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Heliox vs Air-Oxygen Mixtures for the Treatment of Patients With Acute Asthma*: A Systematic Overview FREE TO VIEW

Anthony M.-H. Ho, MD, FCCP; Anna Lee, PhD, MPH; Manoj K. Karmakar, MD; Peter W. Dion, PhD, MD; David C. Chung, MD; LeeAnne H. Contardi, NP
Author and Funding Information

*From the Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR; and Department of Anaesthesia, St. Catharines General Hospital and Hotel Dieu Hospital, St. Catharines, Ontario, Canada.

Correspondence to: Anthony M.-H. Ho, MD, FCCP, Department of Anaesthesia and Intensive Care, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR; e-mail: hoamh@cuhk.edu.hk



Chest. 2003;123(3):882-890. doi:10.1378/chest.123.3.882
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Objective: To evaluate, by systematic review, the efficacy of heliox on respiratory mechanics and outcomes in patients with acute asthma.

Methods: The search strategy included searching electronic databases (MEDLINE, EMBASE, and The Cochrane Library) and the references of relevant articles. Study quality was assessed based on allocation concealment. Randomized controlled trials (RCTs) comparing heliox to an air-oxygen mixture (airO2) as an adjunct treatment in patients with acute asthmatic attacks were analyzed. For the qualitative portion of the analysis, all reports of the use of heliox in patients with acute asthma were included.

Results: Four RCTs (n = 278) were found to have a common respiratory parameter (peak expiratory flow rate as a percentage of predicted) suitable for meta-analysis. Within the 92% confidence interval (CI), there was a small benefit with the use of heliox compared to airO2 (weighted mean difference, + 3%; 95% CI, − 2 to + 8%). There was also a slight improvement in the dyspnea index (weighted mean difference, 0.60; 95% CI, 0.04 to 1.16) with the use of heliox over airO2. Overall, five RCTs, one nonrandomized unblinded parallel trial, one retrospective case-matched control trial, three case series, and one case report had results in favor of heliox; one RCT and one case series showed no improvement with heliox; one RCT showed a possible detrimental effect with heliox; and 1 small RCT was inconclusive. Most investigators did not prevent entrainment of room air during heliox use or compensate for the lower nebulizing efficiency of heliox.

Conclusion: Based on surrogate markers, heliox may offer mild-to-moderate benefits in patients with acute asthma within the first hour of use, but its advantages become less apparent beyond 1 h, as most conventionally treated patients improve to similar levels, with or without it. The effect of heliox may be more pronounced in more severe cases. There are insufficient data on whether heliox can avert tracheal intubation, or change intensive care and hospital admission rates and duration, or mortality.

Figures in this Article

During an asthmatic attack, not all patients respond to treatment with bronchodilators and corticosteroids. Heliox, a mixture of helium and oxygen, by virtue of its low density, flows more efficiently through constricted airways with less turbulence and resistance than oxygen or air-oxygen (airO2) mixtures. Heliox improves breathing in patients with critical upper airway obstruction mainly by increasing ventilation and decreasing work of breathing.1When compared with air, heliox has been found to deposit aerosol particles more peripherally in the lungs in asthmatic subjects2; however, it was less efficient than air in nebulizing albuterol into 1- to 5-μm particles.3Whether heliox is also effective in acute asthma has been studied, with mixed results, in recent years.418

This article reviews the basic principles of gas flow, and the published literature on the use of heliox in children and adults with acute asthma. Specific questions are addressed: (1) Is heliox effective in improving ventilation during an acute asthmatic attack? (2) Is supplementary heliox treatment associated with improved outcomes?

Gas flow in the upper respiratory tract is largely laminar and follows the Hagen-Poiseuille law, which states that fluid flow rate () through a straight tube is related inversely to gas viscosity (μ) and the length (L) of the tube, and is proportional to the pressure gradient (ΔP) and the fourth power of the radius (r): = ΔPπr4/8 μL.1 Helium offers no advantage in laminar flow since gas density (ρ) does not appear in the above-mentioned equation, and gas viscosities are similar among helium, oxygen, and air.

However, turbulence occurs in constricted passages and follows a different law: α(ΔP/ρ)1/2. The ρ for helium is low, giving a high in turbulence.1

Compared to laminar flow, turbulent flow is sluggish. The type of flow is dependent on the Reynold's number (Re) = VDρ/μ, where V is the gas velocity and D for a circular opening is the diameter. For Re > 4,000, flow is turbulent; for Re < 2,100, it is laminar. Decreasing the ρ decreases Re. Although increasing the diameter would appear to increase Re, it actually decreases gas velocity even more, and the net effect is a decreased Re.

With branching in the bronchial tree, the airway cross-sectional area increases. Thus, the 11th generation has some seven times the cross-sectional area that exists at the lobar bronchi. As a result, Re should be small in small airways, often the site of compromise in acute asthma, and where flow may be nondensity dependent.19 However, turbulence still occurs at bifurcations and in constricted, inflamed, and secretion-laden airways. Further, sparing lung parenchyma, the entire bronchial tree is involved in asthma. Finally, physical phenomena are, by nature, chaotic; just as smoke from a smoldering cigarette in a still room does not rise perfectly straight, gas flow in small airways should not be entirely linear.

Search Strategy

MEDLINE (1966 to June 2002), EMBASE (1989 to June 2002), and the Cochrane Controlled Trials Registry were searched for relevant articles. Medical subject headings and text words used in the searches included asthma, helium, and heliox in English. Further articles were identified from the reference lists of relevant articles. Non-English language articles were not included, as they have not been found to add substantially to the body of evidence in reviews.20During article selection, reviewers were not blinded to the names of the authors, their affiliations, and the journal titles, as such efforts have not been found to have a significant effect on the summary odds ratios of meta-analyses.21

Selection Criteria

Studies were selected for review if they met the following research design criteria, determined a priori: systematic reviews, randomized controlled trials (RCTs), cohort, case-controlled studies, and cross-sectional studies. Case series and case reports were included.

Target Population:

The target population was adults and children with acute asthma requiring hospital treatment. Patients with disease without acute exacerbations who were studied with or without artificially induced peripheral airway obstruction were not included.

Intervention:

Interventions were any mixture of helium and oxygen, with or without concurrent β-agonists, parasympatholytics; and corticosteroids, and with or without invasive ventilation.

Outcome Measures:

Outcome measures were peak expiratory flow rate (PEFR), PEFR as a percentage of predicted (PEFR%), forced expiratory flow rate between 25% and 75% of vital capacity (FEF25–75), FEV1, FVC, respiratory rate (RR), clinical asthma scores, dyspnea index/score (DI), Paco2, alveolar-arterial oxygen tension gradient (P[A-a]O2), pulsus paradoxus (PP), length of hospital stay, and incidence of tracheal intubation and mechanical ventilation.

The quality of RCTs was assessed according to the level of allocation concealment (adequate, unclear, or inadequate),22 double blinding, and withdrawals. Meta-analysis was performed with common reported outcomes (PEFR%, DI, hospital admission rate, arterial blood oxygenation [Spo2]) using a random-effects model. A qualitative systematic overview was also performed so as not to miss any effects based on parameters that could not be pooled.

When crossover trials were combined with parallel RCTs, the data from the first arm of the trial were used if there was evidence of a carryover effect.23 Raw data from a crossover trial6 were obtained, and carryover effect was tested to determine whether all data or only those from the first arm of the trial should be used. An attempt was made to obtain raw data on PEFR% from another study.5 The level of confidence was estimated for any improvement in PEFR% using the method outlined by Shakespeare et al.24

A fixed effect meta-regression was used to examine whether baseline PEFR% affected the efficacy of the heliox treatment.25 A weighted linear regression model was used with trials weighted according to the inverse variance in treatment effect, and the SEs were adjusted by division of the residual mean square error.25

Study Selection

Our search yielded 24 articles, of which 15 articles met the inclusion criteria.418 There were minor discrepancies between the selections of articles by the authors, and they were resolved easily by consensus. The articles are presented in descending order in Table 1 according to the strength of the level of evidence. There were eight RCTs,,411 one nonrandomized prospective controlled trial,12one retrospective case-match controlled trial,13four before-after case series,1417 and one case report.18 A separate search without language restriction did not identify any additional RCTs. In the following presentation, all values, where appropriate, are given as mean and mean ± SD unless otherwise stated.

Quantitative Analysis

Five RCTs59 had a common end point (PEFR%). Kudukis et al5only reported the peak flow results, and we were unable to obtain the raw data, so their results could not be pooled with those from the other four RCTs.69 For the crossover trial by Carter et al,6 there was no evidence of carryover effect based on analysis of variance, so the full data set was used for analysis rather than the paired t test as used by the original authors. After contact with the primary author of one trial,,10 we did not pool the results for Spo2 and hospital admission rates with other trials,6,8 because of differences in the delivery of the test gases (80% helium to nebulize albuterol with a semiclosed breathing system10 vs 70% helium minus dilution from entrainment of room air6,8).

The results of the meta-analysis of heliox vs airO2 on PEFR% in asthmatic patients showed no significant difference between the two interventions (weighted mean difference, + 3%; 95% confidence interval [CI], − 2 to + 8%) within the first hour (Fig 1 ). The level of confidence was 92% that heliox provides a benefit as an adjunct to standard medical care in acute asthma.

Post hoc meta-analyses of trials that used the test gases to nebulize albuterol (but with no prevention against entrainment of room air)89 and of trials that did not use the test gases to nebulize albuterol (test gases administered via standard or rebreathing masks)67 showed no difference in PEFR% outcome (weighted mean difference, − 0.03; 95% CI, − 6.43 to 6.37; and weighted mean difference, 7.36; 95% CI, − 1.18 to 15.90, respectively; p = 0.32).

The weighted linear regression model to examine the relationship between baseline PEFR% and treatment effect (weighted mean difference) produced the following equation (Fig 2 ): treatment effect = 23.94 − 0.56 × baseline PEFR%. The slope estimate was significant (− 0.56; 95% CI, − 0.96 to − 0.17), suggesting that there was a relationship between baseline PEFR% and the PEFR% readings obtained after treatment (airO2 or heliox). The model suggests that patients with severe acute asthma (< 43% PEFR) may benefit more from heliox compared with patients with less severe acute asthma.

There was no difference between heliox and airO2 on Spo2 from pooling of data from the trials of Carter et al6 and Dorfman et al8 (weighted mean difference, 0%; 95% CI, − 1.4 to + 1.4%). There was a significant difference between interventions for DI from the trials by Carter et al,6and Kass and Terrigino7(weighted mean difference, 0.60; 95% CI, 0.04 to 1.16). It was not possible to pool actual hospital admission data from the trials of Dorfman et al8and Henderson et al9 because of heterogeneity (Q statistic = 3.73; degrees of freedom = 1; p = 0.05).

Qualitative Analysis
RCTs:

Rose et al4 nebulized continuous albuterol with heliox or airO2 (30% O2 for both) in adults with mean duration of asthma symptoms over 24 h. Patients improved significantly in both groups at the 2-h mark; the differences between groups were not significant for PEFR (95% CI, − 20 to 51), FEV1 (95% CI, − 0.22 to 0.3), RR (95% CI, − 2.7 to 3.8), and Spo2 (95% CI, − 2 to 1.5), but significant for subjective dyspnea (in favor of heliox, 95% CI, 0.3 to 3).

L’Her et al11 studied 16 patients with severe asthma, as defined by PEFR ≤ 200 L/min and/or oxygen desaturation despite medical therapy. Once a patient was enrolled, he/she received nebulized bronchodilators plus a rebreathing mask both driven by a test gas of either heliox (22% O2) or airO2. Supplemental oxygen was administered to adjust the inspired oxygen up to 60% to ensure a Spo2 of ≥ 92%. They found the DI to have improved more significantly in the airO2 group during the first hour, and a significantly higher mean Paco2 and significantly lower mean lactate level in the heliox group at 48 h. Interpretation of these data are difficult due to the small sample size and the use of very low levels (down to 40%) of inspired helium in most patients.

Kress et al10 administered three consecutive treatments of albuterol nebulized with heliox (20% O2) or air in adults with baseline FEV1 < 50% predicted. Each patient also received the test gas via a semiclosed system to ensure no entrainment of air. Among RCTs, the study of Carter et al,6 is the only other study that ensured no room air was entrained. Measurements were obtained 15 min after each treatment to ensure complete helium washout. Improvements in FEV1 after heliox were significantly better than after air (Table 1).

Kudukis et al5 enrolled children with PP > 15 mm Hg despite conventional treatment for > 30 min. After heliox breathing for 15 min, PP decreased from 23.3 to 10.6 mm Hg (p < 0.0001), and DI from 5.7 ± 1.3 to 1.9 ± 1.7 (p < 0.0002), both indexes deteriorating 15 min after discontinuation of heliox (18.5 ± 7.3 mm Hg and 4.0 ± 0.5 [p > 0.15 compared to baseline, respectively]). There were no significant changes in PP and DI at the 15-min and 30-min marks in the control group. The differences in PP and DI between the two groups were significant at the 15-min mark (p < 0.005 for both indexes). Mechanical ventilation was allegedly averted in three patients in whom dyspnea lessened dramatically during heliox breathing.

Carter et al6 studied 11 children: 9 children within 24 h of hospital admission, 1 child on the second day after hospital admission, and 1 child on the third day after hospital admission. All patients received albuterol every 1 to 4 h started within 30 min of entering the study, and steroid every 6 h with at least one dose administered > 3 h before the start of the study. After baseline data were obtained, the patients received either heliox or airO2 (30% O2 for both) for 15 min, had respiratory parameters measured, then received the other test gas for 15 min, had parameters recorded, and again 15 min after stopping the second gas mixture. There were no significant differences between study-entry and study-end FEV1 and FVC. The authors reported that heliox breathing resulted in higher FEF25–75 (p = 0.006) and PEFR% (p = 0.04). Analysis of variance re-analysis of the raw data, taking into account the baseline FEF25–75, showed no difference between the heliox and air groups (p = 0.32). Likewise, reanalysis revealed that there was no difference as measured by PEFR% (p = 0.34).

Kass and Terregino7 studied 23 adults with PEFR < 200 L/min despite treatment. Patients received test gas an hour after initiation of treatment, and respiratory parameters were measured at 20 min and every 2 h, while standard treatment was administered every 2 h starting at the 2-h point. At 20 min, in the heliox (30% O2) group, there was a 58.4% increase in PEFR% from baseline (p < 0.01), whereas in the airO2 group there was a 10.1% increase in PEFR% (p > 0.1). There was not another significant further improvement in PEFR% until 480 min in the heliox group (p < 0.01). For the airO2 group, the first significant improvement in PEFR% from baseline occurred at 360 min (p < 0.05). On discontinuation of heliox, the PEFR% did not change. There were no interactions of test gas and DI, RR, heart rate, and BP vs time between the groups (p < 0.1). However, at 20 min, the heliox group showed a significant drop in DI and RR as compared with baseline. There were no further significant improvements from 20 to 480 min. In the airO2 group, there were no significant decreases for the same variables at 20 min, and there was improvement in the DI between the baseline and at 480 min (p < 0.05), and between the 20-min and 480-min marks (p < 0.05).

Dorfman et al8 enrolled 39 adults presenting to the emergency department. They administered bronchodilators nebulized either with 30% O2 in helium or nitrogen at 2 L/min. After 1 h of continuous treatment, the PEFR% improved in both groups (70% and 68% for heliox and airO2, respectively). The duration of acute symptoms, oxygen saturation, BP, and RR were similar in both groups, but the heliox group had a significantly higher preintervention heart rate (108 beats/min vs 97 beats/min). Five of the 20 patients in the heliox group vs none of the 19 patients in the air group (p < 0.05) were hospitalized for management of their asthma.

Henderson et al9 studied 205 adults as they presented in the emergency department. Each patient received steroid at the onset of treatment, and was administered albuterol every 15 min driven by heliox or airO2 (30% O2 for both). By 30 min, PEFR% in the heliox group was higher than that in the airO2 group (p = 0.05), while FEV1 in the heliox group was nonsignificantly higher (p = 0.08). Both groups showed improvement as measured at the 45-min mark for both PEFR% and FEV1 (p < 0.0001), but showed no difference between them (p = 0.33 for PEFR%, p = 0.47 for FEV1). No interaction was found between time and group for PEFR% or FEV1 (p = 0.56 and 0.37, respectively). Of the 102 patients receiving heliox, 5 patients (4.9%) required hospital admission, and 8 patients (7.8%) of the 102 patients receiving airO2 therapy were admitted to the hospital (p = 0.57).

Nonrandomized Prospective Controlled Trial:

The patients of Manthous et al12 had PP > 15 mm Hg and PEFR < 250 L/min despite 30 min of standard therapy. With time, PP decreased (19.5 ± 3.6 mm Hg at baseline, 17.3 ± 5 mm Hg at 15 min, and 15.5 ± 5 mm Hg at 30 min) and PEFR increased (153 ± 54 L/min at baseline, 164 ± 55 L/min at 15 min, and 168 ± 5.6 L/min at 30 min) in the airO2 group (p < 0.05 for all). Despite a higher baseline PP in the heliox group, PP after breathing heliox for 15 min was lower than that in the airO2 group (12.3 ± 4.8 mm Hg vs 17.3 ± 5 mm Hg, p < 0.01). After cessation of heliox therapy and resumption of air breathing for 15 min, PP rose to 15.6 ± 8.4 mm Hg, a level not different from PP in control patients at 30 min. PEFR increased while breathing heliox, and the increase after 15 min was greater than in control patients (p < 0.001), as was the decrease in PEFR, from 15 to 30 min when air breathing resumed in the heliox group (p < 0.001).

Retrospective Case-Matched Controlled Trial:

Schaeffer et al13 studied 22 patients with status asthmaticus admitted to the hospital for intubation and mechanical ventilation. They found among those who received heliox immediately after initiation of ventilation, P(A-a)O2 decreased from 216 ± 92 to 85 ± 44 mm Hg (p < 0.003) during a 90-min period, whereas it did not change among those who received air. Steroids and bronchodilators were presumably used prior to and during the data collection periods.

Before/After Case Series and Case Reports:

Verbeek and Chopra14 found, in 13 nonintubated adults with acute exacerbation of asthma who had not been administered bronchodilators within the past hour, that breathing heliox for 5 min did not change the FEV1 (1.45 ± 0.46 L vs 1.41 ± 0.47 L).

Kass and Castriotta15 found that in 12 adults with acute asthma already administered steroids and repeated doses of bronchodilators, some for up to 160 min, heliox (60 to 70% helium) breathing led to a drop in Paco2 and a rise in arterial pH (both p < 0.005) after 49.2 ± 25.2 min of spontaneous (through a mask, 7 patients) or mechanical (5 patients) ventilation. Those with symptoms for < 24 h responded the most.

Shiue and Gluck16 found that 10 adults with status asthmaticus had less dyspnea within minutes of starting heliox. Their arterial pH increased, as measured at the 20-min (p < 0.05) and 1-h marks (p < 0.01), and their Paco2 decreased, as measured at those marks (both p < 0.05).

Gluck et al17administered heliox to intubated adults with status asthmaticus and respiratory acidosis 1 h after standard medical treatment. All patients experienced a reduction (decrease of 35.7 mm Hg, p < 0.001) of Paco2 without changes in Pao2 within 20 min heliox use. Six patients had a decrease in peak airway pressure of 32.9 cm H2O at 2.5 min after the onset of heliox use. All patients underwent extubation within 24 h of intubation without complications. The duration of heliox treatment was 6.3 ± 5.6 h. Austan18 described the case of an asthmatic woman who improved after breathing heliox for up to 40 min and who eventually corrected her marked respiratory acidemia after 2 h.

This article reviews the published literature on the use of heliox in patients with acute asthma. The studies included varied widely in design, types of patients recruited, and outcomes collected. Meta-analysis was used only in some of the RCTs,69 based on the common outcomes of PEFR%, Spo2, and DI. For the majority, significant clinical and statistical heterogeneity (as tested by χ2) prevented pooling of outcomes. These meta-analyses demonstrated an advantage with the use of heliox when compared with airO2 at the 92% CI for PEFR%. Conceivably, the CI would be higher had we had the raw data of Kudukis et al,,5which showed a superior improvement after heliox therapy as measured by peak flow. Patients with more severe asthma as measured by flow characteristics may respond better to heliox. With the exception of the study by Carter et al,6 all the analyzed RCTs might have suffered from an important flaw10: entrainment of room air during delivery of the test gases or while albuterol was being nebulized with the test gases, potentially diluting the beneficial effect of helium.10 Of note is the highly significant improvement using heliox found by Kress et al,10 who used 80% helium (as opposed to 70% minus dilution from entrainment in most other studies) to nebulize albuterol in conjunction with a semiclosed breathing system to virtually eliminate entrainment of room air.10 Another important flaw in most of these studies is that spirometry was performed possibly without a washout period, potentially allowing exhaled helium to render spirometric readings inaccurate.10

We ranked among the RCTs411 the level of allocation concealment. Compared to trials with adequate allocation concealment, those with unclear and inadequate allocation concealment may exaggerate the treatment effect by 30% and 41%, respectively.22 Therefore, the results reported by Henderson et al9 should be viewed with caution. Trials that were not double blinded also could yield exaggerated estimates of treatment effect by 17%.22 Blinding was reported to be difficult in some of the articles because of the high-pitch voice that results from heliox breathing.

Our analyses differ in important aspects from a similar report.26 For PEFR%, Henderson et al9 started off with 204 patients, but at 45 min had data on 84 patients in the heliox group and 91 patients in the control group. Rodrigo et al26 used 102 patients in both groups; we used 84 patients and 91 patients, respectively. We used the raw data of Carter et al6 for DI and found significant results, Rodrigo et al26 used rounded-up numbers in the published article.6 We pooled the same studies to examine PEFR% but with the raw data supplied by Dr. Carter, and determined that heliox offered an advantage at the 92% CI, and that patients with more severe attacks may respond to heliox better.

Since PEFR% is but one parameter, we also qualitatively analyzed all studies, and found that five RCTs45,7,910 of the eight RCTs,411 the one nonrandomized controlled trial,12and the one retrospective case-matched study that measured parameters within the first 20 to 30 min after initiation of heliox therapy,13 showed improvements in at least one respiratory parameter, and that this benefit is not sustained beyond the first hour (with the exception of the study of Rose et al,4 which showed less subjective dyspnea in the heliox group at the 2-h mark). The trial that measured only parameters at 1 h,8 and the study that measured at 2 h4 did not show benefits with the use of heliox. Carter et al6 concluded that heliox conferred benefits, but our reanalysis concluded otherwise. With the exception of one before/after case series,14all case series/reports1518 showed acute improvement with heliox substituting airO2.

With the exception of Carter et al6 and Kress et al,10 no investigators explicitly described measures to eliminate entrainment of room air during heliox administration.10 None mentioned the use of a higher heliox flow to compensate for the lower albuterol nebulizing efficiency of heliox as compared to air.3 Conceivably, such experimental flaws, if they existed, could have diluted any beneficial effects of heliox.

Overall, with conventional therapy, most patients with acute asthma improve, but heliox allows them to improve faster, albeit with no intermediate- to long-term advantage. As such, heliox may be a useful bridge before steroid takes effect, and anecdotal evidence suggests that it may allow some patients to avert tracheal intubation. The reports by Carter et al6 and Kass and Castriotta15 suggest that heliox may be less effective in patients who have had prolonged duration of symptoms.

Potential Morbidity Associated With the Use of Heliox

Acute lower airway obstruction causes uneven ventilation of the lungs and air trapping. Theoretically, inspiratory flow to some alveoli could become excessive during administration of heliox, especially when delivered mechanically. This could lead to dynamic hyperinflation of these alveoli and barotrauma.19 Mechanical ventilation was used only in the studies of Gluck et al17 and Kass and Castriotta.15 There is no barotrauma reported in any of the cited work.

Although helium improves flow, the gain in efficiency of oxygen delivery is smaller than the loss of oxygen displaced by helium.1 Heliox is thus useful in decreasing the work of breathing and the Paco2. Hypoxemic patients are not suitable for heliox therapy. Indeed, one patient administered heliox in the study by Henderson et al,9 had to be withdrawn because of hypoxia.

Helium has a higher thermoconductivity27 and heat capacity than nitrogen. However, heat loss during respiration is mainly due to water vaporization, and the extra loss while breathing heliox amounts to, by our estimation, an extra 2.5%, unlikely of significance in adults. None of the studies418 reported hypothermia or subjective feelings of cold by the patients.

Heliox improves certain respiratory (surrogate) parameters in some asthmatic patients during an attack, but not in others. Heliox may offer benefits in patients with acute asthma within the first hour of use, but its advantages become less apparent beyond 1 h, as most conventionally treated patients improve to similar levels, with or without it. The effect of heliox may be more pronounced in more severe cases. Since there is insufficient data, future studies should focus on whether heliox can reduce tracheal intubation rate; the duration of mechanical ventilation, intensive care, and hospital lengths of stay; and mortality. In addition, future investigators should also improve on the levels of allocation concealment, prevent air entrainment during heliox administration,10 consider the use of higher heliox flow to compensate for its lower nebulizing efficiency,3 and allow a period for washout of the test gas before spirometry is performed to minimize the effects of helium on such measurements.10

Abbreviations: airO2 = air-oxygen mixture; CI = confidence interval; DI = dyspnea index/score; FEF25–75 = forced expiratory flow from 25 to 75% of vital capacity; P(A-a)O2 = alveolar-arterial oxygen tension gradient; PEFR = peak expiratory flow rate; PEFR% = peak expiratory flow rate as a percentage of predicted; PP = pulsus paradoxus; ΔP = pressure gradient; = fluid flow rate; ρ = gas density; Re = Reynold's number; RCT = randomized controlled trial; RR = respiratory rate; Spo2 = arterial blood oxygenation

Support of this work was entirely from institutional/departmental resources.

This work was presented in part at the 11th European Congress of Anaesthesiology. June 5–7, 2001; Florence, Italy.

Table Graphic Jump Location
Table 1. Summary of Reports on the Use of Heliox in Patients With Acute Asthma
Figure Jump LinkFigure 1. Effect of heliox vs airO2 on PEFR%.Grahic Jump Location
Figure Jump LinkFigure 2. Treatment effect vs baseline peak expiratory flow (PEF) percentage of predicted at start of treatment for four trials of heliox. The area of each circle is inversely proportional to the variance of the estimated treatment effect of the each trial.Grahic Jump Location

We thank LTC E. R. Carter, MD, of the Madigan Army Medical Center, Tacoma, WA, for providing us with the raw data from his trial6 and for his helpful comments, and J. S. Rose, MD, of the University of California Davis Medical Center, Sacramento, CA, for providing us with the preprint of his article.4 We also thank the reviewers and Dr. J. P. Kress of the University of Chicago for their insightful comments.

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Gluck, EH, Onorato, DJ, Castriotta, R Helium-oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis.Chest1990;98,693-698. [PubMed]
 
Austan, F Heliox inhalation in status asthmaticus and respiratory acidemia: a brief report.Heart Lung1996;25,155-157. [PubMed]
 
Madison, JM, Irwin, RS Heliox for asthma: a trial balloon.Chest1995;107,597-598. [PubMed]
 
Moher, D, Pham, B, Klassen, TP, et al What contributions do languages other than English make on the results of meta-analyses?J Clin Epidemiol2000;53,964-972. [PubMed]
 
Berlin, JA Does blinding of readers affect the results of meta-analyses? University of Pennsylvania Meta-analysis Blinding Study Group.Lancet1997;350,185-186
 
Schulz, KF, Chalmers, I, Haynes, RJ, et al Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials.JAMA1995;273,408-412. [PubMed]
 
Sutton, AJ, Abrams, KR, Jones, DR, et al Systematic reviews of trials and other studies.Health Technol Assess1998;2,1-276
 
Shakespeare, TP, Gebski, VJ, Veness, MJ, et al Improving interpretation of clinical studies by use of confidence levels, clinical significance curves, and risk-benefit contours.Lancet2001;357,1349-1353. [PubMed]
 
Sutton, AJ, Abrams, KR, Jones, DR, et al Methods for meta-analysis in medical research.2000,96 John Wiley & Sons. Chichester, UK:
 
Rodrigo, G, Rodrigo, C, Pollack, C, et al Helium-oxygen mixture for nonintubated acute asthma patients (Cochrane Review). The Cochrane Library, Issue 2. 2001; Update Software. Oxford, UK:.
 
de Gamarra, E, Moriette, G, Farhat, M, et al Heliox tolerance in spontaneously breathing neonates with bronchopulmonary dysplasia.Biol Neonate1998;74,193-199. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Effect of heliox vs airO2 on PEFR%.Grahic Jump Location
Figure Jump LinkFigure 2. Treatment effect vs baseline peak expiratory flow (PEF) percentage of predicted at start of treatment for four trials of heliox. The area of each circle is inversely proportional to the variance of the estimated treatment effect of the each trial.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Summary of Reports on the Use of Heliox in Patients With Acute Asthma

References

Ho, AMH, Dion, PW, Karmakar, MK, et al (2002) Use of heliox in critical upper airway obstruction: physical and physiologic considerations in choosing the proper helium-oxygen mix.Resuscitation52,297-300. [PubMed] [CrossRef]
 
Anderson, M, Svartengren, M, Bylin, G, et al Deposition in asthmatics of particles inhaled in air or in helium-oxygen.Am Rev Respir Dis1993;147,524-528. [PubMed]
 
Hess, DR, Acosta, FL, Ritz, RH, et al The effect of heliox on nebulizer function using a β-agonist bronchodilator.Chest1999;115,184-189. [PubMed]
 
Rose, JS, Panacek, EA, Miller, P Prospective randomized trial of heliox-driven continuous nebulizers in the treatment of asthma in the emergency department.J Emerg Med2002;22,133-137. [PubMed]
 
Kudukis, TM, Manthous, CA, Schmidt, GA, et al Inhaled helium-oxygen revisited: effect of inhaled helium-oxygen during the treatment of status asthmaticus in children.J Pediatr1997;130,217-224. [PubMed]
 
Carter, ER, Webb, CR, Moffitt, DR Evaluation of heliox in children hospitalized with acute severe asthma: a randomized crossover trial.Chest1996;109,1256-1261. [PubMed]
 
Kass, JE, Terregino, CA The effect of heliox in acute severe asthma: a randomized controlled trial.Chest1999;116,296-300. [PubMed]
 
Dorfman, TA, Shipley, ER, Burton, JH, et al Inhaled heliox does not benefit ED patients with moderate to severe asthma [letter].Am J Emerg Med2000;18,495-497. [PubMed]
 
Henderson, SO, Acharya, P, Kilaghbian, T, et al Use of heliox-driven nebulizer therapy in the treatment of acute asthma.Ann Emerg Med1999;33,141-146. [PubMed]
 
Kress, JP, Noth, I, Gehlbach, BK, et al The utility of albuterol nebulized with heliox during acute asthma exacerbations.Am J Respir Crit Care Med2002;165,1317-1321. [PubMed]
 
L’Her, E, Monchi, M, Joly, B, et al Helium-oxygen breathing in the early emergency care of acute severe asthma: a randomized pilot study.Eur J Emerg Med2000;7,271-275. [PubMed]
 
Manthous, CA, Hall, JB, Melmed, A, et al Heliox improves pulsus paradoxus and peak expiratory flow in nonintubated patients with severe asthma.Am J Respir Crit Care Med1995;151,310-314. [PubMed]
 
Schaeffer, EM, Pohlman, A, Morgan, S, et al Oxygenation in status asthmaticus improves during ventilation with helium-oxygen.Crit Care Med1999;27,2666-2670. [PubMed]
 
Verbeek, PR, Chopra, A Heliox does not improve FEV1in acute asthma patients.J Emerg Med1998;16,545-548. [PubMed]
 
Kass, JE, Castriotta, RJ Heliox therapy in acute severe asthma.Chest1995;107,757-760. [PubMed]
 
Shiue, ST, Gluck, EH The use of helium-oxygen mixtures in the support of patients with status asthmaticus and respiratory acidosis.J Asthma1989;26,177-180. [PubMed]
 
Gluck, EH, Onorato, DJ, Castriotta, R Helium-oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis.Chest1990;98,693-698. [PubMed]
 
Austan, F Heliox inhalation in status asthmaticus and respiratory acidemia: a brief report.Heart Lung1996;25,155-157. [PubMed]
 
Madison, JM, Irwin, RS Heliox for asthma: a trial balloon.Chest1995;107,597-598. [PubMed]
 
Moher, D, Pham, B, Klassen, TP, et al What contributions do languages other than English make on the results of meta-analyses?J Clin Epidemiol2000;53,964-972. [PubMed]
 
Berlin, JA Does blinding of readers affect the results of meta-analyses? University of Pennsylvania Meta-analysis Blinding Study Group.Lancet1997;350,185-186
 
Schulz, KF, Chalmers, I, Haynes, RJ, et al Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials.JAMA1995;273,408-412. [PubMed]
 
Sutton, AJ, Abrams, KR, Jones, DR, et al Systematic reviews of trials and other studies.Health Technol Assess1998;2,1-276
 
Shakespeare, TP, Gebski, VJ, Veness, MJ, et al Improving interpretation of clinical studies by use of confidence levels, clinical significance curves, and risk-benefit contours.Lancet2001;357,1349-1353. [PubMed]
 
Sutton, AJ, Abrams, KR, Jones, DR, et al Methods for meta-analysis in medical research.2000,96 John Wiley & Sons. Chichester, UK:
 
Rodrigo, G, Rodrigo, C, Pollack, C, et al Helium-oxygen mixture for nonintubated acute asthma patients (Cochrane Review). The Cochrane Library, Issue 2. 2001; Update Software. Oxford, UK:.
 
de Gamarra, E, Moriette, G, Farhat, M, et al Heliox tolerance in spontaneously breathing neonates with bronchopulmonary dysplasia.Biol Neonate1998;74,193-199. [PubMed]
 
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