know

as

you

goDear Doctor,

In this edition we have added an article on "Post Burn Scar Management" in continuation with the previous series article on Pediatric Burn besides that there is also an article on "Hyponatremia: Diagnosis and Management" which was published in a International Journal. I would like to extend my gratitude to the contributors and also to my colleagues who have helped me to edit & design this publication.

I hope you will enjoy reading and will get back to us with your very constructive criticism to help us to improve our publication.

Your prescription is our strength for our further publications.

Please feel free to send us your comments.

Dr. Afroza AkhterCell: 01713426579e-mail: aakhter.msd@acmeglobal.com

Preface

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CONTENTS

Review Article

Series Article

♦ Post Burn Scar Management Dr. Tanveer Ahmed Dhaka Medical College and Hospital

♦ Hyponatremia: Diagnosis and Management Dr. Ahmed Salam Mir BIHS General Hospital

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Series ArticleSeries ArticleSeries Article

Post Burn Scar ManagementDr. Tanveer Ahmed

MBBS, FCPS (Plastic Surgery), FACS (USA)International Guest Scholar, American College of Surgeons

Assistant Professor of Plastic SurgeryDepartment of Plastic Surgery

Dhaka Medical College and Hospital, BangladeshE-mail: tahimon@gmail.com

The formation of a scar is a natural part of the healing process after any injury like burn. Scars usually vary on individuals, the nature of the burn, the conditions of burn wound healing following dressing and types of dressing etc. Scars may cause itching, tenderness, pain, sleep disturbance, anxiety, depression and disruption of daily activities. Unfortunately, there is no particular treatment which has proved to be effective in the prevention of scar formation. Topical agents play an important role in the treatment of post burn scars. They help to improve the appearance of scar in the skin.

ScarAfter an injury abnormal formation of collagen in the skin causes scar. Scars are usually areas of fi brous tissue that replace normal skin. The formation of a scar is a natural part of the healing process after

Series Article

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burn injury. Normally, skin cells rich in collagen multiply to replace the injured skin following burn unless re-epithelized. The collagen contains fi bres that strengthen the layer of skin below the surface. The collagen adds thickness to the healing skin and this thickness causes scarring. The healing of scar normally depends on individuals, color of skin, age, hereditary factors, conditions of wound healing, severity and location of the burn etc. Scars may cause itching, tenderness, pain, sleep disturbance, anxiety, depression and disruption of daily activities. Scars become troublesome for some patients especially when the scar cannot be hidden by clothes may lead to post-traumatic stress reactions, loss of self esteem and stigmatization leading to a diminished quality of life. Scar contractures may determine disabling physical deformities.

Types of scarThere are several different types of scars:

Hypertrophic Scars: Hypertrophic scars are normally redder in appearance. These scars are lightly raised and thickened.

Fig: Hypertrophic Scars

Keloid Scars: Overproduction of new scar tissue form keloid scars. After burn usually they appear and they also caused by infl ammation from pimple, surgery, or piercings. Keloid scars normally harmless but they cause itchiness, tender, or even painful to the touch. Keloid scars spread beyond the original wound site and they can continue to grow slowly for years. They are normally hereditary and more common in darker skinned people.

Fig: Keloid Scars

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Atrophic Scars: Atrophic scars occur when fat and muscle under the wounded/ burnt skin is damaged or lost. These scars are recessed for instance acne scars.

Fig: Atrophic Scars

Contracture Scars: These scars are mainly caused by burn of the skin and have a pulled taught appearance caused by skin contraction during healing. When underlying muscles, tendons, joints and nerves are affected deep contracture scars can restrict movement. The healing process of contracture scars is slow.

Fig: Contracture Scars

Scar following Burn1. Types of burn and thickness of skin burnt.2. Chemical burn usually causes bad scar due to extensive damage

and coagulation of tissue.3. Advanced burn wound dressing reduces scar, like- hydrocolloid

dressing, collagen sheet, Aquacel Ag, Alginate, ADM, moist dressing technique etc.

4. Prevention of infection.5. Proper splinting or immobilization to give rest to the healing area.6. Nutrition and Scar Healing: Vitamins and mineral supplements

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are known to help promote wound healing and also reduce the development of scar tissue. Protein, and they also help fight infection. Because protein deficiency can delay wound healing.

7. Zinc: Zinc promotes new skin formation and plays an important role in the collagen matrix. It helps to fight infection and heal the wound faster. Zinc supplements or zinc containing food are important to take before surgery as surgical trauma can decrease zinc levels.

8. Vitamin C: Vitamin C accelerates wound healing if taken in doses larger than the recommended daily allowance (RDA).

9. Other vitamins and minerals that reportedly promote skin healing include: bromelain (pineapple), grape seed extract, vitamin A, glucosamine, hyaluronic acid, and collagen supplements.

MassageAs soon as the burn wound heals, patients can begin work on the tissue by massage with some topical agents which is to gently smooth the tissue on the scar, in the direction of the scar which helps the tissue to be more mobile. As a result the scar will also heal in a thinner line with less redness. After few weeks one can begin to go sideways and diagonally with a little more pressure. Another important technique is to lift the scar up very gently from the underlying tissue so it does not adhere to it which is very important for mobility and it helps with sensitivity. The nerves under the scars will remain too sensitive or altered if the scars are never handled or touched. More ever touching the scar while it is forming helps a person to heal emotionally and physically.

Care of scabNormally wounds should not dry in the air as scabs interfere with wound healing which may cause more scar tissue to form. Kim Rock Stockheimer an expert in scars from the University of Wisconsin said ‘A scab will create a barrier to healing’. To create an ideal healing environment it is recommended to keep a wound moist and covered thereby keep the collagen away from the surface of the skin. Various types of wound dressings are available and which dressing is best depends on the type of wound for example the amount of wound fluid exudate etc. Skin should be moisturized to improve wound healing and ensures a balanced release of collagen. Hydration is also how silicone sheets work on scars.

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Fig: scab

Use of topical agents or scar creams after burn healsUnfortunately there is no particular treatment which has proved to be effective in the prevention of scar formation. Vitamin E creams, and silicone gel sheeting are marketed for use on burn scars to prevent excessive scarring but none of the showed to be consistently effective.

In order to improve the appearance of the scars there are wide range of treatment options available. Among them some are specific for certain type of scars and some are more effective than others.

The treatments for scars are discussed below:1. Topical Agents for Scar RemovalPharmacologic topical agents are the most common method of improving a scar. These agents can be applied directly on the scar tissue. They usually come in the form of creams and lotions or ointments. Application of topical agents on the scar is easy and the effect is direct. But apart from the advantages they also have many limitations.

They have to only apply to scars that have been formed recently not in the old scars that may have been present in the person’s life for years and they could not be easily removed. Also it would take a long time before these topical agents would work but rest assured, they will.

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Mechanism of topical agents Topical agents normally worked through the enhanced growth and multiplication of the epithelial skin cells. The upper portion of skin can be easily shed off when the scar is found only on the epidermal or the upper portion of the skin and the after shedding off a new skin layer replace the old one. Normally cell cycle of epithelial skin is at 30 days but topical agents increase its speed as much as two times.

Effectiveness of topical agentsNow a days there are so many topical agents are being advertised in the internet also through media. For this one can easily browse and read the reviews of a certain product to know whether it is effective or not. People can easily know from the reviews if there are any side effects or is it safe to use and if there are any harmful side effects or contraindications with other drugs. But it is always better to consult with an expert before purchasing to stay in the safe side.

Topical Scar TreatmentsTopical treatments are those which are applied to the skin in a non invasive fashion for example, a lotion, a ointment or a cream. Topical agent plays an important role in the treatment of post burn scars. A brief description of each is given below -

A) Vitamin E Cream

Vitamin E speeds wound healing and improve the cosmetic appearance of scars. Vitamin E is recommended topically by many doctors for scar treatment. However, In 1999 an oft-quoted study into the effect of vitamin E on scars revealed that Vitamin E did not improve the appearance of scars. It also caused dermatitis among 33% of participants. It actually worsens the cosmetic appearance of scars in 90% of study participants. To avoid the high risk of dermatitis and allergies it may be best to avoid using vitamin E on scars.

B) Natural Products for Scar HealingThere are numerous natural oils, plants and products which are widely used to help improve the appearance of surgery scars. They are given below -

Allium Bulb Extract - Onion extract has used for scar treatment in so many products, including Derma E Scar Gel and the popular

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Mederma Scar Gel. Their effectiveness on scar though not clear.

Arnica Cream or Gel - Arnica creams and gels promote scar healing. They also use to reduce inflammation and pain. They are used topically. Arnica gels should be avoided as they contain alcohol which dries out the skin. Topical arnica formulated with calendula and silicone can also improve scar healing.

Castor Oil - Castor oil is very good oil for scars as they soften and smooth out some of the fibrous tissue of a scar thus improve scars appearance which makes the scar less noticeable. In order to promote circulation and healing castor oil should be gently massage into scars.

Calendula Gel or Cream - Calendula gel or cream reduces inflammation and increases healing in new scars. They should be used twice a day daily.

Cocoa & Shea Butter - Shea cocoa butter and cocoa butter contain high concentrations of vitamin E, omega-3 fatty acids and antioxidants. Shea butter stimulates collagen production in the skin. They work better for treating atrophic scars.

Horsetail Grass - Horsetail grass used topically on scars. The plant’s stems of horsetail grass have the richest concentration of silica and silicic acids.

Kukui Nut Oil - Kukui Nut Oil also known as Candlenut oil, Hawaiian Kukui nut oil. It is high in vitamins C, D, and E, as well as skin-protecting antioxidants. Kukui Nut Oil stimulates collagen and lock in moisture like silicone.

Rosehip Seed Oil - Rosehip Seed Oil helps to regenerate skin and minimize scar tissue.

Seaweed Extract - Due to its skin healing properties seaweed extract has been used in varieties scar treating products such as Scar Esthetique Scar Crème.

Tamanu Oil - Tamanu Oil along with Rosehip seed oil is among the most healing of the carrier oils for skin. It helps to improve the appearance of scars with significant improvement within 6 weeks.

C) Vitamin AVitamin A helps to improve the appearance of keloid scars when use orally. The topical application of retinoic acid to hypertrophic and keloid scars has also shown success. However, side effects include

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hypervitaminosis and teratogenicity.

D) Vitamin B5 Vitamin B5 helps to moisturize aid in tissue repair and increase cell regeneration. It is also called Panthenol.

E) Botanical-Based Scar Healing Products Bio-Oil – Bio oil is formulated with plant extracts and vitamins suspended in an oil base. Bio oil is a popular scar treatment product. The primary ingredients of bio oils are oils of calendula, lavender, rosemary and chamomile, along with vitamins A and E. Bio-Oil also contain fragrance and artificial color.

Derma E Scar Gel –It works by breaking down scar tissue and encourages tissue growth. Derma E Scar Gel include allicin, the active compound in garlic and onions, panthenol (B5) and allantoin.

Mederma Scar Gel – Mederma contains a proprietary botanical extract made from onion and allantoin and claims to be the number one doctor-recommended” product for scars.Stretch Renew Cream – Stretch renew creams contain collagen, elastin, emu oil, aloe vera, and vitamin E.

Skin Lightening

Skin lightening can be a good option for patients usually recommended by plastic surgeons who haven’t had success reducing darker scars. Chemicals like kojic acid, hydroquinone cream such as Obagi Nu-Derm Clear (4% hydroquinone) are used to reduce the concentration of melanin in the skin. Though the safety of using these creams are under debate.

F) Treatment with Silicon ProductsSilicone is an extremely powerful moisturizer which is made from combining silicon and oxygen atoms. It helps the scar retain moisture by creating a protective barrier over a scar.

It is clinically proven to be effective, easy to use, and low risk. Silicone materials have proved to reduce scar thickness, reduce pain, the amount of scar tissue and are believed even to prevent hypertrophic scar and keloid formation. The researchers in the Journal of Plastic Reconstructive Surgery state “that these are the only treatments for which sufficient evidence exists to make evidence-based

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recommendations.” The Aesthetic Surgery Journal published an article comparing the effectiveness of silicone sheeting with silicone creams and herbal scar treatments for scars. Silicone gel sheets came out on top. Silicon gel is usually on self adhesive sheeting and must be used regularly. The mechanism of silicon on scar reduction is unclear. Silicon sheeting helps to heal the wound by increasing the amount of moisture (hydration) of the wound. Silicone gel dressings are a popular treatment for scars as they are non-invasive and have minimal side effects.

Silicone gel is self-drying spreadable gel which dries within 4-5 minutes that needs no fixation and cannot be seen because of complete transparency. They contain long chain silicone polymer, silicone dioxide and volatile component. Silicone polymers of long chain cross link with silicone dioxide. Silicon gels spreads as an ultra thin sheet. They work 24 hours per day. Silicon gels produce 86% reduction in texture, 84% in color and 68% in height of scars and proven to be effective.

Silicon gel benefit the scars by following ways:

1. Silicon gels facilitate regulation of fibroblast production and reduction in collagen production by increasing hydration of stratum corneum. Silicon gels make the scar flat and soft and also allow the skin to breath.

2. They generally prevents bacteria-induced excessive collagen production in the scar tissue and protects the scarred tissue from bacterial invasion.

3. Silicon gels modulates the expression of fibroblast growth factor β and tumor growth factor β. Tumor growth factor β stimulates fibroblasts to synthesize collagen and fibronectin.

4. Fibroblast growth factor β works by normalizing the collagen synthesis in an abnormal scar and increases the level of collagenases which causes breaks down of the excess collagen.

The administration of silicon gel is easy. They can be used for any irregular skin, any sized scar, scar surfaces, the face, moving parts (joints and flexures) and in children as well. A tube of 15 gram silicone gel is enough to treat 3-4 inches of scar thrice a day for over three months.

Silicone gel sheeting

Silicone gel sheeting is widely accepted in general burn scar

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treatment, along with pressure garments as they are non-invasive and has minimal side effects. The average treatment time of individual scars is 2-4 months. Silicone gel dressings are used to reduce scar thickness, reduce pain, and to prevent hypertrophic or keloid scars. The gel is usually on self adhesive sheeting and must be used regularly. It is unclear exactly how it works, but the sheeting increases the amount of moisture (hydration) of the wound, which helps it heal. Popular brands of silicone gel sheets include: Cica Care Silicone Gel Sheeting, Dermatix® Silicone Sheets, NewGel+ Silicone Gel Sheeting ,ScarAway, Silicone Scar Sheets, Syprex Scar Sheets etc.

The main drawback of scar sheet treatments is like band-aids, the sheeting may not fully conform to skin while moving and may leave part of the scar exposed also these sheets are often the most expensive topical scar treatment.

G) Polyurethane Dressings Polyurethane dressings are considered as effective as silicone in healing scars, but faster. They work within 3-4 weeks, with significant improvement expected after 8 weeks of treatment. Polyurethane especially when used in conjunction with compression is significantly more effective than silicone dressings in reducing the adverse cosmetic effects of mature hypertrophic scars when worn for a period of 8 weeks. According to The American Dermatology Association polyurethane was better tolerated than silicone sheets and also beneficial in the treatment of mature scars.

Sun protection

UV radiation associated with solariums or ‘sunbeds’ causes the patches on the skin that occur following healing of a wound more darker. Sun protection will protect vulnerable new skin from harmful UV radiation by minimising the effect.

Application of cosmetics

Makeup is a very popular technique to cover up scars. It can used at the same time as scar treatment after consultation with a specialist.

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Review ArticleReview Article

Hyponatremia:Diagnosis and ManagementMir AS1, Ahmed T2, Hossain T3, Afsana F4, Akter N5, Amin AH6, Amin MF7, Hasan ABMK8, Khan MS9, Mustari M10, Sultana N11, Talukder SK12,

Qureshi NK13

E-mail: asmir29@gmail.com

AbstractHyponatremia is the most common disorder of electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening and is associated with increased morbidity and mortality. Although classically defi ned as a condition with low serum sodium levels, hyponatremia in a true sense is primarily a disorder of water balance, with a relative excess of body water compared to total body

Review Article

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sodium content. A number of conditions can lead to this imbalance, which include some endocrine diseases also. Hyponatremia has been classically divided into hypovolemic, euvolemic and hypervolemic types depending on the volume status, and hypotonic, isotonic and hypertonic types depending on plasma osmolality. This review focuses on clinical and pathophysiological aspects of hyponatremia with special attention on endocrine disorders.

IntroductionHyponatremia, defined as a serum sodium concentration <135 mmol/L, is the most common disorder of electrolyte balance encountered in clinical practice. Hyponatremia is present in 15–20% of emergency admissions to hospital and occurs in up to 20% of critically ill patients1. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions2,3. Even mild hyponatremia may have detrimental effects on patients, although it is generally thought of as an asymptomatic condition4,5. Hyponatremia is important clinically because: 1) acute severe hyponatremia can cause substantial morbidity and mortality; 2) adverse outcomes, including mortality, are higher in hyponatremic patients with a wide range of underlying diseases; and 3) overly rapid correction of chronic hyponatremia can cause severe neurological deficits and death6.

Although classically defined as a condition with low serum sodium levels, hyponatremia in a true sense is primarily a disorder of water balance, with a relative excess of body water compared to total body sodium content7. A number of conditions can lead to this imbalance, which include some endocrine diseases also. This review focuses on clinical and pathophysiological aspects of hyponatremia with special attention on endocrine disorders.

Table-1: Selected terminology for hypontremia7

Definition of hyponatremia based on biochemical severityMild Serum Sodium 130 to <135 mmol/L*Moderate Serum Sodium 125 to <130 mmol/L*Severe Serum Sodium <125 mmol/L*Definition of hyponatremia based on time of development**Acute Hyponatremia that is documented to exist <48 hours

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Chronic Hyponatremia that is documented to exist for at least 48 hoursDefinition of hyponatremia based on symptomsModerately symptomatic

Any biochemical degree of hyponatremia in the presence of-• Nausea without vomiting• Confusion• Headache

Severely symptomatic

Any biochemical degree of hyponatremia in the presence of-• Vomiting• Cardiorespiratory distress• Abnormal and deep somnolence• Seizures• Coma (Glasgow Coma Scale <8)

* Measured by ion-specific electrode.

** If hyponatremia cannot be classified, it should be considered as chronic, unless there is clinical evidence of the contrary.

PathophysiologyUnder normal conditions, renal handling of water is sufficient to excrete as much as 15-20 L of free water per day. Further, the body’s response to a decreased osmolality is decreased thirst. Thus, hyponatremia can occur only when some condition impairs normal free water excretion8. An exception to this rule is acute primary polydipsia (acute water intoxication) in which the excessive water intake can overwhelm even the normal excretory capacity9. Generally, hyponatremia is of clinical significance only when it reflects a drop in the serum osmolality (ie, hypotonic hyponatremia), which is measured directly via osmometry or is calculated as- [2(Na) mEq/L + serum glucose (mg/dl)/18 + BUN (mg/dl)/2.8]. Urea is not an effective osmole, so when the urea levels are very high, the measured osmolality should be corrected for the contribution of urea.

Taking into account that the suppression of arginine vasopressin (antidiuretic hormone (ADH) secretion is essential for the excretion of any water load, the presence of high serum concentrations of ADH is a condition sine qua non for the development and maintenance of hyponatremia. Virtually all the causes of hyponatremia (except for renal failure, primary polydipsia, beer potomania, and low dietary solute intake) are characterized by an excess of ADH (despite the presence of hypotonicity) most frequently due to the syndrome of inappropriate ADH secretion (SIADH) or to depletion of effective circulating volume, which is a normal stimulus to ADH secretion (i.e. appropriately raised ADH levels)10.

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Hypovolemic Hyponatremia Hypovolemia causes a marked neurohumoral activation, increasing circulating levels of ADH, which in turn helps preserve blood pressure via vascular and baroreceptor V1A receptors and increases water reabsorption via renal V2 receptors. Activation of V2 receptors leads to hyponatremia in the setting of increased free water intake. In nonrenal causes of hypovolemic hyponatremia (GI loss, sweating, burns), urine Na+ concentration is typically <20 mmol/L in the absence of adequate oral replacement. These patients may be mistakenly classified as euvolemic, with only the reduced urinary Na+ concentration to indicate the cause of their hyponatremia.

The renal causes of hypovolemic hyponatremia share an inappropriate loss of Sodium in the urine, leading to volume depletion and an increase in circulating ADH; urine Na+ concentration is typically >20 mmol/L. Aldosterone deficiency can lead to hyponatremia in primary adrenal insufficiency and other causes of hypoaldosteronism. Salt-losing nephropathies may lead to hyponatremia when sodium intake is reduced, due to impaired renal tubular function. Thiazide diuretics cause hyponatremia via a number of mechanisms, including polydipsia and diuretic-induced volume depletion. Thiazides do not inhibit the renal concentrating mechanism, such that circulating ADH retains a full effect on renal water retention. In contrast, loop diuretics, which are less frequently associated with hyponatremia, inhibit Na+-Cl– and K+ absorption, blunting the countercurrent mechanism and reducing the ability to concentrate the urine.

Increased excretion of an osmotically active nonreabsorbable or poorly reabsorbable solute can also lead to volume depletion and hyponatremia; important causes include glycosuria, ketonuria, and bicarbonaturia (e.g., in renal tubular acidosis or metabolic alkalosis). The syndrome of “cerebral salt wasting” is a rare cause of hypovolemic hyponatremia, encompassing hyponatremia with clinical hypovolemia and inappropriate natriuresis in association with intracranial disease; associated disorders include subarachnoid hemorrhage, traumatic brain injury, craniotomy, encephalitis, and meningitis. Distinction from the more common syndrome of inappropriate antidiuresis is critical because cerebral salt wasting will typically respond to aggressive Na+-Cl- repletion11. Hypervolemic Hyponatremia Patients with hypervolemic hyponatremia develop an increase in total-body sodium that is accompanied by a proportionately

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greater increase in total-body water, leading to a reduced plasma Na+ concentration. The causative disorders can be separated by the effect on urine Na+ concentration, with acute or chronic renal failure uniquely associated with an increase in urine Na+ concentration. The pathophysiology of hyponatremia in congestive heart failure, cirrhosis, and nephrotic syndrome is similar to that in hypovolemic hyponatremia, except that arterial filling and circulatory integrity is decreased due to the specific etiologic factors. Urine Na+ concentration is typically very low, i.e., <10 mmol/L, even after hydration with normal saline11.

Euvolemic HyponatremiaThe syndrome of inappropriate antidiuresis (SIADH) is the most frequent cause of euvolemic hyponatremia. The generation of hyponatremia in SIADH requires an intake of free water, with persistent intake at serum osmolalities that are lower than the usual threshold for thirst. Four distinct patterns of AVP secretion have been recognized in patients with SIADH, independent for the most part of the underlying cause. Type 1 shows erratic excess ADH secretion, unrelated to plasma osmolality. It is the commonest of all types (40%), mostly associated with tumours. In type 2 there is ‘reset osmostat’; patients autoregulate around a lower serum osmolality. This type is mostly found in chest and CNS disease. Type 3 denotes ‘leaky osmostat’, i.e.- normal osmoregulation until plasma hypotonicity develops when vasopressin secretion continues. In case of type 4 SIADH there is normal osmoregulated vasopressin secretion; hyponatremia occurs possibly due to receptor defect, or alternative ADH12.

Strictly speaking, patients with SIADH are not euvolemic but are subclinically volume-expanded, due to AVP-induced water and sodium retention. Serum uric acid is often low (<4 mg/dl) in patients with SIADH, consistent with suppressed proximal tubular transport in the setting of increased distal tubular Na+-Cl– and water transport; in contrast, patients with hypovolemic hyponatremia will often be hyperuricemic, due to a shared activation of proximal tubular Na+-Cl– and urate transport11.

Euvolemic hyponatremia can occur in moderate to severe hypothyroidism, with correction after achieving a euthyroid state. The proposed mechanisms by which hypothyroidism induces hyponatremia in patients with normal fluid intake are-The inability to maximally suppress ADH, partly due to a reduced cardiac output, which can lead to the release of ADH via the carotid

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sinus baroreceptors13.

The glomerular filtration rate has been reported to be decreased in hypothyroidism, which leads to diminished water delivery to the diluting segments and subsequently diminished free water excretion14.

The net effect of the impaired water excretion is retention of ingested water and dilutional hyponatremia.

Severe hyponatremia can also be a consequence of secondary adrenal insufficiency due to pituitary disease; whereas the deficit in circulating aldosterone in primary adrenal insufficiency causes hypovolemic hyponatremia, the predominant glucocorticoid deficiency in secondary adrenal failure is associated with euvolemic hyponatremia. Hyponatremia can occur in hypocortisolism due to-Inappropriately excess secretion of ADH because of hypocortisolism15 (Ishikawa 1982). Hypersecretion of ADH in cortisol deficiency may also be due to the reductions of systemic blood pressure and cardiac output16.

Hypocortisolism mediated altered renal sensitivity to ADH, as suggested by aquaporin-2 water channel up-regulation in glucocorticoid-deficient rats17.

ADH-independent factors, such as impaired renal hemodynamics and decreased distal fluid delivery to the diluting segments of the nephron18. In Addison’s disease, not only cortisol deficiency but aldosterone deficiency also contributes to hyponatremia by causing sodium wasting and hypovolemia19.

There may be concomitant primary (due to Hashimoto’s thyroiditis) or secondary hypothyroidism with Addison’s disease and hypopituitarism, respectively contributing to hyponatremia20.

Pseudohyponatremia Marked elevations of either lipids or proteins in plasma can cause artifactual decreases in serum sodium because of the larger relative proportion of plasma volume that is occupied by the excess lipids or proteins. Because the increased protein or lipid will not appreciably change the total number of solute particles in solution, the directly measured plasma osmolality will be normal in such cases and, therefore, the patient will be isotonic rather than hypotonic6.

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Figure-1: Pseudohyponatremia

Normally, serum contains 7% solids by volume. To reduce the volume of blood needed for analysis, serum is frequently diluted before the obtaining the actual measurement. The same volume of diluent is always used, and the degree of dilution is estimated under the assumption that the serum contains 7% solid-phase particles. When the fraction of solid-phase particles is increased (e.g.- Hyperlipidemia), the same amount of diluent results in a greater dilution, which the laboratory personnel is not aware of (right side of figure). Consequently, the calculation of an ion level with the use of a degree of dilution that is based on the incorrect fraction of solid-phase particles will lead to an underestimate. (Adapted from Turchin et al21)

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Table-2: Important causes of hyponatremia

Hypotonic(Plasma osmolality<280 mOsm/Kg)

Hypovolaemic

Renal sodium losses• Diuretic therapy (especially thiazides)• Adrenocortical failureGastrointestinal sodium losses• Vomiting• DiarrhoeaSkin sodium losses• Burns

Euvolaemic• SIADH• Primary polydipsia• Hypothyroidism • Excessive electrolyte-free water infusion

Hypervolaemic

• Congestive cardiac failure• Cirrhosis• Nephrotic syndrome• Chronic renal failure (during free water intake)

Isotonic(Plasma osmolality 280 to 295 mOsm/Kg)

• Hyperglycemia • Hyperlipidemia• Hyperproteinemia

Hypertonic(Plasma osmolality >295 mOsm/Kg)

• Severe hyperglycemia with dehydration Mannitol

Table-3: Causes of Syndrome of Inappropriate ADH secretion22 MALIGNANT NEOPLASIA• Carcinoma: bronchogenic, pancreatic, duodenal, ureteral, prostatic, bladder• Lymphoma and leukemia• Thymoma and mesothelioma

CENTRAL NERVOUS SYSTEM DISORDERS

• Trauma• Infection• Tumors• Porphyria

PULMONARY DISORDERS

• Tuberculosis• Pneumonia• Fungal infections• Lung abscesses• Mechanical positive-pressure ventilation

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DRUG INDUCED

• Carbamazepine• Desmopressin• Oxytocin• Vinca alkaloids• Alkylating agents/antimetabolites• Interferons• Anticonvulsants• Antipsychotic agents• Nicotine• Cyclophosphamide• Morphine• Amitriptyline• Selective serotonin reuptake inhibitors• 3-4-Methylenedioxymethamphetamine (Ecstasy)

Clinical featuresAcute HyponatremiaSymptoms of acute hyponatremia primarily occur with sudden and marked reductions in the serum sodium concentration and reflect neurologic dysfunction induced by cerebral edema and adaptive responses of brain cells to osmotic swelling. The major clinical manifestations of acute hyponatremia include23,24,25.

Nausea and malaise (earliest findings, may be seen when the serum sodium concentration falls below 125 to 130 meq/L).

Headache, lethargy, obtundation, seizures, coma, and respiratory arrest can occur if the serum sodium concentration falls below 115 to 120 meq/L.

Noncardiogenic pulmonary edemaAcute hyponatremic encephalopathy may be reversible, but permanent neurologic damage or death can occur, particularly in premenopausal women23,24.

Chronic hyponatremiaDue to the cerebral adaptation in chronic hyponatremia, many patients may remain asymptomatic despite a serum sodium concentration below 120 mmol/L. When symptoms do occur, they are relatively nonspecific26.

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• Fatigue• Nausea• Dizziness• Gait disturbances• Forgetfulness• Confusion• Lethargy• Muscle crampsSeizures and coma are uncommon and often reflect an acute exacerbation of the hyponatremia.

Figure-2: Effects of Hyponatremia on the Brain and Adaptive Responses (Adapted from Adrogue et al27)

Diagnostic evaluationTo diagnose and manage a case of hyponatremia, we have to answer some questions:

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- Whether it is true hyponatremia or pseudohyponatremia?- Whether the condition is acute or chronic? - What is the volume status of the patient?- What is the urinary osmolality and urine sodium level?- What is the underlying cause?

Acute vs Chronic hyponatremiaFor practical purposes, we can define acute hyponatremia as low serum sodium documented to be of less than 48 hours duration. If the duration is documented to be >48 hours, or if exact duration is not known, it is said to be chronic (Table-1)7.

Determination of volume statusAlthough it seems easy to assess volume status by checking blood pressure, postural hypotension, jugular venous pressure and peripheral edema, in practice it is very difficult. If the volume status is unclear, an infusion of normal saline (e.g. 1 L over 12 h) as a therapeutic trial will often reveal the true situation. Hypovolaemic patients will respond well (typically serum sodium will rise >5 mmol/L), whereas patients with SIADH will often not improve and may experience a worsening of hyponatremia. It is imperative that serum sodium is rechecked 6 h after the infusion is started28.

Detailed clinical and laboratory workupApart from assessment of volume status, the physician should search for a history of gastrointestinal fluid loss, detailed drug history, clinical features consistent with consistent one of the causes of SIADH, such as small cell carcinoma or central nervous system disease, and symptoms and signs suggestive of adrenal insufficiency or hypothyroidism.

The most important investigations to find out the cause of hyponatremia include serum osmolality, urine osmolality and urine sodium, potassium, and chloride concentrations.

Serum osmolalityIdeally, in the face of hyponatremia, serum osmolality should be decreased (<275 mOsm). If the serum osmolality is high or

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‘inappropriately’ normal, one should think of marked hyperglycemia, severe azotemia, and alcohol intoxication. Less common causes of this condition includes infusion or absorption of solutions containing sugars, systemic absorption of irrigant solutions containing glycine, sorbitol, or mannitol (e.g.- during transurethral resection of prostate), and pseudohyponatremia due to hyperlipidemia or hyperproteinemia.

Urine osmolalityIn patients with hyponatremia and a low plasma osmolality, urine osmolality should be high (>100 mOsm/Kg) in most of the cases (SIADH, true hypovolemia, heart failure, and cirrhosis). If urine osmolality is <100 mOsm/Kg, it indicates primary polydipsia, beer potomania syndrome and reset osmostat.

Urine sodium and chlorideIn hypovolemic hyponatremia, urine sodium excretion is <20 meq/L. If it is >20 meq/L, one should think of renal salt-wasting (e.g.- diuretic therapy, adrenal insufficiency, cerebral salt-wasting syndrome).Similarly in hypervolemic patients with low effective circulating volume (e.g.- heart failure, cirrhosis, nephritic syndrome), urine sodium excretion is <20 meq/L. When it goes >20 meq/L, acute or chronic renal failure is suspected.The urine sodium concentration is usually above 20 meq/L in patients with SIADH, hypothyroidism and other causes of euvolemic hyponatremia. In SIADH, typically urine sodium is >40 meq/L.Urine chloride is important in hypovolemic hyponatremic patients who have metabolic alkalosis caused by vomiting, where the urine sodium concentration may be > 25 meq/L, but the urine chloride concentration will be low (less than 25 meq/L).

Other investigations- Renal function tests- Serum potassium- High in adrenal insufficiency, renal failure Low or low-normal in SIADH- Blood glucose and blood lipids (to exclude pseudohyponatremia)- Serum uric acid (<4 mg/dl in SIADH)- Thyroid, adrenal and pituitary hormone evaluation- Radiography of chest and CNS in suspected cases of SIADH

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Figure-3: Suggested algorithm for diagnosis of hyponatremia29

Syndrome of inappropriate ADH secretionSIADH is the most important cause of euvolemic hyponatremia. It can be diagnosed by using predefined criteria (Table-4). Important differential diagnoses are hypothyroidism, hypoadrenalism and true hypovolemia including cerebral salt wasting (CSW). Indeed, it may be very difficult to distinguish SIADH from CSW.

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Table-4: Diagnostic criteria of SIADH30 Essential features Supplemental features• Decreased effective osmolality (<275 mOsm/kg)• Urinary osmolality >100 mOsm/kg • Clinical euvolemia• No clinical signs of volume depletion of extracellular fluid• No orthostasis, tachycardia, de-creased skin turgor, or dry mucous membranes• No clinical signs of excessive volume of extracellular fluid• No edema or ascites• Urinary sodium >40 mmol/liter with normal dietary salt intake• Normal thyroid and adrenal function• No recent use of diuretic agents

• Plasma uric acid <4 mg/dl• Blood urea nitrogen <10 mg/dl• Fractional sodium excretion >1%; fractional urea excretion >55%• Failure to correct hyponatremia after 0.9% saline infusion• Correction of hyponatremia through fluid restriction• Abnormal result on test of water load (<80% excretion of 20 ml of water perkg of body weight over a period of 4 hours), or inadequate urinary dilution (<100 mOsm/kg of water)• Elevated plasma AVP levels, despite the presence of hypotonicity and clini-cal euvolemia

Table 5: Differences between SIADH and cerebral salt wasting7 SIADH Cerebral salt wasting

Serum urea Low normal High normalSerum uric acid Low Low Urine volume Low normal High Urine sodium >40 mmol/L Usually >100 mmol/LBlood pressure Normal Orthostatic hypotensionCentral venous pressure Normal Low

Management of hyponatremiaAcute hyponatremiaTreatment of severe acute symptomatic hyponatremia should include hypertonic 3% saline (513 mmol/L) to acutely increase plasma Na+ concentration by 1–2 mmol/h to a total of 4–6 mmol/L; this modest increase is typically sufficient to alleviate severe acute symptoms, after which corrective guidelines for chronic hyponatremia are appropriate. The traditional approach is to calculate an Na+ deficit, where the Na+ deficit = 0.6 × body weight × (target plasma Na+

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concentration – starting plasma Na+ concentration), followed by a calculation of the required rate. A practical approach can be an infusion of 150 ml of 3% NaCl over a period of 20 minutes, followed by checking the serum sodium concentration while repeating an infusion of 150 ml 3 % hypertonic saline or equivalent over the next 20 min. This procedure can be repeated twice or until a target of 5 mmol/L increase in serum sodium concentration is achieved7. (Spasovski 2014). For mild to moderate symptoms, the rate of infusion of 3% saline should be 0.5-2 ml/kg/hour6. Regardless of the method used to determine the rate of administration, the increase in plasma Na+ concentration can be highly unpredictable during treatment with hypertonic saline, due to rapid changes in the underlying physiology. Therefore, plasma Na+ concentration should be monitored every 2–4h during treatment, with appropriate changes in therapy based on the observed rate of change. AVP antagonists do not have an approved role in the management of acute hyponatremia11.

Chronic hyponatremiaTreatment of underlying cause

In addition to the specific therapies described below that are aimed at correcting the hyponatremia, therapy should also be directed at the underlying disease. This includes administration of saline to patients with true volume depletion, administration of glucocorticoids to patients with adrenal insufficiency, thyroid hormone replacement in patients with hypothyroidism and reversing the cause of SIADH.

Fluid restriction

Fluid restriction to below the level of urine output is indicated for the treatment of symptomatic or severe hyponatremia in edematous states (such as heart failure and cirrhosis), SIADH, and advanced renal failure. Restriction to 50-60% of daily fluid requirements may be required to achieve the goal of inducing negative water balance27. Fluid restriction is also warranted in hyponatremic patients with primary polydipsia in whom increased fluid intake is the primary problem.

Sodium chloride administration

Sodium chloride, usually as isotonic saline or increased dietary salt, is given to hyponatremic patients with true volume depletion and/or adrenal insufficiency and to some patients with SIADH. Salt administration is generally contraindicated for chronic therapy in

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edematous patients. Administration of hypertonic saline is primarily limited to patients with symptomatic or severe hyponatremia or, occasionally, to patients with SIADH and a highly concentrated urine.

Vasopressin receptor antagonists (Vaptans)

The vasopressin receptor antagonists produce a selective water diuresis (aquaresis) without affecting sodium and potassium excretion. The ensuing loss of electrolyte-free water will tend to raise the serum sodium in patients with SIADH and may improve mental status in patients with a serum sodium under 130 meq/L. Thirst increases significantly with these agents, which may limit the rise in serum sodium. They are used in cases of SIADH and hypervolemic hyponatremias31,32.

Table-6: Osmotic demyelination syndrome during correction of chronic hyponatremia6 Factors associated with high risk of developing the osmotic demyelination syndrome• Serum sodium concentration 105 mmol/L• Hypokalemia• Alcoholism• Malnutrition• Advanced liver diseaseMeasures to take for avoiding osmotic demyelination syndromeGoal:

• Minimum correction of serum [Na+] by 4-8 mmol/L per day, with a lower goal of 4-6 mmol/L per day if the risk of ODS is high.

Limits not to exceed:

• For high risk of ODS: 8 mmol/L in any 24-hour period;• For normal risk of ODS: 10-12 mmol/L in any 24-hour period; 18 mmol/L in any 48-hour period.

Table-7: Recommendations for the use of vaptans in the treatment of hyponatremia

Hyponatremia classification

Expert panel recommendation6

European Clinical Practice guidelines7

Hypovolemic Not recommended Not recommended

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Euvolemic Asymptomatic Recommended Not recommendedModerate to severe CNS symptoms

Not recommended Not recommended

HypervolemicAsymptomatic Recommended (except

patients with liver disease)

Not recommended

Moderate to severe CNS symptoms

Not recommended Not recommended

ConclusionThe diagnosis and management of hyponatremia is challenging even for the expert physician. When there is no apparent feature of GI or urinary loss, one should meticulously search for other causes including drugs. In chronic cases, slow correction is better than rapid correction, and oral correction is better than parenteral correction. The primary treatment measure for mild symptoms is water restriction. A decision to correct serum sodium more rapidly depends on the chronicity of the hyponatremic state and whether the patient is symptomatic. Drug treatment causing or contributing to hyponatremia should be carefully monitored at the onset of symptoms. Proper monitoring, awareness of optimal treatment modalities, and active management ensure that a good outcome is likely in all mild cases and in most of the more serious cases of hyponatremia.

References1. Funk GC, Lindner G, Druml W. Incidence and prognosis of dysnatremias present on ICU

admission. Intens Care Med 2010; 36:304–311.2. Beukhof CM, Hoorn EJ, Lindemans J, Zietse R. Novel risk factors for hospital-acquired

hyponatremia: a matched case-control study. Clin Endocrinol 2007; 66:367–372. 3. Upadhyay A, Jaber BL, Madias NE. Epidemiology of hyponatremia. Semin Nephrol 2009;

29:227–238. 4. Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia

is associated with falls, unsteadiness, and attention deficits. Am J Med 2006; 119:71 e 1–8.5. Corona G, Giuliani C, Parenti G, Norello D, Verbalis JG, Forti G et al. Moderate hyponatremia

is associated with increased risk of mortality: evidence from a meta-analysis. PLoS One 2013; 8: e80451.

6. Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, Thompson CJ. Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert Panel Recommendations. The American Journal of Medicine 2013; 126: S1-S42.

7. Spasovski G, Vanholder R, Allolio B, Annane D, Ball S, Bichet D, Decaux G, Fenske W, Hoorn EJ, Ichai C, Joannidis M, Soupart A, Zietse R, Haller M, Van der Veer S, Van Biesen

29

W, Nagler E, on behalf of the Hyponatremia Guideline Development Group. Clinical practice guideline on diagnosis and treatment of hyponatremia. European Journal of Endocrinology 2014; 170: G1–G47.

8. Singhi S, Jayashre M. Free water excess is not the main cause for hyponatremia in critically ill children receiving conventional maintenance fluids. Indian Pediatr. 2009; 46(7):577-83.

9. Milionis HJ, Liamis GL, Elisaf MS. The hyponatremic patient: a systematic approach to laboratory diagnosis. CMAJ. 2002;166:1056 – 62.

10. Liamis GL, Milionis HJ, Elisaf MS. Endocrine disorders: Causes of hyponatremia not to neglect. Annals of Medicine, 2011; 43: 179–187.

11. Mount DB. Fluid and Electrolyte Disturbances. In: Kasper DL, Hauser SL, Jameson JL, Fauci AS, Longo DL, Loscalzo J, Eds. Harrison’s Principles of Internal Medicine. 19th ed. New York: The McGraw Hill Companies. 2015: 295-312.

12. Wass J, Owen K, Turner H, Eds. Oxford Handbook of Endocrinology and Diabetes. 3rd ed. Oxford: Oxford University Press. 2014: 220-221.

13. Hanna FW, Scanlon MF. Hyponatremia, hypothyroidism, and role of arginine-vasopressin. Lancet. 1997; 350:755 – 6.

14. Schmitz PH, de Meijer PH, Meinders AE. Hyponatremia due to hypothyroidism: a pure renal mechanism. Neth J Med. 2001;58:143 – 9.

15. Ishikawa S, Schrier RW. Effect of arginine vasopressin antagonist on renal water excretion in glucocorticoid and mineralocorticoid deficient rats. Kidney Int. 1982; 22: 587-593.

16. Schrier RW. Body water homeostasis: clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. 2006; 17:1820-1832.

17. Saito T, Ishikawa SE, Ando F, Higashiyama M, Nagasaka S, Sasaki S. Vasopressin-dependent upregulation of aquaporin-2 gene expression in glucocorticoid-defi cient rats. Am J Physiol Renal Physiol. 2000; 279: F502 – F508.

18. Raff H. Glucocorticoid inhibition of neurohypophysial vasopressin secretion. Am J Physiol. 1987; 252: R635 – 644.

19. Oelkers W. Adrenal insufficiency. N Engl J Med. 1996; 335: 1206 – 12. 20. Michels AW, Eisenbarth GS. Immunologic endocrine disorders. J Allergy Clin Immunol.

2010;125: S226 – 237.21. Turchin A, Seifter JL & Seely EW. Clinical problem-solving. Mind the gap. N Engl J Med

2003; 349: 1465–1469.22. Slotki I, Skorecki K. Disorders of sodium and water homeostasis. In: Goldman L, Schafer

AI, Eds. Goldman-Cecil Medicine. 25th ed. Philadelphia: Saunders. 2016: 741-755.23. Ayus JC, Wheeler JM, Arieff AI. Postoperative hyponatremic encephalopathy in menstruant

women. Ann Intern Med 1992; 117:891.24. Ayus JC, Varon J, Arieff AI. Hyponatremia, cerebral edema, and noncardiogenic pulmonary

edema in marathon runners. Ann Intern Med 2000; 132:711.25. Moritz ML, Ayus JC. The pathophysiology and treatment of hyponatraemic

encephalopathy: an update. Nephrol Dial Transplant 2003; 18:2486.26. Chow KM, Kwan BC, Szeto CC. Clinical studies of thiazide-induced hyponatremia. J Natl

Med Assoc 2004; 96:1305.27. Adrogue HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342 (21): 1581-1589.28. Grant P, Ayuk J, Bouloux PM, Cohen M, Cranston I, Murray RD, Rees A, Thatcher N,

Grossman A. The diagnosis and management of inpatient hyponatremia and SIADH. Eur J Clin Invest 2015; 45 (8): 888–894.

29. Hyponatremia algorithm: Stellaris Health. Available from: https://www.stellarishealth.org/PDFs/Hyponatremia_Algorithm.pdf. Accessed on 30 June 2017.

30. Ellison DH, Berl T. The Syndrome of Inappropriate Antidiuresis. N Engl J Med 2007;356:2064-72.

31. Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006; 69:2124.32. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-

receptor antagonist, for hyponatremia. N Engl J Med 2006; 355:2099.

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The Importance of Pharmacovigilance

All pharmaceutical products have potential adverse effects; however, the consequences vary in severity and frequency and some pose a greater health risk than others. Most information on medicines and other pharmaceutical products is collected through preauthorization clinical trials carried out under controlled conditions in a sample population for a limited time period. These characteristics can result in a situation whereby information from pre-marketing studies may not suffi ciently represent real-life conditions or the entire population for whom the product is indicated. As a result, the full scope of potential ADRs of pharmaceutical products may not be detected until after they are authorized for use in the general population. PV offers an opportunity for more complete information on pharmaceutical products and their risks and effects.

PV also helps to document and avert the health risks and challenges posed by the increasing availability and trade in substandard and falsifi ed products, including counterfeits. Through quality surveillance of products on the market, defective, deteriorated, adulterated, or poorly manufactured pharmaceutical products can be identifi ed and recalled. In addition, PV aids in the identifi cation of medical products that have lost potency or are decomposing as a result of inappropriate storage conditions. Once identifi ed, these products can be removed from the supply system, and information about the risk they pose can be communicated to heath care professionals, patients, and the public.

PV plays an important role in identifying medication errors so that the frequency of such errors and their effects on patients can be reduced. PV systems collect data and monitor processes and conditions that can facilitate or lead to medication errors. These data, once collected and analyzed, can provide critical information that is ultimately used in the education of health care professionals and the development of effective system control measures to curb the occurrence of medication errors. PV is also used to monitor and review the effectiveness of medications and provide evidence to support changes to treatment protocols.

Source:NATIONAL GUIDELINE ON THE PHARMACOVIGILANCE SYSTEM IN BANGLADESH

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