sign in sign up
<<
Home , Heliox, Oxygen therapy, Spirometry

Review Article

Heliox administration in the pediatric intensive care unit: An evidence-based review

Vineet K. Gupta, MD; Ira M. Cheifetz, MD, FCCM

Objective: To provide a comprehensive, evidence-based review Conclusions: administration is most effective during of – gas mixtures (heliox) in the management of conditions involving -dependent increases in airway resis- pediatric respiratory diseases. tance, especially when used early in an acute disease process. Data Source: A thorough, computerized bibliographic search of Any beneficial effect of heliox should become evident in a rela- the preclinical and clinical literature regarding the properties of tively short period of time. The medical literature supports the use helium and its application in pediatric states. of heliox to relieve respiratory distress, decrease the work of Data Synthesis: After an overview of the potential benefits and , and improve . No adverse effects of technical aspects of helium–oxygen gas mixtures, the role of heliox have been reported. However, heliox must be administered heliox is addressed for , aerosolized medication delivery, with vigilance and continuous monitoring to avoid technical com- upper , postextubation , , bronchi- plications. (Pediatr Crit Care Med 2005; 6:204–211) olitis, and high-frequency ventilation. The available data are ob- KEY WORDS: helium; ; acute injury; jectively classified based on the value of the or interven- gas exchange; pediatrics; ; heliox; ; tion as determined by the study design from which the data are asthma; airway obstruction; ; croup; extubation; obtained. acute lung injury; respiratory distress;

elium as a medical therapy To objectively assess the value of each of Figure 1 demonstrates the differences was first described in 1934 the studies, a classification system is used in relative density between heliox and ox- by Barach (1) for the treat- based on the study type and the rigors of ygen-enriched air at various concentra- ment of asthma and upper the study design. This approach, as detailed tions of oxygen. There is an insignificant airwayH obstruction. Subsequently, heliu- in Table 1, is modeled after the classifica- difference in relative gas density at vari- m–oxygen mixtures (heliox) have been tion system used in the construction of the ous oxygen with nitrogen demonstrated to improve gas exchange in Guidelines for the Acute Medical Manage- as the balance gas. However, with helium patients with asthma, bronchiolitis, up- ment of Severe Traumatic Brain Injury in as the balance gas, there is a wide vari- per airway obstruction, cystic fibrosis, Infants, Children, and Adolescents (13). In ability in relative density between various chronic obstructive pulmonary disease, each section, data are presented in the or- oxygen concentrations. By its lower den- and, most recently, acute lung injury (2– der of the study classification with the most sity, heliox improves gas flow through 12). With the increased use of helium for reliable studies listed first. It should be high-resistance airways. the treatment of respiratory conditions, it noted that all heliox studies in the litera- Gas flow can vary from laminar at one is imperative for the clinician to under- ture are limited by small sample sizes. end of the spectrum to turbulent at the stand the mechanisms of action and sce- other. Laminar flow rate (Q) is deter- narios in which heliox therapy is and is HELIOX: AN OVERVIEW mined by the Hagen-Poiseuille equation: not warranted. By reviewing the litera- Helium is a colorless, odorless gas, ture over the last 70 yrs, it is our hope ϭ ⌬ ␲ 4 ␩ which was first discovered during a solar Q P r /8 l[1] that this evidence-based review eclipse in 1868. Helium is an inert gas will shed light on the clinical applications with no direct pharmacologic or biologic where ⌬P is the drop, r is the of helium. effects. It has no intrinsic bronchodila- radius, ␩ is the gas , and l is the tory or anti-inflammatory properties. The length. Because the viscosity of the gases variable that makes helium so attractive are similar (Table 2) and laminar flow From the Division of Pediatric Critical Care Medi- velocity is independent of density, heliox cine, Duke University Medical Center, Durham, NC. for medical use lies in the differences The authors have no financial interest to disclose. between the density of helium vs. other has no effect on areas of laminar flow. Address requests for reprints to: Vineet Kumar Gupta, gases. The density of helium is one- As flow velocity decreases and/or airway MD, Division of Pediatric Critical Care Medicine, Mercy seventh that of air (Table 2). Helium has resistance increases, there is a critical level Children’s Hospital, 2213 Cherry Street, 6th Floor, Toledo, in which the flow pattern changes from OH 43608. E-mail: [email protected]. the lowest density of any gas except hy- Copyright © 2005 by the Society of Critical Care drogen and, unlike hydrogen, is nonflam- turbulent to laminar. This transitional zone Medicine and the World Federation of Pediatric Inten- mable. Equally important, carbon dioxide is defined by (Re): sive and Critical Care Societies diffuses through helium four to five times DOI: 10.1097/01.PCC.0000154946.62733.94 faster than through air (5, 12, 14, 15). Re ϭ 2Vr␳/␩ [2]

204 Pediatr Crit Care Med 2005 Vol. 6, No. 2 Table 1. Classification system vary. However, gas density and thermal conductivity significantly differ at varying ● Class I evidence represents randomized, controlled trials–the “gold standard” of clinical trials. oxygen concentrations with heliox. Thus, However, some may be poorly designed, lack sufficient patient numbers, or suffer from other helium, with its lower gas density and methodologic inadequacies. ● Class II evidence represents nonrandomized clinical studies in which the data were collected increased heat-carrying capability, re- prospectively and retrospective studies, which were based on clearly reliable data. Types of sults in imprecise pressure and tempera- studies so classified include observational studies, cohort studies, prevalence studies, and case- ture changes, and, subsequently, false control studies. measurements. Therefore, ● Class III evidence represents most retrospective studies. Evidence used in this class indicates in-line respiratory mechanic monitors clinical series, databases, registries, case reviews, case reports, and expert opinion. and/or ventilators with heliox calibration capabilities are needed to accurately de- termine delivered tidal volume with he- Table 2. liox (20–22). Alternatively, mathematic ␩ Viscosity ( ) Density CO2 Coefficient Thermal Conductivity correction factors are required. Gas (micropoises) (␳) (g/L) (cm2/sec) (␮cal cm sec °K) Tanks of 100% helium are available and require a blender to dilute the he- Nitrogen 167.4 1.251 0.165 58 lium to provide a source of oxygen to the Oxygen 192.6 1.429 0.139 58.5 patient. An interruption in oxygen deliv- Air 170.8 1.293 0.138 58 Helium 188.7 0.179 — 352 ery could possibly result in the accidental Heliox (80:20) — 0.43 0.56 — administration of a hypoxic gas mixture, including the possibility of delivering 100% helium (21). Premixed heliox tanks with at least a 20% oxygen avoids this potentially fatal complication. Continuous in-line monitoring of in- spired oxygen concentration to ensure adequate oxygen delivery to the airways is warranted. It is essential to humidify and warm the delivered heliox gas to prevent signif- icant heat loss, especially in the pediatric patient. The thermal conductivity of he- lium is approximately four to six times that of nitrogen (Table 2). It is also es- sential to ensure that there is no acciden- tal contamination of the heliox mixture with air or oxygen. As discussed, any ac- Figure 1. The differences in relative density between heliox and oxygen-enriched air at various cidental introduction of other gases will concentrations of oxygen. lower the helium concentration in the total gas mixture, thus increasing the density of the delivered gas. where ␳ is the gas density and V is gas gas flow allowing for increased bulk flow, Any pressure exerted on the velocity. A Reynolds number Ͻ2,000 pre- increased oxygen flow, and decreased through an endotracheal tube inevitably dicts laminar flow and Ͼ4,000 predicts (17, 18). results in some degree of lung injury turbulent flow. Thus, helium with its (24–30). Because the major determinants lower density will decrease Reynolds HELIOX AND MECHANICAL of ventilator-induced lung injury are air- number in those airways operating in the VENTILATOR FUNCTION way pressure and lung distension, heliox transitional zone of flow patterns and will as the balance gas may allow for similar change turbulent flow into a more lami- The administration of heliox during gas exchange at lower airway . If nar flow type with improved diffusion mechanical ventilation must occur with this is correct, then, theoretically, heliox characteristics. vigilance and continuous monitoring be- administration may decrease the risk of When evaluating extremely turbulent cause helium can interfere with the ac- iatrogenic lung injury. flow patterns, flow rate becomes depen- curacy of pneumotachometers and venti- dent on gas density according to the Ber- lator function (19–23). For example, ASTHMA noulli equation: most modern microprocessor ventilators Q ϭ ͑2⌬P/␳͒1/ 2 [3] use a differential flow pneumotachometer Asthma is a chronic disease with sig- to measure the pressure differential nificant morbidity and mortality. In the Therefore, with a lower gas density, across a resistor or a heated wire sensor 2002 update from the National Asthma helium will provide a higher flow rate to measure changes. These Education and Prevention Program (NA- even if it remains turbulent (16). Thus, measurements are not affected by differ- EPP) (31, 32), the potential benefits of with its lower density, helium as a “car- ent concentrations of oxygen-enriched heliox in the treatment of asthma exac- rier gas” results in a lower resistance to air because density does not significantly erbations was stated, especially as an al-

Pediatr Crit Care Med 2005 Vol. 6, No. 2 205 ternative to intubation. Theoretically, he- study, age-related factors in the disease cedure. Patients receiving heliox reported liox is an ideal treatment strategy for process or compliance with less dyspnea. In addition, heliox patients status asthmaticus because the primary measurements may have been confound- had a more significant improvement in pathophysiology is restricted gas flow ing variables. Additionally, this was an PEF than the air-breathing group (p Ͻ through narrowed airways. inpatient study as compared with previ- .001). This class II study demonstrated In a double-blind, randomized, con- ous ED studies involving early heliox ad- heliox improved expiratory flow, de- trolled trial performed in 18 children ministration. These patients were also creased hyperinflation, and reduced the with status asthmaticus (14), early use of treated with conventional therapy for a work of breathing. 80:20 heliox for 15 mins improved pulsus minimum of 6 hrs before heliox admin- In 1999, Schaeffer et al. (4) presented paradoxus (PP), peak expiratory flow, and istration and possibly already experienced a retrospective class II study comparing dyspnea score as compared with control significant benefit from conventional 11 adults with status asthmaticus who patients breathing oxygen-enriched air. therapy (i.e., corticosteroids). received heliox during the first 2 hrs of The PP and dyspnea score worsened once Recognizing the limitations to the mechanical ventilation vs. 11 case- heliox was discontinued. Heliox pre- Carter study, one can speculate that al- matched control patients ventilated with- vented intubation for three patients who though late heliox use did not benefit out heliox. With no changes in ventilator were felt by clinicians (not involved in the these inpatients, there may be a benefi- settings, a significant drop in alveolar to study and blind to the study gas) to be in cial role for heliox early in the ED course arterial (A-a) gradient (p Ͻ .0003) oc- significant respiratory distress to neces- or in those patients requiring mechanical curred with heliox. The reduction in A-a sitate this intervention. The authors cited ventilation. Thus, this study suggests ad- gradient allowed clinicians to wean the no adverse effects to heliox administra- ministering heliox as a “therapeutic Ϯ Ϯ FIO2 from 0.81 0.25 to 0.37 0.27 and, tion. Thus, this class I study suggests bridge” for the 4- to 12-hr interval be- thus, increase the helium concentration early heliox use relieves dyspnea and im- tween arrival to the ED and onset of cor- in the gas mixture, further enhancing its proves the work of breathing. ticosteroid effect (2, 3, 5, 14, 34, 35). beneficial role in lowering gas density, The next class I study is an unblinded, In another prospective, randomized, improving gas flow characteristics, and prospective, randomized, controlled trial placebo-controlled study in adults who reducing the risk of . in adults with acute severe asthma who presented to the ED with moderate to A recent article describes the effects of presented to the severe asthma, Dorfman et al. (36) com- heliox in children with acute severe (ED) (3). Twenty-three patients were ran- pared 80:20 heliox (n ϭ 20) and air (n ϭ asthma during mechanical ventilation domized to receive either 70:30 heliox or 19) for 1 hr. Both sets of patients had an (19). This retrospective review of 28 pa- oxygen-enriched air (FIO 0.30) within 1 average duration of symptoms of at least 2 tients used helium concentrations from hr of initiating conventional treatment. 40 hrs before study entry and had re- 32% to 74%. With similar ventilator set- Within 20 mins, patients in the heliox ceived continuously nebulized broncho- tings, peak inspiratory pressure (PIP) sig- group had a significant decrease in dys- dilators. Both groups had respiratory nificantly decreased (40.5 Ϯ 4.2 vs 35.3 Ϯ pnea score and . The he- rates in the 20s and room air saturations 3.0 cm H O; p Ͻ .05) with heliox. The liox patients also demonstrated signifi- Ն95% at study entry. No significant dif- 2 effect of heliox on PIP seemed most cantly increased percent predicted peak ferences were noted in the posttreatment Ͼ expiratory flow (PEF) (58.4%) vs. the percent peak expiratory flow rate (PEFR) prominent at higher pressures (PIP 40 control group (10.1%), providing addi- between the two groups. Patients were cm H2O). The authors suggest that heliox tional class I data to suggest a positive studied relatively late in the disease pro- decreases the obstruction to gas flow and, role for early heliox therapy. cess, which may have eliminated any po- thus, augments laminar flow with a re- In a double-blind, prospective, ran- tential heliox benefit. sultant decrease in PIP. The authors also domized, controlled trial, Carter et al. Manthous et al. (35) presented an un- reported significant improvements in (33) presented 11 children hospitalized blind, nonrandomized, prospective study CO2 elimination and pH with heliox. This with status asthmaticus. These patients evaluating the effects of heliox on PP and class III pediatric study suggests that in received inhaled albuterol and intrave- PEF in 27 adult ED patients. The first 16 the early acute phase of asthma, heliox nous corticosteroids before study entry. patients received a 15-min trial of 80:20 can improve gas flow and CO2 elimina- Patients randomly received either 70:30 heliox for which data were collected be- tion while reducing PIP and the potential risk of and air leak. heliox or oxygen-enriched air (FIO2 0.30) fore, during, and after gas administra- for 15 mins and were then switched to tion. Data for the remaining 11 patients Barach (37) was the first to describe the alternate gas mixture after spiromet- were obtained at similar time intervals the role of heliox for severely ill asth- ric values were obtained. This class I during air breathing. All patients received matic patients who were refractory to study demonstrated a small but statisti- inhaled albuterol and intravenous corti- conventional . These patients cally significant improvement in PEF rate costeroids within 1 hr of study entry. demonstrated improved respiratory effort (p ϭ .04) and mean mid-expiratory flow Although PP decreased in both groups within minutes of heliox initiation. Im- rate (FEF25–75) of the predicted value (p (reflecting the effects of standard ther- provements in were ϭ .006) with heliox. Heliox did not im- apy), the change in PP with heliox was associated with decreased cardiovascular prove forced , forced expira- significantly greater than with air breath- side effects and decreased pulmonary Ͻ tory volume in 1 sec (FEV1), clinical signs ing (p .05). No effect on gas exchange edema formation. In this class III study, of asthma, or dyspnea. These authors ac- with heliox was noted by arterial blood patients with mild symptoms experienced knowledge several factors, which may ac- gas measurements obtained before and variable degrees of relief, whereas the count for the lack of significant improve- during administration of the gas for the maximal benefit was seen in patients with ment with heliox. As a dedicated pediatric seven patients who consented to the pro- moderate to severe symptoms.

206 Pediatr Crit Care Med 2005 Vol. 6, No. 2 In 1990, Gluck et al. (5) presented a should see beneficial effects almost in- In a prospective, randomized study of case series of seven adult patients with stantaneously, and if the patient is not 205 nonintubated adults with mild to status asthmaticus who required intuba- improved within a few minutes, heliox moderate asthma exacerbations present- tion. These patients developed a persis- should be abandoned and other therapies ing to the ED, Henderson et al. (48) de- tent respiratory acidosis associated with considered. Heliox is a relatively inexpen- termined no benefit in FEV1 or PEFR high PIPs ranging from 75 to 100 cm sive and safe treatment option with a using heliox vs. oxygen during intermit- ␤ H2O. With 60:40 heliox, the respiratory better side effect profile than many “con- tent nebulization of a -agonist. Patients acidosis dramatically resolved, a mean re- ventional therapies” (eg, aminophylline). were randomized to receive three 5-mg duction in PaCO2 of 35.7 mm Hg within Perhaps with additional study, heliox can doses of albuterol 15 mins apart with 20 mins (p Ͻ .001) and a rise in pH (0.30 be included within the realm of standard either oxygen or 70:30 heliox. Clinical Ϯ 0.06 units, p Ͻ .001). In six patients, therapy for asthma exacerbations. parameters were obtained before medica- PIP significantly decreased by an average tion administration. There was no valida- of 32.9 cm H2O within minutes of heliox Aerosol Delivery tion of a patient’s asthma history, and administration. Thus, similar to Schaef- inclusion for the study was based on pa- fer’s class II study, this class III study Inhaled ␤-agonists are the mainstay tient self-reporting. This study used ef- suggests heliox benefits patients with sta- for patients with acute asthmatic exacer- fort-dependent parameters as a measure tus asthmaticus requiring mechanical bations. Maximal benefit is achieved of efficacy instead of more objective cri- ventilation and may allow for a stepwise when an adequate amount of medication teria. The delivery system was not de- reduction in the fraction of inspired oxy- reaches the lower airways. Unfortunately, scribed, and the actual helium-to-oxygen gen. Ͻ10% of nebulized drug reaches the ratio was not measured with an external Clinical Application. In summary, it is lungs because most is deposited in the oxygen analyzer. Although this study met difficult to form definitive conclusions posterior oropharynx (40, 41). Although class I classification, concerns in the based on these studies involving various the increased use of (42, 43) study design, patient selection criteria, study designs, patient groups, degrees of and meter dose-inhaler spacer devices heliox administration methods, and data illness, treatment settings, time of inter- (44, 45) have improved medical delivery collection exist, which make application vention, and outcome measures. Addi- as compared with traditional metered- of these results difficult. tional studies involving a larger number dose inhalers alone, potential for signifi- In one of the earlier studies (49), 111I- of patients and more definitive study de- cant improvement persists. labeled Teflon particles similar in size to signs and outcome measures are needed Several studies have investigated heli- nebulized medications were administered to clearly define any potential beneficial um’s role in improving nebulized medi- to ten asthmatics in air or heliox. After 24 role of heliox for acute asthma exacerba- cation delivery through constricted air- hrs, there was a greater deposition of tions. ways to more peripheral lung regions. particles to the alveolar level with heliox The addition of heliox to the treat- The associated improved gas flow charac- as the delivery gas. This class II study ment regimen for acute asthma is not teristics of heliox, theoretically, should suggests the administration of inhaled warranted for all patients. Because most facilitate delivery of ␤-agonists further with heliox may be of patients do well with conventional ther- down the tracheobronchiolar tree. therapeutic value by enhanced peripheral apies, there may not be an added benefit In an early pilot class II study (46), no deposition of the agent, thus improving with heliox. However, in select patients difference was detected in spirometry clinical effect and outcome. with severe exacerbations, early heliox measurements between heliox and oxy- Hess and colleagues (50) conducted a therapy may decrease airflow obstruction gen when used to nebulize albuterol. laboratory study investigating the poten- and facilitate gas exchange, especially as These authors believed there was acci- tial differences on function be- conventional therapies are implemented dental entrainment of room air in their tween heliox and air. They investigated but before these therapies achieve full delivery system resulting in the dilution intermittent and continuous delivery of effect. Using heliox as a temporizing mea- of the delivered helium. After modifying albuterol. The amount of albuterol depos- sure may prevent intubation for some the delivery system to prevent this com- ited on a cotton plug placed at the patients. Evidence suggests heliox is plication, the same group later published mouthpiece was spectrophotometrically more effective for the sicker patient (2, 3, a class I study performed in asthmatics determined during a simulated spontane- 14, 35, 38, 39). The beneficial effects of presenting in acute distress to the ED. In ous breathing model. They defined a par- heliox seem most efficacious when used this study (47), the investigators identi- ticle size of 1–5 ␮m to represent the early in the disease course (Ͻ24 hrs). fied 45 adults who met ATS criteria for respirable range (49). Decreased delivery It is important to stress that there are asthma and had severe persistent symp- of albuterol occurred for intermittent and Ͻ no reported adverse effects of heliox. toms as defined by a baseline FEV1 50% continuous delivery systems when heliox Thus, a trial of this gas mixture seems predicted. Using a noninvasive, semi- was used at a similar flow rate as air. The reasonable in patients with significant re- closed delivery system, these authors administration of heliox at a higher flow spiratory distress. Patients with a severe concluded that 80:20 heliox to nebulize rate (8–11 L/min with intermittent deliv- ventilation-to- mismatch may albuterol significantly improved spirom- ery and 2–3 L/min during continuous de- require an elevated FIO2, but, as was re- etry measurements when compared with livery) resulted in significantly increased vealed in the Schaeffer study (4), even oxygen as the driving gas. As this class I delivery of the total mass of albuterol and those patients with high oxygen require- study shows, limiting contamination of the 1- to 5-␮m sized particles. The au- ments (FIO2 0.80 or greater) demon- the lower-density heliox gas with air is thors concluded the use of heliox to strated improved gas exchange with the paramount to providing an improved power a nebulizer affects both the size of ability to wean the FIO2. The clinician clinical effect. the delivered particles and the total

Pediatr Crit Care Med 2005 Vol. 6, No. 2 207 amount delivered. They recommend in- In a double-blind, randomized, con- heliox for “buying time” have been de- creasing flow rates when using heliox as a trolled crossover trial of 13 children with scribed in children (7, 55) and adults with driving gas for nebulizer therapy. In a PES (53), heliox was evaluated. Patients tumor masses causing obstruction lower subsequent study (6), Goode et al. deter- served as their own control and were ran- in the respiratory tree (56–58). mined that heliox in a ventilatory circuit domly administered either heliox or oxy- Clinical Application. In summary, he- could increase aerosol delivery by as gen-enriched air for 15 mins before liox therapy for upper airway obstruction much as 50% for metered-dose inhalers crossing over to the alternate gas. The relieves respiratory distress, decreases and nebulizers in a mechanical ventila- degree of respiratory distress was as- the work of breathing, and improves gas tion model. They also stressed the impor- sessed on a 0–3 scale (respiratory rate, exchange. Heliox may alleviate the need tance of appropriate flow rates. Both of stridor, air movement, retractions, and for reintubation in the postextubation pe- these class II studies demonstrate a oxygen saturations) by physicians blinded riod. higher deposition of albuterol when us- to gas type. In this class I study, respira- ing heliox at an appropriate flow rate. tory scores for heliox were significantly Croup Ͻ Clinical Application. In conclusion, improved (p .005). (Laryngotracheobronchitis) heliox improved delivery of inhaled bron- A prospective study of 18 adult pa- chodilators to the lower airway and im- tients in the immediate postextubation The most common form of the croup proved gas movement as measured by period compared heliox and oxygen- syndrome is acute viral laryngotracheitis. spirometry. It is essential to limit the enriched air to evaluate respiratory effort Croup causes an inflammation affecting accidental entrainment of air or oxygen, (54). After extubation, three trials were the subglottic tissues and sometimes the which may inadvertently result in a lower performed consecutively: oxygen-en- tracheal mucosa. Until the airway inflam- helium concentration and, thus, limit riched air, heliox, and oxygen-enriched mation resolves, severe upper airway ob- any clinical benefit. Higher flow rates air. Transdiaphragmatic pressure (using struction may develop and occasionally may be necessary to produce a beneficial esophageal and gastric balloons), gas ex- may require intubation. Although corti- effect with heliox. change, and a subjective comfort scale costeroids have been demonstrated to re- were the primary end points. Transdia- lieve the associated airway obstruction, phragmatic pressure and, thus, work of this therapy requires several hours for Upper Airway Obstruction breathing, significantly decreased (p Ͻ full effect and is not efficacious in all .05) with heliox. On the readministration patients (59–61). In the early medicinal application of of oxygen-enriched air, the work of A 70:30 mixture of heliox was com- heliox, Barach (1, 37) suggested a bene- breathing returned to baseline. On a dys- pared with racemic epinephrine in a pro- ficial effect could be obtained with heliox pnea scale, patients reported a significant spective, randomized, double-blind trial for pediatric patients with upper airway improvement in comfort while breathing of 29 children with moderate to severe diseases and edema. An obstruction in heliox (p Ͻ .001). No significant differ- croup receiving treatment with humidi- the upper airway results in an increased ences in gas exchange were seen. The fied oxygen and corticosteroids (62). resistance to gas flow, and, results of this class II trial demonstrate Clinical effect was evaluated through a therefore, less efficient gas exchange. Up- heliox may decrease inspiratory effort and modified croup score (skin color, air en- per airway obstruction results from sev- improve comfort in the immediate post- try, retractions, level of consciousness, eral disease processes: postextubation extubation period. and degree of stridor). This class I study stridor (PES), trauma, space-occupying The use of heliox for PES has also demonstrated that heliox administration lesions, infections, and others. As the been described in several case reports. On resulted in similar improvements in density of inspired gas is reduced, there is extubation, a 9-yr-old boy (7) and a 23- croup score as compared with racemic an exponential increase in flow through yr-old woman (51) experienced tachy- epinephrine. areas of constriction for the same pres- pnea, stridor, hypercarbia, and increased In a class I prospective, randomized, sure gradient (51). Regardless of etiology, respiratory effort despite treatment with double-blind, controlled trial of 15 pedi- heliox may improve gas flow, improve racemic epinephrine and corticosteroids. atric patients with mild croup presenting oxygenation, and decrease the work of After the introduction of heliox, both pa- to the ED (63), the group treated with a breathing. tients demonstrated improved respiratory 70:30 heliox gas mixture trended toward Laryngeal edema related to local effort and gas exchange. In these class III a greater improvement in croup score trauma from can re- studies, heliox relieved the increased air- than the oxygen-enriched air treatment sult in increased , in- way resistance and work of breathing as- group, although this difference did not creased work of breathing, and poten- sociated with postextubation stridor, meet statistical significance. tially respiratory failure. Humidified air/ which may have prevented reintubation. In a class III study, Duncan (64) de- oxygen and racemic epinephrine remain In a class III review (51), intubation scribed seven patients with croup and standard treatment adjuncts. Dexameth- was prevented in seven of ten patients critical airway narrowing in whom heliox asone is commonly administered; how- with upper airway obstruction by heliox resulted in a decrease in croup score and ever, its ability to reduce postextubation administration. In three patients with improved gas exchange. No patient re- complications remains controversial and airway narrowing secondary to a tumor, quired intubation. requires several hours for full effect (52). heliox temporarily stabilized the respira- Clinical Application. The results from Not infrequently, the degree of respira- tory status. This intervention afforded the these class I and III studies suggest that tory distress necessitates reintubation, clinicians time to further assess the ob- heliox improves work of breathing as ev- which can further increase local trauma struction and prepare for a safer defini- idenced by croup score but to no greater and swelling. tive intervention. Similar applications of degree than seen with conventional ther-

208 Pediatr Crit Care Med 2005 Vol. 6, No. 2 apies. Although one may argue that he- ated 70:30 heliox in 38 nonintubated in- In a prospective crossover laboratory liox should be the preferred agent be- fants with moderate-to-severe RSV bron- study (11), heliox vs. oxygen-enriched air cause it has a lower side effect profile chiolitis. This study used a modification was evaluated during HFOV in a model of than corticosteroids or racemic epineph- of the Wood’s clinical asthma scoring sys- acute lung injury. This class II study rine, it is important to keep in mind that tem based on , quality demonstrated improved oxygenation and heliox, as is suggested by the asthma lit- of inspiratory breath , expiratory CO2 elimination with heliox. These inves- erature, may act as a “therapeutic wheezing, accessory muscle use, and tigators found a 16% decrease in PaCO2 bridge,” whereas corticosteroids and epi- level of consciousness. Patients receiving with heliox and a modest improvement in nephrine have a direct therapeutic effect. heliox had a more rapid improvement in oxygenation. However, on further inves- Perhaps in those patients in whom the clinical score and a greater magnitude of tigation, it was noted this improvement administration of steroids (65) or racemic clinical improvement based on respira- was related to larger tidal volume delivery epinephrine is contraindicated, heliox tory and heart rates. Heliox did not affect by the oscillator with heliox. Once tidal may be an effective alternative. Addition- gas exchange. Importantly, the length of volume was maintained constant, there ally, heliox may help to prevent intuba- PICU stay was significantly shorter for was no significant improvement in gas tion in those patients with impending the heliox group. exchange (80). respiratory failure. In a nonrandomized, unblinded case Winters et al. (12) reported improved

series involving ten patients (69), heliox CO2 elimination in a series of five chil- Bronchiolitis did not improve gas exchange during me- dren with acute respiratory distress syn- chanical ventilation for bronchiolitis. drome (ARDS) when heliox was adminis- Approximately 91,000 infants are hos- However, higher helium concentrations tered during HFOV. In this class III pitalized with respiratory syncytial virus (60/40 and 70/30 heliox compared with paper, the authors noted a 24% decrease (RSV) infections annually in the United 50/50 heliox) reduced the amount of in- in PaCO2 within 45 mins of initiating he- States (66). Routine supportive therapy trapulmonary shunting as measured by liox and an ultimate decrease of 43%. for RSV-induced bronchiolitis includes the alveolar–arterial oxygen gradient Heliox did not improve oxygenation. It oxygen and intravenous hydration. Bron- (70). The authors of these class III studies must be speculated that this improve- chodilators and corticosteroids are gen- suggest further studies are required to ment in gas exchange was also related to erally not effective; however, this issue determine whether helium can allow for increased tidal volume delivery. remains controversial. Sixteen percent of lower ventilating pressures in patients One of the limiting factors in using hospitalized patients require support in a with more severe lung disease when us- heliox with HFOV is the high bias flow pediatric intensive care unit (PICU) set- ing higher concentrations of helium. requirements of oscillatory ventilation ting, and approximately 50% of these pa- Clinical Application. As is suggested and the resultant rapid consumption of tients require intubation (8). From 1996 by these studies, there may be a beneficial heliox. Recently, this concern was ad- through 1998, 229 bronchiolitis-associ- role for heliox to improve the work of dressed in a study in normal rabbits with ated infant deaths occurred in the United breathing and gas exchange for infants the use of a low bias flow technique in States (67). Because bronchiolitis is asso- with bronchiolitis. The beneficial effect of normocapnic and hypercapnic conditions ciated with airway obstruction and turbu- heliox was greater in patients with a lent gas flow, theoretically, heliox has a (81). By modifying the ventilator circuit, larger degree of respiratory distress, may exhaled gas travels through a canister in beneficial role. prevent the need for intubation and me- In a randomized, double-blind, con- which CO2 is removed, thus allowing for chanical ventilation, and may shorten the the rebreathing of a relatively helium- trolled crossover study heliox was com- length of PICU stay. pared with oxygen-enriched air in 13 in- rich gas. These investigators demon- fants with RSV bronchiolitis (8). Five strated that higher helium concentra- additional patients were considered se- High-Frequency Ventilation tions in the inspired gas resulted in larger verely ill and nonrandomly received he- improvements in CO2 elimination. Fur- liox to prevent intubation. For heliox and Not infrequently, the degree of acute ther studies involving this interesting re- breathing technique are required before a oxygen-enriched air, the FIO2 was ad- lung injury requires a significant escala- Ͼ recommendation for clinical application justed to maintain SpO2 92%. The FIO2 tion in support, including the conversion was maintained constant throughout the from conventional to “nonconventional” can be made. study period. Clinical Asthma Score de- ventilation such as high-frequency oscil- Clinical Application. Based on these creased in the 13 randomized patients (p latory ventilation (HFOV) and high- results, routine heliox use during non- Ͻ .05) and in the 18 patients overall (p Ͻ frequency jet ventilation (HFJV). Despite conventional ventilation cannot be rec- .01) during the 20 mins of heliox delivery. the utilization of these ventilator strate- ommended. Given the high morbidity Beneficial effects were most pronounced gies, significant morbidity and mortality and mortality in patients requiring this in children with the greatest degree of remain (71). Studies have evaluated the escalation in respiratory support, a trial respiratory compromise. This class I combination of these nonconventional of heliox may be attempted in select pa- study demonstrated a significant im- modes of ventilation with adjunct agents tients. Because heliox administration provement in the work of breathing with such as inhaled nitric oxide (iNO) (72– with these nonconventional modes of heliox, and the authors suggest heliox 76), (77, 78), and partial liquid ventilation is less reliable than when used may prevent intubation. ventilation with perflubron (79). Over the during conventional mechanical ventila- In a prospective class II study specifi- last several years, the combination of he- tion, the need for continuous monitoring cally studying patients admitted to the liox with nonconventional modes of ven- of oxygen and gas exchange is again PICU, Martinon-Torres et al. (9) evalu- tilation has been investigated. stressed.

Pediatr Crit Care Med 2005 Vol. 6, No. 2 209 CONCLUSION ventilation. Am J Respir Crit Care Med 2001; tures. Am J Respir Crit Care Med 1999; 160: 163:109–114 22–32 The improved flow properties and 7. Tobias JD: Heliox in children with airway 23. Devabhaktuni VG, Torres A Jr, Wilson S, et higher CO2 diffusion coefficient of heliox obstruction. Pediatr Emerg Care 1997; 13: al: Effect of nitric oxide, perfluorocarbon, make it an interesting adjunct in the 29–32 and heliox on minute volume measurement treatment of acute respiratory failure. It 8. Hollman G, Shen G, Zeng L, et al: and ventilator volumes delivered. Crit Care is imperative to keep in mind that heliox Helium–oxygen improves Clinical Asthma Med 1999; 27:1603–1607 has no direct treatment effects and is only Scores in children with acute bronchiolitis. 24. Whitehead T, Slutsky AS: The pulmonary physician in critical care * 7: Ventilator in- a temporizing measure until more defin- Crit Care Med 1998; 26:1731–1736 duced lung injury. Thorax 2002; 57:635–642 itive therapies become effective or the 9. Martinon-Torres F, Rodriguez-Nunez A, Mar- tinon-Sanchez JM: Heliox therapy in infants 25. Frank JA, Matthay MA: Science review: disease process naturally resolves. Heliox with acute bronchiolitis. Pediatrics 2002; Mechanisms of ventilator-induced injury. may also allow time for the clinician to 109:68–73 Crit Care 2003; 7:233–241 prepare for high-risk interventions such 10. Jolliet P, Tassaux D, Thouret JM, et al: Ben- 26. Pinsky MR: Toward a better ventilation strat- as intubation in certain patient popula- eficial effects of helium:oxygen versus air: egy for patients with acute lung injury. Crit tions (i.e., upper airway compression oxygen noninvasive pressure support in pa- Care 2000; 4:205–206 from tumors or trauma). Throughout tients with decompensated chronic 27. Dreyfuss D, Saumon G: Ventilator-induced this review, studies have both supported obstructive pulmonary disease. Crit Care lung injury: Lessons from experimental stud- and contested a beneficial role for the Med 1999; 27:2422–2429 ies. Am J Respir Crit Care Med 1998; 157: clinical administration of heliox. How- 11. Katz A, Gentile MA, Craig DM, et al: Heliox 294–323 28. Parker JC, Hernandez LA, Peevy KJ: Mecha- ever, most studies agree that heliox ad- improves gas exchange during high-fre- quency ventilation in a pediatric model of nisms of ventilator-induced lung injury. Crit ministration is extremely safe. No adverse Care Med 1993; 21:131–143 effects of heliox have been reported. He- acute lung injury. Am J Respir Crit Care Med 2001; 164:260–264 29. Slutsky AS: Lung injury caused by mechan- liox seems most effective during condi- 12. Winters JW, Willing MA, Sanfilippo D: Heliox ical ventilation. Chest 1999; 116(suppl): tions involving density-dependent in- improves ventilation during high-frequency 9S–15S creases in airway resistance, especially oscillatory ventilation in pediatric patients. 30. International consensus conferences in in- when used early in an acute disease pro- Pediatr Crit Care Med 2000; 1:33–37 tensive care medicine: Ventilator-associated lung injury in ARDS. This official conference cess. 13. Adelson PD, Bratton SL, Carney NA, et al: report was cosponsored by the American In summary, it seems reasonable to Guidelines for the acute medical manage- Thoracic Society, The European Society of consider heliox as a relatively safe “ther- ment of severe traumatic brain injury in in- Intensive Care Medicine, and The Societe de apeutic bridge” for disease processes in- fants, children, and adolescents. Chapter 1: Reanimation de Langue Francaise, and was Introduction. Pediatr Crit Care Med 2003; volving respiratory distress related to tur- approved by the ATS Board of Directors, July 4:S2–S4 bulent gas flow. This bridge may allow 1999. Am J Respir Crit Care Med 1999; 160: 14. Kudukis TM, Manthous CA, Schmidt GA, et time for the planning of more definitive 2118–2124 al: Inhaled helium–oxygen revisited: effect of respiratory support, the onset of thera- 31. National Asthma Education and Prevention inhaled helium–oxygen during the treat- peutic medications, or the natural reso- Program. Expert Panel Report: Guidelines ment of status asthmaticus in children. J Pe- for the diagnosis and management of asthma lution of a disease process. The effects of diatr 1997; 130:217–224 update on selected topics—2002. J Allergy heliox are relatively instantaneous. Thus, 15. Kass JE: Heliox redux. Chest 2003; 123: Clin Immunol 2002; 110(suppl):S141–219 the clinician will quickly know if heliox 673–676 therapy will be beneficial for an individ- 32. National Asthma Education and Prevention 16. Papamoschou D: Theoretical validation of Program (National Heart Lung and Blood ual patient or if heliox should be aban- the respiratory benefits of helium–oxygen Institute): Guidelines for the diagnosis and doned for other therapies. mixtures. Respir Physiol 1995; 99:183–190 management of asthma: Expert panel report 17. Rogers MC: Textbook of Pediatric Intensive 2. Bethesda, MD, US Department of Health Care. Third Edition. Baltimore, Lippincott REFERENCES and Human Services Public Health Service Williams & Wilkins, 1996 National Institutes of Health National Heart 1. Barach AL: Use of helium as a new therapeu- 18. Wolfson MR, Bhutani VK, Shaffer TH, et al: Lung and Blood Institute, 1997 tic gas. Proc Soc Exp Biol Med 1934; 32: Mechanics and energetics of breathing he- 33. Carter ER, Webb CR, Moffitt DR: Evaluation 462–464 lium in infants with bronchopulmonary dys- of heliox in children hospitalized with acute 2. Kass JE, Castriotta RJ: Heliox therapy in plasia. J Pediatr 1984; 104:752–757 severe asthma. A randomized crossover trial. acute severe asthma. Chest 1995; 107: 19. Abd-Allah SA, Rogers MS, Terry M, et al: Chest 1996; 109:1256–1261 757–760 Helium– for pediatric acute 34. Barach AL: The therapeutic use of helium. 3. Kass JE, Terregino CA: The effect of heliox in severe asthma requiring mechanical ventila- JAMA 1936; 107:1273–1280 acute severe asthma: A randomized con- tion. Pediatr Crit Care Med 2003; 4:353–357 35. Manthous CA, Hall JB, Caputo MA, et al: trolled trial. Chest 1999; 116:296–300 20. Berkenbosch JW, Grueber RE, Dabbagh O, et Heliox improves pulsus paradoxus and peak 4. Schaeffer EM, Pohlman A, Morgan S, et al: al: Effect of helium–oxygen (heliox) gas mix- expiratory flow in nonintubated patients with Oxygenation in status asthmaticus improves tures on the function of four pediatric ven- severe asthma. Am J Respir Crit Care Med during ventilation with helium–oxygen. Crit tilators. Crit Care Med 2003; 31:2052–2058 1995; 151:310–314 Care Med 1999; 27:2666–2670 21. Oppenheim-Eden A, Cohen Y, Weissman C, 36. Dorfman TA, Shipley ER, Burton JH, et al: 5. Gluck EH, Onorato DJ, Castriotta R: et al: The effect of helium on ventilator per- Inhaled heliox does not benefit ED patients Helium–oxygen mixtures in intubated pa- formance: Study of five ventilators and a bed- with moderate to severe asthma. Am J Emerg tients with status asthmaticus and respira- side Pitot tube . Chest 2001; 120: Med 2000; 18:495–497 tory acidosis. Chest 1990; 98:693–698 582–588 37. Barach AL: The use of helium in the treat- 6. Goode ML, Fink JB, Dhand R, et al: Improve- 22. Tassaux D, Jolliet P, Thouret JM, et al: Cali- ment of asthma and obstructive lesions in ment in aerosol delivery with bration of seven ICU ventilators for mechan- the and . Ann Intern Med 1935; helium–oxygen mixtures during mechanical ical ventilation with helium–oxygen mix- 9:739–765

210 Pediatr Crit Care Med 2005 Vol. 6, No. 2 38. Ho AM, Lee A, Karmakar MK, et al: Heliox vs Helium–oxygen mixture in the treatment of gas exchange in mechanically ventilated chil- air–oxygen mixtures for the treatment of pa- postextubation stridor in pediatric trauma dren with bronchiolitis. Crit Care 2000; tients with acute asthma: A systematic over- patients. Crit Care Med 1991; 19:356–359 4:188–192 view. Chest 2003; 123:882–890 54. Jaber S, Carlucci A, Boussarsar M, et al: 70. Gross MF, Spear RM, Peterson BM: 39. Rodrigo GJ, Rodrigo C, Pollack CV, et al: Use Helium–oxygen in the postextubation period Helium–oxygen mixture decreases intrapul- of helium–oxygen mixtures in the treatment decreases inspiratory effort. Am J Respir Crit monary shunting in mechanically ventilated of acute asthma: A systematic review. Chest Care Med 2001; 164:633–637 children with bronchiolitis. Crit Care Med 2003; 123:891–896 55. Curtis JL, Mahlmeister M, Fink JB, et al: 1999; 27(suppl):163A 40. Emerman CL, Cydulka RK, McFadden ER: Helium–oxygen gas therapy. Use and avail- 71. Arnold JH: High-frequency ventilation in the Comparison of 2.5 vs 7.5 mg of inhaled al- ability for the emergency treatment of inop- pediatric intensive care unit. Pediatr Crit buterol in the treatment of acute asthma. erable airway obstruction. Chest 1986; 90: Care Med 2000; 1:93–99 Chest 1999; 115:92–96 455–457 72. Campbell D, Steinmann M, Porayko L: Nitric 41. Werner HA: Status asthmaticus in children: 56. Lu TS, Ohmura A, Wong KC, et al: oxide and high frequency jet ventilation in a A review. Chest 2001; 119:1913–1929 Helium–oxygen in treatment of upper airway patient with bilateral bronchopleural fistulae 42. Papo MC, Frank J, Thompson AE: A prospec- obstruction. Anesthesiology 1976; 45: and ARDS. Can J Anaesth 2000; 47:53–57 tive, randomized study of continuous versus 678–680 73. Day RW, Lynch JM, White KS, et al: Acute intermittent nebulized albuterol for severe 57. Mizrahi S, Yaari Y, Lugassy G, et al: Major response to inhaled nitric oxide in newborns status asthmaticus in children. Crit Care airway obstruction relieved by helium/ with respiratory failure and pulmonary hy- Med 1993; 21:1479–1486 oxygen breathing. Crit Care Med 1986; 14: pertension. Pediatrics 1996; 98:698–705 43. Montgomery VL, Eid NS: Low-dose beta- 986–987 74. Dobyns EL, Anas NG, Fortenberry JD, et al: agonist continuous nebulization therapy for 58. Polaner DM: The use of heliox and the laryn- Interactive effects of high-frequency oscilla- status asthmaticus in children. J Asthma geal mask airway in a child with an anterior tory ventilation and inhaled nitric oxide in 1994; 31:201–207 mediastinal mass. Anesth Analg 1996; 82: acute hypoxemic respiratory failure in pedi- 44. Newman SP: Therapeutic agents 208–210 atrics. Crit Care Med 2002; 30:2425–2429 and devices. Effectiveness in asthma and 59. Milner AD: The role of corticosteroids in 75. Kinsella JP, Truog WE, Walsh WF, et al: . Postgrad Med 1984; 76:194–203, bronchiolitis and croup. Thorax 1997; 52: Randomized, multicenter trial of inhaled ni- 197–206 595–597 tric oxide and high-frequency oscillatory 45. Newman SP, Moren F, Pavia D, et al: Depo- 60. Tunnessen WW Jr, Feinstein AR: The steroid- ventilation in severe, persistent pulmonary sition of pressurized suspension aerosols in- croup controversy: An analytic review of hypertension of the newborn. J Pediatr 1997; haled through extension devices. Am Rev Re- methodologic problems. J Pediatr 1980; 96: 131:55–62 spir Dis 1981; 124:317–320 751–756 76. Mehta S, MacDonald R, Hallett DC, et al: 46. Stillwell PC, Quick JD, Munro PR, et al: Ef- 61. Powell CV, Stokell RA: Changing hospital Acute oxygenation response to inhaled nitric fectiveness of open-circuit and oxyhood de- management of croup. What does this mean oxide when combined with high-frequency livery of helium–oxygen. Chest 1989; 95: for general practice? Aust Fam Physician oscillatory ventilation in adults with acute 1222–1224 2000; 29:915–919 respiratory distress syndrome. Crit Care Med 47. Kress JP, Noth I, Gehlbach BK, et al: The 62. Weber JE, Chudnofsky CR, Younger JG, et al: 2003; 31:383–389 utility of albuterol nebulized with heliox dur- A randomized comparison of helium–oxygen 77. Jackson JC, Truog WE, Standaert TA, et al: ing acute asthma exacerbations. Am J Respir mixture (heliox) and racemic epinephrine for Reduction in lung injury after combined sur- Crit Care Med 2002; 165:1317–1321 the treatment of moderate to severe croup. factant and high-frequency ventilation. Am J 48. Henderson SO, Acharya P, Kilaghbian T, et Pediatrics 2001; 107:E96 Respir Crit Care Med 1994; 150:534–539 al: Use of heliox-driven nebulizer therapy in 63. Terregino CA, Nairn SJ, Chansky ME, et al: 78. Davis JM, Richter SE, Kendig JW, et al: High- the treatment of acute asthma. Ann Emerg The effect of heliox on croup: A pilot study. frequency jet ventilation and surfactant Med 1999; 33:141–146 Acad Emerg Med 1998; 5:1130–1133 treatment of newborns with severe respira- 49. Anderson M, Svartengren M, Bylin G, et al: 64. Duncan PG: Efficacy of helium–oxygen mix- tory failure. Pediatr Pulmonol 1992; 13: Deposition in asthmatics of particles inhaled tures in the management of severe viral and 108–112 in air or in helium–oxygen. Am Rev Respir post-intubation croup. Can Anaesth Soc J 79. Doctor A, Mazzoni MC, DelBalzo U, et al: Dis 1993; 147:524–528 1979; 26:206–212 High-frequency oscillatory ventilation of the 50. Hess DR, Acosta FL, Ritz RH, et al: The effect 65. Sholter DE, Armstrong PW: Adverse effects perfluorocarbon-filled lung: Preliminary re- of heliox on nebulizer function using a beta- of corticosteroids on the cardiovascular sys- sults in an animal model of acute lung in- agonist . Chest 1999; 115: tem. Can J Cardiol 2000; 16:505–511 jury. Crit Care Med 1999; 27:2500–2507 184–189 66. Hall CB: Respiratory syncytial virus: A con- 80. Katz AL, Gentile MA, Craig DM, et al: Heliox 51. Skrinskas GJ, Hyland RH, Hutcheon MA: Us- tinuing culprit and conundrum. J Pediatr does not affect gas exchange during high- ing helium–oxygen mixtures in the manage- 1999; 135:2–7 frequency oscillatory ventilation if tidal vol- ment of acute upper airway obstruction. Can 67. Holman RC, Shay DK, Curns AT, et al: Risk ume is held constant. Crit Care Med 2003; Med Assoc J 1983; 128:555–558 factors for bronchiolitis-associated deaths 31:2006–2009 52. Meade MO, Guyatt GH, Cook DJ, et al: Trials among infants in the United States. Pediatr 81. Siddappa R, Dowhy MS, Rotta AT, et al: He- of corticosteroids to prevent postextubation Infect Dis J 2003; 22:483–490 liox enhances carbon dioxide clearance from airway complications. Chest 2001; 68. Deleted in proof lungs of normal rabbits during low bias flow 120(suppl):464S–468S 69. Gross MF, Spear RM, Peterson BM: oscillation. Pediatr Crit Care Med 2003; 53. Kemper KJ, Ritz RH, Benson MS, et al: Helium–oxygen mixture does not improve 4:89–93

Pediatr Crit Care Med 2005 Vol. 6, No. 2 211