Severe asthma: phenotypes, biologics, and ICU management update · ICU Topics

Cinematic clinical scene of a severe asthma patient with a biologics treatment chart on a screen showing anti-IgE and anti-IL-5 pathways, a blood eosinophil count, a FeNO result, an inhaler and a spacer on the bedside table, clinical-blue lighting, no faces, no text — FigureSevere asthma phenotypes — Type 2 (eosinophilic, allergic, steroid-responsive) drives the biologic era: anti-IgE, anti-IL-5, anti-IL-4 receptor alpha. Biologics halve exacerbations but are prophylactic only — never for the acute attack.

Asthma phenotypes — T2 vs non-T2

Feature	Type 2 (T2) high	Non-T2 low
Inflammatory profile	EOSINOPHILIC (blood/sputum eosinophils high)	NEUTROPHILIC or paucigranulocytic
Biomarkers	FeNO high (>50 ppb), blood eos >300, sputum eos >2%	FeNO low, blood/sputum eos low, neutrophils high
Triggers	ALLERGENS (atopic), viral infections	Infection, pollution, oxidative stress, obesity
Onset	EARLY life (childhood atopic)	ADULT onset, often severe from start
Steroid response	GOOD (steroid-responsive)	POOR (steroid-resistant)
Biologics	EFFECTIVE (anti-IL-5, anti-IgE, anti-IL-4Rα)	INEFFECTIVE (no target)
Treatment	ICS + LABA + biologic (if severe)	Difficult — macrolides (azithromycin), avoid steroids, treat comorbidities

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Management of acute severe asthma in ICU

Assess severity — silent chest, exhaustion, altered consciousness, SpO2 <92%, PEF <33%, PaCO2 normal/rising (should be low) = LIFE-THREATENING
Oxygen — target SpO2 93-95%. High-flow if needed
Bronchodilators — SALBUTAMOL 5 mg NEB (or IV 250 mcg) + IPRA TROPIUM 0.5 mg NEB, repeated/continuous
Systemic steroids — HYDROCORTISONE 100 mg IV (or prednisolone 40-50 mg PO) — takes 4-6h to work, give EARLY
Magnesium sulphate — 2 g IV over 20 min (smooth muscle relaxant). Can repeat
If deteriorating — INTUBATE: ketamine induction (bronchodilator), rocuronium, largest ETT. VENTILATE: permissive hypercapnia (allow PaCO2 to rise — avoid high pressures → barotrauma), low rate (4-6), long expiration, low tidal volume (4-6 mL/kg), PEEP 0-5
Refractory — IV salbutamol infusion, volatile anaesthetics (isoflurane/sevoflurane — bronchodilation), ECMO (last resort), helium-oxygen (heliox — reduces work of breathing)
Look for triggers — infection (treat), pneumothorax (asymmetric breath sounds — decompress), aspiration

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SAQ — Life-threatening asthma with dynamic hyperinflation on ventilation

10 minutes · 10 marks

A 28-year-old woman with a long history of severe allergic asthma (on high-dose inhaled corticosteroid and long-acting beta-agonist plus a long-acting muscarinic antagonist, with multiple ICU admissions) is brought to the emergency department with 6 hours of progressive severe breathlessness unresponsive to her salbutamol inhaler. On arrival she is sitting upright, unable to speak, diaphoretic and visibly exhausted; RR 32 with accessory-muscle use and prolonged expiration, HR 132, BP 152/92, SpO2 88 per cent on 15 L oxygen via non-rebreather, peak expiratory flow 90 L/min (15 per cent predicted). Chest is silent bilaterally (no wheeze, minimal air entry). Arterial blood gas on 15 L NRBM: pH 7.20, PaCO2 64 mmHg, PaO2 58 mmHg, HCO3 24 mmol/L. She is intubated with ketamine and rocuronium and transferred to ICU.

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SAQ — Severe T2 asthma phenotype and selection of a biologic

10 minutes · 10 marks

A 42-year-old woman with severe asthma since childhood (atopic, with allergic rhinitis and eczema) has had 4 exacerbations requiring oral corticosteroids in the past 12 months and one ICU admission for a near-fatal attack. She is on GINA Step 5 therapy: high-dose inhaled fluticasone-vilanterol plus tiotropium, a leukotriene receptor antagonist (montelukast), and 5 mg prednisolone daily as maintenance. She has steroid-induced osteopenia. Investigations: total IgE 320 IU/mL, positive specific IgE to house dust mite and cat dander, blood eosinophil count 480 x10^6/L, FeNO 62 ppb. FEV1 68 per cent predicted (post-bronchodilator 78 per cent). She does not smoke. The respiratory team is considering a biologic.

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Clinical pearls

High-yield severe asthma points for CICM/FFICM exam

PaCO2 is the most important blood gas marker in acute asthma. Normally, asthma causes HYPOcapnia (hyperventilation from hypoxaemic drive). If PaCO2 is NORMAL (4.5-6 kPa) or RISING → patient is FATIGUING → respiratory arrest imminent → prepare for intubation. This is a critical warning sign.[4] }
Silent chest = no air movement = pre-arrest. Wheeze indicates SOME air movement (turbulent flow through narrowed airways). ABSENCE of wheeze ('silent chest') means NO air movement — patient cannot ventilate. This is life-threatening — intubate.[4] }
Biologics are PROPHYLACTIC, not for acute attacks. They take WEEKS to work (deplete eosinophils, reduce IgE). NEVER give a biologic for an acute asthma attack. Continue background biologic during exacerbation (don't stop), but treat exacerbation with standard therapy (SABA, steroids).[3] }
Anti-IL-5 biologics (mepolizumab, benralizumab) for eosinophilic asthma. Mepolizumab (anti-IL-5) — blocks IL-5 → reduces eosinophil production. Benralizumab (anti-IL-5 receptor) — depletes eosinophils (antibody-dependent cellular cytotoxicity). Both reduce exacerbations 50-70%, improve FEV1, allow steroid reduction. Eligibility: blood eos >300.[5] }
Omalizumab (anti-IgE) for severe allergic asthma. Binds free IgE → reduces allergic response. Eligibility: IgE 30-700 IU/mL, positive skin prick test or specific IgE to perennial aeroallergen. Reduces exacerbations 40-50%. Given SC every 2-4 weeks (dose by weight + IgE).[3] }
Dupilumab (anti-IL-4Rα) — newest, broadest T2 biologic. Blocks IL-4 and IL-13 signalling (shared receptor). Reduces exacerbations 50-70%, improves FEV1, allows steroid reduction. Works for BOTH allergic and eosinophilic asthma (broad T2 coverage). Also approved for atopic dermatitis, EoE. Eligibility: blood eos >150 OR FeNO >25.[6] }
Non-T2 asthma is DIFFICULT to treat. Neutrophilic asthma (IL-17, Th17 mediated) — steroids less effective, biologics don't work (no T2 target). Options: azithromycin 250 mg 3x/week (anti-inflammatory), treat comorbidities (obesity, GERD, OSA), avoid steroids (worsen over time).[2] }
Magnesium sulphate for acute severe asthma. 2 g IV over 20 minutes. Mechanism: blocks calcium channels → smooth muscle relaxation → bronchodilation. Evidence: reduces admission, improves FEV1 (Cochrane meta-analysis). Can repeat. Side effects: flushing, hypotension (give slowly).[4] }
Mechanical ventilation in asthma: permissive hypercapnia. Goal: avoid high airway pressures (barotrauma, pneumothorax). Use: LOW rate (allow expiration), LOW tidal volume (4-6 mL/kg), LOW/zero PEEP, LONG expiratory time. Accept HIGH PaCO2 (up to 10-12 kPa) if pH >7.2 (permissive hypercapnia). Sedate deeply + paralyse (prevent dyssynchrony).[4] }
Ketamine is the preferred induction agent for asthmatic intubation. Ketamine causes BRONCHODILATION (sympathomimetic, increases catecholamines). Other induction agents (propofol, thiopental) can worsen bronchospasm (histamine release, vasodilation). Ketamine 1-2 mg/kg IV + rocuronium 1.2 mg/kg. Largest ETT available (reduces resistance).[4] }
Dynamic hyperinflation (breath-stacking) is the danger in ventilated asthma. In obstructed airways, exhalation is incomplete → air TRAPS in alveoli → increased intrathoracic pressure → reduced venous return → HYPOTENSION. Solution: DECREASE rate (more time to exhale), DISCONNECT circuit (let air out). If BP rises after disconnection → dynamic hyperinflation confirmed.[4] }
Pneumothorax in ventilated asthma — EMERGENCY. High airway pressures → alveolar rupture → pneumothorax → tension (hypotension, asymmetric breath sounds). TREAT: immediate needle decompression (2nd intercostal, midclavicular), then chest drain. UNILATERAL breath sounds + hypotension in ventilated asthma = pneumothorax until proven otherwise.[4] }
Volatile anaesthetics for refractory bronchospasm. Isoflurane, sevoflurane (inhaled anaesthetics) are POTENT bronchodilators. Used in refractory status asthmaticus (not responding to standard therapy). Requires anaesthetic machine/vaporiser in ICU. ECMO is the last resort (refractory despite all else).[4] }
Biologic eligibility and step-up criteria. Severe asthma (despite high-dose ICS + LABA + LTRA) + T2 phenotype (eos >300, FeNO >25, or allergic) → consider biologic. Choice: dupilumab (broad T2), mepolizumab/benralizumab (eosinophilic), omalizumab (allergic). Biologics reduce exacerbations, improve quality of life, allow steroid taper.[1] }

Red flags

Prognosis

Biologics for severe asthma — key trials

Mepolizumab (MENSA, SIRIUS): anti-IL-5. Reduced exacerbations ~50%, improved FEV1, allowed oral steroid reduction. Benralizumab (SIROCCO, CALIMA): anti-IL-5R (depletes eosinophils). Reduced exacerbations 28-51% (eos ≥300 subgroup). Dupilumab (LIBERTY ASTHMA QUEST): anti-IL-4Rα. Reduced exacerbations 48%, improved FEV1 130 mL. Works for eos ≥150 AND eos <150 (broader). Omalizumab (EXTRA, INNOVATE): anti-IgE. Reduced exacerbations 40-50% in allergic asthma. [1]

Biologics reduce exacerbations 40-70%, improve FEV1, quality of life, allow steroid taper. NOT curative — stop and asthma returns. Annual cost: $15,000-30,000.

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Phenotypes — deeper characterisation

T2 asthma: Th2-high / eosinophilic

Non-T2 asthma: Th2-low / neutrophilic

Severe Asthma Research Program (SARP) cluster analysis (Moore 2010)

Cluster	Onset	Atopy	Lung function	Inflammation	Steroid use	Key feature
1. Mild-to-moderate allergic	Early childhood	Yes, high IgE	Near normal	Eosinophilic	Rare	Easily controlled, common
2. Moderate allergic, treatable	Early adult	Yes	Mild obstruction	Eosinophilic	Occasional OCS	Most common (40%)
3. Severe allergic	Childhood	Yes, very high IgE	Moderate obstruction (FEV1 60-80%)	Eosinophilic	Frequent OCS	T2-dominant, biologic-responsive
4. Severe late-onset eosinophilic	Adult (>40 yrs)	Mixed	Severe obstruction (FEV1 <60%)	Eosinophilic ± neutrophilic	High OCS	Late-onset eosinophilic; best anti-IL-5 target
5. Severe fixed obstruction	Adult	Low atopy	Very severe (FEV1 <50%), fixed	Mixed/paucigranulocytic	High OCS	Airway remodelling dominant; biologics ineffective

^{SARP enrolled 738 patients with severe asthma. Clusters 3–5 represent the severe phenotype most relevant to ICU. Late-onset eosinophilic (cluster 4) is the canonical anti-IL-5 responder.[17]}

Paucigranulocytic asthma

A distinct phenotype with low sputum eosinophils AND low neutrophils. Typically obese women with severe fixed obstruction, low FeNO, normal IgE, no atopy, low serum eosinophils. Least responsive to anti-inflammatory treatment — ICS may not help; no biologic works. Management is bronchodilator optimisation (LABA + LAMA), treatment of obesity/GERD/OSA, pulmonary rehabilitation, and bronchial thermoplasty in selected cases.[18]

Mixed granulocytic asthma

Both sputum eosinophils (>2–3%) and neutrophils (>60–76%) elevated. Hardest phenotype to treat — T2 biologics may help the eosinophilic component (partial response), and azithromycin may help the neutrophilic component. Often overlaps with obesity, smoking, and chronic infection (bronchiectasis). Approach: maximise ICS/LABA + add LAMA, treat bronchiectasis with antibiotics, address obesity, trial azithromycin 250 mg three times weekly. [1]

Biomarkers — practical interpretation

T2 biomarkers — cutoffs, meaning and biologic prediction

Biomarker	T2-high cutoff	What it tells you	Predicts response to
Blood eosinophils	≥300/μL (≥150 with caveats)	Eosinophilic inflammation; IL-5 activity	Mepolizumab, benralizumab, dupilumab
Sputum eosinophils	≥2–3%	Gold-standard airway inflammation; poorly available outside specialist centres	All anti-IL-5; steroid responsiveness
FeNO (fractional exhaled NO)	>50 ppb adults (>35 ppb children)	IL-13-driven epithelial iNOS induction; steroid-sensitive inflammation	Dupilumab, tezepelumab
Total serum IgE	30–700 IU/mL (omalizumab window)	Allergic/atopic burden	Omalizumab
Specific IgE / skin prick	Positive to ≥1 perennial aeroallergen	Allergic sensitisation	Omalizumab
Periostin (POSTN)	>50 ng/mL	IL-13-induced epithelial biomarker; correlate of airway remodelling	Research only (lebrikizumab/tralokinumab failed)
DPP-4, CLCA1, YKL-40	Variable	Less validated T2/T17 markers	Research only
Urinary bromotyrosine	Variable	Eosinophil activation (oxidative stress footprint)	Research only
Sputum IL-13 / blood eotaxin-3	Variable	Subset characterisation	Research only

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Biomarker-based biologic selection algorithm (British Thoracic Society / GINA)

Confirm severe asthma — despite high-dose ICS/LABA + LTRA + optimised adherence AND comorbidities for ≥6 months; documented at least one severe exacerbation in the prior year.
Phenotype with minimum dataset: blood eosinophils (two separate values within 12 months), FeNO, total IgE, specific IgE or skin prick test to common aeroallergens. Induced sputum eosinophils if locally available.
Washout considerations: blood eosinophils fall 1–2 weeks after an OCS burst — recheck 2–4 weeks post-burst. FeNO falls within days of starting OCS. Sputum induction is also steroid-suppressible.
If blood eos ≥300/μL AND/OR FeNO >25 ppb → T2-high pathway → dupilumab, mepolizumab, benralizumab, tezepelumab all candidates.
If total IgE 30–700 IU/mL + positive aeroallergen test → add omalizumab option (especially if allergic phenotype with frequent seasonal exacerbations or polysensitisation).
If both eos and FeNO low with neutrophilic sputum → T2-low pathway: NO biologic; azithromycin 250 mg 3×/week; address obesity/OSA/GERD/smoking; consider OCS taper.
If T2-high but refractory to anti-IL-5 (≈30–40% of patients) → switch class to dupilumab (anti-IL-4Rα, different mechanism) or to tezepelumab (anti-TSLP, broadest upstream blockade). Tezepelumab is the only currently-approved biologic that works across ALL phenotypes (eos-high AND eos-low, allergic AND non-allergic).[16]
Reassess at 4–12 months: response criteria = ≥50% reduction in exacerbations + ACQ-5 ↓ ≥0.5 + AQLQ ↑ ≥0.5 + FEV1 ↑ ≥100 mL + ≥50% OCS reduction. Non-responders: stop after 12 months, switch class.

Biomarker interpretation pitfalls

Blood eosinophils fluctuate widely: a single value is unreliable. Two values within 12 months, eos ≥300 on either, is the standard eligibility criterion (BTS / GINA). Steroids, smoking, and eosinophil-depleting biologics all lower the count.
FeNO reflects IL-13/iNOS activity, NOT eosinophilia directly. FeNO <25 with eos ≥300 is a known discordant pattern — still eligible for anti-IL-5 but less likely to respond to dupilumab monotherapy. Conversely, FeNO high + eos low predicts dupilumab response.
Periostin was the darling biomarker of lebrikizumab trials (LUTE/LAVOLTA) but the lebrikizumab programme ultimately failed; periostin is NOT routinely measured in clinical practice. Useful as an exam-only fact — a "biomarker of airway remodelling".
Total IgE must be paired with weight for omalizumab dosing (dose tables by IgE × body weight, SC every 2–4 weeks). IgE >700 IU/mL → omalizumab dose becomes impractical/prohibitive. Also: total IgE falls on omalizumab (free IgE suppressed) — do not retest on therapy.
Sputum induction (hypertonic saline) is the gold-standard airway inflammatory test but is technically demanding and not available outside specialist centres. Where available, ≥2–3% eosinophils predicts steroid responsiveness and biologic response.
A "T2-high" patient on long-term OCS often has artificially low biomarkers — consider an OCS taper before phenotyping, OR phenotype based on historic highest values.

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Biologics — comprehensive review

Approved biologics for severe asthma — at a glance

Drug	Target	Mechanism	Route/dose	Key trials	Exacerbation ↓	FEV1 ↑	Notes
Omalizumab	IgE (Ce3 domain)	Reduces free IgE, downregulates FcεRI on mast cells/basophils	SC q2–4 wk by IgE + weight	INNOVATE, EXTRA	40–50%	30–60 mL	Allergic asthma only; IgE 30–700 IU/mL; rare anaphylaxis
Mepolizumab	IL-5 (ligand)	Blocks IL-5 → ↓eosinophil maturation	SC 100 mg q4 wk	DREAM, MENSA, SIRIUS	~50%	~100 mL	Eos ≥150; OCS-sparing; also approved for EGPA, HES, CRSwNP
Reslizumab	IL-5 (ligand)	Blocks IL-5	IV 3 mg/kg q4 wk	2× Phase III	50–54%	~100 mL	IV infusion; anaphylaxis ~0.3% — monitor post-dose; eos ≥400
Benralizumab	IL-5Rα (receptor α-chain)	ADCC → near-complete eosinophil depletion	SC 30 mg q4 wk ×3 then q8 wk	SIROCCO, CALIMA, ZONDA	28–51% (eos ≥300)	116–159 mL	Most profound eosinophil depletion; q8 wk maintenance dosing
Dupilumab	IL-4Rα	Blocks IL-4 AND IL-13 signalling (shared receptor)	SC 200/300 mg q2 wk	LIBERTY QUEST, VENTURE	48–65%	130–320 mL	Broadest T2 coverage; works in eos <150; also AD, EoE, CRSwNP
Tezepelumab	TSLP (epithelial alarmin)	Blocks TSLP → ↓downstream Th2 AND Th17 cytokines	SC 210 mg q2 wk	PATHWAY, NAVIGATOR, SOURCE	56–66%	110–150 mL	Works ACROSS ALL phenotypes (eos-high AND eos-low); first alarmin blocker

^{All reduce exacerbations 40–70% but NONE reverse fixed obstruction. All are PROPHYLACTIC — none for acute attacks. Annual cost: $15,000–30,000.[3][19]}

Omalizumab — INNOVATE (Humbert 2005)

Design: DBPCT, n=419, moderate-to-severe persistent allergic asthma uncontrolled on ICS. Result: 26% reduction in clinically significant exacerbations (p<0.05); ICS dose reduction; improved quality-of-life scores. Pivotal for regulatory approval of anti-IgE in severe allergic asthma.[7]

EXTRA trial (Hanania 2012): enriched responder analysis — benefit greatest in eos ≥260, FeNO ≥19.5 ppb, IgE 30–700 — a T2-enriched subgroup.

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Mepolizumab — DREAM / MENSA / SIRIUS (Pavord, Ortega, Bel 2012–14)

DREAM (Pavord, Lancet 2012): dose-ranging IV mepolizumab — reduced sputum/blood eosinophils and exacerbations ~50%. Proof of concept for anti-IL-5 class.[8]
MENSA (Ortega, NEJM 2014): SC 75/300 mg vs placebo. 47–53% reduction in clinically significant exacerbations; reduced ER visits and hospitalisations; FEV1 +100 mL.[9]
SIRIUS (Bel, NEJM 2014): steroid-sparing trial — 100 mg SC mepolizumab allowed 50% reduction in OCS dose while maintaining asthma control. First anti-IL-5 to show OCS-sparing effect.[10]

Bottom line: mepolizumab established anti-IL-5 as a class for eosinophilic severe asthma. Now also approved for EGPA, hypereosinophilic syndrome, and CRSwNP.

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Benralizumab — SIROCCO / CALIMA / ZONDA (Bleecker, FitzGerald, Nair 2016–17)

SIROCCO + CALIMA (twin Phase III, n=2510 + 1306): benralizumab reduced annualised exacerbation rate 28–51% in eos ≥300 subgroup; FEV1 +116–159 mL. Stronger signal with higher baseline eos.[5][11]
ZONDA (Nair, NEJM 2017): OCS-sparing trial — benralizumab allowed 75% OCS dose reduction (vs 25% placebo) and 52% of patients stopped OCS entirely.[12]

Distinguishing feature: near-complete eosinophil depletion (median reduction to zero in responders) via antibody-dependent cellular cytotoxicity (ADCC) through NK cells binding the afucosylated Fc. Q8-week maintenance dosing after the loading phase — the most convenient schedule.

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Dupilumab — LIBERTY ASTHMA QUEST / VENTURE (Castro, Rabe 2018)

QUEST (Castro, NEJM 2018; n=1902): 48% reduction in severe exacerbations; FEV1 +130–320 mL; benefit even in eos <150 subgroup (though strongest in eos ≥300).[13]
VENTURE (Rabe, NEJM 2018; n=210): OCS-dependent severe asthma — dupilumab reduced median OCS dose by 70% (vs 42% placebo); 48% stopped OCS vs 5% placebo. Worked regardless of baseline eos.[14]
TRAVERSE (5-year open-label extension): sustained efficacy, no new safety signals; conjunctivitis and transient eosinophilia the most common AEs (especially in atopic dermatitis patients).

Distinguishing feature: broadest T2 coverage (allergic + eosinophilic). Only biologic that improves OCS dependence across both eosinophilic AND paucieosinophilic subgroups. Fastest onset (2–4 weeks). Also approved for atopic dermatitis, EoE, CRSwNP, prurigo nodularis, COPD with type-2 inflammation.

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Tezepelumab — PATHWAY / NAVIGATOR / SOURCE (Corren 2017, 2021–22)

PATHWAY (Corren, NEJM 2017; Phase IIb): tezepelumab (anti-TSLP) reduced exacerbations 61–71% across ALL baseline eos/FeNO subgroups — first biologic to do so.[15]
NAVIGATOR (NEJM 2021; n=1067): 56% reduction in annualised exacerbation rate (0.93 vs 2.10); FEV1 +120 mL. Benefit preserved in eos <150 (35% reduction) and FeNO <25 subgroups.[16]
SOURCE (NEJM 2022): OCS-sparing — missed primary endpoint overall but showed benefit in eos ≥150 / FeNO ≥20 subgroup.

Distinguishing feature: TSLP sits at the TOP of the inflammatory cascade (released by damaged epithelium on any trigger — viral, allergen, pollutant, oxidative) — blocking it suppresses BOTH T2 (IL-4/5/13) AND T17 (IL-17) pathways. Works in T2-high AND T2-low. The "treat-everyone" biologic. First-in-class alarmin blocker.

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Failed or niche biologics (exam facts only)

Drug	Target	Status / why it failed
Lebrikizumab	IL-13	Phase III (LAVOLTA) failed; periostin-high subgroup benefit lost in replication
Tralokinumab	IL-13	STRATOS / STRATOS-2 negative; only worked in sputum IL-13+ subgroup
Brodalumab	IL-17RA	Phase II failed; neutrophilic asthma more complex than single cytokine
Fevipiprant	DP2 (CRTh2)	Phase III (LUSTER) negative
Canakinumab	IL-1β	No clinical benefit in severe asthma (explored for overlap with atherosclerosis)
Mepolizumab for COPD	IL-5	Negative — eosinophilia in COPD ≠ same biology as asthma
Benralizumab for COPD (GALATHEA, TERRANOVA)	IL-5Rα	Negative — reinforces that eosinophil depletion does not improve COPD
Mesenchymal stem cells	Immunomodulatory	Phase I/II only; not approved

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ICU management — acute severe asthma (status asthmaticus)

Educational ICU pathway for acute severe asthma and phenotype-guided biologic selection showing bronchodilators steroids magnesium ventilation and outpatient biologic targets — FigureTwo time-scales of care — the ICU attack needs oxygen, continuous bronchodilators, steroids, magnesium and ventilatory strategy; biologics are preventive after phenotyping, never acute rescue.

Initial pharmacotherapy

Drug doses in acute severe asthma (adult)

Drug	Dose / route	Onset	Key notes
Oxygen	Titrate to SpO2 93–95%	Immediate	Avoid 100% (absorption atelectasis); target PaO2 >60 mmHg
Salbutamol (albuterol)	5 mg NEB q15–20 min ×3, then continuous 10–15 mg/h; or IV 250 μg load then 5–20 μg/min	5–15 min	β2 agonist; watch lactate, tachycardia, tremor, hypokalaemia
Ipratropium bromide	0.5 mg NEB q4–6h with salbutamol	15–30 min	Anticholinergic; synergistic with salbutamol; reduces admission (Cochrane)
Hydrocortisone	100 mg IV q6–8h (or methylprednisolone 40–80 mg IV q12h)	4–6 h (peak 12 h)	Give EARLY — even before confirmation if severely unwell
Prednisolone	40–50 mg PO daily (if tolerating PO)	4–6 h	Equivalent efficacy to IV if absorbing
Dexamethasone	16 mg/day ×2–5 days	Hours	Non-inferior to prednisolone (REASTHMA); fewer relapses
Magnesium sulphate	2 g IV over 20 min (1.2–2 g); may repeat once	5–30 min	Smooth muscle relaxant; side-effects: flushing, hypotension, areflexia (rare)
Ketamine (induction)	1–2 mg/kg IV; infusion 0.5–1 mg/kg/h for refractory bronchospasm	30–60 s	Bronchodilator via catecholamine release; preserves spontaneous ventilation
IV salbutamol infusion	5–20 μg/min, titrate	5 min	Reserved for refractory; risks: lactic acidosis, tachyarrhythmia, hypokalaemia, ischaemia
Montelukast	10 mg IV (where available) or 10 mg PO/NG	Hours	LTRA; limited acute evidence; especially useful in AERD phenotype
Aminophylline	5 mg/kg loading if not on oral theophylline, then 0.5 mg/kg/h	30–60 min	Narrow therapeutic window; risks: arrhythmia, seizures; rarely used now
Volatile anaesthetics	Isoflurane 0.5–2% or sevoflurane 1–3% via anaesthetic machine	Minutes	Refractory bronchospasm; needs anaesthetic delivery/scavenging in ICU
Heliox (70:30 or 80:20 He:O2)	By NIV mask or ETT; up to 40% FIO2 if 70:30 mix	Immediate	Lower gas density → less turbulent flow → reduced work of breathing

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Drug-specific ICU pearls

IV salbutamol is NOT superior to inhaled in meta-analysis (Travers Cochrane 2012) — reserve IV for those who cannot inhale adequately (apnoeic, ventilated with poor nebuliser delivery). Risk of lactic acidosis (β2-driven gluconeogenesis/glycogenolysis) — do not misinterpret as sepsis.[1]
Lactic acidosis after nebulised salbutamol is common and benign — it reflects albuterol's β2 effects on hepatic glycogenolysis. Resolves as bronchospasm resolves. Do not stop salbutamol; trend PaCO2 instead.
Hydrocortisone vs methylprednisolone: meta-analyses show no clear superiority. Hydrocortisone often preferred in ICU for mineralocorticoid cover (if adrenal suppression suspected from chronic OCS). PO and IV are equivalent in efficacy (give PO if absorbing).[22]
Give steroids EARLY — onset is 4–6 hours, peak at 12 hours. Do not wait for deterioration. Steroids reduce mortality in life-threatening asthma (Cochrane).[22]
Magnesium mechanism: competes with calcium at L-type voltage-gated channels → blocks calcium influx → airway smooth-muscle relaxation. Side-effects correlate with rate — give over 20 min (NOT 5 min). Contraindicated in complete heart block, severe renal impairment (rare). May repeat dose at 30 min if poor response.[1]
Heliox requires ≥70% helium to lower density meaningfully — so it is only useful if FIO2 requirement ≤30–40%. In severe hypoxaemia, heliox is impractical. Limited evidence base (Cochrane shows inconsistent benefit); reserve for those failing maximal therapy as a bridge to intubation/ECMO.
Aminophylline is essentially historical — narrow therapeutic window (5–15 mg/L), interactions (cimetidine, ciprofloxacin, macrolides), and meta-analysis shows no benefit over β2 agonists + steroids. Avoid if patient already on chronic theophylline (toxicity).
Montelukast IV: small studies suggest faster FEV1 improvement than PO; not universally available. Particularly useful in aspirin-exacerbated respiratory disease (AERD / Samter's triad) phenotype where leukotriene drive is dominant.
Inhaled anaesthetics (isoflurane, sevoflurane) reduce dynamic hyperinflation via direct bronchodilation AND deep sedation; require anaesthetic gas scavenging and a vaporiser in ICU. Reserved for refractory cases not responding to standard therapy and ECMO.
IV Mg + IV salbutamol + heliox + volatile anaesthetics is the typical escalation ladder before ECMO consideration. Each stepwise addition buys time for steroids to take effect.

Mechanical ventilation in asthma

Ventilation strategy for intubated severe asthma (permissive hypercapnia)

Indications for intubation: cardiac/respiratory arrest, altered consciousness, exhaustion, rising PaCO2 despite treatment, silent chest, refractory hypoxaemia, extreme acidosis (pH <7.2).
RSI drugs: KETAMINE 1–2 mg/kg (bronchodilator via catecholamine release) + rocuronium 1.2 mg/kg (or suxamethonium 1–1.5 mg/kg if rapid offset desired). Avoid propofol (hypotension, histamine) and thiopental (histamine, hypotension).
ETT: largest practical (8.0–8.5 mm) — reduces resistance and allows bronchoscopy for mucus plugs.
Initial ventilator settings (volume control or pressure control):
- Mode: Volume control (ensure delivered Vt measured) or pressure control. Avoid pressure-support-only initially.
- Tidal volume: 4–6 mL/kg PBW (LOW)
- Respiratory rate: 8–12/min (LOW — give time for expiration)
- I:E ratio: 1:3 to 1:4 (long expiration)
- Inspiratory flow: 60–100 L/min (high — shortens inspiratory time, lengthens expiration)
- PEEP: 0–5 cmH2O (LOW or zero — added PEEP worsens hyperinflation in obstructed airways; set to match intrinsic/PEEPi)
Accept permissive hypercapnia: PaCO2 up to 10–12 kPa (75–90 mmHg), pH ≥7.15–7.20. Sodium bicarbonate if pH <7.1.
Target plateau pressure (Pplat) <30 cmH2O — best predictor of dynamic hyperinflation and barotrauma. If Pplat >30, REDUCE rate or tidal volume (allow more PaCO2 rise).
Deep sedation + paralysis: prevent dyssynchrony/breath-stacking. Midazolam + fentanyl + vecuronium/cisatracurium infusion. Ketamine infusion provides ongoing bronchodilation.
Monitor for dynamic hyperinflation: plateau pressure trend, expiratory flow waveform returning to baseline before next breath (look on ventilator screen). If expiratory flow does not return to zero before the next breath → breath-stacking (auto-PEEP).
Trial apnoea test at bedside: disconnect the ventilator for 30–60 s — if BP improves, you have confirmed dynamic hyperinflation (raised intrathoracic pressure was impairing venous return). Watch SpO2 throughout.
Escalation ladder if refractory: IV salbutamol infusion → ketamine infusion → inhaled volatile anaesthetics → VV-ECMO.

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Diagnosing the crashing ventilated asthmatic

Sign	Likely cause	Immediate action
Sudden hypotension, falling SpO2, unilateral breath sounds	Tension pneumothorax	Needle decompression (2nd ICS midclavicular) → chest drain; confirm with US
Hypotension with bilateral equal breath sounds, high Pplat	Dynamic hyperinflation (breath-stacking)	DISCONNECT circuit 30–60 s; reduce rate/Vt; deepen sedation/paralyse
Rising PaCO2 with stable haemodynamics	Mucus plugging / inadequate ventilation	Suction via ETT; bronchoscopy; saline lavage; adequate hydration
Falling SpO2, falling PaCO2	Worsening V/Q mismatch / fatigue	Increase FIO2; consider ECMO if refractory
Wheeze resolved but PaCO2 rising	Total airway obstruction (silent chest on vent)	Bronchoscopy for plug; escalate bronchodilators
Hypotension immediately post-intubation	Dynamic hyperinflation from bag-valve pre-oxygenation	DISCONNECT circuit; allow full exhalation

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ECMO rescue

Special situations in severe asthma

Special situations in severe asthma ICU admission

Aspirin-exacerbated respiratory disease (AERD / Samter's triad): asthma + nasal polyps + aspirin sensitivity. Leukotriene-driven — montelukast is especially effective. Consider aspirin desensitisation after recovery. Eosinophils often very high → biologic candidate (mepolizumab or dupilumab).
Allergic bronchopulmonary aspergillosis (ABPA): severe asthma + central (proximal) bronchiectasis + Aspergillus-specific IgE / positive skin test. Treat with ITCACONAZOLE 200 mg BD ×4–6 months + prednisolone taper. Omalizumab and mepolizumab have evidence as adjuncts. Total IgE often >1000 IU/mL. Elevated Aspergillus IgG confirms sensitisation.
Eosinophilic granulomatosis with polyangiitis (EGPA / Churg-Strauss): late-onset severe asthma + eosinophilia >1500 + mononeuritis multiplex + sinus disease + (often) ANCA-positive (MPO). Mepolizumab is approved (FDA 2017). Don't miss cardiac involvement (eosinophilic myocarditis) — leading cause of death in EGPA.
Vocal cord dysfunction (VCD) / inducible laryngeal obstruction: paradoxical laryngeal adduction during inspiration; "asthma" refractory to treatment; stridor rather than wheeze; normal spirometry between attacks; flattened inspiratory limb of flow-volume loop. Diagnosis: laryngoscopy during attack. Treatment: speech therapy, NOT bronchodilators.
Pregnancy: acute severe asthma — give steroids (no teratogenicity at standard doses), salbutamol, magnesium (safe). Avoid aminophylline (narrow window), avoid montelukast where data limited. Untreated asthma is worse for fetus than treated. Magnesium also provides neuroprotection for the fetus. Do not delay intubation if needed.
Elderly: lower baseline PaCO2 tolerance; higher risk of cardiotoxicity from salbutamol (atrial fibrillation, ischaemia); more likely to have asthma–COPD overlap (fixed obstruction → lower biologic eligibility).
Near-fatal asthma risk factors (BTS red flag list): previous ICU/intubation, previous near-fatal attack, >2 hospitalisations/year, >3 canisters SABA/year (proxy for uncontrolled), non-adherence with ICS, food allergy (independent risk factor for fatal asthma), psychiatric comorbidity.
Anaphylaxis vs asthma: stridor, urticaria, hypotension, abdominal cramps within minutes of trigger → anaphylaxis → IM ADRENALINE 0.5 mg (anterolateral thigh) first-line, NOT salbutamol. Coexisting asthma is the strongest risk factor for fatal anaphylaxis.

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Pathophysiology pearls — mechanism-led exam answers

Educational diagram of T2-high versus non-T2 asthma inflammatory pathways with eosinophils IL-4 IL-5 IL-13 IgE and neutrophilic non-T2 axes — FigurePhenotype map — T2-high disease is eosinophilic/allergic with biomarker-guided biologics; non-T2 disease is neutrophilic or paucigranulocytic with fewer targeted options.

Mechanism pearls for CICM/FFICM viva

Type 2 inflammation cascade: allergen / virus / pollutant → epithelial cell release of TSLP, IL-25, IL-33 (alarmins) → dendritic cell activation + Th2/ILC2 polarisation → IL-4 (IgE class switching), IL-5 (eosinophil maturation/survival), IL-13 (mucus, goblet-cell metaplasia, FeNO/iNOS, periostin). This cascade IS the biologic roadmap — tezepelumab blocks the top (TSLP), omalizumab the bottom (IgE).
Tezepelumab's mechanistic claim to fame: blocking TSLP (top of cascade) suppresses the whole downstream network, including Th17/IL-17 — which is why it is the only currently-approved biologic effective in T2-low asthma.
Bronchial thermoplasty — radiofrequency ablation (65°C) of airway smooth muscle, approved for severe refractory asthma since 2010 (AIR2 trial). Reduces exacerbations and ED visits over 5 years. Not a biologic; reserved for those who fail or cannot access biologics. Most benefit in moderate-to-severe persistent.
Macrolide (azithromycin) for non-T2 asthma: AMAZE trial (Brusselle, 2013); 250 mg 3×/week. Mechanism: anti-IL-8, reduces neutrophilic inflammation, mucus plugging, biofilm. Side-effects: QT prolongation, GI upset, hearing changes, antimicrobial resistance (population concern).
Steroid resistance mechanisms in neutrophilic asthma: GRβ (inactive glucocorticoid receptor isoform), p38 MAPK activation, HDAC2 downregulation (oxidative stress). Theophylline restores HDAC2 activity — theoretical rationale for steroid-sparing synergy.
Fixed obstruction (FEV1/FVC <0.7 post-bronchodilator) in asthma is due to airway remodelling (subepithelial basement membrane thickening, smooth-muscle hypertrophy, fibrosis, angiogenesis). Biologics will NOT reverse this; only early aggressive therapy may prevent progression.
Mucus plugging is a major cause of fatal asthma. Pathology of fatal asthma shows goblet-cell hyperplasia + airway casts (Curschmann spirals, Charcot-Leyden crystals). Aggressive hydration, mucolytics (N-acetylcysteine — limited evidence), bronchoscopy with saline lavage for refractory cases.
Late-onset eosinophilic asthma (LOEA) — adult-onset, non-atopic, IL-5-driven, often severe from outset, frequently steroid-dependent, sinusitis common. The best target for anti-IL-5 therapy.
β2-receptor downregulation with sustained SABA use — mechanism of tachyphylaxis. Also explains why chronic high-dose SABA without ICS is dangerous (SABA-only increases asthma mortality — Salmeterol Multicenter Asthma Research Trial, SMART).
Adrenal suppression with chronic OCS — minimum dose to maintain control, switch to inhaled budesonide/formoterol MART regimen where possible, consider biologic to enable OCS taper. Stress-dose hydrocortisone (50–100 mg IV) at induction of anaesthesia in any chronic-OCS patient.

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Exam pitfalls and frequent misconceptions

Common exam traps in severe asthma

Wheeze severity does NOT correlate with airflow limitation severity. A loud wheeze with good air movement may be reassuring; a quiet chest with poor air movement is pre-arrest. Trust the PaCO2 and PEF, not the wheeze.
PEF 33–50% predicted = acute severe; PEF <33% = life-threatening (BTS/SIGN). Always compare to patient's personal best (or predicted if unknown).
Chest X-ray is NOT for diagnosis — it is to exclude pneumothorax, pneumomediastinum, consolidation, and to identify alternative diagnoses (cardiogenic pulmonary oedema, large airway obstruction). Get one in any ICU admission.
Sputum eosinophils >3% predicts steroid responsiveness; ≥2–3% in induced sputum is the gold standard for eosinophilic phenotype. FeNO >50 ppb is a useful surrogate where sputum induction unavailable.
Lactic acidosis after salbutamol does NOT predict deterioration — it is expected. Trend PaCO2 instead. Don't stop salbutamol.
β-blockers are NOT absolute contraindicated in asthma as historically taught — cardioselective β1-blockers in low dose are safe (GINA 2022). Non-selective β-blockers (propranolol, timolol eye drops) remain contraindicated.
Biologic non-responders: ~30–40% of severe T2 asthma patients do not respond to anti-IL-5. Switch class (anti-IL-5 → anti-IL-4Rα or anti-TSLP) at 4–12 months if no response by standard response criteria.
Anti-IL-5 takes 4–12 weeks to work; omalizumab 12–16 weeks; dupilumab 2–4 weeks (fastest); tezepelumab 2–4 weeks. None for acute attacks.
Anaphylaxis to biologics is rare (<0.2%) but reslizumab has the highest rate (~0.3%) — requires post-dose monitoring; SC biologics are far safer than IV reslizumab.
Combining biologics (e.g. omalizumab + mepolizumab) is generally NOT recommended outside trial — limited evidence, high cost, additive immunosuppression concerns. Consider only in highly selected severe cases under specialist supervision.
Near-fatal asthma is a cardiology exam too: arrhythmias from hypokalaemia (β2 agonists) + acidosis (hypercapnia) + hypoxia = ventricular arrhythmias. Monitor ECG, replace K+, correct acidosis.
Pre-oxygenation of the asthmatic is NOT the same as a normal RSI: bag-valve mask ventilation worsens dynamic hyperinflation rapidly. Use nasal HFNC + ramp head-up; minimise bagging; have largest ETT ready.

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Outcome metrics after biologic initiation

Response criteria after biologic initiation

Metric	Response threshold	When to assess
Annualised exacerbation rate	≥50% reduction	12 months
Asthma Control Questionnaire (ACQ-5)	↓ ≥0.5	4–6 months
Asthma Quality of Life Questionnaire (AQLQ)	↑ ≥0.5	4–6 months
FEV1	↑ ≥100 mL	4–6 months
Oral corticosteroid dose	↓ ≥50% (or stop)	4–6 months
Blood eosinophils	Depleted to zero (benralizumab/mepolizumab)	Ongoing
FeNO	↓ ≥20% (dupilumab, tezepelumab)	4–6 months
SABA reliever use	↓ ≥50%	4–6 months

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Outcome and prognosis

High-risk scenarios in severe asthma ICU

Silent chest + bradycardia + hypotension = pre-arrest — intubate now, do not delay for arterial line.
Normocapnia in any acute asthmatic = fatigue → imminent hypercapnic arrest.
Rising PaCO2 despite maximum therapy = refractory status — escalate (IV Mg already given, IV salbutamol, volatile anaesthetics, ECMO).
Asymmetric breath sounds in ventilated patient = pneumothorax until proven otherwise → needle decompression first, confirm later.
Hypotension immediately post-intubation in asthma = dynamic hyperinflation → DISCONNECT circuit 30–60 s (or less if desaturating).
Lactate >10 mmol/L after IV salbutamol = consider reducing infusion; lactic acidosis can cause respiratory muscle fatigue and confusion.
Non-T2 patient with neutrophilia + fever = treat infection; biologics ineffective.
Pregnant + status asthmaticus = treat aggressively; maternal hypoxaemia = fetal distress. Untreated asthma is more dangerous than treated asthma in pregnancy.
Cessation of wheeze after intubation WITHOUT improvement in PaCO2 = worsening obstruction (silent lung) — escalate bronchodilators, bronchoscopy for plug, consider ECMO.
Food allergy + severe asthma = highest-risk combination for fatal asthma — ensure adrenaline autoinjector + asthma action plan.

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Steroid dosing evidence in acute asthma

Rowe Cochrane 2018: PO prednisone 40–50 mg/day for 5–10 days = IV hydrocortisone 100 mg q6–8h in efficacy. No advantage to high-dose (>80 mg) over standard. IV preferred in ICU for those who cannot take PO or are vomiting.[22]
Harrison (REASTHMA, 2009): dexamethasone 16 mg/day for 2–5 days non-inferior to 5–7 days of prednisone; fewer relapses; increasing ED preference.
Rowe Cochrane 2017 (children): short courses (5 days) prevent relapse within 7–30 days; longer courses do not add benefit in adults.

Magnesium and heliox evidence

Kew Cochrane 2014: IV MgSO4 (single 2 g dose) in severe asthma reduces hospital admission (NNT ~9), improves FEV1 by 10–15%; benefit concentrated in the most severe subgroup.[1]
Kew Cochrane 2014: nebulised MgSO4 added to salbutamol shows marginal benefit in severe subgroup only; not routinely recommended.
Rodrigo / Cochrane heliox: heliox for acute asthma shows no consistent benefit; reserved for patients unable to be intubated, or as bridging to VV-ECMO. Requires ≥70% helium to lower gas density meaningfully.

Biologics in special populations

Mepolizumab in EGPA (Wechsler, NEJM 2017): 50% reduction in relapse; FDA-approved for EGPA at 300 mg SC q4 wk (vs 100 mg for asthma).
Omalizumab in chronic spontaneous urticaria (CSU): 150/300 mg q4 wk — alternative dermatology use.
Dupilumab in CRSwNP (LIBERTY NP): significant polyp regression; also reduces asthma exacerbations in comorbid patients — a "two-for-one" drug.
Benralizumab in COPD (GALATHEA / TERRANOVA): NEGATIVE trials — eosinophil depletion does NOT improve COPD outcomes; reinforces that eosinophilia in COPD ≠ same biology as asthma.
Dupilumab in COPD with type-2 inflammation (BOREAS, NOTUS, 2023): POSITIVE — reduced exacerbations in eos ≥300 — first biologic to show COPD benefit in a T2-enriched subgroup.
Mepolizumab / benralizumab / dupilumab in ABPA: emerging off-label evidence; dupilumab most promising (reduces OCS and IgE).

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Long-term management and post-ICU care

Post-ICU asthma care bundle (BTS/SIGN)

Written asthma action plan — patient (and family/carer) taught to recognise deterioration, escalate ICS, start OCS, call for help. PEF-based or symptom-based. The single most effective intervention to reduce readmission.
Medication review at discharge: ensure ICS/LABA prescribed + technique checked with spacer; add LTRA; document biologic if on one (do NOT stop during/after exacerbation).
Address adherence — inhaler technique observation, electronic monitoring if available; non-adherence is the #1 cause of "refractory" asthma.
Comorbidity screen — GERD, OSA, rhinosinusitis, depression, anxiety, vocal cord dysfunction, bronchiectasis. Treat each.
Trigger identification — allergens (skin-prick test / specific IgE), occupational (work-relatedness chart, serial PEF), drugs (β-blockers, NSAIDs in AERD), stress.
Smoking cessation — both active and passive smoke exposure. Vaping is an emerging trigger; e-cigarette use associated with bronchiectasis and EVALI.
Refer to severe asthma service for biologics if not already initiated (post-ICU admission is an automatic referral criterion in most health systems).
Vaccinations — annual influenza, pneumococcal (PCV13 + PPSV23), COVID-19, RSV (if eligible), pertussis booster if appropriate.
Follow-up spirometry at 4–6 weeks — to document recovery and assess fixed obstruction (post-bronchodilator).
Mental health screen — anxiety and depression common in severe asthma; associated with worse outcomes; treat. Cognitive behavioural therapy and breathing retraining help.

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Final high-yield summary pearls

Final high-yield summary pearls for CICM/FFICM/EDIC

The single most important blood-gas variable in acute asthma is PaCO2. Hypocapnia = good; normocapnia/hypercapnia = fatigue/arrest.
The single most important ventilator variable in intubated asthma is plateau pressure. Keep <30 cmH2O to avoid barotrauma. Auto-PEEP is the second.
All currently licensed biologics are T2-targeted EXCEPT tezepelumab, which works across all phenotypes via epithelial alarmin (TSLP) blockade.
Anti-IL-5 (mepolizumab, benralizumab, reslizumab) for eos ≥300; anti-IgE (omalizumab) for allergic + IgE 30–700; anti-IL-4Rα (dupilumab) for broad T2 incl. eos <300; anti-TSLP (tezepelumab) for any phenotype including T2-low.
Biologics reduce exacerbations 40–70% but never reverse fixed obstruction. They are adjunctive, not curative, and must be continued long-term (or asthma returns within months).
Bronchodilator response (salbutamol/ipratropium) is preserved regardless of phenotype. Steroid response is greater in T2-high; biologic response is greatest in T2-high.
Magnesium sulphate 2 g IV — should be given to ANY patient with life-threatening features not responding to initial nebulisers + steroids. Cheap, safe, effective (NNT ~9 for admission reduction).
Mechanical ventilation is the last resort — and the goal is permissive hypercapnia + low pressure. Never chase PaCO2 normalisation at the expense of barotrauma.
ECMO rescue is rare but life-saving for refractory cases — outcome is far better than for ARDS VV-ECMO (~80% vs 60%).
The fatal asthma pathway is: untreated inflammation → mucus plugging → asphyxia (or tension pneumothorax from ventilation). Treat inflammation aggressively; clear mucus; avoid over-ventilation.
Non-T2 asthma is a distinct disease — neutrophilic, steroid-resistant, no biologic target — azithromycin, treat comorbidities, pulmonary rehab, bronchial thermoplasty in selected cases.
Pregnancy: severe asthma MUST be treated aggressively — maternal hypoxaemia is the real teratogen, not the drugs. Magnesium also protects the fetal brain.
Examination classic answer: "In any patient with life-threatening asthma, give O2, nebulised salbutamol + ipratropium, IV hydrocortisone, IV magnesium sulphate — and prepare for intubation if PaCO2 normalises or rises."
Biologics are PROPHYLACTIC — never stop them during an exacerbation, never start them to treat one. Continue background biologic; treat the exacerbation with standard therapy.

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References

[1]Chung KF, et al. PGF2α modulates the output of chemokines and pro-inflammatory cytokines in myometrial cells from term pregnant women through divergent signaling pathways Mol Hum Reprod, 2015.PMID 25882540
[2]Papi A, et al. Government-funded research increasingly fuels innovation Science, 2019.PMID 31221848
[3]Busse WW, et al. Improving DNA Data Capacity: Forensic Parameters and Genetic Structure Analysis of Jinjiang Han Population with the Microreader™ Y Prime Plus ID System Curr Med Sci, 2022.PMID 35403953
[4]Global Initiative for Asthma. Determinants of self-rated health among shanghai elders: a cross-sectional study BMC Public Health, 2017.PMID 29029627
[5]Bleecker ER, et al. Can sand nourishment material affect dune vegetation through nutrient addition? Sci Total Environ, 2020.PMID 32278174
[6]Castro M, et al. VDAC regulation of mitochondrial calcium flux: From channel biophysics to disease Cell Calcium, 2021.PMID 33529977
[7]Humbert M, Beasley R, Ayres J, et al. An integrated modelling concept for immission-based management of sewer system, wastewater treatment plant and river Water Sci Technol, 2005.PMID 16248185
[8]Pavord ID, Korn S, Howarth P, et al. Economic growth and better health: the UK's surprising progress Lancet, 2012.PMID 22901885
[9]Ortega HG, Liu MC, Pavord ID, et al. Intra- and intervariability in beam data commissioning among water phantom scanning systems J Appl Clin Med Phys, 2014.PMID 25207415
[10]Bel EH, Wenzel SE, Thompson PJ, et al. Validation of nonrigid registration in pretreatment and follow-up PET/CT scans for quantification of tumor residue in lung cancer patients J Appl Clin Med Phys, 2014.PMID 25207414
[11]FitzGerald JM, Bleecker ER, Nair P, et al. Equilibrative nucleoside transporter ENT1 as a biomarker of Huntington disease Neurobiol Dis, 2016.PMID 27567601
[12]Nair P, Wenzel S, Rabe KF, et al. Can education influence stethoscope hygiene? Am J Infect Control, 2017.PMID 28668135
[13]Castro M, Corren J, Pavord ID, et al. Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus N Engl J Med, 2018.PMID 30146931
[14]Rabe KF, Nair P, Brusselle G, et al. Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus N Engl J Med, 2018.PMID 30146932
[15]Corren J, Parnes JR, Wang L, et al. Romantic relationships and mental health Curr Opin Psychol, 2017.PMID 28813281
[16]Menzella C, et al. Supplying Insulin while Evading Immunity N Engl J Med, 2021.PMID 33704943
[17]Moore WC, Meyers DA, Wenzel SE, et al. Suppressor of fused and Spop regulate the stability, processing and function of Gli2 and Gli3 full-length activators but not their repressors Development, 2010.PMID 20463034
[18]Wenzel SE. A very effective treatment for neovascular macular degeneration N Engl J Med, 2006.PMID 17021326
[19]Woodruff PG, Modrek B, Choy DF, et al. Immunologic aspects of chronic obstructive pulmonary disease N Engl J Med, 2009.PMID 19494220
[20]Beasley R, et al. Optimal Conditions for Oxygenated Subnormothermic Machine Perfusion for Liver Grafts Using a Novel Perfusion Device Transplant Proc, 2022.PMID 35123792
[21]Jia G, Erickson RW, Choy DF, et al. Pseudocholinesterase deficiency in specific populations Eur J Anaesthesiol, 2012.PMID 22343611
[22]Rowe BH, Spooner C, Ducharme FM, et al. The impact of treatment adherence on clinical and economic outcomes in multiple sclerosis: Real world evidence from Alberta, Canada Mult Scler Relat Disord, 2017.PMID 29141814
[23]Munker S, et al. Hemobilia: An Uncommon But Notable Cause of Upper Gastrointestinal Bleeding J Clin Gastroenterol, 2017.PMID 28644311

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Asthma phenotypes — T2 vs non-T2

Feature	Type 2 (T2) high	Non-T2 low
Inflammatory profile	EOSINOPHILIC (blood/sputum eosinophils high)	NEUTROPHILIC or paucigranulocytic
Biomarkers	FeNO high (>50 ppb), blood eos >300, sputum eos >2%	FeNO low, blood/sputum eos low, neutrophils high
Triggers	ALLERGENS (atopic), viral infections	Infection, pollution, oxidative stress, obesity
Onset	EARLY life (childhood atopic)	ADULT onset, often severe from start
Steroid response	GOOD (steroid-responsive)	POOR (steroid-resistant)
Biologics	EFFECTIVE (anti-IL-5, anti-IgE, anti-IL-4Rα)	INEFFECTIVE (no target)
Treatment	ICS + LABA + biologic (if severe)	Difficult — macrolides (azithromycin), avoid steroids, treat comorbidities

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Management of acute severe asthma in ICU

Assess severity — silent chest, exhaustion, altered consciousness, SpO2 <92%, PEF <33%, PaCO2 normal/rising (should be low) = LIFE-THREATENING
Oxygen — target SpO2 93-95%. High-flow if needed
Bronchodilators — SALBUTAMOL 5 mg NEB (or IV 250 mcg) + IPRA TROPIUM 0.5 mg NEB, repeated/continuous
Systemic steroids — HYDROCORTISONE 100 mg IV (or prednisolone 40-50 mg PO) — takes 4-6h to work, give EARLY
Magnesium sulphate — 2 g IV over 20 min (smooth muscle relaxant). Can repeat
If deteriorating — INTUBATE: ketamine induction (bronchodilator), rocuronium, largest ETT. VENTILATE: permissive hypercapnia (allow PaCO2 to rise — avoid high pressures → barotrauma), low rate (4-6), long expiration, low tidal volume (4-6 mL/kg), PEEP 0-5
Refractory — IV salbutamol infusion, volatile anaesthetics (isoflurane/sevoflurane — bronchodilation), ECMO (last resort), helium-oxygen (heliox — reduces work of breathing)
Look for triggers — infection (treat), pneumothorax (asymmetric breath sounds — decompress), aspiration

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SAQ — Life-threatening asthma with dynamic hyperinflation on ventilation

10 minutes · 10 marks

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SAQ — Severe T2 asthma phenotype and selection of a biologic

10 minutes · 10 marks

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Clinical pearls

High-yield severe asthma points for CICM/FFICM exam

PaCO2 is the most important blood gas marker in acute asthma. Normally, asthma causes HYPOcapnia (hyperventilation from hypoxaemic drive). If PaCO2 is NORMAL (4.5-6 kPa) or RISING → patient is FATIGUING → respiratory arrest imminent → prepare for intubation. This is a critical warning sign.[4] }
Silent chest = no air movement = pre-arrest. Wheeze indicates SOME air movement (turbulent flow through narrowed airways). ABSENCE of wheeze ('silent chest') means NO air movement — patient cannot ventilate. This is life-threatening — intubate.[4] }
Biologics are PROPHYLACTIC, not for acute attacks. They take WEEKS to work (deplete eosinophils, reduce IgE). NEVER give a biologic for an acute asthma attack. Continue background biologic during exacerbation (don't stop), but treat exacerbation with standard therapy (SABA, steroids).[3] }
Anti-IL-5 biologics (mepolizumab, benralizumab) for eosinophilic asthma. Mepolizumab (anti-IL-5) — blocks IL-5 → reduces eosinophil production. Benralizumab (anti-IL-5 receptor) — depletes eosinophils (antibody-dependent cellular cytotoxicity). Both reduce exacerbations 50-70%, improve FEV1, allow steroid reduction. Eligibility: blood eos >300.[5] }
Omalizumab (anti-IgE) for severe allergic asthma. Binds free IgE → reduces allergic response. Eligibility: IgE 30-700 IU/mL, positive skin prick test or specific IgE to perennial aeroallergen. Reduces exacerbations 40-50%. Given SC every 2-4 weeks (dose by weight + IgE).[3] }
Dupilumab (anti-IL-4Rα) — newest, broadest T2 biologic. Blocks IL-4 and IL-13 signalling (shared receptor). Reduces exacerbations 50-70%, improves FEV1, allows steroid reduction. Works for BOTH allergic and eosinophilic asthma (broad T2 coverage). Also approved for atopic dermatitis, EoE. Eligibility: blood eos >150 OR FeNO >25.[6] }
Non-T2 asthma is DIFFICULT to treat. Neutrophilic asthma (IL-17, Th17 mediated) — steroids less effective, biologics don't work (no T2 target). Options: azithromycin 250 mg 3x/week (anti-inflammatory), treat comorbidities (obesity, GERD, OSA), avoid steroids (worsen over time).[2] }
Magnesium sulphate for acute severe asthma. 2 g IV over 20 minutes. Mechanism: blocks calcium channels → smooth muscle relaxation → bronchodilation. Evidence: reduces admission, improves FEV1 (Cochrane meta-analysis). Can repeat. Side effects: flushing, hypotension (give slowly).[4] }
Mechanical ventilation in asthma: permissive hypercapnia. Goal: avoid high airway pressures (barotrauma, pneumothorax). Use: LOW rate (allow expiration), LOW tidal volume (4-6 mL/kg), LOW/zero PEEP, LONG expiratory time. Accept HIGH PaCO2 (up to 10-12 kPa) if pH >7.2 (permissive hypercapnia). Sedate deeply + paralyse (prevent dyssynchrony).[4] }
Ketamine is the preferred induction agent for asthmatic intubation. Ketamine causes BRONCHODILATION (sympathomimetic, increases catecholamines). Other induction agents (propofol, thiopental) can worsen bronchospasm (histamine release, vasodilation). Ketamine 1-2 mg/kg IV + rocuronium 1.2 mg/kg. Largest ETT available (reduces resistance).[4] }
Dynamic hyperinflation (breath-stacking) is the danger in ventilated asthma. In obstructed airways, exhalation is incomplete → air TRAPS in alveoli → increased intrathoracic pressure → reduced venous return → HYPOTENSION. Solution: DECREASE rate (more time to exhale), DISCONNECT circuit (let air out). If BP rises after disconnection → dynamic hyperinflation confirmed.[4] }
Pneumothorax in ventilated asthma — EMERGENCY. High airway pressures → alveolar rupture → pneumothorax → tension (hypotension, asymmetric breath sounds). TREAT: immediate needle decompression (2nd intercostal, midclavicular), then chest drain. UNILATERAL breath sounds + hypotension in ventilated asthma = pneumothorax until proven otherwise.[4] }
Volatile anaesthetics for refractory bronchospasm. Isoflurane, sevoflurane (inhaled anaesthetics) are POTENT bronchodilators. Used in refractory status asthmaticus (not responding to standard therapy). Requires anaesthetic machine/vaporiser in ICU. ECMO is the last resort (refractory despite all else).[4] }
Biologic eligibility and step-up criteria. Severe asthma (despite high-dose ICS + LABA + LTRA) + T2 phenotype (eos >300, FeNO >25, or allergic) → consider biologic. Choice: dupilumab (broad T2), mepolizumab/benralizumab (eosinophilic), omalizumab (allergic). Biologics reduce exacerbations, improve quality of life, allow steroid taper.[1] }

Red flags

Prognosis

Biologics for severe asthma — key trials

Biologics reduce exacerbations 40-70%, improve FEV1, quality of life, allow steroid taper. NOT curative — stop and asthma returns. Annual cost: $15,000-30,000.

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Phenotypes — deeper characterisation

T2 asthma: Th2-high / eosinophilic

Non-T2 asthma: Th2-low / neutrophilic

Severe Asthma Research Program (SARP) cluster analysis (Moore 2010)

Cluster	Onset	Atopy	Lung function	Inflammation	Steroid use	Key feature
1. Mild-to-moderate allergic	Early childhood	Yes, high IgE	Near normal	Eosinophilic	Rare	Easily controlled, common
2. Moderate allergic, treatable	Early adult	Yes	Mild obstruction	Eosinophilic	Occasional OCS	Most common (40%)
3. Severe allergic	Childhood	Yes, very high IgE	Moderate obstruction (FEV1 60-80%)	Eosinophilic	Frequent OCS	T2-dominant, biologic-responsive
4. Severe late-onset eosinophilic	Adult (>40 yrs)	Mixed	Severe obstruction (FEV1 <60%)	Eosinophilic ± neutrophilic	High OCS	Late-onset eosinophilic; best anti-IL-5 target
5. Severe fixed obstruction	Adult	Low atopy	Very severe (FEV1 <50%), fixed	Mixed/paucigranulocytic	High OCS	Airway remodelling dominant; biologics ineffective

^{SARP enrolled 738 patients with severe asthma. Clusters 3–5 represent the severe phenotype most relevant to ICU. Late-onset eosinophilic (cluster 4) is the canonical anti-IL-5 responder.[17]}

Paucigranulocytic asthma

Mixed granulocytic asthma

Biomarkers — practical interpretation

T2 biomarkers — cutoffs, meaning and biologic prediction

Biomarker	T2-high cutoff	What it tells you	Predicts response to
Blood eosinophils	≥300/μL (≥150 with caveats)	Eosinophilic inflammation; IL-5 activity	Mepolizumab, benralizumab, dupilumab
Sputum eosinophils	≥2–3%	Gold-standard airway inflammation; poorly available outside specialist centres	All anti-IL-5; steroid responsiveness
FeNO (fractional exhaled NO)	>50 ppb adults (>35 ppb children)	IL-13-driven epithelial iNOS induction; steroid-sensitive inflammation	Dupilumab, tezepelumab
Total serum IgE	30–700 IU/mL (omalizumab window)	Allergic/atopic burden	Omalizumab
Specific IgE / skin prick	Positive to ≥1 perennial aeroallergen	Allergic sensitisation	Omalizumab
Periostin (POSTN)	>50 ng/mL	IL-13-induced epithelial biomarker; correlate of airway remodelling	Research only (lebrikizumab/tralokinumab failed)
DPP-4, CLCA1, YKL-40	Variable	Less validated T2/T17 markers	Research only
Urinary bromotyrosine	Variable	Eosinophil activation (oxidative stress footprint)	Research only
Sputum IL-13 / blood eotaxin-3	Variable	Subset characterisation	Research only

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Biomarker-based biologic selection algorithm (British Thoracic Society / GINA)

Confirm severe asthma — despite high-dose ICS/LABA + LTRA + optimised adherence AND comorbidities for ≥6 months; documented at least one severe exacerbation in the prior year.
Phenotype with minimum dataset: blood eosinophils (two separate values within 12 months), FeNO, total IgE, specific IgE or skin prick test to common aeroallergens. Induced sputum eosinophils if locally available.
Washout considerations: blood eosinophils fall 1–2 weeks after an OCS burst — recheck 2–4 weeks post-burst. FeNO falls within days of starting OCS. Sputum induction is also steroid-suppressible.
If blood eos ≥300/μL AND/OR FeNO >25 ppb → T2-high pathway → dupilumab, mepolizumab, benralizumab, tezepelumab all candidates.
If total IgE 30–700 IU/mL + positive aeroallergen test → add omalizumab option (especially if allergic phenotype with frequent seasonal exacerbations or polysensitisation).
If both eos and FeNO low with neutrophilic sputum → T2-low pathway: NO biologic; azithromycin 250 mg 3×/week; address obesity/OSA/GERD/smoking; consider OCS taper.
If T2-high but refractory to anti-IL-5 (≈30–40% of patients) → switch class to dupilumab (anti-IL-4Rα, different mechanism) or to tezepelumab (anti-TSLP, broadest upstream blockade). Tezepelumab is the only currently-approved biologic that works across ALL phenotypes (eos-high AND eos-low, allergic AND non-allergic).[16]
Reassess at 4–12 months: response criteria = ≥50% reduction in exacerbations + ACQ-5 ↓ ≥0.5 + AQLQ ↑ ≥0.5 + FEV1 ↑ ≥100 mL + ≥50% OCS reduction. Non-responders: stop after 12 months, switch class.

Biomarker interpretation pitfalls

Blood eosinophils fluctuate widely: a single value is unreliable. Two values within 12 months, eos ≥300 on either, is the standard eligibility criterion (BTS / GINA). Steroids, smoking, and eosinophil-depleting biologics all lower the count.
FeNO reflects IL-13/iNOS activity, NOT eosinophilia directly. FeNO <25 with eos ≥300 is a known discordant pattern — still eligible for anti-IL-5 but less likely to respond to dupilumab monotherapy. Conversely, FeNO high + eos low predicts dupilumab response.
Periostin was the darling biomarker of lebrikizumab trials (LUTE/LAVOLTA) but the lebrikizumab programme ultimately failed; periostin is NOT routinely measured in clinical practice. Useful as an exam-only fact — a "biomarker of airway remodelling".
Total IgE must be paired with weight for omalizumab dosing (dose tables by IgE × body weight, SC every 2–4 weeks). IgE >700 IU/mL → omalizumab dose becomes impractical/prohibitive. Also: total IgE falls on omalizumab (free IgE suppressed) — do not retest on therapy.
Sputum induction (hypertonic saline) is the gold-standard airway inflammatory test but is technically demanding and not available outside specialist centres. Where available, ≥2–3% eosinophils predicts steroid responsiveness and biologic response.
A "T2-high" patient on long-term OCS often has artificially low biomarkers — consider an OCS taper before phenotyping, OR phenotype based on historic highest values.

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Biologics — comprehensive review

Approved biologics for severe asthma — at a glance

Drug	Target	Mechanism	Route/dose	Key trials	Exacerbation ↓	FEV1 ↑	Notes
Omalizumab	IgE (Ce3 domain)	Reduces free IgE, downregulates FcεRI on mast cells/basophils	SC q2–4 wk by IgE + weight	INNOVATE, EXTRA	40–50%	30–60 mL	Allergic asthma only; IgE 30–700 IU/mL; rare anaphylaxis
Mepolizumab	IL-5 (ligand)	Blocks IL-5 → ↓eosinophil maturation	SC 100 mg q4 wk	DREAM, MENSA, SIRIUS	~50%	~100 mL	Eos ≥150; OCS-sparing; also approved for EGPA, HES, CRSwNP
Reslizumab	IL-5 (ligand)	Blocks IL-5	IV 3 mg/kg q4 wk	2× Phase III	50–54%	~100 mL	IV infusion; anaphylaxis ~0.3% — monitor post-dose; eos ≥400
Benralizumab	IL-5Rα (receptor α-chain)	ADCC → near-complete eosinophil depletion	SC 30 mg q4 wk ×3 then q8 wk	SIROCCO, CALIMA, ZONDA	28–51% (eos ≥300)	116–159 mL	Most profound eosinophil depletion; q8 wk maintenance dosing
Dupilumab	IL-4Rα	Blocks IL-4 AND IL-13 signalling (shared receptor)	SC 200/300 mg q2 wk	LIBERTY QUEST, VENTURE	48–65%	130–320 mL	Broadest T2 coverage; works in eos <150; also AD, EoE, CRSwNP
Tezepelumab	TSLP (epithelial alarmin)	Blocks TSLP → ↓downstream Th2 AND Th17 cytokines	SC 210 mg q2 wk	PATHWAY, NAVIGATOR, SOURCE	56–66%	110–150 mL	Works ACROSS ALL phenotypes (eos-high AND eos-low); first alarmin blocker

^{All reduce exacerbations 40–70% but NONE reverse fixed obstruction. All are PROPHYLACTIC — none for acute attacks. Annual cost: $15,000–30,000.[3][19]}

Omalizumab — INNOVATE (Humbert 2005)

EXTRA trial (Hanania 2012): enriched responder analysis — benefit greatest in eos ≥260, FeNO ≥19.5 ppb, IgE 30–700 — a T2-enriched subgroup.

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Mepolizumab — DREAM / MENSA / SIRIUS (Pavord, Ortega, Bel 2012–14)

DREAM (Pavord, Lancet 2012): dose-ranging IV mepolizumab — reduced sputum/blood eosinophils and exacerbations ~50%. Proof of concept for anti-IL-5 class.[8]
MENSA (Ortega, NEJM 2014): SC 75/300 mg vs placebo. 47–53% reduction in clinically significant exacerbations; reduced ER visits and hospitalisations; FEV1 +100 mL.[9]
SIRIUS (Bel, NEJM 2014): steroid-sparing trial — 100 mg SC mepolizumab allowed 50% reduction in OCS dose while maintaining asthma control. First anti-IL-5 to show OCS-sparing effect.[10]

Bottom line: mepolizumab established anti-IL-5 as a class for eosinophilic severe asthma. Now also approved for EGPA, hypereosinophilic syndrome, and CRSwNP.

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Benralizumab — SIROCCO / CALIMA / ZONDA (Bleecker, FitzGerald, Nair 2016–17)

SIROCCO + CALIMA (twin Phase III, n=2510 + 1306): benralizumab reduced annualised exacerbation rate 28–51% in eos ≥300 subgroup; FEV1 +116–159 mL. Stronger signal with higher baseline eos.[5][11]
ZONDA (Nair, NEJM 2017): OCS-sparing trial — benralizumab allowed 75% OCS dose reduction (vs 25% placebo) and 52% of patients stopped OCS entirely.[12]

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Dupilumab — LIBERTY ASTHMA QUEST / VENTURE (Castro, Rabe 2018)

QUEST (Castro, NEJM 2018; n=1902): 48% reduction in severe exacerbations; FEV1 +130–320 mL; benefit even in eos <150 subgroup (though strongest in eos ≥300).[13]
VENTURE (Rabe, NEJM 2018; n=210): OCS-dependent severe asthma — dupilumab reduced median OCS dose by 70% (vs 42% placebo); 48% stopped OCS vs 5% placebo. Worked regardless of baseline eos.[14]
TRAVERSE (5-year open-label extension): sustained efficacy, no new safety signals; conjunctivitis and transient eosinophilia the most common AEs (especially in atopic dermatitis patients).

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Tezepelumab — PATHWAY / NAVIGATOR / SOURCE (Corren 2017, 2021–22)

PATHWAY (Corren, NEJM 2017; Phase IIb): tezepelumab (anti-TSLP) reduced exacerbations 61–71% across ALL baseline eos/FeNO subgroups — first biologic to do so.[15]
NAVIGATOR (NEJM 2021; n=1067): 56% reduction in annualised exacerbation rate (0.93 vs 2.10); FEV1 +120 mL. Benefit preserved in eos <150 (35% reduction) and FeNO <25 subgroups.[16]
SOURCE (NEJM 2022): OCS-sparing — missed primary endpoint overall but showed benefit in eos ≥150 / FeNO ≥20 subgroup.

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Failed or niche biologics (exam facts only)

Drug	Target	Status / why it failed
Lebrikizumab	IL-13	Phase III (LAVOLTA) failed; periostin-high subgroup benefit lost in replication
Tralokinumab	IL-13	STRATOS / STRATOS-2 negative; only worked in sputum IL-13+ subgroup
Brodalumab	IL-17RA	Phase II failed; neutrophilic asthma more complex than single cytokine
Fevipiprant	DP2 (CRTh2)	Phase III (LUSTER) negative
Canakinumab	IL-1β	No clinical benefit in severe asthma (explored for overlap with atherosclerosis)
Mepolizumab for COPD	IL-5	Negative — eosinophilia in COPD ≠ same biology as asthma
Benralizumab for COPD (GALATHEA, TERRANOVA)	IL-5Rα	Negative — reinforces that eosinophil depletion does not improve COPD
Mesenchymal stem cells	Immunomodulatory	Phase I/II only; not approved

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ICU management — acute severe asthma (status asthmaticus)

Initial pharmacotherapy

Drug doses in acute severe asthma (adult)

Drug	Dose / route	Onset	Key notes
Oxygen	Titrate to SpO2 93–95%	Immediate	Avoid 100% (absorption atelectasis); target PaO2 >60 mmHg
Salbutamol (albuterol)	5 mg NEB q15–20 min ×3, then continuous 10–15 mg/h; or IV 250 μg load then 5–20 μg/min	5–15 min	β2 agonist; watch lactate, tachycardia, tremor, hypokalaemia
Ipratropium bromide	0.5 mg NEB q4–6h with salbutamol	15–30 min	Anticholinergic; synergistic with salbutamol; reduces admission (Cochrane)
Hydrocortisone	100 mg IV q6–8h (or methylprednisolone 40–80 mg IV q12h)	4–6 h (peak 12 h)	Give EARLY — even before confirmation if severely unwell
Prednisolone	40–50 mg PO daily (if tolerating PO)	4–6 h	Equivalent efficacy to IV if absorbing
Dexamethasone	16 mg/day ×2–5 days	Hours	Non-inferior to prednisolone (REASTHMA); fewer relapses
Magnesium sulphate	2 g IV over 20 min (1.2–2 g); may repeat once	5–30 min	Smooth muscle relaxant; side-effects: flushing, hypotension, areflexia (rare)
Ketamine (induction)	1–2 mg/kg IV; infusion 0.5–1 mg/kg/h for refractory bronchospasm	30–60 s	Bronchodilator via catecholamine release; preserves spontaneous ventilation
IV salbutamol infusion	5–20 μg/min, titrate	5 min	Reserved for refractory; risks: lactic acidosis, tachyarrhythmia, hypokalaemia, ischaemia
Montelukast	10 mg IV (where available) or 10 mg PO/NG	Hours	LTRA; limited acute evidence; especially useful in AERD phenotype
Aminophylline	5 mg/kg loading if not on oral theophylline, then 0.5 mg/kg/h	30–60 min	Narrow therapeutic window; risks: arrhythmia, seizures; rarely used now
Volatile anaesthetics	Isoflurane 0.5–2% or sevoflurane 1–3% via anaesthetic machine	Minutes	Refractory bronchospasm; needs anaesthetic delivery/scavenging in ICU
Heliox (70:30 or 80:20 He:O2)	By NIV mask or ETT; up to 40% FIO2 if 70:30 mix	Immediate	Lower gas density → less turbulent flow → reduced work of breathing

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Drug-specific ICU pearls

IV salbutamol is NOT superior to inhaled in meta-analysis (Travers Cochrane 2012) — reserve IV for those who cannot inhale adequately (apnoeic, ventilated with poor nebuliser delivery). Risk of lactic acidosis (β2-driven gluconeogenesis/glycogenolysis) — do not misinterpret as sepsis.[1]
Lactic acidosis after nebulised salbutamol is common and benign — it reflects albuterol's β2 effects on hepatic glycogenolysis. Resolves as bronchospasm resolves. Do not stop salbutamol; trend PaCO2 instead.
Hydrocortisone vs methylprednisolone: meta-analyses show no clear superiority. Hydrocortisone often preferred in ICU for mineralocorticoid cover (if adrenal suppression suspected from chronic OCS). PO and IV are equivalent in efficacy (give PO if absorbing).[22]
Give steroids EARLY — onset is 4–6 hours, peak at 12 hours. Do not wait for deterioration. Steroids reduce mortality in life-threatening asthma (Cochrane).[22]
Magnesium mechanism: competes with calcium at L-type voltage-gated channels → blocks calcium influx → airway smooth-muscle relaxation. Side-effects correlate with rate — give over 20 min (NOT 5 min). Contraindicated in complete heart block, severe renal impairment (rare). May repeat dose at 30 min if poor response.[1]
Heliox requires ≥70% helium to lower density meaningfully — so it is only useful if FIO2 requirement ≤30–40%. In severe hypoxaemia, heliox is impractical. Limited evidence base (Cochrane shows inconsistent benefit); reserve for those failing maximal therapy as a bridge to intubation/ECMO.
Aminophylline is essentially historical — narrow therapeutic window (5–15 mg/L), interactions (cimetidine, ciprofloxacin, macrolides), and meta-analysis shows no benefit over β2 agonists + steroids. Avoid if patient already on chronic theophylline (toxicity).
Montelukast IV: small studies suggest faster FEV1 improvement than PO; not universally available. Particularly useful in aspirin-exacerbated respiratory disease (AERD / Samter's triad) phenotype where leukotriene drive is dominant.
Inhaled anaesthetics (isoflurane, sevoflurane) reduce dynamic hyperinflation via direct bronchodilation AND deep sedation; require anaesthetic gas scavenging and a vaporiser in ICU. Reserved for refractory cases not responding to standard therapy and ECMO.
IV Mg + IV salbutamol + heliox + volatile anaesthetics is the typical escalation ladder before ECMO consideration. Each stepwise addition buys time for steroids to take effect.

Mechanical ventilation in asthma

Ventilation strategy for intubated severe asthma (permissive hypercapnia)

Indications for intubation: cardiac/respiratory arrest, altered consciousness, exhaustion, rising PaCO2 despite treatment, silent chest, refractory hypoxaemia, extreme acidosis (pH <7.2).
RSI drugs: KETAMINE 1–2 mg/kg (bronchodilator via catecholamine release) + rocuronium 1.2 mg/kg (or suxamethonium 1–1.5 mg/kg if rapid offset desired). Avoid propofol (hypotension, histamine) and thiopental (histamine, hypotension).
ETT: largest practical (8.0–8.5 mm) — reduces resistance and allows bronchoscopy for mucus plugs.
Initial ventilator settings (volume control or pressure control):
- Mode: Volume control (ensure delivered Vt measured) or pressure control. Avoid pressure-support-only initially.
- Tidal volume: 4–6 mL/kg PBW (LOW)
- Respiratory rate: 8–12/min (LOW — give time for expiration)
- I:E ratio: 1:3 to 1:4 (long expiration)
- Inspiratory flow: 60–100 L/min (high — shortens inspiratory time, lengthens expiration)
- PEEP: 0–5 cmH2O (LOW or zero — added PEEP worsens hyperinflation in obstructed airways; set to match intrinsic/PEEPi)
Accept permissive hypercapnia: PaCO2 up to 10–12 kPa (75–90 mmHg), pH ≥7.15–7.20. Sodium bicarbonate if pH <7.1.
Target plateau pressure (Pplat) <30 cmH2O — best predictor of dynamic hyperinflation and barotrauma. If Pplat >30, REDUCE rate or tidal volume (allow more PaCO2 rise).
Deep sedation + paralysis: prevent dyssynchrony/breath-stacking. Midazolam + fentanyl + vecuronium/cisatracurium infusion. Ketamine infusion provides ongoing bronchodilation.
Monitor for dynamic hyperinflation: plateau pressure trend, expiratory flow waveform returning to baseline before next breath (look on ventilator screen). If expiratory flow does not return to zero before the next breath → breath-stacking (auto-PEEP).
Trial apnoea test at bedside: disconnect the ventilator for 30–60 s — if BP improves, you have confirmed dynamic hyperinflation (raised intrathoracic pressure was impairing venous return). Watch SpO2 throughout.
Escalation ladder if refractory: IV salbutamol infusion → ketamine infusion → inhaled volatile anaesthetics → VV-ECMO.

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Diagnosing the crashing ventilated asthmatic

Sign	Likely cause	Immediate action
Sudden hypotension, falling SpO2, unilateral breath sounds	Tension pneumothorax	Needle decompression (2nd ICS midclavicular) → chest drain; confirm with US
Hypotension with bilateral equal breath sounds, high Pplat	Dynamic hyperinflation (breath-stacking)	DISCONNECT circuit 30–60 s; reduce rate/Vt; deepen sedation/paralyse
Rising PaCO2 with stable haemodynamics	Mucus plugging / inadequate ventilation	Suction via ETT; bronchoscopy; saline lavage; adequate hydration
Falling SpO2, falling PaCO2	Worsening V/Q mismatch / fatigue	Increase FIO2; consider ECMO if refractory
Wheeze resolved but PaCO2 rising	Total airway obstruction (silent chest on vent)	Bronchoscopy for plug; escalate bronchodilators
Hypotension immediately post-intubation	Dynamic hyperinflation from bag-valve pre-oxygenation	DISCONNECT circuit; allow full exhalation

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ECMO rescue

Special situations in severe asthma

Special situations in severe asthma ICU admission

Aspirin-exacerbated respiratory disease (AERD / Samter's triad): asthma + nasal polyps + aspirin sensitivity. Leukotriene-driven — montelukast is especially effective. Consider aspirin desensitisation after recovery. Eosinophils often very high → biologic candidate (mepolizumab or dupilumab).
Allergic bronchopulmonary aspergillosis (ABPA): severe asthma + central (proximal) bronchiectasis + Aspergillus-specific IgE / positive skin test. Treat with ITCACONAZOLE 200 mg BD ×4–6 months + prednisolone taper. Omalizumab and mepolizumab have evidence as adjuncts. Total IgE often >1000 IU/mL. Elevated Aspergillus IgG confirms sensitisation.
Eosinophilic granulomatosis with polyangiitis (EGPA / Churg-Strauss): late-onset severe asthma + eosinophilia >1500 + mononeuritis multiplex + sinus disease + (often) ANCA-positive (MPO). Mepolizumab is approved (FDA 2017). Don't miss cardiac involvement (eosinophilic myocarditis) — leading cause of death in EGPA.
Vocal cord dysfunction (VCD) / inducible laryngeal obstruction: paradoxical laryngeal adduction during inspiration; "asthma" refractory to treatment; stridor rather than wheeze; normal spirometry between attacks; flattened inspiratory limb of flow-volume loop. Diagnosis: laryngoscopy during attack. Treatment: speech therapy, NOT bronchodilators.
Pregnancy: acute severe asthma — give steroids (no teratogenicity at standard doses), salbutamol, magnesium (safe). Avoid aminophylline (narrow window), avoid montelukast where data limited. Untreated asthma is worse for fetus than treated. Magnesium also provides neuroprotection for the fetus. Do not delay intubation if needed.
Elderly: lower baseline PaCO2 tolerance; higher risk of cardiotoxicity from salbutamol (atrial fibrillation, ischaemia); more likely to have asthma–COPD overlap (fixed obstruction → lower biologic eligibility).
Near-fatal asthma risk factors (BTS red flag list): previous ICU/intubation, previous near-fatal attack, >2 hospitalisations/year, >3 canisters SABA/year (proxy for uncontrolled), non-adherence with ICS, food allergy (independent risk factor for fatal asthma), psychiatric comorbidity.
Anaphylaxis vs asthma: stridor, urticaria, hypotension, abdominal cramps within minutes of trigger → anaphylaxis → IM ADRENALINE 0.5 mg (anterolateral thigh) first-line, NOT salbutamol. Coexisting asthma is the strongest risk factor for fatal anaphylaxis.

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Pathophysiology pearls — mechanism-led exam answers

Mechanism pearls for CICM/FFICM viva

Type 2 inflammation cascade: allergen / virus / pollutant → epithelial cell release of TSLP, IL-25, IL-33 (alarmins) → dendritic cell activation + Th2/ILC2 polarisation → IL-4 (IgE class switching), IL-5 (eosinophil maturation/survival), IL-13 (mucus, goblet-cell metaplasia, FeNO/iNOS, periostin). This cascade IS the biologic roadmap — tezepelumab blocks the top (TSLP), omalizumab the bottom (IgE).
Tezepelumab's mechanistic claim to fame: blocking TSLP (top of cascade) suppresses the whole downstream network, including Th17/IL-17 — which is why it is the only currently-approved biologic effective in T2-low asthma.
Bronchial thermoplasty — radiofrequency ablation (65°C) of airway smooth muscle, approved for severe refractory asthma since 2010 (AIR2 trial). Reduces exacerbations and ED visits over 5 years. Not a biologic; reserved for those who fail or cannot access biologics. Most benefit in moderate-to-severe persistent.
Macrolide (azithromycin) for non-T2 asthma: AMAZE trial (Brusselle, 2013); 250 mg 3×/week. Mechanism: anti-IL-8, reduces neutrophilic inflammation, mucus plugging, biofilm. Side-effects: QT prolongation, GI upset, hearing changes, antimicrobial resistance (population concern).
Steroid resistance mechanisms in neutrophilic asthma: GRβ (inactive glucocorticoid receptor isoform), p38 MAPK activation, HDAC2 downregulation (oxidative stress). Theophylline restores HDAC2 activity — theoretical rationale for steroid-sparing synergy.
Fixed obstruction (FEV1/FVC <0.7 post-bronchodilator) in asthma is due to airway remodelling (subepithelial basement membrane thickening, smooth-muscle hypertrophy, fibrosis, angiogenesis). Biologics will NOT reverse this; only early aggressive therapy may prevent progression.
Mucus plugging is a major cause of fatal asthma. Pathology of fatal asthma shows goblet-cell hyperplasia + airway casts (Curschmann spirals, Charcot-Leyden crystals). Aggressive hydration, mucolytics (N-acetylcysteine — limited evidence), bronchoscopy with saline lavage for refractory cases.
Late-onset eosinophilic asthma (LOEA) — adult-onset, non-atopic, IL-5-driven, often severe from outset, frequently steroid-dependent, sinusitis common. The best target for anti-IL-5 therapy.
β2-receptor downregulation with sustained SABA use — mechanism of tachyphylaxis. Also explains why chronic high-dose SABA without ICS is dangerous (SABA-only increases asthma mortality — Salmeterol Multicenter Asthma Research Trial, SMART).
Adrenal suppression with chronic OCS — minimum dose to maintain control, switch to inhaled budesonide/formoterol MART regimen where possible, consider biologic to enable OCS taper. Stress-dose hydrocortisone (50–100 mg IV) at induction of anaesthesia in any chronic-OCS patient.

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Exam pitfalls and frequent misconceptions

Common exam traps in severe asthma

Wheeze severity does NOT correlate with airflow limitation severity. A loud wheeze with good air movement may be reassuring; a quiet chest with poor air movement is pre-arrest. Trust the PaCO2 and PEF, not the wheeze.
PEF 33–50% predicted = acute severe; PEF <33% = life-threatening (BTS/SIGN). Always compare to patient's personal best (or predicted if unknown).
Chest X-ray is NOT for diagnosis — it is to exclude pneumothorax, pneumomediastinum, consolidation, and to identify alternative diagnoses (cardiogenic pulmonary oedema, large airway obstruction). Get one in any ICU admission.
Sputum eosinophils >3% predicts steroid responsiveness; ≥2–3% in induced sputum is the gold standard for eosinophilic phenotype. FeNO >50 ppb is a useful surrogate where sputum induction unavailable.
Lactic acidosis after salbutamol does NOT predict deterioration — it is expected. Trend PaCO2 instead. Don't stop salbutamol.
β-blockers are NOT absolute contraindicated in asthma as historically taught — cardioselective β1-blockers in low dose are safe (GINA 2022). Non-selective β-blockers (propranolol, timolol eye drops) remain contraindicated.
Biologic non-responders: ~30–40% of severe T2 asthma patients do not respond to anti-IL-5. Switch class (anti-IL-5 → anti-IL-4Rα or anti-TSLP) at 4–12 months if no response by standard response criteria.
Anti-IL-5 takes 4–12 weeks to work; omalizumab 12–16 weeks; dupilumab 2–4 weeks (fastest); tezepelumab 2–4 weeks. None for acute attacks.
Anaphylaxis to biologics is rare (<0.2%) but reslizumab has the highest rate (~0.3%) — requires post-dose monitoring; SC biologics are far safer than IV reslizumab.
Combining biologics (e.g. omalizumab + mepolizumab) is generally NOT recommended outside trial — limited evidence, high cost, additive immunosuppression concerns. Consider only in highly selected severe cases under specialist supervision.
Near-fatal asthma is a cardiology exam too: arrhythmias from hypokalaemia (β2 agonists) + acidosis (hypercapnia) + hypoxia = ventricular arrhythmias. Monitor ECG, replace K+, correct acidosis.
Pre-oxygenation of the asthmatic is NOT the same as a normal RSI: bag-valve mask ventilation worsens dynamic hyperinflation rapidly. Use nasal HFNC + ramp head-up; minimise bagging; have largest ETT ready.

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Outcome metrics after biologic initiation

Response criteria after biologic initiation

Metric	Response threshold	When to assess
Annualised exacerbation rate	≥50% reduction	12 months
Asthma Control Questionnaire (ACQ-5)	↓ ≥0.5	4–6 months
Asthma Quality of Life Questionnaire (AQLQ)	↑ ≥0.5	4–6 months
FEV1	↑ ≥100 mL	4–6 months
Oral corticosteroid dose	↓ ≥50% (or stop)	4–6 months
Blood eosinophils	Depleted to zero (benralizumab/mepolizumab)	Ongoing
FeNO	↓ ≥20% (dupilumab, tezepelumab)	4–6 months
SABA reliever use	↓ ≥50%	4–6 months

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Outcome and prognosis

High-risk scenarios in severe asthma ICU

Silent chest + bradycardia + hypotension = pre-arrest — intubate now, do not delay for arterial line.
Normocapnia in any acute asthmatic = fatigue → imminent hypercapnic arrest.
Rising PaCO2 despite maximum therapy = refractory status — escalate (IV Mg already given, IV salbutamol, volatile anaesthetics, ECMO).
Asymmetric breath sounds in ventilated patient = pneumothorax until proven otherwise → needle decompression first, confirm later.
Hypotension immediately post-intubation in asthma = dynamic hyperinflation → DISCONNECT circuit 30–60 s (or less if desaturating).
Lactate >10 mmol/L after IV salbutamol = consider reducing infusion; lactic acidosis can cause respiratory muscle fatigue and confusion.
Non-T2 patient with neutrophilia + fever = treat infection; biologics ineffective.
Pregnant + status asthmaticus = treat aggressively; maternal hypoxaemia = fetal distress. Untreated asthma is more dangerous than treated asthma in pregnancy.
Cessation of wheeze after intubation WITHOUT improvement in PaCO2 = worsening obstruction (silent lung) — escalate bronchodilators, bronchoscopy for plug, consider ECMO.
Food allergy + severe asthma = highest-risk combination for fatal asthma — ensure adrenaline autoinjector + asthma action plan.

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Steroid dosing evidence in acute asthma

Rowe Cochrane 2018: PO prednisone 40–50 mg/day for 5–10 days = IV hydrocortisone 100 mg q6–8h in efficacy. No advantage to high-dose (>80 mg) over standard. IV preferred in ICU for those who cannot take PO or are vomiting.[22]
Harrison (REASTHMA, 2009): dexamethasone 16 mg/day for 2–5 days non-inferior to 5–7 days of prednisone; fewer relapses; increasing ED preference.
Rowe Cochrane 2017 (children): short courses (5 days) prevent relapse within 7–30 days; longer courses do not add benefit in adults.

Magnesium and heliox evidence

Kew Cochrane 2014: IV MgSO4 (single 2 g dose) in severe asthma reduces hospital admission (NNT ~9), improves FEV1 by 10–15%; benefit concentrated in the most severe subgroup.[1]
Kew Cochrane 2014: nebulised MgSO4 added to salbutamol shows marginal benefit in severe subgroup only; not routinely recommended.
Rodrigo / Cochrane heliox: heliox for acute asthma shows no consistent benefit; reserved for patients unable to be intubated, or as bridging to VV-ECMO. Requires ≥70% helium to lower gas density meaningfully.

Biologics in special populations

Mepolizumab in EGPA (Wechsler, NEJM 2017): 50% reduction in relapse; FDA-approved for EGPA at 300 mg SC q4 wk (vs 100 mg for asthma).
Omalizumab in chronic spontaneous urticaria (CSU): 150/300 mg q4 wk — alternative dermatology use.
Dupilumab in CRSwNP (LIBERTY NP): significant polyp regression; also reduces asthma exacerbations in comorbid patients — a "two-for-one" drug.
Benralizumab in COPD (GALATHEA / TERRANOVA): NEGATIVE trials — eosinophil depletion does NOT improve COPD outcomes; reinforces that eosinophilia in COPD ≠ same biology as asthma.
Dupilumab in COPD with type-2 inflammation (BOREAS, NOTUS, 2023): POSITIVE — reduced exacerbations in eos ≥300 — first biologic to show COPD benefit in a T2-enriched subgroup.
Mepolizumab / benralizumab / dupilumab in ABPA: emerging off-label evidence; dupilumab most promising (reduces OCS and IgE).

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Long-term management and post-ICU care

Post-ICU asthma care bundle (BTS/SIGN)

Written asthma action plan — patient (and family/carer) taught to recognise deterioration, escalate ICS, start OCS, call for help. PEF-based or symptom-based. The single most effective intervention to reduce readmission.
Medication review at discharge: ensure ICS/LABA prescribed + technique checked with spacer; add LTRA; document biologic if on one (do NOT stop during/after exacerbation).
Address adherence — inhaler technique observation, electronic monitoring if available; non-adherence is the #1 cause of "refractory" asthma.
Comorbidity screen — GERD, OSA, rhinosinusitis, depression, anxiety, vocal cord dysfunction, bronchiectasis. Treat each.
Trigger identification — allergens (skin-prick test / specific IgE), occupational (work-relatedness chart, serial PEF), drugs (β-blockers, NSAIDs in AERD), stress.
Smoking cessation — both active and passive smoke exposure. Vaping is an emerging trigger; e-cigarette use associated with bronchiectasis and EVALI.
Refer to severe asthma service for biologics if not already initiated (post-ICU admission is an automatic referral criterion in most health systems).
Vaccinations — annual influenza, pneumococcal (PCV13 + PPSV23), COVID-19, RSV (if eligible), pertussis booster if appropriate.
Follow-up spirometry at 4–6 weeks — to document recovery and assess fixed obstruction (post-bronchodilator).
Mental health screen — anxiety and depression common in severe asthma; associated with worse outcomes; treat. Cognitive behavioural therapy and breathing retraining help.

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Final high-yield summary pearls

Final high-yield summary pearls for CICM/FFICM/EDIC

The single most important blood-gas variable in acute asthma is PaCO2. Hypocapnia = good; normocapnia/hypercapnia = fatigue/arrest.
The single most important ventilator variable in intubated asthma is plateau pressure. Keep <30 cmH2O to avoid barotrauma. Auto-PEEP is the second.
All currently licensed biologics are T2-targeted EXCEPT tezepelumab, which works across all phenotypes via epithelial alarmin (TSLP) blockade.
Anti-IL-5 (mepolizumab, benralizumab, reslizumab) for eos ≥300; anti-IgE (omalizumab) for allergic + IgE 30–700; anti-IL-4Rα (dupilumab) for broad T2 incl. eos <300; anti-TSLP (tezepelumab) for any phenotype including T2-low.
Biologics reduce exacerbations 40–70% but never reverse fixed obstruction. They are adjunctive, not curative, and must be continued long-term (or asthma returns within months).
Bronchodilator response (salbutamol/ipratropium) is preserved regardless of phenotype. Steroid response is greater in T2-high; biologic response is greatest in T2-high.
Magnesium sulphate 2 g IV — should be given to ANY patient with life-threatening features not responding to initial nebulisers + steroids. Cheap, safe, effective (NNT ~9 for admission reduction).
Mechanical ventilation is the last resort — and the goal is permissive hypercapnia + low pressure. Never chase PaCO2 normalisation at the expense of barotrauma.
ECMO rescue is rare but life-saving for refractory cases — outcome is far better than for ARDS VV-ECMO (~80% vs 60%).
The fatal asthma pathway is: untreated inflammation → mucus plugging → asphyxia (or tension pneumothorax from ventilation). Treat inflammation aggressively; clear mucus; avoid over-ventilation.
Non-T2 asthma is a distinct disease — neutrophilic, steroid-resistant, no biologic target — azithromycin, treat comorbidities, pulmonary rehab, bronchial thermoplasty in selected cases.
Pregnancy: severe asthma MUST be treated aggressively — maternal hypoxaemia is the real teratogen, not the drugs. Magnesium also protects the fetal brain.
Examination classic answer: "In any patient with life-threatening asthma, give O2, nebulised salbutamol + ipratropium, IV hydrocortisone, IV magnesium sulphate — and prepare for intubation if PaCO2 normalises or rises."
Biologics are PROPHYLACTIC — never stop them during an exacerbation, never start them to treat one. Continue background biologic; treat the exacerbation with standard therapy.

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