Abstract
Heliox improves lung deposition of inhaled particles when compared with air or oxygen inhalation. We studied the spirometric effects of albuterol nebulized with heliox during emergency room visits for asthma exacerbations. Forty-five patients were randomized to receive albuterol nebulized with oxygen (control) versus heliox (n = 22 control and 23 heliox subjects). At baseline, demographics, outpatient asthma medications, vital signs, oxygen saturation, and forced expiratory volume in one second were not different between the two groups. Three consecutive albuterol treatments were given to each group. The heliox group had a significantly higher heart rate after albuterol nebulization compared with the control group. Following albuterol Treatment 1, the median change in forced expiratory volume in one second was 14.6% in the control group and 32.4% in the heliox group (p = 0.007). After Treatment 2, the results were 22.7% versus 51.5%, respectively (p = 0.007). After Treatment 3, the results were 26.6% versus 65.1%, respectively (p = 0.016). We conclude that during acute asthma exacerbations, albuterol nebulized with heliox leads to a more significant improvement in spirometry when compared with albuterol nebulized with oxygen. This is likely due to the low-density gas improving albuterol deposition in the distal airways.
Inhaled β2 agonists such as albuterol are a mainstay of therapy for patients with asthma suffering from acute exacerbations. Albuterol is often delivered by jet nebulization—typically using oxygen as the driving gas. Heliox, a blend of helium and oxygen, is a low-density gas that has been shown to improve airflow in patients during asthma exacerbations (1–4). In stable asthmatics, others have previously shown that heliox improves the lung deposition of inhaled particles when compared with air (5). Whether such improved particle deposition can be achieved in acute asthma with resulting improvement in spirometry has not been tested extensively. We sought to determine whether the use of heliox 80:20 to nebulize albuterol would have the therapeutic benefit of improved spirometry compared with albuterol nebulized with oxygen in patients presenting with severe acute asthma exacerbations.
We studied adult patients who presented to the emergency department at the University of Chicago Medical Center for a severe acute exacerbation of asthma. This study was approved by the Institutional Review Board, and all patients enrolled gave written informed consent before beginning the study. Patients 50 years of age or under meeting American Thoracic Society criteria for the diagnosis of asthma (6) were eligible. To ensure that only those with severe persistent asthma were studied, we enrolled only those patients with baseline forced expiratory volume in one second (FEV1) less than 50% predicted.
Patients were randomized to receive albuterol nebulized with either oxygen (control) or heliox 80:20 as the driving gas. We had previously performed a pilot study using a mouthpiece and T-piece adapter (Airlife Misty-Neb; Allegiance Healthcare Corporation, McGaw Park, IL) to nebulize albuterol (Figure 1). In this pilot study, control patients had received albuterol nebulized with oxygen, whereas study patients received albuterol nebulized with heliox through this “open” mouthpiece and T-piece adapter breathing system. From this study, we detected no differences in spirometry between heliox and oxygen albuterol nebulization and hypothesized that entrainment of room air was decreasing the effective concentration of heliox being delivered to the patient with this system (7). Therefore, the protocol for this study was designed to ensure delivery of a high concentration of heliox to the patients' airways. The current heliox delivery system consisted of a facemask connected to a ‘Y’ piece with the nebulizer (Airlife Misty-Neb) on one limb and a nonrebreather bag on the other limb. Heliox flow to the nebulizer limb was set at 10 L/min. A separate flow of 10 L/minute of heliox was delivered to the nonrebreather bag. This noninvasive, semiclosed delivery system has been described in detail previously (8) and is illustrated in Figure 2
Figure 2. Delivery system for albuterol nebulized with heliox. (A) Partial nonrebreather mask; (B) exhalation valve; (C) a 22-mm Id adapter; (D) ventilator Y-piece; (E) airlife Misty-Neb Nebulizer; (F ) one-way valve; (G) connection for tubing to heliox tank; (H) reservoir bag; (I) port for nebulizing medication.
[More] [Minimize]FEV1 was measured at baseline and 15 minutes after completion of each albuterol treatment using a portable Vacumed Micro Spirometer (VacuMed, Ventura, CA). This spirometer is calibrated when manufactured and, according to the owner's manual, does not require recalibration (9). To ensure its accuracy for the purpose of this study, the spirometer was tested every other week with a 3-L syringe. In addition, the accuracy of FEV1 recordings was tested by having subjects perform forced expiratory maneuvers through the portable spirometer at varying flow rates while it was in-line with a Medical Graphics 1070 (Medical Graphics Corporation, St. Paul, MN) pulmonary function testing system (this system is calibrated daily in our pulmonary function laboratory). This test was also performed every other week for the first 3 months of the study and monthly thereafter.
Patients performed a minimum of three forced expiratory maneuvers with values recorded according to the recommendations from the American Thoracic Society (10). All spirometric measurements were made by investigators who were blinded to the gas used for albuterol nebulization. The study investigator was not present during the albuterol treatments and did not enter the patient's room until 15 minutes after the treatment was finished. Patients were not told explicitly to which treatment limb they were randomized; however, because of potential voice changes while breathing heliox, it was not possible to ensure that patients were blinded to which therapy they received.
Demographic data, chronic asthma medications, emergency room corticosteroid administration, vital signs (heart rate, mean arterial pressure, respiratory rate), oxygen saturation by pulse oximetry, emergency room length of stay, and hospital admissions from the emergency room were recorded for all patients. Data are expressed as mean ± SD when normally distributed and median (interquartile range) when not normally distributed. Interval data were compared using a two-tailed Student's t test or Mann Whitney U test according to normality of distribution, and categorical data were compared using chi-square or Fisher's Exact test when appropriate. Percent changes in vital sign measurements from baseline ([vital sign post albuterol treatment − baseline vital sign/baseline vital sign] × 100) after each nebulizer treatment were compared by using two-way repeated-measures analysis of variance. We used the Student-Newman-Keuls test to compare differences between heliox and control groups after each nebulization treatment when appropriate. Raw FEV1 values and percent change in FEV1 from baseline ([FEV1 post albuterol treatment − baseline FEV1/baseline FEV1] × 100) for the two groups were compared using the Mann-Whitney U test with Bonferroni's correction for multiple comparisons. We considered a 25% difference in percent change in FEV1 between the control and heliox groups to be clinically important. By using a SD of 28% (based on preliminary work), an α error of 0.05, and a β error of 0.20, we estimated that a total of 42 patients (21 in each group) would be needed to avoid a type II error. A p value of less than 0.05 was considered to indicate statistical significance, except when Bonferroni's correction for comparisons of three consecutive albuterol treatments was applied. In this situation, a p value of less than 0.0167 was considered to indicate statistical significance.
A total of 45 patients (16 men and 29 women) were enrolled in this study. As seen in Table 1
Control | Heliox | p value | |
|---|---|---|---|
| N | 22 | 23 | |
| Age | 34.7 ± 10.9 | 30.3 ± 8.6 | 0.14 |
| Number of male/female | 9/13 | 7/16 | 0.67 |
| Height, cm | 171.2 ± 10.2 | 167.8 ± 12.3 | 0.33 |
| Baseline FEV1, L | 1.18 ± 0.38 | 1.17 ± 0.40 | 0.93 |
| Baseline FEV1, percentage predicted | 32.8 ± 11.3% | 32.4 ± 9.2% | 0.91 |
| Chronic asthma medications | |||
| β2 agonist, % | 17 (77%) | 20 (87%) | 0.46 |
| Inhaled corticosteroids , % | 9 (41%) | 6 (26%) | 0.35 |
| Systemic corticosteroids, % | 5 (23%) | 1 (4%) | 0.10 |
| Theophylline, % | 4 (18%) | 1 (4%) | 0.19 |
| Leukotriene inhibitors, % | 3 (14%) | 1 (4%) | 0.35 |
| Tobacco use, % | 2 (9%) | 1 (4%) | 0.61 |
Control | Heliox | p value | |
|---|---|---|---|
| n | 22 | 23 | |
| Baseline HR, beats/minute | 103.6 ± 21.2 | 96.2 ± 18.2 | 0.22 |
| Percent change HR by two-way repeated-measures analysis of variance | 0.009 | ||
| Percent change HR postneb 1 (S-N-K) | – 8.7 ± 7.4% | – 0.9 ± 7.8% | 0.01 |
| Percent change HR postneb 2 (S-N-K) | – 4.6 ± 8.7% | 1.0 ± 11.3% | 0.08 |
| Percent change HR postneb 3 (S-N-K) | – 2.7 ± 12.7% | 5.6 ± 12.0% | 0.01 |
| Baseline MAP, mm Hg | 92.7 ± 12.3 | 90.9 ± 14.4 | 0.64 |
| Percent change MAP by two-way repeated-measures analysis of variance | 0.33 | ||
| Baseline RR, breaths/minute | 22.4 ± 4.5 | 20.7 ± 6.3 | 0.29 |
| Percent change RR by two-way repeated-measures analysis of variance | 0.78 | ||
| Baseline SpO2 | 95.9 ± 2.6% | 95.1 ± 2.2% | 0.29 |
| Percent change SpO2 by two-way repeated-measures analysis of variance | 0.51 |
Baseline FEV1 values (both raw and percent predicted) were not different between the two groups (Table 1). Hospital admission rates were similar in both groups (6 of 23 in the heliox group and 6 of 22 in the control group, p = 0.81). There were no differences between the two groups with regard to outpatient use of β2 agonists, inhaled corticosteroids, systemic corticosteroids, theophylline, or leukotriene inhibitors (Table 1). Tobacco use was rare, and there were no differences in smoking habits between the two groups (Table 1). Nineteen of 23 in the heliox group and 20 of 22 in the control group received systemic corticosteroid treatment in the emergency room (p = 0.67).
The accuracy of the portable spirometer remained within American Thoracic Society guidelines for monitoring devices throughout the study. During each check of its calibration, FEV1 values were always within 5% of the value obtained simultaneously from the spirometer in the pulmonary function laboratory. Similar satisfactory results were noted after testing the portable spirometer against the three liter syringe. All patients enrolled in the study were able to perform three forced expiratory maneuvers according to recommendations from the American Thoracic Society (10).
After each of the three albuterol treatments, the heliox group had a higher percent change in FEV1 than the control group. Following albuterol Treatment 1, median percent change in FEV1 was 14.6% in the control group and 32.4% in the heliox group (p = 0.007). After Treatment 2, the results were 22.7% versus 51.5%, respectively (p = 0.007). After Treatment 3, the results were 26.6% versus 65.1%, respectively (p = 0.016). Using Bonferroni's correction for multiple comparisons, the difference was significant after each nebulizer treatment. These results are detailed graphically in Figure 3
Figure 3. Box-and-whiskers plot of FEV1 values for control and heliox groups after each of three treatments. The solid horizontal line within the box is the median value. The box delineates interquartile range. Whiskers are lines that extend from the box to the highest and lowest values, excluding outliers. *p = 0.007 for comparison between control subjects and heliox subjects FEV1 after the first albuterol nebulizer treatment; **p = 0.007 for comparison between control subjects and heliox subjects FEV1 after the second albuterol nebulizer treatment; ^p = 0.016 for comparison between control subjects and heliox subjects FEV1 after the third albuterol nebulizer treatment.
[More] [Minimize]In this study, we have shown that albuterol nebulized with heliox leads to more effective bronchodilation when compared with albuterol nebulized with oxygen in patients presenting to the emergency room with severe acute asthma exacerbations. The use of helium in the treatment of asthma dates back to 1934, when Barach reported improvement in patients presenting with acute asthma exacerbations as well as upper airway obstructive lesions (11). Most studies of heliox use during acute asthma exacerbations have looked at helium gas itself as a means of decreasing airways resistance, improving flow, and potentially averting respiratory failure or facilitating mechanical ventilatory support. These studies have measured changes in endpoints such as peak expiratory flow rate, pulsus paradoxus (1), peak airway pressure during mechanical ventilation (2), and arterial PaCO2 and pH (3) during a time when a patient is actively breathing heliox. Although heliox has no direct bronchodilating properties, by decreasing airway resistance it may improve alveolar ventilation and decrease work of breathing (2). Heliox is only slightly more viscous than air, but its lower density allows for laminar flow of gas to persist at higher rates seen in more distal airways (12), which appears to improve alveolar ventilation in asthma (5). More importantly, the lower density of this gas decreases the pressure gradient associated with a given flow rate through turbulent airways. These properties presumably decrease the work of breathing, providing an effective, albeit temporary benefit until more definitive pharmacologic therapy has time to take effect.
In addition to the benefit derived from breathing heliox related to its physical properties, there is evidence that heliox may be effective in delivering inhaled particles to the distal airways of asthmatics. Anderson and colleagues found that in stable asthmatics, heliox led to more effective deposition of radiolabeled particles in the lung (5). Based on their findings, they speculated that heliox may be a more efficient way of delivering medications by inhalation but did not test clinical effects of enhanced drug delivery. To our knowledge, our is the first study suggesting that heliox is more efficient than oxygen as a vehicle for jet nebulization of albuterol during asthma exacerbations, as manifest by improvements in spirometry. Based on our findings, we speculate that helium (when inhaled in high concentrations) may deliver nebulized albuterol to its site of action more efficiently than oxygen in patients with acute asthma exacerbations. The difference in heart rate responses in the two groups, likely the result of more effective albuterol delivery to distal airways in the heliox group, supports this supposition. Further studies that directly measure serum albuterol concentrations will be needed to confirm this speculation.
The percent change in FEV1 in the heliox group was significantly greater than in control patients with similar degrees of airflow obstruction at baseline. Our patients had severe airflow obstruction based on their baseline percent predicted FEV1 values. In the heliox group, the percent change in FEV1 was more than twice that of the control group at all three points studied. At each posttreatment spirometric measurement, the difference was significant by Mann-Whitney U testing and remained so after Bonferroni correction.
A recent study by Henderson and colleagues found no difference between heliox and oxygen nebulization of albuterol with regard to spirometric evaluations during acute asthma exacerbations (13). We believe the difference between this study and our work may be due to differences in study methods. Henderson and colleagues used a 70:30 heliox mixture, but did not describe their heliox delivery system in detail; therefore, it is not clear whether they succeeded in delivering a high helium concentration to their patients. We made great efforts to ensure that a high concentration of helium was delivered to our patients (heliox fresh gas flow to the nebulizer as well as heliox fresh gas flow into the nonrebreather face mask), because the benefits of heliox therapy seem to be optimized when such a high concentration is inhaled. Entrainment of nitrogen from the environment decreases the concentration of inspired helium, thereby increasing the density of the inhaled gas, which may limit the effectiveness of heliox (7). Indeed, in a preliminary pilot study using heliox to nebulize albuterol with an open system (with a mouthpiece and T-piece adapter, Figure 1), we noted spirometric measurements no different than in control patients. In this pilot study, following albuterol Treatment 1, the median percent change in FEV1 was 15.7% in the control group and 14.5% in the heliox group (p = 0.97); after Treatment 2, the results were 22.2% versus 18.4%, respectively (p = 0.95); after Treatment 3, the results were 24.1% versus 23.7%, respectively (p = 0.65). Likewise, the percent change in heart rate, analyzed by two-way repeated-measures analysis of variance, was not different between open system heliox and control patients (p = 0.65). Another methodologic difference between our study and that of Henderson and colleagues has to do with the time period after breathing heliox before spirometry was performed. We used a 15-minute waiting period following each treatment to allow elimination of helium from the patients' lungs before taking flow directed spirometric measurements, which are not accurate in the presence of a low-density gas such as helium (1, 14). Previous studies have shown that the time to washout of helium from asthmatic lungs is less than 2 minutes (15, 16). Henderson and colleagues measured spirometry at 15, 30, and 45 minutes. They did not state in their methods how much time was allotted after completion of heliox nebulization before spirometric measurements were taken. Assuming that each nebulizer treatment takes approximately 10 minutes to complete (the typical time to completion of a nebulizer treatment in our study), the time for helium to washout of the patients' lungs may have been less than 5 minutes in their study. If there was residual helium in the patients' lungs, this could have led to a decrease in the FEV1 measured with a spirometer not calibrated for the low-density gas.
deBoisblanc and colleagues noted no improvement in spirometry in patients with acute exacerbations of chronic obstructive pulmonary disease who had albuterol and ipratropium nebulized using heliox as the driving gas (17). Patients with chronic obstructive pulmonary disease are typically less responsive to bronchodilator therapy than those with asthma; perhaps this explains the lack of a spirometric response, even if delivery of drugs to the distal airways is improved.
The financial cost of administering heliox is important in an era in which economic pressures may impact clinical care. Heliox 80:20 is stored in G cylinders that have wide variations in cost between institutions (the cost of one G cylinder of heliox at our institution is $30) (8). The semiclosed delivery system used in our study is composed of several different pieces. A single, prepackaged delivery system for heliox such as the one used in this study is not currently available. At our institution, where heliox is commonly used, the total cost per patient is typically less than $100, although costs at other institutions may vary.
Heliox is often viewed as a therapeutic option for severe, refractory asthma exacerbations, including status asthmaticus requiring mechanical ventilation (2, 3). We did not study patients who were mechanically ventilated, and thus, our results do not prove a benefit of heliox for delivering albuterol in this population. Nevertheless, we speculate that albuterol nebulized with heliox may be beneficial in this group as well. Habib and colleagues recently found heliox 70:30 improved albuterol delivery compared with oxygen nebulizer treatments in a pediatric lung model (18). Goode and colleagues observed similar findings in a lung model of mechanical ventilation, whether albuterol was delivered by a metered dose inhaler or a nebulizer (19). Further studies in mechanically ventilated patients will be needed to confirm this hypothesis in vivo.
Our study has several important limitations. Clearly, the effect of heliox on nebulizer performance is an important variable that was not evaluated in this study. Hess and colleagues previously reported that jet nebulizers powered with heliox generated significantly smaller particles and a lower inhaled mass of albuterol. Their study was performed in vitro using a test lung model. They correctly noted that “ … the effects of heliox on aerosol penetration and clinical outcomes might be due to either the effect of heliox on aerosol penetrations in the lung or aerosol generation in the nebulizer” (20). Goode and colleagues noted similar findings when evaluating heliox-driven nebulization in a lung model of mechanical ventilation (19). Again, heliox-driven nebulizers reduced albuterol delivery to a filter when assessed by spectrophotometric analysis. The difference in albuterol delivery between heliox- and oxygen-driven nebulizers was more notable at low heliox flow rates (5 L/minute) than at higher flow rates (10 L/minute), such as those used in our current study. It is certainly possible that the effect of heliox on nebulizer performance may explain partly the observed differences in FEV1 in those patients whose albuterol was nebulized with heliox. We suspect this was not a major contributor to improvement in FEV1, however. This speculation is based on observations from our preliminary study, in which albuterol was nebulized with heliox at the same flow rate as in our current study (10 L/minute) through an open breathing system. If the effects of heliox on nebulizer performance alone explain our findings, we would have expected that nebulizing albuterol with heliox through an open delivery system would have resulted in different spirometric values compared with control patients. In fact, when we nebulized albuterol with heliox using the same nebulizer and heliox flow rate, but through an open system, the FEV1 results were no different than in the placebo group who had albuterol nebulized with oxygen. This speaks against the effect of heliox on nebulizer performance and, rather, in favor of the effects of the gas itself on delivery of albuterol to the distal airways. Likewise, in our preliminary study, albuterol nebulized with heliox through an open delivery system did not significantly change heart rate, as was found in the closed heliox delivery system used in this study. Again, this speaks against the effect of heliox on nebulizer performance and in favor of the effects of the heliox gas itself on delivery of drug to the distal airways.
The exact role for heliox in the management of acute asthma exacerbations is neither clear from data previously published nor from our current work. Intuitively, it would seem for some patients that the impact of standard therapy (inhaled β2 agonists and systemic corticosteroids) would largely outweigh any additional benefit derived from heliox. This speculation is likely to apply whether heliox is used to decrease respiratory work based on its physical gas properties or its activity as a gas to nebulize albuterol to its site of action. Larger studies are needed to define more clearly which subgroups of people with asthma are most likely to benefit from heliox therapy in acute asthma exacerbations. Our study did not demonstrate a benefit with regard to hospital admission rate, although an impressive physiologic benefit was observed. The decision to admit a patient with an acute asthma exacerbation to the hospital is a complex one, in which many variables come into play. In the control group of patients with moderately severe asthma, the average increase in FEV1 after nebulizer Treatment 3 was 26.6%, a clinically important improvement that was likely adequate enough to allow many patients to be discharged from the emergency room (albeit with significantly less robust improvements in spirometry than the heliox group). Indeed, our 27% hospital admission rate is similar to the 34% admission rate reported by Strauss and colleagues (21). Our study was powered to detect a significant and clinically important difference in FEV1; however, it was not powered to detect a difference in hospital admission rates, an endpoint that likely would require much larger numbers of patients to detect a difference. Because the study was not powered to detect a difference in hospital admission rate, we do not believe that we can reliably comment on potential benefits (or lack thereof) of heliox-driven albuterol nebulization with regard to hospitalization rates in acute asthma. Larger studies are needed to address the potential impact of heliox-driven albuterol nebulization on hospital admissions in these patients. Based on these findings, we would recommend considering the use of heliox for severe asthma exacerbations refractory to standard therapy. From a practical standpoint, nebulizing albuterol with heliox serves two purposes: improved airflow based on the physical properties of the gas and improved spirometry, presumably from improved delivery of albuterol to its site of action in the lungs.
In conclusion, we have shown that jet nebulization of albuterol with heliox improves spirometric measurements in patients with acute asthma more than standard oxygen-driven albuterol nebulization. Heliox should be considered as a vehicle for albuterol nebulization in patients presenting with severe acute asthma exacerbations. All patients who are given heliox to breathe for its physical gas properties should receive this treatment using a high-flow, nonrebreathing delivery system. In addition, patients already receiving heliox should have albuterol treatments nebulized with heliox as the gas flowing into the nebulizer.
The authors thank the physicians and nurses from the University of Chicago Department of Medicine, Section of Emergency Medicine, for their cooperation and assistance during the study.
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