Management of Status Asthmaticus in Children Muriel Konickx 2013

Paediatric Respiratory Reviews xxx (2013) xxxxxx

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YPRRV-903; No. of Pages 8

Mini-Symposium: Respiratory Emergencies in Children

Management of status asthmaticus in children

Muriel Koninckx 1,*, Corinne Buysse 2, Matthijs de Hoog 2

1 Paediatric Intensive Care, Middelheim Ziekenhuis, Lindendreef 1, Antwerp, Belgium2 Paediatric Intensive Care, Sophia Childrens Hospital, Dr Molewaterplein 60 Rotterdam, The Netherlands

A R T I C L E I N F O

Keywords:

Paediatric status asthmaticus

Pathophysiology

Assessment

Treatment

S U M M A R Y

Recent literature on paediatric status asthmaticus (PSA) confirms an increasing percentage of admissions

to paediatric intensive care units. PSA is a medical emergency that can be fatal and needs careful and

prompt intervention. The severity of PSA is mainly determined by clinical judgement of signs and

symptoms. Peak flow measurements and serial lung function measurements are not reliable in PSA.

Validated clinically useful instruments are lacking. The three main factors that are involved in the

pathophysiology of PSA, bronchoconstriction, mucus plugging and airway inflammation need to be

addressed to optimise treatment. Initial therapies include supplementation of oxygen, repetitive

administration of rapid acting b2-agonists, inhaled anticholinergics in combination with systemicglucocorticosteroids and intravenous magnesium sulphate. Additional treatment modalities may include

methylxanthines, DNase, ketamine, sodium bicarbonate, heliox, epinephrine, non-invasive respiratory

support, mechanical ventilation and inhalational anaesthetics.

2013 Elsevier Ltd. All rights reserved.

EDUCATIONAL AIMS

The reader will be able to:

Understand the pathophysiology of paediatric status asthmaticus Assess the severity of an asthma exacerbation, Implement different treatment strategies for severe asthma.

Contents lists available at SciVerse ScienceDirect

Paediatric Respiratory Reviews

INTRODUCTION

Paediatric status asthmaticus (PSA) is a medical emergencywarranting prompt recognition and intervention. A status asth-maticus or severe asthma exacerbation is defined as an acuteepisode that does not respond to standard treatment with shortacting b2-agonists and corticosteroids, although a large variationexists in this definition between authors.13 In other definitions,need for hospitalisation, emergency room visit or decline in peakexpiratory flow (PEF) is also taken into account. PSA can result inrespiratory insufficiency as well as circulatory failure and ispotentially life-threatening. The incidence of PSA has to be viewedagainst the background of the total number of asthmatic patients.4

In the United States, the number of patients with asthmaincreased from 20.3 million to 25 million between 2009 and 2011.In 2009 the prevalence among children (less than 18 years old) was

* Corresponding author. Tel.: +0032/496068751; fax: +0032/2810292.

E-mail address: [email protected] (M. Koninckx).

Please cite this article in press as: Koninckx M, et al. Management of stdx.doi.org/10.1016/j.prrv.2013.03.003

1526-0542/$ see front matter 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.prrv.2013.03.003

9.6%. The prevalence in children is higher than in adults (9.6%versus 7.7%). Mortality in children is lower compared to adults.Asthma was linked to 3,447 deaths including 5.4% children (about9 per day) in 2007.5 The prevalence of asthma is increasing,however, mortality is decreasing. This might, in part, be due to acoding change from ICD-9 to ICD-10 (Fig. 1). In the ICD-9classification asthma was subdivided in intrinsic, extrinsic andchronic obstructive asthma. The ICD-10 classification uses thedescriptors of mild, moderate and severe asthma.

The increasing prevalence of asthma is seen mainly indeveloped countries. Environmental factors play an importantrole in this disease, next to genetic predisposition.6 Data on theincidence or prevalence of PSA are scarce. In a New Jersey cohort,admission for status asthmaticus between 1992 and 2006approximately halved from 1.92 to 0.93 per 1000 children. Incontrast, ICU care related to asthma increased from 0.09 to 0.31 per1000 patients. A much higher percentage of children admittedto hospital for status asthmaticus received ICU care, but the rateof children needing mechanical ventilation was the same

atus asthmaticus in children. Paediatr. Respir. Rev. (2013), http://
http://dx.doi.org/10.1016/j.prrv.2013.03.003mailto:[email protected]://dx.doi.org/10.1016/j.prrv.2013.03.003http://dx.doi.org/10.1016/j.prrv.2013.03.003http://www.sciencedirect.com/science/journal/15260542http://dx.doi.org/10.1016/j.prrv.2013.03.003

Figure 1. Number and rate* of asthma deaths, by year and International Classificationof Diseasesy (ICD) United States, 1980-2004.

M. Koninckx et al. / Paediatric Respiratory Reviews xxx (2013) xxxxxx2

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(0.02/1000).7 In Finland about 1% of the hospital admissions forasthma need intensive care, but numbers vary between 1 to 15%.Since indications for PICU admission vary between countries thesenumbers are hard to compare.8 The number of children that needmechanical ventilation is decreasing and varies between 8 and 33%of the PSA related PICU admissions.9 This may be due to theincreasing use of non-invasive respiratory support for severeasthma. It can be concluded that more children with PSA areadmitted to the ICU but the need for invasive mechanicalventilation seems to have decreased, although this is influencedby admission criteria. Mechanical ventilation in PSA is a risk factorfor mortality in the 10 years after discharge and close follow up issuggested.8,9

PATHOPHYSIOLOGY OF STATUS ASTHMATICUS

The three main factors that are involved in the pathophysiologyof asthma are bronchoconstriction, mucus plugging and airwayinflammation, with the exacerbation usually induced by a viralinfection.10 The relative contribution of these factors determinesthe targets for optimal therapy. Some patients underestimate theseverity of airway obstruction: they have a reduced sensation ofdyspnoea while breathing with increased airway resistance andhave decreased hypoxic ventilatory drive, resulting in little reserveat presentation.11 These are patients that are predisposed to nearfatal asthma.

In fatal and near fatal asthma we can distinguish two differentclasses: type I or slow onset fatal asthma and type II or rapid onsetfatal asthma.12 Predisposing factors in type I are inadequatetherapy, inadequate compliance, inappropriate control and psy-chological factors. Type II can occur epidemically (soybean, castorbean or unknown) or sporadically (NSAID, allergen, sulphites, foodor unknown).13

Type I is a progressive obstruction of the airways in patientsalready constantly using bronchodilators. These patients areusually undertreated with inhaled corticosteroids. Bronchodilatingmedications cause a maximal smooth muscle relaxation. Mean-while, the process of inflammation and oedema continues due toinadequate treatment. Only a small increase in oedema orinflammation can be fatal. Given the state of maximal broncho-dilation, further use of short acting b2-agonists will not have muchadditive effect and cannot reverse the bronchial obstruction. Thesepatients are at risk for severe therapy resistant PSA. Airwayplugging is demonstrated and secretions are characterised byeosinophils in pathological examinations.14 In a prospective study


of the characteristics of (near) fatal asthma, about 80% belong totype I.15 These exacerbations are preventable with extensiveasthma control and administration of adequate doses of inhaledcorticosteroids.

Type II is a rapid onset type, also called sudden asphyxialasthma. It is an acute and sudden onset form where death canfollow in only a few hours after start of the clinical symptoms.Severe bronchospasm occurs with little or no mucus plugging andairway inflammation.3,12 In contrast, Type I cases demonstratemainly neutrophilic inflammation. In this type there is a higherincidence of respiratory arrest, impaired consciousness level, alower pH and a silent chest reported. Clinical improvement isdirectly related to improvement of bronchoconstriction. Thesepatients can deteriorate very rapidly, but with appropriateinterventions recovery can be accomplished swiftly, as demon-strated by a shorter length of hospital stay and fewer hours ofmechanical ventilation.15

The previously described mechanisms cause an occlusion of theairway lumen with reduced ventilation leading to low ventilation/perfusion(V/Q) ratios and gas exchange abnormalities. Thedistribution of areas with reduced ventilation and hypoxicvasoconstriction is widespread through the bronchial tree andinterspersed with areas of better V/Q.

An important complication of PSA is airleak which may manifestwith pneumothorax, pneumomediastinum, subcutaneous emphy-sema and pneumopericardium due to increased intrathoracicpressure.4 This is mainly seen in PSA patients ventilated with highpeak pressures and is one of the drivers for the increasing use of non-invasive ventilation in the acute setting.4 Myocardial infarction,hardly seen in children, is possible due to hypotension and elevatedinthrathoracic pressures. This increases left ventricular afterloadwhich can in turn decrease coronary blood flow. Mucus plugging canprovoke atelectasis. Electrolyte disturbances including hypokalemiacaused by salbutamol are possible. Myopathy and rhabdomyolysisare described when giving steroids in combination with neuromus-cular blockers.16 Lactic acidosis and anoxic brain injury have alsobeen described.17 These problems warrant close monitoring andspeedy intervention in a PICU.

DETERMINATION OF ASTHMA SEVERITY

A gold standard for the assessment of the severity of an asthmaexacerbation does not exist. Similar to adults, there is a lack ofvalidated instruments to determine asthma severity in children.The primary importance of defining severity is to determinefurther patient management. Depending on severity patients canbe divided into life threatening asthma, necessitating immediatetherapy and PICU admission, slow responding forms that needhospital admission and patients that can be discharged directlyfrom the emergency department. Second, a tool for definingseverity of PSA can be used to assess the effect of therapeuticinterventions. Peak flow measurements, serial lung functionmeasurements, pulse oximetry and clinical examination andasthma scoring systems are tools that can be potentially helpful.

Peak flow measurements and serial lung function measurements

Peak expiratory flow rates (PEFR) or forced exipiratory volumein one second (FEV1) are difficult to reliably perform in childrenwith acute asthma, especially in those under 5 years of age. Inchildren aged between 6 and 18 years, only 64% were able toperform PEFR adequately.18 Stable peak flow records can bepresent despite severe bronchial hyperresponsiveness resulting infatal asthma.19 Thus, it is not recommended to rely on peak flowmeasurements for assessing severity.

http://dx.doi.org/10.1016/j.prrv.2013.03.003http://dx.doi.org/10.1016/j.prrv.2013.03.003

M. Koninckx et al. / Paediatric Respiratory Reviews xxx (2013) xxxxxx 3

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Pulse oximetry

Measuring SaO2 is an important tool to determine asthmaseverity, but always in combination with other parameters. InitialSaO2 95% 91-95%

PaCO2 < 5.6 kPa < 5.6 kPa

PaO2 Normal > 8 kPa

C.A. Camargo, G. Rachelefsky, M. Schatz. Managing asthma exacerbations in the emergen

expert panel report 3 guidelines for the management of asthma exacerbations. Proc Am

The presence of several parameters, not necessarily all, gives an indication of the seve

Many of these parameters have not been studied systematically, they only serve as gu


are wheezing, work of breathing and prolongation of expiration.This score might have limited clinical use, since these three itemsdo not easily detect subtle changes in the clinical situation.

For clinical purposes, at this point in time, treatment will bemainly driven by clinical signs and symptoms rather than resultsfrom lung function testing.

PICU admission is necessary in a minority of PSA patients.Several predicting factors defining the need for intensive care havebeen identified. A history of three or more emergency presenta-tions in the previous year, an elevated serum IgE level, oxygensaturations of 91% or less on presentation or a longer duration ofasthma can predict the need for intensive care admission.24

Next to these factors, PICU admission in PSA patients wasrecently related to allergies, active or passive smoking, earlierhospitalization for asthma and non-sanitized homes.25

THERAPY

Choices in treatment of PSA are made taking the underlyingpathophysiology into account. Treatment is directed at reversal ofinflammation and bronchoconstriction, and in a later phase also ofrelieving mucus plugging if necessary. The initial goal is correctionof significant hypoxaemia and reversal of the airflow obstruction assoon as possible. Initial therapies for PSA are supplementation ofoxygen, repetitive administration of rapid-acting b2-agonists (e.g.salbutamol), inhaled anti-cholinergics (e.g. ipratropium bromide)in combination with systemic glucocorticosteroids (e.g. predniso-lone) and magnesium sulphate.

Severe Imminent Respiratory

Arrest

(infant-softer

ng;

ing

At rest (infant:

stops drinking)

Gasping

ces Words None

tated Most often agitated Decreased or confused

Often > 30/minute

ncy:

Usually Paradoxal thoracoabdominal

movements

piration Mostly loud in-

and expiratory

Absent

> 120 Bradycardia

Often Absence suggests exhaustion

2040 mm Hg (child)

< 91%

>= 5.6 kPa >= 5.6 kPa

< 8 kPa: possible cyanosis < 8 kPa: possible cyanosis

cy department. Summary of the national asthma education and prevention program

Thoracic Society 2009;6: 357366.83

rity of status asthmaticus.

idance.


Table 2Asthma score

VARIABLE ASTHMA SCORING

1 point 2 points 3 points

Respiratory rate (Breaths/min)

23 yr 34 3539 4045 yr 30 3135 36612 yr 26 2730 31>12 yr 23 2427 28Oxygen saturation (%) >95 with room air 9095 with room air 70 5070 4years) for intermittent administration. A metered dose inhalerwith spacer is equally effective as nebulisation, with the dose beingsix inhalations [total of 600 mcg] or twelve inhalations [1200 mcg]via spacer respectively.31 However, in contrast to adults, a recentCochrane review shows some advantages of an inhalation devicewith holding chamber compared to a nebuliser, with a significantlyshorter length of stay in the emergency department for the first


group.32,33 Conversely, nebulisation has the added advantage ofdelivering high flow oxygen. Comparison of the different studies isdifficult because of the variation in outcome measures and severityof asthma exacerbations.

If nebulisation fails, salbutamol can also be given intravenously,on the assumption that with little air entry only a small amount ofthe drug reaches the target airway receptors. In children, wellconducted studies concerning pharmacokinetics and pharmaco-dynamics of intravenous salbutamol are lacking. An early studyfound that 69% of the patients responded satisfactorily after aloading dose of 10 mg/kg, followed by a continuous infusion of0.2 mg/kg/min, which was increased by 0.1 mg/kg every 15 min-utes.34 This study included only 14 children and the outcomeparameter was a decrease of the pCO2, which gives only scarceinformation about the clinical condition. Another double blindrandomized study in 29 children with severe acute asthmacompared a loading dose of 15 mg/kg intravenous salbutamol tonebulised ipratropium bromide or a combination of both. Bolussalbutamol was more effective, leading to earlier cessation ofnebulisation, less oxygen need and earlier discharge fromhospital.35 Dosing of intravenous salbutamol in children variesbetween 0.1 and 15 mg/kg/min and there is no consensus if aloading dose is needed.36,37

Terbutaline is also used as short acting b2-agonist. When addedto continuous nebulisation, intravenous terbutaline showed a non-significant decrease in clinical asthma scores, duration ofcontinuous nebulisation and PICU length of stay compared tosaline.38 A terbutaline dose of 0.41 mg/kg/min was shown tolower diastolic blood pressure.39 When terbutaline was adminis-tered according to a severity related dosing algorithm, it led toshorter PICU length of stay.40 Although the use of intravenous b2-agonists varies between countries, it is normally only started afterfailure of continuous nebulisation. The relationship between doseand effect has not been studied in children. The drugs are alsoknown for many side effects including hypokalemia, tachycardia,hyperglycaemia and hypotension, warranting close monitoring,most often in the PICU setting. Some children are not as responsiveto b2-agonists as others; this could be explained by geneticpolymorphisms. Recent studies suggested that specific b2adrenoreceptor genotypes are related to shorter ICU length ofstay and shorter duration of continuous b2-agonist therapy inchildren.41



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Anticholinergic agents

These agents can decrease secretions, mucosal oedema andreduce bronchomotor tone. Anticholinergic agents such asipratropium bromide give less bronchodilation and the effectis slower compared to short acting b2-agonists. Adding multipledoses of anticholinergics in moderate and severe acute asthma inchildren to short acting b2-agonists has an additive effect. Thereis a benefit in terms of lung function and hospital admission.42

Recommended doses are 250-500 mg every 20 minutes for up tothree times, followed by administration every three hours ifnecessary.43 In cases where salbutamol is given intravenously,addition of ipratropium bromide does not have an additiveeffect.44,45 Ipratropium bromide has a very low rate of absorp-tion, implying that systemic side effects are rare. There arereported cases of bronchoconstriction, but this adverse effect hasnot been described when current isotonic ipratropium bromidenebuliser solutions are used.46 In summary, ipratropium bromidehas no additional value when it is used in combination withintravenous short acting b2-agonists in the intensive caresetting, but it can have a positive effect in the emergencydepartment.44,45

Steroids

In most cases of PSA, especially with failure to respond torepeated short acting b2-agonists, steroids are added. Their mostimportant effect is controlling, suppressing and reversal ofinflammation. They also potentiate the effect of b2-agonists onsmooth muscle relaxation, decrease b-agonist tachyphylaxis,mucus production and microvascular permeability.47,48 The onsetof action of steroids is two to four hours with a maximum effectafter twelve hours. It is important to administer steroids early inthe disease course of PSA because this can lead to earlier dischargeand fewer relapses.49 Recommended doses of oral prednisone are1-2 mg/kg/day with a maximum dose of 60 mg for 5 to 10 days.Methylprednisolone is dosed 2 to 4 mg/kg/day with a maximum of125 mg per day. Higher doses are not associated with bettereffects.50 The same effect is achieved whether steroids are givenintravenously or orally, although in severely ill and dyspnoeicchildren, the oral form is often difficult to administer. In mild tomoderate exacerbations a single dose of intramuscular dexa-methasone has the same effect as a 5 day oral course withprednisone.51

A study in 100 children with PSA that were randomised eitherto oral prednisone 2 mg/kg or a single dose of 2 mg fluticasonethrough inhalation showed a higher FEV1 and a lower rate ofhospitalisation in the prednisone group.52 In children, adding highdoses of budesonide (1200-2000 mg) to systemic prednisone(1 mg/kg) and nebulised albuterol can prevent or shortenhospitalization.53 A more recent study concluded that adding asingle dose of 2 mg of budesonide to standard treatment of PSA didnot have a positive effect on asthma severity score or short termoutcome.54 Adverse effects of a short course treatment withsystemic steroids are mostly transient and can include hyperten-sion, hyperglycaemia and mood disorders among others. Thesereactions are especially described in high dose steroid pulsetherapy and chronic use. Overall in PSA, addition of systemicsteroids is recommended orally or intravenously. Conflictingresults were reported on the addition of inhaled budesonide tostandard treatment of PSA.

Magnesium

Magnesium sulphate has a proven effect in status asthmaticus.It works through smooth muscle relaxation secondary to inhibition


of calcium uptake leading to bronchodilation. Magnesium can alsoinhibit mast cell degranulation and in this way mitigateinflammation55 and decrease acetylcholine release from nerveterminals. A recent Cochrane review does not support routine useof intravenous magnesium sulphate in patients with acute asthmapresenting to the emergency department. However, it can be usedsafely and is beneficial in patients with severe acute asthma whenadded to bronchodilators.56 Three studies in children demon-strated that early administration of intravenous magnesiumsulphate is beneficial on hospital admission, lung function andclinical symptom score in children treated with bronchodilatorsand steroids.5759 Doses vary between 25 mg/kg and 75 mg/kg.Possible adverse effects are muscle weakness, hypotension,tachycardia, skin flushing and fatigue but these are mostlynegligible.

ADDITIONAL TREATMENT MODALITIES

Standard treatment of PSA in the emergency departmentshould include oxygen, short acting b2-agonists and steroids.In case of further deterioration intravenous salbutamol incombination with anticholinergics and intravenous magnesiumsulphate should be considered. When there is no improvementdespite these therapies there are still some less frequentlyused options. Most of these therapies are not evidencebased and (large) randomised controlled trials are not available.These therapies warrant close monitoring preferably in aPICU.

Methylxanthines

Methylxanthines (theophylline, aminophylline) act throughnon-selective inhibition of a phosphodiesterase [enzyme]and antagonise adenosine receptors in smooth muscle andinflammatory cells. They result in bronchodilation, improvedmucociliary clearance and down-regulation of inflammationand immune cell infiltration. In children, the addition ofaminophylline to short acting b2-agonists and corticosteroidsin an acute asthma exacerbation improves lung function (FEV1and PEF), but there is no reduction in symptoms, number ofnebulised treatments and length of hospital stay.60 In criticallyill children with status asthmaticus admitted to the intensivecare unit with impending respiratory failure, intravenoustheophylline is as safe and effective as intravenously adminis-tered terbutaline.61 Methylxanthines have a small therapeuticwindow with many side-effects including headache, nausea,palpitations and anxiety.62 High theophylline concentrations canresult in severe toxicity and in cardiac arrhythmias, hypotension,seizures and even death. Given the small clinical effect,methylxanthines should be used with caution and only inrefractory PSA.

Deoxyribonuclease (DNase)

Mucus plugging and atelectasis are an important clinicalproblem in PSA. Since inflammation might lead to a high DNAcontent in mucus, the use of recombinant human (rh) DNase astreatment modality has been hypothesized. In children there areonly a few case reports (but no good evidence) which describedpositive effects after intratracheal delivery of DNase in mechani-cally ventilated asthmatic children.63,64 There is no place forroutine addition of nebulised rhDNase to conventional treatmentin children with PSA presenting at the emergency department.65

Treatment with rhDNase might rarely have a place in the PICU forpatients with refractory PSA, sometimes in combination withbronchoscopy.



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Ketamine

Ketamine has bronchodilating properties through increasingcirculating catecholamines after inhibition of the re-uptake ofnoradrenaline in the presynaptic neurons. Ketamine wassuccessfully used to prevent intubation in two children withstatus asthmaticus who received a loading dose of ketamine(2 mg/kg) followed by continuous infusion of ketamine (2 mg/kg/h).66 However, a study in 68 paediatric patients could notdemonstrate an additional benefit of ketamine over conventionalemergency department therapy in PSA. A rather low loadingdose of 0.2 mg/kg followed by continuous infusion of 0.5 mg/kg/h was used in this study.67 In refractory PSA ketamine mighthave a place, especially when sedation and/or intubation areconsidered.

Sodium bicarbonate

Respiratory or metabolic acidosis can be seen in PSA. Thepresence of acidosis can diminish the effect of catecholamines.Therefore, treatment of acidosis with sodium bicarbonate could bebeneficial. Administration of sodium bicarbonate in 17 patientswith life threatening asthma admitted to the PICU showed asignificant decrease in mean pCO2 and a significant increase ofmean pH. Clinical improvement of respiratory distress and level ofconsciousness was seen in individual patients.68 This smallretrospective study suggests sodium bicarbonate could beconsidered in life threatening asthma with severe acidosis (pH


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http://dx.doi.org/10.1016/j.prrv.2013.03.003http://dx.doi.org/10.1016/j.prrv.2013.03.003Management of status asthmaticus in childrenEducational AimsPathophysiology of status asthmaticusDetermination of asthma severityPeak flow measurements and serial lung function measurementsPulse oximetryClinical scoring systemsTherapyOxygenShort acting 2-agonistsAnticholinergic agentsSteroidsMagnesiumAdditional treatment modalitiesMethylxanthinesDeoxyribonuclease (DNase)KetamineSodium bicarbonateHelioxEpinephrine (Adrenaline)Non-invasive respiratory supportMechanical ventilationInhalational anaestheticsExtracorporeal membrane oxygenation (ECMO)ConclusionReferences

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Management of Status Asthmaticus in Children Muriel Konickx 2013