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A DISSERTATION ON

A CLINICAL STUDY OF HYPONATREMIA AND ITS PROGNOSTIC OUTCOME IN CRITICALLY ILL PATIENTS ADMITTED IN INTENSIVE MEDICAL CARE UNIT AT GOVERNMENT MOHAN

KUMARAMANGALAM MEDICAL COLLEGE – SALEM

DISSERTATION SUBMITTED FOR M.D GENERAL MEDICINE

BRANCH – I MAY – 2020

THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY CHENNAI – 600 032

TAMILNADU

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DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation titled “ A CLINICAL STUDY OF HYPONATREMIA AND ITS PROGNOSTIC OUTCOME IN CRITICALLY ILL PATIENTS ADMITTED IN INTENSIVE MEDICAL CARE UNIT AT GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE HOSPITAL, SALEM.” ” is a bonafide and genuine research work carried out by me under the guidance Dr.M.MANJULA MD Professor of the Department, Department of general medicine, Government Mohan Kumaramangalam Medical College Hospital, Salem, Tamil Nadu, India.

Date:

Place: Salem

Signature of the Candidate DR.G.DEVIGA

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CERTIFICATE FROM THE GUIDE

This is to certify that“ A CLINICAL STUDY OF HYPONATREMIA AND ITS PROGNOSTIC OUTCOME IN CRITICALLY ILL PATIENTS ADMITTED IN INTENSIVE MEDICAL CARE UNIT AT GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE HOSPITAL, SALEM.” is the bonafide work done by Dr.DEVIGA.G in partial fulfillment of the university regulations of the Tamil Nadu Dr.M.G.R. Medical University, Chennai, for M.D General Medicine Branch I examination to be held in May 2020.

Signature of the Guide,

Prof DR.M.MANULA M.D Department of General Medicine Govt. Mohana Kumaramangalam Medical college,salem

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CERTIFICATE FROM THE HOD

This is to certify that this dissertation entitled “A CLINICAL STUDY OF HYPONATREMIA AND ITS PROGNOSTIC OUTCOME IN CRITICALLY ILL PATIENTS ADMITTED IN INTENSIVE MEDICAL CARE UNIT AT GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE HOSPITAL, SALEM.”

is the bonafide work done by Dr.DEVIGA .G in partial fulfillment of the university regulations of the Tamil Nadu Dr.M.G.R. Medical University, Chennai, for M.D General Medicine Branch I examination to be held in May 2020.

Signature of the HOD,

Dr.S.SURESH KANNA M.D Professor and HOD, Department of General Medicine

Govt. Mohan Kumaramangalam Medical college, Salem.

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CERTIFICATE FROM THE DEAN

This is to certify that the dissertation entitled “A CLINICAL STUDY OF HYPONATREMIA AND ITS PROGNOSTIC OUTCOME IN CRITICALLY ILL PATIENTS ADMITTED IN INTENSIVE MEDICAL CARE UNIT AT GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE HOSPITAL, SALEM.” is the bonafide work done by Dr.DEVIGA G in partial fulfillment of the university regulations of the Tamil Nadu Dr. M.G.R. Medical University, Chennai, for M.D General Medicine Branch I examination to be held in May 2020.

Signature of the Dean,

DR.K.THIRUMAL BABU M.D DM THE DEAN,

Govt. Mohan Kumaramangalam Medical College, Salem.

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GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE & HOSPITAL

COPYRIGHT

I hereby declare that the Government Mohan Kumaramangalam Medical College Hospital, Salem, Tamil Nadu, India; shall have the rights to preserve, use and disseminate this dissertation / thesis in print or electronic format for academic / research purpose.

Date:

Place: Salem

Signature of the Candidate Dr.G.DEVIGA

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PLAGIARISM CERTIFICATE

This is to certify that this dissertation work titled “A CLINICAL STUDY OF HYPONATREMIA AND ITS PROGNOSTIC OUTCOME IN CRITICALLY ILL PATIENTS ADMITTED IN INTENSIVE MEDICAL CARE UNIT AT GOVERNMENT MOHAN KUMARAMANGALAM, SALEM of the candidate Dr.DEVIGA.G with registration Number 201711403 for the award of M.D DEGREE in the branch of GENERAL MEDICINE - I personally verified the urkund.com website for the purpose of plagiarism Check.I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 7% percentage of plagiarism in the dissertation.

Guide & Supervisor sign with Seal

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Plagiarism result:

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ACKNOWLEDGEMENT

I owe my thanks to the dean, Government Mohan Kumaramangalam Medical College and Hospital Prof. Dr.K.THIRUMAL BABU.D.M, for allowing me to avail the facilities needed for my dissertation work.

I am grateful to Prof. Dr.S.SURESH KANNA.M.D., Professor and Head of the Department of Medicine, Government Mohan Kumaramangalam Medical College and Hospital for permitting me to do the study and for his encouragement.

I have great pleasure in expressing my deep sense of gratitude and respect for Prof. Dr.M.MANJULA. M.D., Professor, Dept. of Medicine, Government Mohan Kumaramangalam Medical College and Hospital for approving this study and giving suggestions and guidance in preparing this dissertation.

I am extremely thankful to my unit assistant professors, Dr. ARUL.M.D., Dr.SADHASIVAM.M.D., and Dr. PALANIVELRAJAN. M.D., Registrar, department of medicine for their valuable guidance and constant encouragement.

I wish to acknowledge all those, including my other postgraduate colleagues and my family who have directly or indirectly helped me to complete this work with great success.

Finally, I thank the patients who participated in the study with their extreme patience and co-operation without whom this project would have been impossible.

Above all, I thank the Lord Almighty for this kindness and benevolence.

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ABBREVIATIONS

S.NO ABBREVIATIONS EXPANSIONS

1 [Na+] Sodium ion concentration

2 ADH Antidiuretic hormone

3 AIDS Acquired immuno deficiency syndrome 4 ANP Atrial natriuretic peptide

5 ATP Adenosine triphosphate

6 AVP ARGININE vasopressin

7 BUN Blood urea nitrogen

8 cAMP Cyclic adenosine monophosphate

9 CHF Congestive heart failure

10 CKD Chronic kidney disease

11 CAP Community acquired pneumonia

12 Cl‾ Chloride ion

13 CNS Central nervous system

14 CPM Central pontine myelinosis

15 CSF Cerebrospinal fluid

16 CSW Cerebral salt wasting

17 dAVP L-deamino-8-D-arginine vasopressin

18 DM Diabetes mellitus

19 ECF Extracellular fluid

20 FENa Fractional excretion of sodium

21 GBS Guillian barre syndrome

22 GFR Glomerular filtration rate

23 Hb Hemoglobin

24 HCO3‾ Bicarbonate iron

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25 HTN Hypertension

26 ICP Intracranial pressure

27 ICF Intracellular fluid

28 ICU Intensive care unit

29 JVP Jugular venous pressure

30 k‾ Potassium ion

31 LRTI Lower respiratory tract infection

32 ME Microscopic examination

33 mOsm/l Milliosmole per day

34 NKCC Sodium potassium -2 chloride cotransporter 35 ODS Osmotic demyelination syndrome

36 OPD Out patient department

37 RE Routine examination

38 SD Standard deviation

39 SIADH Syndrome of inappropriate antidiuretic hormone 40 SSRI Selective serotonin reuptake inhibitors

41 TBW Total body water

42 TB Tuberculosis

43 TSH Thyroid stimulating hormone

44 TLC Total leucocyte count

45 TURP Transurethral resection of prostate

46 V1 Vasopressin

47 V1a Vasopressin 1 a receptor 48 V1b Vasopressin 1 b receptor

49 V2R Vasopressin 2receptor

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TABLE OF CONTENTS

S.NO TITLE PAGE NO.

1 INTRODUCTION 1

2 AIMS AND OBJECTIVES 2

3 REVIEW OF LITERATURE 48

4 MATERIALS AND METHODS 51

5 OBSERVATION AND RESULTS 54

6 DISCUSSION 88

7 LIMITATIONS OF THE STUDY 96

8 CONCLUSION 94

9 ANNEXTURES 97

BIBILIOGRAPHY PROFORMA CONSENT FORM

ABBREVIATIONS FOR MASTER CHART ETHICAL COMMITTEE APPROVAL LETTER ANTI PLAGIARISM CERTIFICATE

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LIST OF TABLES

S.NO TOPICS PAGE NO

1. Composition of major solutes 4

2. Osmotic feedback system 6

3. Regulation of ADH secretion by blood volume and

plasma osmolality 8

4. Etiology of hyponatremia 18

5. Mechanisms of SIADH 23

6. Diagnostic approach to hyponatremia 38 7. Difference between SIADH & Cerebral salt

wasting 38

8. Treatment of acute and chronic hyponatremia 41 9. Summary of treatment of hyponatremia 41 10. Treatment and limits of correction of hyponatremia 44 11. Mechanisms of osmotic demyelination syndrome 46 12. Age distribution among patient with hyponatremia 54 13. Sex distribution among patient with hyponatremia 55 14. Distribution of clinical presentation of

hyponatremia 56

15. Distribution of patients according to the type of

hyponatremia 55

16. Comorbid diseases among patients with

hyponatremia 56

17. Distribution of patients based on the severity of

hyponatremia 57

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18. Hydration status among study population 60 19. Distribution of patients based on urinary sodium

level 61

20. Distribution of patients based on the cause of

hyponatremia 62

21. Duration of ICU stay in patients with hyponatremia 63 22. ventilator requirement in patients with

hyponatremia 64

23. prognostic outcome in patients with hyponatremia 65 24. association of age with severity of hyponatremia 66 25. association of sex with severity of hyponatremia 67 26. Association of asymptomatic hyponatremia with

severity 68

27. Association of nausea and vomiting with severity 69 28. Association of irritability with severity of

hyponatremia 70

29. Association of confusion with severity of

hyponatremia 71

30. Association of seizure with severity of

hyponatremia 72

31. Association of coma with severity of hyponatremia 73 32. Association of cause with type of hyponatremia 74 33. Association of cause with hydration status 75 34. Association of cause with urinary sodium 76 35. Association of severity of hyponatremia with ICU

stay 78

36. Association of severity of hyponatremia with

ventilator requirement 79

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37. Association of asymptomatic hyponatremia with

prognostic outcome 81

38. Association of nausea and vomiting with

prognostic outcome 82

39. Association of irritability with prognostic outcome 83 40. Association of confusion with prognostic outcome 84 41. Association of seizures with prognostic outcome 85 42. Association of coma with prognostic outcome 86

LIST OF FIGURES

S.NO FIGURES PAGE NO

1 Fluid compartments in average adult 3

2 Sodium and water balance 10

3 Astrocyte and neurovascular unit 12

4 Consequences of rapid change in plasma Na 45 5 MRI imaging in osmotic demyelination

syndrome 46

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ABSTRACT

Background and objectives

Hyponatremia is the one of the most common electrolyte disorder in critically ill patients and is a leading cause of morbidity and mortality. This study was done to evaluate the clinical features, etiology, clinical features ,severity and prognostic outcome of hyponatremia in critically ill patients admitted to Medical Intensive Care Unit.

Aims and objectives:

1 To ascertain frequency, predisposing conditions, clinical features, and prognostic outcome of hyponatremia in critically ill patients.

2 To study about the clinical presentation of hyponatremia 3 To classify the severity of hyponatremia

4 To determine its prognostic outcome –morbidity and mortality.

Methodology

The present one year cross sectional observational study was done in the Department of Medicine Government Mohan Kumaramangalam medical college and hospital. A total of 100 patients admitted in MICU with hyponatraemia from February 2018 to June 2019 were studied.

These patients were evaluated for identifying the cause of hyponatremia which includes clinical history, detailed clinical examination which was followed by needed laboratory investigations. All these patients were followed up till correction of hyponatremia and discharge from hospital premises.

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Results

In our study of 100 patients admitted with hyponatremia in critical care unit slight male preponderance (52%) was noted and females were 48%. The male to female ratio was 1.36:1.Most of the patients were in the age group between 61 to 70 years (31%) followed by 71 to 80 yrs (21%).

The commonest presentation was nausea and vomiting (29%) followed by confusion (25% ) ,seizures (14%). Nearly half of the study population had altered sensorium (49%). The commonest system to be involved was central nervous system. Based on the volume status, 55% of patients were had euvolemic hyponatremia ,25% patients had hypovolemic hyponatremia and 20% patients had hypervolemic hyponatremia. 33% of the patients had severe hyponatraemia with confusion being significantly high in such patients. There was a statistically significantly association was found in cause and type of hyponatremia . The commonest cause of hyponatremia was SIADH identified in nearly half of patients with infections (Tuberculosis and pneumonia) were the predominant cause.

Majority (89%) of the patients in the study were improved well. There was positive association between SIADH and euvolemic hypoosmolar hyponatremia (p<0.001) and high urine sodium (p<0.001).

Most of the patients with severe hyponatremia required prolonged duration of ICU stay and ventilator requirement.

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Conclusion

Treating clinicians always need to be aware about the common occurrence of hyponatremia, its early identification and its association with mulititude of diseases. Patients presenting with hyponatraemia should be meticulously screened for the etiology. A proper understanding of the clinical features, pathophysiological process, severity of hyponatremia and its associated risk factor is necessary in prompt management of hyponatremia

Keywords

Hyponatraemia; Severe hyponatraemia; Serum sodium;

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I.INTRODUCTION:

Hyponatremia is one of the commonest electrolyte imbalance seen in critically ill patients and it is the leading cause of morbidity and mortality in ICU patients .Sodium is the principal extracellular cation which determines osmolality .In the total body sodium majority found in blood plasma and in other extracellular fluids, 40% in bone and remaining 2.5% in other cells and organs. The sodium is essential for life and helps in nerve conduction, passage of nutrients into the cell, maintenance of blood pressure and maintaining plasma osmolality. The clinical presentation ranges from asymptomatic one to headache, nausea, vomiting, muscle cramps, lethargy, restlessness, disorientation, confusion and coma. Women and children compared with men having higher risk of developing hyponatremia and its complications owing to the difference in muscle mass, hormonal and anatomical factors 23.

Hyponatremia is defined as serum sodium level less than 135 meq/l. It is the most common electrolyte disturbance in the elderly and in hospitalized patients. Occurrence and complications of hyponatremia are more in elderly patients and in those with comorbidities.

Mild hyponatremia (serum sodium <135mmol/l) occurs in 15 to 20 % patients and approximately 7% of ambulatory patients, moderate hyponatremia (serum sodium <130mmol/l) occurs in 1 to 7% of hospitalized patients. (3)

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It is particularly common in patients in ICU and with comorbidities where access to water, renal handling and urinary dilution function of kidney are impaired in ill patients often associated with multi-organ failure contributes to morbidity and mortality. The economic impact and overall burden of hyponatremia on the patient and the health care facility is evidenced by longer duration of hospital stay, need of mechanical ventilation ,higher risk of death , disability and cost of care. This study is done to know the common clinical features and prognostic outcome of hyponatremia in critically ill patients in IMCU in Government Mohan kumara Mangalam medical college, Salem.

II. AIMS AND OBJECTIVES:

1 To ascertain frequency, predisposing conditions, clinical features, and prognostic outcome of hyponatremia in critically ill patients.

2 To study about the clinical presentation of hyponatremia 3 To classify the severity of hyponatremia

4 To determine its prognostic outcome –morbidity and mortality.

Physiology of sodium and water regulation:

Body fluid compartment:

Body fluid volume and electrolyte concentration are normally maintained within narrow limits in-spite of wide variations in metabolic activity, dietary intake ,fluid intake and environmental stressors .Homeostasis of body fluids is preserved primarily by kidneys.(1) Water and sodium balance

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are closely inter dependent . Total body water is about of 60% of body weight.

Total body water composition in a average 70 kg man.

Figure: 1

The major extracellular cation is sodium; the major intracellular cation is potassium.

Extracellular sodium concentration averages 140 meq/l. Intracellular sodium averages from 12meq/l.

Intracellular potassium concentration averages 140meq/l. Extracellular potassium concentration averages 3.5 to 5 meq/l. The composition of major solutes differs from ICF and ECF as follows as shown in table (table1)

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Fluid movement in between the intravascular and interstitial spaces occurs across the capillary wall and is determined by starling forces,i.e.,capillary hydraulic pressure and colloid osmotic pressure .The transcapillary hydraulic pressure gradient exceeds the corresponding oncotic pressure gradient thereby favoring the movement of plasma ultrafiltrate into the extravascular space(2) .The return of fluid into the intravascular compartment occurs via lymphatic flow.

The solute or particle concentration of a fluid is known as its osmolality, expressed as milli moles per kilogram of water (mOsm/kg).Water easily diffuses across cell membranes to achieve osmotic equilibrium (ECF osmolality =ICF osmolality).Solutes that are restricted to the ECF or the ICF determine the tonicity or effective osmolality of that compartment.

When Na+ balance is disturbed, as a result of mismatch between intake and excretion, any tendency for plasma sodium concentration to change is generally corrected by the osmotic mechanisms controlling H2O balance. The

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major determinant which helps in maintaining the difference in ionic (cationic) concentration between the ICF and ECF is the sodium–potassium pump (Na ,K activated ATPase) which is integral to all cell membranes. Maintenance of this gradient across cell membranes is necessary in various cell processes, including the excitability of conducting tissues such as nerve and muscle. In plasma and the interstitial fluid compartment difference between protein content maintained by the protein permeability barrier at the capillary wall.

This protein concentration gradient contributes to the balance of forces across the capillary wall which favours fluid retention within the capillaries (the colloid osmotic, or oncotic, pressure of the plasma), maintains circulating plasma volume 3 .Sodium gets actively transported via intestinal membrane. 20 to 30 gms of sodium are secreted in the secretions of intestine per day, the average adult consumes 5 to 8 gms of sodium each day. During the time of intestinal losses as in extreme diarrhea sodium reserves of the body depleted.

Sodium plays a main role in absorption of main sugars, amino acids 29.

Osmoreceptor- ADH feedback system:

This feedback system mainly controls extracellular fluid concentration and osmolarity. When osmolality rises above normal because of water deficit, this feedback system gets activated as follows;

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a) Increase in ECF osmolarity causes spinal nerves (osmoreceptor cells) to shrink which are located in the anterior hypothalamus near the supraoptic nuclei.

b) Shrinkage of these osmoreceptor cells stimulates them to fire by sending nerve cells in supraoptic nuclei, these signals relayed in the stalk of pituitary gland)these action potential in posterior pituitary promotes the release of ADH which is stored in secretory granules of nerve endings.

d) This antidiuretic hormone enters blood stream from there transported to the kidneys, where it increases water permeability of late distal tubules, medullary

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and cortical collecting ducts this in turn increases water reabsorption and excretion of small volume of concentrated urine.

The opposite of events occurs when the ECF becomes too dilute (hypo osmotic).For eg: with excess water ingestion there will be a decrease in extracellular osmolality low ADH is formed which acts on renal tubules to decrease their permeability for water, less water reabsorbed and large volume of diluted urine is formed.

Regulation of sodium balance:

A tight balance between sodium and water is maintained by the integrated role of thirst, vasopressin and renal response. So hyponatremia is almost always due to defect in water balance mechanism. The kidney plays major role in handling sodium balance and water homeostasis .The loop of henle and collecting duct regulates urine concentration in the renal medulla by countercurrent mechanism .Dilution of tubular fluid occurs in distal convoluted tubule by active reabsorption of sodium chloride .The collecting duct acts as site of osmotic equilibrium between urine and medullary interstitium which is mediated by the action of vasopressin.

Water channels (aquaporins) in the collecting duct cells facilitate the rapid transport of water across cell membrane. A number of other hormones also influence sodium balance either by increasing sodium reabsorption or by affecting vasopressin action.

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Regulation of ADH secretion by plasma osmolarity and blood volume:

Increased plasma osmolarity stimulates ADH release from posterior

pituitary. Reduced blood volume, sensed by stretch receptors located in the great veins and atria, will stimulates ADH release. This ADH increases H2O and urea permeability of the distal nephrons in the collecting duct, leads to excretion of minimal volume of concentrated urine, thereby diminishes the further loss of blood volume and decreasing the osmolarity of the serum back toward normal. Aldosterone increases net sodium reabsorption through action

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on the cortical and collecting tubules. ANP (atrial natriuretic peptide) inhibits sodium reabsorption and reduces water permeability in the collecting duct causing natriuresis and diuresis (4).

Osmoreceptors also called as tonicity receptors are the hypothalamic neurons that expresses transient receptor potential cation channel subfamily vanilloid member 1(TRPV1) and member 4(TRPV4) channels on their cell membrane. Both vasopressin and thirst response are inhibited when plasma Na+

<135mMol /liter. Urine osmolality reduces to as low as 50mOsm per kg with the absence of vasopressin response (5). V2 receptors are located on the basolateral membranes of principal cells lining the renal collecting ducts vasopressin binds to that. Aquaporins are inserted into the luminal membrane attracted by high solute concentration of the surrounding medullary interstitium in the presence of vasopressin .If plasma Na+ rises >145mmol/l ,vasopressin level will be high normally to result in maximally concentrated urine(about 1200mOsm per kg).Presence of dilute urine with plasma sodium above 145mmol/l indicates either insufficient vasopressin secretion as in neurogenic diabetes insipidus or failure of kidneys to respond vasopressin secretion as in nephrogenic diabetes insipidus.

Serum/plasma osmolality is defined as a measure of different solutes in the plasma .its estimation is indicated to evaluate the cause for hyponatremia and used to screen for alcohol intoxication by means of osmolal gap. The reference range is 275-295mOsm/kg.

Serum osmolality =2Na+glucose in mg/dl/18+BUN mg/dl/2.8

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If the patient has ingested ethanol, the ethanol level should be included in the calculated osmolality.

Figure: 2

Osmolar Gap

It is defined as Ingestion of toxins with low molecular weight will increase the difference between the measured and the calculated plasma osmolarity or osmolar gap.

The calculated osmolarity

=2×Na++blood urea nitrogen/2.8+glucose/18+ethanol/4.6 Osmolar gap=measured Osm−calculated Osm

An osmolar gap>10mOsm suggests osmotically active substances such as ethanol, methanol, isopropyl alcohol, and ethylene glycol. Hospitalized patients

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might develop an osmolar gap from glycerol, intravenous (IV) immunoglobulin, propylene glycol, radiocontrast media, & sorbitol. Propylene glycol is a common medium for intravenous medications and drugs may cause an osmolar gap difference. The metabolite of propylene glycol, lactic acid, might contribute to a high anion gap metabolic acidosis. Accumulation of propylene glycol in patients receiving high doses IV drugs such as diazepam, which have propylene glycol as their medium, may leading to severe acidosis with hemodynamic instability. Occasionally this may require treatment with dialysis especially hemodialysis.

Sodium & blood brain barrier:

Sodium crosses systemic capillary membranes through clefts which are located in between endothelial cells. The Na+ concentration of plasma and interstitial fluid nearly similar in most tissues with minor difference created by intravascular albumin. Brain capillaries have tight endothelial junctions and are lined by astrocytic foot process creating blood brain barrier in which Na+

cannot cross. An abnormal sodium concentration causes fluid to move in and out of the cell. Only small degree of brain swelling or shrinkage is compatible with life (5).

Na+ K+ ATPase pump:

The Na+ K+ ATPase pump is a membrane bound enzyme that takes part in active electrogenic translocation of sodium and potassium ions across the

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plasma membrane. Cellular volume is maintained by Na+ K+ ATPase pump in a normal isoosmolar environment. It controls epithelial transport and ionic balance indirectly. Changes in cytoplasmic concentration of Na+, K+ and calcium can change the activity of pumps (14).

Urine osmolality:

It is a measure of number of dissolved particles per unit of water in the urine. It is useful to diagnose disorders of urinary concentration like diabetes insipidus and in assessing hydration status. Normal 24 hr osmolality ranges

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from 500-800mOsm/kg of water. Random urine osmolality should average 300-900mOsm/kg of water.

Critically ill:

Critically ill patients are defined as those by dysfunction or failure one or more organs which requires intervention. They may need any form of organ support (inotropes ,ventilation ,intubation) or more likely to suffer an acute cardiac ,respiratory ,neurological deterioration requiring such support .critical illness consists of a heterogeneous group of conditions and disorders that share a risk of organ failure ,long term morbidity and mortality .These patients mostly require critical care management in the ICU.

Hyponatremia:

It is defined as serum sodium level less than 135meq/l after the exclusion of “ pseudo hyponatremia” .Moderate hyponatremia is sodium level in between 125-129mmol/l, severe hyponatremia < 125mmol/l. severe hyponatremia is a serious medical emergency which is associated with substantial neurological complications and mortality. Hypernatremia always denotes hypertonicity but hyponatremia can be associated with low, normal or high tonicity.

Symptoms usually occur when serum sodium falls below 125meq/l.

Seizure ,altered sensorium ,coma usually results from rapid decrease in serum

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sodium <110meq/l. In ICU patients the ability of kidney to excrete electrolyte free water is impaired leading to hyponatremia.

Some conditions like sepsis, septic shock, heart failure, multi organ dysfunction syndrome impair glomerular filtration and enhance sodium and water reabsorption at the proximal tubule thereby diminishing delivery of filtrate to the diluting segment.

Drugs like loop diuretics, thiazides, osmotic diuretics and diseases which affects tubules and interstitium also reduce the reabsorption of sodium and chloride in the diluting segment of nephrons.

Increased water reabsorption in the collecting duct segment of nephrons due to non-osmotic stimuli such as pain, nausea, medications can also leads to hyponatremia. Hyponatremia is a common electrolyte abnormality observed in hospitalized inpatients. It is associated with worst outcomes in patients with acute and chronic cardiopulmonary diseases, such as left and right ventricular heart failure, acute myocardial infarction, and pneumonia. In patients with left ventricular heart failure, hyponatremia is strongly correlated with plasma neurohormone concentrations (e.g., norepinephrine, renin, and angiotensin II), all of which predict adverse outcomes. Neuro hormone mediated release of vasopression is responsible for the decrease in serum sodium in these patients.

Age and Sex Differences in Hyponatremia:

Hawkins observed in his studies that advancing age (30 years old), after adjusting for sex, was independently associated with hyponatremia at the time

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of presentation and hospital-acquired hyponatremia (serum sodium 136 mEq/L) 69. In the similar study, male sex was weakly associated with mild or moderate, but not severe, hyponatremia. Females have been shown to be a risk factor for hyponatremia induced by psychotropic medications or diuretics.

Low body weight identified as a strong risk factor for drug-induced hyponatremia in the elderly individuals. In the same way susceptibility of female marathon runners to develop hyponatremia appears to be related more to lower body weight and longer racing time than to sex itself.

Classification of hyponatremia:

It is classified according to volume status as

• Hypovolemic hyponatremia:

Decrease in total body water with greater decrease in total body sodium.

• Euvolemic hyponatremia:

These patients will have normal body sodium with increase total body water.

• Hypervolemic hyponatremia:

Increase in total body sodium in proportion with greater increase in total body water

Subclassification:

Hyponatremia is further sub classified based on the effective serum/plasma osmolality, as follows;

• Hypotonic hyponatremia

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• Isotonic hyponatremia

• Hypertonic hyponatremia Based on the duration:

1. Acute <48hrs 2. Chronic >48hrs Acute hyponatremia:

In acute hyponatremia the onset of symptoms <48hrs. Patient will manifest with early neurological symptoms resulting from cerebral edema produced by water movement into the brain neurons. Clinical features include altered sensorium, seizures and coma.

Chronic hyponatremia:

Hyponatremia developing over >48hrs to be considered chronic. By the production of idiogenic osmoles central nervous system adapts itself to chronic hyponatremia. This is one of the protective mechanism which reduces the degree of cerebral edema. Hyponatremia in elderly people may present with gait disturbances and frequent falls contributing to mortality. In experimental studies conducted in rats, chronic hyponatremia identified to be a cause of osteopenia than vitamin D deficiency & loss of sodium from bone exceeded the loss of calcium due to increased activity of osteoclasts(.6,7).So chronic hyponatremia associated with osteoporosis and fractures in humans.(5)

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Causes of acute hyponatremia:

1. Iatrogenic

2. Postoperative; premenopausal women 3. Hypotonic fluids with cause of ↑vasopressin 4. Glycine irrigation, TURP, uterine surgeries 5. Colonoscopy preparation

6. Recent institution of thiazides 7. Polydipsia

8. MDMA

9. Exercise induced hyponatremia 10. Multifactorial etiology

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Etiology:

A.Isotonic hyponatremia:

Hyponatremia that is hypertonic and isotonic can often be elicited from detailed history or serum osmolality. Pseudo hyponatremia – where the serum osmolality is isotonic does not occur with newer modalities of sodium measurement. It is defined as an exaggeration of the physiologic dilution of plasma sodium by non-aqueous material. Conditions such as multiple myeloma with high amounts of protein and hypertriglyceridemia with excess lipids can dilute the plasma sodium whereas the intracellular and interstititial sodium remains normal. This error occurs when the values are measured using flame

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photometry. With the development of ion-specific-electrode for electrolyte measurement this error is avoided.

Sometimes hyperglycemia is considered to be a cause of pseudo hyponatremia. It actually causes a dilutional hyponatremia by pulling water into vascular space by osmosis because glucose is an osmotically active molecule. One formula used to correct serum sodium levels based on the severity of hyperglycemia.

By adding 1.6mEq/l to measured sodium for every 100 mg/dl rise of glucose above 100mg/dl for up to 400mg/dl then 4mEq/l should be added for every additional 100mg/dl.

B. Hypertonic hyponatremia:

Hypertonic hyponatremia occurs as translocational hyponatremia due to high glucose or mannitol. Both of the above translocate intracellular water into the extracellular compartment thereby lowering the sodium concentration. This can be treated with correction of glucose and if possible discontinuation of mannitol.

C. Hypotonic hyponatremia:

Hypovolemic hyponatremia:

Hypovolemia causes neurohumoral activation, increases the circulating level of AVP which regulates blood pressure via vascular baroreceptor V1a receptors and increases water reabsorption via V2 receptors; activation of this V2 receptor leads to hyponatremia in the setting of free water intake.

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Non renal causes include GI loss (Diarrhoea ,vomiting, tube drainage) and insensible loss (sweating ,burns) of sodium chloride and water in the absence of adequate oral replacement ;urine Na+ concentration typically <20mM . Urinary sodium concentration <20mM with clinical hypovolemic features will respond to intravenous saline/fluids thereby increases plasma Na+ concentration.

Pathophysiology of renal causes is inappropriate loss of Na+ Cl- in the urine leads to volume depletion and elevated AVP levels. Patient presented with hyperkalemia, hyponatremia and hypotension with features indicative of hypoaldosteronism and urine Na+ >20mM strongly suggestive of adrenal insufficiency.

Salt losing nephropathies can also lead to hyponatremia when sodium is intake is reduced because of defective tubular function

Causes are

1. Reflux nephropathy, 2. post obstructive uropathy 3. medullary cystic disease 4. interstitial nephropathies

5. Recovery phase of acute tubular necrosis.

Hypervolemic hyponatremia:

Patients with congestive cardiac failure (CHF), cirrhosis, and nephrotic syndrome will develop an increase in total body Na+ Cl- accompanied by

20

(40)

proportionately greater increase in total TBW leading to hypervolemic hyponatremia. It is characterized by clinically detectable edema, anasarca/ascites that indicates increase in total body water &sodium.

Causes are

• .nephrotic syndrome

• congestive cardiac failure

• .liver failure

• .chronic kidney disease

Normovolemic (euvolemic hyponatremia):

It is the most common cause of hyponatremia in hospitalized patients encountered in clinical practice. It is usually associated with non-osmotic and non –volume related ADH secretion (ie, SIADH) secondary to some clinical conditions, which includes the following.

CNS disturbances:

Infections:

• Meningitis

• Encephalitis

• Brain abscess

• AIDS

• Rocky Mountain spotted fever Bleeding and masses:

• Subarachnoid hemorrhage

21

(41)

• Cerebrovascular accident

• Subdural hematoma

• Brain tumors

• Cavernous sinus thrombosis Hydrocephalus:

• Major surgery, Trauma

• Infection

• Pulmonary disorders Infections

• Bacterial and viral pneumonia

• Pulmonary abscess

• Tuberculosis

• Aspergillosis

• Asthma

• Cystic fibrosis Stress

Certain medications-

• chlorpropamide ,carbamazepine ,cyclophosphamide

• Vincristine ,vinblastine, amitriptyline, haloperidol, selective serotonin reuptake inhibitors ,MAO inhibitors , Desmopressin .

Malignancies

• Carcinoma –lung

22

(42)

• GIT cancers

• Endocrine thymoma

• GUT cancers

• Ewings sarcoma

SIADH : syndrome of inappropriate antidiuretic hormone secretion is the most common cause of euvolemic hyponatremia. Pathophysiology as follows:

23

(43)

Diagnostic criteria for SIADH:

Essential criteria:

• Effective serum osmolality <275mOsm/kg

• Urine osmolality >100mOsm/kg at some level of decreased effective osmolality

• Clinical euvolemic state

• Urine sodium concentration >30mmol/l along with normal dietary and salt and water intake

• Absence of adrenal, thyroid ,pituitary or renal insufficiency

• No recent usage of diuretics Supplemental criteria:

• Serum uric acid <0.24mmol/l (<4mg/dl)

• Serum urea <3.6mmol/l

• Failure to correct hyponatremia after 0.9% saline infusion

• Fractional sodium excretion >0.5%

• Fractional urea excretion >55%

• Fractional uric acid excretion >12%

• Correction of hyponatremia through fluid restriction .

HIV infection:

Hyponatremia seen in 20% ambulatory and 50% hospitalized human immunodeficiency virus infected patients(13).Hospitalized patients infected with

24

(44)

retrovirus have a high incidence of hyponatremia, in which hyponatremia is due to one of the following disorders

1. Increased ADH release secondary to malignancy to occult or symptomatic infestation of CNS, or to pneumonia resulting from pneumocystis jiroveci infection.

2. Adrenal insufficiency due to an adrenalitis secondary to infections by CMV, Mycobacterium avium intracellulare or HIV itself.

3. Effective volume depleted state secondary to fluid loss from GIT primarily by infectious diarrhea.

Hyponatremia in liver and heart failure:

In conditions such as heart failure (low cardiac output) and liver failure (systemic dilatation) the effective arterial blood volume will be low. When the baroreceptor activity is reduced the system to be activated first is the RAAS and with further decrease in arterial filling the vasopressin axis gets activated .As such in cases of heart and liver failure the occurrence of hyponatremia is a poor prognostic indicator and hence hyponatremia itself is an independent predictor of long term mortality and in survivors of acute STEMI. The reason for this is because hyponatremia is useful as marker to identify the extent of neurohumoral response and degree of decompensation.

25

(45)

Medications:

Most common medications to cause hyponatremia are thiazide diuretics predominantly in elderly females due to ADH effect, diuretic induced volume contraction and intact urinary concentrating ability .Whereas loop diuretics have impaired urinary concentration and distorted medullary concentrating gradient and do not cause hyponatremia as often like thiazide diuretics.

NSIADS by causing inhibition of prostaglandins formation increases ADH release resulting in hyponatremia. Increased production and action of ADH due to serotonergic tone of SSRIs can result in hyponatremia in elderly.

During ventricular tachycardia when amiodarone is given hyponatremia is often noted which gets corrected with dose reduction. MDMA (ecstasy) 3,4 - methylenedioxymethamphetamine causes hyponatremia manifesting as seizures ,cerebral edema and brain stem herniation. The mechanism for above is that MDMA and its metabolites cause an increased release of ADH from hypothalamus. In addition MDMA consumers take more fluids to prevent hyperthermia, this primary polydipsia aggravates the electrolyte imbalance.

Cerebral salt wasting:

It is seen in intracranial disorders such as subarachnoid hemorrhage, carcinomatous or infectious meningitis & metastatic carcinoma. Disruption of sympathetic neural input to kidney by direct and indirect mechanisms may cause renal salt wasting and decreased renal volume. Because of disruption of sympathetic nervous system plasma renin and aldosterone levels fail to rise

26

(46)

appropriately in patients with CSW inspite of reduced plasma volume.

Differentiating it from SIADH is the real challenging one because of overlap in clinical presentation. Vigorous salt replacement required in patients with CSW but in patients with SIADH fluid restriction is the treatment of choice. It is usually transient with resolution occurring within 3-4 weeks of disease onset.

Hypovolemic hyponatremia caused by salt wasting nephropathy may develop a range of renal disorders.

Other hyponatremic disorders:

Exercise associated hyponatremia (EAH):

Hyponatremia develops during or after 24 hours of prolonged physical activity. Endurance developing athletes who take part in events such as marathons, triathlons have been reported to have a higher incidence of hyponatremia. Risk factors include low body mass index, over hydration and excessive fluid consumption during such strenuous activities. Female athletes are more prone to develop hyponatremia than their male counterparts. Due to ingestion of hypotonic fluids (water or sports drinks) in excess of sweat, urine and insensible loss mainly respiratory and GI tract, total body water is increased disproportionately to that of total exchangeable body sodium.

Athlete’s who present with altered sensorium, seizures and confusion with body serum sodium less than 135mmol/L are considered to be having exercise induced encephalopathy. The treatment of choice for correcting hyponatremia is administration of 3% hypertonic saline at a rate of 1-2ml/kg/hour. During

27

(47)

treatment, the parameters to be measured include serum electrolytes and urine excretion of sodium and potassium. For correcting hyponatremia due to cirrhosis, heart failure and SIADH drugs such as Vasopressin receptor antagonists (VAR) which include oral lixivaptan, tolvaptan and intravenous conivaptan are useful. In addition after completion of strenuous exercise, there is also risk of development of hypokalemia. Therefore, side by side replacement of potassium loss helps to reduce vigorous correction of hyponatremia since potassium replacement causes sodium to shift out of cell and increases serum sodium.(8)

Beerpotomania:

Unique syndrome of hyponatremia seen in heavy beer drinkers (consuming 5or more drinks per day).Excessive intake of alcohol combined with poor dietary solute intake leading to dizziness, fatigue, muscular weakness. The low solute content in alcohol combined with suppressive effect of alcohol on proteolysis resulting in reduced solute delivery to kidney thereby causes dilutional hyponatremia (11).

Management of beer potomania:

1. Nothing should be given by mouth except medications for 24 hrs.

2. No IV fluids unless patient is symptomatic 3. Prescribe IV fluids in correct amount if needed 4. ICU care status

28

(48)

Check serum Na+ every 2 hrs.

Goal serum sodium increase <10mEq in first 24hrs, <18mEq/l in first 48 hrs Reduce serum sodium levels if necessary

5. Give any intravenous medications in sugar solutions (5% dextrose in water) 6. If caloric intake is needed, use intravenous sugar solutions.

Psychogenic polydipsia:

Excessive free water intake usually >10 l/day might produce hyponatremia.

Urine sodium is elevated >20mEq/l & ADH levels are suppressed. Usually polydipsia seen in psychiatric patients. Psychiatric medications interfere with water excretion and increases thirst through its anticholinergic effects.

Ex:antidepressants –tricyclics ,SSRIs,monoamine oxidase inhibitors.

Reset osmostat:

It is an uncommon cause of low sodium with appropriate ADH regulation in response to water deprivation and fluid challenges. Patients with reset osmostat maintain serum Na+ and serum osmolality around a lower set point, either diluting or concentrating in response to hypo osmolality and hyperosmolality. Mild hypo osmolality seen in pregnancy is a form of reset osmostat (1).

29

(49)

Hyponatremia in the elderly:

Hyponatremia is the most common electrolyte imbalance seen in both hospitalized patients and in community subjects. Elderly patients are the high- risk group for the development of hyponatremia because age is a strong independent predisposing factor for hyponatremia 57. The clinical presentation of acute hyponatremia (developed in 48 hrs) such as nausea, vomiting, headache, stupor, coma and seizures, as well as symptoms (even mild) associated with chronic hyponatremia, such as fatigue, cognitive impairment, gait deficits, falls, adverse effects on bone quality (eg, osteoporosis) and fractures, are more common and worse in elderly individuals 58.

Pathophysiology of hyponatremia in elderly:

The greater intensity of the elderly to develop hyponatremia is mainly due to the following reasons:

1) The aging-related defective water excretory capacity due to age related reduction in GFR.

2) The frequent exposure to drugs and some disorders common in elderly leading to hyponatremia

3) Reduced intrarenal generation of prostaglandins found in advanced age may result in defective ability of geriatric individuals to excrete water.

30

(50)

4) The urinary diluting capacity of the kidney is preserved in elderly persons, even with reduced GFR, and so hyponatremia develops only in the presence of more water intake with additional aggravating factors 62.

5) age-related reduction in the percentage of TBW content, leading to wider fluctuations in serum sodium concentration, because:

Serum sodium levels = exchangeable total (sodium + potassium)/total body water.

6) Higher sensitivity to osmotic stimuli evidenced in geriatric population 7) Frequent intake of drugs for multiple conditions (eg, thiazide diuretics, selective serotonin reuptake inhibitors [SSRIs], serotonin–norepinephrine reuptake inhibitors [SNRIs], nonsteroidal anti-inflammatory drugs [NSAIDs]) or/and affected with diseases [DM], infections, heart failure, liver diseases, malignancies, endocrinopathies) can predispose them to electrolyte imbalance

63.

7) Many elderly patients with SHTN or heart failure adhere to reduced-salt intake that may be associated with decreased plasma Na+ concentration.

8) Reduced consumption of protein (may be habitual or due to superimposed illness) leading to impaired water excretion capacity of kidney.

9) This electrolyte imbalance follows a seasonal variation (higher incidence observed during the summer seasons) because of more frequent derangement of

31

(51)

renal function, increased salt losses through insensible losses, reduced salt intake and more water consumption.

“Tea and toast” hyponatremia:

It can occur in older individuals with a reduced GFR who follows a diet which is poor in salt and protein content but drink more amount of water. In these patients, there will be a low distal delivery of filtrate (due to low GFR may be due to chronic sodium deficit) and increased water reabsorption owing to the reduced rate of osmoles excretion. When water consumption exceeds the excretory capacity of kidney, hyponatremia results 64, 67.

Hyponatremia in pulmonary embolism:

Even though hyponatremia is associated with poor outcome in heart failure, pneumonia, and pulmonary hypertension, the prognostic value of hyponatremia, a marker of neurohormonal activation, in patients with acute pulmonary embolism (PE) is not known. In patients with acute pulmonary embolism, hyponatremia at the time of presentation to hospital is common, and it is associated with a higher risk of 30-day mortality and readmission rates 30. Neurohormonal activation has been

Observed in patients with pulmonary arterial hypertension and occurs in according to the degree of right ventricular dysfunction in pulmonary embolism

39.

32

(52)

Hyponatremia in special situations:

Hyponatremia in the Postoperative Period:

Antidiuresis is a peculiar feature of the postoperative period mainly owing to the nonosmotic release of arginine vasopressin from neuro hypophysis. Chung and coworkers prospectively studied 1,088 patients at the University of Colorado Health Sciences Center in Denver over a 96-day period of admission and observed that 4.4% of patients developed postoperative hyponatremia (serum sodium 130 mmol/L) within 1 week of their operative procedure. AVP was detected in the plasma of all operated patients with hyponatremia in whom it was tested, and 94% of the patients were received hypotonic fluids at the time of onset of hyponatremia. Chung finalized that the frequency of postoperative hyponatremia differed according to the type of procedure, and it appears to be more frequent after organ transplantation and gastroenterologic, cardiovascular, or trauma surgery 50.

Admission versus Hospital-acquired Hyponatremia:

A defect in H20 excretion may develop or worsen during the period of hospitalization as a result of several antidiuretic influences (e.g., medications, pain, severe nausea, organ failure). Such a defect can precipitate the hyponatremia if combined with the intake of electrolyte-free water in amounts which exceeds the capacity for water excretion plus insensible losses 55. Baran and Hutchinson noticed that 67% of hospitalized patients with hyponatremia

33

(53)

(defined as serum sodium 128 mmol/Land 130 mmol/L, respectively) developed the electrolyte disturbance during the course of their hospital stay 56. Clinical features:

The clinical features of hyponatremia occur because of water movement down the osmotic gradient from the hypotonic ECF to ICF which causes generalized cellular swelling. The symptoms are mainly neurological in nature because of cerebral edema occurring within a rigid skull (2). This cerebral edema is due to increase in interstitial pressure which leads to shunting of solutes and fluids from the interstitial space into the CSF and then later on to systemic circulation. This occurs along with efflux of intracellular ions namely Na+, K+, Cl+. The symptoms depend on the disease severity and onset.

Hyponatremia of chronic onset even though it’s severe can be asymptomatic since the brain has adapted itself to the changing levels by reducing its tonicity over weeks to months. Acute onset disease however even if it’s moderate can be severely symptomatic. Hyponatremia that is mild is often asymptomatic.

Initial symptoms begin as nausea and malaise which further develop into lethargy, headache and disorientation as serum level decreases. The life threatening complications that occur are respiratory failure, seizure, coma, permanent brain damage, brainstem herniation and death (8).

Acute hyponatremia can result in respiratory failure that is normocapneic or hypercapneic. The normocapneic respiratory failure that occurs in such settings is often due to neurogenic pulmonary edema with a normal PCWP.

34

(54)

Symptomatic hyponatremia with its neurological sequelae occurs more in women in premenopausal age than men.

Chronic hyponatremia of long duration causes an efflux of osmolytes from the brain cells such as creatine, betaine, taurine, myoinositol and glutamate.

This results in reduction of intracellular osmolality which favours water entry.

Most of this intracellular reduction in osmolytes is complete within 48hours.

However this cellular response does not fully protect patients who manifest some nausea, vomiting, confusion and seizures. Even those who have been labeled asymptomatic may show gait and cognitive defects. Hence, chronic hyponatremia has increased risk of self-fall and bony fractures because of neurologic dysfunction and hyponatremia associated bone density reduction (2).

Diagnostic approach:

Diagnostic approach to hyponatremia includes a careful history (drug history) & physical examination to determine the etiology and course of illness.

In physical examination blood pressure, pulse rate, respiratory rate, JVP, pedal edema, ascites, volume /hydration status also be noted. Before confirming it as true hyponatremia pseudo hyponatremia to be excluded (falsely low sodium with normal serum osmolality10.

Clinical assessment of volume status is essential to identify etiology.Patient may presents with the features of hypovolemia or hypervolemia with neurological findings.Identifying the hydration status might help to determine the cause of hyponatremia and suggests the better prognostic

35

(55)

outcome.Diminished skin turgor,dry mucous membrane & orthostatic hypotension indicates hypovolemic hyponatremia which may be owing to excessive body fluid loss and replacement with inappropriate diluted fluids.Presence of S3 gallop,rales,peripheral edema, ascites indicates hypervolemic hyponatremia due to retention of sodium and water in cases of cirrhosis, nephrotic syndrome,congestive heart failure. It is frequently a multifactorial etiology especially when severe ;evaluation must consider all the possible causes of increased circulating AVP,including volume status ,drugs.

Radiological investigations also helpful to assess pulmonary /CNS pathology.chest x ray may be useful as a screening test to detect pulmonary opacities but fails to detect small cell carcinoma of lung which is revealed by CT thorax.

Three essential laboratory test 1. Serum sodium

2.Serum and urine osmolality 3.Urinary sodium concentration

Other ancillary tests are:

Elevated BUN &Serum creatinine indicates renal failure as the cause.

Seum potassium – hyperkalemia suggests adrenal insufficiency/

hypoaldosteronism

Thyroid, pituitary, adrenal function also be tested in needed cases.

36

(56)

Urine electrolytes & osmolality:

Urine Na+ concentration <20-30mM suggestive of hypovolemic hyponatremia in the absence of hypervolemic state Na+ avid syndrome such as CHF, but the gold standard test for diagnosis is correction of plasma sodium concentration after hydration with normal saline.

A urine osmolality <100mOsm/kg is suggestive of polydipsia;urine osmolality >400mOsm/kg indicates AVP excess.In hypovolemic hyponatremia ,patient has deficit in TBW with disproportionate sodium loss commonly due to renal urinary sodium >30mmol/l or extrarenal urinary Na+<30mmol/l losses from vomiting, diarrhea, pancreatitis, brain injury.11

Cerebral salt wasting is a rare cause of hypovolemic hyponatremia in which CVP<5 cm H2O,hypotension with UNa+ >40mol/l in intracranial diseases(12) as

37

(57)

follows.

DIFFERENCE BETWEEN IN SIADH AND CSW:

38

(58)

Treatment:

Three major considerations which helps in deciding therapy which are 1. Presence and or severity of symptoms

2. Patients presenting with symptoms vary from headache, nausea, and or vomiting, seizures, obtundation, central herniation will usually have acute hyponatremia.

Patient with chronic hyponatremia are at risk of osmotic demyelination syndrome if serum sodium corrected by >8-10mM within first 24hrs and or by

>18mM within first 48 hrs. Response to therapy such as hypertonic saline, isotonic saline or AVP antagonists is highly unpredictable.

Once urgency is corrected therapy should be focused on treatment or withdrawal of underlying cause. Euvolemic hyponatremia patients like SIADH, hypothyroidism, secondary renal failure will respond to successful treatment of underlying cause. Patients with hypovolemic hyponatremia will responds to intravenous hydration with isotonic saline with brisk decrease in AVP and a rapid water diuresis. In CHF hypervolemic hyponatremia may often respond to therapy of cardiomyopathy. e.g; following administration ACE inhibitors.

Patients with beer potomania induced hyponatremia and low solute intake might responds to intravenous saline and normal diet and also these patients are at risk of development of ODS due to associated hypokalemia ,alcoholism, malnutrition.

39

(59)

Water deprivation plays a main role in treatment of chronic hyponatremia.

It is based on the urine to plasma electrolyte ratio. (Urinary [Na+] +[K+] / plasma sodium. Patients with ratio of >1 to be more aggressively fluid restricted (<500 ml/day). Those with the ratio of 1 to be restricted with 500 to 700 ml/day and with <1 ratio to be given less than 1 ltr per day. In patients with hypokalemia potassium replacement will help to increase the plasma sodium concentration. Most of the patients with SIADH respond to combination therapy with oral furosemide 20mg twice a day (increased doses necessary in renal impairment and oral salt tablet). Furosemide acts by inhibiting renal countercurrent mechanism and blunt the concentrating ability but salt tablets counter act diuretic associated natriuresis. In patients whose sodium level does not increase in therapy with furosemide and salt tablets demeclocycline may be used which is a potent inhibitor of principal cells, but it should be avoided in cirrhotic patients in particular who are at increased risk of renal toxicity due to drug accumulation , reduction in GFR, excessive natriuresis.

AVP antagonists (vaptans) or effective in SIADH and in hypervolemic hyponatremia due to cirrhosis or heart failure by increasing the plasma sodium level by their aquaretic effect. Tolvaptan is currently the only oral v2 antagonist to be approved by US Food and drug administration. Conivaptan is the only available intravenous vaptan is a mixed V1A /V2 antagonist with slight risk of hypotension.

40

(60)

Treatment of acute symptomatic hyponatremia:

1 Hypertonic 3% saline (513 mM) to increase the plasma sodium by 122 mM/hr to a total of 4 to 6 mm.

2 Calculation formula for sodium deficit = 0.6 ×bodyweight ×( target plasma sodium concentration – starting plasma sodium concentration )

41

(61)

Consequences of hyponatremia:

Extreme hypertonicity produces break in DNA and damages the cytoskeleton, extreme hypotonicity ruptures cell membrane finally leading to cell apoptosis. Neuronal cells protect their volume and their survival by adjusting intracellular solute contents (15). Hypotonicity stimulates the release of osmolytes from cells via volume sensitive leak pathways along with that osmolyte - accumulating transporters (myo-inositol transporter SMIT and taurine transporter are down –regulated. These transporters are up –regulated in hypertonicity. Osmotic disturbances affect all neuronal cells, manifestations are primarily CNS changes in plasma sodium concentration can cause permanent, severe sometimes lethal brain injury.

Brain swelling due to sudden onset of hyponatremia leading to raised intracranial pressure, impairing cerebral blood flow and occasionally produces herniation. Adaptive mechanisms like release of glutamate, an excitatory neurotransmitter makes the patient susceptible to seizures; reduction of neurotransmitter from nerve endings contributes to neurologic symptoms of hyponatremia. The astrocytic foot process encircles both brain capillaries and neurons which express aquaporin-4 that allow water to cross blood brain barrier (16).

Neurons are protected from osmotic stress by astrocytes; in response to hypotonicity, a cell to cell transfer of taurine to nearby astrocytes allows neurons to maintain their cell volume while astrocytes swell (17). Within 24hrs to 48 hours after transfer, astrocytes regain their volume by loss of organic

42

(62)

osmolytes, but this makes them prone to injury from rapid normalization of plasma sodium. Recovery of this lost brain osmolytes may take a week/ longer because of this down regulation. Hence rapid correction of hyponatremia is a hypertonic stress to astrocytes that are depleted of astrocytes induces cellular apoptosis, breakdown the blood brain barrier and consequently produces brain demyelination (18). Brain demyelination has been prevented in experimental animals by repleting myo –inositol or by administration of minocycline (which prevents proliferation of glial cells) has been proved.

Osmotic demyelination syndrome:

Rapid correction of chronic hyponatremia results in CNS injury which manifests as biphasic neurological illness called as osmotic demyelination syndrome: initial minimal symptoms followed by insidious onset of new neurologic findings. The clinical spectrum varies from behavioural abnormalities, seizures and movement disorders. Because of demyelination of pons some patients may suffer from “locked in,”unable to move, speak or swallow and so. ODS may cause permanent disability or death some patients.

who were in ventilator support had a full functional recovery.

43

(63)

An unusual complication of hyponatremia is a fatal brain swelling which was reported only in hyponatremia patients with intracranial disease and in some conditions susceptible to hyponatremia like self-induced water

intoxication and post-operative hyponatremia . An increase in sodium level of 4 to 6mmol/l is enough to reverse impending brain herniation or stops seizure activities which was achieved by 3 % saline 100 ml bolus infusion given in 10mins intervals to a total of 3 doses if needed. Patients with central pontine myelinolysis may present one or more days after overcorrection with

dysphagia, dysarthria,diplopia,paraparesis/quadriparesis and or

unconsciousness. Chronic hyponatremia is corrected slowly with the use of furosemide, salt tablets, slow infusion of 3% saline, urea, and vasopressin antagonists or by correcting underlying the cause. Extra pontine myelinolysis

44

(64)

can occur in cerebellum, lateral geniculate body, thalamus, putamen, cerebral cortex and subcortex. In patients with risk factors like with alcoholism,

malnutrition, liver diseases, hypokalemia even slow correction also associated with ODS.

45

(65)

Mechanism ofOsmotic demyelination syndrome:

Central pontine myelinolysis can be identified by CT but MRI findings are striking one and the investigations of choice having more sensitivity than CT and superior capacity for identification of lesions of extra pontine myelinolyis.

46

(66)

MRI image shows low attenuation areas in the pons in central pontine myelinolysis. T2 weighted and FLAIR sequences showing symmetrical, trident or Mexican hat shaped high signal in the basal pons.

A consensus statement in 2005 put forward a information that 3%

hypertonic saline can be used for symptomatic patients, either as a 100 mL (513 mEq of Na+/L) rapid infusion followed by 100 ml/h or at a rate of 1 to 2 mL/ kg/h. If a second bolus is needed for the patient, an additional 100 ml of the 3% hypertonic saline may be administered over the next 50 minutes.

Correction of hyponatremia by 4 to 6 mmol/L within 6 hours, with bolus infusions of 3% saline if necessary, is enough to manage most of the severe clinical manifestations of hyponatremia.

47

References

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