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Pneumonia is an infection of the pulmonary parenchyma.

Despite being the cause of significant morbidity and mortality, pneumonia is often misdiagnosed, mistreated, and underestimated.

Classification and Aetiology of pneumonia;

1) Community acquired pneumonia (CAP) commonly due to:-

1. Strep. Pneumoniae

2. H. influenza (esp. elderly patients)

3. Mycoplasma pneumoniae and chlamydia pneumoniae especially in young adults.

4. Viral infection especially in young children.

2) Hospital acquired (Nosocomial) pneumonia commonly due to:-

Gm negative enterobacteriae e.g. E.coli, pseudomonas, klebsiella.
Others –staph aureus, methicillin-resistant Staphylococcus aureus (MRSA), anaerobic organisms.

3) Pneumonia in the immunocompromise host usually due to :-

1. Cytomegalovirus. (CMV)

2. Pneumocystis jirovecii (PCV)

3. Fungal pneumonias

4) Aspiration pneumonia commonly due to:-

1. Strep pneumonia

2. H. influenzae

3. Moraxella Catarrhalis

Other classification;

1) Lobar pneumonia- homogenous consolidation of one or more lung lobes, often with assoc. pleural inflammation. Common in community acquired pneumonia.

2) Bronchopneumonia- patchy alveolar consolidation assoc. with bronchial and bronchiolar inflammation often affecting both lower lobes.Common in nosocomial pneumonia.

Risk Factor For Pneumonia:-

Consider the epidemiological triad.

1. Host factors;

1) Loss or decreased cough reflex- General Anesthesia, muscular disorders, drugs

2) Injury to muco-cilliary apparatus- smoking, hot or corrosive gases, infection- URTI, recent influenza infection etc.

3) Use of bactericidal agents- alcoholism, tobacco smoking, oxygen intoxication

4) Pulmonary congestion and pulmonary edema.

5) Defects in inmate immunity.

6) Accumulation of secretion as in cystic fibrosis.

2. Agent factors;

1) Virulent organisms- type of micro-organism involved.

2) Overwhelming dose of micro-organisms.

3) Drug resistance or drug susceptibility.

3. Environment factors;

1) Poor ventilation.

2) Occupational exposure e.g pneumoconiosis compromises airway.

3) Congestion in prison, dormitories and army barracks.

Portal of entry of pathogens in pneumonia;

1. Main route of infection is droplet inhalation(micro-inhalation).

2. Aspiration e.g in ICU, Theatre and comatose patients. (including drowning)

3. Haematogenous infections can also occur.

Direct spread is rare.

Pneumonia results from the proliferation of microbial pathogens at the alveolar level and the host's response to those pathogens. Microorganisms gain access to the lower respiratory tract in several ways.

Contiguous extension from an infected pleural or mediastinal space

Hematogenous spread

E.g., from tricuspid endocarditis or by contiguous extension from an infected pleural or mediastinal space.

Airway defence mechanism;

1. Cough reflex.

2. Sneeze reflex.

3. Mucocilliary escalator.

4. Resident alveolar macrophages.

Pathological changes associated with pneumonia;

Classic pneumonia evolves through a series of pathologic changes.

1. phase is one of edema:- with the presence of a proteinaceous exudate—and often of bacteria—in the alveoli.

2. Red hepatization phase:- presence of erythrocytes in the cellular intra alveolar exudate, neutrophil influx is more important from the standpoint of host defense. Bacteria are occasionally seen in pathologic specimens collected during this phase.

3. Gray hepatization, no new erythrocytes are extravasating, and those already present have been lysed and degraded. The neutrophil is the predominant cell, fibrin deposition is abundant, and bacteria have disappeared. This phase corresponds with successful containment of the infection and improvement in gas exchange.

4. Resolution, the macrophage reappears as the dominant cell type in the alveolar space, and the debris of neutrophils, bacteria, and fibrin has been cleared, as has the inflammatory response.

Clinical features of pneumonia.

1. Constitutional symptoms- usually acute onset with fever, rigors, headache, vomiting and loss of appetite.

2. Pulmonary symptoms

1) Breathlessness,

2) cough: short painful cough, initially dry and later productive of rusty sputum especially in strep pneumonia infections.

3) Crepitations.

3. Pleuritic chest pain :- may be referred to the shoulder or anterior abdominal wall.

4. Upper abdominal pains sometimes present in pts with lower lobe pneumonia. Or associated hepatitis

Investigations/Dx.

1. CXR-usually provides confirmation of diagnosis. In lobar pneumonia homogeneous opacities in affected lobe appears within 12-18 hours from onset of illness.

Can pick cmx – abscess, empyema, pleural effusion.

1. 1^st – good to do CXR on admission to aid dx and assessment follow up.

2. 2^nd – two weeks later.

3. 3^rd – at least 6/52 later especially those with persistent symptoms.

2. Serological tests/haematology.

1. FBC –Hb, WBC:- Neutrophils and total count.WBC is normal or marginally raised in atypical pneumonia. Where neutrophil leucocytosis of more than 15 × 10⁹/L favors a bacterial etiology. A very high (> 20 × 10⁹/l) or low (< 4 × 10⁹/l) white cell count may be seen in severe pneumonia.

2. ↑C-reative protein (non-specific)

3. Antigen tests- pro Calcitonin test.

4. Urea and electrolytes

5. Blood cultures – positive in 5-14% of cases

Microbiological tests

1. Sputum- all patients for admission, ICU HDU. Specimen taken for Gm stain, C/S.

2. Blood cultures

3. Serological tests- mycoplasma, legionella etc.

4. Bronchoalveolar lavage- especially those in ICU.

5. Throat swab / nasophanyngeal swab

6. Viral cultures

7. Pleural fluid tap- Gms /C and S

Pulse oximetry- HDU, ICU, especially those with respiratory failure.
Urine antigen test for s.pneumoniae and legionella pneumophilia type 1

Assessment of disease severity in pneumonia.

1. CURB- 65 score

Confusion: Defined as a Mental Test Score of 8 or less, or new disorientation in person, place or time

Urea (serum) ->7mmol/l

Respiratory rate >30/min

Blood Pressure of systolic <90mmHg and Diasolic < 60mmHg

Age>65 years

Score one for every present feature.

1) CURB score 0-1 – suitable for home Rx

2) Score of 2 – hospital supervised Rx either short stay inpatient or hospital supervised outpatient.

3) Score ≥3 – admit for inpatient management.

4) Score 4 or 5 – assess for ICU admission

Management of pneumonia.

1. Supportive management

1) Quickly assess patient- RR,PR,BP

2) O₂PRN especially hypoxic, ↓BP, PaO₂ less than 60mmHg & SPO₂<90%

3) Oxygen should be administered to all patients with tachypnoea, hypoxaemia, hypotension or acidosis with the aim of maintaining the PaO₂ ≥ 8 kPa (60 mmHg) or SaO₂ ≥ 92%. High concentrations (≥ 35%), preferably humidified, should be used in all patients who do not have hypercapnia(raised CO2 levels) associated with COPD. Assisted ventilation should be considered at an early stage in those who remain hypoxemic despite adequate oxygen therapy

4) Maintain fluid balance.-

Intravenous fluids should be considered in those with severe illness, in older patients and in those with vomiting. Otherwise, an adequate oral intake of fluid should be encouraged. Inotropic support may be required in patients with circulatory shock

5) Analgesics (be careful with opiates as they can depress respiration.

6) Chest physiotherapy Rx PRN.

2. Antibiotic therapy

1. Uncomplicated CAP- Rx for 10 days.

1) Amoxiclav 1g BD or 2^nd gen. ceph. E.g. cefuroxime 500mg BD

2) Based on findings (lab)

3) Staph aureus-IV flucloxacilin ( floxapen ) 1-2gms 6hly plus Clarithromycin 500 mg BD 12 hourly

4) Mycoplasma / legionella-macrolide-clarithromycin 500mg BD P.O/I.V or erythromycin/azythromycin. Plus Rifampicin 600 mg BD I.V in severe cases.

5) NB: Erythromycin has a lot of GI problems.

2. History of antibiotic use

Fluoroquinolones e.g. levofloxacine 400mgs BD

For hospital admitted cases

Start on Crystalline penicillin and Gentamycin or erythromycin or

IV ceftriaxone 1-2gms/day or cefuroxime 1.5gms 8hrly or co-amoxi-clav 1.2gms 8hly IV

Discharge patient as soon as stable to avoid hospital acquired pneumonia.

Parameters to consider for discharge:

1. Reduced fever.

2. Improved respiration rate.

3. Blood Pressure.

4. Pulse Rate

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Topic 1.1: PNEUMONIA (Cont) II

Complications of pneumonia

1. Parapneumonic effusions ,

2. Empyema

3. Sputum retention leading to Lobar collapse

4. Pneumothorax particularly with staph aureus.

5. Suppurative pneumonia and Lung abscess.

6. Septicaemia

7. Hepatitis, pericarditis, meningoencephalitis.

8. Ectopic abscess formation esp. with staph aureus.

9. Brain abscess

10. Acute Respiratory Distress Syndrome.(ARDS)

11. Progressive organ failure including renal failure

12. Thrombo embolism (DVT & pulmonary embolism)

13. Persistent fevers-may be drug induced.

DDX

Pulmonary infarction
PTB, pleural TB
Pulmonary oedema
Pulmonary eosinophilia syndrome
Malignancy : Broncho-alveolar carcinoma.
Cryptogenic organizing pneumonia / Bronchiolitis obliterans organizing pneumonia. (COP/BOOP)

Prevention Pneumonia;

Proper ventilation
Vaccination---pneucoccal, H-influenza, Viral≤--measlesinfluenza virus.

HOSPITAL ACQUIRED PNEUMONIA (NOSOCOMIAL PNEUMONIA)

DEF: Any new episode of pneumonia occurring at least two days after hospital admission.

It may include post operative pneumonia or pneumonia in patients with chronic lung disease/ ventilation associated pneumonia for ICU patients etc.

The infection should not have been an incubating problem at admission.

Predisposing factors

1. Reduced host defenses against bacteria as occurs in;

· Immunosuppressive therapy I .e corticosteroid treatment, diabetes malignancy.

· Diabetics

· Patients with malignancies

· Impaired cough reflex –e.g. post operative

· Impaired mucociliary clearance (GA)

· Patients with bulbar and vocal cord palsy

2. Patients with nasopharyngeal secretions or during NG tube insertion

This may lead to aspiration of nasopharyngeal or gastric secretions

· Immobile pts or reduced/altered conscious level.

· Vomiting, dysphagia, Achalasia or severe reflux

· Nasogastric intubation

3. Bacterial inoculation into lower resp. tract as in -;

This is introduction of bacteria into lower respiratory tract by:

· Contaminated ventilators/nebulizers/bronchoscopes

· Endotracheal Intubation/ tracheostomy

· Dental or sinus infection

4. Bacterimia as in;-

· Abdominal sepsis

· I.V Canulation

· Infected emboli.

Aetiology

Epidemiology—2-5%of hospital admissions get nosocomial pneumonia and is the leading cause of all hospital acquired infections.Mortality rate is 20—50%.

The organisms commonly involved are;-

GM Negative Bacteria (majority of cases)-E.coli ,pseudomonas,klebsiella
GM positive bacteria such as-; staphylococcus aureus, Methicillin Resistant Staph Aureus.
Multidrug resistant organisms

Clinical features

Most of the features are as for CAP.

HAP should be considered in any hospitalized or ventilated patient who develops purulent sputum (or endotracheal secretions), new radiological infiltrates, an otherwise unexplained increase in oxygen requirement, a core temperature > 38.3°C, and a leucocytosis or leucopenia. Circulating biomarkers may assist with the diagnosis but are currently non-specific

Nosocomial pneumonia commonly occurs in elderly pts.and presents with; New onset difficulty in breathing, cough sputum production, fevers, and central cyanosis may appear.

Crackles in both lung fields

Investigations

· Lower Respiratory tract secretions – Gm stain/c/s

· Tracheobronchial aspirate- Gm stain, c/s

· Bronchoalveolar lavage- Gm stain, c/s

· FBC- neutrophils leukocytosis

· CXR- mottled opacitis in both lung fields.

Management

1. 3^rd gen. cephalosporins e.g. cefotaxime plus aminogycoside e.g. Gentamycin

2. Carbapenems e.g Meropenem,Imipenem - is a carbapenem beta-lactam antibacterial with actions and uses similar to those of imipenem. Slightly more active than imipenem against Enterobacteriaceae and slightly less active against Gram-positive organisms

3. A monocyclic B-lactam e.g. aztreonam plus flucloxacillan.

4. For methicillin-resistant Staph. aureus (MRSA)- use menozellin 600mg BD/

5. Lincosamides;- vancomycin 30mg/kg /LINESOLID 600MG BD

Hospital admission management

Ceftriaxone 2g IV daily

Piperacillin plus tazobactum 4.5g IV OD, levofloxacillin 750mg IV or moxifloxacin 400mg IV OD

In ICU – imipenem or meropenem.

In case of risk factors of MDR Pneumonia.

Use a 3 drug combination therapy from the following:-

1^st drug : antipseudomonas

1. Ceftazidine or cefapine 2g tid. or

2. Imipenem 500mg Q10 or meropenem 1g tid or

3. Piperacillin 4.5g OD

4. Tazobactam

2^nd drug –a. fluoroquinolone

Ciprofloxacim 400mg IV BD
Levofloxacillin 750mg IV OD
Aminoglycoside
Tobramycin 7mg/kg IV or
Amikacin 20mg/kg IV

3^rd drug for methicillin-resistant Staph. aureus

Lenezolid 600mg IV BD or vancomycin 15mg/kg MD

NB: Dose descalation is advisable. Once you get culture results, Rx as per findings.

Treatment duration1-2 weeks.

Once the patient improves and culture results are negative, discontinue antipseudomonas and meticillin-resistant Staph. aureus drugs.

Prevention

· Prevent aspiration

· Chest physioRX, early ambulation.

· Hand washing

· Gloving/ use of masks

· Avoid acid blocking medications. Most organisms are from GI, therefore do not give H₂ blockers especially in patients in ICU.

· Try non-absorbable antibiotics to decontaminate GI and nasopharyngeal tracts.

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Topic 1.1: PNEUMONIA (C0nt) III

PNEUMONIA IN THE IMMUNOCOMPROMISED.

Infections commonly by Gram negative organisms and opportunistic organisms. The offending organisms are often mixed pathogens.

Pseudomonas aeruginosa are more of a problem than Gm negative organisms.

The common etiologies include:-

Presentation

Clinical features are not as dramatic as in other pneumonias.

Commonly, the patient will have a cough, breathlessness for several days or weeks before onset of systemic symptoms especially in PCP.

Diagnosis requires a high index of suspicion.

Investigations

Getting sputum is difficult

· Bronchoalveolar lavage especially those fit.

· Hypertonic saline expectoration

· CXR- pulmonary infiltrates (diffuses as in Cytomegalovirus, PCP, drug reaction)

Localized infiltrates – staph. aureus, aspergillus fumigatus, candida albicans, cryptococcosis and legionella

N/B HRCT is important in differentiating:

Focal unilateral airspace opacification favours bacterial infection, mycobacteria or nocardia.

Bilateral opacification favours P. jirovecii pneumonia, fungi, viruses and unusual bacteria, e.g. nocardia.

Cavitation may be seen with N. asteroides, mycobacteria and fungi.

The presence of a 'halo sign' may suggest Aspergillus .

Pleural effusions suggest a pyogenic bacterial infection and are uncommon in P. jirovecii pneumonia

Management

History and physical examination
Investigations
Specific pathogens treatment

NB: Treatment is usually started empirically with broad spectrum antibiotic therapy.

· 3^rd gen. cephalosporin or a quinolone + anti-staphylococcal or

· anti-pseudomonal pennicillin + aminoglycosides.

ASPIRATION PNEUMONIA

Pneumonia due to pulmonary consequences that result from abnormal entry of fluid, particulate exogenous substances and endogenous secretion into the lower respiratory tract.

It usually occurs due to compromised defenses of the lower respiratory tract e.g. Glottic closure and cough reflex. The inoculum can result into:

· Direct toxicity

· Inflammation

· Obstruction

Risk factor include:-

1. Patients with alt. level of consciousness

· Aspiration of vomitus or septic materials during GA or coma.

2. Patients with oesophageal diseases- Aspiration of acidic gastric contents can give rise to a severe H’gic pneumonia often complicated by ARDS.

This may occur in oesophagealreflux and alcoholism, achalasia, bulbar or vocal cord palsy.

3. Surgery of URT- tracheostomy, bronchoscopy or opn. on the nose, mouth or throat under GA which can cause inhalation of septic material into the lungs

Classification of end results of aspiration into lungs:-

1. Chemical pneumonitis

Aspirated usually acid/ liquid form.

Patient comes with sudden onset dyspnea, tachypnea, cyanosis and bronchospasm.

Management: Positive pressure ventilation and tracheal suction

2. Bacterial infection

Usually with anaerobic bacteria.

Presents with insidious onset- cough, fever, sputum production.

Management: Antibiotics e.g. clindamycin, co-amoxiclav + metromidazole

3. Mechanical obstruction by inert fluid

This causes mechanical obstruction leading to reflex closure.

Management: Positive pressure ventilation & Tracheal suction

4. Mechanical obstruction by particulate matter

Rx- extract obstructing particle

Give antibiotics incase of bacterial super infection.

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Topic 1.2: ASTHMA

Definition;

Asthma is a clinical syndrome of unknown etiology characterized by three distinct components:

1. Recurrent episodes of airway obstruction that resolve spontaneously or as a result of treatment;

2. Exaggerated bronchoconstrictor response to stimuli that have little or no effect in nonasthmatic subjects, a phenomenon known as airway hyperresponsiveness;

3. Inflammation of the airways as defined by a variety of criteria.

Although airway obstruction is largely reversible, it is currently thought that changes in the asthmatic airway may be irreversible in some settings.

Epidemiology;

Asthma is an extremely common disorder affecting boys more commonly than girls and, after puberty, women slightly more commonly than men.

Although most cases begin before the age of 25 years, asthma may develop at any time throughout life.

The worldwide prevalence of asthma has increased more than 45% since the late 1970s.

The greatest increases in asthma prevalence have occurred in countries that have recently adopted an “industrialized” lifestyle. Although a variety of theories have been proposed, the reasons for the overall increase in prevalence of asthma are not known.

Asthma is among the most common reasons to seek medical treatment.

The yearly direct and indirect costs of asthma care are more than $8 billion; more than 80% of these costs are attributable to direct expenditures on medical care encounters or asthma medications

Genetics;

In twin studies, asthma has about 60% heritability, indicating that both genetic and environmental factors are important in its etiology.

Despite this evidence for a substantial genetic contribution to the biology of asthma and identification of a number of candidate genes, no discovered genetic variant has enhanced risk for the asthma phenotype across all populations.

Multiple genetic variants account for the heritability of asthma in a given individual and that variations in different genes contribute to expression of the phenotype across a population. Genetic variants that influence the response to treatment also have been identified.

Pathology of asthma;

The pathology of mild asthma, as delineated by bronchoscopic and biopsy studies, is characterized by edema and hyperemia of the mucosa and by infiltration of the mucosa with mast cells, eosinophils, lymphocytes bearing the T_H2 phenotype, and a newly identified subset of T cells, CD1d-restricted natural killer T cells.

These last cells express a conserved (invariant) T-cell receptor and have potent immunoregulatory function. These cells create an environment that promotes the synthesis of immunoglobulin E (IgE), an important allergic effector molecule. Chemokines such as eotaxin, RANTES, macrophage inflammatory protein 1α, and interleukin-8, produced by epithelial and inflammatory cells, and the loss of the T-cell signaling molecule T-bet serve to amplify and to perpetuate the inflammatory events within the airway.

As a result of these inflammatory stimuli coupled with the mechanical deformation of the epithelium from airway smooth muscle constriction, the airway wall is thickened by the deposition of type III and type V collagen below the true basement membrane. In addition, in severe chronic asthma, there is hypertrophy and hyperplasia of airway glands and secretory cells as well as hyperplasia of airway smooth muscle.

Morphometric studies of airways from asthmatic subjects have demonstrated airway wall thickening of sufficient magnitude to increase airflow resistance and enhance airway responsiveness. During a severe asthmatic event, the airway wall is thickened markedly; in addition, patchy airway occlusion occurs by a mixture of hyperviscous mucus and clusters of shed airway epithelial cells.

The episodic airway narrowing that constitutes an asthma attack results from obstruction of the airway lumen to airflow.

Although it is now well established that asthma is associated with infiltration of the airway by inflammatory cells, the links between these cells and the pathobiologic processes that account for asthmatic airway obstruction have not been clearly delineated. Three possible but not mutually exclusive links have been postulated:

1. The constriction of airway smooth muscle,

2. Thickening of airway epithelium, and

3. Presence of liquids within the confines of the airway lumen.

Among these mechanisms, the constriction of airway smooth muscle due to the local release of bioactive mediators or neurotransmitters is the most widely accepted explanation for the acute reversible airway obstruction in asthma attacks. Several bronchoactive mediators are thought to be the agents that initiate the airway obstruction characteristic of asthma.

Mediators of the Acute Asthmatic Response;

Four different mediators have been identified;

1) Acetylcholine;

Acetylcholine released from intrapulmonary motor nerves causes constriction of airway smooth muscle through direct stimulation of muscarinic receptors of the M₃ subtype.

The potential role for acetylcholine in the bronchoconstriction of asthma primarily derives from the observation that atropine and its congeners have some bronchodilator action, albeit less than β-agonists, when they are administered by inhalation for the treatment of asthma.

2) Histamine;

Histamine, or β-imidazolylethylamine, was identified as a potent endogenous bronchoactive agent nearly 100 years ago.

Mast cells, which are prominent in airway tissues obtained from patients with asthma, constitute the major pulmonary source of histamine.

Clinical trials with novel potent antihistamines indicate a minor role for histamine as a mediator of airway obstruction in asthma.

3) Leukotrienes and Lipoxins;

The cysteinyl leukotrienes, namely, LTC₄, LTD₄, and LTE₄, as well as the dihydroxy leukotriene LTB₄ are derived by the lipoxygenation of arachidonic acid released from target cell membrane phospholipids during cellular activation.

5-Lipoxygenase, the 5-lipoxygenase–activating protein, and LTC₄ synthase make up the cellular protein and enzyme content needed to produce the cysteinyl leukotrienes. The production of LTB₄ requires 5-lipoxygenase, the 5-lipoxygenase–activating protein, and LTA₄ epoxide hydrolase.

Mast cells, eosinophils, and alveolar macrophages have the enzymatic capability to produce cysteinyl leukotrienes from their membrane phospholipids, whereas polymorphonuclear leukocytes produce exclusively LTB₄, which is predominantly a chemoattractant molecule; LTC₄ and LTD₄ are among the most potent contractile agonists ever identified for human airway smooth muscle.

Clinical trials with leukotriene receptor antagonists or synthesis inhibitors have shown significant clinical efficacy in the treatment of chronic persistent asthma, leading to the conclusion that the leukotrienes are important but not exclusive mediators of the asthmatic response. Lipoxins are double lipoxygenase products of arachidonic acid metabolism and are thought to be endogenous downregulators of the inflammatory response. Their role in human asthma remains inferential.

4) Nitric Oxide

Nitric oxide (NO) is produced enzymatically by airway epithelial cells and by inflammatory cells found in the asthmatic lung.

Free NO has a half-life on the order of seconds in the airway and is stabilized by conjugation to thiols to form RS-NO. Both NO and RS-NO have bronchodilator actions and may play a homeostatic role in the airway. Paradoxically, high levels of NO, when it is coavailable with superoxide anion, may form toxic oxidation products, such as peroxynitrite (OONO^-), which could damage the airway.

Patients with asthma have higher than normal levels of NO in their expired air, and these levels decrease after treatment with corticosteroids. Placebo-controlled trials have demonstrated that the fraction of nitric oxide in the exhaled air can serve as a marker for changes in the airway that necessitate escalation of asthma treatment.

Physiologic Changes in Asthma;

An increased resistance to airflow is the consequence of the airway obstruction induced by smooth muscle constriction, thickening of the airway epithelium, or free liquid within the airway lumen.

Resistance to airflow is manifested by increased airway resistance and decreased flow rates throughout the vital capacity.

At the onset of an asthma attack, obstruction occurs at all airway levels; as the attack resolves, these changes are reversed—first in the large airways (i.e., mainstem, lobar, segmental, and subsegmental bronchi) and then in the more peripheral airways.

This anatomic sequence of onset and reversal is reflected in the physiologic changes observed during resolution of an asthmatic episode . Specifically, as an asthma attack resolves, flow rates first normalize at a high point in the vital capacity and only later at a low point in the vital capacity.

Because asthma is an airway disease, not an air space disease, no primary changes occur in the static pressure-volume curve of the lungs. However, during an acute attack of asthma, airway narrowing may be so severe as to result in airway closure, with individual lung units closing at a volume that is near their maximal volume. This closure results in a change of the pressure-volume curve such that for a given contained gas volume within the thorax, elastic recoil is decreased, which in turn further depresses expiratory flow rates.

Clinical Manifestations of asthma;

1. Dyspnoea- shortness of breath.

2. Cough,

3. Wheezing, and

4. Anxiety.

The degree of breathlessness experienced by the patient is not closely related to the degree of airflow obstruction but is often influenced by the acuteness of the attack.

Dyspnea may occur only with;

1) Exercise (exercise-induced asthma),

2) Aspirin ingestion (aspirin-induced asthma),

3) Exposure to a specific known allergen (extrinsic asthma),

4) For no identifiable reason (intrinsic asthma).

Variants of asthma exist in which cough, hoarseness, or inability to sleep through the night is the only symptom.

Identification of a provoking stimulus through careful questioning helps establish the diagnosis of asthma and may be therapeutically useful if the stimulus can be avoided.

Most patients with asthma complain of shortness of breath when they are exposed to rapid changes in the temperature and humidity of inspired air. For example, during the winter months in less temperate climates, patients commonly become short of breath on leaving a heated house; in warm humid climates, patients may complain of shortness of breath on entering a cold dry room, such as an air-conditioned theater.

An important factor to consider in taking a history from a patient with asthma is the potential for occupational exposures leading to the asthmatic diathesis. In such cases, preexisting asthma may be exacerbated or asthma may occur de novo after workplace exposure; it is this clue that eventually leads to the diagnosis of occupational asthma. However, one cannot depend on a reversal of asthmatic symptoms when the patient is removed from the offending environment.

Physical Examination of asthmatic patient;

1. Vital Signs

i. Common features noted during an acute attack of asthma include a rapid respiratory rate (often 25 to 40 breaths per minute),

ii. Tachycardia, and

iii. Pulsus paradoxus (an exaggerated inspiratory decrease in the systolic pressure). The magnitude of the pulsus is related to the severity of the attack.

iv. Pulse oximetry, with the patient respiring ambient air, commonly reveals an oxygen saturation near 90%.

2. Thoracic Examination

i. Inspection may reveal that patients experiencing acute attacks of asthma are using their accessory muscles of ventilation; if so, the skin over the thorax may be retracted into the intercostal spaces during inspiration.

ii. The chest is usually hyperinflated, and the expiratory phase is prolonged relative to the inspiratory phase.

iii. Percussion of the thorax demonstrates hyperresonance, with loss of the normal variation in dullness due to diaphragmatic movement;

iv. Tactile fremitus is diminished.

v. Auscultation reveals wheezing, which is the cardinal physical finding in asthma but does not establish the diagnosis. Wheezing, commonly louder during expiration but heard during inspiration as well, is characterized as polyphonic in that more than one pitch may be heard simultaneously. Accompanying adventitious sounds may include rhonchi, which are suggestive of free secretions in the airway lumen, or rales, which should raise the suspicion of an alternative diagnosis and are indicative of localized infection or heart failure.

vi. The loss of intensity or the absence of breath sounds in a patient with asthma is an indication of severe airflow obstruction.

Diagnosis of asthma;

Laboratory Findings

1. Pulmonary Function Tests;

i. A decrease in airflow rates throughout the vital capacity is the cardinal pulmonary function abnormality during an asthmatic episode.

ii. The peak expiratory flow rate (PEFR), the forced expiratory volume in the first second (FEV1), and the maximal mid-expiratory flow rate (MMEFR) are all decreased in asthma . In severe asthma, dyspnea may be so severe as to prevent the patient from performing a complete spirogram.

TEST	FEV₁ PREDICTED VALUE	LEVEL OF ASTHMA
FEV₁	>80% predicted value	No spirometric abnormalities.
	71-79%	Mild
	45-70	Moderate
	<50%	Severe

2. Exhaled NO;

The fraction of NO in the exhaled air (FENO) is elevated in patients with asthma.

Although the exact concentration considered “elevated” will vary with the details of the technique, a concentration of 15 parts per billion is a convenient and reliable level that can be used to distinguish normal subjects from patients with untreated asthma. Because inhaled steroids suppress Feno levels, these values can guide titration of the dose of inhaled corticosteroids and are better than use of symptoms for this purpose

3. Arterial Blood Gases;

Blood gas analysis need not be undertaken in individuals with mild asthma. If the asthma is of sufficient severity to merit prolonged observation, however, blood gas analysis is indicated; in such cases, hypoxemia and hypocapnia are the rule.

With the subject breathing ambient air, the Pao₂ is usually between 55 and 70 mm Hg and the Paco₂ between 25 and 35 mm Hg. At the onset of the attack, an appropriate pure respiratory alkalemia is usually evident; with attacks of prolonged duration, the pH normalizes as a result of a compensatory metabolic acidemia.

A normal Paco₂ in a patient with moderate to severe airflow obstruction is reason for concern because it may indicate that the mechanical load on the respiratory system is greater than can be sustained by the ventilatory muscles and that respiratory failure is imminent.

When the Paco₂ increases in such settings, the pH decreases quickly because the bicarbonate stores have become depleted as a result of renal compensation for the prolonged preceding respiratory alkalemia. Because this chain of events can take place rapidly, close observation is indicated for asthmatic patients with “normal” Paco₂ levels and moderate to severe airflow obstruction.

4. Serology/Immunoglobulins;

Asthmatic subjects are frequently atopic; thus, blood eosinophilia is common.

In addition, elevated serum levels of IgE are often documented; epidemiologic studies indicate that asthma is unusual in subjects with low IgE levels. If indicated by the patient's history, specific radioallergosorbent tests, which measure IgE directed against specific offending antigens, can be conducted.

In rare instances during severe asthma attacks, serum concentrations of aminotransferases, lactate dehydrogenase, muscle creatine kinase, ornithine transcarbamylase, and antidiuretic hormone may be elevated.

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Topic 1.2: ASTHMA (Cont')

5. Radiographic Findings;

The chest radiograph of a subject with asthma is often normal.

Severe asthma is associated with hyperinflation, as indicated by depression of the diaphragm and abnormally lucent lung fields.

Complications of severe asthma, including pneumomediastinum or pneumothorax, may be detected radiographically. In mild to moderate asthma without adventitious sounds other than wheezing, a chest radiograph need not be obtained; if the asthma is of sufficient severity to merit hospital admission, a chest radiograph is advised.

6. Electrocardiographic Findings;

The electrocardiogram, except for sinus tachycardia, is usually normal in acute asthma. However, right axis deviation, right bundle branch block, “P pulmonale,” or even ST-T wave abnormalities may arise during severe asthma and resolve as the attack resolves.

7. Sputum Findings;

The sputum of the asthmatic patient may be either clear or opaque with a green or yellow tinge.

The presence of color does not invariably indicate infection, and examination of a Gram-stained and Wright-stained sputum smear is indicated.

The sputum often contains

i. Eosinophils,

ii. Charcot-Leyden crystals (crystallized eosinophil lysophospholipase),

iii. Curschmann's spirals (bronchiolar casts composed of mucus and cells), or

iv. Creola bodies (clusters of airway epithelial cells with identifiable cilia), which can affect color without the presence of infection.

Rx of asthma;

1. Rescue treatment.

2. Controller treatment.

Rescue treatment of asthma;

All patients with asthma should be prescribed a rescue inhaler to use if they develop acute asthmatic airway obstruction.

1) β-Adrenergic Agents;

β-Adrenergic agents given by inhalation are the mainstay of bronchodilator treatment of asthma. Constricted airway smooth muscle relaxes in response to stimulation of β₂-adrenergic receptors. β-Adrenergic agonists with varying degrees of β₂-selectivity are available for use in;

a. Inhaled (by nebulizer or metered-dose inhaler;),

b. Oral, or

c. parenteral preparations. Most patients with mild intermittent asthma should be treated with a moderate-duration β₂-selective inhaler on an as-needed basis.

Regardless of the specific type of medication used, rescue treatment should consist of two “puffs” from the inhaler, with the first and second puffs separated by a 3- to 5-minute interval, which is thought to allow enough time for the first puff to dilate narrowed airways, thus giving the agent better access to affected areas of the lung.

Patients should be instructed to exhale to a comfortable volume, to breathe in very slowly (such as they would when sipping hot soup), and to actuate the inhaler as they inspire.

Inspiration to near total lung capacity is followed by holding the breath for 5 seconds to allow the deposition of smaller aerosol particles in more peripheral airways. This treatment can be repeated every 4 to 6 hours.

Patients should receive specific instructions for correct inhaler use. Aerosol “spacers” are available from many manufacturers for patients who have difficulty coordinating their inspiratory effort and inhaler actuation. There is definitive evidence from prospective, randomized, placebo-controlled trials that the regularly scheduled use of prophylactic inhaled β-agonists has no deleterious effects in most patients with asthma.

In 2008, inhalers containing chlorofluorocarbon propellants were withdrawn from the market and replaced by inhalers powered by hydrofluoroalkanes. These new inhalers have a lower velocity aerosol plume, so patients will notice a subjective difference in how the aerosol feels as it is dissipated into the mouth; nevertheless, clinical trials document that most hydrofluoroalkane inhalers will have nearly identical therapeutic effects.

3. Anticholinergics;

Atropinic agents inhibit the effects of acetylcholine released from the intrapulmonary motor nerves that run in the vagus and innervate airway smooth muscle.

Ipratropium bromide, the atropinic agent used therapeutically in asthma, is available in a metered-dose inhaler; the recommended dose is two puffs from a metered-dose inhaler every 4 to 6 hours.

Controller Treatments

1. Inhaled Corticosteroids

Inhaled corticosteroids , which have less systemic impact for a given level of therapeutic effect than systemic steroids, are effective controller treatments for improving lung function and preventing asthmatic exacerbations in patients with persistent asthma.

However, inhaled corticosteroids do not change the natural history of asthma. A wide variety of inhaled corticosteroid products are on the market. All available products are effective treatments of persistent asthma but differ in terms of the;

i. Magnitude of adrenal suppression.

ii. The potential for systemic effects, including;

a. Growth retardation in children,

b. Loss of bone mineralization,

c. Cataracts, and

d. Glaucoma.

Overall, no convincing data are available to suggest that there is reason to prefer one corticosteroid over the others.

An adverse effect common to all inhaled corticosteroids, at recommended doses, is oral thrush and hoarseness of voice (from myopathy of the laryngeal muscles); the risk and severity of this complication can be reduced by use of aerosol spacers and good oropharyngeal hygiene (i.e., rinsing out the mouth by gargling after dosing).

2. Antileukotrienes/Leukotrene antagonists;

Agents with the capacity to inhibit the synthesis of the leukotrienes;

i. Zileuton 600 mg four times daily; liver function should be monitored for the first 3 to 6 months of treatment; if levels rise to more than three times the upper limit of normal, the drug should be stopped)

ii. Action of leukotrienes at the CysLT₁ receptor (montelukast [Singulair], 10 mg once a day;

iii. Pranlukast (Onon, Ultair), 225 mg twice a day, available in Japan only;

iv. Zafirlukast (Accolate), 20 mg twice a day) are effective oral controller medications for patients with mild or moderate persistent asthma.

These treatments can be used on their own for mild persistent asthma or in combination with inhaled steroids for more severe asthma.

3. Long-Acting β-Agonists

In contrast to medium-acting β-agonists, long-acting β-agonists currently available include;

i. Salmeterol (Serevent, 42 μg per puff; the same dose is labeled 50 μg per puff outside of the United States; one or two puffs should be delivered every 12 hours) and

ii. Formoterol Foradil, 12 μg through a proprietary dry powder inhaler every 12 hours) have a duration of action of nearly 12 hours; they are considered a controller rather than a bronchodilator agent.

Randomized controlled trials demonstrate that long-acting βagonists should not be used as a sole controller agent.

Other trials have shown that there are excess asthma deaths (about one for every 650 patient years of treatment) when long-acting β-agonists are used.

Therefore, long-acting β-agonists should be used only when they are given in concert with inhaled corticosteroids. Combination products with both inhaled steroids and long-acting β-agonists in the same aerosol device are available. These agents provide benefit because the patient needs to use only a single device, but they may not be cost-effective and do not allow variation in the proportions of medications delivered.

4. Theophylline;

Theophylline and its more water soluble congener aminophylline are bronchodilators of moderate potency that are useful in both inpatient and outpatient management of asthma.

Theophylline is sold in a large number of formulations that allow therapy to proceed with daily or twice-daily dosing. The mechanism by which theophylline exerts its effects has not been established with certainty but is probably related to the inhibition of certain forms of phosphodiesterase.

The utility of theophylline is limited by its toxicity and by wide variations in the rate of its metabolism, both in a single individual over time and among individuals in a population. There are multiple preparations of theophylline available on the market that vary in their duration of action. As a result of this variability, the starting dose should be about 300 mg/day; the frequency will depend on the preparation used.

Plasma theophylline levels should be monitored to ensure that patients are treated appropriately.

Acceptable plasma levels for therapeutic effects are between 10 and 20 μg/mL; higher levels are associated with gastrointestinal, cardiac, and central nervous system toxicity, including

i. Anxiety,

ii. Headache,

iii. Nausea,

iv. Vomiting,

v. Diarrhea,

vi. Cardiac arrhythmias, and

vii. Seizures.

These last catastrophic complications may occur without antecedent mild side effects when plasma levels exceed 20 μg/mL. Because of these potentially life-threatening complications of treatment, plasma levels need to be measured with great frequency in hospitalized patients receiving intravenous aminophylline and less frequently in stable outpatients receiving one of the long-acting theophylline preparations.

Most asthma care providers use dosing amounts and intervals to achieve steady-state theophylline levels of 10 to 14 μg/mL, thereby avoiding the toxicity associated with decrements in metabolism.

Treatment with theophylline is recommended only for patients with moderate or severe persistent asthma who are receiving controller medications, such as inhaled steroids or antileukotrienes, but whose asthma is not adequately controlled.

5. Systemic Corticosteroids;

Systemic corticosteroids are effective for the treatment of moderate to severe persistent asthma as well as for occasional severe exacerbations of asthma that occur in a patient with otherwise mild asthma, but the mechanism of their therapeutic effect has not been established.

No consensus has been reached on the specific type, dose, or duration of corticosteroid to be used in the treatment of asthma.

In nonhospitalized patients with asthma refractory to standard therapy, a steroid “pulse” with initial doses of prednisone on the order of 40 to 60 mg/day, tapered to zero during 7 to 14 days, is recommended.

For patients who cannot stop taking steroids without having recurrent uncontrolled bronchospasm despite the addition of multiple other controller treatments, alternate-day administration of oral steroids is preferable to daily treatment.

For patients whose asthma requires in-hospital treatment but is not considered life-threatening, an initial intravenous bolus of 2 mg/kg of hydrocortisone, followed by continuous infusion of 0.5 mg/kg/hr, has been shown to be beneficial within 12 hours.

In attacks of asthma that are considered life-threatening, the use of intravenous methylprednisolone (125 mg every 6 hours) has been advocated. In each case, as the patient improves, oral steroids are substituted for intravenous steroids, and the oral dose is tapered during 1 to 3 weeks; addition of inhaled steroids to the regimen is strongly recommended when oral steroids are started.

6. Anti-IgE Treatment;

Subcutaneous administration of omalizumab, a humanized murine monoclonal antibody that binds circulating IgE, is associated with decreased serum free (not total) IgE levels.

In patients who have moderate to severe allergic asthma with elevated levels of serum IgE and who are receiving inhaled corticosteroids, omalizumab treatment improves asthma control even as doses of inhaled steroids are decreased. Dosing is guided by weight and by pretreatment IgE levels: a monthly subcutaneous dose of 0.016 mg × body weight (kg) × IgE level (IU/mL).

7. Other Controller Drugs;

1) Cromolyn sodium (one or two puffs from a metered-dose inhaler three or four times a day) and

2) Nedocromil sodium (two puffs from a metered-dose inhaler three or four times a day)

3) Magnesium Sulphate.

These are nonsteroid inhaled treatments that have proved beneficial in the management of mild to moderate persistent asthma. They appear to be most useful in pediatric populations or when an identifiable stimulus (such as exercise or allergen exposure) elicits an asthmatic response.

The use of systemic gold (as in rheumatoid arthritis), methotrexate, or cyclosporine has been suggested as adjunctive treatment of patients with severe chronic asthma who cannot otherwise discontinue high-dose corticosteroid treatment. However, these agents are experimental, and their routine use is not advocated.

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Topic 1.3: PULMONARY TB

Aetiology; Mycobacterium tuberculosis.

Risk factors for the acquisition of tuberculosis (TB) are usually exogenous to the patient.

1. Host factors.

1) Immune suppression.

2) Stage of infection, patients with bacteriological confirmed TB and not on treatment are highly infectious.

3) Persons who have received anti-TB drugs are much less infectious than those who have not received any treatment. This decline in infectiousness is due primarily to reduction in the bacillary population in the lungs.

4) Bacillary population of TB lesions varies and depends on the morphology of the lesion. Nodular lesions have 100-10,000 organisms, whereas cavitary lesions have 10 million to 1 billion bacilli.

Thus, persons with cavitary lesions are highly infectious.

Also, contacts of persons with sputum-positive smears have an increased prevalence of infection as opposed to contacts of those with sputum-negative smears.

Poor cough hygiene increases infectiousness.

Tuberculosis has been reported in patients treated for arthritis, inflammatory bowel disease, and other conditions with tumor necrosis factor (TNF)-alpha blockers/antagonists

2. Aetiology/agent factors.

1) Virulence of the strain e.g drug sensitive or resistant TB.

Among the several virulence factors in the mycobacterial cell wall are

i. The cord factor- . Cord factor is a surface glycolipid present only in virulent strains that causes M tuberculosis to grow in serpentine cords in vitro.

ii. Lipoarabinomannan (LAM)- LAM is a heteropolysaccharide that inhibits macrophage activation by interferon (IFN)-gamma and induces macrophages to secrete TNF-alpha, which causes fever, weight loss, and tissue damage.

iii. A highly immunogenic 65-kd M tuberculosis heat shock protein.

The organism is slow growing and tolerates the intracellular environment, where it may remain metabolically inert for years before reactivation and disease.

The main determinant of the pathogenicity of TB is its ability to escape host defense mechanisms, including macrophages and delayed hypersensitivity responses.

Although a single organism may cause disease, 5-200 inhaled bacilli are usually necessary for infection.

The small size of the droplets allows them to remain suspended in the air for a prolonged time period.

Primary infection of the respiratory tract occurs as a result of inhalation of these aerosols. The risk of infection is increased in small enclosed areas and in areas with poor ventilation.

Upon inhalation, the bacilli are deposited (usually in the midlung zone) into the distal respiratory bronchiole or alveoli, which are subpleural in location. Subsequently, the alveolar macrophages phagocytose the inhaled bacilli.

However, these naïve macrophages are unable to kill the mycobacteria, and the bacilli continue to multiply unimpeded.

2) Bacterial factors e.g the bilayers lipotechoic membrane giving resistant to lysozymes.

3. Environment.

1) Poor ventilation.

2) Over crowding e.g in army barracks, schools etc.

The infective droplet nucleus is very small, measuring 5 µm or less, and may contain approximately 1-10 bacilli.

Other Mycobateriaceae.

i. Mycobacterium bovis

ii. Mycobacterium Africanum

Factors contributing to decline in TB cases in some settings;

Increased awareness of the disease,
The institution of more aggressive preventive measures,
Improvement in healthcare strategies (eg, prompt identification and treatment of patients with TB), and
Highly active antiretroviral therapy (HAART) for individuals with HIV infection have contributed to this decline.

However, a huge reservoir of individuals who are infected with M tuberculosis remains.

Pathology of TB disease;

From the primary site of infection, transportation of the infected macrophages to the regional lymph nodes then occurs.

Lymphohematogenous dissemination of the mycobacteria travels to other lymph nodes, the kidney, epiphyses of long bones, vertebral bodies, juxtaependymal meninges adjacent to the subarachnoid space, and, occasionally, to the apical posterior areas of the lungs.

In addition, chemotactic factors released by the macrophages attract circulating monocytes to the site of infection, leading to differentiation of the monocytes into macrophages and ingestion of free bacilli. Logarithmic multiplication of the mycobacteria occurs within the macrophage at the primary site of infection.

Immune response to TB infection;

A cell-mediated immune (CMI) response terminates the unimpeded growth of the M tuberculosis 2-3 weeks after initial infection.

CD4 helper T cells activate the macrophages to kill the intracellular bacteria with resultant epithelioid granuloma formation.

CD8 suppressor T cells lyse the macrophages infected with the mycobacteria, resulting in the formation of caseating granulomas.

Mycobacteria cannot continue to grow in the acidic extracellular environment, so most infections are controlled.

TNF is a potent inflammatory cytokine that plays an important role in immune defense against M tuberculosis. TNF-mediated innate immune responses, including phagolysosomal maturation and cell-mediated responses (eg, IFN-gamma secretion by memory T cells, complement-mediated lysis of M tuberculosis –reactive CD8+ T cells) are important immune responses in M tuberculosis infection.

Evidence of infection includes a positive tuberculin skin test (TST) result or a positive IFN-gamma release assay (IGRAs) finding. However, the initial pulmonary site of infection and its adjacent lymph nodes (ie, primary complex or Ghon focus) sometimes reach sufficient size to develop necrosis and subsequent radiographic calcification.

Disease progression

Progression of the primary complex may lead to enlargement of hilar and mediastinal nodes with resultant bronchial collapse.

Progressive primary TB may develop when the primary focus cavitates and organisms spread through contiguous bronchi.

Lymphohematogenous dissemination, especially in young patients, may lead to miliary TB when caseous material reaches the bloodstream from a primary focus or a caseating metastatic focus in the wall of a pulmonary vein (Weigert focus).

TB meningitis may also result from hematogenous dissemination. Bacilli may remain dormant in the apical posterior areas of the lung for several months or years, with later progression of disease resulting in the development of reactivation-type TB (ie, endogenous reinfection TB).

Clinical features of PTB

Constitutional symptoms

1) Fatigue.gen lassitude

2) Weight loss

3) Anorexia

4) Persistent fever

5) Night sweats

Pulmonary symptoms

Cough; initially dry, later productive with haemoptysis.

NB. Upto 5% of cases are diagnosed at autopsy

SIGNS

Wasting due to wt loss poor appetite
Low grade fever
May be pale
Finger clubbing
Decreased Air entry in a specific lobe
Dullness on percussions
Bronchial breathing due to consolidation

The presence of a cavity will give amphoric breath sounds-hollow sounds as in blowing into a jar.
Endobronchial TB gives localized wheeze.

EXTRAPULMONARY TB

Accounts for about 20% of cases in HIV negative pts and is more common in +ve pts.

The most common sites affected are;

LN – lymphademites TB
Bones - TB bone

Serous membranes– tuberculous pericarditis, Tb peritoneum, TB of the gut- ileocaecal disease etc.
GUT- renal TB prostatitis etc
Brain – TBM
Disseminated TB - milliary

NB. The most serious forms are desseminated TB and TBM.

TB EVALUATION BASED ON CLINICAL FINDING AND TREATMENT

Any patient with

1) Cough of any duration.

2) Pneumonia,

3) Pleural effusion, or a cavitary or mass lesion in the lung that does not improve with standard antibacterial therapy

4) Fever of unknown origin.

5) Failure to thrive

6) Significant weight loss.

7) Unexplained lymphadenopathy.

should be evaluated for TB.

TB PLEURAL EFFUSION

Pleural effusions due to TB usually occur in older children and are rarely associated with miliary disease.

The typical history reveals an acute onset of fever, chest pain that increases in intensity on deep inspiration, and shortness of breath.

Fever usually persists for 14-21 days.

Signs include

1. Tachypnea,

2. Respiratory distress,

3. Dullness to percussion,

4. Decreased breath sounds, and,

5. Occasionally, features of mediastinal shift.

REACTIVATION TB

Reactivation of TB disease usually has a subacute presentation with

1. Weight loss,

2. Fever,

3. Cough, and,

4. Rarely, hemoptysis.

This condition typically occurs in older children and adolescent and is more common in patients who acquire TB at age 7 years and older.

Physical examination results may be normal or may reveal posttussive crackles.

TB Lymphadenopathy

Patients with lymphadenopathy (ie, scrofula) may have

1) History of enlarged nodes.

2) Fever,

3) Weight loss,

4) Fatigue, and

5) Malaise. Both usually absent or minimal.

Lymph node involvement typically occurs 6-9 months following initial infection by the tubercle bacilli. More superficial lymph nodes commonly are involved.

Frequent sites of involvement include

i. The anterior cervical,

ii. Submandibular, and

iii. Supraclavicular nodes.

TB of the skeletal system may lead to involvement of the inguinal, epitrochlear, or axillary lymph nodes.

Typically, infected lymph nodes are

1. Firm and nontender with

2. Nonerythematous overlying skin.

3. Initially nonfluctuant.

Suppuration and spontaneous drainage of the lymph nodes may occur with caseation and the development of necrosis.

Endobronchial ultrasound (EBUS) transbronchial needle aspiration (TBNA) for the diagnosis of tuberculous mediastinal lymphadenitis is a safe and well tolerated procedure in the assessment of patients with suspected isolated mediastinal lymphadenitis.

EBUS-TBNA should be considered the procedure of choice for patients in whom TB is suspected.

TB MENINGITIS

One of the most severe complications of TB is TB meningitis.

A subacute presentation usually occurs within 3-6 months after the initial infection. Nonspecific symptoms such as anorexia, weight loss, and fever may be present. After 1-2 weeks, patients may experience vomiting and seizures or alteration in the sensorium. Deterioration of mental status, coma, and death may occur despite prompt diagnosis and early intervention.

Three stages of TB meningitis have been identified.

1. Stage 1 is defined by the absence of focal or generalized neurologic signs. Possibly, only nonspecific behavioral abnormalities are found.

2. Stage 2 is characterized by the presence of nuchal rigidity, altered deep tendon reflexes, lethargy, and/or cranial nerve palsies. TB meningitis most often affects the sixth cranial nerve due to the pressure of the thick basilar inflammatory exudates on the cranial nerves or to hydrocephalus; this results in lateral rectus palsy. The third, fourth, and seventh cranial nerves may also be affected. Funduscopic changes may include papilledema and the presence of choroid tubercles, which should be carefully sought.

3. Stage 3, the final stage, comprises major neurologic defects, including coma, seizures, and abnormal movements (eg, choreoathetosis, paresis, paralysis of one or more extremities). In the terminal phase, decerebrate or decorticate posturing, opisthotonus, and/or death may occur. Patients with tuberculomas or TB brain abscesses may present with focal neurologic signs. Spinal cord disease may result in the acute development of spinal block or a transverse myelitis–like syndrome. A slowly ascending paralysis may develop over several months to years.

MILIARY TB

This is a complication of primary TB . Miliary TB may manifest subacutely with

1. low-grade fever,

2. Malaise,

3. Weight loss, and fatigue.

A rapid onset of fever and associated symptoms may also be observed. History of cough and respiratory distress may be obtained.

Physical examination findings

1. Lymphadenopathy,

2. Hepatosplenomegaly, and systemic signs including fever.

3. Respiratory signs may evolve to include;

1) Tachypnea,

2) Cyanosis, and respiratory distress.

4. Papular, necrotic, or purpuric lesions on the skin or choroidal tubercles in the retina.

BONE OR JOINT TB

Skeletal TB may present acutely or subacutely. Vertebral disease may go unrecognized for months to years because of its indolent nature. Common sites involved include the large weightbearing bones or joints, including

1. The vertebrae (50%),

2. Hip (15%), and

3. Knee (15%).

Destruction of the bones with deformity is a late sign of TB. Manifestations may include

1) Angulation of the spine (gibbus deformity)

2) Pott disease (severe kyphosis with destruction of the vertebral bodies).

3) Cervical spine involvement may result in atlantoaxial subluxation, which may lead to paraplegia or quadriplegia.

DIFFERENTIALS DX OF TB;

The following conditions should also be considered in cases of suspected TB:

SPECIMEN COLLECTION FOR DIAGNOSIS OF TB;

1. Examination of sputum,

2. Gastric lavage,

3. Bronchoalveolar lavage,

4. Lung tissue,

5. Lymph node tissue,

6. Bone marrow,

7. Blood,

8. Liver,

9. Cerebrospinal fluid (CSF),

10. Urine, and

11. Stool may be useful, depending on the location of the disease.

Decontamination of other microorganisms in the specimens obtained may be performed by the addition of sodium hydroxide, usually in combination with N -acetyl-L -cysteine.

Other body fluids (eg, CSF, pleural fluid, peritoneal fluid) can also be centrifuged; the sediment can be stained and evaluated for presence of acid-fast bacilli (AFB).

CSF smear results are positive in fewer than 10% of patients in some series. Enhancement of the yield may be possible by staining any clot that may have formed in standing CSF specimens, as well as using the sediment of a centrifuged specimen. Increased yield may also be obtained from cisternal or ventricular fluid.

Sputum specimens

Sputum specimens is used in adults and older children, but not in very young children (< 6 y), who usually do not have a cough deep enough to produce sputum for analysis. In those younger than 6 years, gastric aspirates are used.

Nasopharyngeal secretions and saliva are not acceptable. In older children, bronchial secretions may be obtained by the stimulation of cough by an aerosol solution of propylene glycol in 10% sodium chloride .

Gastric aspirates

Gastric aspirates are used in lieu of sputum in children younger than 6 years.

Using the correct technique for obtaining the gastric lavage is important because of the scarcity of the organisms in children compared with adults. An early morning sample should be obtained before the child has had a chance to eat or ambulate, because these activities dilute the bronchial secretions accumulated during the night.

Initially, the stomach contents should be aspirated, and then a small amount of sterile water is injected through the orogastric tube. This aspirate should also be added to the specimen.

Because gastric acidity is poorly tolerated by the tubercle bacilli, neutralization of the specimen should be performed immediately with 10% sodium carbonate or 40% anhydrous sodium phosphate. Even with careful attention to detail and meticulous technique, the tubercle bacilli can be detected in only 70% of infants and in 30-40% of children with disease.

Bronchial secretions

Bronchoalveolar lavage may be used in older children (6 y or older). Bronchial secretions may be obtained by the stimulation of cough by an aerosol solution of propylene glycol in 10% sodium chloride. This technique may also be used to provide bronchial secretions for detection of tubercle bacilli.

Urine specimens

Obtain overnight urine specimens in the early morning. Send immediately for analysis, because the tubercle bacilli poorly tolerate the acidic pH of urine.

1. Afb Staining

Because M tuberculosis is an acid-fast bacilli (AFB), AFB staining provides preliminary confirmation of the diagnosis. Conventional methods include

1. The Ziehl-Neelsen staining method.

2. The Kinyoun stain is modified to make heating unnecessary.

3. Fluorochrome stains, such as auramine and rhodamine, are variations of the traditional stains. The major advantage of these methods is that slides can be screened faster, because the acid-fast material stands out against the dark, nonfluorescent background.

However, fluorochrome-positive smears must be confirmed by Ziehl-Neelsen staining.

Staining can also give a quantitative assessment of the number of bacilli being excreted (eg, 1+, 2+, 3+). This can be of clinical and epidemiologic importance in estimating the infectiousness of the patient and in determining the discontinuation of respiratory isolation.

However, for reliably producing a positive result, smears require approximately 10,000 organisms/mL. Therefore, in early stages of the disease or in children in whom the bacilli in the respiratory secretions are sparse, the results may be negative. A single organism on a slide is highly suggestive and warrants further investigation.

A significant drawback of AFB smears is that they cannot be used to differentiate M tuberculosis from other acid-fast organisms such as other mycobacterial organisms or Nocardia species.

2. Mycobacterium Cultures

Culture of mycobacterium is the definitive method to detect bacilli. It is also more sensitive than examination of the smear. Approximately 10 acid-fast bacilli (AFB) per millimeter of a digested concentrated specimen are sufficient to detect the organisms by culture.

Another advantage of culture is that it allows specific species identification and testing for recognition of drug susceptibility patterns. However, because M tuberculosis is a slow-growing organism, a period of 6-8 weeks is required for colonies to appear on conventional culture media.

MANAGEMENT OF TB;

The ultimate goal of treatment is to achieve sterilization of the TB lesion in the shortest possible time. The general rule is strict adherence to TB treatment regimens for a sufficient time period. To prevent the emergence of resistance, the regimens for the treatment of TB always s

hould consist of multiple drugs.

Pharmacotherapy considerations

Anti-TB medications kill mycobacteria, thereby preventing further complications of early primary disease and progression of disease. However, disappearance of caseous or granulomatous lesions does not occur even with therapy. These drugs are classified as first-line and second-line drugs.

First-line drugs have less toxicity with greater efficacy than second-line drugs.

All first-line agents are bactericidal with the exception of ethambutol.

First-line agents include

1) Isomiazid (H) 300mg OD.

2) Rifampicin (R) 600mg OD.

3) pyrazinamide (Z) 25mg/kg /day.

4) Ethambutol (E) 15mg/kg.

Second-line agents are

1) Streptomycin 15mg/kg

2) Amikacin 15mg/kg/day

3) Para Aminosalicylic acid 150mg/kg

4) Capreomycin 15mg/kg/day in divided doses

5) Cycloserine 10-20 mg/kg

6) Ethionamide 10-20mg/kg

7) Ofloxacin 7.5-15mg/kg

8) Kanamycin 15mg/kg

9) Rifabutin 300mg OD

10) Rifapentine 600mg once or twice wkly

INH and rifampin are effective against bacilli in necrotic foci and intracellular populations of mycobacteria.

Streptomycin, aminoglycosides, and capreomycin have poor intracellular penetration.

Multidrug-resistant (MDR) TB is defined as resistance to at least INH and rifampin. The emergence of drug-resistant strains has necessitated the use of second-line agents.

Naturally drug-resistant organisms occur with a frequency of approximately 10^-6; however, individual resistances may vary. The resistance to streptomycin is 10^-5, to INH is 10^-6, and to rifampin is 10^-8.

The chance that an organism is naturally resistant to both INH and rifampin is on the order of 10^-14. Because populations of this size do not occur in patients, organisms naturally resistant to 2 drugs are essentially nonexistent.

If only a single medication is administered to a patient with TB, the subpopulations susceptible to that medication are destroyed, but the other categories continue to multiply. Thus, the use of multiple agents in the treatment of TB is essential.

Adverse drug effects

Adverse effects of isoniazid (INH) (eg, hepatitis) are rare in children; therefore, routine determination of serum aminotransferase levels is not necessary.

Monthly monitoring of hepatic function tests is indicated in the following patients:

1. Those with severe or disseminated TB;

2. Those with concurrent or recent hepatic disease;

3. Those receiving high daily doses of INH (10 mg/kg/d) in combination with rifampin, pyrazinamide, or both;

4. Women who are pregnant or within the first 6 weeks postpartum;

5. Those with clinical evidence of hepatotoxic effects; and

6. Those with hepatobiliary tract disease from other causes.

Bed rest

The advisability of bed rest varies with the type and severity of the disease. No limitation of activity is required in patients with TB infection or asymptomatic primary pulmonary TB. Severely ill patients with miliary TB, TB meningitis, or disseminated TB may require complete bed rest; these individuals may also need transfer to the intensive care unit until their condition is stabilized.

Treatment of Pulmonary TB

Recommendations for the treatment of pulmonary tuberculosis (TB) include a 6-month course of isoniazid (INH) and rifampin, supplemented during the first 2 months with pyrazinamide. Ethambutol (or streptomycin in children too young to be monitored for visual acuity) may need to be included in the initial regimen until the results of drug susceptibility studies are available.

Drug susceptibility studies may not be required if the risk of drug resistance is not significant. Significant risk factors include residence in a community with greater than 4% primary resistance to INH, history of previous treatment with anti-TB drugs, history of exposure to a drug-resistant case, and origin in a country with a high prevalence of drug resistance. The purpose of this recommendation is to decrease the development of multidrug-resistant (MDR) TB in areas in which primary INH resistance is increased.

Another treatment option is a 2-month regimen of INH, rifampin, and pyrazinamide daily, followed by 4 months of INH and rifampin twice a week. Effective treatment of hilar adenopathy when the organisms are fully susceptible is a 9-month regimen of INH and rifampin daily or a 1-month regimen of INH and rifampin once a day, followed by 8 months of INH and rifampin twice a week.

Because poor adherence to these regimens is a common cause of treatment failure, directly observed therapy (DOT) is recommended for treatment of TB. DOT means a healthcare provider or other responsible person must watch the patient ingest the medications. Intermittent regimens should be monitored by DOT for the duration of therapy, because poor compliance may result in inadequate drug delivery.

Another initiative recently launched by the World Health Organization (WHO) is the DOTS-plus strategy, which is based on finding appropriate treatment strategies for MDR TB and drug susceptibility testing, as well as judicious usage of second-line drugs.This initiative also focuses on community involvement and a good recording and reporting system.

Treating Extrapulmonary TB

Most cases of extrapulmonary tuberculosis (TB), including cervical lymphadenopathy, can be treated with the same regimens used to treat pulmonary TB. Exceptions include bone and joint disease, miliary disease, and meningitis. For these severe forms of drug-susceptible disease, the recommendation is a regimen of 2 months of isoniazid (INH), rifampin, pyrazinamide, and streptomycin once a day, followed by 7-10 months of INH and rifampin once a day.

Another recommended regimen is 2 months of INH, rifampin, pyrazinamide, and streptomycin, followed by 7-10 months of INH and rifampin twice a week. Streptomycin may be administered with initial therapy until drug susceptibility is known. Consider administering capreomycin or kanamycin instead of streptomycin in patients who may have acquired TB in areas in which resistance to streptomycin is common.

Prevention of TB Disease

The key method of preventing tuberculosis (TB) is prompt identification and treatment of patients with TB. Other strategies include patient education, treatment of latent infection, and vaccination.

The World Health Organization (WHO) launched the Stop TB strategy in 2006 (modelled after the directly observed therapy [DOT] strategy) and the core components include pursuing high-quality DOT expansion and enhancement; addressing TB and human immunodeficiency (HIV) infection, multidrug-resistant (MDR) TB, and other challenges; contributing to health system strengthening; engaging all care providers; empowering people with TB; and enabling and promoting research.

Patient education

Thoroughly educate patients regarding compliance to therapy, adverse effects of medications, and follow-up care.

Treatment of latent TB infection

Recommendations for preventive therapy are based on a comparative analysis of the risk of administration of isoniazid (INH) versus the risk of acquiring the disease. Adults with a positive tuberculin skin test (TST) result and no clinical or radiographic manifestations who are receiving INH therapy have been demonstrated to have 54-88% protection against the development of the disease, whereas children have been shown to have 100% protection.

The risk of acquisition of TB is particularly high in very young children (< 5 y) and in the adolescent population. Thus, patients in these age groups with a positive TST result and no other manifestations should receive INH therapy. Active TB should be carefully excluded before the initiation of preventive therapy.

For recent contacts of patients with contagious TB (ie, in the past 3 mo), INH therapy is indicated even if the TST result is negative. This is especially true for contacts who are infected with HIV or for household contacts younger than 5 years. Household contacts of any age should be considered for INH therapy if they are from a high-prevalence area, even if the TST result is negative.

The recommendations from the American Academy of Pediatrics (AAP) are to administer 9 months of therapy. The drug of choice is INH. A treatment period of 12 months is recommended for patients with HIV infection. For the management of contacts of INH-resistant cases, rifampin is recommended for 6 months in children.

A newer regimen for latent TB is isoniazid plus rifapentine once-weekly for 12 weeks (administered as directly observed therapy [DOT]).This combination was approved by the FDA in November 2014 is recommended for patients 12 years of age and older with latent TB who are at high risk for developing active TB disease (including those in close contact with active TB patients, recent conversion to a positive tuberculin skin test, HIV-infected patients, or those with pulmonary fibrosis on radiograph). Dosing is weight-based. A study among children 0-18 years of age showed 12 weeks of once-weekly therapy with rifapentine plus isoniazid for treatment of TB infection is associated with fewer side effects with increased completion of treatment compared with traditional 9 months daily isoniazid.

In case of a high probability of infection with MDR TB, observation is recommended, because none of the other drugs have been evaluated for preventive therapy. Several drugs have been used in these circumstances, including pyrazinamide, fluoroquinolones, and ethambutol, depending on the susceptibility patterns.

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Topic 1.4: RHEUMATIC FEVER

Acute rheumatic fever (ARF) is an autoimmune inflammatory process that develops as a sequela of streptococcal infection- Group A beta haemolytic streptococcus.

Pathophysiology

ARF is characterized by nonsuppurative inflammatory lesions of the joints, heart, subcutaneous tissue, and central nervous system.

In developed countries, rheumatic fever follows pharyngeal infection with rheumatogenic group A streptococci. The risk of developing rheumatic fever after an episode of streptococcal pharyngitis has been estimated at 0.3-3%.

More recent investigations of rheumatic fever occurring in the aboriginal populations of Australia suggest that streptococcal skin infections might also be associated with the development of rheumatic fever.

Epidemiology

In developing countries, the magnitude of ARF is enormous. Recent estimates suggest that 33.4 million people worldwide have rheumatic heart disease and that 300,000-500,000 new cases of rheumatic fever (approximately 60% of whom will develop rheumatic heart disease) occur annually, with 230,000 deaths resulting from its complications. Almost all of this toll occurs in the developing world.

Rheumatic fever in the 21st century appears to be largely a disease of crowding and poverty.

Even within developing countries with overall high rates of ARF, the segments of populations of poorer socioeconomic status and with higher rates of malnutrition suffer disproportionately.

History and clinical presentation;

Rheumatic fever manifests as various signs and symptoms that may occur alone or in various combinations.

1. Sore throat

Although estimates vary, only 35%-60% of patients with rheumatic fever recall having any upper respiratory symptoms in the preceding several weeks.

Many symptomatic individuals do not seek medical attention, go undiagnosed, or do not take the prescribed antibiotic for acute rheumatic fever (ARF) prevention.

If a course of penicillin or another appropriate antibiotic is taken at this time, the risk of ARF is reduced by approximately 80%.

2. Arthritis

Overall, arthritis occurs in approximately 75% of first attacks of ARF. The likelihood increases with the age of the patient, and arthritis is a major manifestation of ARF in 92% of adults. The arthritis is typically polyarticular, but monoarthritis may occur with ARF in select high-risk populations.

The arthritis of ARF is usually symmetrical and involves large joints, such as the knees, ankles, elbows, and wrists.

Tenosynovitis is common in adults and may be severe enough to suggest a diagnosis of disseminated gonococcal disease.

Aseptic monoarticular arthritis is seen in a substantial minority of cases from higher-risk areas, especially South Asia and Oceania, and can occur when NSAIDs are used early in the course.

The evolution of polyarthritis in individual joints tends to overlap; therefore, multiple joints may be inflamed simultaneously, causing more of an additive than a migratory pattern.

In most instances, the entire bout of arthritis subsides within 4-6 weeks without any permanent damage. If not, a different diagnosis should be entertained.

3. Carditis

Of first attacks of ARF, carditis occurs in 30%-60% of cases. It is more common in younger children but does occur in adults.

Severe inflammation can cause congestive heart failure (CHF).

Patients with carditis may present with shortness of breath, dyspnea upon exertion, cough, paroxysmal nocturnal dyspnea, chest pain, and/or orthopnea. Carditis may also be asymptomatic and may be diagnosed solely via auscultation or echocardiography.

4. Sydenham chorea

This occurs in up to 25% of ARF cases in children but is very rare in adults. It is more common in girls. Sydenham chorea in ARF is likely due to molecular mimicry, with autoantibodies reacting with brain ganglioside.

Sydenham chorea may occur with other symptoms or as an isolated finding. It typically presents 1-6 months after the precipitating streptococcal infection and usually has both neurologic and psychological features.

In the isolated form, laboratory evidence of a preceding streptococcal infection may be lacking.

Like the arthritis, Sydenham chorea usually resolves without permanent damage but occasionally lasts 2-3 years and be a major problem for the patient and her family.

5. Erythema marginatum

In first attacks of ARF in children, erythema marginatum occurs in approximately 10%. Like chorea, it is very rare in adults.

Patients or parents may report a nonpruritic, painless, serpiginous, erythematous eruption on the trunk. It is usually noted only in fair–skinned patients.

The lesions may persist intermittently for weeks to months.

6. Subcutaneous nodules

Subcutaneous nodules are rarely noticed by the patient

OTHER SYMPTOMS

Other symptoms may include

1. Fever,

2. Abdominal pain,

3. Arthralgia,

4. Malaise, and

5. Epistaxis.

Physical features

1. Arthritis

Joint involvement in ARF may range from arthralgia to frank arthritis characterized by;

1) Swelling,

2) Redness,

3) Warmth, and

4) Joint tenderness.

Monoarticular arthritis may occur if anti-inflammatory agents are used early in the courseand is increasingly seen in areas of medium-high endemicity.

The joints frequently involved include;

i. The knees,

ii. Ankles,

iii. Elbows, and

iv. Wrists.

The small joints of the hands and the spine are rarely involved.

Hand involvement tends to occur in poststreptococcal arthritis, a controversial related syndrome with a lower but apparently nonzero risk of carditis.

Inflammation begins to subside within a few days to a week and disappears within 2-6 weeks.

The arthritis is classically described as migratory, but, in many cases, new joints are affected before the previously involved joints improve, leaving the appearance of an additive arthritis. Monoarthritis can also occur.

In most cases, the process does not leave any residual damage. On very rare occasions, periarticular fibrosis occurs after rheumatic arthritis, the so-called Jaccoud joint.

2. Carditis

Carditis is the only manifestation of ARF with significant potential to cause long-term disability and/or death.

It is usually a pancarditis involving the pericardium, myocardium, and endocardium.

The signs of carditis include

i. The development of new murmurs,

ii. Cardiac enlargement,

iii. CHF,

iv. Pericardial friction rub, and/or

v. Pericardial effusion.

Characteristic murmurs of acute carditis include

a. The high-pitched, blowing, holosystolic, apical murmur of mitral regurgitation;

b. The low-pitched, apical, mid-diastolic, flow murmur (Carey-Coombs murmur); and

c. A high-pitched, decrescendo, diastolic murmur of aortic regurgitation heard at the aortic area.

Murmurs of mitral and aortic stenosis are observed in chronic valvular heart disease. Isolated aortic disease is distinctly unusual.

The features of CHF include;

1) Tachycardia,

2) A third heart sound,

3) Rales, and

4) Edema.

5) Pericarditis presents as a pericardial rub or effusion.

The use of echocardiography to detect carditis often reveals "subclinical" rheumatic cardiac disease (both acute and chronic) not appreciated by the standard examination.

Subclinical carditis has been a controversial topic in rheumatic fever diagnosis, but the 2015 revision of Jones Criteria now includes echocardiographically diagnosed subclinical endocarditis as a major criterion and recommends echocardiography in all proven and suspected cases.

3. Subcutaneous nodules

Subcutaneous nodules are uncommon and are usually associated with severe carditis. They tend to occur several weeks after illness onset, are usually painless, and usually go unnoticed by the patient.

They are found primarily over the bony surfaces or prominences and in tendon sheaths. The common sites include

i. The elbows,

ii. Knees,

iii. Wrists,

iv. Ankles,

v. Over the Achilles tendon,

vi. The back of the scalp, and spinous process of the vertebrae.

They usually persist for 1-2 weeks. The main differential diagnosis is the nodules of rheumatoid arthritis.

4. Erythema marginatum

The individual lesions of erythema marginatum are evanescent, moving over the skin in serpiginous patterns. Likened to smoke rings, they have a tendency to advance at the margins while clearing in the center.

The lesions may be macular and can develop and disappear in minutes, appearing to change shape while being examined.

They are found on the trunk and proximal aspects of the extremities and often go unnoticed by patients and parents, as they are usually covered by clothing.

5. Sydenham chorea

This is a neurological disorder characterized by

i. Emotional lability,

ii. Personality change,

iii. Muscular weakness, and

iv. Uncoordinated, involuntary, purposeless movements.

The classic weakness is characterized by the inability to sustain a tetanic contraction. Patients are unable to maintain a clenched fist when attempting to grip the examiner's hand. Other findings include dysarthric speech, gait problems, and poor fine-motor skills.

The motor symptoms usually disappear during sleep and may be partially suppressed by sedation.

They can involve the face, hands, and feet.

Untreated rheumatic fever/chronic rheumatic fever

The average duration of an untreated ARF attack is 3 months. Chronic rheumatic fever, generally defined as disease persisting for longer than 6 months, occurs in less than 5% of cases.

Aetiology;

1. Group A beta-hemolytic streptococcal infection may lead to rheumatic fever. The overall attack rate after streptococcal pharyngitis 0.3-3%, but certain genetically predisposed individuals, comprising perhaps 3%-6% of the population, account for those who develop rheumatic fever.

Studies in developed countries have established that rheumatic fever followed only pharyngeal infections and that not all serotypes of group A streptococci cause rheumatic fever. For example, some strains (eg, M types 4, 2, 12) in a population susceptible to rheumatic disease do not result in recurrences of rheumatic fever.

The classic rheumatogenic serotypes are thought to include 3, 5, 6, 14, 18, 19, and 24.More recent data, largely from studies of the indigenous peoples of Australia, suggest that;

2. Skin infections (pyoderma) can predispose to ARF and that various other serotypes may be involved.

Pathophysiological anomalies associated with Rheumatic fever;

Two basic theories have been postulated to explain the development of ARF and its sequelae following group A streptococcal infection:

1. A toxic effect produced by an extracellular toxin of group A streptococci on target organs such as the myocardium, valves, synovium, and brain and

2. An abnormal immune response to streptococcal components. Increasing and compelling evidence now strongly favors the autoimmune explanation. It seems clear that an exaggerated immune response in a susceptible individual leads to rheumatic fever. This probably occurs through molecular mimicry, in which the immune response fails to differentiate between epitopes of the streptococcal pathogen and certain host tissues.

DIFFERENTIAL DIAGNOSES OF RF.

LABORATORY STUDIES

No single specific laboratory test can confirm the diagnosis of acute rheumatic fever (ARF).

Evidence of preceding group A streptococcal infection is an integral part of the Jones criteria for ARF diagnosis unless the patient has chorea (which may occur months after the inciting infection) or indolent rheumatic heart disease (see Diagnosis).

1. Throat culture

Throat culture remains the criterion standard for confirmation of group A streptococcal infection. Rapid antigen detection tests are not as sensitive.

If a rapid antigen detection test result is negative, obtain a throat culture in patients with suspected rheumatic fever.

On the other hand, because of the high specificity of these tests, a positive rapid antigen test confirms a streptococcal infection.

2. Antibody titer tests

Antibody titer tests used include ASO test, antistreptococcal DNAse B (ADB) test, and the antistreptococcal hyaluronidase (AH) test.

ASO is a test used to detect streptococcal antibodies directed against streptococcal lysin O. An elevated titer is proof of a previous streptococcal infection. It is usually more elevated after a pharyngeal than skin infection, while the ADB is typically elevated regardless of the site of the infection.

Acute and convalescent sera, if available, are helpful for proving recent streptococcal infection.

The antibody tests must be interpreted with caution in areas with high rates of streptococcal infection and ARF, as relatively high titers are commonly encountered in the population. These tests are of greater utility in areas with lower prevalence (eg, in most Western countries).

3. Acute-phase reactants, erythrocyte sedimentation rate, and C-reactive protein

Acute-phase reactants, the erythrocyte sedimentation rate (ESR), and C-reactive protein levels (CRP) are usually elevated at the onset of ARF and serve as a minor manifestation in the Jones criteria. These tests are nonspecific, but they may be useful in monitoring disease activity.

4. Blood cultures

Blood cultures are obtained to help rule out infective endocarditis, bacteremia, and disseminated gonococcal infection.

Imaging Studies

RADIOIMAGING STUDIES;

1) Chest radiography

Chest radiography can reveal cardiomegaly and CHF in patients with carditis.

2) Echocardiography

Echocardiography may demonstrate valvular regurgitant lesions in patients with ARF who do not have overt clinical manifestations of carditis. This is now considered an integral part of the evaluation of proven or suspected ARF everywhere.

Echocardiography has previously been used as a diagnostic criterion in New Zealand and Australia as it reveals 16%-47% more cases of carditisthan clinical criteria alone. Patients with echocardiographically diagnosed subclinical carditis cases should receive the same long-term penicillin prophylaxis as those with the more classic clinical carditis, ^]since they are also at risk for poor outcomes due to recurrent rheumatic heart disease.

Valvular stenotic lesions, especially of the mitral valve, can be observed in rheumatic heart disease.

In the absence of mitral valve disease involvement, isolated echocardiographic disease of the aortic valve is uncommon in patients with rheumatic heart disease.

OTHER TESTS

The most common finding on electrocardiography is a prolongation of the PR interval, which is a nonspecific finding, but counts as a minor manifestation in the Jones diagnostic criteria. It does not count as proof of carditis. On rare occasions, second- or third-degree heart block is present. In patients with chronic rheumatic heart disease, electrocardiography may show left atrial enlargement secondary to mitral stenosis.

Various other studies may be needed to rule out other illnesses in the differential diagnoses. Common tests would include;

i. Rheumatoid factor, antinuclear antibody (ANA),

ii. Lyme serology,

iii. Blood cultures, and

iv. Evaluation for gonorrhea.

1. Histologic Findings

Rheumatic fever is characterized pathologically by exudative and proliferative inflammatory lesions of the connective tissue in the heart, joints, blood vessels, and subcutaneous tissue.

In the early stage, fragmentation of collagen fibers, cellular infiltration that is predominantly lymphocytic, and fibrinoid deposition followed by the appearance of a myocardial Aschoff nodule (a perivascular focus of inflammation that has an area of central necrosis surrounded by a rosette of large mononuclear and giant multinuclear cells) occur.

The nuclei of these cells resemble owl eyes and are called Anichkov cells.

Subcutaneous nodules histologically resemble Aschoff nodules. The brain may show scattered areas of arteritis and petechial hemorrhages, which have an uncertain relationship to Sydenham chorea.

Diagnosis

Because acute rheumatic fever (ARF) can have diverse manifestations and since no specific diagnostic test for the disease exists, arriving at the correct diagnosis is particularly important. This is essential not only in terms of prescribing appropriate therapy for the acute attack but also because of the necessity for prescribing continuous antistreptococcal prophylaxis to prevent subsequent attacks and additional damage.

The Jones criteria were first established in 1944 and have been modified or updated several times, most recently in 2015. The 2015 revision, for the first time, uses slightly different, more specific, diagnostic criteria in areas of low endemicity than the more sensitive criteria for moderate- to high-risk areas.

Low-risk areas, by this definition, have an ARF incidence of less than 2 per 100,000 school-aged children or an all-age rheumatic heart prevalence of less than 1 per 1000 persons. Medium- to high-risk countries exceed these thresholds. Additional major changes include the recommended use of echocardiography and the inclusion of subclinical carditis as a major criterion, as well as the inclusion of monoarthritis in higher-risk areas.

Jones criteria, 2015 revision, high-risk populations (Oceania, Africa, South Asia, other lower-income areas)

Major criteria are as follows:

Carditis (clinical or echocardiographic diagnosis)
Polyarthritis or monoarthritis: Polyarthralgias can be considered only after careful consideration of the differential diagnoses.
Chorea (rare in adults)
Erythema marginatum (uncommon; rare in adults)
Subcutaneous nodules (uncommon; rare in adults)

Minor criteria are as follows:

Polyarthralgia (cannot count arthritis as a major criterion and arthralgia as a minor criterion)
Fever exceeding 38°C (note lower cutoff)
Elevated ESR (>30 mm/hr; note lower ESR standard) or CRP level (>3 mg/L)
Prolonged PR interval

Universal criteria

In both higher- and lower-risk settings, evidence of group A streptococcal disease is required for diagnosis, except when rheumatic fever is first discovered after a long latent period (eg, Sydenham chorea, indolent carditis), as follows:

1) Evidence of preceding group A streptococcal infection - Positive throat culture or rapid antigen test result

2) Elevated or rising streptococcal antibody titer

Scoring;

If supported by evidence of preceding group A streptococcal infection, the presence of two major manifestations or one major and two minor manifestations indicates a high probability of ARF. Failure to fulfill the Jones criteria makes the diagnosis unlikely but not impossible. Clinical judgment is required.

Recurrent ARF can be diagnosed based on 2 major, 1 major plus 2 minor, or 3 minor criteria.

MEDICAL CARE

Management and prevention of acute rheumatic fever (ARF) can be divided into the following 4 approaches.

Treatment of the group A streptococcal infection that led to the disease

Although never proven to improve the one-year outcome, this is a standard practice.It may at least serve to reduce the spread of rheumatogenic strains.

General treatment of the acute episode

Anti-inflammatory agents are used to control the arthritis, fever, and other acute symptoms. Salicylates are the preferred agents, although other nonsteroidal agents are probably equally efficacious. Steroids are also effective but should probably be reserved for patients in whom salicylates fail, since there is a risk of rebound when they are withdrawn. None of these anti-inflammatory agents has been shown to reduce the risk of subsequent rheumatic heart disease.

Bed rest is a traditional part of ARF therapy and is especially important in those with carditis. Patients are typically advised to rest through the acute illness and to then gradually increase activity; some clinicians monitor the patient’s ESR and restart activity only as it normalizes.

Intravenous immunoglobulin has not been shown to reduce the risk of rheumatic heart disease or to substantially improve the clinical course.

Chorea is usually managed conservatively in a quiet nonstimulatory environment; valproic acid is the preferred agent if sedation is needed. Intravenous immunoglobulin, steroids, and plasmapheresis have all been used successfully in refractory chorea, although conclusive evidence of their efficacy is limited.

Some early but promising work suggests a possible role for hydroxychloroquine in the treatment of ARF, although no clinical data are yet available to recommend its use.

Cardiac management

Bedrest is essential in patients with cardiac involvement. Carditis resulting in heart failure is treated with conventional measures; some use corticosteroids for severe carditis, although data to support this are scant.Diuretics and vasodilators are the mainstays of therapy. Monitor for development of arrhythmias in patients with active myocarditis.

SURGICAL CARE

Surgical care is not typically indicated in ARF. Surgical intervention is required only to treat long-term valvular cardiac sequelae of ARF that cause stenosis.

ANTIBIOTICS

Antibiotic treatment in patients who present with acute rheumatic fever (ARF) is necessary irrespective of the throat culture result. Such therapy probably does not alter the risk of developing rheumatic heart disease but at least minimizes the possible transmission of a rheumatogenic streptococcal strain.

Primary prophylaxis (treatment of streptococcal pharyngitis) dramatically reduces the risk of ARF and should be provided whenever a group A streptococcal pharyngitis is confirmed. Treatment of pharyngitis without proof of group A streptococcal etiology may be reasonable in areas of high endemicity.

Although definitive evidence to support the practice is lacking, secondary prevention is recommended to prevent additional streptococcal infections and is believed by most experts to be a critical step in management of ARF. Patients with a history of rheumatic fever are at a high risk of recurrent ARF, which may further the cardiac damage. The exact duration of chronic antimicrobial prophylaxis remains controversial, but the WHO guidelines are commonly used.There had been concern that sustained benzathine penicillin as secondary prophylaxis would lead to the development of resistant strains of Streptococcus viridans, but a 2008 study found no support for this hypothesis.

Rheumatic fever with carditis and clinically significant residual heart disease requires antibiotic treatment for a minimum of 10 years after the latest episode; prophylaxis is required until the patient is aged at least 40-45 years and is sometimes continued for life.

Rheumatic fever with carditis and no residual heart disease aside from mild mitral regurgitation requires antibiotic treatment for 10 years or until age 25 years (whichever is longer).

Rheumatic fever without carditis requires antibiotic treatment for 5 years or until the patient is aged 18-21 years (whichever is longer).

Children given penicillin G benzathine at a dose of 1.2 million U IM q4wk experienced a recurrence rate of 0.4 cases per 100 patient-years of observation. ARF recurrence rates have been found to be even lower if penicillin is administered q3wk instead of q4wk.

This regimen may be appropriate in patients with severe rheumatic heart disease. Weigh the benefits of a 3-week regimen against patient compliance and cost; compliance is often poor to start with, at least partially due to the pain of the injections.Long-term administration of oral penicillin may be used in lieu of the intramuscular route. Erythromycin or sulfadiazine may be used in patients who are allergic to penicillin.

1. Penicillin G benzathine (Bicillin L-A)

Long-acting depot form of penicillin G. DOC for prophylaxis of streptococcal pharyngitis. Avoids compliance problems of oral regimens.

2. Penicillin VK (Beepen-VK, Betapen-VK, Pen-Vee K, Robicillin VK, V-Cillin K)

Phenoxymethyl derivative of penicillin G is acid-stable, enhancing oral bioavailability. Patient compliance is essential for effectiveness.

3. Erythromycin (E.E.S., E-Mycin, Eryc, Ery-Tab, Erythrocin, E-Mycin)

Macrolides inhibit protein synthesis, in contrast to penicillin cell wall effects. DOC for primary treatment of streptococcal pharyngitis in penicillin allergy. May use for secondary prophylaxis in patients allergic to penicillin.

4. Sulfadiazine (Microsulfon)

Exerts bacteriostatic action through competitive antagonism with para-aminobenzoic acid (PABA). Microorganisms that require exogenous folic acid and do not synthesize folic acid are not susceptible to the action of sulfonamides. Used in secondary prophylaxis of ARF.

ANTI-INFLAMMATORY AGENTS

Salicylates and corticosteroids are the mainstay of the anti-inflammatory treatment of ARF. Avoid anti-inflammatory drugs until diagnosis is confirmed, as they may mask symptoms essential to the diagnosis.

Analgesics without anti-inflammatory properties (ie, codeine) are used for mild disease. Corticosteroids and salicylates cannot prevent or modify the development of subsequent rheumatic heart disease but are used for symptomatic relief. Some experts believe steroids are of value in patients with severe or fulminant carditis, but data are sparse.

Clinical or laboratory manifestations of rheumatic inflammation may recur upon cessation of anti-inflammatory therapy. Rebound occurs frequently with corticosteroids; hence, they require gradual tapering rather than abrupt cessation. Salicylates are usually continued for a month following corticosteroid discontinuance.

1) Aspirin (Anacin, Ascriptin, Bayer Aspirin, Bayer Buffered Aspirin)

Used in patients with moderate-to-severe arthritis and carditis without heart failure. Treatment is administered for at least 8 wk.

2) Prednisone (Deltasone, Liquid-Pred, Meticorten, Orasone, Sterapred)

Used in severe carditis and CHF. High-dose prednisone is administered for 2-3 wk, then tapered over 3 wk. IV corticosteroids are reserved for fulminant case

COMPLICATIONS

1. Immediate complications

Pancarditis that causes CHF, heart blocks, or pericardial effusion requires emergent inpatient care and cardiology evaluation.

Chorea can present months after the inciting infection and can be quite debilitating.

2. Long-term sequelae

The only long-term sequela is rheumatic heart disease, which can present years later as valvular stenosis, most commonly involving the mitral valve. These patients are prone to infective endocarditis and stroke.

Valvular stenosis can lead to heart failure and may require surgery.

PATIENT EDUCATION

Patients, especially children, should receive medical attention when they develop a sore throat. Compliance with oral primary prophylaxis ("strep throat" treatment) and secondary prophylaxis regimens is essential to prevent ARF and its sequelae.

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Topic 1.5: PULMONARY EMBOLISM

Pulmonary embolism (PE) refers to exogenous or endogenous material that travels to the lungs through the pulmonary circulation, causing a potential spectrum of consequences.

Thrombus from the deep veins of the lower extremities is by far the most common material to embolize to the lungs; deep venous thrombosis (DVT) and PE must be recognized as parts of the continuum of one disease entity, venous thromboembolism (VTE).

Other causes of embolism;

1. Tumor cells,

2. Air bubbles,

3. Carbon dioxide,

4. Intravenous catheters,

5. Fat droplets, and

6. Talc in intravenous drug abusers.

Pathology and risk factors;

Venous thrombi develop most commonly in the leg veins .

Virchows triad;

One or more components of Virchow's triad;

1) Stasis,

2) Hypercoagulability, and

3) Intimal injury.

All these are present in the majority of patients. The risk increases with age. Calf vein thrombi often propagate into the proximal veins, including and above the popliteal veins, from which they are more likely to embolize.

More than 95% of these emboli arise from the deep veins of the legs. Emboli from axillary-subclavian vein thromboses often develop in patients with central vein catheters, particularly those with malignant neoplasms, but may also result from effort-induced upper extremity thrombosis (Paget von Schroetter syndrome).

In acute PE, minute ventilation acutely increases with resulting tachypnea, and hypoxemia develops in most patients. The obstruction of blood flow creates alveolar dead space with regions of high ventilation perfusion ratios as well as shunting due to perfusion of atelectatic areas. This imbalance appears to be the principal explanation for hypoxemia in acute PE.

Clinical features of emboli;

The history and physical examination are notoriously insensitive and nonspecific for both DVT and PE.

Patients with lower extremity venous thrombosis often exhibit;

1. Erythema,

2. Warmth,

3. Pain,

4. Swelling, or

5. Tenderness.

These signs are nonspecific but still may merit further evaluation.

6. Homans' sign (pain with dorsiflexion of the foot) may be present in the setting of DVT, but this finding is neither sufficiently sensitive nor specific enough to be relied on.

7. The most common symptom of acute PE is

1) Dyspnea , which is often sudden in onset.

2) Pleuritic chest pain.

3) Hemoptysis occur more commonly with pulmonary infarction.

4) Palpitations,

5) Cough,

6) Anxiety,

7) Lightheadedness.

8) Syncope or sudden death may occur with massive PE.

9) PE should be considered whenever unexplained symptoms including;

i. Dyspnea,

ii. Syncope,

iii. Hypotension, and

iv. Hypoxemia.

v. Tachypnea.

vi. Tachycardia are the most common signs of PE but are also nonspecific.

vii. Fever,

viii. Wheezing,

ix. Crackles,

x. Pleural rub,

xi. Loud pulmonic component of the second heart sound,

xii. Right-sided third or fourth heart sound, and

xiii. Right ventricular lift.

DDx of PE;

1. Myocardial infarction

2. Pericarditis

3. Heart failure

4. Pneumonia

5. Asthma

6. Chronic obstructive pulmonary disease

7. Pneumothorax

8. Pleurodynia

9. Pleuritis from connective tissue disease

10. Thoracic herpes zoster (“shingles”)

11. Rib fracture

12. Musculoskeletal pain

13. Primary or metastatic intrathoracic cancer

14. Infra diaphragmatic processes (e.g., acute cholecystitis, splenic infarction)

15. Hyperventilation syndrome

Dx of PE;

1. Blood Tests

1) Pulse oximetry; Hypoxemia on respiration of ambient air is common in acute PE. Some individuals, particularly young patients without underlying lung disease, may have a normal arterial oxygen tension (Pao₂) and, rarely, a normal alveolar-arterial difference. A sudden decrease in the Pao₂ or in the oxygen saturation in a patient unable to communicate an accurate history (e.g., a mechanically ventilated patient) may be evidence of acute PE.

2) A circulating D-dimer (a specific derivative of cross-linked fibrin) positive test result (i.e., above a designated threshold value) by enzyme-linked immunosorbent assay (ELISA) is 96 to 98% sensitive for acute PE, but its positive predictive value is much lower. In one prospective study, for example, only 1 of 437 patients presenting to the emergency department with suspected PE and with a negative result of the D-dimer test (SimpliRED assay, a non-ELISA, qualitative test) and low clinical probability (score < 2) by the Wells clinical decision rule developed PE during follow-up; thus, the negative predictive value for this strategy was 99.5%.

A number of D-dimer assays are available, and the sensitivity and specificity of these assays vary. A positive D-dimer test result means that DVT or PE is possible, but it is by no means proof of VTE. Similarly, although a negative D-dimer test result may strongly suggest that VTE is absent, D-dimer testing should not be ordered in the setting of a high clinical suspicion for acute VTE; one should instead proceed straight to imaging.

3) Troponin levels may be elevated in acute PE, especially in more massive embolism, when myocyte injury due to right ventricular strain might be expected. Troponin levels cannot, however, be used like D-dimer testing; that is, they are not sensitive enough to exclude PE, even when the clinical suspicion is relatively low, without additional diagnostic testing.

2. Radio Imaging;

1) Electrocardiography

Electrocardiographic findings, which are present in the majority of patients with acute PE, include ST segment abnormalities, T wave changes, and left or right axis deviation.

Only one third of patients with massive or submassive emboli have manifestations of acute cor pulmonale, such as an S1-Q3-T3 pattern, right bundle branch block, P wave pulmonale, or right axis deviation. All of these findings are also nonspecific. Thus, the utility of electrocardiography in suspected acute PE arises more from its ability to establish or to exclude alternative diagnoses, such as acute myocardial infarction rather than from diagnosis or exclusion of PE.

2) Chest Radiography

The chest radiograph is often abnormal in patients with acute PE, but it is nearly always nonspecific. Common findings include

i. Pleural effusion,

ii. Atelectasis,

iii. Pulmonary infiltrates,

iv. Mild elevation of a hemidiaphragm.

v. Classic findings of pulmonary infarction, such as Hampton's hump and

vi. Decreased vascularity (Westermark's sign), are suggestive of the diagnosis but are infrequent.

vii. PE should be considered in patients who have dyspnea and hypoxemia with a normal chest radiograph in the absence of bronchospasm or anatomic cardiac shunt. Under most circumstances, however, the chest radiograph cannot be used for conclusive diagnosis or exclusion. Although the radiograph may exclude other processes, such as pneumonia, pneumothorax, or rib fracture, which may cause similar symptoms, acute PE may frequently coexist with other underlying heart or lung diseases.

3) Spiral Computed Tomography;

Spiral (helical) computed tomography (CT) can be used for diagnosis of both acute and chronic PE and has replaced ventilation-perfusion (VQ) scanning at many centers .

4) Ventilation-Perfusion Scanning

A normal perfusion scan (excludes PE with a high enough degree of certainty that further diagnostic evaluation is almost never necessary. Although large, central, nonocclusive emboli might transiently permit tracer to perfuse the lungs normally, this phenomenon is exceedingly unusual, and PE should be pursued only when the clinical suspicion is exceptionally high.

Matching areas of decreased ventilation and perfusion in the presence of a normal chest radiograph generally represent a process other than PE. However, low- or intermediate-probability (nondiagnostic) VQ scans are commonly found with PE, and further evaluation with pulmonary arteriography or leg studies is often appropriate in such situations.

This technique involves continuous movement of the patient through the CT scanner and allows concurrent scanning by a constantly rotating gantry and detector system. Rapid scanning is performed with continuous acquisitions obtained during a single breath. Retrospective reconstructions can be performed. An intravenous injection of contrast material is required for imaging of the pulmonary vasculature.

5) Pulmonary Arteriography

Pulmonary arteriography, which remains the gold standard for the diagnosis of acute PE, is an extremely sensitive and specific test. Major nonfatal complications occur with 1% of angiograms, and death occurs in 0.5%. Its clinical role has been for patients in whom PE must be diagnosed or excluded, but preliminary testing has been nondiagnostic. However, with the advent of CT, pulmonary angiography is now used infrequently.

6) Magnetic Resonance Imaging

Magnetic resonance imaging can be used in suspected PE, but the main advantage of magnetic resonance imaging at present is its excellent sensitivity and specificity for the diagnosis of DVT. Disadvantages include the potential difficulty in transporting and studying more critically ill patients.

7) Echocardiography

Echocardiography, which can often be obtained more rapidly than either lung scanning or pulmonary arteriography, may reveal abnormalities of right ventricular size or function that strongly support the diagnosis of hemodynamically significant PE. However, because these patients often have underlying cardiopulmonary disease such as chronic obstructive lung disease, neither right ventricular dilation nor hypokinesis can be reliably used even as indirect evidence of PE. In the setting of documented PE, echocardiographic evidence of right ventricular dysfunction can identify patients who may benefit from thrombolytic therapy.

Rx of PE;

Therapy for acute PE overlaps substantially with treatment of DVT.

Parenteral anticoagulation with low-molecular-weight heparin (LMWH) or with standard, unfractionated heparin is initiated unless it is contraindicated.

Depending on the clinical setting,

1. Thrombolytic therapy,

2. Inferior vena cava filter placement,

3. Surgical embolectomy may be considered.

Each approach has specific indications as well as advantages and disadvantages. The unstable patient requires a rapid evaluation and integration of data to optimize therapeutic decisions and outcome.

Bedrest is not generally helpful, except when substantial pain and swelling are present. Otherwise, outpatient therapy is often appropriate.

1. Anticoagulation therapy;

i. Heparin, Low-Molecular-Weight Heparin, and Warfarin

Recommendations for treatment of acute PE with LMWH, unfractionated heparin, and warfarin are based largely on clinical trials in patients presenting with acute DVT because DVT and PE are manifestations of a single clinical entity, and a significant minority of patients presenting with proximal DVT also have symptomatic or asymptomatic PE.

However, therapy may differ in certain specific settings, including massive PE, in which thrombolytic therapy may be considered.

Although heparins do not directly dissolve thrombus or emboli, they allow the fibrinolytic system to proceed unopposed and more readily reduce the size of the thromboembolic burden.

Nevertheless, early recurrence can sometimes develop, even in the setting of therapeutic anticoagulation.

When DVT or PE is diagnosed, anticoagulation should be instituted immediately unless contraindications are present.

It is also appropriate to initiate therapy in patients in whom there is a high index of suspicion for acute PE even while diagnostic testing is under way, as long as the risk of anticoagulation is not excessive. If possible, warfarin therapy should be initiated within the first 24 hours, but premature initiation of warfarin without LMWH or heparin may intensify hypercoagulability and increase the clot burden because of the short half-life of anticoagulation factors that are inhibited by warfarin.

At least 5 days of subcutaneous LMWH or intravenous unfractionated heparin is generally recommended because definitive anticoagulation requires the depletion of factor II (thrombin), a process that takes approximately 5 days. Ideally, the parenteral anticoagulant should be maintained until the international normalized ratio (INR) is stable at 2.0 to 3.0.

Although outpatient therapy for acute DVT is proved to be safe, outpatient therapy for acute, symptomatic PE is not routinely recommended.

However, patients with mild PE who are minimally symptomatic can be treated successfully in the outpatient setting or after a brief hospitalization. No data strongly support a search for asymptomatic PE in patients who present with acute symptomatic DVT.

Bleeding is the major complication of anticoagulation. Heparin-induced thrombocytopenia typically develops 5 days or more after the initiation of heparin therapy. The primary problem is not bleeding but rather venous or arterial thrombosis as a result of platelet and thrombin activation by heparin-dependent immunoglobulin G antibodies that activate the platelets through their Fc receptors.

If a patient is prescribed heparin for acute PE and the platelet count progressively decreases to 100,000/mm³ or less, or to 50% of the initial value, all heparin therapy (including LMWH) should be discontinued, and heparin-induced thrombocytopenia should be considered.

Both argatroban and lepirudin have been FDA approved for use in the setting of VTE with heparin-induced thrombocytopenia . These drugs are not reversible but have relatively short half-lives. Warfarin should not be initiated until the heparin-induced thrombocytopenia is clearly controlled because of the potential for further thrombotic complications, including venous limb gangrene and warfarin-induced skin necrosis.

Advantages of LMWH over Unfractionated heparin;

1. Similar or superior efficacy

2. Similar or superior safety

3. Superior bioavailability

4. Once- or twice-daily dosing

5. No laboratory monitoring; thus, less phlebotomy

6. Potential for earlier ambulation

7. Subcutaneous administration

8. Lower incidence of heparin-induced thrombocytopenia

9. Home therapy in certain subsets of patients

ii. Inferior Venacava filters;

When a patient cannot be anticoagulated in the setting of proven DVT or PE, inferior vena cava filter placement is indicated to prevent lower extremity thrombi from embolizing.

The primary indications for filter placement include contraindications to anticoagulation, significant bleeding complications during anticoagulation, and recurrent embolism with adequate therapy.

Inferior vena cava filters are sometimes placed in the setting of massive PE when it is believed that any further emboli might be lethal, particularly if thrombolytic therapy is contraindicated; however, this indication is not based on firm clinical trial data.

Although filters are effective in reducing PE, they increase DVT and have not been shown to increase overall survival. Filters inserted through the jugular or femoral vein are effective, and complications including insertion-related problems and migration of the filter are unusual.

Retrievable filters can be used when the risk of bleeding appears to be short term; such devices can be removed up to 2 weeks later, and some can be removed as late as 90 days after placement.

iii. Thrombolytic Therapy

Because anticoagulants do not actively lyse emboli, thrombolytic therapy is indicated when PE causes hemodynamic instability with hypotension.

Other settings in which thrombolytic therapy might be considered include;

1) Echocardiographic right ventricular dysfunction without hypotension,

2) Severely compromised oxygenation,

3) Massive radiographic embolic burden even without clear hemodynamic instability,

4) Extensive DVT accompanying non massive embolism.

Currently approved drugs for thrombolysis in acute PE include;

a) Streptokinase (administered as a 250,000-unit bolus during 30 minutes followed by 100,000 units per hour for 12 to 24 hours)

b) Recombinant tissue-type plasminogen activator (100 mg administered intravenously during a 2-hour period).

Contraindications to thrombolytic therapy in PE;

Absolute

1. Intracranial surgery or disease

2. Active or recent internal bleeding

Relative

1. Bleeding diathesis or thrombocytopenia

2. Uncontrolled severe hypertension

3. Cardiopulmonary resuscitation

4. Surgery within the previous 7–14 days

5. Pregnancy

NONTHROMBOTIC PULMONARY EMBOLISM

Because of venous blood return to the lungs, the pulmonary vascular bed is exposed to a wide variety of potentially obstructing and detrimental substances. These substances, which may be exogenous or endogenous in origin, may result in a number of consequences, including dyspnea, chest pain, hypoxemia, and sometimes death.

1. Fat Embolism;

Fat embolism generally occurs in the setting of traumatic fracture of long bones and is usually a more impressive clinical syndrome when larger bones and multiple fractures are involved.

However, orthopedic procedures and trauma to other fat-rich tissues such as the liver or subcutaneous tissue can occasionally result in similar consequences.

Pathobiology;

The physiologic consequences of fat embolism derive from both the obstruction of multiple vessels by neutral fat particles and the deleterious effects of free fatty acids released from neutral fat by lipases. These free fatty acids appear to cause diffuse vasculitis with capillary leak from cerebral, pulmonary, and other vascular beds.

Clinical Manifestations;

After the traumatic event, there is generally a delay of 24 to 48 hours before symptoms develop.

As neutral fat enters the vascular system, a characteristic syndrome of dyspnea, petechiae, and mental confusion often develops.

It is not clear why the syndrome develops in some patients and not in others, even when the extent of injury is comparable, but it is possible that the presence of a patent foramen ovale could render patients more susceptible to the sequelae.

Diagnosis;

The diagnosis is made from the clinical and radiographic findings in the setting of risk factors such as surgery and trauma.

Although fat droplets (by oil red O stain) in bronchoalveolar lavage fluid may be suggestive of fat embolism, this finding does not appear to be sensitive or specific.

The diagnosis of fat embolism syndrome remains a diagnosis of exclusion and is based on clinical criteria. Whereas clinically apparent fat embolism syndrome is uncommon, it also may be masked by the effects of concomitant injuries in more severely injured patients.

Treatment;

Treatment is supportive, including oxygen and mechanical ventilation, and the prognosis is generally good.

Corticosteroid therapy remains controversial and is generally not recommended.

2. Amniotic Fluid Embolism;

Amniotic fluid embolism is an uncommon syndrome but still represents one of the leading causes of maternal death.

It occurs during or after delivery when amniotic fluid gains access to uterine venous channels and then to the pulmonary and general circulations.

The delivery may be either spontaneous or by cesarean section and usually has been without complication. There are no identifiable risk factors in either the mother or the baby.

The primary mechanism of injury appears to involve the thromboplastic activity of amniotic fluid, which leads to extensive fibrin deposition in the pulmonary vasculature and sometimes in other organs.

Clinical Manifestations;

The syndrome is heralded by the sudden onset of severe respiratory distress; hypotension and death frequently result.

A severe consumptive coagulopathy develops, with marked hypofibrinogenemia.

After the acute event, an enhanced fibrinolytic state often is present.

Left ventricular dysfunction may occur, possibly due to the myocardial depressant effect of amniotic fluid. The resulting pulmonary edema may be both hydrostatic and noncardiogenic.

Diagnosis;

The diagnosis may be suspected on the basis of the clinical picture.

The differential diagnosis includes PE, septic and hemorrhagic shock, venous air embolism, aspiration pneumonia, heart failure (from acute myocardial infarction or other causes), abruptio placentae, and ruptured uterus.

Examination of the pulmonary arterial blood may or may not reveal the amorphous fragments of vernix caseosa, squamous cells, or mucin.

Rx of AFE;

Although administration of heparin, antifibrinolytic agents such as ε-aminocaproic acid, and cryoprecipitate has been suggested, the primary treatment is supportive, with oxygen, mechanical ventilation, and any necessary hemodynamic support.

3. Air Embolism;

The incidence of this entity reflects the variety of invasive surgical and medical procedures now available, the frequent use of indwelling venous and arterial catheters, and the frequency of thoracic and other forms of trauma.

With venous embolism in the setting of a patent foramen ovale, embolization to the coronary or cerebral circulation is of most concern. In the absence of a patent foramen ovale, the lungs can filter modest amounts of air, but large single or continuous episodes of air embolism can still gain access to the systemic arterial circulation.

Clinical Manifestations and Diagnosis;

Symptoms and signs are dependent on the severity of the episode, and the consequences of venous air embolism range from none to death. Air in the systemic circulation may be difficult to recognize because only small quantities may cause significant symptoms, yet intravascular air clears quickly. Dyspnea, wheezing, chest pain, cough, agitation, confusion, tachycardia, and hypotension may be evident. A “mill wheel murmur” from air in the right ventricle may sometimes be auscultated. Hypoxemia and hypercapnia are present in severe cases, and the chest radiograph may reveal pulmonary edema or air-fluid levels.

Treatment;

i. Immediate placement of the patient in the Trendelenburg–left lateral decubitus position

ii. Administration of 100% oxygen.

iii. If a central venous catheter is in place near the right atrium, air aspiration should be attempted.

iv. Hyperbaric oxygen should be considered. Anticonvulsants are administered in the presence of seizures.

4. Schistosomiasis;

Schistosomiasis causes severe pulmonary vascular obstruction and pulmonary hypertension from both anatomic obstruction by the organism itself and an inflammatory vasculitic response. In endemic areas such as Egypt, schistosomal disease is a common cause of cor pulmonale.

The liver is always involved, usually extensively, before pulmonary involvement occurs. The disease is refractory to treatment unless it is detected before extensive hepatic and pulmonary inflammation occurs.

5. Septic Embolism;

Septic embolism was first noted as a complication of septic pelvic thrombophlebitis due to septic abortion or postpartum uterine infection. In recent years, however, intravenous drug abuse, infections caused by indwelling intravenous catheters , and right-sided infective endocarditis are the most common causes.

6. Other Emboli;

A variety of other substances can also embolize to the lungs.

i. Cancer cells may enter and adhere to pulmonary vessels, occasionally mimicking PE.

ii. Brain tissue has been discovered in the lungs after head trauma, and liver cells have been found after abdominal trauma.

iii. Bone marrow has been reported in lung tissue after cardiopulmonary resuscitation.

iv. Noninfectious vasculitic-thrombotic complications also occur in intravenous drug users.

v. Materials such as talc, used to “cut” heroin or cocaine, and occasionally the drugs themselves may provoke vascular inflammation and secondary thrombosis. Perfusion scans occasionally demonstrate segmental or smaller defects. Distinguishing these from VTE can be difficult.

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Unit 2: Further reading.

1. Harrison's Principles of internal medicine 17th edition.

2. Davidson's Principles and Practice of medicine, 21st Edition.

3. Tropical Diseases AMREF

4. Kumar and Clerk Text book of clinical Medicine 6E Edition

5. Oxford Textbook of Medicine Michael Glynn, William Drake, Clinical Methods, 23rd Edition, 2012, London UK

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Topic 1.1: HYPERTENSION

HYPERTENSION:

Def: A medical condition in which arterial pressures are persistently > 120/80 mmHg

Epidemiology:

More than 50M people in USA suffer from HTN. A higher proportion of people have pre- HTN.

The disease is responsible for >800,000 deaths per year in the USA. Most deaths are due to MI, stroke and other organ failure.

Classification

1. Essential hypertension (95% cases)

2. Secondary hypertension

3. Malignant HTN

Contributing factors to essential hypertension

1. Genetic factors – Incidence of HTN is higher in monozygotic twins, defects in renal sodium excretion, abnormal sodium transport across cell membranes

2. Race – HTN is more common and severe in blacks

3. Socio-economic factors – HTN is common in people of low educational levels & poverty.

4. Age – increased incidence in older people than young people especially males ≥55yrs and females ≥65yrs

5. Insulin resistance esp. in type 2 DM. Insulin stimulates renal Na+ reabsorption leading to increased intravascular volume. It also stimulates sympathetic system activity by activating the release of catecholamines.

- Insulin is a mitogen which stimulates the rate of mitosis.

- It also causes alteration of cell membrane to transport which increases intracellular calcium.

6. Obesity

7. Smoking

8. Excess alcohol intake

9. Pregnancy

10. Drugs – oral contraceptive pills, corticosteroids & anabolic steroids

11. Others

- Sedentary life style/lack of exercise

- Personality traits, hostile, anxious, impatient people

- IUGR

Secondary hypertension:

Usually due to an identifiable cause

1. Exogenous

Drugs – OCPS, corticosteroids, excessive alcohol consumption, cocaine

- Immunosuppressants e.g. cyclosporin

- Erythropoietin

- Others – ephedrine, dopamine

2. Endogenous

i) Renal diseases

a) Parenchymal

§ AGN, CGN

§ Tubular interstitial nephritis

§ Polycystic kidney disease

§ Chronic pyelonephritis

§ Diabetic nephropathy

§ Obstructive uropathy

b) Vascular diseases (Renovascular)

§ Renal artery stenosis

§ Vasculitides e.g. PAN, systemic sclerosis

ii) Endocrine diseases

- Hyperthyroidism

- Hypothyroidism

- Hyperaldosteronism (Conn’s disease)

- Cushings syndrome – Diastolic HTN

- Phaeochromocytoma – Paroxysmal HTN

- Acromegally

iii) CVS diseases; Coarctation of the aorta

iv) Others – obstructive sleep apnoea due to hypoxic damage to the vasculature

Pathophysiology of hypertension:

HTN is associated with small vessel disease. The adverse effects of HTN principally involve blood vessels, central nervous system, retina, heart and kidneys. These adverse effects are noted once compensatory mechanisms are overwhelmed by the disease process.

In the blood vessels especially smaller arteries, hyaline arteriosclerosis occurs, the lumen narrows esp. in the elderly and even in mild HTN. The arterial structural changes perpetuate and aggravate HTN by increasing vascular resistance and reducing renal fxn.

In the kidneys, nephrosclerosis occurs in renal scarring. Hyperplastic arteriosclerosis esp. in malignant HTN causes thickening of arterioles of basement membrane leading to onion skin appearance. There is fibrin deposition and necrosis of arteriolar wall called necrotizing arteriolitis. Long standing cases cause proteinuria & progressive renal failure.

In the heart, there is LVH due to pressure load on the heart. The brain gets haemorrhagic necrosis, thinning of walls esp. of end-arteries and development of aneurysms. Lacunar infarcts may accompany arteriosclerosis involving deep penetrating arterioles of the brain with slit h’ges in ventricular nucleus and thalamus.

Stroke is a common cmx of HTN and may be due to cerebral h’ge or cerebral infarction. Carotid atheroma and transient cerebral ischaemic attacks are more common in hypertensive Pts. Hypertensive encephalopathy is a rare condition.

In the retina, there is hypertensive retinopathy due to arteriolar damage.

Grades of hypertensive retinopathy:

Grade 1 – Thickening of arterioles, tortuosity and increased reflectiveness (silver wiring).

Grade 2 – Focal arteriolar narrowing due to spasms (arteriovenous nipping).

Grade 3 – Retinal ischaemia; flame shaped or blot h’ges and cotton wool exudates.

Grade 4 – Papilloedema

Staging of HTN

JNC7 – Joint National Committee on prevention, detection, evaluation and treatment of high Bp.

The Patient should not have been on anti-hypertensive or acute illness.

Bp stage	SBP mm/Hg	DBP mm/Hg	Lifestyle modification	Initial drug	Therapy compelling indication
Normal	≤120	≤80	Encourage	No drugs	Drugs
Pre-HTN	120-139	80-89	Encourage	No drugs	Drugs
Stage 1	140-159	90-99	Encourage	Drugs Thiazide + ACE-I or ARB, BB, CCB	Drugs
Stage 2	≥160	≥100- 110	Encourage	Two drugs combination + Thiazide	Drugs
Malignant HTN	≥210 with Retinal changes, ARF, HF	≥120	Encourage	Drugs	Drugs

NB: Malignant hypertension is a hypertensive emergency and rapid lowering of BP is beneficial.

But in hypertensive urgency (Bp ≥210/120) while Pt is asymptomatic, there is no benefit in rapidly lowering the high Bp!

Evaluation of a hypertensive patient:

History

- Symptoms; headache, fatigue, epistaxis, tinnitus. Headache is often occipital.

- Previous history of HTN, duration of symptoms, treatment; drugs, doses and for how long.

- Precipitating factors; OCPS, HRT (females), use of steroids, NSAIDS, alcohol, excessive salt intake.

- Enquire on risk factors

v Diabetes, thyroid disease, paroxysmal palpitations, poor response to medication, paradoxical response to medication etc

v Features of CRF

v Goitre – tremors, palpitations, increased appetite with wt loss, menstrual abnormalities, muscle weakness etc.

- Family history – H/o premature cardiac death, h/o heart disease in the family etc.

- Dietary history – salt intake etc.

- Lifestyle history – smoking etc

- Socio-economic history – level of education, occupation etc.

-

Physical examination:

Bp will be high

Diagnosis is made after ≥2 readings at least taken 1hr apart or Bp ≥180/110 mmHg even in one reading is diagnostic. Rule out white coat HTN; a rise in Bp due to anxiety. Advise Pt to have Bp taken elsewhere in a different setting.

Vital signs – PR; check for radio-femoral delay (coarctation of aorta). Look for JVP; may be raised, thyroid, carotid pulsations.

- Look for features of secondary causes

- Do a fundoscopy

- Check wt, BMI

NB: Look for a carotid bruit. Most of the strokes are due to carotid atherosclerosis.

CVS – Apical heave in LVH; Displaced heaving apex.

- Compare peripheral pulses with HR

- Listen / auscultate for heart sounds because of aortic stenosis →ejection aortic murmur.

R/S –Evidence of heart failure; rhonchi crackles.

P/A – Palpable renal masses due to polycystic kidney, renal artery bruit between flanks and umbilicus, aortic aneurysms

CNS – Look for focal neurological deficits, confusion, blurred vision.

Periphery – Cold extremities, vascular ulcers.

Investigations:

Baseline tests

- FBC

- U/E

- Glucose blood levels

- Urinalysis; blood, protein, glucose

- Urine albumin/ creatinine ratio (UACR)

- Estimate GFR using Cockcroft Gault formula.

- Fasting lipid profiles

- ECG –LVH, ST segment changes, conduction defects.

Others depend on suspected underlying cause;

- Thyroid fxn tests, free T₃, T₄ & TSH.

- Serum uric acid

- Aldosterone hormone levels

- Catecholamines – VMA or plasma metanephrine

- Dexamethasone suppression test R/o Cushings syndrome, or serum cortisol preferred which has a diurnal variation.

- CXR

- Echo –LVH or valvular heart diseases

- Renal scan or renal Doppler scan or MRI especially in young patients to R/o kidney disease or effects of HTN on the kidney.

Treatment:

1. Non pharmacological:

i) Lifestyle modification

- Low salt diet

- Low fat intake

- Weight reduction – dash diet is more important and can reduce the BP by 8-14mmHg.

- Aim for a BMI target of 18-25 and if you reduce weight by 10kg, it can decrease BP by 20mmHg.

- Brisk exercise reduces BP by 4-9mmHg.

- Minimize alcohol intake which can reduce BP by 2-4mmHg.

NB: For plain sodium – aim for <2.4g and for sodium chloride <6g and this salt reduction can reduce the BP by 2-8mmHg.

ii) Treat the underlying cause

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Topic 1.1: HYPERTENSION (Cont')

2. Pharmacological management:

Based on:

- Age of patient

- Cost of medication

- Grade of the disease

- Presence of co-morbidities or compelling indication

- Possible drug side effects.

Drugs used:

a) i) Thiazide diuretics

- Bendrofluomethiazide 5mg daily OR

- Cyclopenthiazide 5mg daily OR

- Hydrochlorthiazide 12.5 – 25mg daily OR

ii) Loop diuretics – Frusemide 40-80mg OD OR

iii) Indapamide – This is good even in substantial renal impairment.

NB: Thiazide diuretics are more preferred because of their CVS effects.

b) ACE –I – May be 1^st choice if co-existing LVF or diabetes

- Enalapril 20mg daily OR

- Lamipril 5-10mg daily OR

- Lisiniopril 10-40mg daily OR

ARB – Losartan 50mg – 100mg daily, Valsartan 40-160mg daily

Caution if valve disease or cardiomyopathy especially when using ARBs.

Other ARBs - Erbesartan or telmisartan 80mg/day

Elbesartan and telmisartan are once per day doses.

NB: ACE –I –Can reduce the filtration pressure in the glomeruli and precipitate renal failure.

c) Beta blockerrs – CI in asthma

- Carvedilol 6.25mg – 25mg BD OR Bisoprolol 5-10mg OD OR Atenolol 50mg -100mg OD

NB: Labetolol can be used in IVI in malignant HTN

d) Calcium channel blockers

i) Dihydropyridine are especially useful in the elderly patients.

- Amlodipine 5-10mg daily

- Nifedipine 30-90mg daily – SE, Gum hypertrophy, ankle oedema.

ii) Rate –limiting calcium antagonists

- Can be used when HTN co-exists with angina but they may cause bradycardia; drugs here include the non –dihydropyridines e.g Diltiazin 200-300mg daily, Verapamil 240mg daily – this causes constipation as SE.

e) Other drugs used in hypertension

i) Vasodilators

- Hydrallazine 25-100mg BD

- Diazocin

- Prazocin

- 1Prazocin is given at 0.5 -20mg daily in divided doses.

ii) Central acting drugs

- Methlydopa 250mg 8hrly initially are effective anti – HTN but these drugs cause fatigue & long term use can lead to depression.

NB: The goal of lowering BP in HTN is to reduce the risk of cardiovascular problems.

For the general population, the aim is to reduce or maintain BP at ≤140/90mmHg.

In diabetics, BP should be maintained at less than 130/80mmHg.

In white coat HTN, BP should be ≤ 140/90mmHg and these patients need no treatment but just lifestyle modifications.

Medical therapy in HTN only comes when there is risk of organ damage.

For any patient with BP higher / greater by ≤20/10 above 140/90 mmHg –use monotherapy but greater than 20/10mmHg above 140/90 mmHg use a combination therapy.

Choose long acting drugs e.g.

- Thiazides but indapamide here is better in terms of long term control.

- CCB – Amlodipine

- ARBs –Erbesartan, Telmesartan

- BB –Atenolol etc

Choose two different agents in combination therapy.

Fixed dose combinations also exists e.g.

ACE – I + diuretics, ARB +diuretics etc

Hypertensive urgencies:

BP ->210/110 mmHg but patient is asymptomatic.

The goal of management is to lower BP to ≤160/100mmHg.

There is no proven benefit of lowering the BP rapidly in these patients.

Strategies in management:

- Put patient in quiet room & this may alone decrease BP by 10-20mmHg.

- For patients already on medication:

i) Increase dose of existing anti –HTN OR add another agent for HTN.

ii) If non compliant patient –Give the same medications & observe patient.

iii) Enforce sodium dietary restriction especially if there is high sodium intake.

- If no previous treatment history

i) Use same principles for treating HTN

- Diuretics –thiazide; HCTZ 12.5 -25mg OD P.O; Ensure normal renal fxn.

- ACE- I OR ARB –long acting drugs.

NB: Most patients do well on two drugs

- Observe patient for 2-6hrs

- Monitor BP & if it drops by 20-30mmHg from the baseline, patient can be sent home on oral medications.

- The goal is to see patient in 2/7 for another check BP, and if BP <160/100mmHg schedule for follow up in MOPC.

Hypertensive emergencies:

Malignant HTN:

- Is more common in patients with long standing uncontrolled BP. In malignant HTN, the BP is ≥210/110 mmHg and patient is symptomatic.

- More often than not, the patients have already been discontinued on anti –HTN therapy.

- It is common in patients with renal artery stenosis or scleroderma.

- Fundoscopy – retinal h’ges and retinal exudates and papilloedema (HTN – retinopathy grade 3 0r 4).

- In the kidney, there is malignant nephrosclerosis that leads to ARF, haematuria, proteinuria (The main problem is fibrinoid necrosis which leads to renal ischaemia that activates aldosterone –renin – angiotensin mechanism →sodium retention and further rise in HTN.

- Neurologic symptoms are commonly due to intracerebral or subarachnoid bleeding, lacunar infarcts or hypertensive encephalopathy.

- The hypertensive encephalopathy is due to cerebral oedema and presents with

Ø Headache

Ø Nausea & vomiting

Ø Restlessness

Ø Confusion

Ø Seizures

Ø Coma

Management of malignant HTN OR Hypertensive encephalopathy:

- Manage in ICUParenteral anti- hypertesives

1. Nitroprusside – arteriolar & venous dilator given as IVI.

- Start at 0.25 – 0.5micrograms/kg/min. It acts within seconds & duration of action is 2-5min. Its usefulness is that it increase BP fast & its easy to reverse the effects as they wear off very fast. SE – cyanide toxicities.

2. Nicardipine (arterial dilator) as IVI at an initial dose of 5mg/hr, max dose 15mg/hr.

3. Labetolol – an alpha – beta adrenergic blocker given as IV bolus at 20mg initially, then 20-80mg every 10min, total max dose 300mg. OR. IVI at 2mg/min.

4. Fenoldopam – a dopamine agonist given as IVI at 0.1kg/kg/min & titrate the dose.

NB: Oral agents are not recommended in malignant HTN because they lower the BP slowly; is difficult to reverse incase of hypotension and in patients with cerebral ischaemia, they can cause stroke.

IV hydrallazine – Not Recommended

Never use sublingual Nifedipine to reduce BP because of risk of rapid / big drop in BP and stroke.

Goal of therapy in malignant hypertension:

- Rapidly lower diastollic BP to 100-105mmHg within 2-6hrs. The max initial fall of BP should not exceed 25% of the initial BP in the first 6hrs. This has been shown to be beneficial to the healing of vascular lesions.

- IV drugs in malignant HTN are for the initial phase. Change to oral medications once the patient is stable.

- Aim to reduce diastolic BP to between 85-90mmHg.

- ACE –I ARE NOT A CHOICE oral anti- HTN agents in malignant HTN because they worsen kidney dysfxn.

Factors that cause resistant HTN:

Refractory HTN is commonly due to

- Secondary HTN e.g. renal artery stenosis or phaechromocytoma.

- Poor compliance - lifestyle modification therapy.

- Sub-optimal therapy / inadequate therapy.

- Drugs – NSAIDS, cocaine, amphetamine, OCPs, corticosteroids.

- White coat HTN –do ambulatory BP monitoring.

Complication of HTN:

Heart – LVF, Coronary artery disease, Aortic aneurysms.

Kidneys – renal failure

Eyes – retinal vein thrombosis, Hypertensive retinopathy

CNS –CVA, Infarction, Hypertensive encephalopathy

Others – metabolic syndrome, Transient ischaemic attacks.

Prognosis

- Most of the patients have a very high mortality.

- Even if BP is brought down, the risk of vascular damage is high.

- 40-50% survival at 10yrs and those with renal insufficiency have a 10% chance of survival at 10yrs.

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Topic 1.2: CONGESTIVE CARDIAC FAILURE (CCF)

CONGESTIVE CARDIAC FAILURE

Def: Congestive cardiac failure is a clinical syndrome resulting from a structural or fxnal cardiac disorder with impaired ability of the ventricles to fill or eject blood at a rate commensurate to the body’s metabolic demands.

Epidemiology

Heart failure is frequently due to coronary artery disease. The prevalence rises from about 1% at 50-59yrs to between 5-10% at 80-89yrs.

In the UK, most of the patients with heart failure are > 65yrs. Congestive cardiac failure carries a poor prognosis with about 50% of patients with LV dysfxn dying within 2 yrs of diagnosis.

Many of the patients with CCF die from:-

· Sudden cardiac dysarrhythmias

· Myocardial dysfxn

Aetiology of CCF

- Pump Failure

§ Muscle dysfxn; IHD, Cardiomyopathy, poisons.

§ Restricted filling; mitral stenosis, pericarditis, cardiac tamponade.

§ Heart rate abnormality

- Excess preload

§ Regurgitant valves

§ High output states; anaemia, thyrotoxicosis, thiamine deficiency.

- Chronic Excess after Load

§ Long standing HTN

- Others

§ infections

§ electrolyte imbalance

Precipitants of heart failure

1. Anaemia

2. Infections including pneumonia and infective endocarditis

3. Uncontrolled HTN

4. Uncontrolled hyperglyceamia

5. Thyrotoxicosis –patients with heart failure must have the thyroid gland examined

6. Excessive exercise

7. Drugs – NSAIDS, steroids, Ca CBs

8. Pulmonary embolism

9. Patients already on medication (for CCF) and are non- compliant

10. Substance abuse

11. A new MI

12. Pregnancy

13. Arrhythmias

14. Electrolyte imbalance of whatever cause

Pathophysiology

The pathophysiologic changes are usually due to overwhelmed compensatory mechanisms for the heart to meet the body’s metabolic demands. The pathology results from:-

i) Haemodynamic changes

- Decreased output due to systolic dysfxn and decreased filling due to diastolic dysfxn

- The ejection fraction; a measure of EDV is decreased in systolic dysfxn as occurs in decreased ventricular contractility like MI, myocarditis, dilated cardiomyopathy.

- Systolic dysfxn also occurs in ventricular outflow obstruction (pressure overload) as in HTN,AS, PS, or it can occur in ventricular inflow obstruction as in MS, TS or in ventricular volume overload like in MR, AR, VSD & ASD.

- Diastolic dysfxn results from impaired relaxation. In normal physiology, the heart’s filling is passive, mostly from the normal atria. A second filling; atrial kick also brings residual blood into the heart.

- The early/atrial kick ratio is normally greater than one (1) or 2 but in diastolic dysfxn, the E.A ratio (measured using echo) is <1. In diastolic dysfxn, the ejection fraction is normal and CO may be initially normal but with time, LV end diastolic pressure is shifted to the left leading to CCF.

- Diastolic dysfxn can occur in:-

§ Constrictive pericarditis

§ Restrictive cardiomyopathy

§ LVH

§ Cardiac tamponade

ii) Neurohormonal changes

A fall in cardiac output usually activates counter regulatory neurohormonal mechanisms that in normal physiological circumstances would support cardiac fxn.

Stimulation of the RAAS leads to vasoconstriction, salt and water retention, and sympathetic activation mediated by angiotensin II, which is a potent constrictor of arterioles both in the kidney and systemic circulation. This may initially maintain cardiac output through increased myocardial contractility, HR and peripheral vasoconstriction. But prolonged sympathetic stimulation leads to cardiac myocyte apoptosis, hypertrophy and focal myocardial necrosis.

Salt and water retention is promoted by the release of aldosterone, endothelin, severe heart failure and ADH. Natriuretic peptides act as physiological antagonists to the fluid conserving effect of aldosterone.

iii) Cellular changes and remodelling

After myocardial infarction, cardiac contractility is impaired and neurohormonal activation may lead to hypertrophy of non –infarcted segments, with thinning, dilatation and expansion of the infarcted segment (remodelling). This may lead to further deterioration in ventricular fxn and worsening heart failure.

Remodelling leads to changes in calcium handling, adrenergic receptors, contractile apparatus and myocyte structure.

NB: Mediators of cardiac remodelling

i) Norepinephrine and epinephrine (toxic to the heart muscles)

ii) Aldosterone

iii) ADH

iv) Cytokines – These are secreted by macrophages, lymphocytes, monocytes which release IL and TNF that are important in the cycle of myocyte hypertrophy and cell death.

IL – 1 may accelerate myocyte hypertrophy, endothelin is a potent vasconstrictor and excessive endothelin release may be responsible for pulmonary arterial HTN and LVF. It’s also associated with myocyte growth and deposition of matrix.

Clinical syndromes of heart failure

1. Left ventricular failure

2. Right ventricular failure

3. Systolic heart failure – inadequate cardiac or forward failure.

4. Diastolic heart failure ( backward failure)

5. High output failure – associated with high cardiac output ( A-V shunt, beriberi, severe anaemia or thyrotoxicosis) and elevation in pulmonary venous pressure.

6. Biventricular heart failure (Lt + Rt ventricular failure)

7. Acute and chronic heart failure

Presentation

S + S are not sensitive and specific and include:

- Dyspnoea, fatigue due to fluid retention.

- Pulmonary or peripheral oedema due to fluid retention. Patient could even have anarsaca.

- Orthopnoea, paroxysmal nocturnal dyspnoea or nocturnal cough with sputum production.

- Wheeze (cardiac asthma)

- Weight loss and muscle wasting ( cardiac cachexia)

- In RVF – patient has peripheral oedema or anarsaca, abdominal distension due to ascites, breathlessness, nausea, anorexia, facial engorgement, pulsation in the neck.

Framingham clinical criteria for the diagnosis of heart failure:

Major criteria

1. Paroxysmal nocturnal dyspnoea (PND) –Depression of resp. centre makes patient wake up at night once PaO₂ levels fall. PND is also called cardiac asthma.

2. Orthopnoea – redistribution of retained fluid leads to increase in venous return to the heart.

NB: The above 2 features occur with fluid retention.

3. Elevated JVP

4. Rales or crackles

5. Cardiomegally on CXR

6. S₃ gallop

7. Plain pulmonary oedema on CXR

8. Weight loss of > 4.5kg in 5 days in response to treatment for heart failure.

Minor criteria

1. Bilateral leg oedema

2. Nocturnal cough

3. Dyspnoea on ordinary exertion

4. Hepatomegally

5. Pleural effusion

6. Tachycardia >120/min

7. Weight loss > 4.5kg in 5 days in response to treatment.

Diagnosis of heart failure

2Major criteria or

1Major and 2 minor

Diagnosis of heart failure is usually made from:-

1. History

i) Precipitants must be looked for in the history

ii) Look for the underlying cause

- Identify the cause and if reversible correct it and the patient will be fine.

- Congenital valvular lesions

· Symptoms of heart failure from childhood.

· Recurrent admissions from childhood

· Failure to thrive

· Slow in educational progression

- Rheumatic fever – may be history of tonsillitis

- History of DM and other risk factors for coronary heart disease; smoking, obesity, alcohol.

- Recent delivery – think of cardiomyopathy

- Drugs – ARVs and their SE

- Chemotherapy –doxorubicin

- Hiv infxn

iii) Enquire on activity and symptoms for

New York heart association classification of heart failure

2. Physical examination

Patient may be ill –looking depending on severity, dyspnoic, tachypnoic, cyanosed, pale, jaundice, leg oedema.

Vital signs –Temp, PR, RR, BP

Hands – pallor, cyanosis, splitter h’ges, finger clubbing, Osler’s nodes, nicotine staining.

Pulse – Rate, rhythm, volume, character compare both Rt and Lt radial pulse and take all other pulses (all of them).

BP – Low systolic Bp or high systolic Bp

- Wide or narrow pulse pressure

Neck – distended neck veins JVP

Examine for thyroid gland enlargement

Chest – Abnormal chest (shape), scars, distended veins

- Hyperactive precordium

- May be displaced apex beat; heaving apex, tapping apex (ms)

- Thrill, Lt parasternal heave

- Palpable P₂

Auscultation – normal S₁, S₂

- S₃ gallop rhythm in systolic failure

- S₄ gallop rhythm in diastolic failure

- + murmurs

R/S – crackles + pleural rub

P/A – Abdo. distension

- Hepatic pulsation – tricuspid regurgitation on left heart failure

- Hepatomegally

- Ascites, thrill, shifting dullness

- Hepatojugular reflux

3. Investigation

i) FBC – Hb, WBC

ii) W/E – Electrolyte imbalance

iii) Serum creatinine

iv) LFTs – Acutely congestive – hepatic failure

- Chronically congestive – cardiac cirrhosis

v) CXR – for Framingham classification to rule out underlying pathology; cardiomyopathy, ventricular hypertrophy, pulmonary oedema, pericardial effusion or pleural effusion.

- Kerley ABC lines –linear opacities seen on CXR in patients with pulmonary oedema.

- Kerley A lines – longer, at least 2cm, unbranching, crossing diagonally from periphery to hilar in the inner ½ of lungs. Are due to distension of anastomotic channels between periphery & central channels.

- Kerley B lines – about 1-2cm long, generally horizontal and meet the pleura at right angles to fat aspect of lungs.

- Typically seen as a ladder from below at costal angle.

- DDX – Pulmonary oedema

-CCF especially, LVF & MS

-Lymphangitis carcinomatosis

-Pulmonary fibrosis

-Parasitic infestation

-Heavy metal particles

-Haemosiderosis

- Kerley C lines –Non – specific reticular patterns. Are the least seen

4. ECG – To detect arrhythmias

5. Echo – is the best way to measure E.A ratio and for proper management.

6. MRI – Gold standard for assessing ventricular volume

7. BNP – Cardiac myocyte necrosis

-Is an expensive test

-A normal plasma level excludes heart failure

Stages of heart failure (structural)

Stage A – A patient who has risk factors for heart failure e.g DM, smoking etc, but has no structural heart disease or symptoms

Stage B- A patient with a structural heart dz e.g cardiomyopathy, valvular heart disease but is asymptomatic.

Stage C – patients with prior or current symptoms of heart failure.

Stage D – refractory or end stage heart failure.

Classification of severity for heart failure

The New York heart association classification

This usually indicates the class or degree of heart failure, associated symptoms and activity limitation.

Class / degree	Symptoms and activity limitation
Class I – None	No symptoms from ordinary activity
Class II – Mild HF	Comfortable at rest or during mild exertion. Dyspnoea on ordinary activity
Class III – Mod. HF	Symptomatic with any activity
Class IV – Severe HF	Symptoms at rest – confined to bed or chair

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Topic 1.2: CONGESTIVE CARDIAC FAILURE (CCF) -C0nt'

Management of heart failure

Aims

- To reduce symptoms

- To reduce morbidity

- To improve the quality of life

A. Quick assessment of patient

- Resuscitate patient with decompensated HF (patient with rapidly developing cardiogenic pulmonary oedema).

- Prop up patient

- Give oxygen while checking O₂ saturation

- I.V frusemide (slowly) is more effective than oral; larger doses are required in renal failure.

- Opiates –Sedates patient, decrease anxiety and helps patient meet metabolic needs.

- Nitrates especially if systolic BP ≥ 100mmHg

B. Non pharmacological management

1. Correct all precipitants

2. Lifestyle modification

- Comply with medications

- Salt restriction (2g/day)

- Alcohol ceasation

- Stop smoking

- Exercise training for ambulatory patients

- Limit fluid intake (input /output chart) to avoid hyponatraemia.

3. Look for underlying cause and treat or modify.

- HTN – optimize anti – HTN regime

- DM – control sugars

- Manage any coronary syndromes

- Arrhythmias – anticoagulate

Pharmacotherapy

- Manage symptoms and improve quality of life.

I) Asymptomatic LV systolic dysfxn

- ACE –I

- Health education

- Risk factors

- Rx precipitants

II) Symptomatic LV systolic failure

1. Start with loop diuretics

- Frusemide 40mg – 80mg preferably as OD dose, all at once rather than divided doses.

- Frusemide gives symptomatic relief of fluid retention.

- Monitor U/E, weight loss 1kg/day. Frusemide is a rapid response drug, if patient not losing weight, change to thiazide diuretic preferably I.V.

2. ACE – I – Consider in all patients with LV systolic dysfxn

ACE –I commonly used

- Captoprill

- Lisinopril

- Enalapril

ACE –I – Improves heart failure symptoms

- Prolongs life

- Reduces mortality

Principles

- Response is immediate

- Once patient is losing fluid, no worsening of symptoms.

- Start with a low dose slowly

Enalapril 10-20mg BD

Captopril 6.25mg TID max 50mg

Lisinopril 5mg OD – max 40 mg OD

Over 1-2 wks – you can double the dose to the max dose depending on response.

Monitor –cough – usually due to increased bradykinin levels

If patient develops uncontrollable cough, change to ARB

U/E – Hyperkalemia, azotemia. Candesartan, valsartan (ARBs) tested and found to be good but do not give in patients with MI.

ARBs usually reserved for patients intolerant of ACE-I.

3. B – Blockers – only given when patient is generally stable and the BP is good.

CI – Asthma

- COPD

- Hypotension

- 2^nd or 3^rd degree heart block, bradycardia & sinus syndrome.

BB commonly used:

- Carvedilol – beta and alpha blocker, anti –oxidant

- Metoprolol (selective B₁)

- Bisoprolol

- Nevibolol

BB – Improve LV ejection fraction & survival in patients with symptomatic LV dysfxn.

Always start at a low dose and titrate to target max doses e.g.

Carvedilol 3.125mg BD – 25 – 50mg BD

Bisoprolol 1.25mg OD – decreased 5-10mg OD

Metoprolol 12.5mg OD – max 25mg

NB: 1^st one month, patient may get worsening of symptoms because of sympathetic effect which is blocked.

Long term effect – down regulation alters over time.

The effects are usually long term, not short term.

4. ARB – Can be used as substitute to ACE –I or as an adl on therapy in HF.

5. Aldosterone blockers / antagonists

- Spironolactone – indicated if low ejection fraction <40%

- Dose 25 -50mg daily

- It improves endothelial dysfxn (nitric oxide bioavailability) and prevents remodelling

- Decreases mortality by 30%

- Is K⁺ sparing

- Eplerenone 25 -50mg OD – New York heart association class III.

6. Digoxin – for purely heart failure, start with low dose digoxin 0.125mg OD.

- It reduces rate of hospitalization

- Offers symptomatic relief benefits

- Good at controlling fibrillation

- No mortality benefits

NB: No significant improvement in survival rates.

7. Vasodilators

- Nitrates together with hydrallazine (combination);

- Indications – failure to control symptoms with all above drugs.

- Hydrallazine 25mg tid plus

- Isosorbide nitrate 40mg tid

The combination of hydrallazine & nitrate has more benefits in blacks than whites.

- Provides an alternative in patients with ACE –I intolerance or those who may require additional therapy for BP.

- Reduces mortality in symptomatic patients ( mortality benefit)

- Reduces rate of hospitalization

- Improves quality of life

D) Management of refractory heart failure

- Implantable cardioverter defibrillator (ICD.

Indications

- After cardiac arrest

- Ventricular tachycardia that is defibrillating

- Lt ventricular assists device indications include;

- Very slow ejection fraction < 30%

- Severe myocardial infarction

- If nothing is working then consider heart transplant.

Diastolic heart failure

Management – manage underlying cause

- Use drugs that manage fluid retention ( diuretics)

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Topic 1.3: ISCHAEMIC HEART DISEASE (IHD)

Ischaemic heart disease:

Is a condition in which there is imbalance between myocardial supply and demand leading to myocardial ischaemia, hypoxia and accumulation of waste metabolites.

The commonest cause is coronary heart disease.

Chronic stable angina

A clinical syndrome characterized by chronic predictable transient exertional angina resulting from myocardial ischaemia and occurs when coronary perfusion is impaired by fixed or stable atheromatous plagues in one or more coronary arteries.

Epidemiology:

In the developed world, it’s the most common and serious chronic heart lesion and is the leading cause of death.

In USA ≥12 million people have IHD and 6.5m people have symptomatic angina pectoris.

In the developing world, it’s a growing problem and globally will soon become the commonest problem.

Aetiology:

1. Coronary artery disease

Risks:

Fixed and non modifiable

- >50yrs

- Male gender

- Positive family history

- Deletion polymorphism in ace gene

Modifiable risk factors

- Hyperlipidaemia

- Cigarette smoking

- HTN

- Diabetes mellitus

- Sedentary work

- Increased levels of CR proteins

- Homocysteinaemia

- Obesity

- Type A personality

- NSAIDS

- OCPs

- Lipoprotein A

- Increased fibrinogen & factor VII

- Heavy alcohol consumption

- Infections e.g. helicobacter

2. Any cause of decreased myocardial oxygen supply

- Hypotension or AR

- Decreased blood oxygen carrying capacity e.g anaemia, carboxyhaemoglobinanaemia.

- Any cause of mechanical obstruction within the coronary vessels –coronary arteritis, emboli, spasms.

- Congenital abnormality of coronary arteries e.g lateral and descending artery originating from pulmonary artery.

3. Any cause in increased oxygen demand

- LV hypertrophy 2⁰ HTN

- Severe aortic stenosis leading to LVH

- HOCM

- Pulmonary HTN

Pathophysiology:

- Most often follows coronary artery disease.

- There is atherosclerotic narrowing of one of the vessels by:-

· Plague formation

· Inappropriate vasoconstriction due to endothelium dysfunction.

There is decreased perfusion especially when there is an increase in oxygen demand. At rest, there may be no problem even with vessel narrowing of up to 70%. The increased myocardial oxygen demand leads to ischaemia as in increased exercise, emotional stress and tachycardia.

Ischaemia manifests as:-

- Angina

- ECG shows ST depression.

There is no myocardial necrosis or scaring (reversible changes)

Consequencies of ischaemia:

- Metabolic products e.g. lactate, adenosine or serotonin accumulate locally, activate pain receptors especially between C7 – T4 leading to the mechanism of angina. The metabolic products together with abnormality of ion transport cause electrical instability leading to tachycardia e.g.ventricular fibrillation & ventricular tachycardia; V.T) which may cause sudden death.

- Ventricular dysfxn may occur that may end up with heart failure.

- Impaired papillary muscle fxn leading to mitral regurgitation.

Presentation:

Symptoms - Patient may be asymptomatic due to silent ischaemia especially patients with diabetes (peripheral neuropathy).

History of predisposing factors or precipitants e.g anaemia, HTN, thyrotoxicosis, tachyarrhythmias, decompensated heart failure, concomitant valvular heart diseases

Angina pectoris – Is the commonest manifestation characterized by:-

- Tightness, heaviness, discomfort, squeezing or constriction on the chest.

- Pain is usually central or substernal.

- Localizing sign – Pressing on sternum with clenched fist (Levin’s sign). The discomfort is classically precipitated by exertion and stops with caesation of activity.

- Pain is relieved by rest and nitroglycerins.

- Other triggers of pain include:-emotional stress, anger, cold weather, a large meal,

- Site - Can occur at any site from the mandible to umbilicus

- Radiation to shoulders and inner aspects of arms especially Lt. side.

- It may be accompanied by autonomic stimulation, diaphoresis, dyspnoea, nausea, fatigue, sweating, tachycardia, collapse & syncope.

NB: Exertion needed to precipitate angina may be constant or variable.

Types of angina

1. Classical / Exertional angina

2. Decubitus angina –occurs when patient is lying down.

3. Nocturnal angina –occurs at night & wakes patient from sleep.

4. Syndrome x- patient has typical symptoms of angina that is reproduced when exercise testing is done & the coronary artery is normal.

5. Unstable angina –sudden increase in frequency and duration or angina becomes worse.

6. Variant angina (Prinzmental angina) due to coronary artery spasm.

Grading of angina:

Canadian Cardiac Society – Just like New –York cardiac association grading of angina / heart failure.

Class I – Ordinary physical activity does not cause angina but streneous or prolonged exertion leads to angina.

Class II – Slight limitation of ordinary activity

Class III – Marked limitation of ordinary activity

Class IV – Inability to carry out any physical activity without any angina symptoms.

Angina may occur even at rest.

Signs

a) During angina episode

- During an attack, the patient is restless, sweating, dyspnoic, tachycardiac, BP often raised, Pallor. Other features depend on cmxs e.g. features of MR + S₄ gallop, may have 3^rd & 4^th heart sounds with features of pulmonary oedema.

b) Other times; when not in attack

- There may be no signs

- Evidence of risk factors – obese etc.

- Females waist circ >35 inch or 89cm

- Males – waist circ >40 inch or 102cm.

- May have nicotine staining – smokers.

- Features of hyperlipidaemia; xanthomas etc.

- Evidence of systemic atherosclerosis e.g. abdo. aortic aneurysms, carotid artery bruit, decreased arterial pulsation in the extremities.

- Evidence of precipitants e.g. anaemia, thyrotoxicosis.

- CVS palpation – cardiomegally evidenced by displaced apex beat. Auscultation reveals AS, MR.

Investigations:

1. Blood tests

- FBC – ↓HB, leucocytosis, ↑ESR

- Fasting blood sugars

- Lipid profiles

- Thyroid function tests

2. CXR – May show consequences of ischaemia e.g. cardiomegally +/- pulmonary oedema.

3. ECG – Is key in diagnosis.

i) Resting ECG – Normal between attacks but during ischaemia, it shows ST segment depression, T- wave flattering or inversion which may be transient.

- A giant T- wave inversion is an important indicator of severe stenosis of LAD artery.

- Pathological Q –wave, LVH, Lt bundle branch block.

ii) Exercise ECG – Use treadmill or bicycle. Has sensitivity of 70%, specificity of 80%

ECG is done before, during and after exercise. A positive test should reproduce the typical features of angina with an ST – segment depression of >1mm.

NB: The above tests are affected by B-blockers and calcium channel blockers.

4. Exercise Echo or Echo using drugs like dobutamine or dipyridamol. Echo is more sensitive than ECG. A +ve test shows ischaemia and ventricular contracted abnormality during the exertion.

5. Myocardial perfusion syntigraphy – uses radionucleotides e.g. Tegmetin or Thalniun I.V; imaging done as patient exercise. Assists in identifying the areas of poor perfusion which will not accumulate the radionucleotides. Its very expensive but has 80-90% specificity & sensitivity

6. Coronary angiography – Identifies site of coronary stenosis.

- It is the gold standard but it only gives anatomic information.

- It is invasive and indications include:

i) Angina refractory to medical treatment.

ii) Angina occurring after MI

Treatment:

Goals –

- To reduce the frequency of angina attacks

- To prevent MI

- To prolong survival

1. General measures to reduce frequency of angina attacks

- Reassure the patient; explain the problem that angina is not heart attack.

- Identify and treat precipitants; anaemia etc.

- Lifestyle modification

Ø Stop smoking

Ø Reduce weight if obese

Ø Control BP

Ø Dietary modifications

Ø Exercise

2. Acute episodes of angina

- Cease physical activity

- Ensure bedrest

- Give nitroglycerin

Ø Sublingual 0.3 – 0.6mg or

Ø Aerosol spray or

Ø Transdermal preparation- Have longer effect of about 24hrs

3. Angina – not in attack

Give maintenance therapy after the acute episode of angina.

i) Nitrates – use long acting nitrates which give symptomatic relief but do not improve survival.

Ø Isosorbide dinitrate 10-20mg 8hrly per oral.

Ø Isosorbide mononitrate 20-60mg OD or BD.

ii) Beta – blockers (BB)

Ø Use atenolol or metoprolol which are B1 receptor blockers.

Ø Atenolol 50- 100mg once a day.

Ø Metoprolol 25 – 50mg BD – Is the best drug if renal function is impaired because it is excreted via the liver.

Ø Monitor heart rate (target HR 55-60/min)

iii) Calcium channel blockers – As add on to BB or as substitutes, they do not improve life expectancy.

If adding to beta blockers – choose dihydropirdines e.g. nifedipine (SR preparation) 30-90 mg daily. If using non –dihydropiridines –do not combine with a BB as this will cause excessive bradycardia; e.g verapamil (SR) 150mg daily

iv) Other drugs:

a) K+ channel activators; Nicorandil 10-30mg BD

- P –fox inhibitors which partially inhibit fatty acid metabolism in myocardium; Ranolazine Trimetazidine (available)

b) Perhexiline –Not available in Kenya.

4. Drugs to prevent M.I

All patients should receive secondary preventive therapy.

i) Anti –platelets; Aspirin (ASA) 75 – 150mg for all patients unless CI. ASA reduces the risk of death and MI in unstable angina. Use Clopidogrel if ASA contraindicated.

ii) Lipid lowering drugs, Statins; Lovastatin 20-80mg nocte (given at night because they cause myalgia as a SE & most cholesterol synthesis occurs at night). Sivastatin 20-80mg nocte.

NB: LDL should not go above 100mg/dl or 2.6mmol/l

Fibrates – useful in lowering triglycerides (TGL) and are given when TGL > 3.5 mmol/l

Drugs used here includes Finofibrates 160mg OD

iii) ACE – I are known to reduce mortality and improve survival.

5. Treatment to prolong survival

- Coronary revascularisation – For patients with drug resistant angina pectoris

i) Percutaneous coronary intervention (PCI) with stenting or balloon angioplasty.

ii) Coronary artery bypass graft (CABG); Can use internal mammary artery, Radial artery, Saphenous vein. CABG is especially important in patients with coronary artery disease involving 3 or more vessels.

6. Treatment for intractable angina

i) Transmyocardial revascularisation

ii) Spinal cord stimulation

iii) Enhanced external counter –pulsation

ACUTE CORONARY SYNDROMES

Def: A clinical syndrome attributable to obstruction of the coronary arteries and consists of:

i) ST – elevation MI (STEMI)

ii) Non – ST –elevation (NSTEMI)

iii) Unstable angina

Diagnosis is based on clinical history, a 12 lead ECG and elevated biochemical cardiac markers.

Measurement of cardiac troponins is an extremely sensitive and specific method of determining myocardial necrosis.

NSTEMI – Is defined as an acute coronary syndrome characterized by myocardial necrosis confined to endocardial layer which usually follows blockage of a small branch artery or an obstruction in which there is collateral circulation.

UNSTABLE ANGINA – Characterized by a new onset exertional angina, increasing in frequency and refractory to treatment or occurs at rest.

NB:

i) STEMI – has an elevated ST – segment, features of myonecrosis (irreversible myonecross).

ii) NSTEMI – Non ST-segment elevation but there is myonecrosis.

iii) Unstable angina – plus or minus ST segment elevation but there is no myonecrosis.

Epidemiology of acute coronary syndromes:

Acute coronary syndromes are quite common in the developed world.

In Britain for example, the annual cases of angina are 1.1/1000 males, 0.5/1000 females in the population aged 31-70yrs.

In Sweden – ischaemic heart diseases affect males mostly between 50 -57yrs forming about 5% of the hospital cases.

In industrialized countries, it occurs in 6/10,000 people.

Thereafter the incidence becomes equal due to cardio- protective effect of oestrogen in women.

Women have more often atypical coronary events/ features which lead to missed diagnosis in some cases.

Age – Acute coronary syndromes becomes more common with increasing age.

Mortality and morbidity – When therapy was only with nitroglycerin & exercise, the mortality was high. Currently, mortality has gone down due to use of ASA & glycoprotein blockers.

Pathophysiology:

Mechanisms involved:

1. Rupture of a coronary artery plague that occurs in 70% of the cases. The rupture of the plaque exposes thrombogenic surface of the artery leading to platelet aggregation, formation of unstable atheromatous plague with a thin fibrous and lipid core.

2. The plague may undergo erosion, calcification or intra-plague h’ge.

3. Extrinisic factors involved are basically vasoconstrictors.

- Increased oxygen demand as in fever, thyrotoxicosis, anaemia, HTN, hypoxemia. Most of these extrinsic factors precipitate unstable angina.

4. Vasculitis - Marfans syndrome, Kawasaki dz, Takayasu arteritis, cystic medial necrosis, malformations or anomalies of the coronary artery.

5. Traumatic myocardial infarction –Accelerated atherosclerosis as in cardiac transplant.

6. Progeria.

Clinical presentation

History –Picks symptoms of acute coronary syndromes; angina pain, palpitations, exertional dyspnoea which resolves at rest, diaphoresis due to increased sympathetic discharge that also leads to nausea, vomiting. Other features include decreased exercise tolerance, atypical features in patients with DM -Nausea vomiting, palpitation, syncope because of autonomic neuropathy.

Risk factors – male, smoking, advanced age, prior CVA or heart attack or coronary artery disease

Differentials of chest pain ruled out from systemic inquiry includes

- CVS- Myocarditis, Pericarditis,

Aortic aneurysm dissection, A. fibs.

- Pulmonary – pneumonia, pulmonary embolism, Pleurisy, Pneumothorax.

- Chest wall – HZV, Fracture Ribs, Costocondritis, Fibromyalgia

- GIT – GERD, Functional dyspepsia, Hiatus hernia.

- Psychological –Panic attack, Anxiety disorder, Somatization disorder, Depression.

- Others – hyperventilation syndrome, High abdo. Pain, Lead poisoning, Da costa syndrome

General examination /signs

Patient is anxious, sweating pale.

Vital signs– increased BP 2⁰ catecholamine release or ↓BP causing the acute coronary syndrome or Rt ventricular infarct.

- CVS – features of heart failure; ↑JVP, S3 gallop, new murmur 2⁰ papillary muscle dysfxn.

R/s – crackles or rales due to LVH

TIMI risk score in acute coronary syndrome.

Risk factor	Score
1. Age >65yrs	1
2. More than (≥) 3 coronary artery dz risk factors (HTN, Hyperlipidaemia, family H/o IHD, DM or smoking.	1
3. Known coronary artery disease (coronary angiography; stenosis >50%	1
4. ASA use in the last 7 days	1
5. Severe angina >2 episodes in the last 24hrs	1
6. ST – deviation on ECG (ST depression or transient ST elevation >1mm	1
7. Elevated cardiac markers (Ck- MB or cardiac troponins)	1

Interpretation

Total score	Rate of death /MI in 14days	Rate of death / MI or urgent revascularization
0-1	3%	4.75%
2	3%	8.3%
3	5%	13.2%
4	7%	19.9%
5	12%	26.2%
6-7	19%	40.9%

Investigations in acute coronary syndromes:

1. ECG – Differentiates STEMI from NSTEMI; Hyper- acute (tall) T- waves, ST elevation or ST depression, T –wave inversion. ECG may be initially normal.

2. Blood tests

a) Biomakers – if normal initially, repeat after 6hrs.

i) Troponin – cardiac troponins are more specific markers for MI.

- Troponin I – Is a more sensitive maker for MI. It is detected within 3-6hrs after MI and remains elevated for 7-10days.

- Troponin T – Better reflects myocardial damage, peaks at 12hrs -24hrs and remains elevated for 7-10/7.

ii) CK –MB and total CK levels

CK –MB begins rising 8-24hrs but subsides after 3 days.

Normal CK-MB levels <5% of total CK levels

iii) LDH – Rises in 6hrs and peaks after 48hrs (2 days) then remains high for 6 – 8/7.

iv) Others

· Myoglobin – Non specific; usually rises very fast in an hour, peaks in 6hrs and is only high for 24hrs.

· Ischaemia modified albumin –Not for acute coronary syndromes.

· Myeloperoxidase

· Glycogen phosphate isoenzyme

· C-R proteins –non specific too

b) Full blood count

c) U/E

d) Blood sugars

e) Lipid profiles

f) Liver function tests

3. Imaging

i) CXR – Cardiomegally, pulmonary oedema or widened mediastinun; R/o Aortic dissection.

ii) Echo

iii) CT scan

iv) Radionucleotide tests.

ST –ELEVATION MI (STEMI):

STEMI usually represents acute MI (AMI)

Def: STEMI is a condition of irreversible necrosis of heart muscle resulting from prolonged ischaemia and characterized by acute infarction & ST elevation on a 12 lead ECG with increased CK – MB.

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Topic 1.3: ISCHAEMIC HEART DISEASE (IHD)- Cont

Epidemiology

STEMI continues to be a problem in the industrialized countries. The incidence is rising in developing countries.

In USA, about 1.6m people are diagnosed annually with acute coronary syndromes and 30% of these patients have STEMI.

Mortality is however decreasing due to health education and early diagnosis.

Aetiology

- Atherosclerosis

- Vasculitis

- Coronary embolism

- Increased blood viscosity – polycythaemia, thrombocytosis

- Congenital anomallies of coronary artery

- Arrhythmias especially V.Fib

- Carbonmonoxide

- Coronary vasospasm – idiopathic or drug induced especially cocaine

- Coronary thrombi

- Collagen diseases

Classification:

Based on invasive evidence procedures

Class I- Conditions in which there is evidence or general agreement in which an invasive procedure or treatment is beneficial or effective.

Class II – Conditions for which there is conflicting events or direction of a particular procedure about the usefulness, efficacy or Rx.

Class IIIa- Weight of events lessens for a particular procedure or treatment.

IIIb – Usefulness / efficacy is less as established by evidence.

Class IV –Conditions for which there is evidence of one or more agreement that a procedure or treatment is not useful.

Pathophysiology:

Basically as for NSTEMI

Most MI occurs in the settings of an underlying coronary artery disease.

The formation of an atherosclerotic plague in a coronary artery is a multi-set process.

STEMI usually occurs when coronary blood flow decreases abruptly after a coronary occlusion by a thrombotic artery previously affected by atherosclerosis. There is spontaneous fissuring & rupture of a plague exposing thrombogenic sites /surface →aggregation and fibrin formation.

The amount of damage on the coronary artery depends on:-

- Partial or complete occlusion

- Duration of occlusion

- Blood supply by collateral vessels

- Oxygen demand by the myocardium

- Territory supplied by the affected vessel.

Functional changes after MI

1. Impaired contractility which leads to systolic dysfxn.

2. A stunt myocardium – Tissues that demonstrate a prolonged systolic dysfxn after a discrete episode of severe ischaemia despite restoration of adequate blood flow to the tissues.

3. Ischaemic pre-conditioning – A brief ischaemic insult to a region in the myocardium may render the tissue more resistant to subsequent episodes of ischaemia.

4. Ventricular remodelling.

Clinical features

History –Provides a clue to severity of infarction. Inquire about diabetes, angina.

In 50% of patients, precipitating factor is present e.g. vigorous exercise, emotional stress, surgical or medical illness.

- STEMI can occur at anytime but it is most common in the AM hours/ morning due to ↑BP with ↑sympathetic activity.

Symptoms – Pain (chest pain) is the most common presenting symptom. The pain is deep, visceral, heavy, crushing or stabbing. The pain lasts for more than 30mins.

- Associated features –Sweating, anxiety, dyspnoea, nausea and vomiting.

NB: Elderly patients may have relatively little pain & may sometimes present with features of LV failure.

The pain may commence when at rest and when it begins with activity, it does not subside after activity.

The chest pain of STEMI can stimulate pulmonary embolism, acute pericarditis and dissecting aortic aneurysm.

Radiation of pain to the trapezius is not a feature of STEMI and differentiates it from acute pericarditis.

The proportion of STEMI is greater in patients with DM.

- Other less common presentations include sudden loss of consciousness, confused state, sensation of profound weakness, appearance of arrhythmias and pulse pressure.

Physical findings

- Patient is extremely anxious, distressed and restless.

- May be in severe pain with breathlessness.

-May be pale with a clammy skin, sweating (cardiogenic shock).

-Look for any sign of chest surgery, features of DVT.

- NB: The combination of a substernal chest pain persisting for >30mins and diaphoresis is a clue to STEMI.

- There may be tachycardia with signs of LV failure or bradycardia in the case of inferior MI.

- The blood pressure may be normal or low, JVP is elevated.

- In anterior infarction there is increased sympathetic activity.

- The precordium is usually quiet and the apex may be difficult to palpate. There may be a displaced apex and in anterior infarction a paradoxical systolic outward movement of ventricular wall may be felt parasternally.

- Audible murmur of MI, a pointer to a papillary muscle rupture. Plus or minus pericardial rub.

- A 4^th heart sound is common with splitting of the second heart sound.

Evolution in AMI

1. Tall symmetric hyper-acute T-waves, then.

2. ST elevation within a few hours, then

3. T- wave inversion and Q waves

There may be features of a new Lt. bundle branch block which indicates myocardial infarction.

WHO criteria for diagnosis

At least 2 or more of the following three features.

1. Typical history of chest pain

2. ECG changes

3. Elevated cardiac enzymes.

KILLIP classification of heart failure in AMI.

KILLIP classifies heart failure in AMI as class I-IV.

Class I- No evidence of heart failure

Class II- Mild –moderate HF evidenced by S3 gallop, pulmonary crackles and JVP distension.

Class III – overt pulmonary oedema

Classs IV – Cardiogenic shock/Hypotension

CXR findings in pulmonary oedema

1. Alveolar oedema – reticular shadowing (Bat’s wings)

2. Kerley B lines –interstitial oedema

3. Cardiomegally – enlarged cardiac shadow.

4. Dilated prominent upper lobe vessels because of thickened interlobular septa.

5. Pleural Effusion

(These are the ABCDE CXR features of pulmonary oedema)

The Management of Acute Coronary Syndrome

Goals:

1. To relieve pain

2. Reduction of myocardial O₂ demand

3. Improvement/ restriction of myocardial perfusion

4. Recognition and treatment of CMXs.

Note: When a pt presents with AMI, it is a medical emergency, thus management of the acute phase is important.

Acute Phase

A. Immediate Management

i. Rapid quick clinical assessment.

- History of cardiovascular disease

- Risk factors for IHD

- CI to thrombolytics

- Vital signs; PR, BP, RR

- Physical examination; JVP, signs of HF, peripheral pulse, scars from previous cardiac surgery, cardiac murmurs

ii. ABC

- Clear the airway

- Pulse oximetry; assess O₂ saturation

- Give supplemental O₂ by facial mask or nasal prongs

- Attach a 12 lead ECG monitor

- Establish an IV access

- Take blood for cardiac enzyme markers

- Keep resuscitation tray ready as the patient may go into cardiac arrest

- Ensure bed rest

- Start on opiate analgesia;

· IV morphine 4mg at a rate of 1mg/min, repeated if necessary at 2 – 4 mg at an interval of 5 – 15 min until pain is completely relieved

· IV dimorphine 2.5-5mg start; may be given as an alternative

- Nitrate; sublingual nitroglycerin at 0.4mg every 5 min (max 3doses)

B. Antithrombotic therapy

i. Anti platelet therapy

- Give a soluble ASA 300mg (cleared) or

- Clopidogrel 300-600mg where ASA is CI

ii. Anti-coagulate

- S/C Heparin 12500 units BD or at 80IU IV as bolus then 18IU as an infusion (unfractionated) Or LMWH (enoxaparin) at 1mg/kg/12hrs preferred.

NB: The above treatment should be given within 10 minutes of STEMI symptoms unlike in STEMI where they may be given after 20 minutes for the therapy to be useful.

iii. Fibrinolytics

Indications

1. Patient coming >12hrs after onset of chest pain.

2. Fibrolytics should be given within 30min of diagnosis (door to needle intervention).

3. PCI with stent in the preffered mode of management but patient must have arrived on 3-12hrs …onset of symptoms.

4. Door to balloon time should be less than 90 mins.

5. Patients who come and have stabilized need not be started on fibrinolytics; do PCI in such patients.

The most commonly used fibrinolytics are;

a) Streptokinase 1.5m units in 100mls of saline as IVI over 1hr.

b) Alteplase – human tissue plasminogen activator’s genetically engineered. It is given as bolus of 15mg followed by 0.75 ( Not exceeding 5mg over 30min)

c) Tenectoplase 30mg bolus in patients < 60kg, 35mg – 60 -69kg, 40mg – 70 -79kg, 45mg 80 – 89kg, 50mg – 90kg.

Indications for thrombolytics

1. History of chest pain within 12hrs (<12hrs)

2. ST elevation >1mm in standard leads or more than 2 limb leads OR

3. ST elevation >2mm in 2 or more chest leads OR

4. Posterior infarction (dorminant R waves and ST depression in V₁–V₃

5. New onset left bundle branch block.

Absolute contrandications

Ø Intracranial lige

Ø CVS or ischaemic stroke in last 3/12

Ø AV malformation in brain

Ø Intracranial malignancies

Ø Aortic dissection

Ø Bleeding diasthesis

Ø Head trauma in previous 3/12

Relative contra-indications

Ø Severe, poorly controlled HTN

Ø Patient who has undergone CPR which is traumatic.

Ø Major surgery in the past 3/12

Ø Pregnancy

Ø Active PUD

Ø Patient on warfarin with elevated INR

Hazards of thrombolytics

1. Bleeding –cerebral h’ge

2. CI in active bleeding with INR >2.5

3. Previous subarachnoid h’ge

4. Uncontrolled HTN > 180/110 mmHg

5. Recent surgery in 1/12

6. Recent trauma

7. Active PUD

8. Pregnancy or <18wks post watal

NB: Thrombolytics are effective in reducing mortality if given early. Greatest benefit is seen if given <12hrs of the onset of chest pain but some benefit upto 24hrs.

2. For STEMI patients – No fibrinolytics but if scoring > 5 do PCI. If score less than 5, consider pharmacotherapy

- beta blockers

If morphine fails & beta blocker is CI, give nitroglycerin

For beta blockers:

- IV atenolol 5mg over 5min, then 10 minutes later repeat at 5mg over 5mins, then 5mg over 5 mins.

- Metoprolol 5mg, at 1mg/min repeat after 5 mins at a dose of 5mg.

- Other drugs –oral carvedilol 6.25mg BP.

- For statins –give at a higher doses to maintain a cholesterol level of < 70mg/dl (1.8mm/l) ut monitor C-R protein which will go down with deceasing cholesterol levels.

C. Percutaneous coronary balloon / emergency catheterization with percutaneous coronary angiography.

- Percutaneous coronary intervention (PCI) are mostly done through the femoral vessels.

- PCI is more effective than thrombolytics therapy. It reduces the mortality by 14%.

ECG criteria for reperfusion therapy

Acute reperfusion therapy reduces mortality by 25 – 50% of the cases.

1. ST elevation > 2mm or 0.2 mv in two contigous chest leads (V₁–V₆)

2. ST elevation >1mm in 2 contiguous limb leads (I, II, III, avR, avF)

3. ST depression >0.5mm in 2 contiguous leads NSTEMI.

4. Q- waves >1mm; A sign of an old infarct, not an acute sign.

5. T – wave inversion >1mm – NSTEMI

NB:

1. In arterior MI

ST elevation at V₁ – V₆, lead I arc

2. Artero septal MI – Lead V_1,2 & V₃

3. Lateral wall MI – lead V₄, 5, 6

4. Inferior MI- lead II, III & avf.

5. Posterior wall MI – Reciprocal changes of ant. MI is ST depression at V₁, V_2,V₃, ST elevation at V₇, 8, 9.

D. On discharge

- To maintain arterial patency

1. Beta blockers

- Lower oxygen demand by myocardium

- Reverse remodelling

- Treat arrthnias

- Modifies HTN

Common beta blockers used are

i) Metoprolol 25-50mg BD OR

ii) Atenolol 50-100 mg OD or

iii) Carvedilol 6.25mg BD

2. ACE –I – for remodelling

- Reduce BP

- Reduces proteinuria (albuminuria)

3. Low dose ASA 75mg daily for life in all patients who have had ACS or MI.

Any patient who had stenting, stroke or cannot tolerate ASA should be given clopidogrel 75mg OD.

For those not able to tolerate ASA or clopidogrel; give them warfamm 5mg and titrate according to INR (2.5 -3)

4. Statins – atovastatin 80mg nocte because of

- High risk of repeat MI or coronary heart disease in 10yrs in >20%.

Ø Patients with >3 risk factors

Ø Patients with previous MI before

Ø Coronary heart disease equivalent

- Kidney disease

- Diabetes

Aim to reduce LDL to <1.8mmol/l & lower triglycerides to < 1.7mmol/l

Target BP < 140/90mmHg

5. General measures

- Stop smoking

- Modest alcohol consumption

Ø At least 2 beers every day (males)

Ø At least 1 beer every day (females)

- Encourage weight reduction; obesity is a significant risk factor. Normal BMI 18-25. In patients with two of the risk factors, take LDL to <2.6mmol/l and TGL <1.7mmol/l

- Waist arc <102cm (males) and <89cm (females).

- Regular exercise – At least 30mins of aerobic exercise at least 5 times a week.

- Diet – Encourage fruit and vegetables diet and low salt diet.

- For diabetics, ensure glycaemic control & aim at HbAC <7%

- Control HTN

E. Coronary artery by-pass graft CABG)

Mainly uses internal mammary vessels.

Indications

1. Failed PCI – persistent pain or haemodynamic instability.

2. Failed fibrinolytics

3. Ventricular septal rupture or papillary muscle rupture.

4. Patients with cardiogenic shock.

5. Patients with life, threatening ventricular arrythmias.

6. Patients with a LT main coronary artery disease or stenosis or a 3 vessel disease.

NB: For non ST elevation MI management

1. Heparin

2. ASA or

3. Clopidogrel

4. GP Iib/ IIIa inhibitors –can be for both STEMI & NSTEMI

- Tirofiba, abciximab, sentifibatide

- No FIBRINOLYTICS IN STEMI

Phases of healing

1. Acute phase - few hrs – 7 days

2. Healing phase – 7-28days

3. Healed phase – 29 days

Complications of ACS

1. Acute cardiac failure (CCF)

2. Mechanical cmx

i) Ventricular rupture / interventricular rupture

ii) Myocardial rupture

- Cardiac tamponade

- USD (Acquired)

iii) Papillary muscle rupture & acute nitral regurgitation.

3. Cardiogenic shock

4. Post –infarct or refractory unstable angina

5. Arrthmnias

- Tachycardias (VF, VT)

- Bradycardias especially in MI of inferior territory

6. Pericardial effusions

7. Pericarditis

8. Post cardiac injury syndrome

9. Sudden cardiac death

Management of complications

CCF

- Prop up patient

- Oxygen of nasal prong at 2-4m

- IV frusemide 49mg 40mg – 80mg.

Serum K+ should be > 4mmg/l

- I.V dobatamide if systolic pressure between 70-100mmHg. Give dobutamide at 2.5ug/kg and titrate to 3-10ug/k/min.

- Administer I.V nitroglycerin at 5mg bolus then increase by 5mg/min to a total of 20-40mg. Decrease if systolic pressure increase.

- Add digoxin 0.25mg start then 0.125mg OD.

- Test dose captopril 3.125mg when BP >100mg (systolic) to avoid hypotension 7 if patient stable for 24hrs, increase dose to 12.5mg BD, then 25mg BD on discharge.

- Arrhythmias management.

- Manage according to type of a arrhythmia

NB: In RV infarction, hypotension & bradycardia are due to sympathetic system which is not activated.

Summary of acute STEMI management

- Quick assessment

- ABC

- Give analgesia –morphine

- Nurse in HDN or ICU

- Ensure strict bed rest

- Immediate treatment includes:

- ASA

- Beta blockers

- ECG criteria for PCI which is treatment of choice.

- Thrombolytic therapy is an effective alternative to PCI

NB: B- blockers and ACE –I therapy should be administered early.

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Topic1.4: ATRIAL TACHYARRHYTHMIAS

ATRIAL TACHYARRHYTHMIAS

Def: A cardiac arrhythmia is a disturbance on the electrical rhythm or activity of the heart.

If there is an arrhythmia, then most often there is a structural cardiac disease, occasionally functional.

Mechanism

1. Increased automaticity

- SAN fibres are the fastest followed by atrial and ventricular fibres.

- SAN sets the pace for the cardiac activity and increased pace→ tachycardia. This may be due to an ectopic focus.

2. Re- entry - Two alternative pathways with different conduction properties. This can occur in IHD →further stimulation and tachycardia.

3. Triggered activity - Incompletely repolarized cell membrane →triggered activity and tachycardia.

Note:

Sinus arrhythmia- Parasympathetic activity is ↓in inspiration. Sinus arrhythmias are more predominant in children.

Sinus bradycardia – HR <60/min

May be physiological as in – athletes or pathological as in

- Myocardial infarction

- Sic sinus syndrome/ sinus node dysfxn

- Hypothermia

- Hypothyroidism

- ↑ICP

- Cholestatic jaundice

- Drugs – digoxin, Beta Blockers, verapamil

Sinus tachycardia

i) Physiological

- Pregnancy

- Exercise increased sympathetic activity

- Emotion

ii) Pathological causes

- Anxiety disorders

- Fever

- Anaemia

- Heart failure

- Hyperthyroidism

- Phaeochromocytoma –paroxysmal tachycardia

- Drugs – beta adrenergic agonists e.g. salbutamol

Atrial Ectopic beats (Premature beats)

- Asymptomatic. There may be missed or extra strong heart beat.

- ECG – p-wave, one p-wave may be abnormal in one or some of the rhythms.

- Rx –rarely necessary

Atrial tachycardia

May be as a result of

- Increased atrial automaticity or

- SAN disease OR

- Digoxin toxicity

ECG – Abnormal p-wave which might not be accompanied by QRS complex

Rx – Beta blockers (To reduce automaticity)

- Class I (Disopyramide, flecainide, propafenone) and class III anti arrhythmias.

- Catheter ablation for recurrent or drug resistant AT.

Atrial flutter

- Is a re-entry circuit in the Rt atrium usually around the tricuspid annulus.

- Atrial rate may be up to 300/min and the ratio between atrial: ventricle rate may be 1:1, 2:1, 3:1 or 4:1.

- ECG findings – Saw toothed flutter p-wave.

NB: Any narrow QRS complex >150 is a suspect for a flutter even in the absence of saw toothed p-wave.

- To confirm the flutter -Massage carotid sinus OR Give IV adenosine to temporarily increase the degree of AV block.

Treatment:

Aims

i) To achieve sinus rhythm

ii) To control ventricular rate so that they relax and fill

iii) To disrupt the circuit through cardioversion.

1. To achieve sinus rhythm

Cardioversion: A mechanical synchronized cardioverter. It’s a form of electrical shock but at a lower voltage.

Cardioversion is not the first choice of therapy. It is used if patient has HF or haemodynamic instability.

2. Rate control

- This is the main mode of therapy. It is the preferred mode of therapy.

i) Pharmacological; Amiodarone, propafenone, procainanide, flecainide are effective and should be used to prevent recurrent episodes of atrial flutter.

- Flecainide should always be prescribed with AV node blocking drug (B- blocker).

ii) Catheter ablation – Gives a 90% cure rate.

ATRIAL FIBRILLATION

Def: Multiple interacting re-entry circuits in the atria leading to rapid uncoordinated, ineffective atrial contractions.

There is irregular atrial rhythm at between 300-600 and irregular ventricular rate.

The main risk is embolic stroke.

Epidemiology

This is the most common sustained cardiac arrhythmia.

In the UK 0.5% of the adults suffer from this problem and the prevalence rises with age reaching 10% by the age of 80yrs.

Aetiology

1. Coronary artery disease (CAD) especially AMI.

2. Valvular heart dz especially RHD (mitral valve).

3. Hypertensive heart disease.

4. Hyperthyroidism

5. Heavy alcohol consumption

6. Cardiomyopathy

7. Chest infxns e.g. pneumonia

8. Pulmonary embolism

9. Any patient with congestive heart disease.

10. Heart surgery –cardiac transplant, CABG

11. Electrolyte imbalance, K⁺, mg²⁺

12. Others

- Sino-atrial node dz – sic sinus syndrome

- Congenital heart disease

- Pericardial dz

- Idiopathic (zone atrial fibrillation) 20% of the cases.

- COPD

- Obstructive sleep apnoea

- Non cardiac surgery – intra-thoracic surgery

- Metabolic syndrome

- Obesity

- Autonomic neuropathy

- Diet especially caffeine

- Endocarditis

- Atrial myoxoma

- Haemochromatosis

- May be genetic

- Drugs – thiophilline, adenosine

- Digitalis

- Lung cancer

- Sarcoidosis

Pathophysiology

Ectopic beats originating from conducting tissues around pulmonary veins or from diseased atrial tissue in the context of dilated atria or slow conducting area. This leads to a rapid, irregular, uncoordinated ineffective contraction of the atrial tissue which will cause irregular ventricular activation. All this will give an irregularly irregular pulse with an irregular QRS which is otherwise normal and also absent P waves.

Classification of atrial fibrillation

1. Paroxysmal atrial fibrillation; Intermittent and self-terminating.

2. Persistent atrial fibrillation; Prolonged but can be terminated by cardioversion.

3. Permanent atrial fibrillation

Clinical features

A. fib may be asymptomatic

Symptoms include – palpitations, light headedness due to fall in Bp.

- Fatigue, breathlessness, chest pain

- Others – symptoms of the underlying disease, or cmxs e.g. HF or systemic embolism.

Signs – irregularly irregular pulse

Apical pulse > rapid pulse

Management

Aims

1. Restore sinus rhythm

2. Prevent recurrence

3. Optimize the HR during episodes

4. Reduce risk of thromboembolism

5. Treat the underlying disease

General measures

1. Full evaluation

- History

- Physical examination

- General

- Systemic

2. 12 lead ECG – Absent p waves, irregular QRS complex

3. Echo

4. Blood tests, Thyroid fxn tests, U/E, cardiac markers

5. Tests for aetiological pathology

Paroxysmal A. fib

i) Pharmacological therapy

- Rate control

- Beta blockers especially in IHD, hypertensive heart disease, heart failure and exercise related fibrillation.

- Rhythm control

- Propafenone and flecainide except in coronary heart disease and LV dysfxn

- Amiodarone is useful for prophylaxis

NB: Digoxin and verapamil –last option especially digoxin. These drugs do not prevent another episode. They are purely for rate control. They are not effective for preventing paroxysmal A. fib.

Treat associated illness.

ii) Non-pharmacological therapy

- Radio frequency ablation

- Pacing

- Over drive pacing

- Cardioversion

Persistent and permanent A. fib

Rhythm control

- Infusion of flecainide 2mg/kg over 30min then amiodarone or BB to prevent relapse.

- Electrical cardioversion

Rate control

- Combination therapy; Two of the following

i) Digoxin

ii) Beta blocker

iii) Verapamil

If combination therapy fails, then put a pacemaker and permanently block the AV node.

Prevention of thrombo-embolism

i) Mod – High and very high risk patients.

1. Age > 75yrs with ↑Bp

2. Previous ischaemic stroke

3. Previous TIA or emboli

4. Co-morbidities; Mitral valve disease, HTN, HF (LV fxn / CCF), DM, Coronary or peripheral arterial disease

Use Warfarin for prevention of thrombo-embolism in all the above cases.

ii) Low risk patients – use aspirin if warfarin is CI or <65yrs + no risk.

CHADS score for risk assessment

C – Congestive heart failure – score 1

H – hypertension – score 1

A – Age >75 – score 1

D – Diabetes mellitus – score 1

S -Secondary prophylaxis for prior stroke or CVA – score 2

High risk 5-7 CHADS score – give warfarin unless CI

- Moderate risk 2-4 – warfarin unless CI

- Low risk 1-2 – junior ASA (Ascard)

Supraventricular tachycardia

Originates from atria and end up in the ventricles

May be

1. AVN re-entry tachycardia ( AVNRT), Rate 140 -220 regular

Management – Rx is not always necessary

- Terminate attack by use of carotid sinus pressure or vagal tone (valsalva manouvre)

- IV adenosine OR Verapamil OR

- B – blockers, flecainide and digoxin

- Emergency cases – cardioversion

- Catheter ablation

2. AVRT – Wolf Parkison White syndrome if symptomatic.

- Digoxin & verapamil – Not useful cos they shorten the refractory period of the accessory pathway.

- Patients for cardioversion must have been on warfarin and sustained INR of between 2-3

- Slowing the rate through vagal manourvers

i) Carotid massage

ii) Pressure over eye ball.

iii) Valsava maneuvers- Ask patient to bear down as if to pass stool or to blow out against a tube.

NB: Rate control is the most important thing in management.

VENTRICULAR TACHYARRHYTHMIAS

This is characterized by a long QRS complex & includes;

1. Ventricular ectopic beats (extra –systoles, premature beats).

2. Ventricular tachycardia (VT)

3. Ventricular fibrillation

4. Torsades de pointes

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Topic1.4: ATRIAL TACHYARRHYTHMIAS-Cont'

Ventricular ectopic beats

- These are premature broad –bizarre QRS complexes which may be unifocal (beats arising from a single ectopic focus) or multifocal (varying morphology with multiple foci).

- Are the commonest post MI arrhythmias but they are also seen in healthy people.

Pathophysiology – ectopic trigger is located in the ventricles leading to a broad QRS complex that is ill synchronized because the excitation has been distributed through H-Purkinje system.

Types of ventricular ectopic beats

1. Ventricular ectopic beats in normal people

Are due to Anxiety, Stress, Alcohol, Tea or caffeine ingestion

- Is prominent at rest and disappears with exercise.

- No treatment is required

- May require low dose BB in anxiety and palpitations.

- If it occurs in sub-clinical heart dz especially CAD then BBs are helpful.

2. Ventricular ectopic beats (VEBs) associated with heart conditions e.g MI (persistent type), Heart failure, Digoxin toxicity

- Clinical features – mostly asymptomatic. Symptoms include- irregular heart beat, missed beats, irregular beats, heavy beats.

- Investigations – ECG –fusion beats – two (2) irregular complexes then a normal complex

- Broad and bizarre QRS complex

Management – symptomatic

- Reassurance

- Beta blockers

- Angioplasty or CABG

Prognosis – good if no associated heart dz. Sudden death occurs in the presence of organic heart dz– HF, MI, AS. The prognosis is worsened by class I anti – arrhythmic drugs. The prognosis depends on the frequency of VEBs (> 10 beats/hr or >10 beats /min.

Ventricular tachycardia (VT)

Three or more consecutive ventricular pre-mature beats with an abnormal rate of 160- 240/min It is always associated serious heart disease and may degenerate into ventricular fibrillation.

Pathology – re-entry

- Abnormal triggered rhythm as in AMI, Myocarditis, Cardiomyopathy, Chronic IHD

Types

1. Non Sustained – A VT that is equal or more than 5 consecutive beats but lasts <30sec. Is found in 6% of normal individuals but in 60-80% in people with heart disease. Its associated with poor prognosis.

2. Sustained type - is symptomatic or sustained VT in the absence of reversible precipitating cause.

Clinical features - Palpitations, dizziness, dyspnoea, syncope

Investigations - ECG – Broad QRS complex tachycardia

Management –Immediate management is to restore sinus rhythm by;

i) Direct current cardioversion – Rx of choice or where not available then IV bolus of lidocaine. Alternatively mexiletine, flecainide or disopyramide.

ii) Correct K⁺, PO₄, acidosis, Mg²⁺ cos they may aggrevate the situation.

iii) Prophylaxis – BB

iv) If the above measures fail –than consider ICD

Ventricular Fibrillation

- A terminal rhythm of a dying heart.

- It is a very rapid and irregular ventricular activity with no mechanical effect.

- Patient is usually pulseless, becomes rapidly unconscious and respiration ceases.

- It is usually associated with VT

Categories

1. Primary V. fib – complicates AMI in the absence of shock or cardiac failure. The success rate of ICD is 95%.

– Short and long term prognosis is excellent

Lidocaine offers no benefit.

2. Secondary V. fib- occurs with AMI with shock with or without HF. It is associated with severe underlying ventricular damage.

Treatment – As for cardiac arrest

Torsades de pointes (Twisting points)

A VT characterized by changing QRS vectors.

The arrhythmia is usually non- sustained and repetitive leading to long QT interval.

Causes

1. Electrolyte imbalance – K⁺, Mg²⁺, Ca⁺

2. Rare congenital syndromes e.g.

i) Jervell – Lange – Nielson syndrome – an autosomal recessive dz

ii) Romano – Ward syndrome- autosomal dorminant.

3. Drugs –Those that give prolonged QRS complex

- Class Ia anti-arrhythmias – Disopyramide

- Class III anti-arrhythmias – Sotalol, amiodarone

- TCA e.g. amitriptylline

- Phenothiazines – CPZ

- Macrolides – Erythromycin etc.

4. Bradycardia

Treatment

i) Treat underlying cause

ii) IV Mg²⁺ 8mmol over 15min, then 75mmol/24hrs in all cases.

iii) BB especially in congenital long QT syndromes

iv) ICD

HEART BLOCK

May be;

1. AV junction block

2. Accelerated conduction block

3. Bundle branch block

1. AV junction

The AV jnx is the only pathway for conduction of the heart. It consists of

i) AV node

ii) Bundle of His

From ECG, heart block is diagnosed on the degree of severity.

i) 1^st degree heart block; Every p-wave is conducted through the AV jnx with a delay of >0.2 secs. The p-wave is >5mm. every p-wave has a QRS following but the PR interval is prolonged.

ii) 2^nd degree heart block; Some of the atrial currents are conducted through AV jnx to the ventricles while some are not. Thus, some p-waves will have QRS complex following them and others will not.

a) Mobitz I- Progressive lengthening of successive PR interval culminating in a dropped beat (Wenkenbach phenomenon) due to impaired conduction of AV node. It may be physiological at rest or during sleep in athletes or young adults with high vagal tone.

b) Mobitz II – No progressive increase in PR interval but some p-waves have QRS complexes following them while others don’t. It is a more serious variety of the 2^nd degree heart block that can lead to higher degree of heart block or serious complications.

NB: Depending on ratio of p-waves to the number of QRS following them 2⁰ heart block is described as 2:1, 3:1, 4:1.

iii) Third degree (complete) heart block; A more severe form of heart block.

There is no relationship between p-waves and QRS complex. No p-wave is conducted & there is no fixed PR intervals as the P and QRS waves are entirely independent of each other.

In this condition, the QRS complexes are produced by the ventricles themselves but at a slow rate with a long R-R interval (The ventricles have their own independent rhythmicity at a slow rate of 30-40/min. The atria, being controlled by the SAN has higher rates of 60-100/min. 3⁰ heart block requires careful observation and treatment.

It requires insertion of permanent artificial pacemaker. The cause of delay of conduction in

AV jnx could be degeneration, fibrosis, destruction, inflammation

Aetiology of complete heart block

1. Congenital

2. Acquired

- Idiopathic fibrosis

- Myocardial infarction / ischaemia

- Inflammation

- Acute e.g. aortic root abscess, infective endorcarditis.

- Chronic –Sarcoidosis, Chaga’s dz

- Trauma especially cardiac surgery

- Drugs, BB, CIB and digoxin

2. Accelerated conduction

- Normally due to by-pass

- Diagnosis – shot PR interval <0.125 or <3mm

- Abnormal notes on the QRS complexes called delta waves.

- Accelerated conduction block occurs in

i) Wolf – Parkinson White syndrome (WPW)

ii) Lowen– Ganong – Levin syndrome

These conditions are associated with clinical & electrocardiographic features.

WPW Syndrome – The impulse is conducted through an accessory path called bundle of Kent.

Lowen – Ganong –Levin Syndrome – unlike in WPW there is no delta waves and QRS duration is normal.

STOKES –ADAM’S

Episodes of ventricular asystole may complicate complete heart block or Mobitz II.

It can also occur in patients with sino-atrial disease leading to recurrent syncope called ‘Stoke’ Adam’s attacks. It is characterized by sudden loss of consciousness which occurs without warning and results in a fall. Convulsions can occur if there is prolonged asystole. Pallor & death like appearance during the attack will occur but when the heart starts beating again, there is a characteristic flush.

Carotid sinus syndrome and vaso-vagal syndrome may also have similar features.

3. Bundle branch block and hemiblock

There is interruption of the Rt or Lt branch bundle of His which delays activation of the appropriate ventricles, broadens QRS complex > 0.1sec and produces characteristic alteration in QRS morphology.

RBBB (Rt bundle branch block) can be a common normal variant but Lt bundle branch block (LBBB) signifies an important underlying dz.

Both forms may be due to a conduction tissue disease or a feature of other heart diseases. The Lt branch of His is divided into ant. and post. fascicles. Damage to conduction tissue at this point (Hemiblock) does not broaden QRS complex and alters the mean direction of ventricular depolarization causing a left axis deviation in Lt anterior hemiblock and a Rt axis deviation in left posterior hemiblock. The combination of the Rt and Lt block is known as Bifascicular block.

Common causes of bundle branch block

a. RBBB

1. Normal variant

2. RVH or strain e.g. PE, embolism

3. CHD e.g. ASD

4. Coronary artery disease (CAD)

b. LBBB

1. CAD

2. HTN

3. Aortic valvular disease

4. Cardiomyopathy

Management of heart block (AV block)

1. AV block complicating AMI

Acute inferior MI – Usually has a reliable escape rhythm and if asymptomatic, no Rx is required.

Symptomatic 2⁰ or complete heart block may respond to:-

i) Atropine 0.6mg IV; repeat PRN. If atropine fails, give temporary pacemaker. In most cases AV block will resolve in 7-10days

2. Chronic AV block

- Symptomatic bradyarrhythmias associated with AV block →permanent pacemaker.

- Asymptomatic heart (1⁰ or Mobitz I) requires no treatment. However:

i) Reverse the underlying cause

ii) Stop any medication slowing the HR

iii) Reverse any condition that increases vagal output.

- Permanent pacemaker is indicated in Mobitz II or complete heart block except in young asymptomatic patients with long, complete heart block which mean daytime rate of >50/min. In Mobitz II- the defect is always below the AV node & management is by giving permanent pacemaker.

Causes of heart block

1. Congenital causes

- Fibrosis and sclerosis of conduction e.g.

- Lev’s dz – sclerosis of Lt side of the cardiac skeleton

- Lenegre’s dz - progressive fibrotic sclerodegenerative changes of the conduction system.

2. Ischaemic heart disease – 40% of AV blocks may be acute or chronic

3. Drugs – mainly

Beta blockers, CCB mainly non-dihydropyridines, Digitalis, Amiodarone, adenosine, quinidine, procainamide, disopyramide

4. Increased vagal tone due to Pain ,Carotid sinus manage, Hypersensitivity carotid sinus syndrome

5. Valvular heart disease; Aortic or mitral valve calcification

6. Congenital heart disease

7. Familial – Association with mutations in the Na⁺ and K⁺ channels

8. Cardiomyopathies

9. Myocarditis

10. Hyperkalaemia

11. Neuromuscular diseases

Dermatomyositis, Rheumatoid arthritis

12. Hypothyroidism

13. Cardiac tumours

14. Myocardial trauma

Clinical features

1. Syncope – due to bradyarrhythmias

2. Sudden fainting

3. Chest pain

4. Dizziness

5. Pre- syncope – sweating, restless before patient falls.

Management

- Asymptomatic cases – No treatment

- Atropine – usually the last option

- 2⁰ heart block – Mobitz II or complete heart block – pacemaker

- Reverse the underlying cause

Course dashboard

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Unit 4: Further reding

1. Harrison's Principles of internal medicine 17th edition.

2. Davidson's Principles and Practice of medicine, 21st Edition.

3. Tropical Diseases AMREF

4. Kumar and Clerk Text book of clinical Medicine 6E Edition

5. Oxford Textbook of Medicine Michael Glynn, William Drake, Clinical Methods, 23rd Edition, 2012, London UK

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