in 1935 , barach first advocated helium - oxygen gas mixtures ( heliox ) as 
		   a therapy for obstructive lesions of the airway . 
		   since then
, heliox has been shown to be efficacious in the treatment of various 
		   disease entities involving narrowed airways .
its safety 
		   has been demonstrated in both mechanically ventilated and spontaneously 
		   breathing patients .
combining 70% helium and 30% 
		   oxygen results in a gas which is much less dense than a nitrogen - oxygen gas 
		   mixture ( nitrox ) and has approximately the same viscosity .
the therapeutic effects of heliox gas mixtures are believed 
		   to relate to its ability to deliver oxygen and gas flow with less turbulence 
		   and resistance through narrowed airways .
since airway resistance is directly 
		   proportional to the density of the gas , the administration of heliox is 
		   expected to improve ventilation by decreasing resistance , reducing turbulence 
		   and promoting laminar gas flow .
although there have been advancements in the treatment of asthma since 
		   barach first studied heliox in 1935 , mortality continues to increase . 
		  
the use of bronchodilators and anti - inflammatory agents have become the 
		   standard of care for reactive airway disease and asthma .
however , some patients 
		   fail to respond to aggressive therapy and require mechanical ventilation . 
		  
mechanical ventilation may result in turbulent gas flow secondary to high gas 
		   velocity which may cause additional difficulty achieving adequate ventilation . 
		  
heliox may , therefore , be most effective in intubated patients with severe 
		   bronchospasm and small diameter airways by decreasing turbulent flow , improving 
		   ventilation and limiting barotrauma while therapies targeted to the underlying 
		   etiology of the bronchospasm are given time to achieve their effect .
several animal and human studies have investigated the effects of 
		   heliox on pulmonary function . although results from these studies have been promising , 
		   the wide variation between each patient 's biological response to 
		   bronchospasm
we have 
		   developed a pediatric porcine , independent lung ventilation model of severe 
		   bronchospasm which allows one of the animal 's lungs to act as a 
		   simultaneous control for the contralateral lung .
this unique model allows each 
		   subject to act as its own control during the same bronchospastic event , thereby 
		   minimizing influence from various systemic variable biological responses to 
		   acute stress and eliminating the need to compare matched control subjects or 
		   different bronchospastic events in the same animal .
our hypothesis is that , 
		   during mechanical ventilation , the low density heliox gas mixture will increase 
		   flow through constricted airways and improve pulmonary mechanics in the lung 
		   receiving heliox compared to the lung receiving nitrox .
this study was approved by the institutional review board at the 
		   alfred i. dupont institute of the nemours foundation .
thirteen pre - adolescent 
		   yucatan swine ( 9.0  1.7 kg ) were pre - anesthetized with 500 mg pentobarbital 
		   intramuscularly .
peripheral hydration was maintained with 10% dextrose in water 
		   at 4 ml / kg per h. following placement of continuous monitors for heart rate , 
		   electrocardiogram ( ecg ) , respirations , and oxygen saturation , 150 mg ( 15 mg / kg ) 
		   pentobarbital was given intravenously .
each pig was initially intubated with a 5.0 mm cuffed endotracheal tube 
		   and mechanically ventilated with a time cycled , pressure limited ventilator 
		   [ peak inspiratory pressure ( pip ) 18 cmh2o , positive end - expiratory 
		   pressure ( peep ) 5 cmh2o , rate 30 breaths / min , inspiratory to 
		   expiratory ratio ( i / e ) 1:1 , fractional inspiratory oxygen concentration 
		   ( fio2 ) 30% ] .
central arterial and venous catheters were placed by 
		   femoral cutdown for continuous monitoring of heart rate , blood pressure and 
		   blood sampling .
a tracheostomy was then performed and , immediately after 
		   removal of the initial endotracheal tube , separate cuffed 3.0 endotracheal 
		   tubes ( 16 cm in length ) were placed through the tracheostomy stoma into the 
		   right and left mainstem bronchi .
correct placement of each endotracheal tube 
		   was verified by auscultation during independent ventilation and later confirmed 
		   by bronchoscopy and/or autopsy .
additional doses of pentobarbital were given to 
		   ensure adequate anesthesia ( titrated to achieve a heart rate of 
		   < 160 beats / min , systolic blood pressure  140 mmhg , and absence of 
		   withdrawal to painful stimuli ) .
each lung was independently mechanically ventilated ( bp 200 , bear 
		   medical systems , riverside , california , usa ) simultaneously with identical 
		   settings .
pulmonary function tests ( pfts ) were recorded for each lung at 
		   baseline while on heliox and nitrox using an infant / pediatric pulmonary 
		   function computer ( peds , medical associated services , inc . ,
hatfield , 
		   pennsylvania , usa ) , calibrated for the gas mixture being delivered to derive 
		   tidal volume , resistance and compliance .
airflow data were obtained by a 
		   fleisch 0 ( pediatric ) tachometer ( oem medical , richmond , virginia , usa ) . 
		  
while ventilating both lungs with nitrox , methacholine 
		   ( 10 mg / ml  1.5ml diluted to 3 ml with buffer ) was aerosolized continuously to 
		   both lungs simultaneously over 3 min until airway resistance of each lung at 
		   least doubled from baseline .
one lung was then randomized to receive nitrox and 
		   the other to receive heliox .
fio2 was not adjusted to either lung , 
		   but remained at 30% throughout the experiment .
pulmonary function testing was 
		   performed every 2 min , alternating lungs until the resistance of one lung 
		   returned to within 15% of baseline or until 16 min had elapsed . as 
		   approximately 2 min was required to complete each pulmonary function assessment 
		   and because of differences in calibration between the two gases used , right and 
		   left lung pfts were not obtained simultaneously .
therefore , the order for each 
		   lung to be tested was determined randomly and data were compared by pulmonary 
		   function assessment number .
results of pfts obtained at 2 min and 4 min are 
		   reported as assessment number 1 ; the results of pfts performed at 6 min and 8 min 
		   are reported as assessment number 2 ; the results of pfts performed at 10 and 
		   12 min as assessment number 3 ; and the results of pfts performed at 14 and 16 min 
		   as assessment number 4 .
the maximum number of pfts performed for each lung was 
		   four per lung . in eight out of 10 piglets ,
the lung gases were then switched 
		   and pfts were measured in each lung after 2 min .
( the protocol was expanded to 
		   include the crossover after the first two piglets had been studied , and three 
		   piglets could not be evaluated due to severe cardiopulmonary compromise 
		   requiring medication intervention during induction of bronchospasm . ) to correct 
		   for differences between right and left lungs in absolute values of tidal 
		   volume , resistance and compliance following induced bronchospasm , outcome 
		   variables are expressed as % improvement from the parameters recorded 
		   immediately after bronchospasm .
percentage improvement in tidal volume , resistance and 
		   compliance after crossover were compared to the measurement immediately before 
		   crossover of gases ( heliox to nitrox or nitrox to heliox ) . upon completion of 
		   the study
, animals were humanely euthanized using intravenous pentobarbital , 
		   15 mg / kg and kcl , 2 meq / kg ( see timeline , fig .
a student t test was used to compare lung resistance , 
			  compliance and tidal volume at baseline ( pre - bronchospasm ) , after methacholine 
			  induction of bronchoscopy and after crossover . in addition , ' heliox 
			  response ' was prospectively defined as a greater than 15% improvement in 
			  resistance of the heliox lung compared to the nitrox lung . using this 
			  definition , if there were no effect of heliox on resistance , we would expect no 
			  ' heliox responders ' .
fisher 's exact test was used to compare 
			  responders versus non - responders . a p value
a student t test was used to compare lung resistance , 
			  compliance and tidal volume at baseline ( pre - bronchospasm ) , after methacholine 
			  induction of bronchoscopy and after crossover .
in addition , ' heliox 
			  response ' was prospectively defined as a greater than 15% improvement in 
			  resistance of the heliox lung compared to the nitrox lung . using this 
			  definition ,
if there were no effect of heliox on resistance , we would expect no 
			  ' heliox responders ' .
two pigs became 
		   severely hypoxemic and dysrhythmic and required resuscitation before 
		   administration of methacholine was completed and data from one pig was 
		   eliminated secondary to failure of the pulmonary function apparatus .
there were 
		   no significant differences found between the two groups with respect to 
		   pulmonary function at baseline before bronchospasm or immediately following 
		   methacholine challenge .
successful methacholine - induced bronchospasm was 
		   documented by a significant deterioration of all pulmonary function parameters 
		   studied ( tidal volume , resistance and compliance ) . the mean  sd resistance 
		   measured after methacholine challenge was 425  234 cm / h2o / l / s 
		   for the lungs randomized to receive heliox and 305  199 cmh2o /
l / s for the lungs randomized to receive nitrox ( difference not 
		   significant ) .
the mean  sd compliance measured after induction of 
		   bronchospasm was for the heliox 0.15  0.14 ml / cmh2o / kg group and 
		   0.23  0.14 ml / cmh2o / kg for the nitrox group ( difference not 
		   significant ) .
the mean  sd tidal volume measured after induction of 
		   bronchospasm was 1.9  1.8 ml / kg for the heliox group and 2.8  1.8 ml / kg 
		   for the nitrox group ( difference not significant ) .
table 1 demonstrates the number of heliox 
		   ' responders ' at each time point measured , including after each lung 
		   was crossed over from nitrox to heliox .
figure 2 shows 
		   the percent improvement of each parameter measured after the gases were 
		   switched from heliox to nitrox and from nitrox to heliox .
eight out of 10 
		   subjects had pulmonary function parameters recorded after the gases delivered 
		   to each lung were crossed over .
all eight subjects showed an improvement in 
		   resistance of greater than 15% after crossover from nitrox to heliox . in 
		   addition , all lungs crossed over from heliox to nitrox showed a deterioration 
		   of resistance and tidal volume of greater than 15% .
the mean  sd 
		   improvement in resistance after crossover from nitrox to heliox was 32.6  
		   14.4% compared with -19.8
eight out of eight pigs met prospectively defined 
		   criteria for a positive ' response ' to heliox therapy with respect 
		   to tidal volume and seven out of eight pigs met prospectively defined criteria 
		   for a positive ' response ' with respect to compliance after 
		   crossover from nitrox to heliox .
the mean  sd compliance and tidal volume 
		   change after crossover from nitrox to heliox was 36.2  20.3% and 
		   65.2  19.1% , respectively , compared with only 3.4  20.3% and 
		   -18.4  14.5% , respectively , after crossover from heliox to nitrox 
		   ( p < 0.001 ) .
since barach first described heliox as an effective treatment for 
		   diseases involving airway obstruction , there have been many studies performed 
		   in both animals and humans examining its effectiveness .
although heliox has been used safely for many years in 
		   the pediatric population for the treatment of severe croup and upper airway 
		   obstruction , it has been an uncommon treatment for severe bronchospasm . 
		  
the success of bronchodilators and anti - inflammatory agents as well as 
		   inconsistent results in clinical studies have resulted in limited application 
		   of heliox in the mechanically ventilated critically ill child .
the complex 
		   pathophysiology of asthma and the variability of disease between patients and 
		   their response to therapy makes the study of a single agent during acute , 
		   severe bronchospasm difficult to extrapolate to the clinical setting .
studies have shown a variable response to heliox therapy in 
		   spontaneously breathing patients with severe bronchospasm .
it has been 
		   suggested that this variability may be due to the greater effectiveness of 
		   heliox in patients with predominately large airway disease .
the beneficial effects 
		   demonstrated in these studies may be due to the decreasing turbulence of bulk 
		   gas flow with heliox during mechanical ventilation . in mechanically ventilated patients with severe bronchospasm
, the 
		   improvement in ventilation during heliox therapy may be due to the mechanism by 
		   which low density gases affect ventilation .
heliox and other low density gases 
		   decrease turbulent gas flow by lowering the reynolds number .
the reynolds 
		   number is measured by the product of the gas velocity , airway diameter , and gas 
		   density divided by viscosity .
it is a unitless 
		   number that predicts whether flow is turbulent or laminar . for a given set of 
		   airway dimensions ,
in addition , mechanical ventilation may further complicate the management 
		   of acute severe asthma by delivering a gas with increased velocity through a 
		   narrow endotracheal tube , particularly in pediatric and neonatal patients .
this 
		   increases the reynolds number , which indicates greater turbulent flow and 
		   airway resistance .
adequate ventilation in mechanically ventilated patients 
		   with severe bronchospasm may be more dependent on the density of the gas than 
		   in spontaneously breathing patients .
several studies have examined the efficacy of heliox in mechanically 
		   ventilated patients with severe bronchospasm or other diseases involving 
		   narrowed airways .
although these studies are small and have not included 
		   children , the results have been promising . in 1990 , gluck et al . 
		    reported an immediate and significant improvement 
		   in seven intubated patients with severe bronchospasm and respiratory acidosis . 
		  
all seven patients showed a significant improvement in pco2 within 
		   20min and six out of the seven patients showed a significant decrease in mean 
		   airway pressure during volume - limited ventilation .
the independent lung ventilation model of acute , severe bronchospasm 
		   used in this study is unique in that it allows each animal 's 
		   contralateral lung to represent its own control .
it eliminates the need to 
		   monitor systemic arterial blood gases , global circulating mediator or hormone 
		   levels and assures that the systemic milieu is identical for comparison of 
		   gross outcome measures .
it is recognized that the model is limited in its 
		   ability to monitor and control local microcirculation .
this model controls for 
		   the variable macrocirculatory responses to methacholine ( e.g. hemodynamic 
		   status : heart rate , blood pressure , temperature , circulating epinephrine level ) 
		   between subjects and allows comparisons of pulmonary mechanics on heliox versus 
		   nitrox gas mixtures within the same animal and during the same bronchospastic 
		   event .
this model allows for a clear determination of response to heliox 
		   without the variable biological responses which may affect studies involving 
		   separate subjects or different bronchospastic events within the same subject as 
		   controls .
it uses the same small ( 3.0 ) sized endotracheal tubes that might be 
		   expected to clinically increase resistance to gas flow in small infants . a 15% 
		   difference in pulmonary function between the lung receiving heliox and
the lung 
		   receiving nitrox ( control ) was prospectively selected as the primary outcome 
		   variable suggesting a favorable response to heliox versus nitrox .
it is 
		   recognized that lung function measurements in human subjects can be very 
		   variable and affected by many factors .
although the coefficient of variation is 
		   extremely small when calibrating the pft machine ( fleisch pneumotach ) using 
		   known standards within the physiologic ranges encountered in this study , 
		   patient factors can introduce intra- and intersubject variability .
for this reason , the calibrated pft computer ( calibrated 
		   both to 70%n/30% o and 70%he/30% o ) was applied serially over a relatively 
		   short time span ( 30 min ) and relative improvement / deterioration rather than 
		   absolute raw numbers were selected as the primary outcome measures to be 
		   compared . in addition , a 15% improvement in pfts is generally accepted as 
		   clinically significant and is well beyond the coefficient of variance for the 
		   pft computer and pneumotachometer when calibrated to a known standard on nitrox 
		   or heliox gas mixture
. of particular interest was the dramatic improvement in resistance and 
		   tidal volume in all lungs after crossover from nitrox to heliox .
conversely , 
		   there was a statistically significant deterioration in pfts for all parameters 
		   studied after crossover from heliox to nitrox .
even the subjects who did not 
		   appear to be responding to heliox therapy still showed a significant and 
		   immediate deterioration in pulmonary function when switched to nitrox .
the results of this study suggest that heliox may be effective in 
		   improving pulmonary mechanics in patients with small endotracheal tubes being 
		   mechanically ventilated for severe bronchospasm .
these results also indicate 
		   that the response to heliox is potentially rapid and persistent during heliox 
		   ventilation .
although the pediatric porcine model of independent mechanical 
		   ventilation and methacholine - induced bronchospasm used in this study is unique 
		   and offers many strengths , we acknowledge the limitations of this study . 
		  
limitations include the small number of subjects , wide variability in lung 
		   response to methacholine challenge and inability to accurately discriminate 
		   between the effect of a lower density gas on the resistance generated by the 
		   endotracheal tube , large and small airways .
pentobarbital was chosen for this study because of 
		   its minimal effects on pulmonary mechanics compared to inhalation or 
		   alternative intravenous agents .
no arterial blood gases were reported because 
		   heliox and nitrox gas mixtures were given to separate lungs simultaneously and 
		   therefore systemic arterial blood gases would not reflect unilateral lung 
		   function or microenvironment . the assessment of right and left independent 
		   pulmonary venous blood gases , although potentially useful , was beyond the scope 
		   of this pilot protocol .
however , documentation of the severity of bronchospasm 
		   was confirmed by at least a 50% increase in total lung resistance in each lung , 
		   prior to the start of the experimental therapy .
percent improvement from 
		   baseline after bronchospasm was prospectively selected for outcome analysis 
		   instead of comparison of raw values for lung resistance and compliance because 
		   of recognition during pilot studies of wide variability between individual 
		   piglets right and left lung baseline lung resistance values after methacholine 
		   challenge . the crossover technique and the desire to use the fewest piglets 
		   possible to demonstrate a treatment effect dictated prospective use of the 
		   percentage improvement compared to baseline bronchospasm .
in a pediatric porcine model of independent lung mechanical 
		   ventilation and severe methacholine - induced bronchospasm , heliox improved 
		   pulmonary mechanics when compared to a nitrogen - oxygen gas mixture during 
		   mechanical ventilation at identical ventilator settings .
this study also 
		   indicates that most subjects responded to heliox within the first 4min of 
		   therapy and that this response was sustained for at least 20 min .
the authors 
		   speculate that heliox may be beneficial to critically ill children requiring 
		   mechanical ventilation with small endotracheal tubes secondary to severe 
		   bronchospasm and high airway resistance with low compliance . in these patients
, 
		   heliox may be expected to improve tidal volume , lung compliance and resistance 
		   and decrease potential ventilator barotrauma while waiting for etiologic 
		   targeted therapies to take effect .
the authors would like to thank susan buck , behzad taghizadeh , bill 
			  hofmann , patty resnik , tina hurst , david corddry , ellen deutsch , brett goudie , 
			  and ilene sivakoff for their assistance and support in completing this 
			  project .
, lungs were randomized to receive either a helium - oxygen gas 
				 mixture ( heliox ) or a nitrogen - oxygen gas mixture ( nitrox ) .
the order in which 
				 each lung received pulmonary function tests ( pfts ) was also randomized .
percentage improvement of resistance , tidal volume and compliance 
				 after lungs were crossed over from a nitrogen - oxygen gas mixture ( nitrox ) to a 
				 helium - oxygen gas mixture ( heliox ) and from heliox to nitrox .
a negative 
				 percentage improvement indicates a deterioration of lung function , i.e. an 
				 increase in resistance is depicted as a negative percentage improvement . the number of helium - oxygen gas mixture ( heliox ) 
			  ' responders ' for tidal volume , compliance and resistance for each 
			  performed including pulmonary function tests after crossover .
co , positive response after crossover from a nitrogen - oxygen gas 
				 mixture ( nitrox ) to heliox .
 background : a helium - oxygen gas mixture ( heliox ) has low gas density and low 
				 turbulence and resistance through narrowed airways . the effects of heliox on 
				 pulmonary mechanics following severe methacholine - induced bronchospasm were 
				 investigated and compared to those of a nitrogen - oxygen gas mixture ( nitrox ) in 
				 an innovative pediatric porcine , independent lung , mechanical ventilation 
				 model.results:all of the lungs showed evidence of severe bronchospasm after 
				 methacholine challenge . 
 prospective definition of ' heliox response ' 
				 was a 15% or greater improvement in lung function in the lung receiving heliox 
				 compared with the matched lung receiving nitrox . 
 seven out of 10 pigs responded 
				 to heliox therapy with respect to resistance and eight out of 10 pigs responded 
				 to heliox therapy with respect to compliance and tidal volume ( p 
				 < 0.03 ) . 
 after crossover from nitrox to heliox , eight out of eight lungs 
				 significantly improved with respect to tidal volume , resistance and compliance 
				 ( p < 0.001 ) . 
 after crossover from heliox to nitrox all eight lungs 
				 showed a significant increase in resistance and a significant decrease in tidal 
				 volume ( p < 0.001).conclusions : in a pediatric porcine model of acute , severe methacholine - induced 
				 bronchospasm and independent lung mechanical ventilation , administration of 
				 heliox improves pulmonary mechanics , gas flow , and ventilation . 
 administration 
				 of heliox should be considered for support of pediatric patients with acute , 
				 severe bronchospasm requiring mechanical ventilation through small artificial 
				 airways . 
Introduction
Methods and materials
Statistical analysis
Results
Discussion
Conclusion
Acknowledgments
Figures and Tables