WORKUP	Section 5 of 9
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Lab Studies:

• Throat culture

• Throat cultures for GABHS infections usually are negative by the time symptoms of RF or RHD appear.

• Make attempts to isolate the organism prior to the initiation of antibiotic therapy to help confirm a diagnosis of streptococcal pharyngitis and to allow typing of the organism if it is isolated successfully.

• Rapid antigen detection test

• This test allows rapid detection of GAS antigen, allowing the diagnosis of streptococcal pharyngitis to be made and antibiotic therapy to be initiated while the patient is still in the physician's office.

• This test reportedly has a specificity of greater than 95% but a sensitivity of only 60-90%. Thus, obtain a throat culture in conjunction with the rapid antigen detection test.

• Antistreptococcal antibodies

• Clinical features of RF begin when antistreptococcal antibody levels are at their peak. Thus, these tests are useful for confirming previous GAS infection. Antistreptococcal antibodies are particularly useful in patients who present with chorea as the only diagnostic criterion.

• Sensitivity for recent infections can be improved by testing for several antibodies. Check antibody titers 2 weeks apart to detect a rising titer. The most common extracellular antistreptococcal antibodies tested include antistreptolysin O (ASO) and anti-DNase B, antihyaluronidase, antistreptokinase, antistreptococcal esterase, and anti–nicotinamide adenine dinucleotide (anti-NAD). Antibody tests for cellular components of GAS antigens include antistreptococcal polysaccharide, antiteichoic acid antibody, and anti-M protein antibody.

• In general, the antibodies to extracellular streptococcal antigens rise during the first month after infection and then plateau for 3-6 months before returning to normal levels after 6-12 months. When the ASO titer peaks (2-3 wk after onset of RF), the sensitivity of this test is 80-85%.

• The anti-DNase B has a slightly higher sensitivity (90%) for revealing RF or acute glomerulonephritis. Antihyaluronidase frequently is abnormal in patients with RF with a normal ASO titer, may rise earlier, and persists longer than elevated ASO titers during incidents of RF.

• Acute-phase reactants: C-reactive protein and erythrocyte sedimentation rate are elevated in individuals with RF due to the inflammatory nature of the disease. Both tests have high sensitivity but low specificity for RF.

• Heart reactive antibodies: Tropomyosin is elevated in persons with acute RF.

• Rapid detection test for D8/17: This immunofluorescence technique for identifying the B-cell marker D8/17 is positive in 90% of patients with RF, and it may be useful for identifying patients who are at risk of developing RF.

Imaging Studies:

• Chest radiography

• Cardiomegaly, pulmonary congestion, and other findings consistent with heart failure may be observed on chest radiograph in individuals with RF.

• When the patient has fever and respiratory distress, the chest radiograph helps differentiate between CHF and rheumatic pneumonia.

• Echocardiography

• In individuals with acute RDH, echocardiography identifies and quantitates valve insufficiency and ventricular dysfunction.

• In persons with mild carditis, Doppler evidence of mitral regurgitation may be present during the acute phase of disease but resolves in weeks to months.

• In contrast, patients with moderate-to-severe carditis have persistent mitral and/or aortic regurgitation. The most important echocardiographic features of mitral regurgitation from acute rheumatic valvulitis are annular dilatation, elongation of the chordae to the anterior leaflet, and a posterolaterally directed mitral regurgitation jet.

• During acute RF, the left ventricle frequently is dilated in association with a normal or increased fractional shortening. Thus, some cardiologists believe that valve insufficiency (eg, from endocarditis), rather than myocardial dysfunction (eg, from myocarditis), is the dominant cause of heart failure in individuals with acute RF.

• In individuals with chronic RHD, echocardiography tracks the progression of valve stenosis and may help determine the time for surgical intervention. The leaflets of affected valves become thickened diffusely, with fusion of the commissures and chordae tendineae. Increased echodensity of the mitral valve may signify calcification.

Other Tests:

• ECG

• Sinus tachycardia most frequently accompanies acute RHD. Alternatively, some children develop sinus bradycardia from increased vagal tone. No correlation exists between bradycardia and severity of carditis.

• First-degree atrioventricular (AV) block (prolongation of PR interval) is observed in some patients with RHD. This abnormality may be related to localized myocardial inflammation involving the AV node or to vasculitis involving the AV nodal artery. First-degree AV block is a nonspecific finding and should not be used as a criterion for the diagnosis of RHD. Its presence does not correlate with the development of chronic RHD.

• Second-degree (ie, intermittent) and third-degree (ie, complete) AV block with progression to ventricular standstill have been described. However, heart block in the setting of RF typically resolves with the rest of the disease process.

• In individuals with acute pericarditis, ST segment elevation may be present, most marked in leads II, III, aVF, and V₄ through V₆.

• Finally, patients with RHD may develop atrial flutter, multifocal atrial tachycardia, or atrial fibrillation from chronic mitral valve disease and atrial dilation.

Procedures:

• Cardiac catheterization: This study is not indicated in acute RF.

Histologic Findings: Pathologic examination of the insufficient valves may demonstrate verrucous lesions at the line of closure. Aschoff bodies (ie, perivascular foci of eosinophilic collagen surrounded by lymphocytes, plasma cells, and macrophages) are found in the pericardium, perivascular regions of the myocardium, and endocardium. The Aschoff bodies assume a granulomatous appearance with a central fibrinoid focus and eventually are replaced by nodules of scar tissue. Anitschkow cells are plump macrophages within Aschoff bodies. In the pericardium, fibrinous and serofibrinous exudates may produce an appearance of “bread and butter” pericarditis.

	TREATMENT	Section 6 of 9
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Medical Care: Direct medical therapy toward eliminating the GAS pharyngitis (if still present), suppressing inflammation from the autoimmune response, and providing supportive treatment of CHF. A recent metaanalysis has supported a protective effect against rheumatic fever when penicillin is used following the diagnosis of GAS pharyngitis. Oral penicillin V remains the drug of choice for treatment of GAS pharyngitis. When oral penicillin is not feasible or dependable, a single dose of intramuscular benzathine penicillin G is therapeutic. For patients who are allergic to penicillin, administer erythromycin or a first-generation cephalosporin. Other options include clarithromycin for 10 days, azithromycin for 5 days, or a narrow-spectrum (first-generation) cephalosporin for 10 days. As many as 15% of penicillin-allergic patients are also allergic to cephalosporins. Do not use tetracyclines and sulfonamides to treat GAS pharyngitis.

• For recurrent GAS pharyngitis, a second 10-day course of the same antibiotic may be repeated. Alternate drugs include narrow-spectrum cephalosporins, amoxicillin-clavulanate, dicloxacillin, erythromycin, or other macrolides.

• GAS carriage is difficult to eradicate with conventional penicillin therapy. Thus, oral clindamycin (20 mg/kg/d PO in 3 divided doses for 10 d) is recommended.

• In general, antimicrobial therapy is not indicated for pharyngeal carriers of GAS. Exceptions include the following:
  • Outbreaks of RF or poststreptococcal glomerulonephritis

  • Family history of RF

  • During outbreaks of GAS pharyngitis in a closed community

  • When tonsillectomy is considered for chronic GAS carriage

  • When multiple episodes of documented GAS pharyngitis occur within a family despite appropriate therapy

  • Following GAS toxic shock syndrome or necrotizing fasciitis in a household contact

• Treatment of the acute inflammatory manifestations of acute RF consists of salicylates and steroids. Aspirin in anti-inflammatory doses effectively reduces all manifestations of the disease except chorea, and the response typically is dramatic.
  • If rapid improvement is not observed after 24-36 hours of therapy, question the diagnosis of RF.

  • Attempt to obtain aspirin blood levels from 20-25 mg/dL, but stable levels may be difficult to achieve during the inflammatory phase because of variable GI absorption of the drug. Maintain aspirin at anti-inflammatory doses until the signs and symptoms of acute RF are resolved or residing (6-8 wk) and the acute phase reactants (APRs) have returned to normal.

  • Anti-inflammatory doses of aspirin may be associated with abnormal liver function tests and GI toxicity, and adjusting the aspirin dosage may be necessary.

  • When discontinuing therapy, withdraw aspirin gradually over weeks while monitoring the APRs for evidence of rebound. Chorea most frequently is self-limited but may be alleviated or partially controlled with phenobarbital or diazepam.

• If moderate-to-severe carditis is present as indicated by cardiomegaly, CHF, or third-degree heart block, add oral prednisone to salicylate therapy.
  • Continue prednisone for 2-6 weeks depending on the severity of the carditis, and taper prednisone during the last week of therapy.

  • Discontinuing prednisone therapy after 2-4 weeks, while maintaining salicylates for an additional 2-4 weeks, can minimize adverse effects.

• Include digoxin and diuretics, afterload reduction, supplemental oxygen, bed rest, and sodium and fluid restriction as additional treatment for patients with acute RF and CHF. The diuretics most commonly used in conjunction with digoxin for children with CHF include furosemide and spironolactone.
  • Initiate digoxin only after checking electrolytes and correcting abnormalities in serum potassium.

  • The total loading dose is 20-30 mcg/kg PO qd, with 50% of the dose administered initially, followed by 25% of the dose 8 and 16 hours after the initial dose. Maintenance doses typically are 8-10 mcg/kg/d PO in 2 divided doses. For older children and adults, the total loading dose is 1.25-1.5 mg PO, and the maintenance dose is 0.25-0.5 mg PO qd. Therapeutic digoxin levels are present at trough levels of 1.5-2 ng/mL.

• Afterload reduction (ie, using ACE inhibitor captopril) may be effective in improving cardiac output, particularly in the presence of mitral and aortic insufficiency. Start these agents judiciously. Use a small, initial test dose (some patients have an abnormally large response to these agents), and administer only after correcting hypovolemia.

• When heart failure persists or worsens during the acute phase after aggressive medical therapy, surgery is indicated to decrease valve insufficiency.

• Preventive and prophylactic therapy is indicated after RF and RHD to prevent further damage to valves. Primary prophylaxis (initial course of antibiotics administered to eradicate the streptococcal infection) also serves as the first course of secondary prophylaxis (prevention of recurrent RF and RHD).

  • An injection of 0.6-1.2 million units of benzathine penicillin G intramuscularly every 4 weeks is the recommended regimen for secondary prophylaxis for most US patients. Administer the same dosage every 3 weeks in areas where RF is endemic, in patients with residual carditis, and in high-risk patients.

  • Although oral penicillin prophylaxis is also effective, data from the World Health Organization indicate that the recurrence risk of GAS pharyngitis is lower when penicillin is administered parentally.

  • The duration of antibiotic prophylaxis is controversial. Continue antibiotic prophylaxis indefinitely for patients at high risk (eg, health care workers, teachers, daycare workers) for recurrent GAS infection. Ideally, continue prophylaxis indefinitely, because recurrent GAS infection and RF can occur at any age; however, the American Heart Association currently recommends that patients with RF without carditis receive prophylactic antibiotics for 5 years or until aged 21 years, whichever is longer. Patients with RF with carditis but no valve disease should receive prophylactic antibiotics for 10 years or well into adulthood, whichever is longer. Finally, patients with RF with carditis and valve disease should receive antibiotics at least 10 years or until aged 40 years.

  • Patients with RHD and valve damage require a single dose of antibiotics 1 hour before surgical and dental procedures to help prevent bacterial endocarditis. Patients who had RF without valve damage do not need endocarditis prophylaxis. Do not use penicillin, ampicillin, or amoxicillin for endocarditis prophylaxis in patients already receiving penicillin for secondary RF prophylaxis (relative resistance of oral streptococci to penicillin and aminopenicillins). Alternate drugs recommended by the American Heart Association for these patients include oral clindamycin (children: 20 mg/kg; adults: 600 mg) and oral azithromycin or clarithromycin (children: 15 mg/kg; adults: 500 mg). Additional guidelines for endocarditis prophylaxis in patients who are allergic to penicillin or who are unable to receive oral antibiotics are discussed in the Bacterial Endocarditis article.

• Control measures for patients with GAS pharyngitis are as follows:

  • Hospitalized patients: Place hospitalized patients with GAS pharyngitis of pneumonia on droplet precautions, as well as standard precautions, until 24 hours after initiation of appropriate antibiotics.

  • Exposed persons: People in contact with patients having documented cases of streptococcal infection first should undergo appropriate laboratory testing if they have clinical evidence of GAS infection and should undergo antibiotic therapy if infected.

  • School and childcare centers: Children with GAS infection should not attend school or childcare centers for the first 24 hours after initiating antimicrobial therapy.

Surgical Care: When heart failure persists or worsens after aggressive medical therapy for acute RHD, surgery to decrease valve insufficiency may be lifesaving. Approximately 40% of patients with acute RF subsequently develop mitral stenosis as adults. Mitral valvulotomy, percutaneous balloon valvuloplasty, or mitral valve replacement may be indicated in patients with critical stenosis. Valve replacement appears to be the preferred surgical option for patients with high rates of recurrent symptoms after annuloplasty or other repair procedures.

Diet: Advise nutritious diet without restrictions except in patients with CHF, who should follow a fluid-restricted and sodium-restricted diet. Potassium supplementation may be necessary because of the mineralocorticoid effect of corticosteroid and the diuretics, if used.

Activity: Initially, place patients on bed rest, followed by a period of indoor activity before they are permitted to return to school. Do not allow full activity until the APRs have returned to normal. Patients with chorea may require a wheelchair and should be on homebound instruction until the abnormal movements resolve.

	MEDICATION	Section 7 of 9
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Treatment and prevention of GAS pharyngitis outlined here are based on the current recommendations of the Committee on Infectious Disease (American Academy of Pediatrics). Medical therapy is directed toward elimination of GAS pharyngitis (if still present), suppression of inflammation from the autoimmune response, and supportive treatment of CHF. Attempts are being made to produce vaccines against GAS infection, but the vaccines will not be available for years.

Antibiotics for endocarditis prophylaxis are administered to patients with certain cardiac conditions, such as carditis caused by rheumatic fever, before procedures that may cause bacteremia are performed. For more information, see Antibiotic Prophylactic Regimens for Endocarditis.

Drug Category: Antibiotics -- The roles for antibiotics are to (1) initially treat GAS pharyngitis, (2) prevent recurrent streptococcal pharyngitis, RF, and RHD, and (3) provide prophylaxis against bacterial endocarditis.

Drug Name	Penicillin VK (Beepen-VK, Pen.Vee K, V-Cillin K, Veetids) -- DOC for treatment of GAS pharyngitis. Although ampicillin or amoxicillin may be used instead, they have no microbiologic advantage. Do not use tetracyclines and sulfonamides to treat GAS pharyngitis. For recurrent GAS pharyngitis, a second 10-d course of same antibiotic may be repeated. Alternate drugs include narrow-spectrum cephalosporins, amoxicillin-clavulanate, dicloxacillin, erythromycin, or other macrolides.
Adult Dose	500 mg PO bid/tid for 10 d
Pediatric Dose	Children: 250 mg (400,000 U) PO bid/tid for 10 d Adolescents: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase effectiveness by decreasing clearance; tetracyclines are bacteriostatic, causing decrease in effectiveness of penicillins when administered concurrently
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Renal impairment, anaphylaxis, thrombocytopenia

Drug Name	Benzathine (Bicillin L-A)/procaine penicillin (Crysticillin A.S., Wycillin) -- Used when PO administration of penicillin is not feasible or dependable. IM therapy with penicillin is painful, but discomfort may be minimized if penicillin G is brought to room temperature before injection or combination of benzathine penicillin G and procaine penicillin G is used. Initial course of antibiotics administered to eradicate streptococcal infection also serves as first course of prophylaxis. An injection of benzathine penicillin G IM q4wk is recommended regimen for secondary prevention for most United States patients. Administer same dosage q3wk in areas where RF is endemic, in patients with residual carditis, and in high-risk patients.
Adult Dose	Eradication: 1.2 million U of benzathine penicillin G or a combination of 900,000 U of benzathine penicillin G with 300,000 U of procaine penicillin G IM as a single dose Secondary prevention: Administer eradication dose q3wk (in high-risk areas, high-risk patients) or q4wk (for most areas in United States)
Pediatric Dose	Eradication <60 lb: 600,000 U of benzathine penicillin G IM as a single dose Secondary prevention: Administer eradication dose q3wk (in high-risk areas, high-risk patients) or q4wk (for most areas in United States)
Contraindications	Documented hypersensitivity
Interactions	Increases risk of bleeding when administered concurrently with warfarin; ethacrynic acid, aspirin, indomethacin, and furosemide may compete with penicillin G for renal tubular secretion, increasing penicillin serum concentrations
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Never use IV route to administer penicillin G procaine; impaired renal function; anaphylaxis; thrombocytopenia

Drug Name	Erythromycin (E.E.S., E-Mycin, Eryc, Ery-Tab, Erythrocin) -- Used for patients who are allergic to penicillin. Other options include clarithromycin, azithromycin, or a narrow-spectrum cephalosporin (ie, cephalexin). As many as 15% of penicillin-allergic patients also are allergic to cephalosporins.
Adult Dose	250 mg erythromycin stearate/base (or 400 mg ethylsuccinate) q6h PO 1 h ac for 10 d
Pediatric Dose	20-40 mg (as base, estolate, or stearate)/kg/d PO divided bid/qid for 10 d; not to exceed 1 g/d Alternatively, 40 mg (as ethylsuccinate)/kg/d PO divided bid/qid for 10 d
Contraindications	Documented hypersensitivity; with terfenadine (off US market) or astemizole (use in combination with erythromycin may cause prolongation of QT interval, with increased risk of ventricular arrhythmias and sudden death)
Interactions	Coadministration may increase toxicity of theophylline, digoxin, carbamazepine, and cyclosporine; may potentiate anticoagulant effects of warfarin; coadministration with lovastatin and simvastatin increases risk of rhabdomyolysis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI adverse effects are common (administer doses pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occurs

Drug Name	Clarithromycin (Biaxin) -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin.
Adult Dose	250-500 mg PO bid for 10 d
Pediatric Dose	7.5 mg/kg PO bid for 10 d
Contraindications	Documented hypersensitivity; coadministration of pimozide; patients taking terfenadine (off US market); patients with long QT syndrome
Interactions	CYP450 1A2 and 3A4 inhibitor; toxicity increases with coadministration of fluconazole and pimozide; clarithromycin effects decrease and GI adverse effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, omeprazole, carbamazepine, ergot alkaloids, triazolam, and HMG CoA-reductase inhibitors; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmias and increase in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25 mL/min; administer one half dose or increase dosing interval if CrCl <30 mL/min; diarrhea may be sign of pseudomembranous colitis; superinfections may occur with prolonged or repeated antibiotic therapies

Drug Name	Azithromycin (Zithromax) -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin.
Adult Dose	12 mg/kg (not to exceed 500 mg) PO qd for 5 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; hepatic impairment; do not administer with pimozide
Interactions	May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in patients who are hospitalized, geriatric, or debilitated

Drug Name	Cephalexin (Keflex, Biocef, Keftab) -- Alternate antibiotic for treating GAS pharyngitis in patients allergic to penicillin.
Adult Dose	250-500 mg PO qid for 10 d
Pediatric Dose	25-50 mg/kg/d PO divided qid for 10 d
Contraindications	Documented hypersensitivity
Interactions	Coadministration with aminoglycosides increases nephrotoxic potential
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment

Drug Name	Amoxicillin (Amoxil, Biomox, Trimox) -- DOC used for bacterial endocarditis prophylaxis. Administered as single PO dose 1 h before dental work or surgery.
Adult Dose	2 g PO once as a single dose
Pediatric Dose	50 mg/kg PO once as a single dose
Contraindications	Documented hypersensitivity
Interactions	None significant for prophylaxis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in renal impairment

Drug Category: Anti-inflammatory agents -- Manifestations of acute RF (including carditis) typically respond rapidly to therapy with anti-inflammatory agents. Aspirin, in anti-inflammatory doses, is DOC. Prednisone is added when evidence of worsening carditis and heart failure exists.

Drug Name	Aspirin (Anacin, Ascriptin, Bayer Aspirin) -- Begin administration immediately after diagnosis of RF. Initiation of therapy may mask manifestations of disease.
Adult Dose	4-8 g/d PO divided q4-6h; maintain aspirin levels in 20-25 mg/dL range until all symptoms have resolved and APRs have returned to normal
Pediatric Dose	80-100 mg/kg/d PO divided q4-6h; maintain aspirin levels in 20-25 mg/dL range until all symptoms have resolved and APRs have returned to normal
Contraindications	Documented hypersensitivity; liver damage; hypoprothrombinemia, vitamin K deficiency; bleeding disorders; asthma
Interactions	Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Pregnancy	D - Unsafe in pregnancy
Precautions	Risk of salicylate intoxication and poisoning; watch for hyperventilation with prolonged expiratory phase with respiratory alkalosis and metabolic acidosis; risk of tinnitus, GI discomfort, and ulceration; when taken during pregnancy, increased risk of pulmonary hypertension exists in fetus in neonatal period

Drug Name	Prednisone (Deltasone, Orasone) -- If moderate-to-severe carditis is present as indicated by cardiomegaly, CHF, or third-degree heart block, use 2 mg/kg/d PO prednisone in addition to or in lieu of salicylate therapy. Continue prednisone for 2-4 wk depending on severity of carditis and taper during last week of therapy. Discontinuing prednisone therapy after 2 wk while adding or maintaining salicylates for additional 2-4 wk may minimize adverse effects.
Adult Dose	2 mg/kg/d PO for 2-4 wk
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Therapy for congestive heart failure -- Heart failure in RHD probably is related in part to severe insufficiency of the mitral and aortic valves and in part to pancarditis. Therapy traditionally has consisted of an inotropic agent (digitalis) in combination with diuretics (furosemide, spironolactone) and afterload reduction (captopril).

Drug Name	Digoxin (Lanoxin, Lanoxicaps) -- Inotropic agent widely used in past. Its efficacy in CHF is under review. Potential for toxicity is present. Therapeutic levels and clinical effects are observed more quickly if loading doses of digitalis are administered before routine maintenance doses. Acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure. Therapeutic digoxin levels are present at trough levels of 1.5-2 ng/mL.
Adult Dose	Total digitalizing dose (TDD) to be administered over 24 h; first dose is one half the TDD; second dose is one fourth the TDD, given 8 h later; third dose is one fourth the TDD, given 8 h after the second TDD: 0.75-1.5 mg PO Maintenance dose: 0.125-0.5 mg PO qd
Pediatric Dose	TDD to be administered over 24 h; first dose is one half the TDD; second dose is one fourth the TDD, given 8 h later; third dose is one fourth the TDD, given 8 h after the second TDD: Preterm infant: 20-30 mcg/kg PO Term infant: 25-35 mcg/kg PO 1 month to 2 years: 35-60 mcg/kg PO 2-5 years: 30-40 mcg/kg PO 5-10 years: 20-35 mcg/kg PO >10 years: Administer as in adults Maintenance dose: Preterm infant: 5-7.5 mcg/kg/d PO divided bid Term infant: 6-10 mcg/kg/d PO divided bid 1 month to 2 years: 10-15 mcg/kg/d PO divided bid 2-5 years: 7.5-10 mcg/kg/d PO divided bid 5-10 years: 5-10 mcg/kg/d PO divided bid >10 years: Administer as in adults
Contraindications	Documented hypersensitivity; beriberi heart disease; idiopathic hypertrophic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome
Interactions	Medications that may increase digoxin levels include alprazolam, benzodiazepines, bepridil, captopril, cyclosporine, propafenone, propantheline, quinidine, diltiazem, aminoglycosides, PO amiodarone, anticholinergics, diphenoxylate, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine, ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and verapamil Medications that may decrease serum digoxin levels include aminoglutethimide, antihistamines, cholestyramine, neomycin, penicillamine, aminoglycosides, PO colestipol, hydantoins, hypoglycemic agents, antineoplastic treatment combinations (eg, carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hypokalemia may reduce positive inotropic effect of digitalis; IV calcium may produce arrhythmias in patients receiving digitalis; hypercalcemia predisposes patient to digitalis toxicity, and hypocalcemia can make digoxin ineffective until serum calcium levels are normal; magnesium replacement therapy must be instituted in patients with hypomagnesemia to prevent digitalis toxicity; patients diagnosed with incomplete AV block may progress to complete block when treated with digoxin; caution in hypothyroidism, hypoxia, and acute myocarditis; initiate digoxin only after checking electrolytes and correcting abnormalities in serum potassium

Drug Name	Captopril (Capoten) -- Systemic afterload reduction may be helpful in improving cardiac output, particularly in setting of mitral and aortic valve insufficiency. Some patients have unusually large hypotensive response. Use small starting dose, particularly with hypovolemia.
Adult Dose	Starting dose: 6.25-12.5 mg PO tid Typical dose: 50-100 mg PO tid
Pediatric Dose	Starting dose: 0.1-0.5 mg/kg/d PO divided tid; typically 1-2 mg/kg/d PO divided tid
Contraindications	Documented hypersensitivity; renal impairment
Interactions	NSAIDs may reduce hypotensive effects of captopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases captopril levels; probenecid may increase captopril levels; hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Pregnancy category D in second and third trimesters; caution in renal impairment, valvular stenosis, or severe CHF

Drug Name	Furosemide (Lasix) -- Diuretics frequently are used in conjunction with inotropic agents for patients with CHF. When used aggressively, may result in hypokalemia and hypovolemia. Risk of hearing loss in premature infants. Increases excretion of water by interfering with chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule.
Adult Dose	20-40 mg PO/IV/IM bid/tid
Pediatric Dose	1-2 mg/kg/dose PO/IV/IM qd/tid
Contraindications	Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion
Interactions	Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced with concurrent administration; increased plasma lithium levels and toxicity are possible with concurrent administration
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Obtain frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Drug Name	Spironolactone (Aldactone) -- Used in conjunction with furosemide as potassium-sparing diuretic. Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.
Adult Dose	100 mg PO divided qd/bid
Pediatric Dose	2-4 mg/kg/d PO divided bid
Contraindications	Documented hypersensitivity; anuria; renal failure; hyperkalemia
Interactions	May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity of spironolactone
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal and hepatic impairment

	FOLLOW-UP	Section 8 of 9
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Further Outpatient Care:

• Patients usually demonstrate significant improvement after initiation of anti-inflammatory therapy; however, do not allow patients to resume full activities until all clinical symptoms and laboratory values have returned to normal.

• Emphasize the importance of prophylaxis against recurrent streptococcal pharyngitis and RF. Each recurrent episode of rheumatic carditis produces further valve damage and the likelihood of valve replacement. Patients should remain on antibiotic prophylaxis at least until the early third decade of life. Many physicians believe lifelong prophylaxis is appropriate.

• Monitor patients routinely for the signs and symptoms of mitral stenosis, pulmonary hypertension, arrhythmia, and CHF.

Complications:

• Potential complications include CHF from valve insufficiency (acute RF) or stenosis (chronic RF).

• Associated cardiac complications include atrial arrhythmias, pulmonary edema, recurrent pulmonary emboli, infective endocarditis, thrombus formation, and systemic emboli.

Prognosis:

• The manifestations of acute RF resolve during a period of 12 weeks in 80% of patients and may extend as long as 15 weeks in the remaining 20% of patients.

• RF was the leading cause of death in patients aged 5-20 years in the US 100 years ago. At that time, the mortality rate was 8-30% from carditis and valvulitis but decreased to a 1-year mortality rate of 4% by the 1930s. Following the development of antibiotics, the mortality rate decreased to nearly 0% by the 1960s in the US. However, the mortality rate has remained 1-10% in developing countries.

• The development of penicillin also has affected the likelihood of developing chronic valvular disease after an episode of acute RF. Prior to penicillin, 60-70% of patients developed valve disease; since the introduction of penicillin, 9-39% of patients develop valve disease.

• In patients who developed murmurs from valve insufficiency from acute RF, numerous factors (eg, severity of initial carditis, presence or absence of recurrences, amount of time since episode of RF) affected the likelihood that valve abnormalities and the murmur would disappear. The type of treatment and the promptness of its initiation did not affect the likelihood that the murmur would disappear. In general, incidence of residual RHD at 10 years was 34% in patients without recurrences but was 60% in patients with recurrent RF. In patients in whom the murmur disappeared, it did so within 5 years in 50%. Thus, a significant number of patients experience resolution of valve abnormalities even 5-10 years after their episode of RF.

• The importance of preventing recurrences of RF is evident.

Patient Education:

• Emphasize measures that minimize further damage to the valves of the heart.

• Timely evaluation and treatment of pharyngitis in children help prevent RF.

• Secondary prophylaxis of patients with previous RF and valve involvement with penicillin injections every 3-4 weeks decrease the recurrence of RHD.

• Additional prophylactic antibiotics prior to dental and surgical procedures decrease the likelihood of bacterial endocarditis.

	BIBLIOGRAPHY	Section 9 of 9
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Bibliography

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Rheumatic Fever excerpt