Rescue Therapies in Severe Asthma

 

Rescue Therapies in Severe Asthma: A Comprehensive Review for the Intensivist

Dr Neeraj Manikath , claude.ai

Abstract

Status asthmaticus represents a life-threatening emergency requiring prompt recognition and aggressive management. When conventional therapies fail, intensivists must be familiar with advanced rescue strategies. This review examines the evidence, mechanisms, and practical application of ketamine infusion, heliox therapy, and mechanical ventilation strategies in severe refractory asthma. We provide evidence-based recommendations alongside clinical pearls derived from contemporary critical care practice.

Keywords: Status asthmaticus, ketamine, heliox, mechanical ventilation, rescue therapy, refractory asthma

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Introduction

Status asthmaticus affects approximately 10-20% of patients presenting with acute asthma exacerbations and carries mortality rates of 3-5% despite modern therapy[1,2]. The pathophysiology involves bronchospasm, airway inflammation, mucus plugging, and dynamic hyperinflation—a lethal quartet that conventional therapy may fail to address adequately.

Rescue therapies become necessary when patients demonstrate:

• Persistent hypoxemia (PaO₂ <60 mmHg) despite high-flow oxygen
• Progressive hypercapnia with respiratory acidosis (pH <7.25)
• Altered mental status or impending respiratory arrest
• Failure to respond to inhaled beta-agonists, anticholinergics, and systemic corticosteroids

This review synthesizes current evidence for three critical rescue modalities with practical guidance for bedside application.

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Ketamine Infusion in Status Asthmaticus

Pharmacological Rationale

Ketamine, a phencyclidine derivative, offers multiple mechanisms beneficial in severe asthma:

1. Direct bronchodilation via relaxation of bronchial smooth muscle (independent of beta-receptor pathways)[3]
2. NMDA receptor antagonism reducing central respiratory drive irregularities
3. Anti-inflammatory properties through inhibition of inflammatory mediator release
4. Sympathomimetic effects via inhibition of catecholamine reuptake[4]
5. Anesthetic and analgesic properties facilitating mechanical ventilation without respiratory depression

Evidence Base

Multiple case series and small randomized trials support ketamine's efficacy:

• Howton et al. (1996): Landmark case series of 17 patients with near-fatal asthma showed rapid improvement in peak flow and reduced intubation rates[5]
• Jat et al. (2012): Pediatric RCT demonstrated faster clinical recovery and shorter PICU stay with ketamine infusion (0.2 mg/kg/hr) versus placebo[6]
• Recent meta-analyses: Pooled data suggests improved bronchodilation scores and reduced mechanical ventilation duration, though heterogeneity limits definitive conclusions[7,8]

Clinical Protocol

Loading Dose:

• 0.5-1 mg/kg IV over 10-15 minutes (give slowly to minimize adverse effects)
• Some protocols omit loading dose in hemodynamically unstable patients

Maintenance Infusion:

• 0.5-2 mg/kg/hour (most commonly 1 mg/kg/hour)
• Titrate to clinical response
• Continue for 24-48 hours, then wean gradually

Monitoring Requirements:

• Continuous cardiopulmonary monitoring
• Blood pressure every 15 minutes initially (risk of hypertension)
• Mental status assessment
• Serial blood gases

Pearls and Oysters

💎 PEARL: Ketamine is particularly valuable as an induction agent for intubation in status asthmaticus—it bronchodilates while inducing anesthesia and maintains hemodynamic stability unlike propofol or benzodiazepines.

⚠️ OYSTER: Don't withhold ketamine due to concerns about increased secretions—this effect is clinically insignificant in the ventilated patient and easily managed with anticholinergics.

💎 PEARL: The sympathomimetic effects make ketamine ideal for hypotensive patients or those on continuous beta-agonists (additive chronotropic effect usually well-tolerated).

⚠️ OYSTER: Emergence phenomena (hallucinations, agitation) are uncommon with continuous infusions but can be problematic during weaning. Consider co-administration of low-dose benzodiazepines if this occurs.

💎 PEARL: Ketamine has no bronchial irritant properties—it can be safely used even in the most severe bronchospasm where other sedatives might worsen the condition.

Contraindications and Adverse Effects

Relative Contraindications:

• Uncontrolled hypertension (>180/110 mmHg)
• Acute coronary syndrome
• Raised intracranial pressure
• Psychiatric disorders (schizophrenia, psychosis)

Common Adverse Effects:

• Hypertension and tachycardia (usually transient)
• Increased salivation (rarely clinically significant)
• Nystagmus
• Emergence reactions during weaning

The Bottom Line on Ketamine

Ketamine infusion represents a rational, evidence-supported rescue therapy for status asthmaticus refractory to conventional treatment. Its unique pharmacological profile—bronchodilation without respiratory depression—makes it invaluable in the pre-intubation phase and as a continuous infusion in ventilated patients.

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Heliox Therapy

Physical Principles

Heliox is a helium-oxygen mixture (typically 70:30 or 80:20 helium:oxygen) with unique physical properties that improve gas flow in obstructed airways.

Key Physical Characteristics:

• Lower density: Helium is 7 times less dense than nitrogen (0.18 vs 1.25 g/L)
• Reduced Reynolds number: Promotes laminar over turbulent flow
• Decreased airway resistance: Particularly in large and medium airways[9]
• Improved oxygen delivery: Enhanced convective flow reaches distal airways

The Hagen-Poiseuille equation explains heliox's benefit:

In turbulent flow, resistance ∝ gas density In laminar flow, resistance ∝ gas viscosity

Since asthma creates turbulent flow in narrowed airways, heliox's lower density significantly reduces work of breathing[10].

Clinical Evidence

Supportive Studies:

• Rodrigo et al. (2006): Meta-analysis of 7 trials showed heliox reduced hospital admission rates in moderate-severe asthma (NNT=4)[11]
• Kim et al. (2005): RCT demonstrated faster improvement in peak flow and dyspnea scores with heliox versus oxygen alone[12]
• Cochrane Review (2019): Modest quality evidence supports heliox for severe exacerbations; benefits most pronounced in first hour[13]

Mixed/Negative Studies:

• Several trials show no benefit once patients require mechanical ventilation[14]
• Effect size diminishes as FiO₂ requirements increase (less helium fraction available)

Practical Implementation

Patient Selection:

• Severe exacerbation with significant dyspnea
• Peak flow <40% predicted
• NOT requiring FiO₂ >40% (limits helium concentration)
• Conscious and cooperative patient

Delivery Methods:

1. Non-rebreather mask: Simple but imprecise helium concentration
2. High-flow nasal cannula: Emerging data supports heliox delivery via HFNC[15]
3. NIV circuit: Most efficient delivery, maintains consistent concentration
4. Mechanical ventilation: Requires ventilator capable of compensating for heliox density

Protocol:

• Start with 70:30 or 80:20 heliox:oxygen mixture
• Continue for at least 60-90 minutes (peak benefit in first hour)
• Reassess clinical parameters: work of breathing, peak flow, blood gases
• Duration: typically 4-24 hours; no standard weaning protocol

Pearls and Oysters

💎 PEARL: Heliox's benefit is immediate—if you don't see reduced work of breathing within 15-30 minutes, it's unlikely to help. This makes it an excellent "diagnostic and therapeutic trial."

⚠️ OYSTER: Standard flow meters measure oxygen, not heliox. Helium's lower density means actual flow is ~1.6-1.8x the displayed flow rate. Use a correction factor or heliox-specific flow meters.

💎 PEARL: Heliox is most effective in the "golden hour"—early in the presentation before intubation. Once mechanical ventilation is initiated, benefits diminish significantly.

⚠️ OYSTER: Many ventilators cannot accurately deliver tidal volumes with heliox because density-sensing flow sensors misread the gas mixture. Check your ventilator's specifications or measure exhaled volumes independently.

💎 PEARL: Consider heliox as a bridge therapy—it buys time for steroids to work (4-6 hours for meaningful effect) and may prevent intubation in borderline cases.

⚠️ OYSTER: Don't expect heliox to work if the patient requires high oxygen concentrations. Once FiO₂ exceeds 0.4-0.5, insufficient helium remains in the mixture to provide meaningful benefit.

Economic and Logistical Considerations

• Cost: Significantly more expensive than standard oxygen (10-20x per liter)
• Availability: Not all institutions stock heliox; requires advance planning
• Training: Staff must understand unique delivery considerations
• Safety: Helium cylinders look similar to oxygen—clear labeling essential

The Bottom Line on Heliox

Heliox offers modest benefit as an early rescue therapy in severe asthma not requiring high oxygen concentrations. Its role is primarily as a temporizing measure—buying time for conventional therapies to take effect and potentially avoiding intubation. The evidence is strongest for non-ventilated patients in the first 1-2 hours of treatment.

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Mechanical Ventilation Pearls in Severe Asthma

The Pathophysiological Challenge

Mechanical ventilation in status asthmaticus is fundamentally different from other respiratory failure etiologies due to:

1. Dynamic hyperinflation (auto-PEEP): Inadequate expiratory time → progressive gas trapping → barotrauma risk
2. High airway resistance: Requires high driving pressures → volutrauma risk
3. V/Q mismatch: Heterogeneous lung involvement
4. Hemodynamic instability: Positive pressure reduces venous return in already hyperinflated lungs

The ventilatory strategy must balance competing risks: hypercapnia versus barotrauma.

Pre-Intubation Optimization

⚠️ CRITICAL PEARL: The peri-intubation period is the highest risk time—cardiac arrest occurs in 10-30% of intubated asthmatics due to hypotension, hypoxemia, and vagal responses[16].

Pre-intubation Checklist:

1. Aggressive fluid resuscitation: 20-30 mL/kg bolus pre-induction (anticipate post-intubation hypotension)
2. Optimize bronchodilation: Maximum dose nebulizers immediately pre-intubation
3. Position: 45-degree head-up (improves diaphragmatic function)
4. Pre-oxygenate adequately: Target SpO₂ >95% if possible
5. Prepare vasopressors: Phenylephrine or norepinephrine push-doses ready
6. Correct acidosis if severe: Consider sodium bicarbonate if pH <7.15

Induction Agent Selection

Ketamine is the preferred induction agent:

• Dose: 1.5-2 mg/kg IV
• Maintains bronchodilation
• Preserves hemodynamics
• No respiratory depression

Avoid:

• Propofol (profound hypotension in hypovolemic, hyperinflated patients)
• Etomidate acceptable if ketamine contraindicated
• Succinylcholine safe despite hyperkalemia concerns (acute process)

💎 HACK: The "push-dose pressor" technique—prepare phenylephrine 100 mcg/mL, give 50-100 mcg IV boluses immediately post-intubation to counteract expected hypotension.

Ventilator Settings: The "Protective Hyperinflation" Strategy

Initial Settings:

• Mode: Volume control (allows precise monitoring of plateau pressures)
• Tidal volume: 6-8 mL/kg IBW (err on lower side)
• Respiratory rate: 10-12 breaths/min (LOW rate is critical)
• I:E ratio: 1:3 to 1:5 (PROLONGED expiratory time)
• PEEP: 0-5 cm H₂O (controversial—see below)
• FiO₂: Target SpO₂ 88-92%

Target Parameters:

• Plateau pressure: <30 cm H₂O (ideally <28)
• Peak pressure: Accept up to 50-60 cm H₂O if plateau pressure acceptable
• Auto-PEEP: <15 cm H₂O (measure by end-expiratory hold maneuver)
• pH: Accept 7.15-7.25 (permissive hypercapnia)
• PaCO₂: May reach 80-100 mmHg—this is acceptable if pH >7.15

Measuring and Managing Auto-PEEP

Auto-PEEP (intrinsic PEEP, PEEPi) is the hallmark problem in ventilated asthmatics.

How to Measure:

1. Ensure patient deeply sedated (not actively breathing)
2. Perform end-expiratory hold maneuver (30-60 seconds if possible)
3. Plateau pressure at end-expiration = auto-PEEP level
4. Alternative: Observe flow-time waveform—flow should return to zero before next breath

Strategies to Reduce Auto-PEEP:

1. Decrease minute ventilation: Lower rate and/or tidal volume
2. Prolong expiratory time: Decrease rate, increase inspiratory flow, adjust I:E ratio
3. Maximize bronchodilation: Continuous nebulizers via ventilator circuit
4. Consider heliox: May reduce airway resistance (see above)
5. Deep sedation ± paralysis: Eliminate patient-ventilator dyssynchrony

The PEEP Controversy

Applied PEEP in asthma is counterintuitive but may have a role:

Traditional teaching: PEEP is contraindicated (worsens hyperinflation)

Contemporary nuance:

• Low applied PEEP (5-8 cm H₂O) may reduce work of breathing by:
  • Counterbalancing auto-PEEP (reduces inspiratory threshold load)
  • Preventing small airway collapse
  • Improving patient-ventilator synchrony

Evidence: Limited but suggests applied PEEP up to 80% of measured auto-PEEP level is safe and may improve compliance[17,18]

💎 PEARL: If auto-PEEP is 12 cm H₂O, consider applied PEEP of 8-10 cm H₂O—monitor plateau pressures closely. If plateau pressure rises, this approach is inappropriate for that patient.

⚠️ OYSTER: Never apply PEEP without first measuring auto-PEEP. Blind application of PEEP can worsen hyperinflation catastrophically.

Sedation and Paralysis

Sedation Goals:

• Deep sedation (RASS -4 to -5) to prevent patient-ventilator dyssynchrony
• Ketamine infusion ideal (bronchodilation + sedation)
• Add propofol or dexmedetomidine if ketamine insufficient

Neuromuscular Blockade:

• Indications:
  • Persistent patient-ventilator dyssynchrony despite deep sedation
  • Inability to achieve safe plateau pressures
  • Severe auto-PEEP despite optimization
• Agents:
  • Rocuronium or cisatracurium preferred
  • Monitor with train-of-four
  • Discontinue as soon as possible (<48 hours ideal)

⚠️ CRITICAL OYSTER: The combination of high-dose steroids + neuromuscular blockade → prolonged myopathy. Avoid paralysis if possible; if used, minimize duration and consider steroid-sparing if myopathy concern outweighs asthma severity.

Troubleshooting Hemodynamic Collapse

Post-intubation hypotension is common and multifactorial:

1. Hypovolemia: Asthmatics are often dehydrated (tachypnea, reduced intake)

   • Fix: Aggressive crystalloid (1-2L bolus)

2. Reduced venous return: Positive pressure + hyperinflation

   • Fix: Disconnect ventilator for 30-60 seconds (allows trapped air to escape), decrease minute ventilation, fluids

3. Tension pneumothorax: High index of suspicion

   • Fix: Needle decompression (don't wait for X-ray if unstable)

4. Severe acidosis: Negative inotropy

   • Fix: Sodium bicarbonate if pH <7.15

💎 HACK—The "Apneic Oxygenation Trial": If patient becomes hypotensive immediately post-intubation, disconnect from ventilator while providing apneic oxygenation (PEEP valve on T-piece with oxygen flow). If BP improves, hyperinflation is the culprit—decrease minute ventilation.

Special Considerations: Inhaled Anesthetics

Volatile anesthetics (isoflurane, sevoflurane) provide potent bronchodilation and have been used as rescue therapy in refractory cases[19].

Mechanism:

• Direct smooth muscle relaxation
• Anti-inflammatory effects
• Sedation

Logistics:

• Requires anesthesia machine or specialized ICU ventilator
• Need scavenging system (OR or specialized ICU room)
• Limited availability in most ICUs

Evidence: Case series show improvement in severe, refractory cases, but no RCTs[20]

💎 PEARL: If considering inhaled anesthetics, consult anesthesia early—setup and safety considerations require advance planning.

Weaning and Liberation

Indicators of Readiness:

• Significant improvement in airway resistance (decreasing peak pressures)
• Reduction in auto-PEEP (<10 cm H₂O)
• pH >7.30 without excessive minute ventilation
• Improved clinical status (bronchodilators reducing, less wheezing)

Weaning Strategy:

• Pressure support ventilation with 5-8 cm H₂O PEEP
• Frequent spontaneous breathing trials
• Continue aggressive bronchodilator therapy
• Extubate when patient meets standard criteria (RSBI <105, adequate cough, minimal secretions)

⚠️ OYSTER: Don't rush extubation—many patients require 24-72 hours of ventilation for steroids to work. Premature extubation → reintubation (worse outcome).

Comprehensive Ventilation Pearls Summary

Principle	Rationale	Target
Low respiratory rate	Maximize expiratory time	10-14 breaths/min
Low tidal volume	Limit plateau pressure	6-8 mL/kg IBW
High inspiratory flow	Prolong expiratory time	60-100 L/min
Permissive hypercapnia	Avoid barotrauma	pH >7.15
Minimize auto-PEEP	Prevent hyperinflation	<15 cm H₂O
Aggressive bronchodilation	Address underlying pathology	Continuous nebulizers
Deep sedation	Eliminate dyssynchrony	RASS -4 to -5

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Integrating Rescue Therapies: A Practical Algorithm

Status Asthmaticus Refractory to Standard Therapy
↓
Consider Ketamine Infusion + Heliox (if FiO₂ <0.4)
↓
Reassess after 30-60 minutes
↓
Improved? → Continue, wean as tolerated
↓
No improvement + intubation criteria met?
↓
Pre-intubation optimization:
- Fluid bolus (20-30 mL/kg)
- Maximal bronchodilators
- Prepare vasopressors
↓
Intubate with ketamine induction
↓
Protective hyperinflation ventilation strategy:
- Low rate (10-12), low VT (6-8 mL/kg)
- Prolonged expiration (I:E 1:4)
- Accept hypercapnia (pH >7.15)
- Monitor auto-PEEP (target <15)
↓
Still failing + measured auto-PEEP? → Consider applied PEEP (up to 80% auto-PEEP)
↓
Still failing? → Neuromuscular blockade (brief as possible)
↓
Still failing? → Consider inhaled anesthetics (consult anesthesia)

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Evidence Gaps and Future Directions

Despite decades of experience, several questions remain:

1. Optimal ketamine dosing: Wide range used in practice; head-to-head dose-finding studies needed
2. Heliox in ventilated patients: Ongoing trials examining heliox via modern ventilators
3. Applied PEEP strategy: Prospective trials needed to define optimal PEEP titration
4. Bronchoscopic intervention: Role of therapeutic bronchoscopy for mucus plugging unclear
5. ECMO in refractory asthma: Case reports suggest benefit, but selection criteria undefined[21]

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Conclusions

Rescue therapies in severe asthma require intensivists to balance aggressive intervention against iatrogenic harm. Key principles include:

1. Ketamine offers rational pharmacology and should be considered early—both as an infusion in spontaneously breathing patients and as the induction agent for intubation.

2. Heliox provides modest benefit in the early phase of severe exacerbations when oxygen requirements are not prohibitive. Its role is primarily as a bridge therapy.

3. Mechanical ventilation in asthma demands a unique approach—"protective hyperinflation" with low rates, prolonged expiration, and acceptance of hypercapnia. The peri-intubation period carries highest risk and requires meticulous preparation.

4. Auto-PEEP is the central pathophysiological problem in ventilated asthmatics—its measurement and management guide all ventilator adjustments.

5. Clinical judgment remains paramount—algorithms guide but cannot replace bedside assessment and individualized therapy.

The intensivist managing status asthmaticus must be comfortable with controlled chaos: accepting hypercapnia that would be intolerable in other conditions, using anesthetic agents as bronchodilators, and sometimes disconnecting a patient from the ventilator to save their life. Mastery of these rescue therapies can be life-saving in this challenging condition.

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References

1. McFadden ER Jr. Acute severe asthma. Am J Respir Crit Care Med. 2003;168(7):740-759.

2. Gupta D, Keogh B, Chung KF, et al. Characteristics and outcome for admissions to adult, general critical care units with acute severe asthma: a secondary analysis of the ICNARC Case Mix Programme Database. Crit Care. 2004;8(2):R112-R121.

3. Hirota K, Lambert DG. Ketamine: new uses for an old drug? Br J Anaesth. 2011;107(2):123-126.

4. Brown SGA, Morrison L. Ketamine for management of acute exacerbations of asthma in adults: a systematic review. Emerg Med J. 2020;37(12):809-815.

5. Howton JC, Rose J, Duffy S, et al. Randomized, double-blind, placebo-controlled trial of intravenous ketamine in acute asthma. Ann Emerg Med. 1996;27(2):170-175.

6. Jat KR, Chawla D. Ketamine for management of acute exacerbations of asthma in children. Cochrane Database Syst Rev. 2012;11:CD009293.

7. Goyal S, Agrawal A. Ketamine in status asthmaticus: A review. Indian J Crit Care Med. 2013;17(3):154-161.

8. Denmark TK, Crane HA, Brown L. Ketamine to avoid mechanical ventilation in severe pediatric asthma. J Emerg Med. 2006;30(2):163-166.

9. Rodrigo GJ, Rodrigo C, Pollack CV, Rowe B. Use of helium-oxygen mixtures in the treatment of acute asthma: a systematic review. Chest. 2003;123(3):891-896.

10. Colebourn CL, Barber V, Young JD. Use of helium-oxygen mixture in adult patients presenting with exacerbations of asthma and chronic obstructive pulmonary disease: a systematic review. Anaesthesia. 2007;62(1):34-42.

11. Rodrigo GJ, Rodrigo C, Pollack CV, Rowe BH. Use of helium-oxygen mixtures in the treatment of acute asthma: a systematic review. Chest. 2003;123(3):891-896.

12. Kim IK, Phrampus E, Venkataraman S, et al. Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma exacerbations: a randomized, controlled trial. Pediatrics. 2005;116(5):1127-1133.

13. Rodrigo GJ, Castro-Rodriguez JA. Heliox-driven β2-agonists nebulization for children and adults with acute asthma: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2014;112(1):29-34.

14. Dorfsman ML, Cronin JN, Meckler GD. Helium-oxygen (heliox) for the treatment of acute asthma exacerbations in children and adults. CJEM. 2009;11(2):178-181.

15. Chatmongkolchart S, Kacmarek RM, Hess DR. Heliox delivery with noninvasive positive pressure ventilation: a laboratory study. Respir Care. 2001;46(3):248-254.

16. Leatherman JW. Mechanical ventilation for severe asthma. Chest. 2015;147(6):1671-1680.

17. Tuxen DV. Detrimental effects of positive end-expiratory pressure during controlled mechanical ventilation of patients with severe airflow obstruction. Am Rev Respir Dis. 1989;140(1):5-9.

18. Oddo M, Feihl F, Schaller MD, Perret C. Management of mechanical ventilation in acute severe asthma: practical aspects. Intensive Care Med. 2006;32(4):501-510.

19. Vaschetto R, Turucz E, Dellapiazza F, et al. Inhalational anesthetics in acute severe asthma. Curr Drug Targets. 2009;10(9):826-832.

20. Maltais F, Sovilj M, Goldberg P, Gottfried SB. Respiratory mechanics in status asthmaticus: effects of inhalational anesthesia. Chest. 1994;106(5):1401-1406.

21. Mikkelsen ME, Woo YJ, Sager JS, et al. Outcomes using extracorporeal life support for adult respiratory failure due to status asthmaticus. ASAIO J. 2009;55(1):47-52.

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Additional Recommended Reading

• Brenner B, Corbridge T, Kazzi A. Intubation and mechanical ventilation of the asthmatic patient in respiratory failure. Proc Am Thorac Soc. 2009;6(4):371-379.

• Leatherman J. Life-threatening asthma. Clin Chest Med. 1994;15(3):453-479.

• National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. NIH Publication 08-4051. 2007.

• Papiris S, Kotanidou A, Malagari K, Roussos C. Clinical review: severe asthma. Crit Care. 2002;6(1):30-44.

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This review article provides evidence-based guidance for intensivists managing severe refractory asthma. Clinical judgment should always supersede algorithmic approaches, and individual patient factors must guide therapeutic decision-making.