Leukocyte Adhesion
6. Free Radical Scavengers and Anti-Oxidants 7. Promotors of Membrane Repair
The most extensively studied and the promising neuroprotective agents are the hyperacute magnesium therapy, therapeutic hypothermia, high dose human albumin, calcium channel blockers, GABA agonists, glutamate antagonists, antioxidants, free radical scavengers, down- regulators of the nitric oxide signal transduction.
Unlike the other majority neuroprotective agents, magnesium is used extensively for many clinical conditions like arrhythmias, myocardial infarction and pre-eclampsia/ eclampsia. So these major clinical experiences
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confirm its tolerability, efficacy and safety. In recent times, many clinical trials conducted had proved the neuroprotection offered by magnesium and improvement inneurological outcome in patients with ischemic stroke.
MAGNESIUM :
The fourth most abundant mineral in our body is magnesium. Around 99% of the total body magnesium (Fig 5) is present in the bone, muscle and the soft tissue. Magnesium ion is present inside the cells at a concentration of 5-20mmol/L; present in the ionized form in around 1-5%, remaining is bound to the proteins, and adenosine tri phosphate (ATP). During states of acute deficiency, large amount of exchangeable pool for magnesium is from the bones. As age increases, the magnesium content of bone also decreases.
Only 1% of the total intracellular magnesium is present extracellularly. The primary extracellular concentration is present in the red blood cells (RBCs) and serum. Similar to calcium, magnesium is present in three forms free/ionized, bound to proteins and anions like phosphate, bicarbonate, citrate or sulphate. The biological activity of magnesium is greater with the ionized form.
MAGNESIUM HOMEOSTSIS
Magnesium homeostasis23 is achieved mainly through the bones, intestines and the kidneys. It is absorbed mainly in the small intestine by the passive transport. Only 25 – 75% of the total magnesium consumed is
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absorbed. The remaining is excreted in the faeces. The absorption of magnesium in the intestines depends not on the levels consumed, but on its status of the body.
Lower the magnesium levels, higher the ion is absorbed. Serum magnesium levels are principally regulated by the kidneys. Around 95% of the filtered magnesium is reabsorbed and only 3 -5% is excreted in the urine. The thick ascending limb of the loop of Henle is the primary site for reabsorption.
MAGNESIUM - NATURE’S PHYSIOLOGICAL CALCIUM CHANNEL BLOCKER 37
Many calcium channels are found to be magnesium dependant.
Higher levels of magnesium inhibit the flux of calcium from the sarcoplasmic reticulum and through the intra and extra cellular channels. So during deficiency state, there is unopposed influx of calcium and its levels increase intracellularly.
Magnesium acts as a competitive antagonist of calcium as Mg2+ is a bivalent ion resembling Ca2+. (Fig 12) Both calcium and magnesium have opposite effects on the vascular tone. So hypomagnesemia causes spasm of the blood vessels and increases resistance in the blood vessels.
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An average 60 kg adult contains around 2000 mEq in the body. The normal serum magnesium values range between 1.5 - 2.5 mEq/L.
HYPOMAGNESEMIA
Serum magnesium levels less than 1.5 mEq/L is defined as hypomagnesemia.
The factors that influence magnesium levels are 1. Inadequate dietary intake
2. Decrease in the absorption of magnesium in the gastrointestinal tract a. Diarrhoea, vomiting
b. Gastro intestinal suction
c. In chronic malabsorptive problems like Crohn’s disease, regional enteritis, intestinal surgeries and gluten sensitive enteropathy.
d. Steatorrhoea e. Acute pancreatitis
3. Increase in the renal excretion a. Renal tubular defect
b. Alcoholism
c. Diuretics- thiazides and loop diuretics
d. Antimicrobials – aminoglycosides, amphotericin B
e. Chemotherapeutic drugs – cisplatin, cyclosporine, tacrolimus
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In terms of symptoms development the rate of development is more important than the absolute value. Cardiovascular and the nervous systems are the most affected in magnesium deficiency. The other systems are less commonly affected.
Cardiovascular manifestations
Prolonged QT/QU interval, increased digitalis toxicity, torsades de pointes, ventricular fibrillation.
Neuromuscular manifestations:
Tremors, paresthesias, seizures, weakness of muscles, fasciculations tetany, letharginess, confusion, disorientation, irritability, agitation and psychosis.
Physical examination:
In patients with serum levels less than 1mEq/L develop muscular fibrillations, tremor, carpopedal spasms can progress to tetany, deep tendon reflexes. Cardiac arrhythmias and respiratory failure can occur in patients with severe hypomagnesemia.
MAGNESIUM DEFICIENCY AND ATHEROSCLEROSIS 26 Atherosclerosis is the most important risk factor for the cardiovascular diseases mainly stroke and myocardial infarction. Large amount of evidence supports that the main causative factor responsible for
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the atherosclerotic burden in cardiovascular disease is the inflammation and the endothelial dysfunction. Various epidemiological studies from animal models suggest that magnesium deficiency at the cellular level accelerates the inflammation and intensifies the lipid deposition in the blood vessel wall and there is an inverse correlation cardiovascular incidence and the dietary magnesium. In the follow up of the ARIC study, it was demonstrated that for every 0.1mm decline there was increase in the thickness of carotid intima- media thickness with the development of carotid plaques.
In magnesium deficiency, 27
1. In the endothelium, (Fig 19) upregulation of the adhesion molecules like VCAM (vascular cell adhesion molecule), MCP- 1(monocyte chemoattractantprotein -1) and release of cytokines like platelet derived growth factor (PDGF), NFkβ (nuclear factor kappa- light chain- enhancer of activated B cells, interferons (IFs), interleukins (IL-1) etc are enhanced.
2. This leads to adhesion and migration (chemotaxis) of monocytes into the arterial wall and transformed into macrophages in the intimal layer.
3. It enhances the permeability of the LDL cholesterol and promotes the oxidation of LDL in the carotid intima.
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4. In the carotid intima, there is increase in the uptake of oxidized LDL by the macrophages and the formation of foam cells thereby accelerating the inflammation and the atherogenic plaque formation which is the initiating event for all the cardiovascular diseases.
So magnesium which is a natural and a safe element can be used as an adjuvant therapy for the prevention of atherosclerosis.
MAGNESIUM- ANTITHROMBOTIC WITH CARDIOPROTECTIVE EFFECT 28
The protective mechanisms of magnesium are 1. Reduction of the proinflammatory process
2. Stabilization of the membrane of platelets as magnesium is needed to maintain the shape of the platelets.
3. Inhibition of thrombogenesis through inhibition of ADP - platelet aggregation and adhesion.
4. The release of the platelets is dependent on the calcium and so magnesium physiologically inhibits its release.
5. The platelet dependant thrombosis was inversely correlated with the serum magnesium levels and its supplementation positively reduced the size and the number of platelet clumps and increased the number of discrete platelets.
6. Increase in the fibrinolytic activity.
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7. By lowering the intracellular calcium concentrations, it decreases the tonicity of the blood vessels and also inhibits the vascular calcification.
8. Against oxidative stress, it helps to increase the protective enzymes.
9. Increases the nitric oxide (NO) release and enhances the endothelial dependant vasodilatation and inhibits the aggregation of platelets.
LOW MAGNESIUM AND DYSLIPIDEMIA 29
Magnesium has an important role in control of the lipid metabolism.
Dyslipidemia is found to be strongly associated with magnesium deficiency.
The antiatherogenic effects of Mg2+ are due to the lipoprotein lipase, HMG CoA reductase, and lecithin acyltransferase enzyme modification of the lipid metabolism and turnover. It also modulates HMG-CoA reductase which is the main enzyme catalizing the rate limiting step in the cholesterol metabolism. So magnesium acts as a “physiological statin”. 29 Clinicians from the British Commonwealth have reported that treatment with magnesium has resulted in the reduction of β- lipoproteins and increments in lecithin/cholesterol ratio and α- lipoproteins. Its deficient state is associated with decrease in HDL-C fraction, inhibition of the enzyme lipoprotein lipase and causes elevation in the levels of TGL associated lipoproteins and plasma apolipoprotein B.30
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MAGNESIUM AND BLOOD PRESSURE 28
A clinical trial, DASH study (Dietary Approaches to Stop Hypertension) suggested that high intake of foods rich in magnesium, calcium and potassium and low in sodium like fruits and vegetables had significantly lowered the high blood pressure.28 In an observational study, the ARIC (Atherosclerosis Risk in Communities) study was conducted in 8000 men and women who were initially free of hypertension was followed up for six years. In this study, during follow up, the patients who consumed diet more in magnesium, potassium and dietary fibres were found to be at a lower risk of developing hypertension.28 Joint National Committee stated that the diets that provide higher magnesium are positive lifestyle modifications for people with hypertension and there is a dose dependant improvement in blood pressure with magnesium supplementation.
MAGNESIUM DEFICIENCY IN TYPE 2DIABETES:31
Magnesium has an important role in carbohydrate metabolism.
Magnesium is required in the glucose metabolism for three critical enzymatic reactions namely pyruvate carboxylase, phosphoenol pyruvate carboxykinase, fructose 1,6 biphosphatase. It also plays key enzymatic roles in various hormones like insulin, glucagon, adrenaline and cortisol which have a regulatory effect on gluconeogenesis. Hypomagnesemia may worsen the insulin resistance .Diabetes and metabolic syndrome are strongly linked to magnesium deficiency. Type 2 diabetics are always in an
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overactive dominant sympathetic state, which leads to elevated blood glucose and blood pressure. Magnesium inhibits this excess activation of the sympathetic nervous system thereby preventing the development of hypertension and hyperglycemia. Researchers have found that people who had taken more magnesium from food and various vitamin supplements were half as less likely to develop type 2 diabetes than people who took the least amount of magnesium.
MAGNESIUM AND CORONARY ARTERY DISEASE32
Anderson et al. (1969) gave a hypothesis that there is an environmental factor magnesium, alters the excitability of the myocardium, which in deficient levels causes hyperexcitability of the myocardium and causes an increasing incidence in the cardiac arrhythmias like ventricular fibrillation leading on to sudden cardiac death and also noted that the decreasing hardness of water is associated with an acute and chronic coronary artery disease and an increase in the sudden death rate. 32 R.
Parsons et al., found that the hardness of water was due to the protective factor magnesium. Marier et al., (1968) postulated that the higher serum magnesium levels provides protection for the myocardium against the ischemic injury and also resists the damage caused by the cardiotoxic agents. Magnesium deficiency causes high serum calcium concentration and causes spasm of the coronary arteries and also it potentiates the actions of
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norepinephrine, angiotensin, potassium, acetylcholine, and serotonin on the coronary arteries and can lead onto increased incidence in coronary artery disease and sudden cardiac deaths due to arrhythmias.
MAGNESIUM AS A THERAPEUTIC AGENT
1. For decades, magnesium sulphate has been used safely and successfully to prevent eclamptic seizures in the management of pre- eclampsia and eclampsia
2. In the management of arrhythmias like digoxin induced arrhythmias and torsades de pointes with long QT syndrome.
3. The role of magnesium in atrial fibrillation needs further studies for evaluation.
INTRAVENOUS MAGNESIUM SULFATE 21
The ideal neuroprotective agent for stroke would be inexpensive, readily available, easy to administer and have no significant adverse side effects. Intravenous Magnesium sulphate offers promise as just such an agent. Multiple randomized controlled trials had suggested that magnesium has a demonstrable neuroprotective potential in acute ischemic strokes, head trauma, spinal cord damage and any excitotoxic injury. The readily available source of ionized magnesium is the Magnesium sulfate which has an established safety and efficacy profile in myocardial infarction, eclampsia and cardiac resuscitation.
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EFFECTS OF MAGNESIUM IN STROKE22 ANTAGONISM OF INTRACELLULAR CALCIUM
Cerebral ischemia by lowering the transmembrane potential opens up the calcium channels causing the release of calcium from the sarcoplasmic reticulum and the mitochondria. This released calcium hydrolyze the membrane phospholipids by the activation of the phospholipases. The damaged membrane further increases the influx of calcium producing a positive feedback mechanism, by which ischemia produces higher calcium levels. The high levels of calcium inside the cell disturb the mitochondrial phosphorylation and increase the calcium dependant processes which utilize large amounts of ATP. This along with decreased ATP production causes depletion of ATP reserves thereby resulting in irreversible cell death.
During ischemia, calcium entry into the cell is through the N-methyl-D- aspartate (NMDA) subtype of glutamate receptor.33 Many calcium channel blockers were used in the setting of ischemia mainly to prevent the vasospasm. They have effect mainly on the calcium channels and do not affect the intracellular release of calcium in the damaged membranes. Thus magnesium has an advantage in that it has effect on antagonizing the intracellular calcium and preventing the positive feedback mechanisms.
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MAGNESIUM: A HIGHLY PROMISING NEUROPROTECTIVE THERAPY FOR STROKE
NEUROPROTECTIVE EFFECTS 1. VASCULAR EFFECTS 19
Magnesium stimulates the release of prostacyclin from the endothelium. Prostacyclin causes vasodilatation and inhibition of the aggregation of the platelets. So in deficient states increases the thromboxane/ prostacyclin ratio induces platelet aggregation and vasoconstriction. Also magnesium increases the endothelial dependant cerebral vasodilatation by stimulating the release of NO (nitric oxide) and inhibiting the potent vasoconstrictors mainly calcium and PGF2α This decreases the cerebral vascular resistance thereby increasing the cerebral blood flow. It inhibits the aggregation of platelets and prevents the propagation of thrombus and re-occlusion of the thrombosed vessels after recanalization.
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2. NEURONAL EFFECTS: ANTIEXCITOTOXIC36
In the process of ischemic cascade, magnesium prevents the various excitatory events leading to ischemic neuronal death which are as follows.
1. Magnesium is an anti-excitotoxic agent, as it provides a voltage dependent block, through which it causes the inhibition of ischemia induced glutamate release.
2. Magnesium binds with ATP and blocks the voltage dependant ion channel of the NMDA receptor complex (Fig 25) and in higher doses acts as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist.
3. By the inhibition of NMDA receptor, the release of the major excitatory neurotransmitter, glutamate is inhibited, which is released excessively from the presynaptic neurons by the ischemic damage thereby causing a reduction in the post synaptic neurotoxicity.
4. Magnesium at the presynaptic level prevents the release of excitatory neurotransmitters thereby inhibiting the entry of calcium through the voltage gated channels. Intracellular magnesium concentrations are sufficiently high to antagonise a number of voltage gated ion channels including calcium, sodium and potassium, all implicated in cerebral ischemia.
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5. After an ischemic event, it enhances the recovery of cellular energy metabolism.
6. By preventing the cortical spreading depression and by suppression of anoxic depolarization, magnesium has the most effective potential neuroprotection.
7. There is a considerable reduction in the volume of the cerebral infarct.
8. The reasons for this improvement are due to the effects of increasing regional cerebral blood flow to the ischemic areas, or primarily neuronal actions, or a combination of these effects. Thus magnesium provides neuroprotection by boosting the tolerance to the ischemic insult such that the tissue retains the viability till other defence mechanisms come into play.
POTASSIUM:
The studies of pathogenetic potential role of potassium deficiency in various medical conditions have scored the importance of prevention and correction of the deficiency. Thus maintenance of normal serum potassium is essential in reducing the risk of life threatening cardiac arrhythmias and increased intake of potassium can lower blood pressure and reduce the risk of stroke.
58 Foods high in potassium:35
1. Highest content:(>1000mg) - Dried figs
- Molasses
2. Very High Content(>500mg) - Dried fruits
-Nuts - Avocados -Bran cereals - Wheat germ - Lima beans
3. High Content (>250 mg)
-Vegetables –Spinach, tomatoes, broccoli, winter squash, beets, carrots, cauliflower, potatoes
- Fruits_- bananas, cantaloupe, kiwis, oranges, mangoes - Meats – Ground beef, steak, pork, veal, lamb
HYPOKALEMIA:
Hypokalemia is generally defined as a serum potassium level of less than 3.5 mEq/L.
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POTENTIAL CAUSES OF HYPOKALEMIA
Inadequate dietary intake
Diuretic therapy
High dietary Sodium supplement
Hypomagnesemia
Prolonged diarrhea
Vomiting
Primary or secondary aldosteronism
Cushing syndrome
Large doses of corticosteroids
Ectopic corticotrophin
Barter syndrome
Liddle syndrome
Urinary loss in congestive Heart Failure
Catecholamines
POTASSIUM HOMEOSTASIS:
Potassium homeostasis is achieved by renal excretion matching oral intake (50to 150mmol/day).Virtually all filtered potassium is reabsorbed in the proximal convoluted tubule.The remainder is crucial because potassium excretion is dependant on the distal nephron’s seecretory mechanism.This is
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affected by tubular and peritubular factors. Aldosterone and vasopressin stimulate potassium secretion by upregulating the luminal sodium potassium ATPase pump and opening luminal sodium and potassium channels.
Total body potassium is 3,500 mmol,with 98% intracellular. Serum potassium is maintained between 3.5 and 5.3 mmol/l by renal excretion and shift between intracellular and extracellular fluid compartments. The sodium potassium ATPase pump preserves a high intracellular potassium concentration despite an adverse concentration gradient.It is stimulated by hyperkalemia, aldosterone, catecholamines and insulin.
HYPOKALEMIA AND HYPERTENSION :35
From the epidemiologic and clinical studies it has been evidencd that low levels of potassium has been implicated in the pathogenesis and maintenance of essential hypertension.
Increasing the intake of potassium appears to have an antihypertensive effects that is mediated by the following mechanisms:
1. Increased Natriuresis
2. Improved Baroreflex sensitivity 3. Direct vasodilatation
4. Lower cardiovascular reactivity to norepinephrine or angiotensin II.
61 HYPOKALEMIA AND CHF:35
Hypokalemia is commonly seen in CHF ,a condition that is characterised by several physiological abnormalities that predispose to the development of electrolyte abnormalities. Associated pathogenetic factors are:
1.Renal dysfunction
2.Neurohumoral activation
Which causes the stimulation of the renin angiotensin aldosterone axis,enhanced sympathetic nervous tone, and hypersecretion of catecholamines.
HYPOKALEMIA AND ARRYTHMIA35
Resting membrane potential depends on intracellular and extracellular potassium concentration. Hypokalemia causes
-cellularhyperpolarity, - increases resting potential, - lengthens action potential - hastens depolarisation and
- increases automaticity and excitability.
Thus hypokalemia increases risk of ventricular arrhythmia and sudden cardiac death.
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HYPOKALEMIA AND HYPOMAGNESEMIA:35
Magnesium is an important cofactor for potassium uptake and for the maintenance of intracellular potassium levels. whang and colleagues demonstrated that coexisting magnesium and potassium depletion could lead to refractory potassium repletion, which is the inability to replete potassium in the presence of unrecognised and continuing magnesium deficiency.
Hypomagnesemia increases potassium excretion and hypokalemia is difficult to remedy with concurrent hypomagnesemia because the sodium potassium ATPase pump requires the presence of magnesium ions.
HYPOKALEMIA AND STROKE:34
Studies on diuetary potassium suggests that increased intake is associated with lower blood pressure and decreased stroke risk in hypertensive and non hypertensive adults.
Hypokalemia increases the risk of ischemic and hemorrhagic stroke when compared to normal serum potassium levels.
High serum potassium levels are reported to have vasoprotective effects such as
- Inhibiting free radical formation34
- Inhibiting proliferation of smooth muscle
63 - Inhibiting platelet aggregation - Inhibiting arterial thrombosis
- Reduces hypertension induced arterial lesions
Ultimately decreasing the risk of ischemic and hemorrhagic stroke.
Thus potassium exhibits cerebroprotective effects in the following ways:
1. Improves endothelial function with vasodilation 2. Increases vascular nitric oxide
3. Decreases vascular intracellular calcium &sodium
4. Alteration in DNA synthesis and proliferation in cerebral vascular smooth muscle
5. Decreases vascular neointimal formation and lowers thrombosis risk 6. Reduces the production of free radicals
7. Reduces macrophage adherence to the vascular wall( an important factor in the development of arterial lesions).
Materials & methods
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MATERIALS AND METHODS
SETTING
This study was conducted at the Institute of Internal Medicine, Rajiv Gandhi Government General Hospital (RGGGH), Madras Medical College, Chennai. This study was approved for research studies by the Ethics committee Madras Medical College, Chennai.
STUDY DURATION
This study was conducted over a period of six months.
STUDY POPULATION
Patients who got admitted with Acute cerebrovascular accidents to the medical wards at the Institute of Internal Medicine.
SAMPLE SIZE : 100 Patients
TYPE OF STUDY : Observational study
INCLUSION CRITERIA
• Patients with acute cerebrovascular accidents lasting < 72 hours
• Patients above age 25
• Both sexes were included
