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

Definition & Context

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Pathophysiology of the Acute Attack

• The fundamental abnormality is high resistance to airflow due to airway obstruction (bronchospasm + mucosal edema + mucus plugging).
• Most patients in an attack present with hypocapnia (low PCO2) due to a high respiratory rate driven by dyspnea.
• A normal or near-normal PCO2 in a patient in respiratory distress is an ominous sign - it indicates the patient is tiring and is no longer able to maintain the hyperventilation needed to compensate. This signals impending respiratory failure.

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Assessment in the Urgent/Emergency Setting

1. Measure PEFR or FEV1 immediately.
2. Patients with PEFR >60% of predicted frequently respond to beta2-agonists alone.
3. Failure to achieve PEFR >60% or persistent severe tachypnea over 4-6 hours should prompt consideration of hospital admission.

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Step-by-Step Management (Harrison's Framework)

Step 1 - Initial (Mild to Moderate)

• Inhaled beta2-agonist up to every 1 hour.
• Consider increasing ICS dose 4- to 5-fold.
• If no adequate control and beta2-agonists needed hourly for several hours → refer for urgent care.

Step 2 - Urgent Care Setting

Step 3 - In-Hospital Management

• Continuous bronchodilator nebulization
• Noninvasive positive-pressure ventilation (NIV/BiPAP) to prevent respiratory exhaustion and avoid intubation
• Helium-oxygen (Heliox) mixtures to decrease the work of breathing
• Antibiotics only if there are signs of infection (not routinely)

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Mechanical Ventilation in Status Asthmaticus

• Indication: Respiratory failure, rising PCO2, exhaustion
• Strategy:
  • Low respiratory rates and/or low tidal volumes to decrease peak airway pressures
  • "Permissive hypercapnia" - allow PCO2 to rise deliberately rather than risk barotrauma
  • If critical acidosis develops: temporarily correct with IV sodium bicarbonate to raise pH
  • Neuromuscular paralysis may sometimes be beneficial
  • Bronchoscopy to clear mucus plugs has been described but is potentially dangerous in the context of difficult ventilation

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High-Risk Patients (Table 298-6) - Factors Associated with Asthma Mortality

1. History of ICU admission for asthma
2. History of intubation for asthma
3. Illicit drug use
4. Depression
5. New diagnosis within the past year
6. ≥2 emergency department visits in the past 6 months
7. Severe psychosocial problems
8. Lower socioeconomic status
9. On daily prednisone prior to admission

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Key Clinical Pearls (Harrison's)

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Summary of Drug Choices

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Acute Exacerbation of COPD - Harrison's Principles of Internal Medicine (22nd Edition, 2025)

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Definition

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Epidemiology & Natural History

• Exacerbations are a prominent feature of the natural history of COPD.
• The strongest single predictor of future exacerbation is a history of previous exacerbation.
• Frequency increases as airflow obstruction worsens: patients with FEV1 <50% predicted average 1-3 exacerbations per year.
• Some individuals with severe obstruction still do not exacerbate frequently.
• Additional risk factors: current smoking, elevated pulmonary artery-to-aorta diameter ratio on CT, gastroesophageal reflux.
• COPD exacerbations account for the majority of the $50 billion annual COPD-related healthcare expenditures in the United States.

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Precipitating Causes

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Patient Assessment

History

• Degree and change in dyspnea (activities of daily living)
• Fever, change in sputum character
• Associated symptoms: wheezing, nausea/vomiting, diarrhea, myalgias, chills
• Prior exacerbation history - previous hospitalization is the single greatest risk factor for re-hospitalization

Physical Examination

• Tachycardia, tachypnea
• Use of accessory muscles
• Perioral or peripheral cyanosis
• Ability to speak in complete sentences
• Mental status (confusion/sleepiness = red flag)
• Chest: focal findings, air movement, wheezing, asymmetry (suggests large airway obstruction or pneumothorax), paradoxical abdominal wall motion

Investigations

Key ABG finding: PCO2 >45 mmHg (hypercarbia) has critical implications for treatment (drives NIV decision).

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Criteria for Hospital Admission

1. Respiratory acidosis and hypercarbia (PCO2 >45 mmHg, pH ≤7.35)
2. New or worsening hypoxemia
3. Severe underlying COPD
4. Significant comorbidities (e.g., heart failure)
5. Living situation not conducive to careful observation or delivery of treatment

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Treatment of Acute Exacerbations

1. Bronchodilators

• Inhaled beta-agonists + muscarinic antagonists - may be given separately or combined.
• Initially given as nebulized therapy (easier in respiratory distress).
• Conversion to metered-dose inhalers is equally effective when accompanied by education - has economic benefits and eases transition to outpatient care.

2. Antibiotics

• Used in moderate or severe exacerbations for 5-7 days, even without a specific identified pathogen.
• Choice based on local antibiotic susceptibility patterns.
• Common pathogens: S. pneumoniae, H. influenzae, M. catarrhalis, C. pneumoniae.

3. Glucocorticoids

• In hospitalized patients: systemic steroids reduce length of stay, hasten recovery, and reduce risk of subsequent exacerbation/relapse.
• Dose: Oral prednisone 40 mg (or equivalent) for 5 days (current recommendation).
• Most frequent acute complication: hyperglycemia (especially in known diabetics).

4. Supplemental Oxygen

• Target oxygen saturation: 88-92%
• Supplemental O2 does not reduce minute ventilation in patients with hypercarbia.
• It may cause modest increases in arterial PCO2 by altering V/Q relationships - but this should not deter clinicians from correcting hypoxemia.

5. Noninvasive Positive-Pressure Ventilation (NIPPV / NIV)

• Mortality rate
• Need for intubation
• Therapy complications
• Hospital length of stay

• Cardiovascular instability
• Impaired mental status / inability to cooperate
• Copious secretions or inability to clear secretions
• Craniofacial abnormalities or trauma (mask fitting not possible)

6. Invasive Mechanical Ventilation

• Severe respiratory distress
• Hypoxemia
• Severe hypercarbia and/or acidosis despite NIPPV
• Markedly impaired mental status
• Respiratory arrest
• Hemodynamic instability
• Other complications

• Provide sufficient expiratory time (severe airflow obstruction = air trapping)
• Watch for auto-PEEP (intrinsic PEEP) - patients may need to generate significant effort to trigger a breath in demand mode

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Prognosis

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Post-Exacerbation Management (Preventing Future Exacerbations)

• Triple inhaled therapy (LABA + LAMA + ICS) - reduces mortality in selected patients
• Smoking cessation - improves rate of lung function decline and survival
• Pulmonary rehabilitation after hospitalization
• Noninvasive PPV in severe chronic hypercapnia
• Pneumococcal and annual influenza vaccination

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GOLD 2025 Guidelines: Management of COPD Exacerbations

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Definition (GOLD 2025)

"An event characterized by increased dyspnea and/or cough and sputum that worsens in <14 days, which may be accompanied by tachypnea and/or tachycardia, and is often associated with increased local and systemic inflammation caused by infection, pollution, or other insult to the airways."

• Exacerbations negatively impact health status, accelerate lung function decline, and are associated with significant mortality.
• More than 80% of exacerbations are managed in the outpatient setting.
• Some patients fail to return to their pre-exacerbation functional state after recovery.

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Goals of Treatment

1. Minimize the negative impact of the current exacerbation
2. Prevent subsequent events

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Differential Diagnosis - Always Exclude

• Pneumonia
• Congestive heart failure
• Pulmonary embolism
• Pneumothorax, arrhythmia, pleural effusion

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Severity Classification (GOLD 2025 - Figure 4.2)

GOLD 2025 emphasizes that in hospitalized patients, severity should be based on the patient's clinical signs - not just spirometry or a single parameter.

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Indications for Hospitalization Assessment (Figure 4.3)

• Severe dyspnea not responding to initial treatment
• Acute respiratory failure (hypoxemia, hypercarbia, acidosis)
• New or worsening cyanosis
• Peripheral edema (new onset)
• Reduced consciousness / confusion
• Failure to manage at home (inadequate support, inability to sleep, eat, ambulate)
• Significant comorbidities (cardiac disease, diabetes, renal/hepatic failure)
• Diagnostic uncertainty

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ICU / Respiratory ICU Admission Indications (Figure 4.7)

• Severe dyspnea unresponsive to initial emergency therapy
• Altered mental status (confusion, lethargy, coma)
• Persistent or worsening hypoxemia (PaO2 <40 mmHg) and/or respiratory acidosis (pH <7.25) despite supplemental O2 and NIV
• Need for invasive mechanical ventilation
• Hemodynamic instability

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Pharmacological Treatment

1. Bronchodilators

• Short-acting inhaled beta2-agonists (SABA), with or without short-acting anticholinergics (SAMA), are the recommended initial bronchodilators.
• Note: High-quality RCT evidence is limited, but this is standard of care.
• Long-acting bronchodilators (LABA/LAMA) should be initiated as soon as possible - do not wait for full recovery. In patients with frequent exacerbations and elevated blood eosinophils, adding ICS to double bronchodilator therapy should be considered.
• Methylxanthines (theophylline/aminophylline) are NOT recommended due to increased side effects with no added benefit.

2. Systemic Corticosteroids

• In severe exacerbations: systemic corticosteroids improve FEV1, oxygenation, and shorten recovery time including hospitalization duration.
• Duration: ≤5 days (no benefit from longer courses; shorter courses are equally effective and safer).
• Recommended dose: oral prednisone 40 mg/day for 5 days (or IV equivalent).
• Watch for: hyperglycemia (most common acute complication).
• New GOLD 2025 note: In patients with frequent exacerbations and elevated blood eosinophil levels, addition of ICS to the LABA+LAMA regimen should be considered for ongoing prevention.

3. Antibiotics

• When indicated, antibiotics shorten recovery time, reduce risk of early relapse, treatment failure, and hospital length of stay.
• Duration: 5 days
• Indications for antibiotics in AECOPD:
  • Increased dyspnea + increased sputum volume + purulent sputum (all 3 Anthonisen criteria) → highest benefit
  • 2 of the 3 criteria if purulent sputum is one of them
  • Requiring mechanical ventilation (invasive or non-invasive)
• Common pathogens: H. influenzae, S. pneumoniae, M. catarrhalis, Chlamydia pneumoniae; consider Pseudomonas in severe/recurrent cases or those with prior Pseudomonas isolation.
• Choice based on local resistance patterns.

Supporting evidence: A 2024 meta-analysis (Suzuki et al., PMID 38761481) confirmed antibiotics significantly reduce treatment failure vs. placebo in AECOPD (OR 0.50, 95% CI 0.35-0.71), with no difference in mortality or adverse events.

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Respiratory Support

Oxygen Therapy

• Target SpO2: 88-92% (controlled/titrated oxygen)
• Avoid uncontrolled high-flow O2 (risk of hypercapnic respiratory failure by worsening V/Q mismatch and Haldane effect)
• Recheck ABG 30-60 min after initiating O2

Non-Invasive Ventilation (NIV) - First-Line Ventilatory Support (Figure 4.8)

• Respiratory acidosis: pH ≤7.35 and PaCO2 >45 mmHg
• Severe dyspnea with clinical signs of respiratory muscle fatigue, increased work of breathing (accessory muscle use, paradoxical breathing, intercostal retractions)
• Persistent hypoxemia despite supplemental O2

• Reduces mortality
• Reduces need for intubation
• Reduces treatment complications
• Reduces hospital length of stay
• Reduces in-hospital complications (e.g., VAP)

• Respiratory arrest
• Cardiovascular instability (hypotension, arrhythmias, MI)
• Impaired mental status/inability to cooperate
• High aspiration risk, copious secretions unable to be cleared
• Recent facial/upper airway/upper GI surgery
• Craniofacial trauma, fixed nasopharyngeal abnormality

Invasive Mechanical Ventilation (Figure 4.9)

• Unable to tolerate or failure of NIV
• Respiratory or cardiac arrest
• Life-threatening hypoxemia unresponsive to O2/NIV
• Severe acidosis (pH <7.25) with hypercarbia
• Severely impaired consciousness
• Massive aspiration, inability to clear secretions
• Hemodynamic instability not responding to fluids/vasopressors

• Allow sufficient expiratory time (prevent dynamic hyperinflation/air trapping)
• Be aware of auto-PEEP - raises effective trigger threshold and can cause hemodynamic compromise
• Consider permissive hypercapnia (controlled elevation of PCO2 to reduce plateau pressures)

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Additional Hospital Management Considerations

• Heparin/LMWH thromboprophylaxis for immobile hospitalized patients (VTE risk is elevated during and for 90 days after AECOPD)
• Cardiovascular risk: During and for at least 90 days after AECOPD, there is significantly increased risk of cardiovascular events (MI, stroke, unstable angina, TIA) - particularly in those with known IHD
• Mucolytics: May be considered in patients with purulent/viscous sputum; insufficient evidence for routine use
• Physiotherapy/chest physiotherapy for secretion management where appropriate

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Discharge Criteria (Figure 4.10)

• SABA required no more than every 4 hours
• Patient can walk across the room (if previously ambulatory)
• Patient can eat and sleep without frequent awakening from dyspnea
• Clinically stable for 12-24 hours
• ABG stable for 12-24 hours
• Patient/caregiver understands correct inhaler use
• Follow-up arranged (within 4-6 weeks of discharge)

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Post-Exacerbation Follow-Up & Prevention

• Review and optimize maintenance inhaler therapy (LABA + LAMA ± ICS)
• Assess and manage comorbidities
• Pulmonary rehabilitation - should be initiated within 4 weeks of hospitalization (reduces re-hospitalization)
• Ensure pneumococcal, influenza, COVID-19, and RSV vaccination status
• Consider long-term azithromycin (reduces exacerbations in selected patients, especially ex-smokers)
• Consider roflumilast (PDE4 inhibitor) in patients with chronic bronchitis, FEV1 <50%, and frequent exacerbations
• SGLT-2 inhibitors (e.g., empagliflozin): emerging evidence from a 2025 meta-analysis (Satapathy et al., PMID 40220861) suggests SGLT-2i may reduce COPD exacerbations in patients with comorbid T2DM

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Interventions That Reduce Future Exacerbation Frequency (GOLD Figure 4.11)

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Key GOLD 2025 Updates vs. Prior Years

• Expanded definition of ECOPD now explicitly includes tachypnea/tachycardia as possible features.
• Eosinophil-guided therapy more prominently featured - both for ICS addition and biologic eligibility.
• Dupilumab (anti-IL-4/IL-13): newly endorsed for COPD with type 2 inflammation (eosinophils ≥300/µL).
• Strengthened emphasis on early initiation of long-acting maintenance therapy during or immediately after exacerbation.
• Cardiovascular risk during the 90-day post-exacerbation window is explicitly highlighted as a management consideration.

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SIRS (Systemic Inflammatory Response Syndrome) - Harrison's Principles of Internal Medicine (22nd Edition, 2025)

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Historical Context & Definition Evolution

Sepsis-1 (1992) - Where SIRS Was Born

Diagnosis of SIRS: ≥2 of the above 4 criteria must be present.

Sepsis-2 (2003)

Sepsis-3 (2016) - Current Definition

• Is overly sensitive and non-specific (can be triggered by any physiologic stress)
• Does not adequately capture the "life-threatening organ dysfunction" element that defines true sepsis

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Current (Sepsis-3) Definitions Used in Harrison's

Sepsis

• Operationalized as: Increase of ≥2 points in SOFA score from baseline in a patient with suspected or confirmed infection.

Septic Shock

qSOFA Score (Quick Bedside Screening Tool)

qSOFA ≥2 = associated with poor outcome. More specific but less sensitive than SIRS for identifying end-organ dysfunction due to infection.

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SOFA Score - Organ Systems Assessed

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Why SIRS Still Matters (Non-Infectious Causes)

"Cytokine-mediated exuberant inflammatory responses" that can occur in many non-infectious settings.

• Severe trauma
• Burns
• Acute pancreatitis (SIRS and ARDS may arise from local and distant effects of pancreatic enzyme cascade)
• Alcohol-associated hepatitis
• Heatstroke (many heatstroke patients meet SIRS criteria)
• Major surgery
• DIC / cytokine storm

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Pathogenesis of SIRS/Sepsis

• Myeloid cells: Neutrophils, monocytes, macrophages, dendritic cells
• Lymphoid cells: NK cells, lymphocytes
• Parenchymal cells: Endothelial and epithelial cells
• Pathologic responses impair adaptive immunity and tissue repair
• Endothelial damage → loss of native antithrombotic properties → DIC (especially in sepsis and trauma)

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Sepsis Phenotypes (Harrison's 22e - New)

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Epidemiology & Risk Factors

• ~88% of sepsis cases are community-onset (within 48 h of admission); ~12% are hospital-onset (after 48 h).
• ~53% of US sepsis cases are culture-positive; roughly equal gram-positive vs gram-negative split.
• Most common gram-positive: S. aureus, Streptococcus spp., Enterococcus spp.
• Most common gram-negative: E. coli, Klebsiella spp., Pseudomonas aeruginosa
• Most common source: urinary tract (48.9%), respiratory tract (32.9%), intraabdominal (13.6%), skin/soft tissue (10.3%)
• Mortality increases with age; higher in men across all age groups.
• Risk factors for increased mortality: diabetes, obesity, cardiac/respiratory/neurologic/renal/hepatic disease, cancer, immunosuppression, recent hospitalization (3x increased risk within 90 days).

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Recognition of Sepsis

• 2023 CDC Hospital Sepsis Program and 2021 Surviving Sepsis Campaign both recommend dedicated hospital sepsis improvement programs with standardized screening and treatment protocols.
• No single screening tool is preferentially endorsed - each has advantages and limitations.
• Available tools: SOFA, qSOFA, National Early Warning Score (NEWS), Modified Early Warning Score (MEWS), AI-based TREWS (Targeted Real-Time Early Warning System).

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Initial Management of Sepsis/Septic Shock

1. Antibiotics - Most Critical Intervention

• In bacterial septic shock: 7-8% increase in mortality for every 1-hour delay in appropriate antibiotic administration after shock recognition.
• Septic shock: Administer empiric antibiotics within 1 hour of shock recognition.
• Sepsis without shock (less certain diagnosis): Allow time-limited clinical evaluation. If no alternative diagnosis in 3 hours, start empiric antibiotics.
• De-escalate once culture data available (antibiotic stewardship).

Empiric Antibiotic Selection by Site

• Consider remdesivir (SARS-CoV-2) or oseltamivir (influenza) in viral sepsis.

2. Fluid Resuscitation

• IV crystalloid therapy for life-threatening hypotension.
• Balanced crystalloids (e.g., lactated Ringer's) are preferred over normal saline (less hyperchloremic acidosis).

3. Vasopressors

• Target MAP >65 mmHg.
• Norepinephrine is first-line vasopressor.
• Vasopressin can be added to reduce norepinephrine dose.
• Dopamine reserved for select patients (bradycardia, low risk of arrhythmia).

4. Source Control

• Identify and eliminate source of infection as rapidly as possible.
• Examples: drain intraabdominal abscess, manage bowel perforation, treat pyelonephritis/cholangitis, debride necrotizing skin/soft tissue infections.
• Remove infected indwelling catheters promptly.

5. Respiratory Support

• Supplemental oxygen, airway management, mechanical ventilation when indicated.
• Target ICU admission within 6 hours of initial stabilization in critically ill or shock patients.

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Key Clinical Pearl - Harrison's 22e

"Except on few occasions, the patient appears to die from the body's response to infection rather than from it." — Sir William Osler (19th century), quoted in Harrison's as context for understanding SIRS/sepsis pathobiology.

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Summary: SIRS vs Current Sepsis-3 Framework

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