Anna McFarlin, MD

Most common chronic disease of childhood◦ 9.5% of children in the US

More than 1 million ED visits per year◦ 1/4 children ages 0-4 with asthma visit the ED annually◦ 2005-2007: 174 deaths/year in children from asthma

Current evidence clearly supports the use of inhaled bronchodilators and systemic steroids as first-line agents.

In those who fail to respond to initial therapies, a variety of adjunct therapies and interventions are available with varying degrees of evidence to support their use

Akinbami 2011

To review current national guidelines for standard management of acute asthma

To describe strategies for refractory “near-fatal” asthma including mechanical ventilation and adjunct therapies

Diagnosis Pathophysiology Long term management Asthma Severity Assessment Asthma Action Plans Prevention

3 yo male with history of asthma presented to ED in respiratory arrest◦ HPI ~1 day URI sx. No previous admits for asthma◦ PE: Cyanotic, unresponsive, strong tachycardic

pulse, undetectable SaO2 Difficult BVM with minimal air mvmt

Next steps? Medications? Ventilation strategies?

Airway narrowing Extensive plugging of airways with mucus

and inflammatory infiltrates Hyperinflation Atelectasis Ventilation and perfusion mismatch

Doubling of beta agonist usage in the previous month◦ Overdependence on beta agonists (>1-2 canister monthly)

Current/recent use of glucocorticoids or not on ICS Frequent admissions (≥2/yr) or ED visits (≥3/yr) Admission to ICU or intubation Adolescents Non-Hispanic black Low socioeconomic status Illicit drug use History of psychiatric disease Difficulty recognizing severity of symptoms No written action plan

Mitchell, Martin, Belessis

Work-up◦ Vitals◦ Pulse ox◦ H&P◦ Blood gas◦ CXR

Therapy◦ Oxygen◦ Beta-agonists◦ Ipratropium◦ Corticosteroids

Routine use of ABG testing in all children with acute asthma is NOT justified◦ Pulse ox to evaluate oxygenation

No set values for pH, PCO2, PO2 that are diagnostic for respiratory failure

Do NOT be reassured by a normal blood gas In a child with severe, acute asthma, a rising

PCO2 is worrisome and predictive of respiratory failure

Moses, Casati, Langhan, Kanis, Carruthers

Rarely affect patient management Usually abnormal: Hyperinflation, atelectasis Consider if:◦ Fever◦ Hypoxia◦ Focal abnormalities on exam◦ Not responding to treatment◦ No personal or family history of asthma ◦ R/O foreign body, Pneumothorax,

pneumomediastinum

Tsai, Roback, Mahabee-Gittens

>90% of children with asthma exacerbations have a transient VQ mismatch and hypoxemia ◦ Temporarily worse by inhaled β-agonist treatment

Oxygen is recommended for most patients Guidelines:◦ >90-93% for severe exacerbations◦ >95% in children (GINA), pregnant women (NIH),

patient’s with heart disease (NIH)

GINA 2014, NAEPP 2007

Firmly established as the standard first-line therapy in the treatment of children with asthma

MDI with spacer: most cost effective & efficient Nebulized dose: 0.15-0.3 mg/kg/treatment◦ Max: 10 mg per treatment

Evidence supports continuous therapy◦ 0.5 mg/kg/h (Max 20-45 mg/hr)

Side effects: tremors, tachycardia, headache, hypokalemia◦ Clinical significance of hypokalemia?

No evidence for IV or oral β2 agonists

NAEEP 2007, Sabato 2000

R-enantiomer In vitro studies: S-enantiomer may have

detrimental effects tachycardia and jitteriness NIH: “Clinically comparable” No clinical benefit vs albuterol◦ No decrease in tremor, vomiting, palpitations,

nervousness◦ No difference in hospitalization or ED length of stay◦ Higher cost◦ ? Modest decrease in tachycardia ?Cardiac history

NAEPP 2007, Qureshi 2005, Rubin 2012

Anticholinergic Beneficial adjunct – ineffective monotherapy Acute setting only – no benefit to the addition

of ipratropium in the inpatient setting Severe asthma (PEF <40% predicted)◦ Improves pulmonary function◦ Reduces hospitalizations ◦ 1-3 doses during 1st hour of treatment

Moderate asthma (PEF 40-70% predicted)◦ May reduce hospitalizations◦ May reduce length of ED treatment

NAEPP 2007

“Recommended for all but the mildest cases” Reduced symptoms, hospitalizations, relapses Early use decreases hospitalization rates◦ Clinical effect begins within 4 hours◦ Triage nurse initiated corticosteroids Time-series controlled trial (n=644) Admission less likely (OR = 0.56, 95% CI: 0.36-0.87) Improved time to steroid receipt (P<0.001) Improved time to achieving mild status (P=0.04) Improved time to discharge (P=0.02)

NAEPP 2007, Zemek 2012

PO preferred over IV ◦ Equal efficacy (Class A Evidence)◦ Less invasive

1-2 mg/kg Max 40-60 mg Continue in hospital (Class A Evidence) Give supplemental doses to patients who take

them regularly, even if exacerbation mild (Class D Evidence)

NAEPP 2007, Qureshi 2001

Recommendations between 3-10 days Noncompliance with 5 days is common Decadron (0.6 mg/kg)◦ 5d prednisone = dexamethasone (IM/IV x 1d, PO x 2d) Decreased ED relapses and admissions 7-10 days post

discharge Significant cost savings Decreased vomiting Increased compliance

Andrews 2012, Gordon 2000, Greenberg 2008, Gries 2000

Inadequate evidence to recommend their use alone in acute asthma (Evidence B)

Early guidelines: double the dose of inhaled corticosteroid during asthma exacerbation ◦ Not effective

New evidence: ◦ ICS initiated early in adults may obviate the need for

systemic corticosteroids 2 mg flunisolide/hr or 3mg fluticasone/hr x 3hr Data in children inconsistent Data suggestive but not yet enough evidence

Edmonds 2003, FtizGerald 2004, Garrett 1998, Harrison 2004, Rice-McDonald 2005, Rodrigo 2005

Magnesium Methylxanthines Leukotriene Modifiers Terbutaline Antibiotics Mucolytics CPT Isoproteronol Epinephrine

Smooth-muscle relaxation and bronchodilator◦ Effect in 2 min after infusion, plateau 20-25 min,

lasts 1-2 hours Meta-analysis: ◦ Decrease hospital admissions (p=0.0006; NNT=4)

May improve lung function with severe exacerbations

Hypotension, flushing, changes in heart rate, muscle weakness

Blitz 2005, Cheuk 2005, NAEEP 2007

NIH (Evidence B)◦ Indicated for children whose FEV1 fails to improve

above 60% predicted after 1 hour of care Cochrane◦ No clinically important changes in all comers◦ Severe asthma Improved FEV1 by 9.8% (95%CI: 3.8-15.8) Admissions reduced (OR 0.10, 95% CI: 0.04-0.27)◦ Safe and beneficial in severe acute asthma

NAEPP2007, Rowe 2009

Decreased admission and improved pulmfunction?

NIH: May be beneficial, more research needed Cochrane: 16 trials, n=896 (adults & kids)◦ Inhaled Mg vs albuterol ?poor lung function, no improvement in admissions

◦ Inhaled Mg plus albuterol No improvement in pulmonary function (95% CI -0.27 to

0.74, n=188) or admissions (95% CI 0.49-1.16, n=249)◦ Inhaled Mg plus albuterol and atrovent +improvement in pulm function

◦ Possible benefit in severe asthma in addition to albuterol +/- atrovent

Blitz 2005, NAEPP 2007, Powell 2012

Direct bronchodilator Immunomodulator, antiinflmmatory effects Theophylline, aminophylline Cochrane: Methodological quality high◦ Improves FEV1 and PEF within 6 hrs

Mitra 2005

NIH: Not recommended (Evidence A)◦ No apparent reduction in symptoms◦ Does not reduce number of treatments or LOS◦ Does not prevent intubation◦ Does not avoid ICU admission◦ May increase critical care unit length of stay and

time to improvement◦ Vomiting, headache, abd pain,

palpitations/arrhythmias, intractable seizures◦ Requires serum drug levels

Dalabih 2012, Mitra 2005, NAEEP 2007

Binds leukotriene in the lungs reducing bronchoconstriction and inflammation

No role oral dose in acute asthma Adult study:◦ Significant improvement in FEV1 after IV Singular◦ Reduction in the risk of hospital admission

Peds study:◦ No benefit, no improvement in FEV1

Camargo 2010, NAEPP 2007, Watts 2012

IV, SQ, nebulized Nebulized terbutaline not as good as

nebulized albuterol Retrospective chart review (n=120)◦ Early administration of continuous IV terbutaline in

the ED resulted in decrease in mechanical ventilation (16 vs 60%, p=0.001) over late administration

Doymaz 2014

Prospective, double blind, RCT pediatric acute severe asthma (n=49)◦ PICU, continuous albuterol, not intubated◦ Continuous IV terbutaline vs NS◦ Terbutaline group Fewer hrs of albuterol (38 vs 52 hrs; p=0.073) Shorter PICU LOS (13 hrs longer for placebo group;

p=0.345) None were statistically significant Terbutaline group had 3 pts with elevated troponin

Bogie 2007

No GINA, NAEPP/NIH recommendations Cochrane◦ Beta2-agonists: IV vs nebulized No evidence to support the use of IV β2-agonists

alone. These drugs should be given by inhalation.◦ IV β2-agonists in addition to continuous nebulized β2-agonists Limited evidence to suggest shorter recovery time and

improved pulmonary index scores

Travers 2001, Travers 2012

NIH (Evidence B)◦ Antibiotics are generally not recommended for the

treatment of acute asthma exacerbations◦ Unless… Evidence for pneumonia Strong suspicion of bacterial sinusitis Fever and purulent sputum

NIH (Evidence C)◦ Avoid mucolytic agents (acetylcysteine, potassium

iodide) because they may worsen cough and airflow obstruction ◦ ?Pulmozyme, Atrovent

NIH (Evidence D)◦ CPT is not beneficial and unnecessarily stressful for

breathless asthma patient◦ Further studies needed for ventilated patients

NAEPP 2007

Β-agonist NIH does not recommend use of IV

isoproterenol in treatment of asthma because of the danger of myocardial ischemia in children

NAEPP 2007

Paucity of literature Systemic (IV, IM, SQ) vs inhaled Beta agonist properties may result in

bronchodilation Vasoconstriction may decrease mucus

production Potential for excessive cardiac stimulation

Retrospective review adults with severe asthma◦ No efficacy data◦ Low rate of major and moderate rate of minor adverse

events SVT, CP with EKG changes, elevated troponin

Randomized controlled crossover study:◦ SQ terbutaline demonstrated better improvement in

RR, HR and wheezing than comparable epinephrine Prospective, RCT: ◦ Sus-Phrine plus albuterol vs albuterol alone◦ No significant difference

Kornberg 1991, Putland 2006, Victoria 1989

GINA◦ SQ or IM not indicated for acute asthma

NIH◦ Non-selective beta agonists including epinephrine

are not recommended due to their potential for excessive cardiac stimulation◦ 1:1,000 0.01 mg/kg up to 0.3-0.5 q20 min x 3◦ No proven advantage of systemic therapy over

aerosol

GINA 2014, NAEPP 2007

Double blind, RCT of racemic epinephrine versus albuterol ◦ No significant difference in pulmonary index score,

length of stay, admission, or relapse◦ Epi group had significantly more minor side effects

Meta-analysis of nebulized epinephrine versus β2 agonists in adults and kids◦ Nonsignificant improvement in Peak Flow and FEV1

compared to patients getting epi v salbutamol or terbutaline

Plint 2000, Rodrigo 2006

Ketamine NIPPV/BiPAP Heliox

Bronchodilation and bronchorrhea◦ May aid in clearing mucus plugs

Induction agent of choice in asthma Side effects: Laryngospasm, emergence

phenomenon, lowers seizure threshold

Prospective observational study children with refractory acute asthma in the ED (N=10)

Loading dose of 1 mg/kg followed by 0.75 mg/kg/hr x 1 hr

1 hour post ketamine infusion:◦ Clinical asthma score

decreased from 14 to 9.5 (p<0.05)

◦ RR decreased from 39-30 (p<0.05)

Petrillo 2001

Double-blinded, randomized, placebo-controlled trial

2-18 years with Pulmonary Index Score of 8-14 after 3 nebs/steroids (n=68)

Loading dose 0.2 mg/kg followed by 0.5 mg/kg/hr infusion x 2 hr vs placebo along with continuous albuterol neb

No significant difference in groups◦ Pulmonary Index Scores decreased by 3.2 in

ketamine group and 3.6 in placebo group (95% CI -0.4 to 1.3)

Allen 2005

Case reports using ketamine successfully to avoid mechanical ventilation

Case reports in pediatric ventilated status asthmaticus◦ Continuous infusion of ketamine (1.0-2.5 mg/kg/h)

immediately improved airway obstruction

Denmark 2005, Rock 1986

Cochrane◦ Only single study of non-intubated children◦ Did not show significant benefit◦ No review for adults◦ No studies available for intubated patients◦ Future study needed

NIH◦ Despite theoretical benefits as premedication for

intubation, clinical trials in non-intubated patients have not shown clinical benefit

Jat 2012, NAEPP 2007

BiPAP may facilitate administration of inhaled beta agonists◦ Recruits small airways

May improve oxygenation, decrease WOB/fatigue Safe, well tolerated Requires cooperative patient with spontaneous

respirations No clear age cutoff◦ One study ages 2-11 years◦ Clear guidelines not yet established

May offer alternative to intubation

◦ Retrospective review (n= 83) of ED patients initially designated for admit to PICU 88% tolerated 77% decreased RR (by 24% on average) 88% improved oxygenation (by 7% on average) 10% rescued from PICU admit No adverse events

Beers 2006

Retrospective analysis (n=165) of mod/sevasthmatics <20kg in PED

Improvement in Pediatric Asthma Score (12.1 6.3)

5% patients discharged

Williams 2011

Crossover study (n=20) in PICU◦ 1 intubated◦ 3 discontinued due to discomfort

Clinical Asthma Score and Respiratory Rate improved in all patients

Discontinuation of NIPPV associated with increased RR and CAS

Thill 2004

Prospective, RCT (n=20) in PICU Standard care +/- NIPPV In NIPPV group: ◦ Improvement in CAS improved at 2, 4-8, 12-16,

and 24 hrs after initiation of interventions (P<0.01)◦ Improvement in RR (p=0.01)◦ Fewer children required adjunct therapy (11% v 50%,

p=0.07)◦ No major adverse events◦ 9/10 tolerated NIPPV

Basnet 2012

Cochrane◦ Paucity of data◦ Suggestion of decreased need for intubation in adults◦ Meta-analysis not possible◦ No pediatric recommendations

NIH◦ No recommendations

Possible additional benefit

Lim 2012

Mixture of helium and oxygen Promotes less-turbulent airflow through

narrowed airways Increased laminar flow may reduce WOB and

promote inhaled drug delivery May enhance diffusion effect on elimination of

CO2 Decreases auto-PEEP May prevent respiratory failure in children when

used early Oxygen concentrations >30% significantly reduce

the efficacy of heliox

Lee 2001

Much literature is anecdotal Controlled cohort of 2m-12y with mod-sev

obstructive disease in the ED Nebs x 6 in Heliox (80:20) v O2 over 2 hours

in ED (n=60)◦ 55% required more treatment in Heliox group v 95%

in O2 group (p=0.034)◦ At 12 hr: 35% of Heliox group still requiring obs v

68% O2 group (p=0.02)

Braun Filho 2010, Lee 2005

RCT of Albuterol in Heliox v control (n=40) No statistically sig difference at 10-20 min

with Heliox (p=0.169 and p=0.062) No statistically sig difference in admission

rate

Rivera 2005

Study: RCT of 2-18 yrs with mod-sev asthma received nebs via 100% O2 v 70:30 Heliox◦ Change in Pulmonary index scores: Heliox 6.67 v

O2 3.33 (p = <0.001)◦ Discharge: Heliox 73% v O2 33% (p = 0.05)

Kim 2005

Case series of pediatric ventilated patients◦ Addition of Heliox Decreased PIP (40.5 to 35.3) Increased pH (7.26 to 7.32) Decreased CO2 (58.2-50.5)

Abd-Allah 2003

Cochrane Review◦ 10 trials (3 pediatrics)◦ Total 544 patients◦ No significant differences in admission or pulm function◦ Some improvement in pulm function only pts with the

most severe pulmonary function impairment◦ Interpret with caution: “No role to play in initial

treatment of patients with acute asthma” NIH: ◦ Discrepancy in findings due to small sample sizes◦ “Consider heliox-driven albuterol nebulization for

patients who have life-threatening exacerbations and for those patients whose exacerbation remain in the severe category after 1 hours of intensive conventional therapy”

NAEPP 2007, Rodrigo 2014

Mechanical Ventilation Precedex Inhalational Anesthetics ECMO

Poor response to therapy Rising CO2 (PCO2 >50) Severe hypoxia (PaO2 <60) Waning mental status Impending respiratory arrest Cardiopulmonary arrest

Avoid if possible:◦ High risk of worsened hyperinflation, barotrauma &

hypotension◦ ETT is noxious stimuli – worsens bronchospasm◦ Longer PICU duration and longer length of stay

when adjusted for severity Concerns:◦ High lung inflation pressures◦ Auto-PEEP◦ Dynamic changes in lung compliance, airway

resistance, VQ mismatch

Roberts 2002, Sabato 2000

No gold standard Cuffed ETT Anticipate hypotension Pressure vs Volume Modes◦ PCV has decelerating inspiratory flow Ideal for short inspiratory time Consistent MAP, requires less FiO2

◦ PCV decreased duration of ventilation (29 vs 24-52 hrs) and time to achieve normocarbia (5 vs 15-20 hrs)

◦ Dual-control mode – Pressure control with volume assured ventilation ideal?

HFOV contraindicated due to dynamic air-trapping

Sabato 2000, Sarnaik 2004, Stewart 1996

NIH Class C evidence Goal: ◦ Adequate oxygenation and ventilation ◦ Minimizing high airway pressures and barotrauma

Hypercapnia due to increased physiologic dead space from hyperinflation

No controlled studies comparing normocapnia with hypercapnia

Underventilation agitates patients – generous sedation/muscle relaxation may be required

Leatherman 2007, Mutlu 2002, NAEPP 2007

No consensus Animal studies: CO2>100 decreased

perfusion Increased intracranial pressure◦ Extreme = myocardial depression, cerebral

hemorrhage, herniation, quadriparesis (>120-135) Decreased cardiac contractile force Avoid with preexisting cerebral disease or

myocardial dysfunction Keep PCO2<90-100 and pH>7.15-7.2◦ May buffer with tromethamine

Leatherman 2007, Mutlu 2002, NAEPP 2007

“Low and slow”◦ Low tidal volume: 5-6 mL/kg◦ RR = half normal for age◦ Minute ventilation ~100 mL/kg

Goal plateau pressures <25-30 Allow time for exhalation◦ I:E ratio = 1:3 or longer

PEEP:◦ Initial PEEP = 0-3◦ Adjust PEEP to measured auto-PEEP Expiratory hold maneuver

◦ PEEP above auto-PEEP is not recommended

NAEPP 2007, Duval 2000; Sabato 2000, Sarnaik 2004, Stewart 1996

Every attempt should be made to keep ventilator days to a minimum

EtCO2 monitoring◦ EtCO2 does not reflect PaCO2 well in VQ mismatch◦ Capnogram Assess severity of air trapping, eval bronchodilator

therapy, guide appropriate ventilation paramenters

Sabato 2000

Selective alpha2-adrenoceptor agonist In vitro studies:◦ Smooth muscle relaxation and prevention of

bronchoconstriction Animal studies:◦ Completely blocked histamine-induced

bronchoconstriction in 5 dogs Case reports: ◦ Facilitates induction of NPPV in adults

Groeben 2004, Takasaki 2009

Airway smooth muscle relaxation Within 30 min Anecdotal case reports Practical limitations Safety: ◦ Hypotension◦ Withdrawal/encephalopathy◦ ?renal or hepatic injury

Restrepo 2005, Shankar 2006, Tobias 2009, Wheeler 2000

Retrospective case series of 6 children with PIP >40◦ Isoflurane: ↓ PIP, ↑ pH, ↓ PaCO2

Retrospective case series of 10 children with PIP >45, pH <7.25, PaCO2>80◦ Improved minute ventilation, decreased peak

pressures, shortened expiratory phase, improved PaCO2 (p=0.032) and pH (p=0.028)

Restrepo 2005, Shankar 2006, Wheeler 2000

Evidence?◦ Database review of >40 children’s hospitals 2004-

2008 3% of asthmatic pts requiring mechanical ventilation

(n=47) Longer lengths of stay, duration of ventilation, and

higher hospital charges No mortality benefit

Possible additional benefit above conventional therapy

Char 2013

Indication◦ Severe refractory respiratory

acidosis, hypercarbia ECMO ◦ ELSO registry data 1986-2007 64 children with severe refractory asthma Ages 1-10, median PCO2 = 130, pH = 6.89 Survival = 83% -95%

Pumpless Extracorporeal Lung Assist Risks hemolysis, post-decannulation thrombosis,

sepsis, renal insufficiency, neurologic sequelae

Florchinger 2008, Hebbar 2009, Tobias 1997

Diagnosis/Predictive◦ Exhaled nitric oxide in diagnosis◦ Urinary leukotriene E4

Treatment: ◦ Nebulized lidocaine◦ Nebulized Heparin◦ Nebulized TPA◦ Anti-IgE therapy with omalizumab◦ IVIG, hydroxychloroquine, colchicine, cyclosporin,

methotrexate◦ Antifungal therapy◦ Complimentary and alternative treatments

Intubated after induction with Ketamine Treated in ED with continuous albuterol,

magnesium, solumedrol, and terbutaline Initial blood gas: 6.80/110 Remained mechanically ventilated using

permissive hypercapnia strategies in the PICU x 2 weeks on high dose continuous albuterol, magnesium, Precedex, ketamine, terbutaline, solumedrol◦ Severe VQ mismatch – high need for FiO2◦ Bacterial trachiitis

O2 to relieve hypoxemia SABA for all patients (Evidence A) Inhaled ipratropium in severe exacerbations

in ED (Evidence A) Systemic corticosteroids (Evidence A) Adjunct treatments (magnesium, heliox)

merit consideration to decrease likelihood of intubation (Evidence B)

Does not recommend methylxanthines, antibiotics, aggressive hydration, CPT, mucolytics, sedation, increased dosing of ICS

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