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IJCP Group of Publications Dr Chopra Prof. of Medicine & Faculty Dean Harvard Medical School Group Consultant Editor

Volume 26, Number 8, January 2016 FROM THE DESK OF THE GROUP EDITOR-IN-CHIEF

705 Revisiting Cardiology 2015

Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal Group Editor-in-Chief IJCP Group, eMedinewS and eMediNexus Dr Veena Aggarwal

AMERICAN FAMILY PHYSICIAN

707 Rosacea: Diagnosis and Treatment

Obstetrics and Gynaecology Dr Alka Kriplani Dr Thankam Verma, Dr Kamala Selvaraj Cardiology Dr Praveen Chandra, Dr SK Parashar Paediatrics Dr Swati Y Bhave Diabetology Dr CR Anand Moses, Dr Sidhartha Das Dr A Ramachandran, Dr Samith A Shetty ENT Dr Jasveer Singh Dr Chanchal Pal Dentistry Dr KMK Masthan Dr Rajesh Chandna Gastroenterology Dr Ajay Kumar Dr Rajiv Khosla Dermatology Dr Hasmukh J Shroff Dr Pasricha Dr Koushik Lahiri Nephrology Dr Georgi Abraham Neurology Dr V Nagarajan Dr Vineet Suri Journal of Applied Medicine & Surgery Dr SM Rajendran, Dr Jayakar Thomas Orthopedics Dr J Maheshwari

Anand Gopal Bhatnagar Editorial Anchor Advisory Bodies Heart Care Foundation of India

717 Photo Quiz CARDIOLOGY

719 Comparative Evaluation of Cost-effectiveness Between Ramipril versus Telmisartan in Cases of Hypertension Associated with Type 2 Diabetes Mellitus

Pankaj Kumar, AK Kapoor, HK Singh, Malini Kulshrestha

CRITICAL CARE

726 Hyperlactatemia in Critically Ill: A Review

Subhranshu Sekhar Kar

ENDOCRINOLOGY

737 Posology of Antidiabetic Drugs and Insulins: A Review of Standard Textbooks

Garima Bhutani, Sanjay Kalra

743 Hypothyroidism in Metabolic Syndrome

Darshana Makwana, Jignesh Tank, Deepak Kumar

INTERNAL MEDICINE

747 Study of Prevalence of Hypothyroidism and Effect of Treatment with L-thyroxine in Patients of Chronic Kidney Disease

NS Sengar, Nipun Gupta, Nandita Prabhat

755 Volkmann’s Ischemic Contracture: A Late Complication of Snakebite

Lubna Zafar, Shahna Ali, Anjum Parvez

OBSTETRICS AND GYNECOLOGY

758 Retrospective Study of Inpatients Admitted Following Medical Abortion

Veena Vidyasagar

763 Colposcopic and Pap Smear Evaluation and Therapeutic Role of Cryotherapy in Cervical Erosion

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Linda K. Oge, Herbert L. Muncie, Amanda R. Phillips-Savoy

716 Practice Guidelines

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IJCP Editorial Board

KK Aggarwal

Rachana Agarwal, Ajay Halder, Urvashi Verma, Mohita Agarwal, Saroj Singh

ONCOLOGY

768 Short (Single Dose) versus Long-course Radiotherapy for Palliation of Painful Bone Metastases

Meena J Shah

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IMAGING AND INVESTIGATIONS

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PICTORIAL CME

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INSPIRATIONAL STORY

788 The Rebellion Against the Stomach AROUND THE GLOBE

789 News and Views LIGHTER READING

794 Lighter Side of Medicine

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Revisiting Cardiology 2015 ÂÂ

PCSK9 inhibitors released into the real world: FDA approved the injectable monoclonal antibodies evolocumab and alirocumab, which induce dramatic drops in low-density lipoprotein (LDL) cholesterol.

ÂÂ

SPRINT: SPRINT compared lowering blood pressure (BP) to 120 mmHg against a more lenient goal of 140 mmHg in high-risk older adults. The data safety monitoring board stopped the trial early because of an increased number of cardiac events in the lenient-BP arm. Efficacy of intense BP control came at a cost: more drugs were required and more subjects in the intense-BP arm experienced syncope, acute kidney injury and electrolyte abnormalities.

ÂÂ

Coffee and fat are back: Two major reversals included the allowance of moderate caffeine intake and removal of limits on dietary cholesterol. In 2015, a consensus grew that refined sugars promote illness.

ÂÂ

AF treatment: STAR-AF 2 trial found that additional ablation beyond pulmonary-vein isolation in patients with advanced forms of AF did not improve outcomes.

ÂÂ

LEGACY trial and CARDIO-FIT trials showed that both weight loss and gains in cardiorespiratory fitness delivered potent antiarrhythmic effects.

ÂÂ

ARREST-AF substrate study, showed that risk-factor modification worked by improving electrical and structural properties of human atria.

ÂÂ

The EMPA-REG outcome trial has been hailed as a landmark trial because it's the first time a drug for diabetes, empagliflozin (a sodium glucose co-transporter-2 (SGLT-2) inhibitor), has lowered death rates in patients with type 2 diabetes. However, the FDA has issued a warning about ketoacidosis and bone fractures with these drugs.

ÂÂ

Idarucizumab (Praxbind, Boehringer Ingelheim), the dabigatran reversal agent received FDA approval in October.

ÂÂ

Andexanet alfa, the factor Xa reversal agent safely reversed the anticoagulant effect of apixaban and rivaroxaban in older volunteers (November issue of New England Journal of Medicine).

ÂÂ

A wireless revolution in cardiac pacing began this year with both the NanoStim LP leadless pacemaker (St Jude Medical) and the Micra TPS (Medtronic) performing well. Both devices have earned CE Mark in Europe, and FDA approval is likely.

ÂÂ

Five clinical trials demonstrated clear benefit for the use of endovascular treatments alone or as an add-on to tPA in patients who present with acute stroke.

ÂÂ

Periprocedural bridging with LMWH in patients taking warfarin and undergoing elective surgery resulted in higher bleeding rates and no lowering in thrombotic events. But, the BRIDGE trial researchers excluded highrisk patients with mechanical valves and previous stroke. So, we don't know the answer for these patients. For most, though, less is clearly more.

■■■■

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

705

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AMERICAN FAMILY PHYSICIAN

Rosacea: Diagnosis and Treatment LINDA K. OGE, HERBERT L. MUNCIE, AMANDA R. PHILLIPS-SAVOY

ABSTRACT Rosacea is a chronic facial skin condition of unknown cause. It is characterized by marked involvement of the central face with transient or persistent erythema, telangiectasia, inflammatory papules and pustules, or hyperplasia of the con­nective tissue.

Transient erythema, or flushing, is often accompanied by a feeling of warmth. It usually lasts for less than five minutes and may spread to the neck and chest. Less common findings include erythematous plaques, scaling, edema, phymatous changes (thickening of skin due to hyperplasia of sebaceous glands), and ocular symptoms. The National Rosacea Society Expert Committee defines four subtypes of rosacea (erythematotelangiectatic, papulopustular, phy­matous, and ocular) and one variant (granulomatous). Treatment starts with avoidance of triggers and use of mild cleansing agents and moisturizing regimens, as well as photoprotection with wide-brimmed hats and broad-spectrum sunscreens (minimum sun protection factor of 30). For inflammatory lesions and erythema, the recommended ini­tial treatments are topical metronidazole or azelaic acid. Once-daily brimonidine, a topical alpha-adrenergic receptor agonist, is effective in reducing erythema. Papulopustular rosacea can be treated with systemic therapy including tet­racyclines, most commonly subantimicrobial-dose doxycycline. Phymatous rosacea is treated primarily with laser or light-based therapies. Ocular rosacea is managed with lid hygiene, topical cyclosporine, and topical or systemic antibiot­ics.

Keywords: Rosacea, erythematotelangiectatic, photoprotection, papulopustular rosacea, phymatous rosacea, ocular rosacea

R

osacea is a chronic facial skin con­dition characterized by marked involvement of the central face with transient or persistent ery­thema, inflammatory papules or pustules, telangiectasia, or hyperplasia of the con­nective tissue.1,2 Transient erythema, or flushing, usually lasts less than five minutes and may spread to the neck and chest, often accompanied by a feeling of warmth.

Less common findings include erythematous plaques, scaling, edema, phymatous changes (thickening of skin due to hyperplasia of sebaceous glands), and ocular symptoms. Rosacea can be associated with low selfesteem, embarrassment, and diminished quality of life. In a national survey, 65% of patients with rosacea reported symptoms of depression.3 The exact prevalence of rosacea in the United States is unknown4,5; however,

LINDA K. OGE’, MD, is an assistant clinical professor and chief of family medicine at Louisiana State University Family Medicine Residency at Uni­versity Hospital and Clinics in Lafayette.

HERBERT L. MUNCIE, MD, is a professor of family medicine and director of predoctoral education at Louisiana State University School of Medicine in New Orleans.

AMANDA R. PHILLIPS-SAVOY, MD, MPH, is an assistant clinical professor in the Department of Family Medicine at Louisiana State University Family Medicine Residency at University Hospital and Clinics.

Source: Adapted from Am Fam Physician. 2015;92(3):187-196.

it is probably between 1.3% and 2.1%, and may be as high as 5%.6 Women are affected more often than men, but men are more likely to have phymatous changes, especially rhinophyma.7 SUBTYPES The National Rosacea Society Expert Com­mittee defined four subtypes (Table 1) and one variant.8 Granulomatous rosacea is the sole variant with firm, indurated papules or nodules. Many dermatologists consider rosacea fulminans and perioral dermatitis as rosacea variants. Patients may experience fluctuation in symptoms and overlapping of symptoms between subtypes.9 PATHOPHYSIOLOGY The etiology of rosacea is unknown but is likely multifactorial. Factors involved in the pathophysiology include the dense presence of sebaceous glands on the face, the physiol­ogy of the nerve innervation, and the vas­cular composition of the skin.10 Numerous triggers initiate or aggravate the clinical manifestations of rosacea, including ultra­violet light, heat, spicy foods, and alcohol (Table 2).4,11 A predilection for fair-skinned individu­ als of Celtic or northern European descent suggests a genetic component to rosa­cea.10 However,

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

707

AMERICAN FAMILY PHYSICIAN Table 2. Triggers Associated with Worsening Rosacea Symptoms Trigger

Patients with rosacea who report trigger (%)

Sun exposure

81

Emotional stress

79

Hot weather

75

Wind

57

Strenuous exercise

56

Alcohol consumption

52

Cold weather

46

Spicy foods

45

Certain skin care products

41

Heated beverages

36

Certain cosmetics (comedogenic)

27

Medications (topical steroids, niacin, beta blockers)

15

Dairy products

8

Other factors

24

Information from references 4 and 11.

A

B

C

Figure 1. Facial erythema with telangiectasia. (A) Frontal view of centrofacial erythema. (B) Close-up view of centrofa­cial erythema with scaling. (C) Close-up view of telangiectasias on lateral chin.

no specific gene has been identified.4 Patients with the genetic predisposition have a receptor that mediates neovascular regulation. When exposed to triggers, neuropeptide release (flushing, edema) occurs, resulting in recruitment of proinflam­matory cells to the skin.10 DIAGNOSIS Rosacea is diagnosed based on a compatible history and physical examination12 (Table 38). One of the following centrofacial features is required: flushing, nontransient erythema (Figures 1A and 1B), telangiectasia (Figure 1C), or papules/pustules8 (Figures 2A and 2B). Laboratory testing is not useful. Patients may receive a misdiagnosis of skin condi­tions that share similar features. Rosacea is commonly misdiagnosed as adult acne vulgaris, photodermatitis, seborrheic dermatitis, or contact dermatitis. Table 4 lists features that distinguish these conditions from rosacea. Less common mimicking conditions include systemic lupus erythematosus, atopic dermatitis, folliculitis, bro­moderma, and mastocytosis.

TREATMENT

General Measures Although rosacea findings may change over time, no proven natural progression exists.13 Treatment decisions

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

A

B

Figure 2. Inflammatory lesions (papules and pustules).

(A) Papulopustu­lar lesions and scaling on the lateral nose.

(B) Close-up view of papulo­pustular rosacea.

are based on the patient’s current clinical manifestations (Table 5). Because rosacea can be triggered by a variety of stim­uli, avoidance of known triggers is recommended.

To identify potential triggers, patients should be encour­aged to keep a journal documenting exposures, diet, and activities that cause flare-ups.14 Properly selected skin care products improve and maintain the integrity of the stratum corneum permea­bility barrier and reduce skin sensitivity.15 Mild cleansing and moisturizing regimens improve patient satisfac­tion. Cleansers should be fragranceand abrasive-free with a mildly acidic to neutral pH. Recommended skin cleansers include lipid-free, nonalkaline cleansers (e.g., Cetaphil) and sensitive skin synthetic detergent bars (e.g., Dove Sensitive

AMERICAN FAMILY PHYSICIAN Table 4. Skin Conditions That Share Similar Features with Rosacea Condition

Distinguishing features

Acne vulgaris

Comedone formation No ocular symptoms

Contact dermatitis

Associated with itching and often improves over time when causative agent is removed

Photodermatitis

Rash appears on multiple body parts with sunlight exposure

Seborrheic dermatitis

Has distinct distribution pattern involving the scalp, eyebrows, and nasolabial folds

Systemic lupus erythematosus

Rarely has pustules

Skin Bar).16 Patients should cleanse gently with their fingertips, avoid use of abrasive mate­rials, and pat dry for better absorption of moisturizers. Moisturizers should contain emollients and occlusives.14 Although no individual skin care product has been well studied, some products found to improve dry­ness include polyhydroxy acid, lipid-free nonalkaline, and ceramide-based formulas.16 Patients should avoid astringents, toners, sen­sory stimulants, and potentially irritating ingredients.16 Photoprotection is universally recommended, including the use of screens wide-brimmed hats and broad-spectrum sun­ (minimum sun protection factor [SPF] of 30).13 Dimethiconeand simethicone-based products containing titanium dioxide and zinc oxide may be better tolerated.2 Cos­metics with green or yellow tint applied to the central facial erythema may conceal redness.14

FDA-Approved Topical Therapies Topical agents are first-line therapy in the treatment of mild to moderate rosacea (Table 6).17,18 Medication therapy is based on the presence or absence of persistent central facial erythema or inflamma­tion (e.g., papules, pustules, lesional and perilesional erythema), the severity of symptoms, and the patient’s response to previous therapeutic interventions. Five topical agents are approved by the U.S. Food and Drug Administration (FDA) for the treatment of rosa­cea: metronidazole 0.75% lotion, 0.75% cream, and 1% gel; azelaic acid 15% gel; sulfacetamide 10%/sulfur 5% cream, foam, lotion, or suspension; brimonidine 0.33% gel; and most recently, topical ivermectin 1% cream.

Metronidazole Metronidazole is hypothesized to reduce oxidative stress, and has proven effective in reducing erythema and inflammation.19 No significant difference in clinical benefit was found using different vehicles (gel, cream, or lotion) or strengths (0.75% or 1%).

Adverse effects were mild, including pruritus, irri­tation, and dryness.14 Azelaic Acid Azelaic acid is effective against erythema and inflammatory lesions via inhibiting production of reactive oxygen species in neutrophils.19 No difference in effectiveness was found between once- or twice-daily dosing.20 Adverse events include mild and transient burning, stinging, and irritation.19 Metronidazole vs. Azelaic Acid Three studies assessed the effectiveness of metronidazole vs. azelaic acid. Although physician-assessed outcomes suggested that azelaic acid may be more effective than metronidazole, patient evaluations found no statistically significant dif­ferences. Azelaic acid had a higher incidence of adverse events, including dryness, stinging, scaling, itching, and burning. Symptoms were mild to moderate, and tran­sient in both groups. Neither agent was found to be effec­tive against telangiectasia.19 Sulfacetamide/Sulfur FDA approval of sulfaceta­mide/sulfur was granted primarily based on historical use before the implementation of more rigorous stan­dards. Studies demonstrated effectiveness, but were also characterized by high or uncertain risk of bias.17,19 Transient application site reactions occur, and some patients comment about the odor. Use of this second-line agent should be avoided in persons with sulfa allergy.

Brimonidine Topical metronidazole, topical azelaic acid, and oral doxycycline reduce erythema related to vascular inflammation; however, they have neg­ ligible effects on background erythema caused by permanently dilated superficial vessels. Conversely, alpha-adrenergic receptor agonists promote vasocon­ striction but have no effect on papulopustular rosacea.

Once-daily brimonidine, a topical alpha-adrenergic receptor agonist, is effective in reducing erythema. No tachyphylaxis, rebound erythema, or aggravation of inflammatory lesions was noted. Adverse events were mild, including irritation, burning, dry skin, pruritus, and erythema.21 Oxymetazoline 0.05% nasal solution,

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

709

AMERICAN FAMILY PHYSICIAN Table 5. Management of Rosacea Central facial erythema Without papulopustular lesions

With papulopustular lesions Mild to moderate

General measures

Evaluate severity of erythema, inflammation, telangiectasia, and associated symptoms Begin mild nonalkaline skin cleansing and moisturizing regimen Avoid astringents, toners, abrasives, fragrances, and sensory stimulants (e.g., camphor, menthol, alcohol, acetone) Use broad-spectrum sunscreen; sun protection factor (SPF) 30 or greater (zinc oxide or titanium dioxide) Educate on trigger avoidance Consider use of yellow- or green-tinted cosmetics to conceal redness

First-line therapy

Topical metronidazole; azelaic acid, or brimonidine for erythema Vascular laser therapy (pulsed dye laser, intense pulsed light, Nd:YAG laser) for erythema and telangiectasia

Second-line therapy

—

Topical metronidazole or azelaic acid for inflammation and erythema Topical brimonidine for erythema if needed as adjunctive therapy; may be used in combination with metronidazole or azelaic acid for erythema Topical ivermectin for inflammation; may be used in combination with azelaic acid or metronidazole Vascular laser therapy (pulsed dye laser, intense pulsed light, Nd:YAG laser) for telangiectasia Alternate topical therapies (sulfacetamide/sulfur, benzoyl peroxide,erythromycin, clindamycin) or Subantimicrobial (anti-inflammatory) dose doxycycline, 40 mg once per day or 20 mg twice per day, alone or in combination with topical agents

Third-line therapy

—

If limited or no response at 8 to 12 weeks, consider antimicrobial (antibiotic) dose of doxycycline (100 to 200 mg once per day) Topical retinoids

Refractory

Consider treatment in the moderate to severe category

Nd:YAG = Neodymium:yttrium-aluminum-garnet.

also an alpha-adrenergic receptor agonist, applied once daily reduces diffuse central erythema based on case reports.22 Ivermectin Topical ivermectin was approved by the FDA in 2014 for the treatment of papulopustular rosa­cea.23 Two studies demonstrated effectiveness vs. pla­cebo, and a third found that ivermectin was slightly more effective than topical metronidazole in patient- and physicianassessed outcomes and quality of life.18,23

comparable effectiveness in reducing erythema and papules but not pustules.19 Benzoyl peroxide alone or in combination with clindamycin has proven effective; however, adverse events included burning, stinging, and itching.19 Eryth­romycin 2% gel had no statistically significant effective­ness in physician- or patient-assessed outcomes.17,19

Non–FDA-Approved Topical Therapies

Pimecrolimus 1% cream, when compared with placebo, did not improve participant-assessed outcomes. Experts recommend considering use in patients with erythema that does not respond to other treatments.17,19

One study of permethrin vs. azelaic acid vs. metronidazole demonstrated similar effectiveness in reducing erythema and lesion counts. Two additional studies of permethrin vs. metronidazole demonstrated

Topical retinoids have limited data to support their use. One small study suggested a reduction in papulo­pustular lesions. A randomized, double-blind, placebo-controlled study of combination clindamycin

710

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

AMERICAN FAMILY PHYSICIAN

Phymatous

Ocular

Same as for mild to moderate

Same as for central facial erythema

Lid hygiene (warm compresses and cleansing of lashes and lids with baby shampoo scrubs)

Topical metronidazole or azelaic acid for inflammation plus subantimicrobial (anti-inflammatory) dose of doxycycline, 40 mg once per day or 20 mg twice per day

Isotretinoin, 0.3 to 1 mg per kg per day for 12 to 28 weeks

Topical antibiotics (metronidazole or erythromycin)

Moderate to severe

Topical brimonidine for erythema if needed as adjunctive therapy

Microdose therapy for maintenance

Vascular laser therapy (pulsed dye laser, intense pulsed light, Nd:YAG laser) for telangiectasia If limited or no response at 8 to 12 weeks, consider antimicrobial (antibiotic) dose of doxycycline (100 to 200 mg once per day)

Vascular laser therapy (pulsed dye laser, intense pulsed light, Nd:YAG laser, and carbon dioxide laser) Dermabrasion, electroscalpel, electrosurgery, loop cautery

Oral tetracyclines (preferred), or metronidazole or azithromycin Cyclosporine ophthalmic emulsion Ophthalmologic referral

If limited or no response at reassessment, consider alternative oral antibiotic (tetracycline, minocycline, metronidazole, azithromycin) and/or topical treatment (sulfacetamide/sulfur, benzoyl peroxide, erythromycin, clindamycin, permethrin) If refractory to treatment, consider oral isotretinoin (requires participation in online risk reduction program, iPledge: https://www. ipledgeprogram.com)

1.2%/tretinoin 0.025% gel suggested benefit in the reduction of telangiectasia and erythema.17,24 Cream containing 1% extract of a flavonoid-rich plant (Chrysanthellum indicum) demonstrated effectiveness based on patient and physician assessment of rosacea severity.19

Therapies for Diffuse Central Erythema and Telangiectasia Pulsed dye laser, intense pulsed light, and near infrared lasers appear to be effective in treating facial erythema and telangiectasia, although not papulopustular lesions.

The cost of these modalities is significant and may not be covered by insurance. Intermittent retreatment is neces足sary. Adverse events include blistering, purpura, loss of pigmentation, ulceration, and scarring. Near infrared lasers have a greater risk of complications and should be reserved for prominent telangiectasias.25

Systemic Therapies for Facial Erythema with Papulopustular Rosacea Tetracycline and its derivatives have historically been used for the treatment of papulopustular and ocular rosacea. However, the only FDA-approved oral agent is modified-release doxycycline capsule, 40 mg. Subantimicrobial-dose doxycycline at 40 mg once daily or 20 mg twice daily is recommended as initial oral therapy26 (eTable A). Use of subantimicrobialdose doxycycline avoids development of bacterial resistance while enhancing safety and tolerability.19,27 Adverse reac足tions include photosensitivity, candidal vaginitis, pill esophagitis, diarrhea, and pseudotumor cerebri. Mino足cycline has limited data to support its use and uncommon but serious complications, including autoimmune hepatitis, cutaneous hyperpigmentation, vertigo, and drug-induced eosinophilia with systemic

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

711

AMERICAN FAMILY PHYSICIAN Table 6. Topical Therapies for Rosacea Therapy

Formulation and dosage

Effectiveness

Adverse effects

Metronidazole†

0.75% gel, cream, or lotion: twice per day

Papules, pustules, erythema

Pruritus, stinging, irritation, dryness

1% gel: once per day Azelaic acid†

15% gel once or twice per day

Papules, pustules, erythema

Stinging, irritation, burning

Sulfacetamide/sulfur† (several brands)

10%/5% cream and other formulations; once or twice per day

Papules, pustules, erythema

Irritation, malodorous, avoid in persons with sulfa allergy

Brimonidine†

0.33% gel once per day

Erythema

Pruritus, burning, irritation, dryness, erythema; use with caution in patients with CAD or CVD

Ivermectin†

1% cream once per day

Papules, pustules

Burning, skin irritation

Permethrin

5% cream once per day

Papules, erythema

Irritation, burning

Benzoyl peroxide

5% gel once or twice per day

Papules, pustules, erythema

Erythema, burning

Clindamycin

1% gel twice per day

Papules, pustules

Pruritus, burning, irritation, dryness

Erythromycin

2% gel twice per day

Papules, pustules

Pruritus, erythema, irritation, dryness

Pimecrolimus

1% cream twice per day

Erythema

Burning

Tretinoin

Cream: 0.025%, 0.05%, 0.1%

Papules, pustules, erythema, possibly telangiectasia

Peeling, erythema, pruritus, dryness, irritation, may exacerbate rosacea photosensitivity

Erythema

Irritation, burning

Gel: 0.01%, 0.025% Once per night at bedtime Oxymetazoline

0.05% nasal solution every six hours

Cyclosporine

0.5% ophthalmic emulsion every 12 hours Ocular

Hyperemia, burning, blurred vision, tearing

CAD = Coronary artery disease; CVD = Cardiovascular disease; KLK5 = Kallikrein-related peptidase 5; NA = Not available; OTC = Over the counter; RCTs = Randomized controlled trials. †U.S. Food and Drug Administration–approved therapies.

Information from references 17 and 18.

symptoms. Patients with symptoms that do not respond to initial therapy may be prescribed antimicrobialdose doxycycline, tetracycline, minocycline, or other antibiotics.19,26 Ampicillin, erythromycin, and clarithromycin, although effective against papulopustular rosa­cea in a few studies, are not oral agents of choice because of drug interactions, gastrointestinal intolerance, and concerns about promoting antibiotic resistance. Azithro­mycin has greater tolerability, but use has been supported only by case reports and small studies.19,26 Oral metronidazole has demonstrated simi­lar effectiveness when compared with tetracyclines in four studies,18 but the risk of a disulfiramlike reaction with alcohol (i.e., nausea, vomiting, dia­phoresis, flushing of the skin, tachycardia, shortness of breath, headache, confusion, dizziness), and the rare risk of neuropathy and seizures, relegates its use to patients experiencing treatment failures or intolerance of other agents.19,26 Oral isotretinoin may have a role in the management of refractory papulopustular and

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phymatous rosacea.19,28 One study found low-dose isotretinoin to be more effec­tive than doxycycline in physician- and patient-assessed outcomes.18 For patients with moderate to severe papulopustular rosacea or those experiencing an inadequate response to topical therapy, limited studies support combination therapy (usually oral subantimicrobial-dose doxycycline and topical metronidazole or azelaic acid).18,26,29 THERAPY FOR PHYMATOUS ROSACEA Phymatous rosacea (Figure 3) can be disfiguring and difficult to treat. Best results are achieved when treatment is instituted early. Oral isotretinoin may be effec­tive in reducing nasal volume in early disease (Table 5); however, recurrence is likely after discontinuation, and mucinous and fibrotic changes are unresponsive.26,28 Surgical techniques including laser- or light-based therapies (pulsed dye laser, intense pulsed light, carbon dioxide laser), electrosurgery, dermabrasion, tangential excision, electroscalpel, loop

AMERICAN FAMILY PHYSICIAN

Mechanism of action

Evidence

Antioxidant, antiinflammatory

RCTs

Antioxidant; decreases KLK5 and cathelicidin

RCTs

Antibacterial

Small studies and historical precedent

Vasoconstriction

RCTs

Antiparastic/antiinflammatory

RCTs

Antiparasitic

Limited studies

Antibacteriala

Limited studies

Antibiotic

Limited studies

Antibiotic

Limited studies

Anti-inflammatory

Limited studies

Stimulates epithelial cell turnover

Limited studies

Vasoconstriction

Case studies

Immunomodulation

RCTs

Figure 3. Phymatous changes on tip of nose, inflamma­tory lesions (papules and pustules) visible laterally, and telangiectasia.

cautery, and scissor sculpt­ing are effective in correcting or minimizing phymatous changes and may be lifechanging.25,26 THERAPY FOR OCULAR ROSACEA More than 50% of patients with cutaneous rosacea have ocular symptoms that may include tearing, for­ eign body sensation, itching, photophobia, and blurred vision. Ophthalmology consultation is recommended because complications (e.g., corneal ulcerations, scleri­ tis, episcleritis, iritis, persistent hordeola and chalazia) may occur.30 Blepharitis, recurrent hordeola, chalazia, and telangiectasias can affect the lid margin (Figure 4). Mild symptoms can be managed with artificial tears, warm compresses, and cleansing the eyelashes with baby shampoo.30 Long-term consumption of omega-3 fatty acids may improve meibomian-gland dysfunc­tion.31 Topical ophthalmic cyclosporine drops demonstrate statistically significant improvement in common signs and symptoms compared with artificial tears.19 Topical metronidazole and erythromycin may be useful for eyelid symptoms. Patients may be treated with systemic therapy using tetracyclines or azithromycin.

Figure 4. Ocular rosacea. (top) Telangiectasia of the upper lid. (middle) Lower-lid granuloma secondary to meibomian gland dysfunction; inflammation and scar­ring; mild conjunctivitis is also present. (bottom) Scarring of the lower lid margin secondary to recurrent bouts of inflammation.

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Teratogenicity, hyperlipidemia, hepatotoxicity, depression, dry skin, photosensitivity, impaired night vision

High incidence of GI adverse effects, prolonged QT interval

High incidence of GI adverse effects, prolonged QT interval

Candidiasis

Disulfiram reaction with alcohol, seizures, neuropathy

Drug rash with eosinophilia and systemic symptoms

Vertigo/dizziness, autoimmune hepatitis, drug-induced lupus-like syndrome

Tetracycline-related adverse effects as above

Candidiasis

Tetracycline-related adverse effects as above

U.S. Food and Drug Administration–approved systemic therapy for the treatment of rosacea.

Refractory papulopustular and phymatous subtypes

Patients must enroll in National iPledge Program; physicians require special training to prescribe

Caution in older patients

High incidence of drug interactions

Caution in older patients

High incidence of drug interactions

Caution in older patients

Drug interaction with lithium, anticoagulants, phenytoin

Contraindicated in pregnancy and lactation

Must be taken at least one hour before or two hours after meal

Contraindicated in pregnancy and lactation

Decreased absorption with vitamins, antacids, metal ions

Contraindicated in pregnancy and lactation

Decreased absorption with vitamins, antacids, metal ions

No generation of antibiotic resistance demonstrated

RCTs (few)

Small studies

Small studies

Small studies, case reports

Small studies

Historical use

RCTs (few) and historical use

RCTs (few) and historical use

RCTs and open-label studies (large, high-quality studies)

Decreased absorption with vitamins, antacids, metal ions Contraindicated in pregnancy and lactation

Evidence

Caveats

Information from: Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies. Cutis. 2014;93(1):18-28.

†Only

GI = Gastrointestinal; NA = Not available; RCTs = Randomized controlled trials.

Note: Therapies are listed in order of preference.

0.3 mg per kg per day or 10 to 20 mg per day initially for 4 to 6 months, followed by microdose therapy (0.03 to 0.17 mg per kg per day)

Isotretinoin

250 mg once per day for three days per week

250 to 500 mg twice per day

500 mg once per day for three consecutive days per week

Azithromycin

Clarithromycin

250 mg once per day

Metronidazole

250 mg twice per day

Candidiasis

50 to 100 mg twice per day or once per day for long-acting

Minocycline

Erythromycin

GI adverse effects, prolonged QT interval, hepatotoxicity, cholestasis

250 to 500 mg twice per day

Tetracycline

Candidiasis

100 mg once or twice per day

Doxycycline (antimicrobial dose) Tetracycline-related adverse effects as above

Dose-related phototoxicity, GI adverse effects, pill esophagitis, pseudotumor cerebri, cutaneous hyperpigmentation (bluish/ brownish discoloration of skin, mucous membranes)

40 mg once per day (30 mg per 10-mg modified-release capsule)

Doxycycline (anti-inflammatory/ subantimicrobial dose)†

20 mg twice per day

Adverse effects

Dosage

Therapy

eTable A. Systemic Therapy for Rosacea

AMERICAN FAMILY PHYSICIAN Note: See for complete article visit: www.aafp.org/afp.

REFERENCES 1. Blount BW, Pelletier AL. Rosacea: a common, yet commonly overlooked, condition. Am Fam Physician.

2002;66(3):435-440.

2. Powell FC. Clinical practice. Rosacea. N Engl J Med. 2005;352(8): 793-803.

3. Gupta MA, Gupta AK, Chen SJ, Johnson AM. Comorbidity of rosacea and depression: an analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Care Survey—Outpatient Department data collected by the U.S. National Center for Health Sta­tistics from 1995 to 2002. Br J Dermatol. 2005;153(6):1176-1181.

4. Kligman AM. A personal critique on the state of knowledge of rosacea. Dermatology. 2004;208(3):191-197.

5. Spoendlin J, Voegel JJ, Jick SS, Meier CR. A study on the epidemiology of rosacea in the U.K. Br J Dermatol.

2012;167(3):598-605.

6. Elewski BE, Draelos Z, Dréno B, Jansen T, Layton A, Picardo M. Rosa­cea—global diversity and optimized outcome: proposed international consensus from the Rosacea International Expert Group. J Eur Acad Der­matol Venereol. 2011;25(2):188-200.

7. Tan J, Berg M. Rosacea: current state of epidemiology.

J Am Acad Der­matol. 2013;69(6 suppl 1):S27-S35.

8. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea.

J Am Acad Dermatol. 2002; 46(4):584-587.

9. Tan J, Blume-Peytavi U, Ortonne JP, et al. An observational cross-sectional survey of rosacea: clinical associations and progression between subtypes. Br J Dermatol.

2013;169(3):555-562.

10. Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea patho­physiology: a review of recent findings.

J Am Acad Dermatol. 2013;69 (6 suppl 1):S15-S26.

11. Cohen AF, Tiemstra JD. Diagnosis and treatment of rosacea. J Am Board Fam Pract. 2002;15(3):214-217.

12. Kligman AM. An experimental critique on the state of knowledge of rosacea. J Cosmet Dermatol. 2006;5(1):77-80.

13. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 1: a status report on the disease state, general measures, and adjunctive skin care. Cutis. 2013;92(5):234-240.

14. Odom R, Dahl M, Dover J, et al.; National Rosacea Society Expert Com­mittee on the Classification and Staging of Roasacea. Standard man­agement options for rosacea, part 1: overview and broad spectrum of care. Cutis.

2009;84(1):43-47.

15. Del Rosso JQ. The role of skin care and maintaining proper barrier function in the managment of rosacea.

Cosmet Dermatol. 2007;20(8):485-490.

16. Levin J, Miller R. A guide to the ingredients and potential benefits of over-the-counter cleansers and moisturizers for rosacea patients. J Clin Aesthet Dermatol. 2011;4(8):31-49.

17. Del Rosso JQ, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 2: a status report on topical agents. Cutis.

2013;92(6):277-284.

18. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MM, Charland L. Inverventions for rosacea. Cochrane Database Syst Rev. 2015;(4):CD003262.

19. van Zuuren EJ, Kramer S, Carter B, Graber MA, Fedorowicz Z. Interven­tions for rosacea. Cochrane Database Syst Rev. 2011;(3):CD003262.

20. Thiboutot DM, Fleischer AB Jr, Del Rosso JQ, Graupe K. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008;7(6): 541-546.

21. Fowler J, et al.; Brimonidine Phase II Study Group.

Once-daily topical bri­monidine tartrate gel 0.5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. 2012;166(3): 633-641.

22. Shanler SD, Ondo AL. Successful treatment of the erythema and flushing of rosacea using a topically applied selective alpha1-adrenergic receptor agonist, oxymetazoline. Arch Dermatol. 2007;143(11):1369-1371.

23. Layton A, Thiboutot D. Emerging therapies in rosacea.

J Am Acad Der­matol. 2013;69(6 suppl 1):S57-S65.

24. Chang AL, Alora-Palli M, Lima XT, et al. A randomized, double-blind, placebo-controlled, pilot study to assess efficacy and safety of clindamy­cin 1.2% and tretinoin 0.025% combination gel for the treatment of acne rosacea over 12 weeks. J Drugs Dermatol. 2012;11(3):333-339.

25. Tanghetti E, Del Rosso JQ, Thiboutot D, et al. Consensus recommenda­tions from the American Acne & Rosacea Society on the management of rosacea, part 4: a status report on physical modalities and devices. Cutis.

2014;93(2):71-76.

26. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommenda­tions from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies. Cutis. 2014; 93(1):18-28.

27. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating antiinflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56(5):791-802.

28. Park H, Del Rosso JQ. Use of oral isotretinoin in the management of rosacea. J Clin Aesthet Dermatol.

2011;4(9):54-61.

29. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommenda­tions from the American Acne & Rosacea Society on the management of rosacea, part 5: a guide on the management of rosacea. Cutis. 2014;93(3):134-138.

30. Vieira AC, Mannis MJ. Ocular rosacea: common and commonly missed. J Am Acad Dermatol. 2013;69(6 suppl 1): S36-S41.

31. Oltz M, Check J. Rosacea and its ocular manifestations.

Optometry. 2011;82(2):92-103.

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Practice Guidelines ECG, ECHOCARDIOGRAPHY, OR MPI FOR CARDIAC SCREENING: GUIDANCE FROM THE ACP In the United States, one in three deaths is from cardio­ vascular disease; coronary heart disease is the leading cause of death. Screening for coronary heart disease can be performed with resting or stress electrocardiography (ECG), stress echocardiography, or myocardial perfusion imaging (MPI). This guideline from the American Col­lege of Physicians (ACP) provides recommendations on cardiac screening using these modalities.

Recommendations and Practice Although the benefit of cardiac screening in adults at low-risk of coronary heart disease is questionable, it is often still performed. The American Heart Association, among other organizations, does not recommend performing ECG for cardiac screening in low-risk adults, and the U.S. Preventive Services Task Force specifically recommends against it. With regard to stress echocardiography and MPI, the American College of Cardiology Foundation and the American Heart Association recommend against using either to evaluate cardiovascular risk in adults at low risk without symptoms.

Despite this, a study of national data determined that the use of ECG for screening purposes at general physician office visits increased from 6.1% in 1999 to 11.3% in 2009, and a systematic review concluded that the rates of overuse were 9.2% for ECG and 3% to 52% for cardiac stress tests. Additionally, based on data from three studies, approximately 15% of MPI and stress echocardiography fail to meet criteria for appropriate use.

Benefits and Harms Benefits of screening with imaging include detecting cor­onary heart disease that has not yet been diagnosed, and determining if a person has a higher risk of a cardiovas­cular event, such as myocardial infarction or arrhythmia.

Harms associated with stress tests include sudden death or an event in which a patient needs to be hospital­ ized; however, the risk is minimal, estimated at one per 10,000 exercise ECGs performed. Pharmacologic agents used to induce stress can have adverse effects, such as hypotension or myocardial ischemia, but the rates of serious effects appear to be low.

There are also harms stemming from false-positive results, such as anxiety and unnecessary treatments or follow-up tests, and from true-positive results, such as disease labeling and health insurance issues (e.g., increased cost). Downstream harms are also possible from follow-up tests and treatments.

High-value Care Recommendations Cardiac disease screening using resting or stress ECG, stress echocardiography, or stress MPI should not be performed in low-risk adults without symptoms.

Instead, the focus should be on decreasing each patient’s risk by addressing adjustable factors that increase the patient’s risk (e.g., smoking, diabetes mellitus, being overweight) and promoting exercise. Global risk calculators such as the Framingham Risk Score (http:// cvdrisk.nhlbi.nih.gov/calculator.asp), SCORE (www. heartscore.org/Pages/welcome.aspx), and PROCAM (www.myhealthywaist.org/evaluating-cmr/assessingcvd-risk-traditional-approaches/procam/page/5/index. html) can be used to help assess risk for heart disease.

■■■■

Source: Adapted from Am Fam Physician. 2015;92(6):531.

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AMERICAN FAMILY PHYSICIAN

Photo Quiz RAPIDLY PROGRESSING RASH IN AN ADULT A 40-year-old woman with no significant medical history presented with a nonpruritic rash that developed rapidly over three days and was progressively worsening. Three days before the rash appeared, she had a fever of 103°F (39.4°C), sore throat, and head­ache.

Diphenhydramine provided no relief. Ten days before her own symp­toms developed, the patient’s eight-yearold daughter had a fever, diarrhea, and a similar rash on her feet. The patient had not been exposed to any new medications, foods, or soaps and had not traveled recently.

On physical examination, the patient’s temperature was 101°F (38.3°C). She had a diffuse erythematous papulovesicular rash on her distal upper and lower extremities, including her palms and soles (Figure 1).

She had a similar rash on her face, predomi­nantly around her lips (Figure 2), and an isolated macule on her soft palate. There was no rash on her trunk. The remainder of her examination was unremarkable.

Figure 1.

Question Based on the patient’s history and physical examination findings, which one of the fol­lowing is the most likely diagnosis?

A. Disseminated herpes simplex virus infection.

B. Hand-foot-and-mouth disease.

C. Secondary syphilis.

D. Varicella (chickenpox).

Figure 2.

SEE THE FOLLOWING PAGE FOR DISCUSSION.

Source: Adapted from Am Fam Physician. 2015;92(6):525-526.

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AMERICAN FAMILY PHYSICIAN DISCUSSION

Summary Table

The answer is B: hand-foot-and-mouth disease. This is a clinical syndrome characterized by clusters of erythema­tous papulovesicular lesions with perilesional erythema. The lesions appear throughout the body but are com­monly present on the hands, feet, knees, perioral areas, oral mucosa, and buttocks/genital areas.1,2 Coxsackievirus A16 and enterovirus A71 are the most common causes.3 The coxsackievirus A6 strain has been associated with worldwide outbreaks and leads to more severe dis­ease.4 Hand-foot-and-mouth disease generally occurs following oral ingestion of the virus shed from the upper respiratory tract or the gastrointestinal system of an infected patient, usually a child.5 The average incubation period is three to 10 days.

Although hand-foot-and-mouth disease is most com­mon in children 10 years and younger, it is becoming more common in adults. Patients often report fever and constitutional symptoms before development of the rash. The diagnosis is clinical, based on the history and the characteristic rash. It is mild and self-limited, with symptoms generally resolving within seven to 10 days. Treatment is supportive and includes fluids, antipyret­ics, and analgesics. Topical lidocaine and mouthwashes can be used for pain relief if oral ulcers are present. Complications are uncommon but may include finger­nail or toenail loss,2 meningitis, encephalitis, myocardi­tis, and other neurologic sequelae.

Disseminated herpes simplex virus infection may present in individuals with a local herpes infection, and is most common in immunocompromised and pregnant patients. It is characterized by monomorphic umbilicated vesicles or ulcerated, hemorrhagic lesions.

Although this rash can appear almost anywhere on the body, the palms and soles are generally spared.

Secondary syphilis occurs with an untreated primary infection. Patients present with a nonpruritic, papu­lar, pink and violaceous, scaly rash on the trunk and extremities, including the palms and soles. Gray plaques and ulcers may occur on the mucosal areas.

Systemic symptoms are often present, including fatigue, fever, lymphadenopathy, and gastrointestinal and neurologic abnormalities. Some patients are asymptomatic.

Condition

Description

Area affected

Disseminated herpes simplex virus infection

Monomorphic umbilicated vesicles or ulcerated, hemorrhagic lesions

Distributed almost anywhere on the body; tends to spare the palms and soles

Hand-foot-andmouth disease

Clusters of erythematous papulovesicular lesions with perilesional erythema

Hands, feet, knees, perioral area, oral mucosa, and buttocks/genital areas

Secondary syphilis

Nonpruritic, papular, pink and violaceous, scaly rash

Trunk and extremities, including the palms and soles; gray plaques and ulcers may occur on the mucosal areas

Varicella (chickenpox)

Pruritic and painful lesions at multiple stages of development

Lesions often spare the palms and soles

form fluid-filled vesicles (“dew drops on a rose petal”).

Vesicles often appear in the nasopharynx but may also be found in the rectum, conjunctiva, and vagina. Palms and soles are often spared.

REFERENCES 1. Hand-foot-and-mouth disease. Updated 2014. BMJ Best Practices. http://us.bestpractice.bmj.com/best-practice/ monograph/685.html (subscription required). Accessed January 31, 2015.

2. Centers for Disease Control and Prevention. Hand, foot, and mouth disease (HFMD). Signs and symptoms. http:// www.cdc.gov/hand-foot-mouth/about/signs-symptoms. html. Accessed June 4, 2014.

3. Enteroviruses. In: Cecil RL, Goldman L, Schafer AI, eds.

Gold­man’s Cecil Medicine. 24th ed. Philadelphia, Pa.: Elsevier-Saunders; 2012:2140-2143.

4. Downing C, Ramirez-Fort MK, Doan HQ, et al.

Coxsackievirus A6 asso­ciated hand, foot and mouth disease in adults: clinical presentation and review of the literature. J Clin Virol. 2014;60(4):381-386.

5. Romero JR, Modlin JF. Introduction to the human enterovirus and parechoviruses. In: Bennett JE, Dolin R, Blaser MJ, et al., eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed.

Philadelphia, Pa.: Elsevier-Saunders; 2014.

■■■■

Varicella, or chickenpox, is most common in children.

It causes constitutional symptoms and a rash that starts on the face or scalp, then moves toward the extremities.

The rash begins as pruritic and painful macules that

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CARDIOLOGY

Comparative Evaluation of Cost-effectiveness Between Ramipril versus Telmisartan in Cases of Hypertension Associated with Type 2 Diabetes Mellitus PANKAJ KUMAR*, AK KAPOOR†, HK SINGH†, MALINI KULSHRESTHA‡

ABSTRACT Objective: To determine cost-effectiveness of ramipril versus telmisartan in relation to different measures of effectiveness in hypertensives associated with type 2 diabetes mellitus. Material and Methods: A prospective, randomized, interventional, comparative study of 1 year duration was undertaken in patients of hypertension with type 2 diabetes mellitus. A total of 222 patients were recruited of which only 192 patients completed the study. Patients were administered either ramipril (5 mg/day) or telmisartan (40 mg/day) for 1 year. Results: The baseline mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) in ramipril group was 152.08 and 88.59 mmHg, whereas comparable values for telmisartan group were 151.8 and 87.78 mmHg. Both agents caused statistically significant consistent fall in SBP and DBP at each follow-up. Ramipril (5 mg) decreased SBP from 152.08 to 109.48 and DBP from 88.59 to 70.90 mm Hg, whereas telmisartan (40 mg) decreased SBP from 151.8 to 109.55 and DBP from 87.78 to 70.97 mmHg. Thus in the assigned doses both the drugs caused decrease in BP with almost similar efficacy and there was statistically no significant difference in the three brands each of ramipril and telmisartan available, though their cost varied considerably. It was noted that telmisartan 40 mg compared to ramipril 5 mg per tablet had the lowest cost to achieve the target BP values. Besides, in the doses used there was no major difference in the incidence of adverse events between the two agents, which could be responsible for escalation of cost of the agent. Conclusion: If a relationship between efficacy and cost-effectiveness is portrayed (the level of effectiveness is set at achieving target BP values) then telmisartan would be more cost-effective as compared to ramipril.

Keywords: Hypertension, ramipril, telmisartan, cost-effectiveness

H

igh blood pressure (BP) is a major modifiable risk factor for coronary heart disease (CHD), myocardial infarction (MI), heart failure and stroke.1 Because of increasing obesity and population aging, the global burden of hypertension is rising and projected to affect 1.5 billion persons – onethird of the world’s population-by the year 2025.1 Thus, high BP remains the leading cause of death worldwide and one of the world’s great public health

*Assistant Professor †Professor Dept. of Pharmacology ‡Professor Dept. of Medicine Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh Address for correspondence

Dr Pankaj Kumar Assistant Professor Dept. of Pharmacology Rohilkhand Medical College and Hospital, Bareilly, Uttar Pradesh E-mail: drpankajrkumar@yahoo.com

problems.1 Hypertension is an important risk factor for cardiovascular diseases (CVDs), which are responsible for roughly 30% of deaths worldwide.2,3 Reduction in high BP to normotensive values reduces the risk of coronary death by 47%.4 The rennin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the pathogenesis of atherosclerosis and pathophysiology of CVDs. Thus, angiotensinconverting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are recommended as the first-line agents for the treatment of hypertension and hypertension associated with type 2 diabetes. Despite a large number of antihypertensive agents currently available, yet in the present study of cost-effectiveness only ACEIs (ramipril) and ARBs (telmisartan) are considered because these agents not only are long-acting, but have shown clinically documented antihypertensive efficacy; better compliance and tolerability as well as prevented hypertension related end-organ damage thus conferring cardiovascular protection.5 Additionally, modulation of RAAS with ACEI and ARB not only

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CARDIOLOGY reduces a range of adverse cardiovascular outcomes, but also affords renoprotection. Moreover, ACEI, like ramipril have proven that even with small reduction in BP, there is reduction in overall mortality and cardiovascular endpoints.6 Besides, hypertension is an extremely common comorbid condition in diabetes, affecting 20-60% patients with diabetes.7 Further, 75% of all deaths in diabetic patients result from CHD.8,9 In the United Kingdom Prospective Diabetic Study (UKPDS) each 10 mmHg decrease in mean systolic BP (SBP) was associated with reduction in risk of 12% for any complication related to diabetes, 15% for death related to diabetes, 11% of MI and 13% for microvascular complications.7 The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII) defines different stages of hypertension.10 The current classification of hypertension as recommended by JNC VII lists-normal BP: SBP <120, diastolic <80 mmHg; prehypertension: systolic 120-139, diastolic 80-89 mmHg; Stage 1 hypertension: systolic 140-159, diastolic 90-99 mmHg; Stage 2 hypertension: systolic >160, diastolic >100 mmHg. It recommended ACEI and ARB use for control of hypertension in diabetic patients for renal protection.10 Besides, ACEI and ARBs have become keystones of therapy of hypertension in diabetes because of their broadly demonstrated favorable effects on diabetic nephropathy and CVD outcomes, as well as their modest favorable effects on measures of glucose metabolism.11 Moreover, renin-angiotensin system blockade delays or avoids the onset of type 2 diabetes and prevents cardiovascular and renal events in diabetic patients.12-17 Since, the treatment has to be continued for whole life hence the cost-effectiveness between these two treatment groups is of prime importance.

AIMS AND OBJECTIVES The aims and objectives of the present study are: to assess difference in efficacy between ramipril (5 mg) versus telmisartan (40 mg) if any, to examine the cost-effectiveness between ramipril and telmisartan depending upon similar magnitude of effect (fall in BP) by a given amount of drug i.e., effectiveness per unit dose, whether differences exist between these two classes of agents in cost-effectiveness on longterm basis, and for the chosen patients, which of the two agent is most cost-effective and showing minimal adverse effect profile.

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MATERIAL AND METHODS A prospective, randomized, interventional open label comparative clinical study of 1 year duration (January 2013 to January 2014) was undertaken amongst the patients attending the medicine outdoor patient department of Rohilkhand Medical College and Hospital, Bareilly, diagnosed as hypertension (JNC VII Stage 1) associated with uncomplicated type 2 diabetes mellitus. Written informed consent from all the participants was undertaken before starting the study and the participants were free to withdraw without prejudice at any time. The study protocol was approved

by Institutional Ethical Committee. All patients aged 30-80 years and diagnosed as hypertensives (JNC VII Stage 1) with uncomplicated type 2 diabetes were enrolled. Both newly diagnosed patients and those who had voluntarily discontinued antihypertensive medication for more than 4 weeks comprised study population.

The exclusion criteria were patients of secondary hypertension, symptomatic heart failure, significant valvular heart disease, pericardial constriction or effusion, congenital heart disease, uncontrolled hypertension, pregnant and lactating mothers, females using oral contraceptives, significant liver or kidney diseases, known hypersensitivity to ACEI and ARBs and inability to tolerate ramipril or telmisartan.

A total of 222 eligible patients who fulfilled the inclusion criteria were recruited for the study. Thirty patients did not turn up for regular follow-up either because of adverse effects, high cost of medicine or due poor compliance based on tablet counts, or owing to unawareness that they have to take medicine (both antihypertensive and antidiabetic) each day continuously despite adequate control almost throughout their lifetime, were excluded for the purpose of study. Hence, only 192 patients eventually completed the study and were finally evaluated for cost-effectiveness. All recruited patients were divided into two groups by simple randomization, thus all odd number patients were assigned ramipril (5 mg once-daily in the morning) and even study numbers to telmisartan (40 mg once-daily in the morning), respectively continuously for 12 months.

The selection of the doses of these two agents was based on previous studies18,19 inclusive of our study,20 which had observed that 5 mg of ramipril caused a fall of BP almost equivalent to 40 mg of telmisartan (equally effective doses) in Stage 1 hypertension. The ramipril treated group received ramipril 5 mg and the

CARDIOLOGY telmisartan group received telmisartan 40 mg, the two least expensive brands from our hospital pharmacy.

Doses of the antihypertensives were fixed throughout the study period and no upward titration of the dose was done, since all patients achieved target BP values <140/90 mmHg.

included headache, dizziness, fatigue, back pain, dyspepsia, myalgia, pruritus, nausea, dry irritating cough. Adverse effects following therapy, if any, were noted down for both regimens for tolerability profile.

Demographic informations viz. name, age, sex, informations about social and cultural factors, educational and socioeconomic status was collected. All patients underwent a detailed clinical assessment pertaining to hypertension and diabetes and relevant investigations were conducted at baseline, and at each follow-up, BP was recorded with standardized technique with mercury column type sphygmomanometer and stethoscope.

Throughout the study period BP <140/90 mmHg was targeted and all test subjects were well-controlled with the prescribed amount of the two drugs. No upward titration of the dose was required and the targeted BP was achieved following 2 weeks of antihypertensive therapy. Still lower limits of BP <120 systolic and <80 mmHg diastolic (the goal BP) was achieved in about 8-15 cases with both these regimen and in these cases no further reduction in the doses of individual agent was undertaken.

Tables 1 and 2 shows comparative reduction of SBP and DBP between baseline and at end of treatment (10th follow-up) with both regimens. Majority of patients in our study were in the age group of 41-50 years and both the treatment groups were comparable. The baseline mean SBP and mean diastolic BP (DBP) in ramipril group was 152.08 and 88.59 mmHg, whereas mean SBP and mean DBP in telmisartan groups was 151.8 and 87.78 mmHg, respectively. A regular follow-up of SBP and DBP in ramipril group showed statistically significant regular, consistent reduction at each followup till the end of study (p < 0.0001). The SBP decreased from 152.08 to 109.48 mmHg and DBP reduced from 88.59 to 70.90 mmHg at end of study. Similarly, telmisartan also significantly decreased SBP from 151.8 to 109.55 mmHg and DBP from 87.78 to 70.97 mmHg at end of study (p < 0.0001). As the observation that SBP and DBP had been reduced in all the follow-ups with ramipril and telmisartan, it is reasonable to note that both these agents caused a regular, consistent, statistically significant fall in BP to the desired targeted values. Thus, these agents were equally effective as was reflected by the fact that there was statistically no significant difference (p > 0.05) between values of BP achieved by these two agents in different follow-ups.

For type 2 diabetes either metformin (500 mg) once- or twice-daily was used or else a combination of metformin (500 mg) and glimepiride (1 mg) once- or twice-daily was administered to achieve the adequate glycemic control of blood sugar. Further, at each visit the patients were inquired for the objective and subjective systemic adverse effects of the drugs. The subjective symptoms

RESULT

Table 1. Comparative Reduction of SBP Between Baseline and at End of Treatment in Both Regimens SBP Baseline 10th follow-up Reduction from baseline P value

Ramipril

Telmisartan

Difference

152.08 ± 6.04

151.8 ± 5.56

0.28

109.48 ± 0.925

109.55 ± 08375

0.07

-42.6 (95% CI [41.29-43.83])

-42.25 (95% CI [41.09-43.42])

0.35

<0.0001

<0.0001

>0.05

P value <0.0001 = Highly significant and >0.05 = Not significant.

Table 2. Comparative Reduction of DBP Between Baseline and at End of Treatment in Both Regimens DBP Baseline 10th follow-up Reduction from baseline P value

Ramipril

Telmisartan

Difference

88.59 ± 8.34

87.78 ± 7.92

0.81

70.90 ± 1.0008

70.97 ± 1.0005

-0.07

-17.69 (95% CI [16-19.42])

-16.81 (95% CI [15.18-18.44])

0.88

<0.0001

<0.0001

>0.05

P value <0.0001 = Highly significant and >0.05 = Not significant.

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CARDIOLOGY Table 3. Comparative Cost Monthly, 6-monthly and Yearly Cost of Acquisition of Both Regimens Daily cost (Rs.) Monthly cost (Rs.) Six-monthly cost (Rs.) Yearly cost (Rs.)

Ramipril (Ramipril - 5 mg)

Telmisartan (Telmisartan - 40 mg)

Cost difference (Per patient)

10.90

6.90

4.00

10.90 × 30 = 327

6.90 × 30 = 207

120

10.90 × 180 = 1962

6.90 × 180 = 1242

720

10.90 × 365 = 3978.50

6.90 × 365 = 2518.50

1460

The brands of ramipril and telmisartan available in our hospital pharmacy, which were least expensive, were used in the present study.

Table 3 shows comparative monthly, 6-monthly and yearly costs of acquisition and cost-effectiveness expressed as reduction in BP by ramipril (5 mg) and telmisartan (40 mg) from hospital pharmacy. It can be well-visualized that cost of acquisition of telmisartan is fairly low as compared to cost of ramipril.

DISCUSSION Hypertension and diabetes mellitus are both highly prevalent, chronic, incurable ailments which require continuous, regular, palliative therapy almost throughout the life of the individual. These clinical conditions, thus require continuous monitoring to prevent various complications as well as the progression of the disease hence, proper optimal therapy is a must to achieve treatment goals as suggested by latest guidelines with minimal costs. Hypertension not only is inadequately treated, but also is associated with risk for cardiovascular morbidity and mortality.21-23 Monotherapy with once-daily administration is not only convenient, but also improves treatment adherence and compliance. In the present study, monotherapy with fixed doses of ramipril or telmisartan have been used.

Interestingly, both agents do not produce tolerance even on long-term use, hence in none of the case an upward titration of the doses has been required.24 Since, the two groups are well-balanced in respect to BP, and magnitude of fall in BP, hence efficacy between the two groups can well be accounted for. Other workers in the field have also reported similar baseline values of SBP and DBP.6,25,26 Our observations are qualitatively and quantitatively similar to observations reported by the Heart Outcomes Prevention Evaluation (HOPE) investigators,6 the ONgoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) investigators,27 Yusuf et al,28 Teo et al29 and other studies25,26,30 in respect of ramipril. Similarly, telmisartan also showed a significant reduction in SBP and these results are in conformity with other authors.

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In summary, both ramipril and telmisartan caused decrease in SBP and DBP in hypertensive patients with type 2 diabetes mellitus and the onset of action is within 2 weeks.20 Furthermore, on comparing the effectiveness, ramipril has caused a reduction of -42.6 mmHg (95% confidence interval [CI], 41.29-43.83) in SBP in comparison to telmisartan reduction of -42.25 mmHg (95% CI, 41.09-43.42) in SBP. Additionally, ramipril has caused a reduction of -17.69 mmHg (95% CI, 16-19.42) in DBP, in comparison telmisartan has caused a reduction of -16.81 mmHg (95% CI, 15.18-18.44).

Thus, both the agents have shown a consistent and statistically markedly significant reduction in SBP and DBP in all 10 follow-ups.

Our findings of comparative SBP reduction with the two regimens are in line with those of ONTARGET investigators.27 Regarding the comparative antihypertensive efficacy between ramipril and telmisartan on DBP, it has been observed that both these agents decrease DBP with almost similar efficacy and there is no statistically significant difference. The results of the ONTARGET study27 have also demonstrated that telmisartan, is as effective as the ACEI, ramipril.

In contrast to our observations, a meta-analysis of 28 randomized controlled trials involving 5,157 patients, telmisartan had a superior BP control over different ACEIs (enalapril, ramipril and perindopril).31 In a nutshell, we have also observed similar effectiveness between ramipril, (5 mg) and telmisartan (40 mg) as regards their antihypertensive efficacy.20 Moreover, ONTARGET demonstrated that the two agents, telmisartan and ramipril are equally effective in reducing the primary composite outcome of cardiovascular death, MI, stroke or hospitalization due to heart failure (relative risk [RR] 1.01, 95% CI, 0.94-1.09), but telmisartan is better tolerated than ramipril.27 The cost-effectiveness ratio usually referred to in pharmacoeconomics is the incremental costeffectiveness ratio, which compares the costs and effects of one treatment (here ramipril) with those of another (telmisartan). The incremental cost-effectiveness ratio

CARDIOLOGY is defined as the difference in the cost of the two treatments (ramipril and telmisartan) divided by the difference in their effectiveness:

Cost-effectiveness =

Cost (Ramipril) Cost (Telmisartan) Effectiveness (Ramipril) Effectiveness (Telmisartan)

For the cost-effectiveness study, we have used fixeddose schedule of these agents, and the cost implications of ramipril and telmisartan monotherapy have been reported. Alternate treatments (here telmisartan) typically vary both in their cost and in their effectiveness.

The goal is to find the treatment with least cost for the greatest effectiveness i.e., the treatment with the smallest (most favorable) cost-effectiveness ratio. It can be visualized from the above equation that the costeffectiveness ratio can be reduced by decreasing the cost of treatment or increasing the effectiveness. However, the shortcoming of the above equation is, it does not mention how costs and effectiveness are to be defined.

The cost is expressed in currency, but the effectiveness can be expressed in number of ways. For the purpose of the present study, the measures of effectiveness which has been taken into account are the average percent reduction in BP values per patient, and the proportion (percent) of the patients reaching the goal values of BP with fixed-dose schedule of antihypertensive agent.

These different measures necessitate different time horizons to achieve goal values and corresponding differences in the costs that must be considered.

have been arrived at by the observations of previous studies including those of ourselves, based on equal magnitude of fall of BP. If a relationship between efficacy and cost-effectiveness is portrayed (the level of effectiveness is set at achieving target BP values) then telmisartan (40 mg) has the lowest cost compared to ramipril (5 mg) at that level of effectiveness. When effectiveness is measured in terms of proportion of patients reaching the goal BP values then ramipril (5 mg/d) beyond 4 weeks treatment also caused greater number of patients reaching goal BP values compared to telmisartan (40 mg/d), although effectiveness is dependent on patients initial BP level and on their goal BP level. Outcome studies have shown that many patients in low risk categories do not reach their goal BP level. The failure to reach BP goal level may be due, in part, to low adherence, inadequate treatment due to failure to titrate and appearance of adverse effects. It may be emphasized that the use of percent of patients reaching target BP values as a measure of effectiveness ignores any potential benefit of reducing BP level to recommended goal values. Although JNC guidelines recommend drug titration until patients reach their treatment goal (or maximum dose), if the initial dose is inadequate. In this scenario, effectiveness is appropriately measured as the percentage of patients reaching their goal BP values to minimize the cardiovascular risk factors.

Three different brands of ramipril and telmisartan are available in our hospital pharmacy supply and these vary considerably in price and possibly efficacy.

Efficacy is defined here as the magnitude of the effect or effectiveness (fall in BP) produced by given amount of drug. It can be understood as the inverse of potency, which is the amount of drug required to produce given effect. The differences in effectiveness may be due to unequal bioequivalence amongst different available brands, although it has been argued that the good brands are clinically interchangeable. In the present study, we have not tried to raise the dose to increase the effectiveness.

In the present study, telmisartan has been found to be cost-effective i.e., Rs. 1460/patient/year cheaper in comparison to ramipril. The costs that should be considered are all those which are associated with measuring and re-measuring patients BP, and cost of hospital visits and other related laboratories investigations, as well as drug acquisition costs. This is the actual scenario in pharmacoeconomic analysis based on 52 weeks, randomized clinical study. Note, however, that once the targeted treatment goal is achieved, the costs of long-term maintenance therapy are principally the hospital visit cost plus direct drug acquisition costs.

A limitation of the study was actual purchase cost of the two agents namely ramipril and telmisartan may differ if procured from different medical shops, and this may change the cost-effectiveness rankings of the two agents in long run at any given level of effectiveness.

The differences in effectiveness and price have important repercussions in the determination of effectiveness between the two treatment regimens on long-term basis. In the present pharmacoeconomic analysis study, almost equally effective starting doses of the two treatment groups (ramipril vs. telmisartan)

It can therefore be assumed that in cases of Stage 1 hypertension associated with uncomplicated type 2 diabetes, it is exclusively the drug price rather than the effectiveness/efficacy (which is almost equal in prescribed doses in both regimens), is more important determinant of cost-effectiveness. In contrast, Lamy et al32

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CARDIOLOGY while analyzing the cost implications of the use of telmisartan versus ramipril monotherapy observed that the use of telmisartan instead of ramipril increased cost by 6.3% as their observations were based on direct healthcare system costs based on the ONTARGET study data, and pattern of cost calculation was also bit different, since the authors obtained country-specific unit costs to the different care resources consumed.

It has been observed that both ramipril and telmisartan have fairly good tolerability and adverse effects have been noted in 0.15% in case of ramipril and 0.8% in case of telmisartan. However, the incidence of dry cough and dizziness was more with ramipril compared to telmisartan, thus telmisartan has a better tolerability profile. In brief, the overall incidence of adverse effects in both groups of treated subjects was fairly less and it can be safely assumed that both agents are fairly safe with minimal adverse effect profile this is in contrast to earlier studies, which has reported higher incidence of adverse effects with ramipril group.5,27 It may be mentioned that management of adverse events has not substantially escalated the cost of therapy for both agents and has played only a minor role in the present study. Though choice of agent should be based on patientâ&#x20AC;&#x2122;s susceptibility to specific adverse events to minimize the cost implications.

One important aspect which has not been worked out in this study is cost per life-year saved, since hypertension is clinically silent, hence survival is the ultimate measure of antihypertensive efficacy, not the lowering of BP. Hence, when effectiveness is measured in terms survival as the number of life years saved, the costs that must be considered include not just cost of antihypertensive therapy to bring the BP values to targeted level but also medical treatments for preventing CHD and also the measures for controlling diabetes, which also is an important risk factor. Life years saved usually depend on the number of coronary events avoided, which is greater in high risk population. This aspect has not been worked out, since in the present study, the patients were of low risk nature; however, it may be mentioned that none of the patient died or suffered prolonged morbidity or had coronary events, during the study period.

It is noteworthy that as many as 148 patients were overweight/obese, of these 116 (52%) patients were overweight (body mass index [BMI] 26-30 kg/m2) and 32 (14.5%) subjects had BMI >30 kg/m2. Since, a high BMI is usually associated with hypertension and diabetes, and this too may escalate the overall cost of medical management, thus apart from administering

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antihypertensives and antidiabetics, drastic measures should be taken to bring down the weight of individuals besides a positive correction in respect to lifestyle changes are also needed so as to further enhance the efficacy of these agents.

CONCLUSION In conclusion, comparative evaluation of efficacy profile have shown that monotherapy with fixed doses of both ramipril and telmisartan are equally effective in lowering SBP and DBP in cases of Stage 1 hypertensives with diabetes mellitus. The incremental cost-effectiveness ratio can be reduced by decreasing the cost of medicines or increasing the effectiveness of therapy. Since, the selected doses of the two agents have produced almost similar fall in BP, hence in the present study only cost of medicine per se are of prime importance. When effectiveness is expressed as percent reduction in BP to achieve targeted BP, (as may be the case in low-risk patients) drug price may be more important factor and telmisartan is more cost-effective.

The same relationship between cost-effectiveness ratio and ramipril efficacy and price are also seen when effectiveness is expressed as the proportion of patients reaching the goal BP values. When greater BP-lowering is required (goal BP) as is the case with patients with CHD associated with type 2 diabetes, telmisartan scores over ramipril as it has more prolonged duration of action, due to its pleotropic action and minimal adverse events profile.

REFERENCES 1. Victor RG. Systemic hypertension: Mechanisms and diagnosis. In: Bonow RO, Mann DL, Zipes DP, Libby P (Eds.). Braunwaldâ&#x20AC;&#x2122;s Heart Disease: A Textbook of Cardiovascular Medicine. 9th Edition, Philadelphia, Pa: Saunders Elsevier; 2011. pp. 935-54.

2. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension. 2004;44(4): 398-404.

3. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365(9455):217-23.

4. Lawes CM, Vander Hoorn S, Rodgers A; International Society of Hypertension. Global burden of blood-pressurerelated disease, 2001. Lancet. 2008;371(9623):1513-8.

5. Victor RG. Pathophysiology of target-organ disease: does angiotensin II remain the key? J Clin Hypertens (Greenwich). 2007;9(11 Suppl 4):4-10.

6. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor,

CARDIOLOGY ramipril, on cardiovascular events in high-risk patients.

The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):145-53.

7. Arauz-Pacheco C, Parrott MA, Raskin P; American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26 Suppl 1:S80-2.

8. Ingelsson E, Sundström J, Arnlöv J, Zethelius B, Lind L. Insulin resistance and risk of congestive heart failure.

JAMA. 2005;294(3):334-41.

9. Ridker PM, Libby P. Risk markers for atherothrombotic disease. In: Bonow RO, Mann DL, Zipes DP, Libby P (Eds.). Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th Edition, Philadelphia, Pa: Saunders Elsevier; 2011. pp. 914-34.

10. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-72.

11. McGuire DK. Diabetes and the cardiovascular system. In: Bonow RO, Mann DL, Zipes DP, Libby P (Eds.). Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th Edition, Philadelphia, Pa: Saunders Elsevier 2011. pp. 1392-409.

12. Schmieder RE, Hilgers KF, Schlaich MP, Schmidt BM. Renin-angiotensin system and cardiovascular risk. Lancet.

2007;369(9568):1208-19.

13. Braga MF, Leiter LA. Role of renin-angiotensin system blockade in patients with diabetes mellitus. Am J Cardiol.

2009;104(6):835-9.

14. Nakao K, Hirata M, Oba K, Yasuno S, Ueshima K, Fujimoto A, et al; CASE-J Trial Group. Role of diabetes and obesity in outcomes of the candesartan antihypertensive survival evaluation in Japan (CASE-J) trial. Hypertens Res. 2010;33(6):600-6.

15. Narumi H, Takano H, Shindo S, Fujita M, Mizuma H, Kuwabara Y, et al; Valsartan Amlodipine Randomized Trial Investigators. Effects of valsartan and amlodipine on cardiorenal protection in Japanese hypertensive patients: the Valsartan Amlodipine Randomized Trial. Hypertens Res. 2011;34(1):62-9.

16. Bethel MA, Holman R, Haffner SM, Califf RM, HuntsmanLabed A, Hua TA, et al. Determining the most appropriate components for a composite clinical trial outcome. Am Heart J. 2008;156(4):633-40.

17. Shiga T, Kasanuki H, Hagiwara N, Sumiyoshi T, Honda T, Haze K, et al; Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease (Hij-Create) Investigators. Angiotensin receptor blocker-based therapy and cardiovascular events in hypertensive patients with coronary artery disease and impaired renal function. Blood Press. 2010;19(6):359-65.

18. World Health Organization Global Health Repository.

Available from: URL: http://www.who.int/gho/ncd/ risk_factors/blood_ pressure_ prevalence_text /en/ index. html. Last accessed April 24, 2013.

19. World Health Report-2002. Reducing Risks, Promoting Healthy Life. Chapter 4, p-12. Available from: URL: http://www.who.int/ whr/2002/en/whr02_ch4.pdf. Last accessed April 24, 2013.

20. Kumar P, Kapoor AK, Singh HK, Kulshrestha M. Randomized, interventional, prospective, comparative study to evaluate the antihypertensive efficacy and tolerability of ramipril versus telmisartan in stage 1 hypertensive patients with diabetes mellitus. Internet J Med Update. 2015;10(1):15-25.

21. Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, 19882008. JAMA. 2010;303(20):2043-50.

22. Ezzati M, Oza S, Danaei G, Murray CJ. Trends and cardiovascular mortality effects of state-level blood pressure and uncontrolled hypertension in the United States. Circulation. 2008;117(7):905-14.

23. Ostchega Y, Dillon CF, Hughes JP, Carroll M, Yoon S. Trends in hypertension prevalence, awareness, treatment, and control in older U.S. adults: data from the National Health and Nutrition Examination Survey 1988 to 2004.

J Am Geriatr Soc. 2007;55(7):1056-65.

24. Soni U, Moghe VV, Jain P, Upadhyaya P. A comparative study of efficacy and tolerability of telmisartan and ramipril. Int J Pharma Sci. 2013;3(3):240-3.

25. Williams B, Lacourcière Y, Schumacher H, Gosse P, Neutel JM. Antihypertensive efficacy of telmisartan vs ramipril over the 24-h dosing period, including the critical early morning hours: a pooled analysis of the PRISMA I and II randomized trials. J Hum Hypertens. 2009;23(9):610-9.

26. Gosse P, Neutel JM, Schumacher H, Lacourcière Y, Williams B, Davidai G. The effect of telmisartan and ramipril on early morning blood pressure surge: a pooled analysis of two randomized clinical trials. Blood Press Monit. 2007;12(3):141-7.

27. ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547-59.

28. Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, et al. Effects of the angiotensinreceptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet.

2008;372(9644):1174-83.

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CRITICAL CARE

Hyperlactatemia in Critically Ill: A Review SUBHRANSHU SEKHAR KAR

ABSTRACT Context: Hyperlactatemia is a common finding in critically ill patients and lactate is being used as a prognostic marker of outcome in a variety of underlying conditions. Lactic acid is produced as a product of anaerobic glycolysis and is reversibly converted to pyruvate under normal physiologic state. High initial blood lactate levels and persistently high lactate levels have been correlated with poor outcome. Need and purpose: Though many studies and clinical trials have been instituted in past, it still remains a real challenge to analyze and manage hyperlactatemia in critical care setting. This article aims to review the lactate metabolism, etiopathological basis of lactic acidosis and role of lactate as a prognostic marker in critically ill patients. Evidence acquisition: Articles were retrieved from the Medline, Cochrane Database, Google Scholar, CINAHL, Uptodate and Medscape using the following terms which were searched and combined - ‘Hyperlactatemia’, ‘metabolic acidosis’, ‘lactic acidosis’, ‘shock’, ‘sepsis’, ‘hypoperfusion’ and ‘elevated lactate’. In addition, references from each identified article were carefully reviewed for additional suitable references. Studies involving humans or animals were examined and the search was restricted to articles published in the English language. Conclusion: Hyperlactatemia is an independent predictor of mortality in different groups of critically ill patients. Serial lactate levels are more significant for predicting the patient outcome and effectiveness of the therapy. Treating the underlying disease is the best measure to control lactic acidosis. Cessation of acid production via the improvement of tissue oxygenation is the ultimate goal.

Keywords: Hyperlactatemia, shock, metabolic acidosis, lactic acidosis, lactate, sepsis, hypoperfusion

E

levated lactate levels in blood (Hyperlactatemia) has been shown to be an independent predictor of mortality in different groups of critically ill patients such as those with sepsis with or without organ failure.1-13 In critically ill patients, therefore, blood lactate level assessment is an established investigation.14 Although shock is the commonest indication of lactate measurement in the intensive care settings, the physiologic basis of lactate generation during shock has been recently a matter of debate and research. A perfusion related mechanism seems to be involved at least in early stages of shock.15-17 Recent clinical studies have confirmed the strong prognostic value of hyperlactatemia and its association to other hemodynamic and perfusion abnormalities in septic shock.4,18,19 Though mostly found in shock states,

Associate Professor Dept. of Pediatrics RAK Medical and Health Sciences University Al Qusaidat – Ras-al-khaimah, United Arab Emirates Address for correspondence Dr Subhranshu Sekhar Kar Associate Professor Dept. of Pediatrics RAK Medical and Health Sciences University Al Qusaidat – Ras-al-khaimah, United Arab Emirates E-mail: drsskar@gmail.com

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hyperlactatemia can also occur in many other clinical conditions as well as administration of drugs.

HISTORICAL ASPECTS In 18th century, Johann Joseph Scherer found lactic acidosis in postmortem blood of two puerperal sepsis patients and in 1858, Folwarczny described elevated lactate levels in a patient with leukemia.20 Fletcher first described the mechanism of lactic acid production in skeletal muscles under anaerobic conditions, highlighting the role of oxygen on its removal and production.21 Clausen in 1925, identified lactic acidosis as a cause of acid-base disorder. In 1976, Woods and Cohen classified lactic acidosis broadly into type A and B based on Huckabee’s seminal work, establishing the relationship of lactic acidosis with tissue hypoperfusion.22,23 By 20th century, many physicians found that critically ill patients can have metabolic acidosis without elevated ketones or other measurable anions. The work of Khosravani and colleagues corroborates with prior clinical studies showing that even mild-hyperlactatemia portends a poor outcome in critically ill patients.2 These include the early observations of increased blood lactate during hemorrhagic shock, the classic work of Weil and Afifi in cardiopulmonary resuscitation, and more recent

2016

CRITICAL CARE studies showing mortality rates of nearly 70% being independently associated with lactate levels of at least 3.5 mmol/L.2,24-26 HYPERLACTATEMIA VERSUS LACTIC ACIDOSIS22,23 The normal blood lactate level is 0.5-2 mmol/L. Hyperlactatemia is defined as persistent increase (>2 mmol/L) in blood lactate concentration without associated metabolic acidosis. So, it can occur in the setting of normal tissue perfusion and oxygenation. In contrast, lactic acidosis is defined as persistent increase in blood lactate levels (mostly >5 mmol/L) with presence of metabolic acidosis. It is associated with tissue hypoperfusion, carbohydrate metabolism defects, inborn errors of metabolism, drugs or toxin ingestion, post-seizure status and overall metabolic dysregulation. Lactic acidosis may not always produce acidemia. The development of lactic acidosis depends on the magnitude of hyperlactatemia, body’s buffering capacity and other coexisting factors. The blood pH in hyperlactatemia or lactic acidosis can be acidemic, alkalemic or even normal.

LACTATE METABOLISM Lactate is formed from pyruvate in the cytosol as a part of glycolysis. The enzyme involved in reduction of pyruvate is lactate dehydrogenase (LDH). The reduction of pyruvate is the only known pathway for lactate production, making this an unique way of monitoring anaerobic metabolic processes. The equation is represented as follows: Pyruvate + NADH + H+ = lactate + NAD+.

Two molecules of ATPs are only produced by this method. At a basal physiologic state, their action favors lactate formation from pyruvate in an approximately 10:1 ratio.23 In normal physiological conditions, approximately 1,500 mmol of lactate are produced daily (20 mmol/kg/day) primarily from skeletal muscle, skin, brain, intestine and red blood cells.27-29 Majority of lactate produced is metabolized in the liver (60%), kidney (30%) and to a lesser extent in other organs (heart and skeletal muscle).30 Utilization occurs via the Cori cycle where lactate is converted back to pyruvate and eventually to glucose through gluconeogenesis.31 LACTATE CLEARANCE Clearance represents the removal of a substance from a unit of volume over time, typically expressed in milliliters per minute. The concept of lactate clearance has recently generated a lot of debate and research.

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In addition to single measurements, changes in lactate concentrations over time may have additional predictive value for organ failure and mortality.8 Serial measurements have shown to improve prognostic ability in septic shock patients and are even superior to oxygen-derived variables (delivered oxygen [DO2] and oxygen consumption [VO2]).32 Nguyen and colleagues reported that “lactate clearance”, defined as the percentage decrease in lactate from emergency department presentation to 6 hours later, is an independent predictor of mortality.33 They concluded that “lactate clearance” in the early hospital course may indicate a resolution of global tissue hypoxia with improved survival rates. Jones and colleagues extended the concept of targeting resuscitation in sepsis to achieve a “lactate clearance” of at least 10% as a marker of restoration of oxygen delivery to the tissues.34 The most recent Surviving Sepsis Campaign guidelines recommend “targeting resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion” (Grade 2C).35 McNelis and colleagues demonstrated 100% mortality in surgical intensive care unit (ICU) patients who had persistently elevated lactate levels.36 Those who cleared their blood lactate (lactate level <2 mmol/L) in the first 24 hours had a mortality of 3.9%, while patients with delayed blood lactate clearance (>48 hours to lactate level <2 mmol/L) had a mortality of 42.5%. Husain et al emphasized the importance of lactate clearance in critically ill surgical ICU patients when they risk-stratified 95 trauma and nontrauma patients into four groups based on their ability to clear lactate: (a) clearance in the first 24 hours, (b) clearance in 24-48 hours, (c) greater than 48 hours to normalize or (d) never normalized.37 Predicted mortality was calculated as 10%, 20%, 23% and 67%, respectively, in the four groups. Initial and serial lactate measurements predicted survival with statistical significance. For many years, it was felt that the lactate itself was harmful and contributed to the worsening acidosis. This has since been shown not to be true. In an effort to actively lower lactate levels; however, Stacpoole et al performed a series of experiments with dichloroacetate (DCA).38 DCA stimulates the pyruvate dehydrogenase (PDC) complex by binding to and inhibiting PDH kinase, which inactivates the PDH enzyme. Increasing flux through the PDH enzymatic pathway seemed an ideal way to reduce lactate levels and has been studied in a variety of patient population like children with congenital lactic acidosis, patients with myocardial ischemia and critically ill patients with shock.39-42 All the studies

CRITICAL CARE have shown that DCA safely lowers circulating lactate levels in the blood. The only controlled trial of DCA; however, by Stacpoole et al for the treatment of lactic acidosis showed a lowering of lactate levels, but no change in any significant hemodynamic measurements or survival.42 Nonetheless, DCA has never proved useful in treating critically ill patients with elevated lactate levels. Logically, it is impossible to know if the rate and/or amount of decline in lactate is due to increased removal, decreased production, dilution because of fluid administration during resuscitation or all the above in variable combinations. Moreover, increased lactate production can remain concealed by increased utilization in septic patients, suggesting that a normal blood level of lactate does not prove that its metabolism is also normal.43 ARTERIAL VERSUS VENOUS LACTATE LEVELS A comparison of arterial versus venous lactate levels was done in a series of 74 emergency department adult patients who had arterial and venous lactate drawn within 5 minutes of the other.44 The correlation between arterial and venous lactate was 0.94 (95% confidence interval [CI], 0.91-0.96). There was a mean venous minus arterial lactate difference of 0.22 mmol/L (95% CI, 0.04-0.41), which ranged from 1.3 to 1.7 mmol/L in individual patients. Of the sample patients, 30% had arterial lactate levels <1.6.44 LACTATE USE DURING STRESS The heart takes up and oxidizes lactate at rest.45 The uptake in heart increases during exercise, β-adrenergic stimulation, elevated after load, fast pacing and during shock.46-48 During hyperlactatemia, lactate can account for up to 60% of cardiac oxidative substrate and exceeds glucose as a source of pyruvate.47 During shock, the heart oxidizes lactate for the majority of its energy needs.46 Lactate infusion increases cardiac output in anesthetized pigs and cardiac performance in patients with acute heart failure and both in cardiogenic as well as septic shock.43,49 Systemic lactate deprivation is shown to be associated with cardiovascular collapse and early death of these animals.43,50 Interestingly, the human brain changes to a lactate consumer during increased metabolic demand.51 Lactate accounts for about 7% of cerebral energy requirement under basal conditions and up to 25% during exercise.28 Blood lactate is oxidized by neurons in the conscious healthy human brain or gets converted to glycogen in astrocytes. The contribution of lactate as a brain energy source increases during hyperlactatemia.51,52 Lactate is

used as a primary energy source during experimental insulin-induced hypoglycemia and is readily oxidized by the brain in an activity-dependent manner.53 SOURCE OF LACTATE IN SYSTEMIC INFLAMMATORY RESPONSE SYNDROME AND SEPSIS Systemic inflammatory response syndrome (SIRS) is typically associated with type A lactic acidosis due to the presumption that the hemodynamic instability leads to inadequate DO2.54 There is also evidence that increased production of pyruvate and decreased activity of PDH (in part due to increased PDH kinase, lactate production by the lung and decreased lactate clearance) are contributors to lactic acidosis in SIRS.55-58 Limited information exists about the source of lactate in sepsis. Using experimental models, it is found that lung is the major source of lactate.59 Also, it is seen that muscle and liver lactate fluxes are neutral and lactate uptake predominantly occurred in the gut and kidneys before and after endotoxemia. Levy and colleagues found that lactate and pyruvate concentrations measured by microdialysis are higher in muscle than in arteries (muscles are 40% of total cell mass) during septic shock.17 Muscles could, therefore, have an important role in lactate production. De Backer and colleagues demonstrated that the splanchnic region is an uncommon source of net lactate generation in septic patients, even when arterial lactate concentrations are very high.60 In sepsis, the splanchnic area consumes lactate rather than producing it. In general, although not specifically studied in sepsis, the brain seems to be a major consumer rather than a lactate producer.

As shown in critically ill patients before and after liver transplantation with or without hyperlactatemia, there is a net lactate uptake by the brain.61 During sepsis, the heart changes its metabolic substrate. It shifts from using free-fatty acids to increased lactate utilization.

Thus, the heart also helps in removal of lactate.

CLASSIFICATION Cohen and Woods divided lactic acidosis into two categories, type A and type B.22,62,63 Type A: Hyperlactatemia with clinical evidence of impaired tissue perfusion or oxygenation (Table 1). Type B: No clinical evidence of impaired tissue perfusion or oxygenation (Table 2).

Type A Lactic Acidosis It encompasses hyperlactatemia associated with clinical evidence of impaired tissue perfusion or oxygenation. The only treatment is, therefore, cessation

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CRITICAL CARE Table 1. Causes of Type A Hyperlactatemia22,62,63 (Tissue Hypoperfusion and Decreased Oxygen Delivery) Intense exercise Seizures Shock Cardiac arrest Regional ischemia (mesenteric ischemia) Pulmonary hypoxia Carbon monoxide Severe anemia

Table 2. Causes of Type B Hyperlactatemia22,63-65 Type B1: Associated with systemic diseases Renal failure, hepatic failure, diabetes mellitus, malignancy Human immunodeficiency virus Type B2: Drugs and toxins Paracetamol Alcohol - Ethanol, methanol, diethylene glycol, isopropanol, propylene glycol Antiretroviral nucleoside analogs - Zidovudine, didanosine, lamivudine β-adrenergic agonists - Epinephrine, ritodrine, terbutaline Biguanides - Phenformin, netformin Sugars - Fructose, sorbitol, xylitol Miscellaneous - Diethyl ether, fluorouracil, halothane, iron, niacin, propofol salicylates, strychnine, cocaine, methamphetamine Type B3: Inborn errors of metabolism Glucose-6-phosphatase deficiency (von Gierke’s disease) Fructose-1,6-diphosphatase deficiency Pyruvate carboxylase deficiency PDH deficiency Methylmalonic aciduria Kearns-Sayre syndrome Pearson syndrome Mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS) and Myclonic epilepsy with ragged red fibers (MERRF)

of acid production via the improvement of tissue oxygenation. The effective modalities include shock management with restoration of the circulating fluid volume, augmentation of cardiac function, resection of ischemic areas and treatment of sepsis. Sodium bicarbonate (NaHCO3) therapy is of little value for type A lactic acidosis. Carbicarb is a mixture of Na2CO3 and

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NaHCO3 that buffers similarly to NaHCO3, but without production of CO2. The results from clinical trials are sparse. Animal experiments done by Bersin and Arieff showed that muscle O2 consumption increased with carbicarb and decreased with NaHCO3.66 There is less fall of arterial pressures with carbicarb (-12 vs -46 mmHg, p < 0.006). Cardiac output was more stable with carbicarb, but decreased with NaHCO3 (from 143 to 98 mL/kg/min, p < 0.004). Stroke volume also improved without a change in pulmonary capillary wedge pressure, suggesting that carbicarb has beneficial effects on myocardial contractility. Rhee et al administered carbicarb, NaHCO3 and NaCl, in random order, to dogs with hypoxic lactic acidosis.67 NaHCO3 increased PCO2 and lactate production. Carbicarb increased pH and cardiac index without increasing lactate levels. But, in another dog study, Blecic et al found that carbicarb was not superior to other regimens in a model of cardiac arrest.68 DCA exerts multiple effects on pathways of intermediate metabolism and stimulates peripheral glucose utilization and inhibits gluconeogenesis, thus reducing hyperglycemia in diabetes mellitus. It also inhibits lipogenesis and cholesterol genesis. By stimulating the activity of PDH, DCA facilitates oxidation of lactate and decreases morbidity. However, in a randomized controlled trial in patients with lactic acidosis, DCA was disappointing.

Stacpoole et al studied this compound in patients with severe type A lactic acidosis.41,42 They observed that it decreased the lactate concentrations in the treated patients, but had no beneficial effects on outcomes.

In conclusion, DCA treatment in severe lactic acidosis results in statistically significant, but clinically unimportant changes in arterial blood lactate concentrations and pH and fails to alter either hemodynamics or survival rates. Lastly, hemofiltration and “continuous renal replacement therapies” have been advocated as effective modalities for treatments of lactic acidosis.69 Controlled studies are, however, lacking. Hilton et al claimed that, in their trial, they were able to correct lactic acidosis without inducing either extracellular volume expansion or hypernatremia.70 Significant differences at presentation for the group of patients who survived, compared with those who died, were observed in age, mean arterial pressure and Acute Physiology and Chronic Health Evaluation II scores.

Neither the severity of the presenting acidosis nor the arterial blood lactate concentrations appeared to predict outcomes in that series.70 Mariano et al reported success in using continuous renal replacement therapy for the management of phenformin-induced lactic acidosis.71 Levraut et al investigated the effects of continual renal

CRITICAL CARE replacement therapy on lactate clearance.72 They found that, at the end of the lactate infusion, the median blood lactate concentration increased despite renal replacement therapy. These investigators concluded that continuous veno-venous hemofiltration with dialysis cannot meet lactate overproduction.70-72

Type B1—Lactic Acidosis Systemic Disease In critically ill patients with cirrhosis, lactic acidosis indicates a grim prognosis with a 7.64 (95% CI, 3.0119.34) odds ratio for ICU mortality.73 Individuals with the combination of cirrhosis, acidemia, lactic acidosis and acute renal failure had 86% ICU mortality and 94% hospital mortality. Liver failure is associated with decreased lactate clearance, which is further exacerbated in sepsis. In cases of severe liver failure, the liver can be a source of lactate production.

When lactate measurements were added to King’s College Hospital criteria for determining outcome after paracetamol intoxication, an early lactate of >3.5 mmol/L or a post-resuscitation lactate of >3.0 mmol/L increased sensitivity for predicting death to 95%, whereas specificity was relatively unchanged at greater than 90%.74 Research using more sophisticated methods to assess tissue perfusion have now shown that occult tissue hypoperfusion is present in many cases of type B acidosis.74

Type B2—Lactic Acidosis Drugs and Toxins Acetaminophen: In an animal model, the inhibition of mitochondrial respiration preceded overt hepatic necrosis and was completely prevented by treatment with N-acetyl-L-cysteine. Inhibition of mitochondrial oxidative phosphorylation by acetaminophen and its toxic metabolite eventually results in a shift toward lactate production. This suggests that earlier the treatment with N-acetyl-L-cysteine is initiated, better the outcome.75-77 Antiretroviral drugs: Nucleoside/tide reverse transcriptase inhibitors (NRTIs) have revolutionized treatment of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS).

Toxicities due to NRTIs are likely due to mitochondrial toxicity. Although there is no clinical correlation at present, studies have shown that zalcitabine causes the greatest inhibition of DNA polymerase-g and lamivudine, abacavir and tenofovir have very less inhibitory effect.78

β-adrenergic agent: β-agonists stimulate muscle and hepatic phosphorylase and inhibit glycogen synthetase.

Thus glycolysis is stimulated with an increase in pyruvate production.79 In skeletal muscle, β-agonists stimulate Na+-K+ATPase via up-regulation of cyclic AMP leading to generation of ADP and accelerated glycolysis by phosphofructokinase. The β-agonists also inhibit PDH, leading to decreased oxidation of pyruvate to acetyl coenzyme A (CoA) and resulting in increased reduction of the pyruvate to lactate.80 Thiamine, biotin and iron: Thiamine deficiency resulting in lactic acidosis is most often described in patients with alcoholism, patients receiving total parenteral nutrition and infants receiving a defective soy-based formula.81-83 In a study, lactate level up to 20 mmol/L has been reported.84

TYPE B3—Lactic Acidosis Inborn Errors of Metabolism Disorders resulting in oxidative phosphorylation deficiency, such as Kearns-Sayre syndrome, Pearson syndrome, myoclonic epilepsy with ragged red fiber (MERRF) and mitochondrial encephalomyopathy, lactic acidosis and stroke (MELAS) syndrome are commonly associated with lactic acidosis. A trial was discontinued, after DCA use to lower lactic acid in patients with MELAS, resulted in peripheral nerve toxicity.85 Fructose-1, 6-diphosphatase deficiency results in life-threatening hypoglycemia and lactic academia during fasting as gluconeogenesis is impaired.86 This is more pronounced in glycogen storage disease type 1 (von Gierke disease). A deficiency of glucose-6phosphatase, glucose-6-phosphate translocase or the endoplasmic reticulum phosphate translocase results in compromised glycogenolysis and gluconeogenesis.87 PDH deficiency can be due to several mutations with a gradation in phenotype.

The impairment may range from fatal infantile lactic acidosis to ataxia as the primary impairment. Pyruvate carboxylase deficiency also has different phenotypic expressions depending on the degree of impairment.

It is also characterized by hypoglycemia, lactic acidosis and ketosis.88,89 Methylmalonic aciduria is caused by a deficiency of methylmalonyl-CoA mutate or by defects in the transport, uptake or synthesis of 5°–deoxyadenosylcobalamin. Clinical presentation varies but may include lactic acidosis, hypoglycemia, ketosis and hyperammonemia. Dialysis has been used to clear the academia during metabolic crises, but there has been little success in curtailing the end-organ

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CRITICAL CARE damage, which results from the accumulation of the toxic organic acids.87 ROLE AS A PROGNOSTIC MARKER IN CRITICALLY ILL PATIENTS

Shock and Sepsis In low-flow states, increased lactate is related to tissue hypoxia by hypoperfusion.54-58 In sepsis, increased glycolysis, increased production by the gut, lung or white blood cells are involved in nonhypoxic hyperlactatemia.15 Regardless of metabolism and catecholamine effects on lactate metabolism, lactate clearance seems a useful endpoint.15,17,29 De Backer et al, studying local sublingual capillary perfusion in patients with septic shock, showed that lactate clearance was independently correlated to capillary reperfusion.15 Simultaneous superior vena cava oxygen saturation (ScvO2) and lactate clearance were also measured in a study of 203 patients with septic shock in which reaching only the ScvO2 goal was inferior to reaching only the lactate clearance goal.35 Rivers participated in a noncomparative study in which both ScvO2 and lactate clearance were used as subsequent endpoints.90 In a large randomized control trial (RCT) in septic shock, Jones et al showed that ScvO2 or lactate clearance performed similarly and concluded that lactate clearance could be used instead of ScvO2.4 However, the real question is not whether lactate clearance should replace ScvO2, but if it should be an additional endpoint. Strikingly, while Jones et al did not find any difference when replacing ScvO2 by lactate clearance, Nguyen et al, in a study of sepsis bundles, showed that by adding lactate clearance to ScvO2, mortality decreased even further from 24.5% to 17.9%.3 Lactate is one of many markers used for prognosis in critically ill patients and a value >4 mmol/L is associated with poor outcome.87 Huckabee performed the first analyzes of elevated lactate levels in patients of varying degrees of shock and later Weil and Afifi and Cady et al expanded on Huckabeeâ&#x20AC;&#x2122;s experiments.23,25,91,92 He noted elevated lactate levels indicative of widespread tissue hypoxia but no apparent cause of the hypoxia.

More recently, in 2007, Trzeciak et al observed initial serum lactate levels in more than 1,100 patients.93 They found blood lactate level of >4 mmol/L to be highly specific (89-99%) for predicting death in acute phase and in-hospital death. The values were calculated after

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correction for organ dysfunction with APACHE II scores, showing the predictive power of initial lactate level uniquely as a biomarker.

The surviving sepsis campaign recommends early goal directed therapy in individuals with severe sepsis or septic shock, particularly if blood lactate level is >4 mmol/L. Jansen and colleagues showed that serum lactate levels were strongly associated with sequential organ failure assessment (SOFA) scores, especially early in the ICU stay.6 Lactate has again been found to be an early predictor of sepsis and necrotizing enterocolitis in preterm neonates.94 Bronchial asthma: Use of β- agonist may lead to increase in blood lactate level with hypokalemia and respiratory alkalosis. Hyperlactatemia has been shown to decrease the bronchodilator response, produce dyselectrolytemia and affect the cardiovascular system.95 Traumatic brain injury: As a prognostic marker, arterial to venous blood lactate difference can be used in judging the severity of the traumatic brain injury with good correlation.96 Acute liver failure: Hyperlactatemia is common in acute liver failure and after liver transplantation, the levels get normalized because the transplanted liver efficiently utilizes lactate.61,73,74 Acute lung injury: Lactate levels are found to be high with exaggerated arterial to venous difference across the lungs, in the setting of lung injury. Normal lactate levels have been found in other types of respiratory failures.4,6,9,23 Acute cyanide poisoning: Hyperlactatemia (>8 mmol/L) is a sensitive (94%) and specific (>70%) indicator in cyanide poisoning in the absence of catecholamine use.97 CONCLUSION Lactate is a carefully regulated substance under normal physiologic state. Hyperlactatemia and elevated lactate to pyruvate ratio with concomitant lactic acidosis points to a serious underlying pathological process.

The lactate level on admission can help in judging the severity of initial insult.

Serial rather than single lactate measurements are more significant in predicting response to therapy and eventual outcome. Routine blood lactate measurement in critically ill patients is therefore, highly recommended in conjunction with other tests.

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65. MĂŠgarbane B, Brivet F, GuĂŠrin JM, Baud FJ. Lactic acidosis and multi-organ failure secondary to antiretroviral therapy in HIV-infected patients. Presse Med. 1999;28(40):2257-64.

66. Bersin RM, Arieff AI. Improved hemodynamic function during hypoxia with Carbicarb, a new agent for the management of acidosis. Circulation. 1988;77(1):227-33.

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68. Blecic S, De Backer D, Deleuze M, Vachiery JL, Vincent JL. Correction of metabolic acidosis in experimental CPR: a comparative study of sodium bicarbonate, carbicarb, and dextrose. Ann Emerg Med. 1991;20(3):235-8.

69. Schetz M. Non-renal indications for continuous renal replacement therapy. Kidney Int Suppl. 1999;(72):S88-94.

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A single infusion of a powerful antibody called VRC01 can suppress the level of HIV in the blood of infected people who are not taking antiretroviral therapy (ART), reported scientists at the National Institutes of Health in a paper published December 23 in Science Translational Medicine.

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A new study suggests that the fear of spiders could be eradicated in just 2 minutes with a single dose of a commonly used β-blocker – propranolol - and exposure to the creepy critters themselves. The findings are published in the journal Biological Psychiatry.

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Switching from the older Zapletal reference values to the newer Global Lung Function Initiative (GLI) values can result in improved asthma treatment, suggests new research to be published online in Pediatrics.

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An article, published recently in the SIAM Journal on Applied Mathematics, introduces a new mathematical model which offers a simplified approach to studying the spread of the infectious virus, Dengue fever, in urban areas, specifically breaking down the epidemic dynamics across a city and its varying neighborhoods and populations. The model is important for studying how varying neighborhood conditions affect the spread of Dengue fever and how to contain it.

...Cont’d from page 725

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30. Black HR, Graff A, Shute D, Stoltz R, Ruff D, Levine J, et al. Valsartan, a new angiotensin II antagonist for the

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treatment of essential hypertension: efficacy, tolerability and safety compared to an angiotensin-converting enzyme inhibitor, lisinopril. J Hum Hypertens. 1997;11(8):483-9.

31. Zou Z, Xi GL, Yuan HB, Zhu QF, Shi XY. Telmisartan versus angiotensin-converting enzyme inhibitors in the treatment of hypertension: a meta-analysis of randomized controlled trials. J Hum Hypertens. 2009;23(5):339-49.

32. Lamy A, Wang X, Gao P, Tong W, Gafni A, Dans A, et al; ONTARGET Investigators. The cost implications of the use of telmisartan or ramipril in patients at high risk for vascular events: the ONTARGET study. J Med Econ.

2011;14(6):792-7.

ENDOCRINOLOGY

Posology of Antidiabetic Drugs and Insulins: A Review of Standard Textbooks GARIMA BHUTANI*, SANJAY KALRAâ&#x20AC;

ABSTRACT Objectives: The aim of this bibliographic review is to assess whether standard pharmacology, endocrinology and diabetology textbooks adequately mention the details regarding timings of administration, frequency and dose of various oral and injectable antidiabetic drugs. Material and methods: Four standard textbooks of pharmacology, two of diabetology and three of endocrinology were assessed for the published information regarding dose, timing and frequency of antidiabetic drugs. Results: Various omissions and contraindications were found in the coverage of glucose-lowering drugs in standard textbooks. Proper timing and frequency of administration of sulfonylureas, thiozolidinediones, SGLT2 inhibitors, GLP receptor agonists and DPP-4 inhibitors have been omitted in majority of the textbooks. Conclusions: This article stresses upon the need of a uniform source of information for providing adequate and standardized knowledge regarding timing, frequency and dose of antidiabetic drugs.

Keywords: Posology, antidiabetic drugs, postprandial hyperglycemia

C

orrect timing of glucose-lowering therapy is an important aspect of diabetes pharmacotherapeutics. Matching the dose of a particular drug with meals depends upon its mechanism of action and pharmacokinetic profile.

This timing varies from class-to-class and drug-todrug. Each drug has a specific time action profile. This should match with food absorption. Inappropriate timing/frequency/dose of administration may lead to unwanted hyperglycemia or hypoglycemia leading onto poor glycemic control or complications in the patients.

This glycemic variability is easily avoidable with the better knowledge and understanding of appropriate dose, timing of administration and frequency of drug administration. Pharmacology, diabetology and endocrinology textbooks are an important and reliable source of such information, both for students and clinicians. This article aims at assessing the adequacy

*Assistant Professor Dept. of Pharmacology BPS Govt. Medical College for Women, Khanpur Kalan, Sonepat, Haryana â&#x20AC; Consultant Dept. of Endocrinology Bharti Hospital and BRIDE, Karnal, Haryana Address for correspondence

Dr Garima Bhutani H No. 517, Sector 15-A, Hisar, Haryana E-mail: garimaahuja2010@yahoo.com

of the knowledge provided by these textbooks regarding posology (i.e., dose, frequency and timing of antidiabetic drugs).

MATERIAL AND METHODS Some of the most popular and most commonly read textbooks of pharmacology, diabetology and endocrinology were included in the study. Four standard textbooks of pharmacology (2 by Indian authors and 2 by US authors) were analyzed. Two textbooks of diabetology were also studied, out of which 1 textbook is by Indian author and other is by US author. Three textbooks of endocrinology (2 US and 1 Indian in origin) were also assessed for the desired information. Latest available editions of the textbooks were taken for analysis.

RESULTS The results of the analysis have been tabulated in Table 1, which shows the comparison of information about antidiabetic drugs available in different textbooks.

DISCUSSION This bibliometric analysis highlights various omissions and contraindications in the coverage of glucoselowering drugs in standard textbooks.

Metformin is covered well by 8 out of 9 textbooks, with 6 of them mentioning relatively concordant doses, and

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

737

5-20 mg daily

-

Glipizide extended release

Gliclazide

180-360 mg, 1-10 min before a meal

Nateglinide

5-40 mg o.d. or b.i.d.

0.5-16 mg preprandially

Repaglinide

4-8 mg o.d.

Rosiglitazone

Sulfonylureas Glipizide

Meglitinide analog

15-45 mg o.d.

Pioglitazone

Max dose is 2 g o.d., with meals

Metformin SR

Thiazolidinediones

0.5-2.5 g b.i.d., with meals

Metformin

Biguanides

Goodman and Gilmanâ&#x20AC;&#x2122;s the Pharmaceutical Basis of Therapeutics1

Drug

Drug class

-

40-240 mg in 1-3 doses, 20-30 min before meals8

40-320 mg6

-

40-240 mg, o.d. or b.i.d.

-

40-250 mg o.d. or b.i.d.

-

-

2.5-5 mg initially.

20 mg o.d. max dose

2.5-5 mg initially.

Max 40 mg divided b.i.d.

Once-daily dose6

Once-daily morning dose, max 20 mg/day

5-20 mg o.d. or b.i.d.

1.25-15 mg in 2-3 doses, 20-30 min before meals8

5-20 mg, o.d. or b.i.d.

2.5-20 mg6

5-30 mg, 30 min before breakfast

60-180 mg in 3-4 doses, just before or soon after starting a meal8

60-180 mg t.d.s., preprandial use6

60-120 mg t.i.d. with each meal

60-120 mg, shortly before each meal

180-480 mg, 3-4 doses per day, 10 min before meal

60-120 mg, just before meals

0.5-4 mg in 3-4 doses, just before or soon after starting a meal8

0.5-4 mg, 15-30 min before each main meal6

0.5-2 mg t.i.d. with each meal

-

4-8 mg6

0.25-4 mg shortly before each meal

-

15-45 mg/day6

1-8 mg, 3-4 doses/day, before each major meal

2-8 mg daily

15-45 mg daily

-

Once-daily in morning or b.i.d. (morning and evening)6

0.25-4 mg, just before each meal (max 16 mg/day)

11-45 mg o.d.

With evening meal

4-8 mg o.d.

15-45 mg o.d.

-

-

2-8 mg o.d. or b.i.d.

15-45 mg o.d.

-

-`

-

500 mg o.d.2,550 mg (divided doses) with meals or immediately before meals6

Start with 500 mg o.d.

Titrate up to 500-1,000 g b.i.d., given with meals

500 mg before breakfast and 500 mg with evening meal

0.5-2.5 mg, 1-2 doses per day

500 mg-2.55 g at bedtime for fasting hyperglycemia and before meals for postprandial hyperglycemia

RSSDI Text book of Diabetes Mellitus8-10

Textbook of Diabetes6,7

Endocrinology5

Basic and Principles of Essentials Clinical Pharmacology4 of Medical Pharmacology2 Pharmacology3

Table 1. Comparison of Information in Pharmacology, Endocrinology and Diabetology Textbooks

-

5-20 mg/day

5-40 mg/day

Preprandial dosing

Preprandial dosing

-

15-45 mg/ day o.d.

-

500 mg o.d. to 2,500 mg in divided doses

Manual of Clinical Endocrinology11

-

Conâ&#x20AC;&#x2122;td...

Initial 5 mg. Max 20 mg o.d.

Initial 5 mg, Max 40 mg, divided b.i.d.

120 mg with each meal

Max 4 mg with each meal

-

-

-

At least b.i.d.

Williams Textbook of Endocrinology12

DPP-4 inhibitors

αGlucosidase inhibitors

...Con’td

50-100 mg daily

-

100 mg daily

2.5-5 mg daily

-

Linagliptin

Sitagliptin

Saxagliptin

Alogliptin

25-100 mg before meals

Vildagliptin

Miglitol

-

1-8 mg o.d.

Glimepiride

Voglibose

0.75-12 mg daily

Micronized glyburide

25-100 mg, before meals

1.25-20 mg o.d. or b.i.d.

Glyburide (glibenclamide)

Acarbose

-

Gliclazide MR

-

2.5-5 mg daily

100 mg orally o.d.

-

-

25-100 mg just before ingesting the final portion of each meal

-

25-100 mg, just before ingesting the final portion of each meal

1-8 mg o.d.

-

1.25-20 mg, single morning dose

-

-

5 mg o.d.

100 mg o.d.

-

-

-

100 mg o.d. before meals

-

50 mg o.d. before meals

-

25-100 mg daily

25-100 mg o.d.

-

-

25-100 mg t.i.d. with first bite of carbohydrate containing meal

-

25-100 mg t.d.s. at the beginning of each major meal

50-100 mg o.d. or b.i.d.

-

25-100 mg t.i.d. with first bite of carbohydrate containing meal

1-2 mg initially.

Maximum dose is 8 mg o.d.

1.5-3 mg initial dose.

Max dose is 6 mg, b.i.d.

1.25-5 mg initially. Max dose 20 mg, divided b.i.d.

-

-

50-100 mg t.d.s. at the beginning of each major meal

1-6 mg o.d.

-

5-15 mg o.d. or b.i.d.

-

200-300 mg t.d.s. just before meals

50-100 mg t.d.s., at the beginning of each major meal

1-6 mg o.d. or b.i.d.

-

2.5-15 mg o.d. or b.i.d.

-

-

-

100 mg o.d. in morning6

12.5-25 mg/day

12.5-25 mg10

100 mg/day

5 mg/day

50 mg b.i.d.

-

-

-

1-8 mg/day

0.75-12 mg/day

1.25-20 mg/day

-

5 mg/day10

100 mg

o.d.10

50 mg o.d. or b.i.d., with or without food10

50 mg b.i.d.6

-

-

With meals6

-

0.2 mg t.d.s., just before each meal- max of 0.3 mg t.d.s.9

1-8 mg o.d., 20-30 min before meals8

1-6 mg6

With meals6

-

-

25 mg t.d.s. at the start of each main meal to max of 100 mg t.d.s.9

1.25-20 mg in 1-3 doses/day, 20-30 min before meals8

1.25- 15 mg6

50 mg o.d. to 200 mg t.d.s., with meals6

-

30-120 mg o.d.6

-

-

-

-

-

-

-

-

Con’td...

1-8 mg o.d.

Initial 3 mg.

Max 6 mg b.i.d.

Initial dose 2.5 mg.

Max dose 20 mg, divided b.i.d.

-

Bromocriptine

Pramlintide

Colesevelam

Amylin analog

Bile acid binding resin

3 tab (625 mg) b.i.d. before lunch and dinner or 6 tab prior to largest meal

1,875 mg b.i.d. or 3,750 mg o.d. orally

15-60 μg s/c inj in type 1 DM, 60-120 μg s/c inj in type 2 DM. Injected immediately before eating

15-60 μg s/c inj in type 1 DM, 60-120 μg s/c inj in type 2 DM. Injected prior to meals

-

s/c inj before meal

0.8-4.8 mg o.d., early in the morning

-

1.6-4.8 mg, with food in the morning within 2 h of awakening

-

o.d.

-

-

-

Ipragliflozin

-

-

-

-

-

-

s/c inj oncedaily

-

s/c inj

-

-

-

Dapaglifozin

Canagliflozin

-

Lixisenatide

-

-

-

-

Dulaglutide

Semaglutide

-

-

Albiglutide

Started at 0.6 mg injectable dose

-

5-10 μg s/c b.i.d. inj, within 60 min before a meal

s/c inj o.d.

-

0.01-0.02 mg s/c inj, before meals

Liraglutide

Exenatide QW

Exenatide

Dopamine D2 receptor agonist

SGLT2 inhibitor

GLP receptor agonist

...Con’td

-

-

-

60-90 μg, 3-4 times/day s/c prior to meals (type 1 DM).

Higher doses s/c b.i.d. in type II DM7

60-120 μg t.i.d. (for DM type II), 15-30 μg (for DM type I), s/c before meals

15-60 μg s/c inj before meals as an adjunct to insulin in DM type 1 cases and 60-120 μg s/c inj before meals with insulin in type 2 DM. -

-

-

-

-

-

-

-

-

1.6-4.8 mg o.d. within 2 h after waking in the morning, with food9

-

-

-

-

-

-

-

-

-

-

-

Once weekly

weekly10 -

-

-

30 mg weekly7 Once

0.6-1.8 mg/day

-

-

Once weekly

5-10 µg b.i.d., s/c, 60 min prior to meals

Once-daily10

-

Once weekly10

Once weekly7

5-10 μg b.i.d. within 60 min of morning and evening meals7

-

-

-

-

-

-

-

-

-

-

5-10 μg b.i.d. s/c up to 60 min before main meals

-

-

-

-

-

-

-

-

-

-

5-10 μg b.i.d., 30-60 min before meals

-

15-60 µg before meals in type 1 DM; max 120 µg before meals in type 2 DM

Within 2 h of rising in the morning

-

-

-

-

-

-

-

-

-

-

ENDOCRINOLOGY 2 describing only frequency of administration. Timing of administration was reported by 5 books. Metformin SR preparation was listed by only 3 textbooks, both American in origin, though its use is widespread across the world. Pioglitazone usage is covered in 7 textbooks, with similar dosages, but relationship with meal timings is not stated by any author.6 Rosiglitazone, which is used in a restricted subset of patients, is covered by 5 texts. But none of the textbooks mention timings of this drug. The omission of this molecule’s details from majority of endocrinology and diabetology books reflects the decline in its popularity.

Meglitinide analogs are discussed in uniform detail by all 9 textbooks surveyed. This is a pleasant (and perhaps superfluous) exercise, as nateglinide is rarely used in clinical practice and repaglinide is relatively less commonly prescribed than sulfonylureas.

Sulfonylureas are the oldest class of glucose-lowering drugs currently in use. A large number of drugs and preparations are available, and are well-covered by most textbooks. Micronized glyburide, glipizide ER and gliclazide, which are not available in all countries, are discussed by relatively less authors (5 and 4, respectively). While information related to glipizide and glibenclamide is uniform in most books, there is conflicting advice regarding the frequency of dosage of glimepiride. Timing of administration is not mentioned by many authors. A blanket recommendation to prescribe all sulfonylureas 20-30 minutes before meals is given by the leading Indian textbook of diabetes. The maximum dose of glimepiride is mentioned as 6 mg by three, and 8 mg by six authors. This may reflect the difference in maximum doses approved by various regulatory authorities. A similar lack of consensus is seen for gliclazide, where maximum doses vary from 240 to 320 mg and frequency of dosage ranges from 1 to 3 per day.

Alpha-glucosidase inhibitors are discussed in detail by seven (acarbose), four (miglitol) and two (voglibose) authors. Most of the advice contained in these texts is concordant with each other. The dipeptidyl peptidase-4 (DPP-4) inhibitors are relatively newer class of drugs, which may explain why their dose is not mentioned in many texts. The timing of administration; however, is written differently in various books. While some authors omit this aspect of posology, others recommend vildagliptin and sitagliptin before meals, and yet others advise no regard to meal times. The glucagon-like peptide-1 (GLP-1) receptor agonists are covered by some, but not all, books. While exenatide’s timing of administration is discussed by six authors,

no book makes mention of the timing of dosage of liraglutide. New once-weekly GLP-1 receptor agonists are discussed by one (dulaglutide, semaglutide) and three (exenatide QW) textbooks. Bromocriptine and colesevelam are nondiabetic drugs, which have recently been approved for use in type 2 diabetes.

They are prescribed infrequently. While four books mention bromocriptine, in a uniform manner, only two US textbook covers colesevelam. This poor coverage reflects the poor availability of this molecule. Another molecule which has limited availability, relevance and usage, is pramlintide. Approved for the management of postprandial hyperglycemia in both type 1 and type 2 diabetes, this is well-described, in a similar manner, by five texts. Sodium glucose co-transporter 2 (SGLT2) inhibitors, which are the latest class of oral glucoselowering drugs, have found mention in one current US pharmacology textbook.

CONCLUSION This bibliometric analysis highlights the need to have standardized, uniform sources of information regarding posology of glucose-lowering drugs. Such information will be of importance to students and professionals of diabetology, and will benefit their patients as well.

LIMITATIONS All textbooks of pharmacology, diabetology and endocrinology were not analyzed for the review.

However, the textbooks analyzed here are the most commonly used ones.

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RSSDI Textbook of Diabetes Mellitus. 3rd Edition, New Delhi: Jaypee Brothers Medical Publishers; 2014. pp.

527-37.

■■■■

Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus.

In: Melmed S, Polonsky KS, Larsen PR, Kronenberg HM (Eds.). Williams Textbook of Endocrinology. 12th Edition, Philadelphia: Elsevier Saunders; 2011. pp. 1371-435.

ÂÂ

One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH) and they could benefit from testosterone treatment, reported a small trial published online in Diabetes Care. Researchers noted that testosterone treatment increases insulin sensitivity and lean mass and decreases subcutaneous fat.

ÂÂ

Elevated testosterone levels may raise women’s risk for developing uterine fibroids, suggest new data published online December 15 in the Journal of Clinical Endocrinology & Metabolism.

ÂÂ

Combining palbociclib with fulvestrant is an effective strategy to overcome endocrine resistance in women with hormone receptor positive (HR+), HER2 negative (HER2-) advanced breast cancer, suggested new study presented at the first ESMO Asia 2015.

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

ENDOCRINOLOGY

Hypothyroidism in Metabolic Syndrome DARSHANA MAKWANA*, JIGNESH TANK†, DEEPAK KUMAR†

ABSTRACT Background: Metabolic syndrome (Syndrome X/Insulin resistance syndrome) consists of central obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, hyperglycemia and hypertension as its major features. All of them can be influenced by the functioning of a 20 g endocrine organ, the thyroid gland. Aims and objectives: To study the proposed association between metabolic syndrome and thyroid dysfunction. Material and methods: Hundred subjects aged more than 18 years, willing to participate in the study and fulfilling criteria of the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) for diagnosis of metabolic syndrome were included. Detailed clinical examination and laboratory investigations of all subjects were done. Risk factors were identified and analyzed by comparing the subjects with and without thyroid dysfunction. Results: Eighty-one out of 100 subjects with metabolic syndrome belonged to the age group between 41 and 70 years. Females comprised 60% of the total patient population with sedentary lifestyle as the major risk factor, whereas males comprising rest of the 40% had addictive behaviors as major risk factors. Observation of individual parameters under NCEP-ATP III showed that 57 patients fulfilled all 5 criteria, 34 patients fulfilled 4 and 9 patients fulfilled 3 criteria. Obesity and dyslipidemia were common among female subjects, whereas impaired glucose tolerance and hypertension were common among males. Thyroid dysfunction in the form of hypothyroidism was present in 30 subjects with females (23 patients) being the statistically significant population (p < 0.0001). Hypothyroidism was of subclinical type in 21 of these 30 subjects. None had hyperthyroidism. Left ventricular ejection fraction (mean ± SD) was lowered to 42.67 ± 6.53 from 49.07 ± 7.48 in presence of thyroid dysfunction in these subjects with metabolic syndrome (p < 0.0001). Conclusion: Metabolic syndrome and hypothyroidism (even subclinical) are both individual as well as combined risk factors for development of atherogenic dyslipidemia, diabetes mellitus and cardiovascular disease with elderly females comprising the high risk group.

Keywords: Metabolic syndrome, thyroid dysfunction, hypothyroidism

P

revalence of both metabolic syndrome and thyroid dysfunction depend on features like age, sex, ethnicity and geographic factors.1 With increasing global industrialization and rising rates of obesity, prevalence of metabolic syndrome is expected to increase. Metabolic syndrome and hypothyroidism share insulin resistance as the common pathophysiologic mechanism manifesting as obesity, dyslipidemia and hypertension.2,3 Study of association between these two disorders will help early identification of at risk group and initiation of treatment for thyroid dysfunction in individuals with metabolic syndrome.

MATERIAL AND METHODS This was an observational and noninterventional study conducted in our Government Medical College and attached tertiary care hospital.

*Assistant Professor †Resident Dept. of Medicine Civil Hospital, BJ Medical College, Ahmedabad, Gujarat

Study Group Inclusion Criteria Total of 100 subjects aged more than 18 years, willing to participate in the study and fulfilling criteria of the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) for diagnosis of metabolic syndrome were included (Table 1).

Exclusion Criteria ÂÂ

Patients already diagnosed dysfunction, thyroid malignancy.

with

thyroid

ÂÂ

Pregnant females.

ÂÂ

Patients receiving drugs interfering with thyroid function.

Methods ÂÂ Detailed history of the patient including symptoms, past illness, occupation, lifestyle, familial and other comorbid illness obtained. ÂÂ General and systemic clinical examination of the patient was performed. Waist circumference and blood pressure (BP) were recorded.

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

743

ENDOCRINOLOGY ÂÂ

ÂÂ

Following investigations were carried out: zz

Serum fasting lipid profile

zz

Fasting blood sugar (FBS), postprandial blood sugar (PPBS), A1C

zz

Thyroid function tests - Serum thyroidstimulating hormone (TSH), free T3, free T4 (Table 2)

zz

Complete blood count

zz

Renal and liver function tests

zz

Urine analysis

zz

2D ECHO

zz

Chest radiograph

zz

Ultrasonography abdomen with kidney, ureter and bladder

zz

Electrocardiograph

Blood pressure

zz

Fundus examination.

≥130/≥85 mmHg

Fasting glucose

≥110 mg/dL

Triglycerides

≥150 mg/dL

Statistical analysis done for better understanding and to provide logical support to results.

RESULTS Patient population was largely comprised of middleaged individuals with 81 out of 100 subjects with metabolic syndrome belonging to the age group between 41 and 70 years. Females comprised 60% of the total patient population with sedentary lifestyle as the major risk factor, whereas males comprising rest of the 40% had addictive behaviors as major risk factors (Table 3). Observation of individual parameters under NCEP-ATP III showed that 57 patients fulfilled all 5 criteria, 34 patients fulfilled 4 and 9 patients fulfilled 3 criteria. Sixty-six patients had waist circumference that satisfied the criteria for metabolic syndrome, whereas 73 patients had body mass index (BMI) of >25 kg/m2.

Sixty-six patients had hypertension and 33 had prehypertension. Only three patients were normotensive.

Fifty patients had FBS between 100 and 125 mg/dL and 39 patients had frank type 2 diabetes. Eighty patients had triglyceride (TG) values >150 mg/dL and 4 among them had values >200 mg/dL. Thirty-one (78%) males had high-density lipoprotein (HDL) of <40 mg/dL and 56 (93%) females had HDL of <50 mg/dL. Total cholesterol and low-density lipoprotein (LDL) (not included in definition of metabolic syndrome) too were elevated among these patients.

Obesity and dyslipidemia were common among female subjects attributable to sedentary lifestyle, whereas impaired glucose tolerance and hypertension were common among male subjects attributable to presence

744

of addicting habits. Incidence of thyroid dysfunction was more common in patients satisfying more than three criteria for metabolic syndrome, in women with waist circumference >88 cm and in patients with diabetes mellitus (Table 4).

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

Prevalence of thyroid dysfunction in the form of hypothyroidism was statistically significant (p < 0.0001) Tables 1. Clinical Identification of the Metabolic Syndrome: Any Three of the Following )NCEPATP III Criteria)4 Defining level

Risk factor Abdominal obesity

Waist circumference

Men

>102 cm

Women

>88 cm

HDL cholesterol Men

<40 mg/dL

Women

<50 mg/dL

Table 2. Thyroid Function Test Thyroid status

Serum TSH (µIU/mL)

Serum free T4 (ng/dL)

Eu

0.27-4.2

0.93-1.7

SCH

4.3-10

0.93-1.7

OH

>10

<0.93

Eu = Euthyroidism; SCH = Subclinical hypothyroidism; OH = Overt hypothyroidism.

Table 3. Parameters of the Study Population Parameters

Results

Age (years)

57.63 ± 10.58

Sex (M:F)

40:60

Waist circumference (cm) Men

101.43 ± 7.93

Women

89.93 ± 9.04

Blood pressure (mmHg)

146.06/90.4

Fasting glucose (mg/dL)

133.71 ± 26.21

Total cholesterol (mg/dL)

233.45 ± 49.76

Serum triglycerides (mg/dL)

167.43 ± 20.53

Serum HDL (mg/dL) Men Women

37.18 ± 8.10 39.18 ± 7

ENDOCRINOLOGY Table 4. Association of Components of Metabolic Syndrome with Thyroid Function Thyroid status

Waist circumference (cm)

Blood pressure (mmHg)

Fasting glucose (mg/dL)

Serum Triglycerides (mg/dL)

Serum HDL (mg/dL)

Total cholesterol (mg/dL)

Eu

95.91

142.8/84.3

123.36

161.97

39.16

214.03

SCH

91.67

146.6/88.6

130.38

172.29

37.33

262.67

OH

91.14

150.4/94.8

144.22

198.56

34.78

316.86

Table 5. Comparison of Parameters of Metabolic Syndrome with Thyroid Dysfunction Between Genders Parameters

Male (Mean ± SD)

Female (Mean ± SD)

91.58 ± 7.75

101.60 ± 7.84

Blood pressure (mmHg)

145.5/90.9 (mean)

148.4/91.7 (mean)

Fasting glucose (mg/dL)

132.69 ± 27.12

135.4 ± 24.98

Serum triglycerides (mg/dL)

167.60 ± 22.02

167.18 ± 18.32

Waist circumference (cm)

Serum HDL (mg/dL)

39.33 ± 6.89

37.2 ± 8.86

240.22 ± 45.66

226.55 ± 59.19

Serum TSH (µIU/mL)

7.62 ± 8.36

4.95 ± 3.64

Serum free T4 (ng/dL)

1.08 ± 0.26

1.16 ± 0.24

Total cholesterol (mg/dL)

DISCUSSION Metabolic syndrome is a cluster of cardiometabolic risk factors and hypothyroidism is an independent risk factor for cardiovascular disease.5-9 Both share insulin resistance as the central pathophysiologic mechanism.

Insulin resistance favors lipolysis causing development of dyslipidemia and impaired glucose tolerance.10 Abdominal obesity further increases insulin resistance by producing inflammatory cytokines like tumor necrosis factor-ά (TNF-ά) and interleukin-6 (IL-6).11

Euthyroid males

Subclinical hypothyroid males

Euthyroid females

Subclinical hypothyroid females

Over hypothyroid males

Over hypothyroid females

Figure 1. Thyroid status.

in females than in males with 23 out of 60 female and only 7 out of 40 male subjects diagnosed with hypothyroidism (Table 5 and Fig. 1). Hypothyroidism was of subclinical type in 21 (16 females and 5 males) out of these 30 patients. None had hyperthyroidism.

Left ventricular ejection fraction (LVEF) (mean ± SD) was lowered to 42.67 ± 6.53 from 49.07 ± 7.48 in presence of thyroid dysfunction in these subjects with metabolic syndrome (p < 0.0001).

Adiponectin released by adipose tissue enhances the action of insulin, but is deficient in obese persons.12,13 BMI >25 kg/m2 definitely forms a risk factor for atherogenic dyslipidemia and insulin resistance.14,15 Patients not having frank diabetes at present are prone to develop it in the future. Atherogenic dyslipidemia is reflected in the form of high serum TG, total cholesterol, LDL and low HDL. Studies suggest presence of linear correlation between dyslipidemia (high serum TG and cholesterol) and serum TSH values.16,17 Thyroid hormone affects tissue thermogenesis, erythropoiesis, lipid metabolism, systemic vascular resistance, blood volume, cardiac contractility, heart rate and cardiac output. Any thyroid dysfunction, therefore, alters cardiovascular dynamics significantly. Cardiac output increases 50-300% higher than in normal individuals in hyperthyroidism, whereas it may decrease by

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

745

ENDOCRINOLOGY 30-50% in hypothyroidism. However, restoration of normal cardiovascular hemodynamics is possible with treatment of thyroid dysfunction.6-8

5. Tkác I. Metabolic syndrome in relationship to type 2 diabetes and atherosclerosis. Diabetes Res Clin Pract.

2005;68 Suppl 1:S2-9.

Present study reiterates that metabolic syndrome and hypothyroidism are both individual as well as combined risk factors for development of disease processes like cardiovascular disease and diabetes mellitus with elderly females comprising the high risk group.

7. Dillmann WH. Cellular action of thyroid hormone on the heart. Thyroid. 2002;12(6):447-52.

CONCLUSION Patients with metabolic syndrome and hypothyroidism (even subclinical) are prone to atherogenic dyslipidemia and cardiovascular events. Early thyroxine replacement can prevent cardiovascular events in these patients.

Hence, we recommend routine screening for thyroid dysfunction in females with metabolic syndrome.

However, theoretical benefits of thyroxine replacement in subclinical hypothyroidism is to be confirmed by future randomized trials.

REFERENCES 1. Delange F. The disorders induced by iodine deficiency.

Thyroid. 1994;4(1):107-28.

2. Roos A, Bakker SJ, Links TP, Gans RO, Wolffenbuttel BH. Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. J Clin Endocrinol Metab. 2007;92(2):491-6.

3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285(19):2486-97.

6. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344(7):501-9.

8. Danzi S, Klein I. Thyroid hormone and the cardiovascular system. Minerva Endocrinol. 2004;29(3):139-50.

9. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 2000;132(4):270-8.

10. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595-607.

11. Ruan H, Lodish HF. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha.

Cytokine Growth Factor Rev. 2003;14(5):447-55.

12. Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes. 2003;52(7):1779-85.

13. Hara T, Fujiwara H, Shoji T, Mimura T, Nakao H, Fujimoto S. Decreased plasma adiponectin levels in young obese males. J Atheroscler Thromb. 2003;10(4):234-8.

14. Grundy SM, Mok HY, Zech L, Steinberg D, Berman M. Transport of very low density lipoprotein triglycerides in varying degrees of obesity and hypertriglyceridemia.

J Clin Invest. 1979;63(6):1274-83.

15. Egusa G, Beltz WF, Grundy SM, Howard BV. Influence of obesity on the metabolism of apolipoprotein B in humans.

J Clin Invest. 1985;76(2):596-603.

16. Bauer DC, Ettinger B, Browner WS. Thyroid functions and serum lipids in older women: a population-based study.

Am J Med. 1998;104(6):546-51.

4. National Institutes of Health, Third Report of the National Cholesterol Education Program Expert Panel on Detection, 17.

Evaluation and Treatment of High Blood Cholesterol in Adults (Adults Treatment Panel III); executive summary.

Publication No.01-3670. Bethesda: National Institutes of Health: 2001.

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

Asvold BO, Vatten LJ, Nilsen TI, Bjøro T. The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study. Eur J Endocrinol. 2007;156(2):181-6.

INTERNAL MEDICINE

Study of Prevalence of Hypothyroidism and Effect of Treatment with L-thyroxine in Patients of Chronic Kidney Disease NS SENGAR*, NIPUN GUPTA†, NANDITA PRABHAT‡

ABSTRACT Objective: There is scarcity of literature regarding prevalence and severity of thyroid abnormalities in chronic kidney disease (CKD) patients. This study (i) estimated the prevalence of hypothyroidism in CKD patients, (ii) investigated the effect of thyroid hormone replacement therapy (THRT) on changes in estimated glomerular filtration rate (eGFR) in CKD patients.

Material and methods: This was a descriptive longitudinal study conducted in MLB Medical College, Jhansi over a period of 1 year, on patients with CKD. A total of 120 CKD patients with serum creatinine levels available at least two times in previous 6 months were enrolled, screened for thyroid function and those detected with hypothyroidism were treated with L-thyroxine.

Before and after treatment, comparisons were made and for statistical analysis, paired t-test was used for association. Results: Out of 120 study subjects, maximum patients were in the age group of 51-60 years (36.67%) with 65% being males and 35% females. Twenty-one (17.5%) were found to have hypothyroidism, 18 (15%) had subclinical hypothyroidism and 3 (2.5%) had overt hypothyroidism. The stage-wise distribution of hypothyroidism in CKD patients was 15.6% in stage III, 16.67% in stage IV and 20% in stage V. The rate of decline in eGFR over 6 months was significantly reduced from 3.05 ± 2.02 mL/min/1.73 m2 before the THRT to 1.02 ± 2.5 mL/min/1.73 m2 after giving thyroid hormone replacement (p < 0.001). Among the patients given thyroid hormone replacement for 6 months, 61.9% showed slower decline in eGFR, 19% showed unchanged decline, 9.5% patients showed a faster decline in eGFR and 9.5% patients showed an improvement in eGFR after THRT. Conclusion: Hypothyroidism (15% subclinical and 2.5% overt) is a relatively common condition in CKD patients. Prevalence of hypothyroidism increased with progressively lower levels of GFR i.e., declining renal function. THRT attenuated the rate of decline in renal function in CKD patients with hypothyroidism, suggesting that THRT may delay reaching end-stage renal disease in these patients.

Keywords: Hypothyroidism, chronic kidney disease, estimated glomerular filtration rate, thyroid hormone replacement

therapy

T

hyroid hormones are important in cellular growth and differentiation, and modulation of physiological functions in all human tissues including the kidney. They also play a role in maintenance of water and electrolyte homeostasis.

Therefore, thyroid dysfunction, either hypothyroidism or hyperthyroidism is accompanied by alterations in the metabolism of water and electrolytes, as well as cardiovascular function. On the other hand, the kidney

is an important target organ for thyroid hormone actions and for the metabolism and elimination of the thyroid hormones. Derangement in kidney function is associated with abnormalities in the thyroid hormone physiology.1

*Professor and Head †Associate Professor ‡Junior Resident Dept. of Medicine MLB Medical College, Jhansi, Uttar Pradesh Address for correspondence

Replacement of thyroid hormone is fundamental to the treatment of primary hypothyroidism. It relieves the symptoms of hypothyroidism and also alleviates the deleterious effects of overt hypothyroidism on the kidney.3 Even though previous studies have demonstrated that L-thyroxine improves cardiac

Dr Nipun Gupta 296/1, Jhokan Bagh, Behind Bank of Baroda, Jhansi - 284 001, Uttar Pradesh E-mail: drnipungupta@rediffmail.com

Chronic kidney disease (CKD) affects both hypothalamus-pituitary-thyroidal axis and thyroid hormone peripheral metabolism. The effects of impaired kidney function may lead to hypothyroidism, hyperthyroidism and nonthyroidal illness, which are associated with deranged cardiovascular function, which will adversely affect the prognosis of CKD.2

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

747

INTERNAL MEDICINE function and dyslipidemia in patients with subclinical hypothyroidism (SCH),4,5 there is still a lack of consensus in current guidelines on whether to treat SCH patients with thyroid hormone or not.6 In particular, little is known about the effect of thyroid hormone replacement on the changes in glomerular filtration rate (GFR) in CKD patients with SCH. The direct impact of thyroid hormone treatment on the changes in GFR in the same individuals with SCH could not be evaluated.7 In the present study, we compared the changes in GFR before and after thyroid hormone replacement in the same population of adult CKD patients with hypothyroidism. This study was done to simplify the importance of interactions between thyroid functions and kidney disease. This information is essential as it shows a link between two separate conditions.

Information obtained from this study will help to increase clinical knowledge and enable clinicians to provide better management for their patients who have thyroid or kidney dysfunction.

AIMS AND OBJECTIVES ÂÂ

To estimate the prevalence of hypothyroidism in CKD patients.

ÂÂ

Effect on progression of chronic renal failure after treatment of hypothyroidism in CKD patients.

MATERIAL AND METHODS

Study Design This was a descriptive longitudinal study and patients detected with hypothyroidism were subjected to before and after comparison studies.

Study Site and Population This study was conducted on 120 patients of CKD, selected randomly; attending the Nephrology Clinic and admitted in wards of Dept. of Medicine, MLB Medical College, Jhansi, Uttar Pradesh between March 2014 and April 2015. There were no dropouts or deaths during the study.

Methodology Inclusion Criteria ÂÂ

Patients with CKD, between 20 and 75 years of age with serum creatinine levels available at least two times in previous 6 months before the start of study.

ÂÂ

Informed consent.

748

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

Case Definition Kidney damage for >3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, that can lead to decreased GFR, manifest by either: Pathologic abnormalities or markers of kidney damage, including abnormalities in the composition of the blood or urine, abnormalities in imaging tests.

Estimated GFR (eGFR) <60 mL/min/1.73m2 for >3 months, with or without kidney damage.8 Estimation of eGFR done using the 4-variable Modification of Diet in Renal Disease (MDRD) formula: GFR (mL/min/1.73 m2) = 175 × (Standardized SCr [µmol/L])-1.154 × (age [years])-0.203 × 1.212 (if black) × 0.742 (if female) Exclusion Criteria ÂÂ

Decline consent.

ÂÂ

Patients <20 or >75 years of age.

ÂÂ

Patients with heavy proteinuria including nephrotic syndrome or terminal malignancy.

ÂÂ

Patients who experienced acute exacerbation of underlying renal insufficiency due to dehydration, radiocontrast dye, urinary tract obstruction, etc.

ÂÂ

Patients previously being treated for thyroid disease.

Thyroid Function Test and Definition: In all patients, serum free tri-iodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) concentrations were measured. These levels were determined by chemiluminescent microparticle immunoassay. The diagnosis of SCH was solely based upon the results of a thyroid function test and was defined as a normal serum FT4, but elevated TSH levels, irrespective of clinical symptoms of hypothyroidism. Normal reference changes FT3 = 2.30-4.20 pg/mL FT4 = 0.89-1.75 ng/dL, TSH = 0.55-4.780 IU/mL. Treatment of Hypothyroidism and CKD: All the patients with SCH took L-thyroxine, initially administered at lowest doses necessary to normalize serum TSH levels, which was 25 ug daily. Patients with overt hypothyroidism were prescribed L-thyroxine at 50 ug daily dose. The dose of L-thyroxine was adjusted every 3 months according to the follow-up levels of TSH. The treatment of CKD was continued as before the start of study: the patients on conservative management were prescribed oral hematinics, calcium supplements and antihypertensives and oral hypoglycemic agents (OHAs)

FOR PRODUCTIVE COUGH

FOR DRY, IRRITATING AND ALLERGIC COUGH

FOR NOCTURNAL COUGH

2015

in Cough Management

Every citizen of India should have the right to accessible, affordable, quality and safe heart care irrespective of his/her economical background

Sameer Malik Heart Care Foundation Fund An Initiative of Heart Care Foundation of India E-219, Greater Kailash, Part I, New Delhi - 110048 E-mail: heartcarefoundationfund@gmail.com Helpline Number: +91 - 9958771177

“No one should die of heart disease just because he/she cannot afford it” About Sameer Malik Heart Care Foundation Fund

Who is Eligible?

“Sameer Malik Heart Care Foundation Fund” it is an initiative of the Heart Care Foundation of India created with an objective to cater to the heart care needs of people.

Objectives Assist heart patients belonging to economically weaker sections of the society in getting affordable and quality treatment.

Raise awareness about the fundamental right of individuals to medical treatment irrespective of their religion or economical background.

Sensitize the central and state government about the need for a National Cardiovascular Disease Control Program.

Encourage and involve key stakeholders such as other NGOs, private institutions and individual to help reduce the number of deaths due to heart disease in the country.

To promote heart care research in India.

All heart patients who need pacemakers, valve replacement, bypass surgery, surgery for congenital heart diseases, etc. are eligible to apply for assistance from the Fund. The Application form can be downloaded from the website of the Fund. http://heartcarefoundationfund.heartcarefoundation. org and submitted in the HCFI Fund office.

Important Notes The patient must be a citizen of India with valid Voter ID Card/ Aadhaar Card/Driving License.

The patient must be needy and underprivileged, to be assessed

by Fund Committee.

The HCFI Fund reserves the right to accept/reject any application for financial assistance without assigning any reasons thereof.

The review of applications may take 4-6 weeks.

All applications are judged on merit by a Medical Advisory Board who meet every Tuesday and decide on the acceptance/rejection of applications.

The HCFI Fund is not responsible for failure of treatment/death of patient during or after the treatment has been rendered to the patient at designated hospitals.

To promote and train hands-only CPR.

Activities of the Fund Financial Assistance

The HCFI Fund reserves the right to advise/direct the beneficiary to the designated hospital for the treatment.

Financial assistance is given to eligible non emergent heart patients.

Apart from its own resources, the fund raises money through donations, aid from individuals, organizations, professional bodies, associations and other philanthropic organizations, etc.

The financial assistance granted will be given directly to the treating hospital/medical center.

After the sanction of grant, the fund members facilitate the patient in getting his/her heart intervention done at state of art heart hospitals in Delhi NCR like Medanta – The Medicity, National Heart Institute, All India Institute of Medical Sciences (AIIMS), RML Hospital, GB Pant Hospital, Jaipur Golden Hospital, etc. The money is transferred directly to the concerned hospital where surgery is to be done.

The HCFI Fund has the right to print/publish/webcast/web post details of the patient including photos, and other details. (Under taking needs to be given to the HCFI Fund to publish the medical details so that more people can be benefitted).

The HCFI Fund does not provide assistance for any emergent heart interventions.

Check List of Documents to be Submitted with Application Form Passport size photo of the patient and the family A copy of medical records

Drug Subsidy

Identity proof with proof of residence

The HCFI Fund has tied up with Helpline Pharmacy in Delhi to facilitate

BPL Card (If Card holder)

patients with medicines at highly discounted rates (up to 50%) post surgery.

Details of financial assistance taken/applied from other sources (Prime Minister’s Relief Fund, National Illness Assistance Fund Ministry of Health Govt of India, Rotary Relief Fund, Delhi Arogya Kosh, Delhi Arogya Nidhi), etc., if anyone.

Income proof (preferably given by SDM)

The HCFI Fund has also tied up for providing up to 50% discount on imaging (CT, MR, CT angiography, etc.)

Free Diagnostic Facility

Free Education and Employment Facility

The Fund has installed the latest State-of-the-Art 3 D Color Doppler EPIQ 7C Philips at E – 219, Greater Kailash, Part 1, New Delhi.

HCFI has tied up with a leading educational institution and an export house in Delhi NCR to adopt and to provide free education and employment opportunities to needy heart patients post surgery. Girls and women will be preferred.

This machine is used to screen children and adult patients for any heart disease.

Laboratory Subsidy HCFI has also tied up with leading laboratories in Delhi to give up to 50% discounts on all pathological lab tests.

About Heart Care Foundation of India

Help Us to Save Lives

The Foundation seeks support, donations and contributions from individuals, organizations and establishments both private and governmental in its endeavor to reduce the number of deaths due to heart disease in the country. All donations made towards the Heart Care Foundation Fund are exempted from tax under Section 80 G of the IT Act (1961) within India. The Fund is also eligible for overseas donations under FCRA Registration (Reg. No 231650979). The objectives and activities of the trust are charitable within the meaning of 2 (15) of the IT Act 1961.

Heart Care Foundation of India was founded in 1986 as a National Charitable Trust with the basic objective of creating awareness about all aspects of health for people from all walks of life incorporating all pathies using low-cost infotainment modules under one roof.

HCFI is the only NGO in the country on whose community-based health awareness events, the Government of India has released two commemorative national stamps (Rs 1 in 1991 on Run For The Heart and Rs 6.50 in 1993 on Heart Care Festival- First Perfect Health Mela). In February 2012, Government of Rajasthan also released one Cancellation stamp for organizing the first mega health camp at Ajmer.

Objectives Preventive Health Care Education Perfect Health Mela Providing Financial Support for Heart Care Interventions Reversal of Sudden Cardiac Death Through CPR-10 Training Workshops Research in Heart Care

Donate Now...

Heart Care Foundation Blood Donation Camps The Heart Care Foundation organizes regular blood donation camps. The blood collected is used for patients undergoing heart surgeries in various institutions across Delhi.

Committee Members

Chief Patron

President

Raghu Kataria

Dr KK Aggarwal

Entrepreneur

Padma Shri, Dr BC Roy National & DST National Science Communication Awardee

Governing Council Members Sumi Malik Vivek Kumar Karna Chopra Dr Veena Aggarwal Veena Jaju Naina Aggarwal Nilesh Aggarwal H M Bangur

Advisors Mukul Rohtagi Ashok Chakradhar

Executive Council Members Deep Malik Geeta Anand Dr Uday Kakroo Harish Malik Aarti Upadhyay Raj Kumar Daga Shalin Kataria Anisha Kataria Vishnu Sureka

This Fund is dedicated to the memory of Sameer Malik who was an unfortunate victim of sudden cardiac death at a young age.

Rishab Soni

HCFI has associated with Shree Cement Ltd. for newspaper and outdoor publicity campaign HCFI also provides Free ambulance services for adopted heart patients HCFI has also tied up with Manav Ashray to provide free/highly subsidized accommodation to heart patients & their families visiting Delhi for treatment.

http://heartcarefoundationfund.heartcarefoundation.org

INTERNAL MEDICINE if required, and the patients who were earlier on hemodialysis were continued with the same.

with decline in eGFR - 15.6% in stage III, 16.67% in stage IV and 20% in stage V (Table 1).

Statistical Analysis

Hypothyroidism was found to be more common in females (19.04%) as compared to males (16.66%) (Table 3).

The prevalence of hypothyroidism was 18.88% in patients with conservative management and 13.33% in study subjects on hemodialysis. The rate of decline in eGFR over 6 months was significantly reduced from 3.05 ± 2.02 mL/min/1.73 m2 before the thyroid hormone replacement therapy (THRT) to 1.02 ± 2.5 mL/min/1.73 m2 after giving thyroid hormone replacement (p < 0.001) (Tables 4 and 5; Fig. 1).

Statistical analysis was performed using SPSS trial version. The data was entered into Microsoft Excel Software. Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as number (percentage). We compared patients clinical and biochemical parameters at following time points: 6 and 3 months before L-thyroxine, time of initiation of thyroid hormone supplement and at 3 and 6 months after L-thyroxine treatment. For association, paired t-test was applied and p value <0.001 was considered statistically significant.

Table 2. Thyroid Profile in CKD Patients

OBSERVATIONS AND RESULTS The distribution of study subjects was done according to the age (20-75 years) with maximum study subjects in the age group of 51-60 years (36.67%), with 65% being males and 35% females, stage-wise distribution of study subjects (Table 1) showed majority of participants in stage IV (40%) followed by stage III and V (36.67% and 33.33%, respectively). None of the study subjects included was in stage I or II. Among the study subjects, 75% were on conservative management and 25% were on hemodialysis.

The primary disease process, leading to CKD was diabetes mellitus type II (DM II) (36.67%), followed by hypertension (25%), obstructive uropathy (15%), glomerulonephritis (11.67%), cystic diseases (3.33%) and other causes (8.33%). Twenty-one subjects out of 120 study subjects were found to have hypothyroidism (17.5%) out of which 3 were overt hypothyroid (2.5%) and 18 were subclinical hypothyroid (15%) (Table 2).

The distribution of hypothyroidism stage-wise in CKD showed an increasing prevalence of hypothyroidism Table 1. Stage-wise Distribution of Hypothyroidism in CKD Patients Stage I

Stage II

Stage III

Stage IV

Stage V

Total no. of subjects

0

0

32

48

40

No. of hypothyroid subjects

0

0

5

8

8

Percentage of hypothyroidism

0

752

0

15.6

16.67

20.0

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

Euthyroid

Overt hypothyroid

Subclinical hypothyroid

No. of subjects

99

3

18

Percentage (%)

82.50

2.50

15.0

Table 3. Gender Distribution of Hypothyroidism in CKD Patients Gender

Total no. of subjects

No. of hypothyroid subjects

Percentage of hypothyroidism

Male

78

13

16.66

Female

42

8

19.04

Table 4. Changes in eGFR Over Time in CKD Patients

eGFR mL/ min/1.73 m2

-6

-3

0 Baseline

+3

+6

25.45 ± 11.15

23.92 ± 11.56

22.39 ± 11.63

21.76 ± 12.14

21.35 ± 13.2

Table 5. Comparison of Rate of Decline in eGFR Before and After THRT

Rate of decline of eGFR in mL/min/1.73 m2 in 6 months

6 months before THRT (-6 to 0 months)

6 months after THRT (0 to 6 months)

P value

3.05 ± 2.02

1.02 ± 2.5

<0.001

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26

eGFR mL/min/1.73 m2

25.45 ± 11.15

25

eGFR →

24 23 22.39 ± 11.63 22 21

21.35 ± 13.20

20 19 -6

-3

-0

3

6

Time (months) →

Figure 1. Changes in eGFR over time in CKD patients.

DISCUSSION The presented study was conducted in Dept. of Medicine, MLB Medical College, Jhansi on 120 subjects from March 2014 to April 2015. The subjects were of CKD, distributed according to the age groups starting from 20 years of age, up to 75 years of age, with maximum study subjects in the group of 51-60 years (36.67%). Of these, 78 (65%) were males and 42 (35%) were females. Classification of CKD into different stages in this study was done as per National Kidney Foundation guidelines, with eGFR using the fourvariable MDRD formula.8 Majority of the participants were CKD stage IV (40%). Number of participants in CKD stage III and V were 26.67% and 33.33%, respectively. None of the participants sampled were in CKD stage I or II. This could be attributed to delay in seeking medical treatment; hence, patients were seen when the disease has progressed to more severe stages.

According to the 2003-2006 NHANES (National Health and Nutrition Examination Survey) data of US adults >20 years age, 15.32% is the most recent CKD prevalence with estimated stage-wise prevalence - stage I - 4.1%, stage II - 3.2%, stage III - 6.5% and stage 4 + 5 - 0.6%.9 Among the 120 patients of CKD included in the study, 90 subjects (75%) were on conservative management and 30 subjects (25%) were on hemodialysis.

Among the primary disease processes leading to CKD, the most common cause was found to be DM II (36.67%), followed by hypertensive nephrosclerosis (25%), glomerulonephritis (11.67%), obstructive uropathy (15%), cystic disease (3.33%) and other causes including human immunodeficiency virus (HIV) infection, pyelonephritis and cardiomyopathies included (8.33%).

These results were in concordance with NHANES 2003-2006 data of US, except the percentage prevalence of obstructive uropathy, which was found to be higher in our study subjects of Bundelkhand region.

In our study, the prevalence of hypothyroidism was found to be 17.5% i.e., 21 subjects including 18 subjects of SCH (i.e., 15%) and 3 subjects of overt hypothyroidism (i.e., 2.5%). The stage-wise distribution of hypothyroidism in CKD patients showed the prevalence of hypothyroidism to be 15.6% in stage III, 16.67% in stage IV and 20% in stage V. We concluded that the prevalence of hypothyroidism increased with lower levels of eGFR. This was in concordance with previous study done by Lo et al10 who used data from NHANES III and revealed the prevalence of hypothyroidism, occurring in 10.9% of patients with stage II CKD, 21% with stage III CKD and 23.1% with stage IV or V CKD. Among these hypothyroidism patients, 56% were considered subclinical. Moreover, Chonchol et al11 showed that the prevalence of SCH increased from 7% at an eGFR >90 mL/min/1.73 m2 to 17.9% at an eGFR <60 mL/min/1.73 m2 in 3,089 outpatient adults.

In our study, the prevalence of hypothyroidism was found to be more in females (19.04%) as compared to males (16.66%). This was not in concordance with previous studies. Study among 137 subjects concluded at Kenyatta National Hospital, Kenya concluded that there was no statistically significant difference between prevalence of hypothyroidism in males and females.

A study conducted by Allawi et al12 on prevalence of hypothyroidism concluded it to be more in males (20%) as compared to females (6%). In relation to the type of treatment in CKD, the prevalence of hypothyroidism was found to be 18.88% on patients with conservative management and 13.33% in patients on hemodialysis.

At the time of commencement of thyroid hormone therapy in 21 hypothyroid subjects, the baseline characteristics were as shown in Table 6. The overall rate of decline in eGFR over 6 months was significantly blunted from 3.05 ± 2.02 to 1.02 ± 2.5 (mL/min/1.73 m2) (p < 0.001) by THRT (Tables 4 and 5). The numbers of patients who had a slower fast or unchanged eGFR decline after THRT were determined, 61.9% patients had a slower decline in eGFR, 19% had unchanged decline, 9.5% had a faster decline and 9.5% patients showed an improvement in eGFR after thyroid replacement.

Among the patients who had a slower decline and improvement in eGFR, 20% (i.e., 3 patients) were of DM II, 53.3% (i.e., 8 patients) had systemic hypertension and 26.7% patients had other etiologies. These results were in concordance with the previous studies conducted.

A study conducted by Shin et al13 on 113 CKD patients with SCH showed similar results with rates of decline in eGFR significantly attenuated by THRT (-4.31 ± 0.5 vs. -1.08 ± 0.36) (p < 0.001), but there was no significant

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INTERNAL MEDICINE REFERENCES

Table 6. Baseline Characteristics of Hypothyroid Patients

1. Asvold BO, Bjøro T, Vatten LJ. Association of thyroid function with estimated glomerular filtration rate in a population-based study: the HUNT study. Eur J Endocrinol. 2011;164(1):101-5.

Total (n = 21) (mean ± SD) Age

44.1 ± 8.41

Men

13

Women

8

DM II

4

HTN

11

Obstructive uropathy

2

Others

2. Iglesias P, Díez JJ. Thyroid dysfunction and kidney disease. Eur J Endocrinol. 2009;160(4):503-15.

3. den Hollander JG, Wulkan RW, Mantel MJ, Berghout A. Correlation between severity of thyroid dysfunction and renal function. Clin Endocrinol (Oxf). 2005;62(4):423-7.

4

SBP

136.57 ± 19.15

DBP

82.19 ± 9.44

4. Caraccio N, Ferrannini E, Monzani F. Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study.

J Clin Endocrinol Metab. 2002;87(4):1533-8.

Thyroid function test FT3

2.33 ± 0.49

FT4

0.89 ± 0.32

S. TSH

9.32 ± 3.52

S. creatinine

3.56 ± 1.39

eGFR

5. Monzani F, Di Bello V, Caraccio N, Bertini A, Giorgi D, Giusti C, et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J Clin Endocrinol Metab.

2001;86(3):1110-5.

6. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291(2):228-38.

22.39 ± 11.63

S. albumin

3.34 ± 0.42

change in serum FT3 and T4 levels. Slower decline in eGFR was seen in 63.7% patients in this study.

A similar study by Shin et al7 conducted previous to the above mentioned study also demonstrated that thyroid hormone replacement preserved renal function, but in that study, the changes in eGFR were just compared between two different study populations, SCH patients with and without THRT. al14

A study by Hataya et showed that eGFR increased rapidly over first 6 months after THRT in CKD patients, followed by a plateau. The improvement in eGFR was up to 30% overall.

CONCLUSION The present study concluded that thyroid impairment in the form of hypothyroidism is common in CKD patients with SCH being more common and the prevalence of hypothyroidism increases with decline in eGFR levels. Since, thyroid dysfunction can cause significant changes in renal and cardiovascular functions, there is an increasing need to detect hypothyroidism earlier in CKD patients and to initiate early treatment to prevent morbidity and mortality associated. This study emphasized the role of THRT in patients of CKD with subclinical and overt hypothyroidism, as this alleviates the rate of decline in eGFR in these patients and may delay reaching end-stage renal disease in these patients.

7. Shin DH, Lee MJ, Kim SJ, Oh HJ, Kim HR, Han JH, et al.

Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 2012;97(8):2732-40.

8. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-266.

9. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489-99.

10. Lo JC, Chertow GM, Go AS, Hsu CY. Increased prevalence of subclinical and clinical hypothyroidism in persons with chronic kidney disease. Kidney Int. 2005;67(3):1047-52.

11. Chonchol M, Lippi G, Salvagno G, Zoppini G, Muggeo M, Targher G. Prevalence of subclinical hypothyroidism in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2008;3(5):1296-300.

12. Allawi et al. Prevalence of hypothyroidism in CKD among sample of Iraqi patients. J Fac Med Baghdad 55(2):97-101.

13. Shin DH, Lee MJ, Lee HS, Oh HJ, Ko KI, Kim CH, et al. Thyroid hormone replacement therapy attenuates the decline of renal function in chronic kidney disease patients with subclinical hypothyroidism. Thyroid. 2013;23(6):654-61.

14. Hataya Y, Igarashi S, Yamashita T, Komatsu Y. Thyroid hormone replacement therapy for primary hypothyroidism leads to significant improvement of renal function in chronic kidney disease patients. Clin Exp Nephrol. 2013;17(4):525-31.

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INTERNAL MEDICINE

Volkmann’s Ischemic Contracture: A Late Complication of Snakebite LUBNA ZAFAR*, SHAHNA ALI†, ANJUM PARVEZ‡

ABSTRACT India is estimated to have the highest snakebite mortality in the world. The World Health Organization (WHO) estimates place the number of bites to be 83,000 per annum with 11,000 deaths. It is mainly an occupational problem of farmers, fishermen and plantation workers, mainly in the third world countries. This case report highlights a case of chronic physical handicap that resulted due to ignorance, illiteracy and lack of proper awareness of proper management of snakebite in the rural population.

This problem needs to be emphasized because of a substantial incidence of morbidity and mortality due to inadequate or improper treatment of snakebite.

Keywords: Snakebite, Volkmann’s ischemic contracture

S

nakebite is a public health problem of concern, especially in the rural India, occurring mostly in summers and rainy season. The World Health Organization (WHO) estimates place the number of bites to be 83,000 per annum with 11,000 deaths.1 Out of nearly 300 species of snakes found in India, the four major ones responsible for mortality and morbidity are cobra (Naja naja), Russell’s viper (Daboia russelii), saw-scaled viper (Echis carinatus) and common krait (Bungarus caeruleus).2 It may be termed as an occupational hazard of farmers, plantation workers and fishermen. Males are more often affected than females and because of the complications of snakebite, it has significant implications on the nutrition and economy of the country3 as well as the family. Most of the fatalities are not only due to the delay in reaching the hospital, but also harmful first aid practices such as tourniquets, cutting and suctioning. Studies reveal that primary care doctors do not treat snakebite patients mainly due to lack of confidence.4 Snakebite is an important cause

*Assistant Professor, Dept. of Medicine †Assistant Professor, Dept. of Anesthesiology ‡Associate Professor, Dept. of Medicine Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh Address for correspondence Dr Anjum Parvez Associate Professor Dept. of Medicine Jawaharlal Nehru Medical College, Aligarh Muslim University Aligarh - 202 002, Uttar Pradesh E-mail: anjumparvez66@yahoo.com

of chronic physical handicap/disability, which may be the result of either the snakebite itself or as a result of inappropriate and often harmful first aid remedies that are in practice due to illiteracy and ignorance. This case report describes development of chronic physical handicap in a young male i.e., contracture of hand that resulted due to application of a tight tourniquet after snakebite.

CASE REPORT A 24-year-old male presented to Jawaharlal Nehru Medical College Hospital for release of the contractures of right hand. The patient had a history of being bitten by a snake on the hand about 8 years back, while sleeping on the floor at night. Following the bite, he started experiencing pain in his right upper limb. He then went to a local/traditional practitioner who gave him some oral medicines and applied a tight rope above the wrist. This is a common practice in treatment of snakebite and tight tourniquets are applied to area proximal to bite with aim to prevent further spread of snake venom. Few hours later, he developed abdominal pain and bilateral ptosis. He was then shifted to a tertiary care center where the tourniquet was removed and he received polyvalent anti-snake venom (ASV), analgesics and tetanus toxoid. The patient recovered, however, about 12 hours post snakebite his right hand became swollen with signs of ischemia, necrosis and gangrene for which an urgent fasciotomy was performed. The patient later presented to this hospital with contractures and loss of fingers of the right hand (Fig. 1).

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

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INTERNAL MEDICINE On examination, there was no pain, edema or skin changes and the neurological examination was normal.

But there was definite functional limitation of the right hand and wrist, due to contractures present in flexion of index finger with loss of little finger. X-ray right hand with wrist (anteroposterior and lateral view) revealed multiple deformed metacarpals and phalanges of 2nd and 5th digits with distal metacarpal and phalangeal fusion (Fig. 2).

Overlying soft tissues also appeared irregular and prominent. Thumb and soft tissues were not involved.

A diagnosis of Volkmannâ&#x20AC;&#x2122;s ischemic contracture was made and the release of these contractures was planned.

Figure 2. X-ray right hand and wrist anteroposterior and lateral view showing multiple deformed metacarpals and phalanges.

DISCUSSION

a

b

Figure 1 a and b. Contractures and loss of fingers of the right hand.

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

Snakebite is an alarming problem leading to loss of life and disability in rural India. Delay in accessing appropriate care and ASV treatment, compounded with the use of ineffective, time wasting and often potentially harmful remedies can lead to disability.

There are two aspects of snakebite management protocol, which consists of initial first aid measures and then timely and specific medical management.5 Most of the first aid methods used in rural India, because of ignorance and illiteracy have proved to be ineffective and potentially dangerous. These methods include various bizarre and unscientific methods ranging from making local incisions, sucking out venom, freezing the site and applying tight bands around the affected limbs. The most commonly used first aid method is the tourniquet. Various research have shown that the technique carries the risk of ischemic damage and increases the necrotic action of venom, the dangers of neurotoxic blockage and clotting when the tourniquet is released and also the ineffectiveness of the method in retarding spread of venom. A newer technique, which has a popular following, is the pressure immobilization method (PIM). This advocates tying elasticated or crepe bandage around the affected limb including an integral splint, similar to that for a sprain. It was developed in Australia and was advocated as a reliable method to inhibit venom flow into the system, but later showed that differential pressure was required depending on whether lower or upper limb was involved and that if pressure applied was outside the range it could increase the venom flow and that the immobilization of victim should be immediate and complete. In view of these restrictions, both tourniquets and PIM are not

INTERNAL MEDICINE recommended. Some researchers have suggested that a “Pressure Pad” at the site of bite may be beneficial.6 In our patient, a tight rope was applied and there was a delay in the primary and effective management. The median delay to hospital following the bite was about 6 hours. By the time, the patient reached the hospital he developed compartment syndrome for which a fasciotomy was performed to save the limb, which yielded no positive result. Compartment syndrome is a serious potential complication of trauma to the extremities. Increase in intracompartmental tissue pressure results from increases in fluid pressure plus the contribution of cells, fibers, gels and matrices. The result is an increased venous pressure that lowers the aortic valve (AV) gradient resulting in decrease in blood flow and leading to ischemia and necrosis.

The long-term sequelae is development of Volkmann’s ischemic contracture as a result of muscle fibrosis and tendon shortening.7 Application of a tight tourniquet also aggravates the local effects of venom, which may further result in ischemia and necrosis.8 Immobilization of the bitten limb is an effective first aid management, which should have been done using a splint or sling to delay the spread of venom. There is a relative scarcity of literature on complications caused as a result of harmful remedies and the true incidence leading to disability is unknown. However, the magnitude of the problem i.e., disability, limb contracture and loss is likely to be much higher in areas where victims rarely attended hospitals as a result of ignorance or due to unavailability of facilities. Moreover, the physical and psychological impact of such disabilities occurring in affected patients is immense and has direct implications on the socioeconomic status of the family.

The point of emphasis is that general population, especially in rural areas should be informed about the proper first aid measures and the ‘dont’s ‘of snakebite management, and the complications that may arise due to delay in instituting appropriate care. This can be done through proper education about this occupational hazard and development of better and specialized referral and rehabilitation centers, particularly near villages.

Traditional and unscientific first aid methods and

remedies should be discouraged altogether. Emphasis should also be given on measurement of direct intracompartmental pressure in order to determine its impact on the reduction of amputations and disabilities.9 This case report thus underlines the dangers involved due to improper management of snakebite as a result of ignorance and lack of availability of proper specialist care in rural India scenario.

REFERENCES 1. Kasturiratne A, Wickremasinghe AR, de Silva N, Gunawardena NK, Pathmeswaran A, Premaratna R, et al.

The global burden of snakebite: a literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Med. 2008;5(11):e218.

2. Simpson ID, Norris RL. Snakes of medical importance in India: is the concept of the “Big 4” still relevant and useful? Wilderness Environ Med. 2007;18(1):2-9.

3. Williams D, Gutiérrez JM, Harrison R, Warrell DA, White J, Winkel KD, et al; Global Snake Bite Initiative Working Group; International Society on Toxinology. The Global Snake Bite Initiative: an antidote for snake bite.

Lancet. 2010;375(9708):89-91.

4. Simpson ID. A study of the current knowledge base in treating snake bite amongst doctors in the high-risk countries of India and Pakistan: does snake bite treatment training reflect local requirements? Trans R Soc Trop Med Hyg. 2008;102(11):1108-14.

5. WHO/SEARO Guidelines for the clinical management of snake bites in the Southeast Asian region. Southeast Asian J Trop Med Public Health. 1999;30 Suppl 1:1-85.

6. Tun-Pe, Aye-Aye-Myint, Khin-Ei-Han, Thi-Ha, TinNu-Swe. Local compression pads as a first-aid measure for victims of bites by Russell’s viper (Daboia russelii siamensis) in Myanmar. Trans R Soc Trop Med Hyg. 1995;89(3):293-5.

7. Mars M, Hadley GP. Raised intracompartmental pressure and compartment syndromes. Injury. 1998;29(6):403-11.

8. Abubakar SB, Habib AG, Mathew J. Amputation and disability following snakebite in Nigeria. Trop Doct.

2010;40(2):114-6.

9. Whitesides TE, Haney TC, Morimoto K, Harada H. Tissue pressure measurements as a determinant for the need of fasciotomy. Clin Orthop Relat Res. 1975;(113):43-51.

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

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OBSTETRICS AND GYNECOLOGY

Retrospective Study of Inpatients Admitted Following Medical Abortion VEENA VIDYASAGAR

ABSTRACT Objective: To conduct retrospective study of patients admitted as cases of retained products of conception (RPOC) following self-medication for inducing abortion. Study design: A retrospective study was undertaken of patients admitted as cases of RPOC following self-administration of drugs for inducing abortion. The time period of the study was 1st January 2012 to 31st August 2014. The details of patients were noted down from their documents. Details of OPD patients who underwent homebased medical abortion were noted from medical termination of pregnancy register of OPD. Statistical analysis of the data was done. Results: There were 243 patients who were admitted as cases of RPOC with past history of self-intake of abortifacients and there were 233 OPD cases during the study period. The mean parity of inpatients was 2.48 and outpatients was 1.66. The mean gestation at which abortifacient was taken was 7.68 weeks in inpatients and 5.61weeks in outpatients. Two hundred thirty-three women of inpatients reported with complaint of bleeding per vaginum. Conclusion: A retrospective study was undertaken of patients admitted as cases of RPOC following self-medication for induction of abortion. The study period covered 32 months. There were 243 inpatients who took self-medication and 233 outpatients who had medical abortion as per WHO recommendation. Higher parity was noted in self-medication group. Women took self-medication at higher period of gestation as compared to those who took advice from Gyne OPD.

Keywords: Retained products of conception, medical abortion, self-medication

M

edical termination of pregnancy (MTP) has undergone a number of changes in the past 20 years. One of them has been liberal use of medical abortion. Medical abortion is one of the safest medical procedures available for terminating pregnancy in the early stages. In the main, the changes can be attributed to the use of ultrasound, which has enabled an accurate diagnosis of the gestation of the pregnancy and the introduction of several management options. Medical abortion consists of using drugs to terminate a pregnancy. It is an important alternative to surgical methods.

The World Health Organization (WHO)1 recommendations on medical abortion are restricted to early first trimester (up to 63 days since the first day of the last menstrual period [LMP]). Antiprogesterone drugs such as mifepristone (RU486), prostaglandins like

Dept. of Obstetrics and Gynecology School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh Address for correspondence

Dr Veena Vidyasagar F-208, Sector, Beta-2, Greater Noida, Uttar Pradesh E-mail: vinav2002@yahoo.co.in

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

misoprostol have been approved by the United States Food and Drug Administration (US FDA) for medical abortion.2 As per MTP Act of India, this method can only be administered by Gynecologists and Registered Medical Practitioners recognized for performing MTPs up to 63 days, since the first day of LMP. Federation of Obstetrics and Gynecological Societies of India (FOGSI) recommends close monitoring of distribution of these drugs and that the medical profession and pharmaceutical industry should exercise due diligence in the promotion and usage of drugs that are used for medical abortion. Despite this, it has been perceived by the society that, medical abortions are extremely safe option even in hands of untrained personnel, leading to itâ&#x20AC;&#x2122;s over the counter dispensing and possibly increase in unsupervised determinations and life-threatening complications.3 Although many different drugs have been used, alone and in combination, to induce abortion, a regimen composed of mifepristone plus misoprostol has been the one most widely used. The WHO recommends this drug combination, with an initial dose of mifepristone followed by misoprostol 36-48 hours later, for early medical abortion.

OBSTETRICS AND GYNECOLOGY Retained products of conception (RPOC) are a known complication of medical abortion. The reported incidence of RPOC varies widely and depends on several factors, including initial treatment (higher with nonsurgical vs. surgical management), criteria for diagnosis (signs/symptoms vs. laboratory/pathology/ imaging results) and duration of follow-up.4 The present study was undertaken to study cases admitted as those with retained products of conception following self-medication for induced abortion.

MATERIAL AND METHODS A retrospective study was undertaken of cases admitted as cases of patients RPOC following self-medication for inducing abortion, at Sharda Hospital, Greater Noida. The time period of the study was 1st January 2012 to 31st August 2014. The inclusion criteria of cases for the purpose of study were history of intake of drugs for induction of abortion by self-medication, evidence suggestive of RPOC on clinical examination and/or by ultrasound and cases that underwent uterine evacuation. Case documents of patients who satisfied the inclusion criteria were studied and the available details noted down.

The details noted included patient’s particulars, dates of admission/evacuation/discharge, duration of gestation at the time of intake of drugs for induction of abortion, time elapsed between intake of drugs and admission, complaints before admission and their duration, laboratory investigation reports, ultrasound findings, any specific treatment given, blood transfusion administered and any complications encountered.

Reports of histopathological examination of specimen of evacuation were noted from records maintained

by Histopathological Section of Central Laboratory of Sharda Hospital, Greater Noida. Details of patients who underwent medical abortion on OPD basis and whose details were maintained in the MTP register of Gyne OPD at Sharda Hospital, Greater Noida during the study period were also noted down. The data were subjected to statistical analysis.

RESULTS There were 243 inpatients, during the study period, which were admitted as cases of RPOC and fulfilled the inclusion criteria. Details of drugs taken for induction of abortion were not available from the case documents. The number of cases, who had taken advice for medical abortion from the Gyne OPD, during the study period, was 233. Drugs used for medical abortion

were mifepristone and misoprostol and they were administered as per WHO recommendation, mentioned above.

The mean age of inpatients in the study was 27.71 ± 4.57 years. The mean age of OPD cases during the same period was 27.94 ± 4.52 years. The mean parity of inpatients was 2.4 ± 1.21. There were 10 nullipara and three patients were unmarried. The highest parity was 7.

The mean parity of OPD cases reporting to Sharda Hospital during the study period was 1.66 ± 0.99.

There were 24 nullipara and eight were unmarried.

The highest parity of OPD cases was 6. Distribution of patients according to parity is shown in Table 1. The average gap between last delivery and last conception (which was terminated by medical abortion) was 3.57 ± 2.46 years. Mean gestation at which inpatients took medication for abortion was 7.68 ± 0.5 weeks. Details about gestation of OPD cases were mentioned till April 2014 in the MTP register. The mean gestation of OPD cases till April 2014 was 5.61 ± 0.86 weeks. Distribution of patients according to period of gestation is shown in Table 2.

As a routine, evacuation was done on the day or next day of admission. Similarly, patients were discharged either on the day of evacuation or the next day.

However, in some cases, this routine was not followed.

Evacuation was done 2 days after admission in 5 (2.06%) cases. Reasons included patient being stabilized for medical problem like diabetes, patient having signs of sepsis and decision of administration of parenteral antibiotics before evacuation and repeat administration of misoprostol in a case of a failed medical abortion where gestation was 16 weeks. There were 38 patients who were discharged more than 1 day after uterine evacuation. Main reason for delay in discharge was Table 1. Distribution of Patients According to Parity Parity

Indoor cases

OPD cases

0

10

24

1

44

79

2

85

94

3

70

30

4

23

4

5

6

1

6

3

1

7

2

0

243

233

Total

Mean ± SD 2.4 ± 1.21

Mean ± SD 1.66 ± 0.99

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OBSTETRICS AND GYNECOLOGY Table 2. Distribution of Patients According to Period of Gestation When Drugs for Abortion were Taken Period of gestation (weeks)

Indoor cases

OPD cases

<5

10

13

5-6

29

97

6-7

90

60

7-8

23

13

8-9

59

3

9-10

0

1

10-11

18

0

11-12

1

0

≥12

13

0

Total

243

187

Mean ± SD 7.68 ± 0.5 weeks

Mean ± SD 5.61 ± 0.86 weeks

because of blood transfusion and parenteral therapy administered in anemic cases. Other reasons were evidence of infection, diabetes, hypertension, urinary tract infection (UTI), etc.

Average number of days between intake of abortifacient and reporting for admission was 19.33 ± 16.26 days.

Two hundred thirty-three (95.88%) women in the study period reported with the main complaint of bleeding per vaginum (PV). Ten (4.12%) cases didn’t have bleeding PV at the time of admission. They had pain lower abdomen and found to have ultrasonographic (USG) features suggestive of retained products of conception. Twelve (4.94%) cases had mild-to-moderate fever. Average number of days of bleeding PV before admission was 14.03 ± 14.44. In 121 (51.93%) cases bleeding PV started the same day when the abortifacient was taken. In other cases, the average gap between the intake of abortifacient and onset of bleeding PV was 11.37 ± 15.38 days.

Other miscellaneous features of patients were history of previous cesarean section in 26 cases, ligation failure in 1 and past history of ectopic pregnancy in two cases.

Medical disorders encountered were hypertension in three patients, diabetes in 4 and hypothyroidism in 3.

Three patients had presented with UTI. Three (1.23%) patients had undergone dilatation and evacuation (D&E) following medical abortion at some other hospital, before reporting to Sharda Hospital. Three (1.23%) cases were brought in a state of shock. Routine investigations like complete blood count (CBC), Rh and ABO grouping, human immunodeficiency virus (HIV)

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

and hepatitis B surface antigen (HbsAg) were done in all cases. Average value of hemoglobin (Hb) of patients was 9.35 ± 2.21 gm%. There were 26 patients (10.7%) whose Hb was <6.5 gm%. Eleven (42.3%) of these cases received blood transfusions, five cases refused blood transfusion. Decision regarding blood transfusion was decided upon clinical estimation/laboratory report of Hb and amount of bleeding PV at the time of admission. Overall, 34 cases received parenteral iron therapy. Distribution of Hb of these 34 patients is shown in Table 3. Six cases (2.47%) had Rh-negative blood group, three cases (1.23%) were HbsAg-positive, one case was HIV I-positive, one was hepatitis C virus (HCV)-positive and one was Venereal Disease Research Laboratory (VDRL) reactive.

All patients received antibiotics. The antibiotic used was mostly single antibiotic of cephalosporin group.

Seventeen patients received more than one parenteral antibiotic. They had features of infection at the time of admission detected clinically and/or based on laboratory parameters. Ultrasound was performed in 172 cases. In other cases, USG was not done in view of clinical diagnosis of incomplete abortion and/or patient presented with excessive bleeding PV, which required immediate attention. Details of ultrasound features are shown in Table 4. One hundred fifty-two (88.37%) cases in which ultrasound was done, showed features Table 3. Distribution of Patients who Received Parenteral Iron Therapy and their Hemoglobin Levels Hemoglobin (gm%)

Number

<4

2

4-5

6

5-6

8

6-7

8

7-8

7

≥8

3

Total

34

Table 4. Distribution of Patients According to USG Reports USG report

Number

Intrauterine live gestation

9

Missed abortion

7

Irregular gestational sac

4

Features suggestive of RPOC

152

Total

172

OBSTETRICS AND GYNECOLOGY Table 5. Distribution of Cases According to Histopathology Reports Histopathology report Consistent with products of conception

Number 123

Infected products of conception

9

Chorionic villi with endometrial glands

1

Features suggestive of hydropic degeneration

1

Decidua

12

Infected decidua

13

Decidua with endometrial glands

8

Chronic endometritis

6

Secretory endometrium

7

Proliferative endometrium

1

Fragmented endometrial, endocervical and/or ectocervical glands

9

Total

190

suggestive of RPOC and 9 (5.23%) cases showed intrauterine live gestation.

As a protocol of the institution, all the products of evacuation are routinely subjected for histopathological examination. Fifty-three specimens were not tested.

Sharda Hospital, being private hospital, nominal charge is levied for histopathological examination.

These patients had not made payment for the same.

Of the remaining 190 specimens, 123 (64.74%) specimens showed features consistent with products of conception. The details of histopathological reports of specimens are shown in Table 5.

DISCUSSION Case of RPOC following abortion can present with symptoms of uterine bleeding, pelvic pain, fever and/or uterine tenderness. Evaluation for RPOCs is indicated in women whose symptoms fall outside the normal range, such as those with bleeding that is heavy or prolonged and those with fever, uterine tenderness or significant abdominopelvic pain. Combined clinical, laboratory and sonographic evaluation of these patients can help direct management.5 The goal of the evaluation is to determine whether RPOC are the probable source of the woman’s symptoms, or whether another diagnosis is more likely. If RPOC are thought to be causing the symptoms, treatment with surgical evacuation or medication is warranted. Since, RPOC and other post abortal complications can be life-threatening, prompt assessment for severe hemorrhage or sepsis is crucial.

The present retrospective study was undertaken with

the aim of determining the presenting pattern of cases of RPOC following self-induced medical abortion.

In our study, the mean ages were 27.71 ± 4.57 years in the indoor group and 27.94 ± 4.52 years in the outdoor group. In the study by Thaker et al,6 which were followup cases of self-medication of abortifacient, majority of cases (54.05%) were in the age group of 20-29 years.

In our study also, majority of inpatients (65.43%) were in the age group of 20-29 years. In a WHO 2011 bulletin review article on “Comparative effectiveness, safety and acceptability of medical abortion at home and in a clinic”7 age of participants ranged from 24.7 to 32.2 years. In our study, majority of cases were para 2 or above; 189 (52.42%) cases in the indoor group and 200 (85.84%) cases in the OPD group. This figure was 19 (51.35%) in the study by Thaker et al.6 The average gestation at which patients took abortifacient was 7.68 ± 0.5 weeks in the indoor group, in our study. In the study by Thaker et al, 51.3% women took abortion pill within 6 weeks of gestation. In our study, 11.93% inpatients took abortion pill within 6 weeks of gestation. Cases with intrauterine gestation of 9 weeks or less and in who medical abortion was indicated were offered home-based management at Sharda Hospital. These patients were advised to take 200 mg of mifepristone orally followed by 800 µg of misoprostol to be inserted vaginally after 48 hours.

Studies evaluating regimens consisting of mifepristone and misoprostol in various combinations suggest that home-based medical abortion is effective and safe.

This holds true, provided, the advice has been given

by Gynecologist or recognized Registered Medical Practitioner. In all studies, in WHO bulletin review article,7 oral mifepristone and misoprostol were used in combination to produce a medical abortion. In all studies, women were given mifepristone at the clinic but could choose between taking misoprostol at home and returning to take it at the clinic. Observational studies8 have shown that home-based medical abortion is well-accepted and effective, with 86-98% of women reporting satisfaction with the method and complete abortion achieved in 87-98% of cases. In our study, none of the OPD cases administered with mifepristone and misoprostol, reported back with any major complication. Seven cases (3%) reported for follow-up for abortion related complication and were managed on OPD basis.

In the study by Thaker et al,6 majority of women (24.3%) had taken abortion pill 6-10 days before coming to the hospital. In our study, majority of women (19.75%) had taken abortifacient 0-5 days before admission. This was

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

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OBSTETRICS AND GYNECOLOGY followed by those who had taken it 6-10 days before admission (17.28%). Majority (89.1%) of women had complaint of bleeding PV in the study by Thaker.6 In our study, 233 (95.88%) women presented with complaint of bleeding PV. Prospective studies of women with miscarriage report an average of 8-11 bleeding days after identification of the miscarriage; however, the bleeding often lasts 2 weeks or more.4,9 Following medical treatment of miscarriage, the average number of bleeding days was 9-12, but many women bled for more than 14 days in some studies.4,10 The duration of vaginal bleeding was significantly shorter after surgical evacuation of the uterus. These studies generally included an intervention if symptoms continued beyond 7-21 days; few allowed the bleeding to continue for more than 3-6 weeks. In our study, the average duration of bleeding PV after intake of abortifacient was 14.03 ± 14.44 days. About 56.7% cases had severe anemia and 13.5% cases had moderate anemia in the study by Thaker. In our study, 42 (17.28%) indoor cases had severe anemia and 51 (20.99%) cases had moderate anemia.

Histopathological examination was done in 190 (78.19%) cases, in our study. According to the study by Alsibiani,11 it may not appear reasonable to perform histopathological examinations routinely after all firsttrimester miscarriage. It was recommended that this examination be performed in select instances. Heath et al12 found 2 (0.13%) molar changes and two had tubal ectopic pregnancies in their study following first trimester evacuation. In our study, one case (0.53%) had features suggestive of hydropic degeneration.

CONCLUSION A retrospective study was undertaken of patients admitted as cases of ‘RPOC’ following self-medication for induction of abortion. The study period covered 32 months. There were 243 patients who fulfilled inclusion criteria. During similar period, as per the MTP register maintained in the Gyne OPD, there were 233 outpatients who had sought and were advised medical abortion as per WHO recommendation. Higher parity was noted in self-medication group. Women took selfmedication at higher period of gestation as compared to those who took advice from Gyne OPD. None of the OPD cases had to be admitted for abortion related complication. There were 6.58% inpatients that required blood transfusion. Most of the ultrasounds done of inpatients were suggestive of RPOC. Most of the evacuation specimen submitted for histopathological

examination showed features consistent with products of conception.

REFERENCES 1. International Consensus Conference on Non-surgical (Medical) Abortion in Early First Trimester on Issues Related to Regimens and Service Delivery. Frequently asked clinical questions about medical abortion. Geneva: World Health Organization; 2006. ISBN 92-4-159484-5.

2. Ellertson C, Waldman SN. The mifepristone-misoprostol regimen for early medical abortion. Curr Womens Health Rep. 2001;1(3):184-90.

3. Guin G, Gupta A, Khare S, Chandra M, Kalkur S. A study of septic abortions: trends in a tertiary hospital. J Obstet Gynecol India. 2005;55(3):257-60.

4. Trinder J, Brocklehurst P, Porter R, Read M, Vyas S, Smith L. Management of miscarriage: expectant, medical, or surgical? Results of randomised controlled trial (miscarriage treatment (MIST) trial). BMJ. 2006;332(7552):1235-40.

5. Wolman I, Altman E, Faith G, Har-Toov J, Amster R, Gull I, et al. Combined clinical and ultrasonographic workup for the diagnosis of retained products of conception.

Fertil Steril. 2009;92(3):1162-4.

6. Thaker RV, Deliwala KJ, Shah PT. Self-medication of abortion pill: Women’s health in jeopardy. NHL J Med Sci. 2014;3(1):26-31.

7. Ngo TD, Park MH, Shakur H, Free C. Comparative effectiveness, safety and acceptability of medical abortion at home and in a clinic: a systematic review. Bull World Health Organ. 2011;89(5):360-70.

8. Clark WH, Hassoun D, Gemzell-Danielsson K, Fiala C, Winikoff B. Home use of two doses of misoprostol after mifepristone for medical abortion: a pilot study in Sweden and France. Eur J Contracept Reprod Health Care. 2005;10(3):184-91.

9. Nielsen S, Hahlin M. Expectant management of firsttrimester spontaneous abortion. Lancet. 1995;345(8942): 84-6.

10. Davis AR, Hendlish SK, Westhoff C, Frederick MM, Zhang J, Gilles JM, et al; National Institute of Child Health and Human Development Management of Early Pregnancy Failure Trial. Bleeding patterns after misoprostol vs surgical treatment of early pregnancy failure: results from a randomized trial. Am J Obstet Gynecol. 2007;196(1):31. e1-7.

11. Alsibiani SA. Value of histopathologic examination of uterine products after first-trimester miscarriage. Biomed Res Int. 2014;2014:863482.

12. Heath V, Chadwick V, Cooke I, Manek S, MacKenzie IZ. Should tissue from pregnancy termination and uterine evacuation routinely be examined histologically? BJOG. 2000;107(6):727-30.

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

OBSTETRICS AND GYNECOLOGY

Colposcopic and Pap Smear Evaluation and Therapeutic Role of Cryotherapy in Cervical Erosion RACHANA AGARWAL*, AJAY HALDER†, URVASHI VERMA*, MOHITA AGARWAL*, SAROJ SINGH‡

ABSTRACT Objectives: Pre- and post-treatment colposcopic and Pap smear study of cervical erosion and to evaluate the efficacy of cryo-freeze in treatment of cervical erosion. Material and methods: A total of 100 patients were selected for the study with the following symptoms persistent abnormal vaginal discharge, backache, pain in abdomen, burning micturition, deep dyspareunia and contact bleeding. A detailed obstetrics and menstrual history including use of contraceptives was taken and thorough general, systemic, per speculum and pelvic examination was done excluding pregnancy and malignancy. All patients underwent pre- and post-cryotherapy paps and colposcopy examination and follow-up was done after 4, 6, 8 weeks. Results: Before cryosurgery majority of cervical smears were of inflammatory type with or without erosion (82%). On colposcopy, typical transformation zone was found in 44% and erosion was found in 34% cases. Among 14 cases of dysplasia, 11 cases showed benign changes while 3 had atypical changes on colposcopy. All these dysplastic cases underwent biopsy and were confirmed as benign. There was marked (81%) improvement in all symptoms after cryosurgery. Conclusion: It is concluded that cryosurgery is an effective, cheap and safe method for treatment of benign cervical lesions after excluding malignancy.

The main advantage of cryotherapy is that it is a simple procedure that requires inexpensive equipments and can be done as OPD procedure without anesthesia.

Keywords: Pap smear, colposcopy, cervical erosion, cryotherapy

C

ommon benign lesions of cervix i.e., cervical erosion, chronic cervicitis present as excessive vaginal discharge, post-coital bleeding, deep dyspareunia, dysmenorrhea backache, recurrent cystitis, etc. Cervical erosion is the inflammation of cervical cells, which occurs when the inner lining of the cervical canal (columnar epithelium) comes out onto the part of the cervix that appears as a red, velvet-like area. It is also called ectopy. Cervix is neither eroded nor ulcerated. It is essential to ensure that there is no premalignant change in the cervix before destroying the surface. This is not because a cervical erosion is premalignant, but it is important to be certain that

*Lecturer Dept. of Obstetrics and Gynecology SN Medical College, Agra, Uttar Pradesh †Assistant Professor Dept. of Obstetrics and Gynecology, AIIMS, Bhopal, Madhya Pradesh ‡Professor and Head Dept. of Obstetrics and Gynecology SN Medical College, Agra, Uttar Pradesh Address for correspondence Dr Rachana Agarwal 211-D, Nehru Nagar Apartment, Gandhi Nagr, Agra - 282 002, Uttar Pradesh E-mail: rachanaagrawal7@yahoo.co.in

there is no premalignancy that is being inadvertently and perhaps inadequately treated. Premaligancy is diagnosed by cytology, colposcopic or colposcopic directed biopsy if needed.

Cryosurgery works on basic principle of JouleThompson effect and is done by using compressed (CO2 N2O) refrigerant with the aim of creating an ice ball with a depth of freeze denoted by a peripheral margin of 4-5 mm of frost. Crystallization of cervical tissue, leading to tissue destruction (cryonecrosis), which sheds afterwards in heavy watery discharge.

Now-a-days, the double freeze technique which acts by applying coolant continuously for a 3-minute freeze, 5-minute thaw, followed by another 3-minute freeze is more in use than single freeze technique (continuous freezing for 5 minutes) for mild and focal moderate dysplasia of cervix.

The success of cryotherapy is determined by five factors: Patient anatomy i.e., location of lesion and vascular supply. Lesion size and severity of disease determine pathologic factors. Other factors include equipment technique and physician skill. For cryotherapy to be effective - entire squamo-columnar junction must be visualized and should not go into

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

763

OBSTETRICS AND GYNECOLOGY canal >5 mm. A minimal lateral spread of freeze of 7 mm as 2 mm recovery zone and 5 mm lethal zone is clinically necessary for satisfactory treatment of cervical intraepithelial neoplasia Grade 2 (CIN2).

AIMS AND OBJECTIVES Pre-treatment colposcopic and Pap smear study of cervical erosion. Colposcopic and Pap smear study of the cervix 4, 6 and 8 weeks after cryo-freeze.

To evaluate the efficacy of cryo-freeze in treatment of cervical erosion.

MATERIAL AND METHODS The prospective study was carried out in Dept. of Obstetrics and Gynecology of tertiary care SN Medical College, Agra. A total of 100 patients were selected after informed consent for this study with the following symptoms: Persistent abnormal vaginal discharge, backache, pain in abdomen, burning micturition, deep dyspareunia, contact bleeding and pruritus.

test, in 75% cases cervix turned dark-brown while in 25% cases, it turned pale yellow with 5% solution of iodine. Before cryotherapy, majority of cervical smears were of inflammatory type with or without erosion i.e., 82% and 11 patients with dysplasia Grade I and III with dysplasia Grade II (Table 2 and Fig. 2).

On colposcopy, typical transformation zone was found in 44% and erosion in 34% cases (Table 3). Among 14 cases of dysplasia, 11 showed benign changes, while three had atypical changes on colposcopy (Table 4 and Fig. 3). All these dysplastic cases underwent biopsy and were confirmed as benign. None of the workers who had done cryo mentioned colposcopic diagnosis Table 1. Patients Profile Patient particular

Observations

Age

20-50 years (90%)

Parity

2nd-5th (76%)

Socioeconomic status

Lower-upper lower

A detailed obstetrics and menstrual history of including that of contraceptives use was taken and thorough general, systemic, per speculum and pelvic examination was done excluding pregnancy and malignancy. All patients underwent pre- and post-cryotherapy paps and colposcopy examination and follow-up was done after 4, 6 and 8 weeks to know the effect of cryotherapy on cervical erosion.

Contraceptive use

Nonuser

Common presenting symptoms

Excess vaginal discharge, backache, lower pain abdomen, dyspareunia, contact bleeding

Cryotherapy was done in minor OT without anesthesia by using nitrous oxide gun type unit using a 18 mm flat tipped probe and single/double freeze technique depending on size of lesion. Cryoprobe was kept in place till ice ball spread 2-3 mm beyond lesion on normal cervix. This takes 2-3 minutes freezing time varies from 3 to 9 minutes depending on lesion size.

None of the patients were hospitalized or anesthetized before or during therapy. They were sent home after the procedure. No local medication, douching or packing was advised.

3%

DISCUSSION Regarding patients profile, most of the patients belonged to 20-50 years age, 2nd-5th para with lower-upper lower socioeconomic status, not using contraceptive and commonly presenting with vaginal discharge backache, contact bleeding, lower pain abdomen (Table 1). According to type of cervical lesion with naked eye, erosion of both lips was most common finding and next was cervicitis (Fig. 1). During Schillerâ&#x20AC;&#x2122;s

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

21% 1% 4%

35% 10% 26%

1 1 1 2

Erosion of both lips Small Large Endocervicitis

3 Nabothian follicles 4 Polyp 5 Cervicitis

Figure 1. Type of cervical lesions on the basis of naked eye appearance.

Table 2. Cytological Findings Before and After Cryosurgery Type of smear

Before cryosurgery

After cryosurgery

Normal

0

35

Inflammatory

82

60

Dysplasia Grade I

11

2

Dysplasia Grade II

3

0

Other organism

1

0

Unsatisfactory

3

3

OBSTETRICS AND GYNECOLOGY 160 Before cryosurgery

of the lesion treated. Ostergard (1967) assessed healing with colposcope and that the lesions were benign.

Symptomatic improvement in all symptoms like vaginal discharge, backache, pain abdomen and contact bleeding was statistically significant i.e., p â&#x2030;¤ 0.05. Both the polyps were benign on colposcopic examination (Table 5).

After cryosurgery

140 120 100 82

80

60

60 40

35 11

0

3 0

at or y Dy s G pl ra as de ia I Dy s G p ra la de sia II

m In fla m

No rm

al

0

2

There was marked (81%) improvement in all symptoms after cryosurgery. All over 84% of lesions treated were completely healed at 8 weeks. Repeat cryosurgery was done in only 10.90% cases, which healed within a further 8 weeks (Table 6 and Fig. 4). Most frequent complaint (92%) after cryosurgery was profuse watery discharge lasting up to 2 weeks. Next was spotting (12%)

3 3

1 0

or Oth ga e ni r sm Un sa tis fa ct or y

20

Figure 2. Cytological findings before and after cryosurgery.

Table 3. Colposcopic Finding Before and After Cryosurgery Colposcopic finding

Before cryosurgery

Normal Typical transformation zone Erosion Endocervicitis Increased vascularity Nabothian follicle Polyp Atypical transformation zone Abnormal blood vessels Partial healed transitional epithelium

4 weeks 16 8 16 12

44 34 5 2 6 2 5 2 -

After cryosurgery 6 weeks 17 5 11 7

8 weeks 27 10 3 12

Table 4. Correlation of Cytology with Colposcopy Cytology Acute and chronic inflammation (82) Mild dysplasia Grade I Moderate dysplasia Grade II Unsatisfactory Total

Colposcopy benign changes 80 9 2 3 94

Atypical 2 2 1 5

Table 5. Presenting Symptoms After First Cryosurgery Symptoms

No. of cases

Vaginal discharge

95

Follow-up

Cured

Improved

Persistent

No.

%

No.

%

No.

%

No.

%

88

84

28

30

55

58.3

11

11

Backache

78

66

85

31

40

22

28.75

24

31

Pain abdomen

57

40

71

30

53

16

28.57

10

18

Contact bleeding

17

16

05

15

90

-

-

2

10

Dyspareunia

29

26

91

22

75

-

-

7

25

Total

276

236

81.9

126

49.8

93

31.5

54

18.6

X = 11.326, p â&#x2030;¤ 0.05,df = 4.

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

765

OBSTETRICS AND GYNECOLOGY

Colposcopy benign changes 80

No. of cases during procedure

Atypical

No. of cases after procedure

80 100 90

60

80 40

70 60

20

50

9 2

2

0

3 0

2 1

Acute and Mild dysplasia Grade I chronic inflammation

Moderate dysplasia Grade II

40

Unsatifactory

30 20 10

Figure 3. Correlation of cytology with colposcopy.

ss kn e

g ot tin

W ea

Sp

Va so va g

al

at ta ck

rg e

ng di

sc ha

di ee

ht sli g

al in Va g

in pa

tio ica pl

fo rt to

co m

om

of Di

sc

No .

Bl

ns

0

11% 10%

Figure 5. Complications of the procedure.

30%

60%

probably due to shedding of eschar (Fig. 5). Table 7 shows the comparative study by different authors, which shows our study is comparable to others.

CONCLUSION

Single

Double

Three

Repeat cryo

Figure 4. Distribution of cases according to number of application of cryosurgery.

Table 6. Distribution of Cases According to Number of Application of Cryosurgery Diagram No. of application

No. of cases

Percentage (%)

Single

60

60

Double

30

30

Three

10

10

Repeat cryo

11

11

Total

111

111

It is concluded that cryosurgery is an effective, cheap and safe method for treatment of benign cervical lesions after excluding malignancy. No specific complications were noted after cryosurgery. The main advantage of cryotherapy is that it is a simple procedure that requires inexpensive equipment and can be done as OPD procedure without anesthesia.

Other treatment modalities available are chemical/ thermal/electric cauterization, conization, laser therapy (CO2, N2O). In the present scenario, when we are equipped with Nd:YAG laser, CO2 laser, cryosurgery still hold promise because of its simplicity and lower maintenance cost.

SUGGESTED READING

Table 7. Comparative Study by Different Authors Author (Year) Our study (2012)

Healing rates (%) 84.69

Jobson and Homesley (1984) Townsend and Richart (1985)

93

Engineer et al. (1986)

95

Mitchell et al. (1998)

95

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

1. Kumar N. Cryotherapy as a modality for treatment of cervical intraepithelial neoplasia. Int J Biomed Adv Res. 2012;3(11):858-60.

2. Frye CA, Weisberg RB. Increasing the incidence of routine pelvic examinations: behavioral medicineâ&#x20AC;&#x2122;s contribution.

Women Health. 1994;21(1):33-55.

3. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide

OBSTETRICS AND GYNECOLOGY [Internet]. Version 2.0. Lyon, France: IARC Press; 2004.

Available at: http://www-dep.iarc.fr/. Accessed Dec 21, 2007.

7. Engineer J, Bandi S, Maru L, Mukherjee A. Cryosurgery “a new modality in the treatment of benign diseases of the uterine cervix”. J Obstet Gynecol India. 1986;36(2):313-6.

4. Critchlow CW, Wölner-Hanssen P, Eschenbach DA, Kiviat NB, Koutsky LA, Stevens CE, et al. Determinants of cervical ectopia and of cervicitis: age, oral contraception, specific cervical infection, smoking, and douching. Am J Obstet Gynecol. 1995;173(2):534-43.

8. Papanicolaou GN. Atlas of Exfoliative Cytology. The Commonwealth Fund by Harvard University Press: Cambridge, Mass; 1954.

5. Hicks ML, Piver MS. How to obtain an accurate pap smear. Med Aspects Hum Sex 1991;25:36-43.

9. Wespi H. Early Carcinoma of the Uterine Cervix; Pathogenesis and Detection. New York: Grune and Stratton; 1949.

10. Castro W, Gage J, Gaffikin L, Ferreccio C, Sellors J, Sherris J, et al. Effectiveness, safety, and acceptability of 6. Jackson WD. Comparative trial of cryosurgery and cryotherapy: a systematic literature review. In: Cervical diathermy cauterization in the treatment of cervical erosion.

Cancer Prevention Issues in Depth #1. Seattle, WA: Alliance for Cervical Cancer Prevention (US);2003. p. 63.

J Obstet Gynaecol Br Commonw. 1972;79(8):756-60.

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ACOG Releases Updated Guidelines on Prenatal Obesity and Exercise Two new guidelines from the American College of Obstetrics and Gynecology (ACOG) emphasize the need for exercise during pregnancy and the postpartum period to prevent or correct maternal weight issues. Practice Bulletin Number 156, “Obesity in Pregnancy” and Committee Opinion Number 650, “Physical Activity and Exercise during Pregnancy and the Postpartum Period,” appear in the December issue of Obstetrics & Gynecology.

Together, the documents address the clinical management of overweight and obese women before and during pregnancy, and the need for women to exercise regularly to prevent or correct overweight or obesity.

Indian Women more Prone to Miscarriages A study conducted in five cities of India and published in The Journal of Obstetrics and Gynecology of India reported that Indian women seem more likely than other ethnicities to miscarry their first pregnancy or suffer recurrent miscarriages. In the study, 32% of the participants had suffered spontaneous miscarriage. Miscarriage or spontaneous abortion without medical means to terminate a pregnancy, has so far been presumed to be 10% across the globe. Recurrent spontaneous abortions were as high as 7.46% compared to the figure of 0.8-1.4% of all pregnancies globally… (ET Healthworld)

Prenatal Test Identifies Cancer in Pregnant Women Noninvasive prenatal testing (NIPT), which identifies abnormalities in the fetus, can also identify cancer in pregnant women before they experience any symptoms. A review of three case reports was published online in JAMA Oncology. NIPT analyzes cell-free DNA present in maternal plasma. In pregnant women, the plasma contains fetal DNA, which is analyzed for abnormalities in the fetus, but in women who also have cancer, the plasma also contains cancer DNA, explained lead author Joris Robert Vermeesch, PhD, of the Center for Human Genetics, in Leuven, Belgium. The findings could potentially change clinical practice… (Medscape)

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

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ONCOLOGY

Short (Single Dose) versus Long-course Radiotherapy for Palliation of Painful Bone Metastases MEENA J SHAH

ABSTRACT Purpose: To answer the question whether a single fraction of radiotherapy (that is considered more convenient to the patient) is as effective as a dose of multiple fractions for palliation of painful bone metastases. Material and methods: A retrospective study of palliative radiation therapy was conducted for patients with breast, lung or prostate cancer who had painful bone metastases and moderate-to-severe pain between 2010 and 2013. We investigated whether 8 Gy delivered in a single treatment fraction provides pain relief that is equivalent to that of the standard treatment course of 30 Gy delivered in 10 treatment fractions over 2 weeks. There were 45 patients in 8-Gy arm (arm-1) and 50 patients in 30-Gy arm (arm-2). Pre-treatment characteristics were equally balanced between arms. With maximum follow-up of 12 months, response to treatment was evaluated particularly pain relief. Results: A total of 95 patients were evaluable for response. The two groups did not differ with respect to age, sex, primary tumor, metastasis localization, performance status, prior systemic treatment, degree of pain and quality-of-life. All the patients tolerated the treatment well with acute toxicity of Grade I and II only. The most common acute toxicity, particularly gastrointestinal (Grade I and II) was more frequent in arm-2 (15 patients, 30%) than arm-1 (7 patients, 15.5%). Late toxicity was not observed in either arm. The overall response rate was similar in patients receiving single fractions (32 patients; 71%) and multiple fractions (35 patients; 70%). Complete response rates were 9 of 45 (20%) in the single fraction arm and 11 of 50 (22%) in the multiple fraction arm. No significant difference was seen in overall or complete response rates. Pathological fracture was not observed in either arm. Re-treatment rate was significantly higher in the 8 Gy arm (8 patients, 17.7%) than in the 30 Gy arm (3 patients, 6%). Conclusion: Single fraction radiotherapy is a successful and time efficient method to palliate pain of bone metastases and should be the preferred standard dose-fractionation for patients with uncomplicated painful bone metastases. It is an attractive treatment in reducing the number of visits to radiotherapy departments for patients with painful bone metastases. The saving of radiotherapy capacity is considered the major economic advantage of the single dose schedule.

Keywords: Bone metastasis, radiotherapy, pain relief

E

xternal beam radiotherapy, the mainstay for the treatment of pain caused by bone metastases is quite effective in providing relief from painful bone metastases in 50-80% of patients with up to one-third of patients achieving complete pain relief at the treated site.1 A wide-spread variation exists in worldwide practice patterns for palliative radiation dose fractionation schedules.2 Various fractionation schedules can provide significant palliation of symptoms and/or prevent the morbidity of bone metastases.

A shorter course of treatment has the advantages that it

Associate Professor Government Medical College and New Civil Hospital, Surat, Gujarat Address for correspondence

Dr Meena J Shah B-404, Arjun Complex, Opp. Ratnadeep Society Behind Police Tenament, Bhatar-Althan Road, Surat - 395 017, Gujarat E-mail: drmeena.maheshwari@gmail.com

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is logistically much easier for patients and their families to arrange for one session rather than 10 daily sessions and that it has less impact on the timing of other treatments (e.g., systemic therapy). These advantages are most applicable if the shorter course of treatment is as effective as the longer course of treatment. The longer course of treatment would be preferred if there were an advantage in pain relief, decreased risk of pain recurrence or a decrease in the risk of pathologic fracture (i.e., a fracture caused by the tumor).

The Radiation Therapy Oncology Group (RTOG) has previously studied various treatment fractionation regimens for palliation of bone metastases and found that shorter treatments were as effective as longer treatments in achieving pain relief.3 The primary objective of the study was to determine whether 8 Gy of radiation therapy delivered in a single treatment fraction provides pain relief that is equivalent to 30 Gy of radiation therapy delivered in 10 treatment

ONCOLOGY fractions for patients with painful bone metastases. The study was limited to patients whose primary cancers were breast, lung and prostate cancers to evaluate a more relatively homogeneous group of patients with sufficient life expectancy to adequately evaluate length of response and the risk of pathologic fracture.

of 30 Gy (arm-2). The treatment volume included the radiographic abnormality with a margin of at least 2 cm in long bone lesions. Treatments to the spinal bones was prescribed to the mid-vertebral body, with inclusion of at least one vertebral body above and below the painful vertebral body level or levels.

MATERIAL AND METHODS

Other sites was prescribed as an applied dose for single incident fields and a mid-plane dose for opposed fields. Response to treatment was assessed by followup questionnaires at 2 and 4 weeks and at 2, 3, 6, 9, 12 months. The primary outcomes of interest were complete and overall pain relief. Complete response meant complete pain relief, and partial response meant more than 50% and less than complete pain relief. Time to maximal pain relief was defined as the time from the first day of irradiation until the lowest pain score for worst pain after radiation therapy.

Among the patients treated with palliative radiotherapy for symptomatic bone metastasis between 2010 and 2013, only 95 patients were eligible for study and were retrospectively analyzed. Pre-treatment characteristics were well-balanced between the two arms (Table 1).

There were 45 patients in 8 Gy arm and 50 patients in 30 Gy arm. Bone metastases were located in the spine in 32 (33.7%), pelvis in 33 (34.6%), femur in 10 (10.5%), ribs in 8 (8.4%), humerus in 4 (4.2%) and other sites in 8 patients (8.4%). Eligibility requirements were: ÂÂ

Age of 18 years or older

RESULTS

ÂÂ

Histologically proven primary malignancy of breast, lung or prostate

ÂÂ

Radiographic evidence of bone metastasis

ÂÂ

Moderate-to-severe pain corresponding to the area of bone metastasis

ÂÂ

Karnofsky performance status of at least 40

ÂÂ

An estimated life expectancy of at least 3 months.

Treatment was well-tolerated by patients in both arms with more acute toxicities (Grades I-II) in arm-2. None of the patients in either arm developed Grade III and 4 acute toxicity. The most common acute toxicity, gastrointestinal toxicity was observed in 7 patients (15.5%) in arm-1 and 15 patients (30%) in arm-2. There were no late toxicities in any arm. Complete response was observed in 20% (9 patients) and partial response rate in 51% (23 patients) in arm-1. In arm-2, complete response was observed in 22% (11 patients) and partial response in 48% (24 patients). Overall, 71% patients in arm-1 and 70% in arm-2 experienced a response at 3 months. Overall response to treatment at 3 months is shown in Table 2.

Eligible treatment sites were classified as weightbearing sites (i.e., pelvis, femur, tibia, sacrum and/or sacroiliac joints) or nonweight-bearing sites. Patients receiving bisphosphonates or systemic therapy (hormonal therapy, chemotherapy, immunotherapy) were eligible as long as there had been no introduction of any systemic therapy within the 30 days before entry into the study. Reasons for ineligibility were:

The degree of pain relief did not differ between the two treatment arms and two treatment schedules were equivalent in terms of palliation. With regard

ÂÂ

Prior radiation therapy or palliative surgery to painful area

ÂÂ

Pathologic fracture or impending fracture of the treatment site

Table 1. Pre-treatment Characteristics

ÂÂ

Planned surgical fixation of the bone or clinical or radiographic evidence of spinal cord or cauda equina compression.

No. of patients

The two groups did not differ with respect to age, sex, primary tumor, metastasis localization, performance status, prior systemic treatment, degree of pain and quality-of-life. Patients were treated with external beam irradiation using Telecobalt unit with one of two treatment schedules: 8 Gy of radiation therapy delivered in one fraction (arm-1) or 3 Gy of radiation therapy delivered in 10 fractions over 2 weeks to a total

8 Gy arm-1

30 Gy arm-2

45

50

35-77

33-75

Male

22

24

Female

23

26

Breast

24 (53.3%)

28 (56%)

Lung

12 (26.6%)

11 (22%)

Prostate

9 (20%)

11 (22%)

Age range (years) Sex

Primary site

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ONCOLOGY Table 2. Overall Response to Treatment at 3 Months Response

No. of patients (%), arm-1

No. of patients (%), arm-2

Complete

9 (20)

11 (22)

Partial

23 (51)

24 (48)

Stable

11 (24.4)

12 (24)

2 (4.4)

3 (6)

Progressive

to pain medication, quality-of-life and side effects no differences between the two treatment groups were found.

A correlation was also found between the incidence of pain relief and the site of bone metastases, in that a lower response was shown in limb localizations.

Also, the number of metastatic sites did not influence the complete response rate. Eight patients (17.7%) in the 8Â Gy Ă&#x2014; 1 arm and 3 patients (6%) in the 30 Gy in 10 fractions arm required re-irradiation. The level of pain was an important reason to retreat and time to re-treatment was substantially shorter. There were no pathologic fractures in either arm.

DISCUSSION During the past decade, significant clinical trial efforts have been devoted to comparing single largedose radiation (8-10 Gy) with multifraction regimens (5-10 fractions).4-10 Randomized trials have found that a shorter course of radiation therapy (1-5 treatments) may give substantial pain relief, perhaps the equivalent of that observed with more standard longer treatment courses (10-15 treatments).3,9-14 The RTOG 74-02 trial compared 1,500 cGy in five treatment fractions to 3,000 cGy in 10 treatment fractions for multiple bone metastases and 2,000 cGy in five treatment fractions to 4,050 cGy in 15 treatment fractions for patients with a solitary metastasis.

Overall, 89% eventually experienced at least minimal relief of pain, with 53% obtaining complete relief and another 30% experiencing partial relief. There was no statistically significant difference in pain relief rates among the differing treatment schedules.

Ratanatharathorn et al15 reviewed many studies and concluded that higher dose, longer course regimens provided better pain outcomes than low-dose regimens.

In contrast, Wu et al16 and Sze et al17 found that both regimens resulted in equivalent levels of pain relief but in different rates of re-treatment and pathologic fractures between arms. A subset analysis from RTOG 97-14 showed no difference in pain in spine sites compared to

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extremity sites and no difference in response between cervical spine, thoracic spine or lumbar spine sites.18 Acute radiation reactions are generally greater and are more prolonged during multi-fraction radiation (smaller radiation dose per fraction over many weeks) versus a single large fraction of radiation over a single treatment day.18 Even if there is a real increase in the need for re-treatment among patients receiving a single-dose treatment, this problem may be counterbalanced by the reduced rate of acute toxicity in these patients. Numerous prospective, randomized trials have failed to show any significant difference in long-term toxicity between a single 8 Gy fraction and more prolonged therapy courses for uncomplicated, painful bone metastases.

The most recently completed trials that compare singleto multi-fraction radiotherapy schedules suggest either a statistically insignificant or clinically insignificant difference in the rates of late fractures of the treated bones, with incidences ranging from 2% to 11%.6,7,18-23 Single fractionation is associated with a 20% incidence of re-treatment versus 8% with fractionated therapy.6,18-23 It is unclear whether the higher rate of re-treatment following single fraction radiotherapy results in part from the radiation oncologistâ&#x20AC;&#x2122;s belief that the combined total dose will not exceed the normal tissue tolerance of the adjacent organs included in the treatment volume when compared to the risks of re-treatment following a multi-fractionated course to a higher total dose.

Sites of recurrent pain in spine bones can be successfully palliated with external beam radiation therapy re-treatment, though the available data do not allow for conclusive statements regarding dosing and fractionation. Wide-spread variation exists in worldwide practice patterns for palliative radiation dose fractionation schedules. Still, a few radiation oncologists employ a single fraction of palliative radiation for bone metastases in peripheral bones and in the spine cases where patients fit the eligibility criteria.

In our study, external beam radiation therapy was effective at palliating pain from bone metastases, with complete or partial improvement in pain observed in 71% of patients in arm-1 and 70% of patients in arm-2.

Treatment was well-tolerated with a few acute adverse effects and no late adverse effects. No difference was found between two arms in terms of pain relief. Reirradiation rate was higher in single fraction arm. Care must be taken when the re-irradiated volume contains the spinal cord, and it may be appropriate to sum the biologically effective doses from the initial and

ONCOLOGY re-treatment regimens to estimate the risk of radiation myelopathy. Thus single dose irradiation schedule should be recommended for palliation of patients with uncomplicated painful bone metastases.

CONCLUSIONS Despite abundant evidence, most radiation oncologists continue to prescribe multi-fraction schedules. For patients where the treatment objective is pain relief, a single 8 Gy treatment, prescribed to the appropriate target volume, should be the standard dose schedule for all patients with symptomatic and uncomplicated bone metastases, including patients with an expected favorable survival. Single-dose or short-course irradiation is an attractive treatment in reducing the number of visits to radiotherapy departments for patients with painful bone metastases. It optimizes patient and caregiver convenience. The saving of radiotherapy capacity is considered the major economic advantage of the single dose schedule.

REFERENCES 1. Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastases: a systematic review. J Clin Oncol. 2007;25(11):1423-36.

2. Fairchild A, Barnes E, Ghosh S, Ben-Josef E, Roos D, Hartsell W, et al. International patterns of practice in palliative radiotherapy for painful bone metastases: evidence-based practice? Int J Radiat Oncol Biol Phys.

2009;75(5):1501-10.

3. Tong D, Gillick L, Hendrickson FR. The palliation of symptomatic osseous metastases: final results of the Study by the Radiation Therapy Oncology Group. Cancer.

1982;50(5):893-9.

4. Roos DE, Oâ&#x20AC;&#x2122;Brien PC, Smith JG, Spry NA, Hoskin PJ, Burmeister BH, et al. A role for radiotherapy in neuropathic bone pain: preliminary response rates from a prospective trial (Trans-Tasman Radiation Oncology Group, TROG 96.05). Int J Radiat Oncol Biol Phys. 2000;46(4): 975-81.

5. Kirkbride P, Warde PR, Panzarella T, Aslanidis J, McKenzie M, Sun A. A randomised trial comparing the efficacy of single fraction radiation therapy plus ondansetron with fractionated radiation therapy in the palliation of skeletal metastases. Int J Radiat Oncol Biol Phys. 2000;48(3):185.

6. Bone Pain Trial Working Party. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up.

Radiother Oncol. 1999;52(2):111-21.

7. Steenland E, Leer JW, van Houwelingen H, Post WJ, van den Hout WB, Kievit J, et al. The effect of a single fraction compared to multiple fractions on painful bone

metastases: a global analysis of the Dutch Bone Metastasis Study. Radiother Oncol. 1999;52(2):101-9.

8. Koswig S, Budach V. Remineralization and pain relief in bone metastases after different radiotherapy fractions (10 times 3 Gy vs. 1 time 8 Gy). A prospective study.

Strahlenther Onkol. 1999;175(10):500-8.

9. Nielsen OS, Bentzen SM, Sandberg E, Gadeberg CC, Timothy AR. Randomized trial of single dose versus fractionated palliative radiotherapy of bone metastases.

Radiother Oncol. 1998;47(3):233-40.

10. Gaze MN, Kelly CG, Kerr GR, Cull A, Cowie VJ, Gregor A, et al. Pain relief and quality of life following radiotherapy for bone metastases: a randomised trial of two fractionation schedules. Radiother Oncol. 1997;45(2):109-16.

11. Cole DJ. A randomized trial of a single treatment versus conventional fractionation in the palliative radiotherapy of painful bone metastases. Clin Oncol (R Coll Radiol).

1989;1(2):59-62.

12. Niewald M, Tkocz HJ, Abel U, Scheib T, Walter K, Nieder C, et al. Rapid course radiation therapy vs. more standard treatment: a randomized trial for bone metastases. Int J Radiat Oncol Biol Phys. 1996;36(5):1085-9.

13. Okawa T, Kita M, Goto M, Nishijima H, Miyaji N. Randomized prospective clinical study of small, large and twice-a-day fraction radiotherapy for painful bone metastases. Radiother Oncol. 1988;13(2):99-104.

14. Rasmusson B, Vejborg I, Jensen AB, Andersson M, Banning AM, Hoffmann T, et al. Irradiation of bone metastases in breast cancer patients: a randomized study with 1 year follow-up. Radiother Oncol. 1995;34(3):179-84.

15. Ratanatharathorn V, Powers WE, Moss WT, Perez CA. Bone metastasis: review and critical analysis of random allocation trials of local field treatment. Int J Radiat Oncol Biol Phys. 1999;44(1):1-18.

16. Wu JS, Wong R, Johnston M, Bezjak A, Whelan T; Cancer Care Ontario Practice Guidelines Initiative Supportive Care Group. Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys. 2003;55(3): 594-605 17. Sze WM, Shelley MD, Held I, Wilt TJ, Mason MD. Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of randomised trials. Clin Oncol (R Coll Radiol).

2003;15(6):345-52.

18. Hartsell WF, Scott CB, Bruner DW, Scarantino CW, Ivker RA, Roach M 3rd, et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97(11):798-804.

19. Jeremic B, Shibamoto Y,Acimovic L, Milicic B, Milisavljevic S, Nikolic N, et al. A randomized trial of three single-dose radiation therapy regimens in the treatment of metastatic bone pain. Int J Radiat Oncol Biol Phys. 1998;42(1):161-7.

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SURGERY

Rapunzel Syndrome in a 6-year-old Child: A Case Report SHIVANAND REDDY KV*, RAMESH H†

ABSTRACT Rapunzel syndrome is a rare presentation of trichobezoar with extension of hair into small bowel. Trichobezoar is a tuft of undigested hair mass commonly found in young females with psychiatric disorders. Rapunzel syndrome occurs when gastric trichobezoar extends beyond the pylorus into the small bowel. Twenty-eight cases have been reported in English literature till 2012. The diagnosis of trichobezoar may be difficult due to nonspecific presentation. We present a case in a 6-year-old child who came with history of pain abdomen and features of intermittent gastric outlet obstruction. She was successfully managed by laparotomy, which revealed trichobezoar with a tail measuring 48 cm in length extending till the proximal ileum. Child also had transient jejuno-jejunal intussusception.

Keywords: Rapunzel syndrome, trichobezoar, bezoar

B

ezoars are collection of undigested materials that accumulate to form a mass in the gastrointestinal tract most commonly found in stomach. Various types of bezoars like trichobezoar, phytobezoar, lactobezoar, pharmacobezoar have been reported depending on their compositions. Trichobezoar is a tuft of undigested hair mass commonly found in young females with psychiatric disorders.1 Rapunzel syndrome is a rare condition and occurs when gastric trichobezoar extends beyond the pylorus into the small bowel. Twenty-eight cases have been reported in English literature till 2012.2

revealed a palpable mass in the epigastrium. There was no definite history of trichophagia on questioning and child had no alopecia. Earlier ultrasonography done elsewhere was reported as intussusception.

Computed tomography (CT) abdomen (Fig. 1) showed a hypoechoic mass lesion in the body of stomach measuring about 8 × 7 cm. Barium meal (Fig. 2) revealed a filling defect in the lumen of stomach extending

CASE PRESENTATION A 6-year-old female child presented with pain abdomen since 1 month for which she approached a family physician and was treated as a case of worm infestation.

However, the pain in the epigastric region progressively increased since past 15 days, which was more after having food. Mother noticed fullness in the epigastric region after taking food since past 10 days, which was followed by pain abdomen and vomiting. Fullness and pain used to subside after vomiting. Examination

*Postgraduate †Senior Resident Dept. of General Surgery JSS Medical College and Hospital, Mysore, Karnataka

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

Figure 1. Computed tomography abdomen showing a

hypoechoic mass lesion in the body of stomach.

SURGERY into the deuodenum with linear streaks of barium within the filling defect suggestive of a trichobezoar.

Endoscopy (Fig. 3) was done to confirm the diagnosis, which showed a trichobezoar with its tail extending into the pylorus. With these findings and repeated questioning child’s mother admitted that she had a habit of plucking and eating hair with frontal hair loss when she was 2 years old. Endoscopic extraction using a snare was attempted but failed.

A laparotomy was performed which showed a transmural ulcer adherent to the anterior abdominal

Figure 4. A 12 × 5 cm gastric trichobezoar of the shape of the stomach with a 48 cm tail.

wall. Gastrotomy was done and a gastric trichobezoar of 12 × 5 cm, which had taken the shape of the stomach was extracted along with 48 cm tail in continuity (Fig. 4).

A small segment of tail which was left in the jejunum was removed by enterotomy. Postoperative course was uneventful. Child was started orally on postoperative Day 3 and discharged on postoperative Day 7 after psychiatric counseling.

DISCUSSION Figure 2. Barium meal revealed a filling defect in the lumen of stomach extending into the deuodenum.

Figure 3. Endoscopy showing a trichobezoar with its tail

extending into the pylorus.

Trichobezoar is a tuft of hair mass in the digestive tract, which is a complication of trichotillomania (plucking of hair) and trichophagia (eating hair). Although about 1 of 2,000 children suffer from trichotillomania, trichophagia is rarely seen and a bezoar does not occur in all children with trichophagia.3 Stomach is the most common site for a trichobezoar as it is not able to exteriorize hair and other substances out of its lumen because the surface friction is not sufficient for propulsion by peristalsis. Rarely, these bezoars can extend beyond duodenum up to ileocecal junction, a condition termed as Rapunzel syndrome.1 It can present with the symptoms of pain abdomen, vomiting, perforation, mass per abdomen, intestinal obstruction, intussusception, pancreatitis and ulceration.1 In our case, the child presented with the symptoms after a period of 4 years from the time of ingestion of hair. The tail of the gastric trichobezoar was about 48 cm in length extending till the terminal jejunum with transient intussusception. Imaging modalities like

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773

SURGERY CT and barium meal help in establishing diagnosis.

Magnetic resonance imaging (MRI) is less useful compared to a CT as the signal density is low in MRI and is confused with air.4 Endoscopy can be used as a mode of diagnosing and also as a method of management. Endoscopic removal of trichobezoar have been tried in 40 patients and only two were successful according to the literature.5 In case of Rapunzel syndrome, endoscopic removal should not be tried as it is not possible to remove the entire length of the tail, which can lead to left over segments in small bowel. Surgery is the preferred treatment in most of the cases where a gastrotomy and the enterotomy can be performed for the complete removal of the trichobezoar along with the tail.

In our case a gastrotomy was done and the gastric trichobezoar was removed in continuity with its tail of about 48 cm and a small leftover segment was removed by a separate enterotomy. The complications of Rapunzel syndrome ranges from attacks of incomplete pyloric obstruction to complete obstruction of the bowel, ulceration, perforation, pancreatitis, peritonitis and mortality.6 DeBakey and Oschner reported a surgical mortality of 10.4%.7 It is mandatory to perform a thorough exploration of all the small intestine and stomach searching for retained bezoars. Underlying psychological causes have to be treated as a part of management to prevent recurrences.1 Few cases of recurrences have been reported even after successful surgery.

CONCLUSION Trichobezoar should be considered as a differential diagnosis in a female patient presenting with nonspecific abdominal complaints. Endoscopy as a preoperative management should be done to visualize extension of trichobezoar into the small bowel. In case of Rapunzel syndrome extraction of the mass by endoscopy can be incomplete because of fragmentation, so laparotomy is considered as the preferred choice of treatment modality for complete extraction of the trichobezoar along with its tail.

REFERENCES 1. Chana RS, Viral A, Kumar R. Gastrointestinal bezoars in children with special reference to recurrent trichobezoar.

J Indian Assoc Paediatr Surg. 2004;9:25-9.

2. Naik S, Gupta V, Naik S, Rangole A, Chaudhary AK, Jain P, et al. Rapunzel syndrome reviewed and redefined.

Dig Surg. 2007;24(3):157-61.

3. Pul N, Pul M. The Rapunzel syndrome (trichobezoar) causing gastric perforation in a child: a case report. Eur J Pediatr. 1996;155(1):18-9.

4. O’Sullivan MJ, McGreal G, Walsh JG, Redmond HP. Trichobezoar. J R Soc Med. 2001;94(2):68-70.

5. Gorter RR, Kneepkens CM, Mattens EC, Aronson DC, Heij HA. Management of trichobezoar: case report and literature review. Pediatr Surg Int. 2010;26(5):457-63.

6. Al Wadan AH, Al Kaff H, Al Senabani J, Al Saadi AS. ‘Rapunzel syndrome’ trichobezoar in a 7-year-old girl: a case report. Cases J. 2008;1(1):205.

7. DeBakey M, Oschner A. Bezoars and concretions. Surgery.

1938;4(6):934-63.

■■■■

...Cont’d on page 771

20. Roos DE, Turner SL, O’Brien PC, Smith JG, Spry NA, Burmeister BH, et al; Trans-Tasman Radiation Oncology Group, TROG 96.05. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol.

2005;75(1):54-63.

21. Kaasa S, Brenne E, Lund JA, Fayers P, Falkmer U, Holmberg M, et al. Prospective randomised multicenter trial on single fraction radiotherapy (8 Gy x 1) versus multiple fractions (3 Gy x 10) in the treatment of painful bone metastases. Radiother Oncol. 2006;79(3):278-84.

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22. Foro Arnalot P, Fontanals AV, Galcerán JC, Lynd F, Latiesas XS, de Dios NR, et al. Randomized clinical trial with two palliative radiotherapy regimens in painful bone metastases: 30 Gy in 10 fractions compared with 8 Gy in single fraction. Radiother Oncol. 2008;89(2): 150-5.

23. Sande TA, Ruenes R, Lund JA, Bruland OS, Hornslien K, Bremnes R, et al. Long-term follow-up of cancer patients receiving radiotherapy for bone metastases: results from a randomised multicentre trial. Radiother Oncol.

2009;91(2):261-6.

IMAGING AND INVESTIGATIONS

Understanding the Basics of a Coronary Angiogram KAMAL KUMAR*, SHIVANJALI KUMAR†, OMER MUSTAFA HASAN‡, RANJANA KUMAR†, MRIGANKA MEHRA

M

odern cardiology is based on performing and interpreting a coronary angiogram.

To do this, we need to understand the surgical anatomy of the coronary arteries followed by an idea of the radiological views and planes and how these vessels appear in them on injecting a dye.

ANATOMY OF THE CORONARY TREE1 The coronary circulation (Fig. 1) is provided by two coronary arteries originating from the root of the aorta just superior to the aortic semilunar valves.

The Left Coronary Artery Arises from the left posterior aortic sinus. It distributes blood to the left side of the heart, the left atrium and ventricle and the interventricular septum. It runs for about 10-25 mm as the left main (LM) and bifurcates into: ÂÂ

ÂÂ

The circumflex artery that follows the coronary sulcus running first to the left and then to the right till it reaches the posterior longitudinal sulcus. It supplies the posterolateral left ventricle, the anterior papillary muscle and in almost 38% of people the sinoatrial node. About 15-25% of the left ventricle in right-dominant and 40-50% in left-dominant circulations gets its supply from the circumflex artery. The circumflex gives off one or more branches, known as the left marginal arteries or obtuse marginal (OM) branches and continues as the posterior left ventricular branch or posterolateral artery.

The left anterior descending (LAD) artery or the anterior interventricular artery, also called the ‘widow maker’ follows the anterior interventricular sulcus around the pulmonary trunk reaching the apex in about 78% of cases.

It supplies almost 45-55% of the left ventricle. The LAD gives off two types of branches:

*Senior Consultant †Consultant ‡Director and Chief †Consultant Allahabad Heart Centre, Allahabad, Uttar Pradesh

zz

Septals that perforate the myocardium at 90 degrees and supply the anterior two-third of the interventricular septum.

zz

Diagonals that run along the surface of the heart and supply the lateral wall of the left ventricle and the anterolateral papillary muscle.

The Right Coronary Artery Arises from the anterior aortic sinus and proceeds along the right atrioventricular groove towards the crux of the heart. The right coronary artery (RCA) gives off the conus artery and then branches into the posterior interventricular artery or posterior descending artery (PDA) and the right marginal artery. It supplies blood to the right atrium, the right ventricle, 25-30% of the left ventricle and in about 60% of subjects to the sinoatrial node. The PDA supplies the inferior wall, ventricular septum and posteromedial papillary muscle.

ANASTOMOSES There is an extensive network of anastomoses between the coronary arteries. Most commonly this occurs at three levels: ÂÂ

Small branches of the LAD join branches of the PDA in the interventricular groove.

ÂÂ

More superiorly, branches of the circumflex artery anastomose with branches of the RCA in the atrioventricular groove.

ÂÂ

Septal branches of the two coronary arteries anastomose in the interventricular septum.

The coronary arteries are functionally end arteries and these anastomoses are ‘anatomical anastomoses’ unlike the ‘functional or physiological anastomoses’ seen in the palm. Sudden blockade of one branch would therefore still cause ischemia or infarction unless the blockade is slow and gives the anastomoses time to proliferate.

CORONARY ARTERY DOMINANCE Coronary artery dominance is decided on the basis of the artery that supplies blood to the PDA that in turn

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775

IMAGING AND INVESTIGATIONS

Arch of aorta

Superior vena cava Pulmonary trunk Left coronary artery (main stem) Sinoatrial nodal artery

Left atrial auricle Left atrial rami

Right coronary artery Outlines of: Anterior aortic sinus Right posterior aortic sinus Left posterior aortic sinus Right conus artery

Left conus artery Circumflex artery Left (obtuse) marginal artery Diagonal artery

Right anterior ventricular arteries

Anterior interventricular (descending) artery

Atrioventricular nodal artery

Interventricular anterior septal branches

Posterior interventricular (descending) arteries Right (acute) marginal artery

Figure 1. Coronary arteries.

supplies the atrioventricular node. This is recognized by identifying whether the septal perforating branches are arising from the RCA or the circumflex artery. We have: ÂÂ

Right-dominant: The RCA supplies the PDA

ÂÂ

Left-dominant: The circumflex artery supplies blood to the RCA

ÂÂ

Co-dominant: Both the RCA and the circumflex supply the PDA.

Approximately 80% of the population is right-dominant, 10% left-dominant and 10% co-dominant.2 COMMON ANOMALIES OF THE CORONARY ARTERIES3,4 ÂÂ

The circumflex may arise from the RCA.

ÂÂ

Both, the right and the left, coronary arteries may arise from a common trunk.

ÂÂ

There may be a small third posterior coronary artery.

ÂÂ

Left main coronary artery (LMCA) may originate from right sinus of Valsalva.

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

ÂÂ

RCA may originate from left sinus of Valsalva.

ÂÂ

RCA may originate above the sinus of Valsalva or from anterior aortic wall.

ÂÂ

LAD may originate from right sinus of Valsalva.

ÂÂ

LAD and circumflex may originate from separate ostia.

ANGIOGRAPHIC VIEWS AND PROJECTIONS5,6 In all Cath Lab machines the X-ray source is beneath the table with the image intensifier directly above the patient. The surface of the patient’s body that faces the image intensifier determines the specific view. To obtain specific views, the image intensifier is moved to face the patient’s body, the right shoulder, the left shoulder or side. For all descriptive purposes, left refers to the patients left side and right to the patient’s right. Cranial and caudal views are obtained by moving the C-arm cranially or caudally. Commonly, the views studied are the anteroposterior (AP) cranial and caudal, left lateral, right anterior oblique (RAO) cranial and caudal, and the left anterior oblique (LAO) cranial and caudal (Fig. 2).

We can know the tomographic view from which an

IMAGING AND INVESTIGATIONS image has been taken by looking at the position of the spine, the catheter and the diaphragm. In the LAO views the catheter and spine are seen on the left side of the image, in the RAO views they are on the right and in the AP views they are in the center. The diaphragm is seen in cranial views and is absent in the caudal projections (Fig. 3).2 Certain guiding rules are followed. The segment or lesion should be delineated in at least two octagonal

40°

60°

R60°

AO

L40° AO

20°

30°

CR30° A

views. Caudal views are better for proximal segments, cranial views for middle and distal segments. The circumflex moves with the image intensifier. In LAO views, the circumflex is to the left and LAD to right while in RAO the circumflex is to the right and LAD to the left. In caudal views, the LAD and circumflex move away from each other.

We use different views or a combination of views for each particular component of the coronary tree. Some commonly used combinations are: ÂÂ

Left main: AP, LAO-cranial, LAO-caudal

ÂÂ

Proximal LAD: RAO-cranial, RAO-caudal

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Mid-LAD: LAO-cranial, RAO-cranial, lateral

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Distal LAD: AP-cranial, RAO-cranial, lateral

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Diagonals: LAO-cranial, RAO-cranial

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Proximal circumflex: LAO-cranial, LAO-caudal

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Intermediate: LAO, LAO-caudal

ÂÂ

Obtuse marginal: RAO-cranial, LAO-caudal, RAOcaudal

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Proximal RCA: LAO-cranial, lateral

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Mid-RCA: LAO-cranial, lateral, RAO

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Distal RCA: LAO-cranial, lateral

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PDA: LAO-cranial, AP-cranial, RAO

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Posterolateral: LAO-cranial, AP-cranial

Let us now look at the left coronary artery as seen in the different views (Figs. 4-10). Now the right coronary artery in the various views (Figs. 11-14).

CA20° A

Figure 2. Views studied during a coronary angiogram.

L

R Clues to RAO and Caudal Angulation

Clues to PA and Cranial Angulation

Figure 4. LCA-AP caudal view.

Catheter and Spine in image center

Catheter and Spine to the right of image

No Diaphragmatic Shadow

Clues to LAO angulation

Diaphragmatic Shadow

Spine on the left of image

Figure 3. Position of spine, catheter and diaphragm in different views.

Figure 5. LCA-AP cranial view.

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IMAGING AND INVESTIGATIONS

Figure 6. LCA-LAO caudal view.

Figure 11. RCA-left lateral view.

Figure 7. LCA-LAO cranial view.

Figure 12. RCA-AP cranial view.

Figure 8. LCA-RAO caudal view.

Figure 13. RCA-LAO caudal view.

Figure 9. LCA-RAO cranial view.

Figure 14. RCA-LAO cranial view.

ASSESSMENT OF STENOSIS

Figure 10. LCA-left lateral view.

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To assess the degree of stenosis we identify the projection that shows the most severe narrowing. The area of narrowing is compared to an adjacent normal segment and the stenosis is estimated as a percent reduction either by visual assessment (common practice) or by Quantitative Coronary Analysis (QCA).6,7

IMAGING AND INVESTIGATIONS The distal angiographic contrast run-off is then assessed: ÂÂ

Normal contrast run-off: TIMI III

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Good distal run-off: TIMI II

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Poor distal run-off: TIMI I

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Absent distal run-off: TIMI 0

The collateral circulation is next assessed: ÂÂ

Grade 0: No collateral circulation

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Grade I: Very weak re-opacification

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Grade II: Re-opacified segment less dense than the feeding vessel with slow filling

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Grade III: Re-opacified segment as dense as the feeding vessel with rapid filling.

REFERENCES

arterial dominance decreases with increasing age of patients at autopsy. A postmortem coronary angiograms study. Cardiovasc Pathol. 2013;22(1):49-53.

3. Roberts WC. Major anomalies of coronary arterial origin seen in adulthood. Am Heart J. 1986;111(5):941-63.

4. Perloff JK. Congenital anomalies of the coronary circulation. In: Perloff JK (Eds.). The Clinical Recognition of Congenital Heart Disease. 4th Edition, Philadelphia: WB Saunders; 1994. p. 738.

5. Kern M. (2011) Angiographic Projections Made Simple: An Easy Guide to Understanding Oblique Views - Cath Lab Digest. 19(8), pp. undefined [Online]. Available at: http://www.cathlabdigest.com/issue/6888 (Accessed 25th December 15).

6. Mann D, Zipes D, Libby P, Bonow R. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th Edition, USA: Saunders; 2015.

1. Standring S. Gray’s Anatomy - The Anatomical Basis of Clinical Practice. Expert Consult-Online and Print, 40th Edition, UK: Churchill Livingstone; 2009.

7. Jiangping S, Zhe Z, Wei W, Yunhu S, Jie H, Hongyue W, et al. Assessment of coronary artery stenosis by coronary angiography: a head-to-head comparison with pathological coronary artery anatomy. Circ Cardiovasc 2. Knaapen M, Koch AH, Koch C, Koch KT, Li X, van Rooij PC, et al. Prevalence of left and balanced coronary Interv. 2013;6(3):262-8.

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PICTORIAL CME

Cutaneous Larva Migrans BHAVANA VENKATA NAGABHUSHANA RAO*, CH VNGR RAMANUJAM†

A

34-year-old male patient came to our clinic with an itchy brownish eruption over the dorsum of the right foot of a week’s duration. It originated as a small itchy papule and gradually spread like thread over the dorsum of the foot reaching a length of 25 cm (Fig. 1). He was a dog lover; he owns plenty of pet dogs at home. He participates in Dog shows, he got a “the best dog award” for his German shepherd this year. He had no systemic symptoms; pulse, temperatures and blood pressure were normal. He was given albendazole 400 mg orally for 3 days along with antihistamine fexofenadine for 3 days. Itching subsided in 3 days and eruption in 10 days time. He was advised to deworm his pet dogs regularly.

Cutaneous larva migrans is a dermatological lesion that occurs when humans accidentally get infected by dog or cat hookworms Ancylostoma braziliense and Ancylostoma caninum. It may also be caused by larvae of other non-human parasites. Creeping eruption is a sign that refers to the erythematous migrating cutaneous thread like serpiginous track that is produced by migration of larvae in the skin. Hookworms that are responsible for these kind of lesions are distributed worldwide, but infections are more common in tropical and subtropical countries. Those who are at risk include travelers, children, swimmers, pet lovers and laborers whose activity bring their skin in contact with contaminated soil. Eggs that are passed out from a dog or cat hatch out rhabditiform larvae in 1 or 2 days.

In 5-6 days, they become a filariform larvae. When they come in contact with a definite host i.e., dog they penetrate the skin, enter circulation, reach the lungs and ascend to pharynx. They are then swallowed and reach the intestines. Humans may get infected by this filariform larva, they cannot complete their life cycle in

*Dept. of Medicine †Dept. of Surgery Queen’s NRI Hospital, Visakhapatnam, Andhra Pradesh Address for correspondence

Dr Bhavana Venkata Nagabhushana Rao Dept. of Medicine Queen’s NRI Hospital, Visakhapatnam - 530 013, Andhra Pradesh E-mail: bhavanavnrao@gmail.com

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Figure 1. Cutaneous 25 cm long lesion on the dorsum of the foot.

humans. They creep within the epidermis and produce an inflammatory track along the migration. Rarely pulmonary eosinophilic syndrome can happen either by direct invasion or due to systemic immunological reaction. Cutaneous larva migrans occurs frequently in the lower extremities. It starts as pruritic papule and spreads as an elevated serpiginous track at the rate of several millimeters a day. It is usually 3 mm broad and 15-20 mm in length and the larva is located 2 cm ahead of the lesion. If exposed to highly contaminated soils multiple eruptions may appear at the same time.

Strongyloidiasis can also produce similar eruptions, but they progress fast at a rate of 1 cm in 5 minutes, hence is called larva currens (running larva).

Antihelmenthic therapy is useful for early resolution of symptoms and prevents secondary infections.

Symptoms disappear 1 week after therapy, pruritus earlier than dermatitis. Ivermectin 200 µg/kg as a single dose or albendazole 400 mg once a day for 3 days, usually suffice, but a weeks therapy with albendazole may be warranted in multiple eruptions. Addition of antihistamines will reduce the intensity of itching.

Topical thiabendazole or albendazole has also been reported to halt progress of disease and reduce the itching.

2016

EXPERTS’ VIEW

Is There any Role of Other Systems of Medicines in Managing High Blood Pressure?

KK AGGARWAL

T

he Vedic concept of health is based on ancient Eastern philosophy, which deals with health not merely on physical grounds but also has mental, social, spiritual and environmental aspects. Vedic medicine integrates western technology with eastern philosophy.

Health is not merely absence of disease but a state of physical, mental, social, spiritual and environmental well-being. Western science deals with more of physical health. Mental health is mainly dealt by psychiatrists.

Spiritual health finds no place in western science.

Eastern sciences (Ayurveda, Yoga and Vedic medicine) adopt a holistic approach; they cover all aspects of health but lack technologies and advancements. While making a choice between the western and eastern systems of medicine, the appropriate answer would be a combination of the two. According to the Vedic concept, mind and body are spiritually one.

Every disease for practical purposes can be traced to an emotional imbalance. Emotions like fear and anxiety are associated with high blood pressure (BP); anger and jealousy with heart attack and paralysis and greed and possessiveness with obesity, diabetes and heart failures (HFs). “You are what your deep rooted desires are.” This is the classical teaching of the ancient Upanishads. A proper selection of the choices consists of the interpretation of these thoughts. By changing the interpretations, one can alter the reality including the outcome of a disease. Instead of worrying about the past or being anxious about the future, one should learn to live in the present.

The body is not a fixed structure but a thinking organism. Each and every cell of the three trillion cells in the body is a thinking cell. They are concentrated in the heart, stomach, kidney, colon and bronchial tubes.

According to Vedic medicine, mind is not confined to the brain but is present in each and every cell of the body.

Senior Physician and Cardiologist, Moolchand Medcity, New Delhi Group Editor-in-Chief, IJCP Group, eMedinewS and eMediNexus

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Many of these cells are even more reliable thinkers than the brain. For example, people often say they have a gut feeling. In such situations gut makes the same chemicals, which the brain makes when it thinks. Every thought is metabolized into a neuropeptide, which acts on the receptor and has an action similar to any drug.

There are 180 of such neuropeptides known; out of these, 60 have already been isolated and defined. Each and every experience creates neuropeptides required by the body at that particular time. The thought of tranquility produces a neuropeptide that has an action similar to that of diazepam. Unlike the external pharmacy, the inner pharmacy produces the drug in the right dosage so that the question of side effects does not arise. Human body is the largest pharmaceutical industry in the world and has the capacity to produce each and every drug, provided the right thoughts initiate production of the right neuropeptides. The very fact that the body has a receptor for each and every drug means that it also has the capacity to produce similar neuropeptides.

The human mind is a field of information and knowledge, which is not confined to the brain but present everywhere at the same time. A disease occurs when we do not live according to our inner intelligence known as the Dharma. The responsibility for the illnesses and cures resides within us. Living with the law of nature and understanding these laws can help to prevent most of the diseases. According to Deepak Chopra, our inherited expectation that the body must wear out all the time, coupled with deep belief and thinking that we are fated to suffer, grow old and die, creates the biological phenomenon called aging; but, the fact is that 90% atoms of the body are exchanged with the new ones in a year’s time.

Today, the western approach is geared for advances in the treatment of acute illnesses, which of course are life-saving but when it comes to chronic illnesses, they do not have much to offer. The western model has been framed on the concept of understanding the mechanism of disease while the eastern model is based on the philosophy of understanding the origin of the disease.

EXPERTS’ VIEW The mechanism of the disease deals with identifying the organisms or an outside influence. Understanding the origin of disease deals with eating, breathing, digestion, metabolism, eliminating thoughts, feelings, emotions, desires, memories, sleep and relational aspects of a human being. By concentrating on the genesis of a disease, one can influence up to 90% of the outcome of a chronic disease. In the western model, there is a scientist who observes the phenomenon.

These scientists project this phenomenon in an objective manner and then classify them and finally draw out the specific laws, which operate. On the other hand, the eastern model of medicine originated with the help of present experiences and finally discrimination of these experiences came about. Ayurveda, is a science but with a difference. The word Ayurveda is the combination of two Sanskrit words meaning ‘life’ and ‘knowledge’. The 6,000-year-old holistic system of healing and prolonging life considers all aspects of patient’s existence from life and environment through mind and consciousness.

While dealing with addiction, the western model, for example, will ask the patient to quit smoking. On the other hand, the eastern approach deals with the origin of addiction at the level of the mind itself and motivates the circumstances by which the patient would himself give up his addiction. We are not human beings who have occasional spiritual experiences. We are spiritual beings with occasional human experiences. This is the gist of the eastern model.

Coronary artery disease (CAD), paralysis, high BP, diabetes, insomnia, cancer, acid peptic disease, infertility, dysmenorrhea, etc. are lifestyle disorders.

To a large extent these can be controlled and prevented by changing the lifestyle, the body-mind way. Lifestyle diseases are nothing but manifestations of the mind.

By improving the power of interpretation and analysis and by cultivating good thoughts one can change the present situation and alter the outcomes of a disease.

By combining the eastern philosophy with the western technologies and advancements, one can prevent diseases, control the ongoing biological process, regress the damage done, curtail the dose of various medicines and even avoid using these medicines in future. The inward journey from the disturbed state of consciousness to the undisturbed state of consciousness is what is called meditation. When this is attained with the help of primordial sounds, it is called primordial sound meditation. The primordial sound is a Bija sound calculated keeping in mind the time, place and date of birth of a particular individual.

Meditation is not acquiring Samadhi or a thoughtless state of mind but is the process of attaining that state of mind as described earlier. The silent spaces in between the thoughts consist of the space for a pure potentiality with infinite possibilities. Inserting intents in that state of mind is what the sutra or advance meditation indicates. It has been scientifically proven that people who meditate have lower BP, lower risk of acquiring lifestyle disorders and can regress existing diseases.

According to eastern philosophy, the human body can be defined as made up of three components. The physical body consisting of food and pranic layer, the subtle layer consisting of mind, intellect and ego and the causal body consisting of soul, consciousness or the spirit.

The soul can be equated to the undisturbed state of consciousness and subtle layer to the disturbed state.

It is like an ocean where superficial layers represent the subtle body and the calm and still bottom, the consciousness. Yoga is nothing but the union of physical body with the causal body, which can only be achieved by controlling the subtle body. The mind-body concept basically works when the subtle body is under control.

Intellect and ego are responsible for wavering thoughts in the mind. The mind is the receiving faculty, which receives impressions gathered by the senses from the outside world. Intellect is the discriminating faculty and ego classifies these impressions and facts and shows them as individual knowledge for future use and comparison.

The software of actions, memories and desires basically governs the subtle body. Any action leads to memory and these memories when egocentric create desires.

Desires, if fulfilled lead to action; if not fulfilled, they lead to anger. Anger leads to loss of intellect, which in turn leads to bodily destruction. The vicious cycle of action, memories and desires can keep the mind in a turbulent state and not allow an individual to be in touch with his own consciousness. Various yogic techniques including Pranayama are the process of controlling the thoughts in the mind so as to achieve this silent state and once the silent state is achieved one can with the use of this acquire anything in the life.

The first basic principle of yogic meditation involves acquiring efficiency in any action performed and being consciously aware of the present. The conscious awareness leads one away from the miseries of the past and anxieties of the future. To give an example, while eating breakfast one should concentrate on the meal and not think about something else. Practicing conscious awareness of each and every action is the first step in

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EXPERTS’ VIEW acquiring spiritual health. Breathing awareness, eating awareness, thinking awareness, etc. all are practical ways of doing the same thing. The second step in Yoga is to balance oneself in loss and gain and to maintain tranquility of mind at all times, places and situations.

Every opportunity good or bad should be taken as an opportunity to learn for the future betterment. Various mental exercises are taught to acquire this state of mind. Let go of the attachment, the results of an action is what the third step propagates for acquiring internal Yoga.

Repression and suppression of the thoughts are the fundamental cause of diseases. Fear, doubts and attachments are the three fundamental causes for the development of diseases. According to Bhagwad Gita, the five gateways to hell or acquiring a disease are attachment, anger, greed, desire and ego. Many scientists considered doubts, expectations and denials (DED) to be the root cause of a disease. Persistence of negativity in the mind is what is responsible for most of the disorders. According to Yogasutras of Patanjali, opposite thoughts should be cultivated to remove the negative thoughts of mind. The eastern philosophy basically teaches us the ways to acquire and cultivate these thoughts of love, compassion and happiness.

The scientific Vedic knowledge also lays special emphasis on various health aspects of religion and tries to get rid of the myths clouding various religions.

Primordial sound Hooooong in Buddhism, Aum in Hinduism and Amen and Amin in Christianity and Islam have a spiritual healing in common. Vowel sounds produce physical heating and the nasal sounds n, m, ong produce mental relaxation. Spiritual mantras are nothing but the combination of these, which produces spiritual healing.

The body-mind way of handling high BP is to use the Ayurvedic body type as the basis for governing the internal healing. The concept of Vata (movement), Pitta (metabolism) and Kapha (structure) help to decide about the proper lifestyle for any individual. Balancing the three doshas help in regression and control of the disease. The same is done by the use of proper diet, massage, elimination therapies, aromatherapy, etc. Vedic knowledge adds to the Yogic lifestyle and meditation.

The body-mind way of controlling the high BP involves the following: ÂÂ

Identifying the Ayurveda body type

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Balancing the doshas

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Removing the toxic residues from the body (ama) via Panchkarma

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Ayurvedic Vata-, Pitta- and Kapha-pacifying diet

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Regular pranayama

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Practicing the eight limbs of Yoga

ÂÂ

Understanding and practicing Bandhas and Chakra breathing exercises

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Subtle exercises to remove negativity from the mind and building a positive mental attitude

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Meditation involving the present moment awareness, using the Bija sounds and breathing

ÂÂ

Sutra heart meditation

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Adding the intentions to heal and imagery (the Sutra, Siddhi or the advanced meditation techniques) while meditating.

Some homeopathy drugs have allopathic like action: ÂÂ

Cretigus has action like angiotensin-converting enzyme (ACE) inhibitors

ÂÂ

Punarnava (Boerhavia diffusa), mandur guggul aristha are potent diuretics

ÂÂ

Cardiac glycosides equivalent is dig strophentus (safer digitalis)

ÂÂ

Antiangina drugs are Spigeria, glonine, amyl nitrate, cactus

ÂÂ

Convelleria is used in failure (no hypertrophy), Adonis (with hypertrophy), stropenthus (hypertrophy, anticoagulant, b-blocker like action)

Ayurvedic Drugs ÂÂ

B. diffusa (punarnava, ghetuli) as diuretic

ÂÂ

Rauvolfia serpentina (Sarpagandha) is a hypertensive

ÂÂ

Vata, Pitta and Kapha pacifying diets

Yoga and naturopathy practice allows a shift from sympathetic to para sympathetic mode.

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MEDILAW

Right to Healthcare in Constitution of India KK AGGARWAL

Is right to health a fundamental right in India?

Right to health is not included directly as a fundamental right in the Indian Constitution. However, the draft National Health Policy, 2015 released by health ministry in December 2014 and which was available for public comments till March 10, 2015 has suggested that health should be made a fundamental right similar to education and which if denied will be punishable.

The draft national health policy states: “12.2 One of the fundamental policy questions of our times is whether to pass a health rights bill making health a fundamental right- in the way that was done for education... The Center shall enact, after due discussion and on the request of three or more States (using the same legal clause as used for the Clinical Establishments Bill) a National Health Rights Act, which will ensure health as a fundamental right, whose denial will be justiciable.

States would voluntarily opt to adopt this by a resolution of their Legislative Assembly...”

What are the provisions on right to healthcare in the Constitution of India?

Health is a State subject in India. The State has a duty to create conditions that are favorable to good health as outlined in Articles 38, 39 (e) (f), 42, 47 and 48 A, in Chapter IV of the Constitution, the Directive Principles of State Policy.

Article 38. State to secure a social order for the promotion of welfare of the people.

(1) The State shall strive to promote the welfare of the people by securing and protecting as effectively as it may a social order in which justice, social, economic and political, shall inform all the institutions of the national life.

(2) The State shall, in particular, strive to minimise the inequalities in income, and endeavour to eliminate inequalities in status, facilities and opportunities, not only amongst individuals but also amongst groups

Senior Physician and Cardiologist, Moolchand Medcity, New Delhi Group Editor-in-Chief, IJCP Group, eMedinewS and eMediNexus

of people residing in different areas or engaged in different vocations.

Article 39. Certain principles of policy to be followed by the State: The State shall, in particular, direct its policy towards securing (e) that the health and strength of workers, men and women, and the tender age of children are not abused and that citizens are not forced by economic necessity to enter a vocation unsuited to their age or strength; (f) that children are given opportunities and facilities to develop in a healthy manner and in conditions of freedom and dignity and that childhood and youth are protected against exploitation and against moral and material abandonment.

Article 41. Right to work, to education and to public assistance in certain cases. The State shall, within the limits of its economic capacity and development, make effective provision for securing the right to work, to education and to public assistance in cases of unemployment, old age, sickness and disablement, and in other cases of undeserved want.

Article 42. Provision for just and humane conditions of work and maternity relief.

Can the patient ask for his/her medical records?

Yes. A patient has the right to get a copy of his/her medical records if he/she asks for it. The Medical Council of India (MCI) Code of Ethics Regulations 2002 states as follows: “If any request is made for medical records either by the patients/authorised attendant or legal authorities involved, the same may be duly acknowledged and documents shall be issued within the period of 72 hours. (1.3.2.)”

What responsibility does the State have towards raising the level of nutrition and standard of living and improving of public health?

Article 47 of the Constitution of India has laid down the responsibility of the State with regard to raising the level of nutrition and the standard of living and to improve public health. It reads as follows: “The State shall regard the raising of the level of nutrition and the standard of living of its people and the improvement

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MEDILAW of public health as among its primary duties and, in particular, the State shall endeavour to bring about prohibition of the consumption except for medicinal purposes of intoxicating drinks and of drugs which are injurious to health.”

What does the United Nations say about the right to healthcare?

What responsibility does the state government have towards environmental protection under the Indian Constitution?

“Article 1. All human beings are born free and equal in dignity and rights. They are endowed with reason and conscience and should act towards one another in a spirit of brotherhood.

The state government has a responsibility towards protection and improvement of the environment.

Article 48 A of the Constitution reads as follows: “The State shall endeavour to protect and improve the environment and to safeguard the forests and wildlife of the country.” ÂÂ

In Bandhua Mukti Morcha v. Union of India, the Supreme Court of India held “... there can be no doubt that pure drinking water is absolutely essential to the health and well-being of the workmen and some authority has to be responsible for providing it ... The other matter in regard to which we find it necessary to give directions relates to the tremendous pollution of air by dust thrown out as a result of operation of the stone crushers ... also affect the visibility and constitute a serious health hazard to the workmen.”

ÂÂ

In Rural Litigation and Entitlement Kendra v State of UP, the Supreme Court of India ordered lime stone quarries to be closed down stating that “It is a price that has to be paid for protecting and safeguarding the right of the people to live in healthy environment with minimal disturbance of ecological balance and without avoidable hazard to them and to their cattle, homes and agricultural land and undue affectation of air, water and environment.”

ÂÂ

In the case of Subhash Kumar v State of Bihar 1991 AIR 420, 1991 SCR (1) 5, the Supreme Court held that “Right to live is a fundamental right under Art 21 of the Constitution and it includes the right of enjoyment of pollution free water and air for full enjoyment of life.”

ÂÂ

786

In M.C. Mehta and Anr vs Union Of India & Ors on 20 December, 1986 Equivalent citations: 1987 AIR 1086, 1987 SCR (1) 819, the Supreme Court held “Chlorine gas is admittedly dangerous to life and health. If the gas escapes either from the storage tank or from the filled cylinders or from any other point in the course of production, the health and well-being of the people living in the vicinity can be seriously affected ... is engaged in an activity which has the potential to invade the right to life of large sections of people.”

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The United Nations Universal Declaration of Human Rights 1948 has recognised the rights of all human beings in its preamble and Article 1, 3 and 25.

Article 3. Everyone has the right to life, liberty and security of person.

Article 25 1. Everyone has the right to a standard of living adequate for the health and well-being of himself and of his family, including food, clothing, housing and medical care and necessary social services, and the right to security in the event of unemployment, sickness, disability, widowhood, old age or other lack of livelihood in circumstances beyond his control.

2. Motherhood and childhood are entitled to special care and assistance. All children, whether born in or out of wedlock, shall enjoy the same social protection.”

In its judgement in C.E.S.C. Ltd. Etc vs Subhash Chandra Bose And Ors on 15 November, 1991 (1992 AIR 573, 1991 SCR Supl. (2) 267), the Supreme Court of India has cited Article 25(1) of Universal Declaration of Human Rights, 1948 saying “Article 25(2) of Universal Declaration of Human Rights, 1948 assures that everyone has the right to a standard of living adequate for the health and well-being of himself and of his family ... including medical care, sickness, disability ...”

What is the International Covenant on Economic, Social and Cultural Rights with regard to right to healthcare?

The International Covenant on Economic, Social and Cultural Rights (ICESCR) is a multilateral treaty, which ensures granting of important rights such as right to work, health, education, housing, etc. It was adopted by the United Nations General Assembly resolution 2200A (XXI) on 16th December 1966, and came in force from 3rd January 1976.

The Supreme Court of India has cited Article 7 (b) Safe and healthy working conditions of the ICESCR, 1966 in its judgement in C.E.S.C. Ltd. Etc vs Subhash Chandra Bose And Ors on 15 November, 1991 (1992 AIR 573, 1991

MEDILAW SCR Supl. (2) 267) and stated “... Art. 7(b) of the ICESCR, 1966 recognises the right of everyone to the enjoyment of just and favourable conditions of work which ensure, in particular, safe and healthy working conditions.”

What are the rights of the patient as defined by the American Medical Association?

Opinion 10.01 of the American Medical Association’s Code of Medical Ethics - Fundamental Elements of the Patient-Physician Relationship has defined the following rights of the patient.

1. The patient has the right to receive information from physicians and to discuss the benefits, risks and costs of appropriate treatment alternatives. Patients should receive guidance from their physicians as to the optimal course of action. Patients are also entitled to obtain copies or summaries of their medical records, to have their questions answered, to be advised of potential conflicts of interest that their physicians might have, and to receive independent professional opinions.

2. The patient has the right to make decisions regarding the healthcare that is recommended by his/her physician. Accordingly, patients may accept or refuse any recommended medical treatment.

3. The patient has the right to courtesy, respect, dignity, responsiveness and timely attention to his/ her needs.

4. The patient has the right to confidentiality.

The physician should not reveal confidential communications or information without the consent of the patient, unless provided for by law or by the need to protect the welfare of the individual or the public interest.

5. The patient has the right to continuity of healthcare.

The physician has an obligation to cooperate in the coordination of medically indicated care with other healthcare providers treating the patient.

The physician may not discontinue treatment of a patient as long as further treatment is medically indicated, without giving the patient reasonable assistance and sufficient opportunity to make alternative arrangements for care.

6. The patient has a basic right to have available adequate healthcare. Physicians, along with the rest of society, should continue to work toward this goal.

Fulfillment of this right is dependent on society providing resources so that no patient is deprived of necessary care because of an inability to pay for the care. Physicians should continue their traditional assumption of a part of the responsibility for the medical care of those who cannot afford essential healthcare. Physicians should advocate for patients in dealing with third parties when appropriate.

(I, IV, V, VIII, IX)

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INSPIRATIONAL STORY

The Rebellion Against the Stomach

O

nce a man had a dream in which his hands and feet and mouth and brain all began to rebel against his stomach. “You good-fornothing sluggard!” the hands said. “We work all day long, sawing and hammering and lifting and carrying.

By evening we’re covered with blisters and scratches, and our joints ache, and we’re covered with dirt. And meanwhile you just sit there, hogging all the food.”

as it always did when it was hungry. But after a while it was quiet. Then, to the dreaming man’s surprise, he found he could not walk. He could not grasp anything in his hand. He could not even open his mouth. And he suddenly began to feel rather ill. The dream seemed to go on for several days. As each day passed, the man felt worse and worse. “This rebellion had better not last much longer,” he thought to himself, “or I’ll starve.”

“We agree!” cried the feet. “Think how sore we get, walking back and forth all day long. And you just stuff yourself full, you greedy pig, so that you’re that much heavier to carry about.”

Meanwhile, the hands and feet and mouth and brain just lay there, getting weaker and weaker. At first they roused themselves just enough to taunt the stomach every once in a while, but before long they didn’t even have the energy for that.

“That’s right!” whined the mouth. “Where do you think all that food you love comes from? I’m the one who has to chew it all up, and as soon as I’m finished you suck it all down for yourself. Do you call that fair?”

“And what about me?” called the brain. “Do you think its easy being up here, having to think about where your next meal is going to come from? And yet I get nothing at all for my pains.” And one by one the parts of the body joined the complaint against the stomach, which didn’t say anything at all.

“I have an idea,” the brain finally announced. “Let’s all rebel against the lazy belly, and stop working for it.” “Superb idea!” all the other members and organs agreed. “We’ll teach you how important we are, you pig. Then may be you’ll do a little work of your own.”

So they all stopped working. The hands refused to do lifting and carrying. The feet refused to walk. The mouth promised not to chew or swallow a single bite.

And the brain swore it wouldn’t come up with any more bright ideas. At first the stomach growled a bit,

Finally, the man heard a faint voice coming from the direction of his feet. “It could be that we were wrong,” they were saying. “We suppose the stomach might have been working in own way all along.” “I was just thinking the same thing,” murmured the brain. “It’s true that he’s been getting all the food. But it seems he’s been sending most of it right back to us.”

“We might as well admit our error,” the mouth said.

“The stomach has just as much work to do as the hands and feet and brain and teeth.” “Then let’s get back to work,” they cried together. And at that the man woke up.

To his relief, he discovered his feet could walk again.

His hands could grasp, his mouth could chew, and his brain could now think clearly. He began to feel much better.

“Well, there’s a lesson for me,” he thought as he filled his stomach at breakfast. “Either we all work together, or nothing works at all.”

■■■■ “Friendship is born at that moment when one person says to another: ‘What! You too? I thought I was the only one.” ―CS Lewis “Friendship marks a life even more deeply than love. Love risks degenerating into obsession, friendship is never anything but sharing.” ―Elie Wiesel “Friendship is the hardest thing in the world to explain. It’s not something you learn in school. But if you haven’t learned the meaning of friendship, you really haven’t learned anything.” ―Muhammad Ali

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AROUND THE GLOBE

News and Views ÂÂ

Eating potatoes may increase the risk of type 2 diabetes and replacing them with whole grains may lower this risk, suggested a study published online in Diabetes Care.

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For patients with gram-negative bloodstream infections (BSI) who present with a beta-lactam (BL) allergy, treatment with a BL antibiotic from an alternative class carries a lower risk of clinical failure than treatment with a non-beta-lactam (NBL) antibiotic, suggested a new study published online in the Journal of Allergy and Clinical Immunology.

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A meta-analysis including more than 6,00,000 patients in more than 100 studies revealed that antihypertensive therapy significantly decreased the risks of major cardiovascular (CV) events, including stroke and heart failure, and all-cause mortality, almost regardless of baseline blood pressure (BP) levels and comorbidities. The findings are published December 23 in the Lancet.

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New research, published in PLOS ONE, has found that lower levels of antibodies in saliva are associated with of an elevated risk of mortality and could be an early indicator of risk.

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Zinc levels in breast milk may serve as an indicator of breast function during lactation, suggests new research published online in the Journal of Mammary Gland Biology and Neoplasia.

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An analysis based on data from previously published literature suggests it is more cost effective to treat all suspected cases of onychomycosis with oral terbinafine than to perform confirmatory diagnostic tests beforehand, although confirmatory testing before treatment with the expensive topical medicine efinaconazole, 10 percent, was associated with reduced costs, suggested an article published online in JAMA Dermatology.

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New research published in the journal Neurology suggests that individuals infected with hepatitis C virus may be at greater risk for Parkinson’s disease.

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Fibroblast growth factor 21 (FGF21), a hormone derived from the liver, can prevent overconsumption of sugar, suggest two new studies published in Cell Metabolism.

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Patients with stable angina taking the heartrate reducing drug ivabradine had similar

self-reported physical limitation scores as patients taking placebo, but better quality of life on other measures, suggested a substudy of the SIGNIFY trial published online in the journal Circulation: Cardiovascular Quality and Outcomes. ÂÂ

Low aerobic fitness during late adolescence increases the risk for early death, reported a study published online in the International Journal of Epidemiology.

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Immune cells - resident memory T cells - known to fight the flu in mice may also help fight RSV, a virus that is one of the main causes of the common cold in humans, suggested a new study published in the journal Nature Communications. Researchers noted that people with high levels of these cells appear less likely to show symptoms of RSV infection.

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Non-steroidal anti-inflammatory drugs (NSAIDs) were safe and worked as well as opiates for managing pain from chest tube insertion and pleurodesis due to malignant pleural effusion, suggests new research published in the Journal of the American Medical Association.

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Active and passive exposure to tobacco may increase the risk for infertility and lower the age of natural menopause, reported a study published online in Tobacco Control.

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A recent study of elderly men, published in the Annals of the American Thoracic Society, found no evidence that obstructive sleep apnea (OSA) increased in severity (or prevalence) as a result of vitamin D deficiency.

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On a population level, universal new born hearing screening (UNHS) has led to improved language outcomes at school age, reported an Australian study scheduled for online publication in Pediatrics.

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Two studies and an editorial, published online in JAMA Dermatology, identified the relationship between skin disorders and endocrine diseases.

While the first study revealed that the prevalence of insulin resistance was higher among the men with acne compared with the healthy control patients, the second study found that 91.7% women who met the criteria for PCOS had at least one skin finding.

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

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AROUND THE GLOBE ÂÂ

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Environmental factors may lead to autism, and the condition is far more prevalent in those who were extremely premature babies, suggests new research published in Cerebral Cortex.

Human papillomavirus (HPV) testing, as well as vaccination, should become an essential part of cervical cancer screening and prevention, suggests an update of cervical cancer screening guidelines released by the American College of Obstetricians and Gynecologists (ACOG). The practice bulletin was published in Obstetrics & Gynecology.

In patients with bipolar depression, adding the anticonvulsant medication lamotrigine to quetiapine may improve outcomes in comparison with quetiapine monotherapy; however, concurrent use of folic acid may reduce the additive effect of lamotrigine, suggests a new study published online in Lancet Psychiatry.

Researchers at the University of Georgia have found that pathogens, like salmonella, can survive for at least 6 months in cookies and crackers.

The findings are published in the Journal of Food Protection.

Sleeping more than 9 hours a night, and sitting too much during the day could be a hazardous combination, particularly when added to a lack of exercise, suggests a new study published in the journal PLOS Medicine. Researchers noted that a person who sleeps too much, sits too much and isn’t physically active enough is more than four times as likely to die early as a person without those unhealthy lifestyle habits.

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A new study, published in the Journal of Heart and Lung Transplantation, demonstrated a definitive connection between frailty and survival after a lung transplant procedure. Researchers suggest that we may be able to help patients live longer with fewer complications after a transplant by intervening early to prevent or lessen the severity of frailty.

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A one-step screening approach (International Association of the Diabetes and Pregnancy Study Groups [IADPSG]) for gestational diabetes (GDM) increased the rate of diagnosis and treatment of the disease in mothers, but did not improve neonatal outcomes compared with the more commonly used two-step screening (using the Carpenter-Coustan criteria cutoffs), suggested a new study published online in Obstetrics & Gynecology.

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Patients with chronic heart failure (CHF) are likely to have intestinal overgrowth of pathogenic gut flora and permeability that is associated with

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

disease severity, suggests new research published online in JACC: Heart Failure. ÂÂ

Updated guidelines by the Infectious Diseases Society of America (IDSA), published in the journal Clinical Infectious Diseases, recommend that candidiasis - a serious, life-threatening fungal infection - needs to be treated early, aggressively and appropriately. The guidelines recommend a shift from fluconazole to echinocandins for the initial treatment of invasive infections.

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Women with type 2 diabetes have a higher risk for vascular dementia than men with diabetes, reported a new meta-analysis published in Diabetes Care.

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The brains of children who suffer clinical depression as preschoolers develop abnormally, compared with the brains of preschoolers unaffected by the disorder, suggested new research published December 16 in JAMA Psychiatry.

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Laparoscopic liver resection (LLR) is associated with fewer complications and shorter hospital stay, with no increase in mortality, compared with open liver resection (OLR), reported a systematic review of more than 9,000 LLR cases and 2,900 OLR cases worldwide. The findings are published online in Annals of Surgery.

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Previous studies have linked obesity with persistent sleepiness, lack of energy during the day, and poor sleep quality. Now, a new study, published in the journal Sleep, has suggested that weight loss due to dietary changes can improve sleepiness at any weight.

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A uniquely acting antiplatelet agent, PZ-128, appears to be safe and fast for preventing blood clots and its effects are reversible, reducing the risk for excessive bleeding, suggested new research published in Arteriosclerosis, Thrombosis and Vascular Biology. The drug helps prevent dangerous clotting in patients undergoing angioplasty and other such cardiac procedures.

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To prevent preeclampsia, new research suggests that low-dose aspirin should be given prophylactically to all women at high-risk - those with diabetes or chronic hypertension - and any woman with two or more moderate risk factors - including obesity, multiple gestation and advanced maternal age. The report is published in the December 2015 edition of Obstetrics & Gynecology.

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Herpes zoster is linked to increased rates of acute cardiovascular events such as ischemic stroke and

AROUND THE GLOBE The findings are published online in Obstetrics & Gynecology.

myocardial infarction, or heart attack, suggested new research published in PLOS Medicine. ÂÂ

A new study, published in the Journal of Health and Social Behavior, revealed that women who had their first child between the age of 25-35 reported better health at the age of 40 than those who had their first child as a teenager (15-19) or in early adulthood (20-24).

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A step-wise approach to ablation for persistent atrial fibrillation (afib) did not offer any benefits over pulmonary vein isolation alone, reported the randomized, single-center CHASE-AF study published in the December 22 issue of the Journal of the American College of Cardiology.

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The interaction of two appetite hormones, leptin and ghrelin, may prove key to developing new drugs to treat alcohol use disorder (AUD), suggests a new study presented at the American Academy of Addiction Psychiatry (AAAP) 26th Annual Meeting.

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Breast cancer patients treated with trastuzumab had significantly lower risk for left ventricular (LV) dysfunction and consequent treatment interruptions when treated prophylactically with heart failure medications, suggests new research presented at San Antonio Breast Cancer Symposium (SABCS) 2015.

The psoriasis drug ustekinumab can spur hair regrowth and normalize immune function in patients with alopecia areata, suggested the results of a study in three patients published online in a letter to the Journal of Allergy and Clinical Immunology. First author Dr Emma GuttmanYassky stated that this opens the door for targeted treatment of alopecia areata.

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Patients whose inflammatory bowel disease (IBD) was managed with a tumor necrosis factor (TNF) inhibitor but whose treatment was changed for reasons other than safety or efficacy typically had worse outcomes than those who continued with the successful treatment, reported a real-world study presented at the Advances in Inflammatory Bowel Diseases meeting.

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A new study, published in JAMA Pediatrics, finds a link between antidepressant use during pregnancy and an increased risk of autism in offspring.

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In patients with mild Alzheimer’s disease (AD), consumption of moderate amounts of alcohol is associated with a lower risk for death than those who drink only occasionally, suggested a new analysis published online in BMJ Open.

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The risks for late lung cancer and ischemic heart disease among women who undergo irradiation for breast cancer are both reassuringly low, unless the patient is a smoker who just can’t kick the habit, reported researchers at the San Antonio Breast Cancer Symposium (SABCS) 2015.

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Findings from a new study, presented at the San Antonio Breast Cancer Symposium and published on December 10 in The Lancet, suggest that in postmenopausal women with ductal carcinoma in-situ (DCIS) who underwent lumpectomy plus radiotherapy, those given tamoxifen complained of more severe hot flashes, while anastrozole users reported greater severity of vaginal dryness and muscle and joint pains. Additionally, hot flashes, weight problems, vaginal symptoms and gynecological symptoms were worse in women <60 years old than those 60 years or older.

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Smoking high-potency cannabis may cause white matter damage in the corpus callosum, thus interfering with communication between the right and left hemispheres of the brain, suggests new research published online in Psychological Medicine.

A new study, published in the journal Preventing Chronic Disease, revealed that employees enrolled in a workplace intervention program as a group lost more weight, showed greater reductions in fasting blood sugar and ate less fat than employees who received only written health guidelines for diabetes prevention.

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Active individuals who enjoy participating in higher impact activities may need to maintain higher vitamin D levels to reduce their risk of stress fractures, suggests new research published in The Journal of Foot & Ankle Surgery.

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Central venous pressure (CVP) – Guided fluid administration before, during, and after coronary angiography can significantly reduce the risk of contrast-induced nephropathy (CIN) and major adverse clinical events compared with standard protocols, suggests a new study published online in JACC: Cardiovascular interventions.

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New research suggests that the use of adhesionreducing substances, known as adhesion barrier, is associated with slightly increased incidence of fever and ileus after myomectomy and hysterectomy, and with small bowel obstruction after hysterectomy.

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

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AROUND THE GLOBE ÂÂ

A recent study published in Pediatric Obesity suggests that young girls who are either overweight or obese during childhood were more likely to remain obese as they progressed into young adulthood compared to boys.

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A new study presented at the annual meeting of the American College of Neuropsychopharmacology revealed that female infants have larger volumes of gray matter around the temporal-parietal junction of the brain than males at the time of birth. Sex differences in this area of the brain may be a clue as to why males are at higher risk for certain forms of autism spectrum disorders.

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More than 90% of patients with sickle cell disease remained alive and free of clinical events 3 years after receiving HLA-matched sibling stem-cell transplantation, reported data from an international registry presented at the American Society of Hematology meeting.

The birth rate is declining in all industrialized countries, and besides socioeconomic factors and women’s age, male reproductive health and environmental factors are also significant contributors, concluded a new scientific review article published in the journal Physiological Reviews.

Researchers stated that environmental factors had a significant role to play in male reproductive problems.

Spending large amounts of time participating in sedentary behaviors, such as watching TV and checking the computer, by patients with CAD can worsen various cardiometabolic markers— even if the patients also spend time exercising, suggests a secondary analysis of the Efficacy and Economics of Exercise Maintenance Post-Cardiac Rehabilitation (ECO-PCR) study, published online in the European Journal of Preventive Cardiology.

Canakinumab and tocilizumab are more effective biologic agents than rilonacept in treating systemic juvenile idiopathic arthritis (sJIA), reported a new meta-analysis of short-term, randomized controlled trials published in Rheumatology.

Evaluating and treating patients suspected of having an acute stroke in a mobile unit using telemedicine to communicate with a neuroradiologist and stroke physician is feasible, and it may be a cost-effective way of introducing prehospital stroke treatment.

The study published in JAMA Neurology also showed that patients cared for by the mobile unit received tissue plasminogen activator (tPA) more quickly than those who received treatment in the hospital.

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

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Pregnant women who take the oral antifungal drug fluconazole for vaginal candidiasis are at a significantly increased risk for miscarriage, suggests new research published in JAMA.

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Depression in early childhood is associated with reductions in gray matter development in the brain during early adolescence, with the reductions linked to the number of depressive symptoms, suggests a longitudinal study published online in JAMA Psychiatry.

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A new study, scheduled to be presented at the Genitourinary Cancers Symposium (GUCS), suggests that in men with prostate cancer, regular aspirin use is associated with a slower rate of disease progression and a reduced risk of dying from the disease.

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Use of a simple filtration mask could reduce the adverse endothelial effects and increase in natriuretic peptides caused by some forms of air pollution in patients with heart failure, suggests a small randomized controlled pilot trial published in the January 2016 issue of JACC: Heart Failure.

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Obese young people can avoid developing life threatening illness if they change before middle age, suggests new research published in BMJ Open. Researchers noted that men who had high BMI levels at 21, but had lowered their BMI by the age of 50, had similar or lower rates of diabetes as people who were normal weight when younger.

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Intracerebral hemorrhage patients can present with rapidly resolving symptoms that imitate transient ischemic attack (TIA), pointing towards a need for rigorous evaluation of suspected TIA, suggests new research published in JAMA Neurology.

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Robotic and single-incision minimally invasive gallbladder surgery offer substantially less surgical value than traditional laparoscopic cholecystectomy, reported a new study published online in the Journal of the American College of Surgeons.

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Joint best practice recommendations from American College of Surgeons and American Geriatrics Society, published online in the Journal of the American College of Surgeons, address unique care required for older adults facing surgery. The guideline was released for optimal care of older adults immediately before, during, and after surgical operations.

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A wearable device appears to be just as good at measuring lactate thresholds for endurance runners as older, more complicated methods,

AROUND THE GLOBE suggested a new study published online in the Journal of Strength and Conditioning Research. The wearable device sleeve fits on the lower leg and is non-invasive. ÂÂ

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The odds of major depressive disorder and generalized anxiety disorder were markedly greater among women who earned less than their male counterparts, with whom they were matched on education and years of experience, suggested new research published online in the journal Social Science & Medicine.

The US Food and Drug Administration (FDA) has reclassified surgical mesh for transvaginal repair of pelvic organ prolapse (POP) from a moderate–risk device (class ll) to a high–risk one (class lll) and gave manufacturers 30 months to prove that their products are safe and effective.

Higher monthly doses of vitamin D may not improve the function of lower extremities, instead they may increase the risk of falls in senior patients, suggests new research published online in JAMA Internal Medicine.

Abbreviated dosing of the monoclonal antibody palivizumab adequately protected infants at risk for respiratory syncytial virus (RSV) hospitalization in a real–world setting, suggested findings from a new study reported in a research letter published online December 28 in JAMA Pediatrics.

research published online in the Scandinavian Journal of Gastroenterology. ÂÂ

Doctors are more likely to give smokers antibiotics for an infection, a habit that may promote antibiotic resistance, suggests a new study published online in the American Journal of Preventive Medicine.

Researchers noted that smokers were 20% to 30% more likely than non-smokers to get an antibiotic prescription.

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Patients with gout are at significantly increased risk for atrial fibrillation (Afib), reported a population– based study published online in Rheumatology.

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Neuromuscular electrical stimulation (NMES) transiently improves exercise capacity in patients with severe COPD, suggests new research published online in The Lancet Respiratory Medicine.

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A new study, published in the journal Cancer Research, suggests that high sugar intake can increase the risk of breast cancer and hasten spread of the disease to the lungs.

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Developmental delays in young children were not found to be linked to infertility treatments that their mothers had undergone in comparison with children born to women who did not undergo those treatments, suggested a population–based study published in JAMA Pediatrics.

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Prosthetic replacement of the ocular surface ecosystem (PROSE) continues to offer benefits several years after patients have been fitted with the scleral lenses, suggested a new review of data published online in the British Journal of Ophthalmology.

Levels of fecal calprotectin, a biomarker of intestinal inflammation, vary in patients with inflammatory bowel disease (IBD), suggests new ■■■■

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

793

LIGHTER READING

HUMOR

Masterpiece One day a girl came home crying to her mom.

The mom asked what was wrong. The girl responded, “I’m not a creation, God made men first! I’m nothing!”

Then the mom said, “Oh baby that’s not true, God may have made men first, but there’s always a rough draft before the masterpiece.”

The Physician Writing Out a Prescription The physician writing out a prescription for his hypertensive cardiac patient: “Diazepam 5 mg (tranquilizer) TDS”. The patient’s wife asks, “Doctor, when are these medicines to be given?”

Doctor: “These are to be taken by you. He needs rest”.

Threatening Letters The fellow stormed into the postmaster’s office in a fury. “I’ve been getting threatening letters in the mail for months and I want them stopped.”

“Of course,” said the postmaster.

“Sending threatening letters through the mail is a federal offense. Do you know who’s sending them?” “Yes,” shouted the man. “It’s those idiots down at the Internal Revenue Service.”

Mind Trivia There are three houses one is red one is blue band one is white. If the red house is to the left of the house in the middle and the blue house is to the right to the house in the middle where is the white house?

Ans: In Washington DC !

If an electric train is going 150 miles per hour north and the wind is blowing the same south, which way does the smoke blow?

Ans: It is an electric train there is no smoke!

QUOTES

LAUGH-A-WHILE

Lighter Side of Medicine

“High achievers spot rich opportunities swiftly, make big decisions quickly and move into action immediately. Follow these principles and you can make your dreams come true.” ―Robert H. Schuller “The best and most beautiful things in the world cannot be seen or even touched – they must be felt with the heart.” ―Helen Keller

Dr. Good and Dr. Bad SITUATION: A patient with COPD needed oxygen.

Nobel Prize A man is driving down a country road, when he spots a farmer standing in the middle of a huge field of grass. He pulls the car over to the side of the road and notices that the farmer is just standing there, doing nothing, looking at nothing.

Use binasal cannula

Use Venturi mask

© IJCP Academy

The man gets out of the car, walks all the way out to the farmer and asks him, “Ah excuse me mister, but what are you doing?”

The farmer replies, “I’m trying to win a Nobel Prize.” “How?” asks the man, puzzled.

“Well I heard they give the Nobel Prize to people who are outstanding in their field.”

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Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

LESSON: Venturi mask helps to wash out carbon dioxide.

Information for Authors Manuscripts should be prepared in accordance with the ‘Uniform requirements for manuscripts submitted to biomedical journals’ compiled by the International Committee of Medical Journal Editors (Ann. Intern. Med. 1992;96: 766-767).

Indian Journal of Clinical Practice strongly disapproves of the submission of the same articles simultaneously to different journals for consideration as well as duplicate publication and will decline to accept fresh manuscripts submitted by authors who have done so.

The boxed checklist will help authors in preparing their manuscript according to our requirements. Improperly prepared manuscripts may be returned to the author without review. The checklist should accompany each manuscript.

Authors may provide on the checklist, the names and addresses of experts from Asia and from other parts of the World who, in the authors’ opinion, are best qualified to review the paper.

Covering letter –

–

–

The covering letter should explain if there is any deviation from the standard IMRAD format (Introduction, Methods, Results and Discussion) and should outline the importance of the paper.

Principal/Senior author must sign the covering letter indicating full responsibility for the paper submitted, preferably with signatures of all the authors.

Articles must be accompanied by a declaration by all authors stating that the article has not been published in any other Journal/Book. Authors should mentioned complete designation and departments, etc. on the manuscript.

Manuscript Three complete sets of the manuscript should be – submitted and preferably with a CD; typed double spaced throughout (including references, tables and legends to figures).

–

The manuscript should be arranged as follow: Covering letter, Checklist, Title page, Abstract, Keywords (for indexing, if required), Introduction, Methods, Results, Discussion, References, Tables, Legends to Figures and Figures.

–

All pages should be numbered consecutively beginning with the title page.

Note: Please keep a copy of your manuscript as we are not responsible for its loss in the mail. Manuscripts will not be returned to authors.

Title page Should contain the title, short title, names of all the authors (without degrees or diplomas), names and full location of the departments and institutions where the work was performed,

name of the corresponding authors, acknowledgment of financial support and abbreviations used.

– The title should be of no more than 80 characters and should represent the major theme of the manuscript.

A subtitle can be added if necessary.

– A short title of not more than 50 characters (including inter-word spaces) for use as a running head should be included.

– The name, telephone and fax numbers, e-mail and postal addresses of the author to whom communications are to be sent should be typed in the lower right corner of the title page.

– A list of abbreviations used in the paper should be included. In general, the use of abbreviations is discouraged unless they are essential for improving the readability of the text.

Summary – The summary of not more than 200 words. It must convey the essential features of the paper.

– It should not contain abbreviations, footnotes or references.

Introduction – The introduction should state why the study was carried out and what were its specific aims/objectives.

Methods – These should be described in sufficient detail to permit evaluation and duplication of the work by others.

– Ethical guidelines followed by the investigations should be described.

Statistics The following information should be given: – The statistical universe i.e., the population from which the sample for the study is selected.

– Method of selecting the sample (cases, subjects, etc. from the statistical universe).

– Method of allocating the subjects into different groups.

– Statistical methods used for presentation and analysis of data i.e., in terms of mean and standard deviation values or percentages and statistical tests such as Student’s ‘t’ test, Chi-square test and analysis of variance or non-parametric tests and multivariate techniques.

–

Confidence intervals for the measurements should be provided wherever appropriate.

Results – These should be concise and include only the tables and figures necessary to enhance the understanding of the text.

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

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Discussion –

This should consist of a review of the literature and relate the major findings of the article to other publications on the subject. The particular relevance of the results to healthcare in India should be stressed, e.g., practicality and cost.

References These should conform to the Vancouver style. References should be numbered in the order in which they appear in the texts and these numbers should be inserted above the lines on each occasion the author is cited (Sinha12 confirmed other reports13,14...). References cited only in tables or in legends to figures should be numbered in the text of the particular table or illustration. Include among the references papers accepted but not yet published; designate the journal and add ‘in press’ (in parentheses). Information from manuscripts submitted but not yet accepted should be cited in the text as ‘unpublished observations’ (in parentheses).

At the end of the article the full list of references should include the names of all authors if there are fewer than seven or if there are more, the first six followed by et al., the full title of the journal article or book chapters; the title of journals abbreviated according to the style of the Index Medicus and the first and final page numbers of the article or chapter. The authors should check that the references are accurate. If they are not this may result in the rejection of an otherwise adequate contribution.

Examples of common forms of references are: Articles Paintal AS. Impulses in vagal afferent fibres from specific pulmonary deflation receptors. The response of those receptors to phenylguanide, potato S-hydroxytryptamine and their role in respiratory and cardiovascular reflexes.

Q. J. Expt. Physiol. 1955;40:89-111.

Figures – Two complete sets of glossy prints of high quality should be submitted. The labelling must be clear and neat.

– All photomicrographs should indicate the magnification of the print.

– Special features should be indicated by arrows or letters which contrast with the background.

The back of each illustration should bear the first – author’s last name, figure number and an arrow indicating the top. This should be written lightly in pencil only. Please do not use a hard pencil, ball point or felt pen.

Color illustrations will be accepted if they make a – contribution to the understanding of the article.

–

Do not use clips/staples on photographs and artwork.

–

Illustrations must be drawn neatly by an artist and photographs must be sent on glossy paper. No captions should be written directly on the photographs or illustration. Legends to all photographs and illustrations should be typed on a separate sheet of paper. All illustrations and figures must be referred to in the text and abbreviated as “Fig.”.

Please complete the following checklist and attach to the manuscript: 1. Classification (e.g. original article, review, selected summary, etc.)_______________________________ 2. Total number of pages ________________________ 3. Number of tables ____________________________ 4. Number of figures ___________________________

Books

5. Special requests _____________________________

Stansfield AG. Lymph Node Biopsy Interpretation Churchill Livingstone, New York 1985.

Indian 1.____________Foreign 1.________________

Articles in Books

2.____________ 2.________________

Strong MS. Recurrent respiratory papillomatosis. In: Scott Brown’s Otolaryngology. Paediatric Otolaryngology Evans JNG (Ed.), Butterworths, London 1987;6:466-470.

3.____________ 3.________________

4.____________ 4.________________

Tables –

These should be typed double spaced on separate sheets with the table number (in Roman Arabic numerals) and title above the table and explanatory notes below the table.

Legends These should be typed double spaces on a separate – sheet and figure numbers (in Arabic numerals) corresponding with the order in which the figures are presented in the text.

–

796

The legend must include enough information to permit interpretation of the figure without reference to the text.

Indian Journal of Clinical Practice, Vol. 26, No. 8, January 2016

6. Suggestions for reviewers (name and postal address)

7. All authors’ signatures________________________ 8. Corresponding author’s name, current postal and e-mail address and telephone and fax numbers __________________________________________

Online Submission Also e-Issue @ www.ijcpgroup.com For Editorial Correspondence

Dr KK Aggarwal Group Editor-in-Chief Indian Journal of Clinical Practice E-219, Greater Kailash, Part-1 New Delhi - 110 048. Tel: 40587513 E-mail: editorial@ijcp.com Website: www.ijcpgroup.com

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