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Acute Pancreatitis — Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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Epidemiology

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Etiology

Common Causes

Uncommon Causes

• Drugs: azathioprine, 6-mercaptopurine, sulfonamides, estrogens, tetracycline, valproic acid, 5-ASA, DPP4 inhibitors (e.g., sitagliptin)
• Connective tissue disorders and TTP
• Pancreatic cancer
• Hypercalcemia
• Periampullary diverticulum
• Pancreas divisum
• Hereditary pancreatitis
• Cystic fibrosis
• Renal failure
• Infections (mumps, coxsackievirus, CMV, echovirus, parasites)
• Autoimmune pancreatitis (type 1 and 2)
• Trauma (especially blunt abdominal)
• Postoperative

Causes of Recurrent Pancreatitis Without Obvious Etiology

• Occult biliary disease or microlithiasis/biliary sludge
• Drugs
• Hypertriglyceridemia
• Pancreas divisum
• Pancreatic duct strictures
• Ampullary or duodenal abnormalities
• Genetic mutations (PRSS1, SPINK1, CFTR, CTRC, CASR, CLDN2)
• Autoimmune pancreatitis

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Pathogenesis

1. Phase 1 - Intrapancreatic enzyme activation: Lysosomal hydrolases (e.g., cathepsin B) colocalize with digestive enzymes, activating trypsinogen prematurely within the acinar cell. Trypsin activation leads directly to acinar cell injury.
2. Phase 2 - Inflammatory cascade: Leukocytes and macrophages are activated, chemically attracted, and sequestered in the pancreas. Neutrophils can themselves activate trypsinogen (an early neutrophil-independent and a later neutrophil-dependent process).
3. Phase 3 - Systemic effects: Activated proteolytic enzymes (trypsin, elastase, phospholipase A2) and cytokines are released, causing:
   • Proteolysis, edema, interstitial hemorrhage, vascular damage
   • Fat necrosis and coagulation necrosis
   • Release of bradykinin, vasoactive substances, and histamine
   • Profound systemic effects: SIRS, ARDS, multi-organ failure

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Clinical Features

Symptoms

• Abdominal pain: The dominant symptom. Steady, boring, constant, located in the epigastrium, radiating to the back, chest, flanks, or lower abdomen. Ranges from mild to severe and incapacitating.
• Nausea, vomiting
• Abdominal distension (due to gastric/intestinal hypomotility)

Signs

• Distressed, anxious patient
• Low-grade fever, tachycardia, hypotension
• Shock (from: hypovolemia due to exudation into retroperitoneal space; kinin release; effect of proteolytic enzymes on vascular permeability)
• Abdominal guarding and rigidity
• Decreased/absent bowel sounds (ileus)
• Cullen's sign (periumbilical ecchymosis) - rare, indicates hemorrhagic pancreatitis
• Grey Turner's sign (flank ecchymosis) - rare, same significance

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Diagnosis

Laboratory Tests

• Serum amylase: Rises within 6-12 hours, returns to normal in 3-5 days. Sensitivity ~85%; not specific (can be elevated in intestinal obstruction, perforated ulcer, renal failure, salivary gland disease).
• Serum lipase: More specific than amylase; remains elevated longer. Preferred test.
• Elevated amylase + lipase together increases diagnostic accuracy.
• Hematocrit >44% (hemoconcentration): marker of severity.
• BUN >20 mg/dL on admission: associated with increased severity.
• C-reactive protein (CRP) >100 mg/L: elevated in severe disease.
• Leukocytosis, hyperglycemia, hypocalcemia (indicative of fat necrosis), elevated LFTs (if gallstone etiology), elevated triglycerides.

Imaging

• CT scan (contrast-enhanced): The standard for assessing severity, detecting necrosis, and identifying complications. Best performed at 48-72 hours if diagnosis is uncertain or patient is not improving.
• Abdominal ultrasound: First-line to identify gallstones; poor visualization of the pancreas due to bowel gas.
• MRI/MRCP: Alternative to CT, especially to detect biliary stones and ductal anatomy without radiation.
• ERCP: Reserved for suspected choledocholithiasis with cholangitis, not routinely early in acute pancreatitis.

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Severity Assessment

Revised Atlanta Classification

Prognostic Scoring Systems (Table 359-3 in Harrison's)

• (B) BUN >25 mg/dL
• (I) Impaired mental status (Glasgow Coma Scale <15)
• (S) SIRS: ≥2 of 4 criteria present:
  • Temp <36°C or >38°C
  • Heart rate >90 bpm
  • Respirations >20/min or PCO2 <32 mmHg
  • WBC >12,000/μL, <4,000/μL, or >10% bands
• (A) Age >60 years
• (P) Pleural effusion on imaging

• APACHE II ≥8 at 24 h
• Hematocrit >44%
• Admission BUN >20 mg/dL
• Organ failure (Modified Marshall Score):
  • Cardiovascular: SBP <90 mmHg, HR >130 bpm
  • Pulmonary: PaO2 <60 mmHg
  • Renal: serum creatinine >2.0 mg/dL

• CRP >100 mg/L
• Persistent organ failure (≥48 h)
• Pancreatic or extrapancreatic necrosis

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Management

Initial Resuscitation

• Aggressive IV fluid resuscitation is the cornerstone of early management
• Lactated Ringer's (LR) is preferred over normal saline (reduces risk of SIRS)
• A decrease in hematocrit and BUN within the first 12-24 hours confirms adequate resuscitation
• A rising BUN during hospitalization signals inadequate hydration and is associated with higher in-hospital mortality
• A less aggressive strategy may suffice in milder pancreatitis
• Adjustments needed in cardiac, pulmonary, or renal disease

Analgesia

• Adequate pain control is essential; opioids are acceptable

Nutrition

• Mild pancreatitis: Oral feeding can resume when pain and nausea improve and bowel sounds return (often within 24-48 h)
• Severe pancreatitis: Enteral nutrition (via nasojejunal or nasogastric tube) is strongly preferred over parenteral nutrition - it maintains gut mucosal integrity and reduces infectious complications
• Total parenteral nutrition (TPN) is reserved for cases where enteral feeding is not tolerated

NPO (Nothing by Mouth)

• Maintained until pain resolves and oral feeding can be tolerated

Triage / Hospital Admission Level

• BISAP score, hematocrit, and BUN guide triage:
  • Low scores + no SIRS at 24h → regular ward
  • SIRS present, elevated markers → step-down unit or ICU

Role of ERCP

• Urgent ERCP (within 24 h) is indicated in acute biliary pancreatitis with cholangitis or persistent biliary obstruction
• Not indicated routinely in mild gallstone pancreatitis without obstruction

Antibiotics

• Not routinely indicated in acute pancreatitis
• Indicated only when infected pancreatic necrosis is confirmed or strongly suspected (fine-needle aspiration with Gram stain/culture, or CT-guided)
• Prophylactic antibiotics do NOT prevent infection of pancreatic necrosis

Management of Gallstone Pancreatitis

• Cholecystectomy should be performed during the same admission (or soon after) in mild gallstone pancreatitis to prevent recurrence

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Complications

Local Complications

Systemic Complications

• ARDS, SIRS, multi-organ failure
• Pleural effusion (usually left-sided)
• Acute kidney injury
• Hemorrhage
• Hypocalcemia (saponification of fat)
• Hyperglycemia
• Disseminated intravascular coagulation (DIC)

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Recurrent Acute Pancreatitis

• Defined as two or more documented episodes
• Workup should include: repeat ultrasound, MRCP to evaluate ductal anatomy, EUS to detect microlithiasis, serum triglycerides, calcium, IgG4, genetic testing
• Around 25% of patients previously labeled idiopathic may have an underlying genetic predisposition

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Key Points Summary

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Acute Rheumatic Fever (ARF)

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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Definition

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Global Considerations

• Improved living conditions (less crowded housing, better hygiene)
• Reduced GAS transmission
• Antibiotic availability and improved medical systems

• >40 million people worldwide affected by RHD
• >300,000 deaths per year attributable to RHD
• 95% of ARF cases and RHD deaths occur in developing countries
• Highest burden: sub-Saharan Africa, Pacific nations, Australasia, China, South and Central Asia
• RHD is the most common cause of acquired heart disease in children in LMICs
• WHO adopted a Global Resolution on RF and RHD in 2018

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Epidemiology

• Primarily a disease of children aged 5-14 years
• Initial episodes are rare after age 30
• Recurrent episodes remain common in adolescents and young adults
• No clear gender association for ARF, but RHD affects females more (up to 2x more frequently than males)
• RHD prevalence peaks between 25-40 years of age

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Pathogenesis

Organism Factors

• Caused by Group A Streptococcus (GAS) pharyngeal infection
• Certain M-serotypes (particularly types 1, 3, 5, 6, 14, 18, 19, 24, 27, 29) are classically "rheumatogenic"
• GAS skin infections are generally not considered a trigger for ARF (unlike post-streptococcal glomerulonephritis)

Host Factors

• Only a small proportion (~3%) of individuals develop ARF after GAS pharyngitis
• Susceptibility is partly genetic (familial clustering)
• HLA class II antigens play a role in predisposition

Autoimmune Mechanism - Molecular Mimicry

• GAS surface proteins (particularly M protein) share structural similarity with human cardiac proteins (myosin, laminin, tropomyosin, vimentin)
• Antibodies generated against GAS cross-react with cardiac tissue
• This leads to valvular endocarditis, myocarditis, and pericarditis
• T-cell mediated immunity also contributes to cardiac injury
• This explains why carditis tends to be the most dangerous long-term manifestation

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Clinical Features - The Jones Criteria (Revised 2015)

Major Criteria

Minor Criteria

Evidence of Preceding GAS Infection (Required)

• Elevated or rising antistreptolysin O (ASO) titer
• Elevated anti-DNase B
• Positive throat culture for GAS
• Positive rapid GAS antigen test

Diagnostic Rule

Exception: Chorea alone, or indolent carditis alone, may be sufficient for diagnosis without fulfilling the full Jones Criteria.

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Carditis (Rheumatic Carditis)

• Occurs in ~50-60% of first ARF episodes
• Pancarditis - all three layers may be involved:
  • Endocarditis: most clinically significant; valvulitis causes valvular regurgitation (mitral > aortic)
  • Myocarditis: can cause heart failure and cardiomegaly
  • Pericarditis: friction rub, chest pain, effusion
• Subclinical carditis: detected only on echocardiography (no murmur audible)
• Pathological finding: Aschoff bodies - granulomatous lesions with central fibrinoid necrosis surrounded by lymphocytes and Aschoff giant cells (pathognomonic)
• Mitral regurgitation is the most common valvular lesion acutely; mitral stenosis develops with repeated attacks over years

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Arthritis

• The most common major manifestation (~75% of cases)
• Migratory polyarthritis: moves from joint to joint over days
• Large joints preferentially affected: knees, ankles, hips, wrists, elbows
• Exquisitely painful - often disproportionate to visible signs
• Responds dramatically and completely to salicylates/NSAIDs (failure to respond should question the diagnosis)
• No permanent joint damage

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Sydenham's Chorea

• Occurs in 10-30% of cases
• Latency: may appear 1-6 months after GAS infection (longest latent period of all manifestations)
• Features: involuntary, non-rhythmic, purposeless movements; emotional lability; speech disturbance; muscle hypotonia
• Often occurs in isolation without other ARF manifestations
• Resolves spontaneously over weeks to months

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Laboratory and Investigations

• ECG (prolonged PR interval)
• Echocardiogram (all suspected cases - to assess subclinical carditis and establish baseline severity)
• CBC (leukocytosis)
• CRP (elevated)
• ASO and anti-DNase B (streptococcal serology)

• Throat/skin swab culture
• Blood cultures
• Synovial fluid aspirate
• Autoantibodies (to exclude lupus, JIA)
• Pregnancy test
• Creatinine (before NSAID use)
• Serologic testing to exclude viral arthritis, Yersinia, parvovirus B19, gonorrhea

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Differential Diagnosis

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Management

1. Antibiotics (Eradication of GAS)

• All patients receive antibiotics to eradicate the precipitating streptococcal infection
• Drug of choice: Penicillin
  • Oral: Phenoxymethylpenicillin (Penicillin V)
  • Parenteral: Single IM injection of benzathine penicillin G
• Penicillin allergy: Erythromycin or a narrow-spectrum cephalosporin
• Note: This treats the initial infection but does NOT alter the course of ARF or prevent RHD

2. Anti-inflammatory Therapy (Symptomatic)

3. Bed Rest

• Recommended during acute phase, especially with carditis
• Duration depends on severity

4. Secondary Prophylaxis (Most Critical Long-Term Intervention)

• Most effective regimen (superior to oral therapy due to compliance)
• Oral alternative: Penicillin V 250 mg twice daily

A 2024 Cochrane systematic review (PMID 39312290) on long-term antibiotic prophylaxis confirmed benefit in preventing recurrence and progression to RHD, supporting current guideline recommendations.

5. ARF Registry and Health Education

• All confirmed/possible cases should be registered in an ARF/RHD registry
• Health education for patients and families on streptococcal infection recognition, sore throat treatment, and prophylaxis compliance

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Complications and Long-term Consequences

Rheumatic Heart Disease (RHD)

• The only manifestation with permanent sequelae
• Results from repeated ARF attacks causing progressive valvular scarring and deformity
• Mitral stenosis is the classic late lesion (leaflet fusion, subvalvular fibrosis, calcification)
• Other lesions: mitral regurgitation, aortic regurgitation, aortic stenosis, tricuspid involvement
• Complications: atrial fibrillation, thromboembolic events, pulmonary hypertension, heart failure, infective endocarditis
• Surgical or transcatheter intervention (valvuloplasty, valve replacement) may ultimately be required

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Key Summary Points

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📌 Recent Evidence Note: A 2024 Cochrane meta-analysis (PMID 39312290) on long-term antibiotic prophylaxis confirmed that regular benzathine penicillin G reduces ARF recurrence and RHD progression, reinforcing current guideline-based recommendations.

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Bronchial Asthma - Clinical Features & Treatment

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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Definition

• Episodic and variable airflow obstruction (often reversible)
• Airway hyperresponsiveness (AHR) to various stimuli
• Underlying airway inflammation (predominantly eosinophilic/type 2 in classic atopic asthma)
• Airway remodeling with structural changes over time

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Epidemiology & Risk Factors

1. Allergen exposure in those with a predisposition to atopy
2. Occupational exposures (isocyanates, animal dander, flour, latex)
3. Air pollution (particulate matter, ozone, NO2)
4. Infections (viral - especially rhinovirus, RSV; Mycoplasma)
5. Tobacco (active and passive smoking)
6. Obesity
7. Diet (low antioxidants, high omega-6)
8. Fungi in allergic airway mycoses
9. Acute irritants (reactive airway dysfunction syndrome - RADS)
10. High-intensity exercise in elite athletes

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Pathophysiology

Three Core Mechanisms of Airway Obstruction

• Hallmark of asthma
• Defined as an exaggerated narrowing response of airways to stimuli (methacholine, histamine, allergens, cold air, exercise) that don't cause obstruction in normal individuals
• Component occurs at the level of airway smooth muscle itself
• In many patients, AHR is due to mucosal inflammation and remodeling reducing the threshold for smooth muscle activation

• Triggers (allergens, irritants, exercise, drugs - see below) activate mast cells and other inflammatory cells
• Release of histamine, leukotrienes, prostaglandins → acute smooth muscle contraction
• Neurogenic mechanisms also contribute (parasympathetic, sensory neuropeptides)

• Leads to persistent symptoms and fixed airflow obstruction
• Airway remodeling components:
  • Subepithelial fibrosis (reticular basement membrane thickening)
  • Airway smooth muscle hypertrophy and hyperplasia
  • Mucus gland hyperplasia → mucus hypersecretion and mucus plugging
  • Angiogenesis
  • Epithelial goblet cell metaplasia

Inflammatory Cells and Mediators

• Driven by IL-6, IL-17, TNF-α, IL-1β, IL-8
• Associated with obesity, smoking, late-onset asthma, and poor steroid response

• Cysteinyl leukotrienes (LTC4, LTD4, LTE4): produced by eosinophils and mast cells; potent bronchoconstrictors; promote mucus secretion, vascular leakage, and inflammatory cell recruitment - targeted by leukotriene modifiers
• Prostaglandin D2 (PGD2): produced by mast cells; activates CRTH2 receptors on type 2 cells, upregulating inflammation
• LTB4: potent neutrophil chemoattractant

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Triggers of Airway Narrowing

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Clinical Features

Symptoms

• Episodic wheezing (expiratory, sometimes audible)
• Dyspnea / shortness of breath - variable, episodic
• Chest tightness
• Cough (especially nocturnal and early morning; can be the sole symptom in cough-variant asthma)
• Symptoms are often worse at night and in the early morning (circadian variation in airway tone)
• Symptoms triggered by known precipitants

Signs

• Expiratory wheeze on auscultation (may be absent at rest)
• Prolonged expiratory phase
• Hyperinflation (increased anteroposterior diameter, hyper-resonant percussion) in severe/chronic disease
• Accessory muscle use during acute attack
• Pulsus paradoxus (>10 mmHg drop in systolic BP during inspiration) in severe attack
• Silent chest = ominous sign in acute severe asthma (no wheeze due to minimal airflow)

Features Suggesting Severity of Acute Attack

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Diagnosis and Evaluation

Clinical Diagnosis

• Compatible history of recurrent wheezing, dyspnea, chest tightness, or cough related to known precipitants
• Confirmed with pulmonary function testing (PFT) or demonstration of AHR

Pulmonary Function Tests

• Obstructive pattern: FEV1/FVC ratio < 0.70
• Reversibility: ≥12% AND ≥200 mL improvement in FEV1 after inhaled bronchodilator (albuterol) - confirms asthma diagnosis
• Lung volumes: air trapping (increased RV and TLC) in severe disease

• Used when spirometry is normal but asthma is suspected
• Positive if FEV1 falls ≥20% at a methacholine concentration of ≤8 mg/mL (PC20)
• High sensitivity (~95%), lower specificity - a negative test effectively rules out asthma

• Serial home PEF monitoring: diurnal variation >20% supports asthma diagnosis
• Useful for monitoring and guiding treatment adjustments

Additional Evaluation

• Fractional exhaled nitric oxide (FeNO): marker of eosinophilic airway inflammation; elevated (>25 ppb) supports type 2 asthma; guides ICS dosing
• Blood eosinophil count and serum IgE: assess atopy and eligibility for biologics
• Allergy skin testing / RAST (specific IgE): identify allergen sensitization
• CXR: usually normal; may show hyperinflation; rules out pneumothorax, infiltrate
• Sinus CT: if chronic rhinosinusitis suspected
• Induced sputum eosinophils (if available)

Differential Diagnosis

Comorbidities That Make Asthma Difficult to Control

1. Chronic rhinosinusitis ± nasal polyposis
2. Obesity
3. Gastroesophageal reflux disease (GERD)
4. Inducible laryngeal obstruction (vocal cord dysfunction)
5. COPD (asthma-COPD overlap)
6. Anxiety/depression
7. Obstructive sleep apnea

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Classification of Asthma Severity

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Treatment

Goals of Therapy (GINA/NAEPP)

1. Achieve and maintain symptom control (minimal/no daytime or nocturnal symptoms)
2. Prevent exacerbations (reduce frequency and severity)
3. Maintain normal lung function (FEV1/FVC near normal)
4. Maintain normal activity level (including exercise)
5. Minimize side effects of medications

1. Reducing Triggers

• Remove occupational exposures where possible (may lead to resolution)
• Allergen mitigation (impermeable mattress/pillow covers, pet removal, pest control)
• Eliminate secondhand smoke and cannabis combustion products
• Flu vaccine (yearly), pneumococcal vaccine, COVID-19 and RSV vaccines
• Allergen immunotherapy: evidence supports use in mild-moderate atopic asthma under control; reduces IgE-mediated responses

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2. Medications

A. Reliever (Rescue) Medications

• E.g., albuterol (salbutamol), levalbuterol, terbutaline
• Mechanism: activate β2-receptors on smooth muscle → cAMP → smooth muscle relaxation
• Onset: 5-15 minutes; duration: 4-6 hours
• Use: on-demand relief of acute bronchospasm; pre-exercise prophylaxis
• Risk: regular use → tachyphylaxis of bronchoprotective effect; potential for increased airway reactivity with Arg/Arg polymorphism at codon 16 of β2-receptor
• GINA now recommends ICS/formoterol as preferred reliever at all steps (Anti-Inflammatory Reliever - AIR strategy) due to evidence it reduces severe exacerbations compared to SABA alone

• Combination of ICS + fast-onset LABA (formoterol) used as-needed
• Provides both anti-inflammatory and bronchodilator effects with each puff
• Reduces exacerbation risk even in mild asthma (Step 1)
• NAEPP recommends ICS/formoterol as reliever at Steps 3-4

• Recently introduced in the US as an alternative anti-inflammatory reliever

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B. Controller (Maintenance) Medications

• E.g., budesonide, fluticasone, beclomethasone, ciclesonide, mometasone
• Mechanism: bind glucocorticoid receptors → reduce transcription of inflammatory cytokines (IL-4, IL-5, IL-13); reduce eosinophilic inflammation; decrease AHR
• Effect: reduce symptoms, exacerbations, and airway remodeling over time
• Side effects: oral candidiasis (use spacer, rinse mouth), dysphonia, adrenal suppression at high doses, osteoporosis with long-term use
• Dose categories: low, medium, high (vary by drug - e.g., budesonide low = 200-400 mcg/day, high = >800 mcg/day)

• E.g., salmeterol, formoterol, vilanterol, indacaterol
• Duration: 12-24 hours
• Must NOT be used as monotherapy in asthma (black box warning in US) - only as add-on to ICS
• ICS/LABA combination = cornerstone of Steps 3-5 therapy
• Formoterol has rapid onset (can serve as both controller and reliever - SMART/MART strategy)

• Leukotriene Receptor Antagonists (LTRAs): montelukast, zafirlukast
  • Block cysteinyl leukotriene receptors (CysLT1)
  • Reduce bronchospasm, mucus secretion, and eosinophilic inflammation
  • Alternative to low-dose ICS in Step 2 (mild persistent)
  • Particularly useful in: aspirin-exacerbated disease (AERD), exercise-induced asthma, allergic rhinitis comorbidity
  • ⚠️ FDA warning (2020): montelukast associated with serious neuropsychiatric effects including suicidal ideation - use with caution
• 5-Lipoxygenase inhibitor: zileuton - reduces leukotriene synthesis; requires liver function monitoring

• E.g., tiotropium (18 mcg/day inhaled)
• Mechanism: block muscarinic M3 receptors → reduce bronchoconstriction and mucus secretion
• Role: add-on therapy at Steps 4-5; particularly useful in asthma-COPD overlap and those with significant cholinergic triggers
• Improves FEV1 and reduces exacerbations when added to ICS/LABA

• Mechanism: phosphodiesterase inhibitor → increases cAMP → bronchodilation; also has mild anti-inflammatory and immunomodulatory effects
• Narrow therapeutic index: target serum level 5-15 mcg/mL
• Side effects: nausea, headache, tachyarrhythmia, seizures at toxic levels; multiple drug interactions
• Role: rarely used today; considered an add-on option in Step 4-5 when biologics unavailable; requires serum level monitoring

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C. Biologic (Targeted) Therapies - Step 5

• Blood eosinophils (≥150-300/μL → IL-5 pathway agents)
• Total serum IgE + sensitization → omalizumab
• FeNO >25 ppb → type 2 inflammation, supports ICS/biologic response
• TSLP → tezepelumab (works regardless of eosinophil count)

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D. Systemic Corticosteroids

• Oral prednisone (30-50 mg/day for 5-7 days) for moderate-severe exacerbations
• IV methylprednisolone for acute severe exacerbations requiring hospitalization
• Minimize long-term systemic use due to adrenal suppression, osteoporosis, diabetes, weight gain, cataracts

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3. Stepwise Management (GINA/NAEPP Adapted)

MART strategy = Maintenance And Reliever Therapy: same ICS/formoterol inhaler used for both daily maintenance AND as-needed relief

Key GINA 2025 update: As-needed ICS/formoterol is recommended as the reliever at all steps, including Step 1 (intermittent asthma), replacing SABA monotherapy as preferred reliever due to reduced severe exacerbation risk.

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4. Management of Acute Asthma Attack

• SABA (albuterol) via MDI + spacer: 4-8 puffs every 20 minutes x 3 doses, then reassess
• Or nebulized albuterol 2.5 mg every 20 min x 3
• Oral prednisolone 40-50 mg/day if not responding quickly
• Supplemental oxygen to maintain SpO2 ≥94%
• Monitor PEF, SpO2, RR, HR

• Continuous nebulized SABA or high-dose MDI with spacer
• Ipratropium bromide (SAMA) added to albuterol (reduces hospitalizations - synergistic bronchodilation)
• IV methylprednisolone 40-80 mg/day or oral prednisolone
• Supplemental O2 (target SpO2 93-95%)
• IV magnesium sulfate 2 g over 20 minutes - causes smooth muscle relaxation; recommended for acute severe asthma (Evidence: 2024 meta-analysis [PMID 38395640] confirms benefit in children)
• Heliox (helium-oxygen mixture) - reduces work of breathing in near-fatal asthma

• Intensive care admission
• IV bronchodilators (terbutaline, salbutamol)
• Non-invasive ventilation (NIV/BiPAP) in selected cases
• Mechanical ventilation: last resort; risk of dynamic hyperinflation (auto-PEEP)
• Ketamine anesthesia - has bronchodilator properties

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5. Special Considerations

• Triad: asthma + nasal polyposis + NSAID/aspirin sensitivity
• Mechanism: COX-1 inhibition → shunting of arachidonic acid to leukotriene pathway → massive bronchoconstriction
• Treatment: avoid NSAIDs; leukotriene modifiers are particularly effective; aspirin desensitization in select cases

• Cold, dry air during exercise triggers bronchospasm 5-15 min after exercise
• Prevention: pre-exercise SABA (or ICS/formoterol); warm-up; LTRA

• Patients with features of both; often older smokers with partially reversible obstruction
• Treat with ICS + LABA + LAMA; avoid LABA monotherapy

• Prior near-fatal asthma (ICU admission, intubation)
• ≥2 hospitalizations or ≥3 ED visits in past year
• Current use or recent discontinuation of oral steroids
• Poor perception of symptoms (blunted dyspnea response)
• Low socioeconomic status, poor adherence
• Major psychosocial problems

• Asthma requiring high-dose ICS/LABA and/or oral corticosteroids to maintain control, or remaining uncontrolled despite this therapy
• Requires evaluation for biologic eligibility

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Recent Evidence Note

A 2025 JAMA systematic review and network meta-analysis (PMID 39465893) on inhaled reliever therapies confirmed that ICS/formoterol combination reliever significantly reduces severe asthma exacerbations compared to SABA monotherapy, supporting the GINA recommendation to replace SABA alone as the preferred reliever across all asthma severity steps.

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Key Summary

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Iron Deficiency Anemia - Etiology & Treatment

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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Definition and Concept

• Absolute iron deficiency: iron stores completely exhausted
• Functional iron deficiency: erythropoiesis is iron-restricted but stores may be adequate or even elevated (as in inflammation, CKD, heart failure on ESA therapy)

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Iron Metabolism - Brief Overview

• Daily dietary iron: ~15 mg; only 1-2 mg absorbed from the intestine per day
• Transferrin: hepatic glycoprotein (204-360 mg/dL) that carries iron in plasma; fast turnover; carries 3-4 mg at any time
• Erythroid precursors need 20-25 mg/day for red cell production - most is recycled from macrophages
• Hepcidin: key regulatory hormone produced by the liver
  • Binds and degrades ferroportin (the sole iron exporter) on enterocytes and macrophages
  • Elevated hepcidin (in inflammation, infection) → blocks iron absorption and release from stores → functional iron deficiency
  • Suppressed hepcidin (in iron deficiency, hypoxia, hemorrhage) → increases iron absorption

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Epidemiology

• ~1.2 billion individuals affected worldwide - roughly half of all anemic people globally
• One of the leading causes of years lived with disability globally
• Highest-risk groups:
  • Preschool children: prevalence ~25%
  • Young women (12-21 years): 38.6% iron deficiency; 6.3% IDA (US data)
  • Pregnant women: >40% with severe forms in low-income countries
• Especially prevalent in low-income countries, but high-income countries are not spared

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Etiology / Causes of Iron Deficiency

1. Excessive Demand / Increased Requirements

2. Inadequate Intake / Poor Nutrition

3. Defective Absorption (Malabsorption)

4. Blood Loss - The Most Common Cause in Adults

Gastrointestinal (Most Common Source in Men and Post-Menopausal Women)

Gynecological (Most Common Source in Pre-Menopausal Women)

Urological / Other

5. Genetic / Rare Causes

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Clinical Features

Symptoms of Anemia

• Fatigue, lethargy, reduced exercise tolerance
• Dyspnea on exertion
• Palpitations, tachycardia
• Dizziness, headache
• Pallor (conjunctival, palmar, nail bed)

Symptoms Specific to Iron Deficiency (Beyond Anemia)

• Pica: craving for non-food substances (ice - pagophagia, dirt - geophagia, clay, starch)
  • Pagophagia (ice craving) is highly specific for iron deficiency
• Restless leg syndrome: strong urge to move legs, especially at rest
• Koilonychia: spoon-shaped nails (brittle, concave nails) - in severe/chronic IDA
• Angular cheilitis (stomatitis): cracking at corners of mouth
• Glossitis / atrophic tongue
• Dysphagia + upper esophageal web = Plummer-Vinson (Paterson-Kelly) Syndrome (rare, severe IDA)
• Impaired cognition and learning in children
• Blunted immune response: lymphocytes require iron for metabolic burst
• Cardiac effects: in CHF, iron deficiency causes symptoms even independently from anemia (functional impairment of cardiomyocytes)

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Laboratory Diagnosis

Complete Blood Count and Red Cell Indices

Iron Studies

Ferritin is an acute-phase reactant - it can be falsely normal or elevated in IDA with co-existing inflammation. A ferritin <100 μg/L in a patient with inflammation still likely indicates iron deficiency. sTfR or sTfR/log ferritin ratio is more reliable in this setting.

Peripheral Blood Smear

• Hypochromic, microcytic red cells (pale cells with central pallor >1/3 diameter)
• Pencil cells (elongated elliptocytes)
• Anisocytosis and poikilocytosis
• Target cells (less common)

Bone Marrow

• Absent iron stores on Prussian blue stain (definitive test, rarely needed)
• Absent hemosiderin and ferritin in macrophages

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Differential Diagnosis of Microcytic Anemia

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Treatment

Principles of Treatment

1. Identify and treat the underlying cause (mandatory - do not just replace iron without investigating the source of blood loss or malabsorption)
2. Replenish iron stores (not just correct hemoglobin)
3. Continue iron until stores are fully restored (typically 3-6 months after Hb normalizes)

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A. Oral Iron Therapy - First Line

• Adults: 150-200 mg elemental iron per day (e.g., ferrous sulfate 325 mg TID)
• Children: 3-6 mg/kg/day elemental iron in divided doses

• Take on empty stomach (best absorbed) - though GI side effects increase
• Take with vitamin C (ascorbic acid) - reduces Fe³⁺ to Fe²⁺, enhances absorption
• Avoid co-administration with: calcium supplements, antacids, PPIs, tetracyclines, fluoroquinolones, tea, coffee, cereals, dairy (all reduce absorption)
• Alternate-day dosing (every other day) - recent evidence shows it may improve absorption compared to daily dosing by allowing hepcidin to reset between doses; reduces GI side effects

• Reticulocyte rise in 7-10 days (first sign of response)
• Hemoglobin rise ~1 g/dL per week
• Hb should normalize in 6-8 weeks
• Continue iron for 3-6 months after Hb normalization to replenish stores

• Constipation, nausea, epigastric discomfort, diarrhea, dark stools
• Manage by: taking with food (reduces but doesn't eliminate GI effects), lower-dose preparations (ferrous gluconate, bisglycinate), liquid formulations, or switching to IV iron

• Non-compliance (most common)
• Ongoing blood loss exceeding replacement
• Malabsorption (celiac disease, H. pylori, IRIDA)
• Incorrect diagnosis (thalassemia, inflammation)
• Drug interactions reducing absorption

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B. Intravenous (IV) Iron Therapy

1. Intolerance of oral iron (significant GI side effects)
2. Poor oral iron absorption (celiac disease, IBD, bariatric/gastric surgery, achlorhydria)
3. Chronic kidney disease (CKD) patients on dialysis or with EPO therapy
4. Heart failure with iron deficiency (even without anemia - IV iron improves functional capacity and reduces hospitalizations)
5. IRIDA (oral iron refractory - specifically requires IV iron)
6. Need for rapid repletion (pre-operative anemia, severe symptomatic anemia)
7. Pregnancy (second/third trimester, when oral therapy inadequate or fails)
8. Active IBD (functional + absolute iron deficiency; oral iron may worsen inflammation)
9. Inflammatory bowel disease, chronic kidney disease, cancer patients

Total iron dose (mg) = Body weight (kg) × (Target Hb - Actual Hb in g/dL) × 2.4 + Iron stores (500 mg)

• Infusion reactions: flushing, hypotension, arthralgia, myalgia (especially with rapid infusion)
• Anaphylaxis: rare but serious (most risk with iron dextran); always have resuscitation ready
• Delayed reactions: arthralgia, myalgia 24-48 h post-infusion
• Hypophosphatemia: particularly with ferric carboxymaltose (transient, FGF23-mediated)
• Hypersensitivity: avoid in first trimester of pregnancy

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C. Red Blood Cell Transfusion

• Severe symptomatic anemia (Hb <7-8 g/dL) with hemodynamic instability, angina, or cardiac decompensation
• Perioperative situations requiring rapid correction
• Patients with compromised cardiopulmonary reserve

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D. Treatment of Underlying Cause (Mandatory)

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E. Special Populations

• Oral iron first line; IV iron in second/third trimester if oral fails or is not tolerated
• Routine supplementation recommended in all pregnant women (30-60 mg elemental iron/day; WHO)

• IV iron preferred especially in dialysis patients
• Target ferritin 200-500 μg/L; Tsat 20-50%
• IV iron reduces ESA dose requirement

• IV iron (especially ferric carboxymaltose) improves symptoms, 6-minute walk test, and quality of life in HF patients with iron deficiency even without anemia
• 2025 meta-analysis in Nature Medicine (PMID 40159279) confirmed IV iron reduces hospitalizations in HF with iron deficiency

• Oral iron may worsen mucosal inflammation and GI symptoms; IV iron preferred in active disease
• During remission, oral iron with close monitoring is acceptable

• Oral iron is ineffective due to persistently elevated hepcidin
• IV iron required; response may be partial

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Key Summary

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📌 Recent Evidence: A 2025 Nature Medicine meta-analysis (PMID 40159279) on IV iron in heart failure with iron deficiency confirmed significant reduction in hospitalizations, supporting its use even in non-anemic iron deficiency in HF. A 2023 meta-analysis (PMID 36728680) confirmed ferrous bisglycinate as an effective oral iron option with improved Hb and ferritin outcomes across populations.

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Stroke - Risk Factors & Emergency Treatment

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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Types of Stroke

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PART I: RISK FACTORS FOR STROKE

A. Non-Modifiable Risk Factors

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B. Modifiable Risk Factors

1. Hypertension - The Single Most Important Modifiable Risk Factor

• Increases stroke risk 4-fold for ischemic stroke and up to 10-fold for hemorrhagic stroke
• Risk is proportional to BP level - even "high normal" BP (130-139/80-89 mmHg) carries elevated risk
• Treating hypertension reduces stroke risk by 35-44%
• Both systolic and diastolic hypertension are risk factors; isolated systolic hypertension (elderly) is particularly important

2. Atrial Fibrillation (AF)

• Increases ischemic stroke risk 5-fold
• Responsible for ~15-20% of all ischemic strokes; up to 30% in elderly patients
• Cardioembolic strokes from AF tend to be large, severe, and more disabling
• CHA₂DS₂-VASc score guides anticoagulation decisions
• AF may be paroxysmal and silent - often discovered only after a stroke

3. Diabetes Mellitus

• Increases stroke risk 2-6-fold
• Accelerates atherosclerosis; promotes small vessel disease (lacunar infarcts)
• Hyperglycemia at time of stroke worsens outcome (extends infarct size)
• Metabolic syndrome and insulin resistance also increase risk independently

4. Dyslipidemia

• Elevated LDL-cholesterol promotes large-vessel atherosclerosis (carotid, intracranial arteries)
• Statin therapy reduces ischemic stroke risk by ~25-30%
• Low HDL is an independent risk factor
• High triglycerides associated with increased risk through VLDL/remnant particles

5. Smoking

• Increases ischemic stroke risk 2-fold; increases SAH risk 3-10-fold
• Promotes atherosclerosis, increases platelet aggregation, elevates fibrinogen, causes arterial wall injury
• Risk decreases significantly within 2-5 years of cessation

6. Cardiac Disease

7. Carotid Artery Disease

• Symptomatic carotid stenosis >70%: ~26% stroke risk within 2 years without intervention
• Asymptomatic carotid stenosis >60%: ~2%/year stroke risk
• Carotid endarterectomy or stenting reduces risk significantly

8. Obesity

• BMI >30 increases stroke risk by ~64% independent of other risk factors
• Promotes hypertension, diabetes, AF, dyslipidemia, and sleep apnea

9. Physical Inactivity

• Sedentary lifestyle independently associated with ~2x increased stroke risk
• Regular moderate exercise (150 min/week) reduces risk by ~25%

10. Alcohol Use

• Heavy alcohol use (>5 drinks/day): increases ischemic and hemorrhagic stroke risk significantly
• Moderate alcohol use: potentially modestly protective for ischemic stroke (controversial; no longer recommended as preventive measure)
• Binge drinking is a clear risk factor regardless of average intake

11. Drug Use

12. Hyperhomocysteinemia

• Elevated homocysteine promotes endothelial injury and thrombosis
• Treatable with folate, B6, B12 supplementation
• MTHFR mutations contribute

13. Coagulation / Hematologic Disorders

14. Obstructive Sleep Apnea (OSA)

• Independently increases stroke risk ~2-3-fold
• Promotes nocturnal hypertension, cardiac arrhythmias (AF), hypercoagulability
• CPAP therapy reduces risk

15. Migraine with Aura

• ~2-fold increased ischemic stroke risk, especially in young women
• Risk multiplied significantly with OCP use and smoking

16. Other Conditions

• Inflammatory states (lupus, vasculitis, giant cell arteritis)
• Chronic kidney disease (promotes hypertension, atherosclerosis, AF)
• Peripartum state (hypercoagulability, eclampsia, cardiomyopathy)
• SARS-CoV-2 infection (COVID-19): associated with coagulopathy and stroke

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Summary of Stroke Risk Factors by Modifiability

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PART II: EMERGENCY TREATMENT OF ACUTE ISCHEMIC STROKE

The "Time is Brain" Principle

1.9 million neurons die every minute during a large vessel occlusion without treatment. Rapid recognition and treatment is the single most important factor in improving outcome.

Six Categories of Treatment (Harrison's 22E)

1. Medical support
2. IV thrombolysis
3. Endovascular revascularization
4. Antithrombotic treatment
5. Neuroprotection
6. Stroke centers and rehabilitation

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Step 1: Immediate Assessment (First 10-15 Minutes)

• Activate stroke code / call ahead to hospital for pre-alert
• ABCs: Airway, Breathing, Circulation - stabilize
• Finger-stick glucose: treat hypoglycemia (glucose <3.3 mmol/L/60 mg/dL) or hyperglycemia immediately
• IV access, cardiac monitoring, pulse oximetry
• Neurological examination: use NIHSS (NIH Stroke Scale) to quantify deficit
• BP measurement: document and manage appropriately (see below)
• Symptom onset time: exact time last known well (LKW) is critical for treatment eligibility

• Balance loss, Eyes (vision loss), Face droop, Arm weakness, Speech difficulty, Time to call emergency

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Step 2: Emergency Imaging

• Performed immediately on arrival ("CT first, ask questions later")
• Primary purpose: rule out hemorrhagic stroke (appears as hyperdense)
• Also detects: large established infarct (if >1/3 MCA territory → thrombolysis relatively contraindicated), hyperdense MCA sign (clot)
• No reliable clinical features alone can distinguish ischemic from hemorrhagic stroke

• CT Angiography (CTA): rapidly identifies large vessel occlusion (LVO) for thrombectomy planning; simultaneous with NCCT
• CT Perfusion (CTP): defines ischemic core (irreversibly infarcted) vs. penumbra (salvageable tissue); guides treatment in late window (6-24 hours)
• MRI/DWI: more sensitive for early ischemia (detects within minutes); not always available acutely

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Step 3: Medical Support (Concurrent with Imaging)

Blood Pressure Management

• Routine BP lowering below 220/120 mmHg worsens outcomes in acute ischemic stroke (removes collateral perfusion pressure)
• Agents: IV labetalol, nicardipine, or clevidipine for controlled reduction
• Avoid: aggressive lowering; sublingual nifedipine (unpredictable drops)

Glucose Management

• Target glucose: 3.3-10.0 mmol/L (60-180 mg/dL)
• Hyperglycemia worsens infarct extension; hypoglycemia can mimic stroke and worsen injury
• Give IV dextrose immediately for hypoglycemia (<60 mg/dL)
• Intensive glucose control (tight control) does NOT improve outcome

Fever

• Detrimental - increases metabolic demand in ischemic penumbra
• Treat aggressively with antipyretics (paracetamol/acetaminophen) and surface cooling
• Target normothermia (≤37.5°C)

Cerebral Edema

• 5-10% of patients develop significant cerebral edema
• Peaks at day 2-3 but can cause mass effect for ~10 days
• Larger infarcts → greater edema risk ("malignant MCA infarction")
• Treatment: IV mannitol, water restriction, head-of-bed elevation 30°
• Decompressive hemicraniectomy: life-saving in malignant MCA territory infarction with clinical deterioration; reduces mortality significantly (especially <60 years of age)

DVT Prevention

• Subcutaneous heparin (LMWH or UFH) safe to use concomitantly
• Pneumatic compression stockings: proven benefit, safe alternative

Airway/Oxygenation

• Supplemental oxygen only if SpO2 <94% (routine oxygen in normoxic patients does not improve outcome)
• Intubation and mechanical ventilation for reduced consciousness/airway protection

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Step 4: IV Thrombolysis (tPA/Alteplase)

• Dose: 0.9 mg/kg IV (maximum 90 mg); 10% as bolus over 1 minute, remainder over 60 minutes
• Mechanism: activates plasminogen → plasmin → clot lysis

• Standard window: within 4.5 hours of symptom onset (last known well time)
• Earlier treatment = better outcome: "time is brain"
• Greatest benefit when given within 3 hours

• Age >80 years (relative)
• Prior stroke + diabetes together
• NIHSS >25
• Anticoagulant use

• 1/3 MCA territory infarction on imaging

📌 2025 Cochrane Review (PMID 40271574): Endovascular thrombectomy with vs. without prior IV thrombolysis - current evidence suggests IV tPA before thrombectomy remains the standard when eligible, though direct-to-thrombectomy is being studied.

📌 2025 Meta-analysis (PMID 39882605): Thrombolysis beyond the 4.5-hour window (using perfusion imaging to select salvageable tissue) showed benefit in selected patients, supporting extended window protocols with CTP guidance.

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Step 5: Endovascular Thrombectomy (EVT/Mechanical Thrombectomy)

• Large vessel occlusion (LVO): ICA, M1/M2 MCA, basilar artery, vertebral artery
• NIHSS ≥6 (significant deficit)
• Time window: 0-6 hours from onset (standard); up to 24 hours with favorable CT perfusion mismatch (DAWN/DEFUSE-3 trial criteria)
• No large established core infarct (>1/3 MCA territory or large DWI lesion)
• Modified Rankin Scale (mRS) 0-1 premorbidly (functionally independent before stroke)

• Femoral artery access → catheter advanced to occluded vessel
• Stent retriever or aspiration catheter mechanically removes clot
• Target: TICI 2b-3 reperfusion (>50-90% territory reperfusion)
• "Door-to-groin" time target: <90 minutes

• 2x more likely to achieve functional independence compared to IV tPA alone in LVO
• Benefit shown even in extended windows with perfusion imaging guidance
• Basilar artery occlusion: thrombectomy is lifesaving; associated with "locked-in" syndrome if untreated

• If patient is eligible for both: IV tPA first (bridge therapy), then proceed immediately to thrombectomy
• IV tPA does not delay and may facilitate EVT

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Step 6: Antithrombotic Treatment

• 325 mg orally within 24-48 hours of ischemic stroke onset
• Contraindicated within 24 hours of IV tPA (increases hemorrhagic transformation risk)
• Reduces early recurrent stroke risk

• NOT routinely recommended in acute ischemic stroke (risk of hemorrhagic transformation outweighs benefit)
• Exceptions: cardioembolic stroke with high recurrence risk, cerebral venous sinus thrombosis, arterial dissection

• Aspirin + clopidogrel for 21 days: indicated for minor ischemic stroke (NIHSS ≤3) or high-risk TIA (ABCD2 score ≥4)
• Based on POINT and CHANCE trials
• Reduces early recurrent stroke without significantly increasing bleeding risk

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Step 7: Stroke Unit / Specialized Care

• All stroke patients should be admitted to a dedicated stroke unit - reduces mortality and disability by 20-25% vs. general ward
• Multidisciplinary team: neurology, nursing, PT, OT, speech therapy, dietitian, social work
• Early mobilization (within 24-48 hours for mild-moderate strokes)
• Dysphagia screening before oral intake (prevent aspiration pneumonia - major cause of post-stroke mortality)
• Cardiac monitoring for 24-72 hours: detect paroxysmal AF (identifies cardioembolic source)

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Hemorrhagic Stroke - Emergency Management Differences

• No thrombolysis or thrombectomy (contraindicated - would worsen bleeding)
• Reverse anticoagulation immediately:
  • Warfarin → IV Vitamin K + prothrombin complex concentrate (PCC)
  • DOACs → specific reversal agents (idarucizumab for dabigatran; andexanet alfa for Xa inhibitors)
  • Heparin → protamine sulfate
• Aggressive BP control: target SBP <140 mmHg within 1 hour (AHA/ASA 2022)
• Surgical evacuation: for cerebellar hematoma >3 cm with mass effect (life-saving); selected supratentorial hemorrhages
• ICP management: osmotherapy (mannitol, hypertonic saline), sedation, positioning, ventriculostomy for hydrocephalus

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Emergency Stroke Algorithm Summary

Symptom onset → 911 call → Pre-alert hospital

ARRIVAL:
├── ABCs + IV access + monitor
├── Finger-stick glucose → correct if abnormal
├── Immediate NCCT head (±CTA)
│
├── HEMORRHAGE → ICH/SAH protocol (reverse anticoagulation, BP control, neurosurgery)
│
└── ISCHEMIC STROKE:
    ├── <4.5 h + eligible → IV ALTEPLASE 0.9 mg/kg
    ├── LVO detected → THROMBECTOMY (up to 24 h with imaging selection)
    ├── Aspirin 325 mg (after tPA window or if tPA not given)
    ├── BP: do not lower unless >220/120 (>185/110 if tPA planned)
    ├── Glucose: 60-180 mg/dL
    ├── Treat fever
    └── Admit to STROKE UNIT

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Key Numbers to Remember

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Ventilator-Associated Pneumonia (VAP)

Harrison's Principles of Internal Medicine, 22nd Edition (2025)

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Definition

• Non-ventilated HAP: pneumonia in hospitalized patients not on mechanical ventilation
• Ventilated HAP: HAP in patients requiring ventilation but acquired before intubation

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Epidemiology

• Prevalence estimates: 6-52 cases per 100 mechanically ventilated patients (varies by population, ICU type)
• On any given ICU day, ~10% of ventilated patients have VAP
• Frequency was declining due to prevention bundles, but COVID-19 increased its incidence
• Highest risk in the first 5 days of mechanical ventilation (highest hazard ratio in early period)
• Crude mortality: 20-50% in VAP; attributable mortality ~10-15% when controlling for confounders
• Increases ICU stay by 5-10 days and hospital costs significantly
• ~30% of all HAP occurs in the ICU; 35% of all HAP patients eventually require mechanical ventilation

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Pathogenesis / Risk Factors

How VAP Develops

1. Colonization of oropharynx and/or stomach with pathogenic bacteria (including MDR organisms)
2. Aspiration of contaminated secretions past the ETT cuff into the lower airways
3. Impaired host defenses: mucociliary clearance bypassed by ETT; cough reflex suppressed; impaired alveolar macrophage function (sedation, malnutrition, immunosuppression)

Risk Factors for VAP

Risk Factors Specifically for MDR Pathogens in VAP

• Prior antibiotic therapy (especially β-lactams, cephalosporins → MRSA, ESBL)
• Hospitalization ≥5 days before VAP onset ("late-onset VAP")
• Mechanical ventilation ≥5 days
• Prior hospitalization within 90 days
• Nursing home or long-term care facility residence
• Prior culture positive for MDR organism
• High local prevalence of MDR pathogens in the ICU
• Immunosuppression
• Septic shock at VAP onset

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Microbiology / Etiology

Non-MDR "Core Pathogens" (Early-Onset VAP, No MDR Risk Factors)

• Streptococcus pneumoniae
• Haemophilus influenzae
• Methicillin-sensitive Staphylococcus aureus (MSSA)
• Antibiotic-sensitive Enterobacteriaceae: Escherichia coli, Klebsiella pneumoniae, Proteus spp., Enterobacter spp., Serratia marcescens

MDR Pathogens (Late-Onset or with MDR Risk Factors) - The Critical Difference

Key principle: The relative frequency of individual MDR pathogens varies hospital by hospital and even ICU by ICU. Local antibiogram data is essential for empirical therapy selection.

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Diagnosis

Clinical Criteria

• New or progressive pulmonary infiltrate on chest X-ray/CT
• Plus ≥2 of the following:
  • Fever (>38.3°C) or hypothermia (<36°C)
  • Purulent tracheal secretions
  • Leukocytosis (>12,000/μL) or leukopenia (<4,000/μL)
  • Worsening oxygenation (↑FiO2 requirement, ↑PEEP, ↓PaO2/FiO2 ratio)

Important caveat: Clinical criteria alone have low specificity in mechanically ventilated patients - fever, leukocytosis, and pulmonary infiltrates have many non-infectious causes (ARDS, pulmonary edema, atelectasis, drug reactions).

Clinical Pulmonary Infection Score (CPIS)

• CPIS >6 suggests VAP
• More useful for monitoring response than initial diagnosis

Microbiologic Sampling - Critical for Diagnosis and De-escalation

• Gram stain from lower respiratory sample provides early (1-hour) guidance
• Blood cultures: positive in ~15-25% of VAP (identifies bacteremic spread)
• Urinary antigen tests: Legionella antigen (urine) - especially if outbreak suspected
• Serum procalcitonin (PCT): useful to monitor treatment response and guide duration of therapy; declining PCT supports discontinuation

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Treatment

Principle: "Start Broad, De-escalate Early"

1. Initiate empirical therapy immediately after microbiologic specimens collected - delay increases mortality
2. Broaden or narrow based on 48-72h culture/sensitivity results (de-escalation)
3. Shorten duration to avoid resistance selection (target 7-8 days for most VAP)

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A. Empirical Antibiotic Therapy

1. Are there risk factors for MDR pathogens?
2. Is the predicted mortality risk high (>15%) or low (≤15%)?

Group 1: No MDR Risk Factors (Low Mortality Risk) → Monotherapy

• Single agent sufficient; mortality is lower with monotherapy vs. combination in low-risk patients
• Covers core pathogens + non-resistant P. aeruginosa
• If atypical pathogens not a concern (unlike CAP), dedicated atypical coverage not routinely needed

Group 2: MDR Risk Factors and/or High Mortality Risk → Triple Therapy (Three Antibiotics)

Special Pathogens:

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B. De-escalation (48-72 Hours)

• Once culture results are available: narrow antibiotics to the narrowest effective agent
• If cultures are negative and clinical improvement: strongly consider stopping antibiotics (especially if CPIS improving, PCT declining)
• De-escalation reduces:
  • Selection pressure for MDR organisms
  • Antibiotic side effects (nephrotoxicity, C. difficile)
  • Costs
• De-escalation is safe and does not worsen outcomes in VAP

C. Duration of Therapy

• Standard: 7-8 days for most VAP (including P. aeruginosa if clinically responding)
• Shorter courses (7 days) are recommended over longer (14-21 days) by IDSA/ATS guidelines
• Exceptions requiring longer therapy:
  • Bacteremia (especially S. aureus bacteremia → 14+ days)
  • Necrotizing pneumonia or lung abscess
  • Immunocompromised patients
  • Inadequate initial therapy
  • Poor clinical response

D. Monitoring Treatment Response

Failure to improve at 48-72 hours should prompt: review of culture sensitivities, broaden to cover MDR organisms, consider non-infectious causes (ARDS, PE, drug fever), or look for complications (empyema, lung abscess)

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Prevention - The VAP Bundle

1. Head-of-Bed Elevation

• Semi-recumbent position (30-45°) at all times during mechanical ventilation
• Reduces aspiration of gastric contents
• Simple, zero-cost, proven effective

2. Oral Decontamination

• Chlorhexidine gluconate (0.12-0.2%) oral rinse every 6-12 hours
• Reduces oropharyngeal colonization with gram-negative bacteria
• Particularly beneficial in cardiac surgery patients
• Evidence for non-cardiac ICU patients is strong but slightly less consistent

3. Subglottic Secretion Drainage (SSD)

• Specialized ETTs with a separate suction lumen above the cuff
• Continuously or intermittently drains secretions pooling above the cuff (main reservoir before aspiration)
• Reduces early-onset VAP by ~50% in patients expected to require ventilation >48-72 hours

4. Endotracheal Tube Cuff Pressure Management

• Maintain cuff pressure 20-30 cmH₂O (prevents aspiration around cuff while avoiding mucosal ischemia)
• Use continuous cuff pressure monitoring in high-risk patients

5. Minimize Sedation / Early Liberation from Ventilator

• Daily sedation interruption ("sedation holidays") - reduces ventilator days
• Spontaneous breathing trials (SBT) daily - once stable, assess readiness for extubation
• Shortest ventilation duration possible = most effective VAP prevention
• SAT + SBT protocol (Spontaneous Awakening Trial + Spontaneous Breathing Trial) linked in the ABCDE bundle

6. Selective Oral Decontamination (SOD) / Selective Digestive Decontamination (SDD)

• SDD: topical antibiotics in oropharynx/GI tract + short systemic antibiotics
• Reduces VAP rates but concerns about antibiotic resistance selection limit widespread adoption
• Considered in specific ICUs with known low MDR burden

7. Avoid Unnecessary Gastric Acid Suppression

• Limit H2 blockers and PPIs to patients with genuine indications (high GI bleeding risk)
• Sucralfate as alternative in lower-risk patients (does not raise gastric pH, may reduce VAP)

8. Proper Hand Hygiene and Infection Control

• Hand hygiene (soap + water or alcohol-based handrub) before/after patient contact
• Contact precautions for MDR-colonized patients
• Routine environmental cleaning

9. Ventilator Circuit Management

• Change circuits only when visibly soiled or malfunctioning (not on scheduled intervals)
• Drain condensation away from patient
• Heat-moisture exchangers (HME) rather than heated humidifiers reduce circuit colonization

10. Avoid Re-intubation

• Non-invasive ventilation (NIV) as bridge to prevent re-intubation where appropriate
• Careful extubation planning reduces failed extubation and need for re-intubation

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Summary Table

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