Eric Dumas

MD La Roque

Clotilde Bertrand

MD Olivier Tandonnet

MD Muriel Rebola

MD Emilie Roquand

MD Laurent ; Renesme

M.Sc. ; Christophe Elleau

Dumas De La Roque

Eric Dumas De

MD Eric Dumas De La Roque

Nasal High Frequency Percussive Ventilation Versus Nasal Continuous Positive Airway Pressure In Transient Tachypnea of the Newborn : A Pilot Randomized Controlled trial (NCT00556738)

Keywords: Transient Tachypnea of the Newborn, High Frequency Ventilation, Newborn, Respiratory Distress, Intensive Care, Non-Invasive Ventilation Transient tachypnea of the newborn, respiratory distress, intensive care, newborn, randomized trial, continuous positive airways pressure, high frequency ventilation, noninvasive ventilation NHFPV, nasal high frequency percussive ventilation, NCPAP, nasal continuous positive airway pressure, GA, gestational age, HMD, hyaline membrane disease, FiO Transient tachypnea of the newborn, respiratory distress, intensive care, newborn, randomized trial, continuous positive airways pressure, high frequency ventilation, noninvasive ventilation. Abbrevations: NHFPV, nasal high frequency percussive ventilation, NCPAP, nasal continuous positive airway pressure, GA, gestational age, HMD, hyaline membrane disease, FiO 2 , fraction of inspired oxygen, SEM, standard error

come

Results. In the NHFPV group the duration of TTN was half the time of NCPAP group (105 min ± 20 and 377 min ± 150 respectively) (p < 0.0001). There was a significant decrease in duration of oxygen supplementation in the NHFPV group (6.3 min ± 3.3) compared to the NCPAP group (19.1 min ± 8.1) (p < 0.001), and a significant decrease in level of oxygen supplementation [(FiO 2 -0.21)/time of O 2 therapy] in the NHFPV group (0.29 min -1 ± 0.16) compared to the NCPAP group (0.46 min -1 ± 0.50) (p < 0.001). There was no complication and NHFPV was as well tolerated as NCPAP.

INTRODUCTION

Transient tachypnea of the newborn (TTN) is, with more than 40 percent of cases, the most common cause of neonatal respiratory distress (1,2). TTN occurs when residual pulmonary fluid remains in lungs after delivery. Prostaglandins and catecholamines released during and after delivery induce lung fluid clearance as pulmonary circulation increases with the first breath. The persistence of lung fluid despite these mechanisms can induce TTN. The pathophysiology involves a lack of appropriate cathecholamine release and/or the inability of fetal lung to switch from fluid secretion to fluid absorption and this is related to insufficiency and or dysfunction of the epithelial Na + channel (3)(4)(5). Risk factors include maternal asthma, male sex, macrosomia, maternal diabetes, and caesarean delivery (2,6). The clinical presentation includes tachypnea and signs of respiratory distress immediately after birth or within two hours. Symptoms can last from a few hours to three days with possible complications such as pneumothorax or pulmonary hypertension (2,6). Treatment of neonatal respiratory distress is initially non-invasive ventilation with facial oxygen, nasal continuous positive airway pressure (NCPAP) eventually associated with oxygen therapy and mechanical ventilation in severe cases (6). Oral furosemide has not been shown to significantly improve status and should not be given (7). High frequency percussive ventilation (HFPV) is a pressure limited, time-cycled, high-frequency mode of ventilation that delivers subphysiologic tidal volumes at rapid rates and that can be used via an endotracheal tube, a nasal probe or a face mask (8)(9)(10). In the endotracheal mode, in adults it has been shown to provide the same or improved oxygenation and ventilation at lower peak, mean and end-expiratory pressures when compared with conventional ventilation (11,12). In neonates, HFPV has been described in hyaline membrane disease and acute respiratory failure ventilation with improvement in oxygenation, significant decrease in P CO2 and no change in central hemodynamics (13,14). In the non endothracheal mode it has the potential to improve secretion clearance and has been (15)(16)(17)[START_REF] Deakins | A comparison of intrapulmonary percussive ventilation and conventional chest physiotherapy for the treatment of atelectasis in the pediatric patient[END_REF](19)(20) and more recently as a therapeutic option in exacerbations of patients with chronic obstructive pulmonary disease (21)(22)(23). We hypothesized that the use of nasal HFPV may be well tolerated and effective in TTN thus reducing the duration of respiratory distress when compared with the conventional NCPAP mode. were evaluated every 5 minutes by an independent observer. Respiratory and cardiac monitoring (oxygen saturation, respiratory rate, heart rate) were continuously recorded and the end points were evaluated secondarily by an independent observer. The fraction of inspired oxygen (FiO 2 ) was adjusted continuously to keep saturations at 90% to 96%. The newborns were monitored during 72 hours following birth in order to record eventual complications (pneumothorax and pulmonary infection).

METHODS

Patients, Randomization, and Study Criteria

Study Definitions

We undertook a «simplified Silverman score» defined by the Silverman score without the item regarding chest wall retraction (chest movements, expiratory grunting and nasal flaring ) in order to avoid the inclusion of patients presenting with another diagnosis such as HMD (24). HMD was defined in the presence of clinical features and a positive chest x-ray (atelectasis, air bronchograms, diffuse reticular-granular pattern). Air leaks were documented by clinical features and a positive chest x-ray evidence of pneumothorax. Sepsis was diagnosed by a positive blood culture or suggestive clinical and laboratory presentation.

Recovery of the TTN was defined by absence of clinical sign of respiratory distress (modified Silverman score equal to zero), arterial transcutaneous oxygen saturation > 90% without oxygen, respiratory rate < 60 /min, without any respiratory support. For the quantification of oxygen supplementation without invasive measurement, we used the level of FiO (8,22). Airway pressures oscillates between 2 to 35 cmH 2 O and the airway walls vibrate in synchrony with these oscillations. In non endotracheal mode, HFPV can be delivered via a facial mask or a nasal probe (9, 10)(Fig 2B).

Respiratory Management

CPAP or NHFPV were delivered via a heated humidified nasal probe. In the CPAP group the PEEP was delivered via a conventional time cycled, pressure limited ventilator (Babylog 8000, Drager). NCPAP setting was 5 cm H 2 O and fraction of inspired oxygen (FiO 2 ) adjusted to keep saturations at 90% to 96%. The setting of NHFPV was as follows : pressure of 5 cm H 2 O, high-frequency ventilator at 5Hz as previously described for non-endotracheal respiratory support (9,26) and fraction of inspired oxygen (FiO 2 ) adjusted to keep saturations at 90% to 96% (Fig 2). The O 2 saturation probe placement was standardized on preductal location. The HFPV and NCPAP setting were not changed during the procedure. There was no systematic control of the PCO2, but infants who exhibited a deterioration of the respiratory distress under nasal ventilation were monitored by blood gas analyses, x-ray, blood testing, in order to look for a differential diagnosis of TTN (HMD, infection, pneumothorax…). Patient characteristics were summarized using observed proportions, means and standard error of the mean (SEM), medians and quartiles for discontinuous variables. Using a preliminary cases series, we calculated our sample size to detect a 20% reduction of the respiratory distress duration with HFPV compared with NCPAP. With α = 0.05 and a power of 80%, we estimated that 20 infants were needed in each group. Comparisons between the two groups were tested using the Mann-Whitney test or χ 2 test, as appropriate. A p-value of less than 0.05 was considered to indicate statistical significance.

Ethics

The research protocol for this study was approved by the institutional review board of the University Hospital of Bordeaux (France). The research protocol was registered in ClinicalTrials.gov (NCT00556738).

RESULTS

Between November 2007 and September 2009, 46 infants were enrolled in the study.

infants were excluded after randomization because of secondary diagnosis of HMD and 2 because of diagnosis of neonatal asphyxia associated with TTN (Fig 1)

. There were no statistical differences between the 2 groups with regard to any of the baseline maternal and infant characteristics (table 1). There was no complication (pneumothorax, pulmonary

DISCUSSION

In this prospective, randomized, controlled study, we showed that NHFPV is a well tolerated mode of nasal ventilation for neonates. Moreover we showed a superiority of NHFPV for ventilation care of TTN in comparison to NCPAP. There was a significant decrease of respiratory distress and oxygen therapy duration and a significant decrease of oxygen therapy level in the NHFPV group. NHFPV is a new approach to ventilation assistance of respiratory distress and in our knowledge this is the first prospective randomized controlled study of HFPV in the newborn population.

To date, few studies have been published on the use of HFPV in paediatric patients with pulmonary disease. HFPV has been used in a non endotracheal mode for the treatment of atelectasis and retained secretions in cystic fibrosis or neuromuscular diseases (15)(16)(17)[START_REF] Deakins | A comparison of intrapulmonary percussive ventilation and conventional chest physiotherapy for the treatment of atelectasis in the pediatric patient[END_REF]20). Pfenninger et al. described endotracheal use of HFPV in two studies of neonates with hyaline membrane disease and acute respiratory failure. They showed improvement in oxygenation, a significant decrease of PCo 2 and no change in central hemodynamics (13,14).

Transient tachypnea of the newborn is a self limited disease which is common in infants and may be prolonged over a 24-72 hour period with few potential complications including hypoxia, respiratory fatigue or air leaks (pneumothorax, pneumomediatinum) (6). This usually benign respiratory distress was studied as a proof of concept of the usefulness of HFPV in neonates. TTN is the result of a delay in clearance of fetal lung liquid. For effective gas exchange to occur, alveolar spaces must be cleared of excess fluid and the pulmonary blood flow increased to match ventilation with perfusion. Failure of these events can cause the infant to develop respiratory distress (27)(28)(29). An additional proposed benefit of HFPV is the generation of intrapulmonary mechanical percussive waves, which may aid in the lysis and clearance of airway mucus and secretions (10,(30)(31)(32)(33)(34). The increase of the fetal lung liquid clearance by HFPV could explain in part the results of our study.

The significant decrease of duration and level of oxygen delivered in the NHFPV group was hardly of clinical importance but this result confirms an effective and well tolerated mode of ventilation. Moreover respiratory distress could induce excess cost (35) and NHFPV could be significant in term of workload and cost reduction for respiratory distress care in this population. This ventilation mode is a low cost device and is easily used. It was well tolerated by the infants with no complication observed even if the small sample size of our study do not allow a full safety evaluation. No serious adverse effects of HFPV have been reported in previous adult or infant studies (10, 13-17, 34, 36, 37).

Our study has several limitations. Firstly this is not a blinded study, secondly the inclusion criteria and primary endpoint were defined by clinical criteria like Silverman score.

It could have induced bias of interpretation by minimizing the severity of infants included or modify the interpretation of respiratory distress recovery. To correct this bias, the inclusion criteria were reinforced by oxygen saturation as objective element and a delay of 20 minutes after birth to evaluate the infant after the common birth transition period. Moreover the neonate include were filmed before the randomization and the inclusion criteria were checked by an independent observer. At last, the respiratory distress recovery was also defined by a respiratory rate ≤ 60 per minute and a saturation ≥ 95 % without oxygen, wich are not (3)(4)(5). Risk factors include maternal asthma, male sex, macrosomia, maternal diabetes, and caesarean delivery (2,6). The clinical presentation includes tachypnea and signs of respiratory distress immediately after birth or within two hours. Symptoms can last from a few hours to three days with possible complications such as pneumothorax or pulmonary hypertension (2,6). Treatment of neonatal respiratory distress is initially non-invasive ventilation with facial oxygen, nasal continuous positive airway pressure (NCPAP) eventually associated with oxygen therapy and mechanical ventilation in severe cases (6). Oral furosemide has not been shown to significantly improve status and should not be given (7). High frequency percussive ventilation (HFPV) is a pressure limited, time-cycled, high-frequency mode of ventilation that delivers subphysiologic tidal volumes at rapid rates and that can be used via an endotracheal tube, a nasal probe or a face mask (8)(9)(10). In the endotracheal mode, in adults it has been shown to provide the same or improved oxygenation and ventilation at lower peak, mean and end-expiratory pressures when compared with conventional ventilation (11,12). In neonates, HFPV has been described in hyaline membrane disease and acute respiratory failure ventilation with improvement in oxygenation, significant decrease in P CO2 and no change in central hemodynamics (13,14). In the non endothracheal mode it has the potential to improve secretion clearance and has been (15)(16)(17)[START_REF] Deakins | A comparison of intrapulmonary percussive ventilation and conventional chest physiotherapy for the treatment of atelectasis in the pediatric patient[END_REF](19)(20) and more recently as a therapeutic option in exacerbations of patients with chronic obstructive pulmonary disease (21)(22)(23). We hypothesized that the use of nasal HFPV may be well tolerated and effective in TTN thus reducing the duration of respiratory distress when compared with the conventional NCPAP mode. meconium aspiration; neonatal infection with hemodynamic alteration; neonatal asphyxia (pH < 7.1); clinical signs of chest wall retraction (that could be a differential diagnosis of TTN such as a hyaline membrane disease (HMD)). Newborn infants with secondary diagnosis of HMD were discontinuated from the study. The clinical symptoms of the neonates included were evaluated every 5 minutes by an independent observer. Respiratory and cardiac monitoring (oxygen saturation, respiratory rate, heart rate) were continuously recorded and the end points were evaluated secondarily by an independent observer. The fraction of inspired oxygen (FiO 2 ) was adjusted continuously to keep saturations at 90% to 96%. The newborns were monitored during 72 hours following birth in order to record eventual complications (pneumothorax and pulmonary infection).

METHODS

Patients, Randomization, and Study Criteria

Study Definitions

We undertook a «simplified Silverman score» defined by the Silverman score without the item regarding chest wall retraction (chest movements, expiratory grunting and nasal flaring ) in order to avoid the inclusion of patients presenting with another diagnosis such as HMD (24). HMD was defined in the presence of clinical features and a positive chest x-ray (atelectasis, air bronchograms, diffuse reticular-granular pattern). Air leaks were documented by clinical features and a positive chest x-ray evidence of pneumothorax. Sepsis was diagnosed by a positive blood culture or suggestive clinical and laboratory presentation.

Recovery of the TTN was defined by absence of clinical sign of respiratory distress (modified

Silverman score equal to zero), arterial transcutaneous oxygen saturation > 90% without oxygen, respiratory rate < 60 /min, without any respiratory support. For the quantification of oxygen supplementation without invasive measurement, we used the level of FiO

Respiratory Management

CPAP or NHFPV were delivered via a heated humidified nasal probe. In the CPAP group the PEEP was delivered via a conventional time cycled, pressure limited ventilator (Babylog 8000, Drager). NCPAP setting was 5 cm H 2 O and fraction of inspired oxygen (FiO 2 ) adjusted to keep saturations at 90% to 96%. The setting of NHFPV was as follows : pressure of 5 cm H 2 O, high-frequency ventilator at 5Hz as previously described for non-endotracheal respiratory support (9,26) and fraction of inspired oxygen (FiO 2 ) adjusted to keep saturations at 90% to 96% (Fig 2). The O 2 saturation probe placement was standardized on preductal location. The HFPV and NCPAP setting were not changed during the procedure. There was no systematic control of the PCO2, but infants who exhibited a deterioration of the respiratory distress under nasal ventilation were monitored by blood gas analyses, x-ray, blood testing, in order to look for a differential diagnosis of TTN (HMD, infection, pneumothorax…).

Statistical Methods and Data Analysis

Patient characteristics were summarized using observed proportions, means and standard error of the mean (SEM), medians and quartiles for discontinuous variables. Using a preliminary cases series, we calculated our sample size to detect a 20% reduction of the respiratory distress duration with HFPV compared with NCPAP. With α = 0.05 and a power of 80%, we estimated that 20 infants were needed in each group. Comparisons between the two groups were tested using the Mann-Whitney test or χ 2 test, as appropriate. A p-value of less than 0.05 was considered to indicate statistical significance.

Ethics

The research protocol for this study was approved by the institutional review board of the University Hospital of Bordeaux (France). The research protocol was registered in ClinicalTrials.gov (NCT00556738).

RESULTS

Between

DISCUSSION

In this prospective, randomized, controlled study, we showed that NHFPV is a well tolerated mode of nasal ventilation for neonates. Moreover we showed a superiority of NHFPV for ventilation care of TTN in comparison to NCPAP. There was a significant decrease of respiratory distress and oxygen therapy duration and a significant decrease of oxygen therapy level in the NHFPV group. NHFPV is a new approach to ventilation assistance of respiratory distress and in our knowledge this is the first prospective randomized controlled study of HFPV in the newborn population.

To date, few studies have been published on the use of HFPV in paediatric patients with pulmonary disease. HFPV has been used in a non endotracheal mode for the treatment of atelectasis and retained secretions in cystic fibrosis or neuromuscular diseases (15)(16)(17)[START_REF] Deakins | A comparison of intrapulmonary percussive ventilation and conventional chest physiotherapy for the treatment of atelectasis in the pediatric patient[END_REF]20). Pfenninger et al. described endotracheal use of HFPV in two studies of neonates with hyaline membrane disease and acute respiratory failure. They showed improvement in oxygenation, a significant decrease of PCo 2 and no change in central hemodynamics (13,14).

Transient tachypnea of the newborn is a self limited disease which is common in infants and may be prolonged over a 24-72 hour period with few potential complications including hypoxia, respiratory fatigue or air leaks (pneumothorax, pneumomediatinum) (6). This usually benign respiratory distress was studied as a proof of concept of the usefulness of HFPV in neonates. TTN is the result of a delay in clearance of fetal lung liquid. For effective gas exchange to occur, alveolar spaces must be cleared of excess fluid and the pulmonary blood flow increased to match ventilation with perfusion. Failure of these events can cause the infant to develop respiratory distress (27)(28)(29). An additional proposed benefit of HFPV is the generation of intrapulmonary mechanical percussive waves, which may aid in the lysis and clearance of airway mucus and secretions (10,(30)(31)(32)(33)(34). The increase of the fetal lung liquid clearance by HFPV could explain in part the results of our study.

The significant decrease of duration and level of oxygen delivered in the NHFPV group was hardly of clinical importance but this result confirms an effective and well tolerated mode of ventilation. Moreover respiratory distress could induce excess cost (35) and NHFPV could be significant in term of workload and cost reduction for respiratory distress care in this population. This ventilation mode is a low cost device and is easily used. It was well tolerated by the infants with no complication observed even if the small sample size of our study do not allow a full safety evaluation. No serious adverse effects of HFPV have been reported in previous adult or infant studies (10, 13-17, 34, 36, 37).

Our study has several limitations. Firstly this is not a blinded study, secondly the inclusion criteria and primary endpoint were defined by clinical criteria like Silverman score.

It could have induced bias of interpretation by minimizing the severity of infants included or modify the interpretation of respiratory distress recovery. To correct this bias, the inclusion criteria were reinforced by oxygen saturation as objective element and a delay of 20 minutes after birth to evaluate the infant after the common birth transition period. Moreover the neonate include were filmed before the randomization and the inclusion criteria were checked by an independent observer. At last, the respiratory distress recovery was also defined by a respiratory rate ≤ 60 per minute and a saturation ≥ 95 % without oxygen, wich are not

  To determine whether nasal high frequency percussive ventilation (NHFPV) would decrease duration of transient tachypnea of the newborn (TTN) compared to nasal continuous positive airway pressure (NCPAP) in newborn infants. Methods. A prospective, unmasked, randomized, controlled clinical trial was conducted in 46 eligible newborn infants who were hospitalized for TTN in the University Hospital of Bordeaux (France) between 2007 and 2009. Infants born by caesarian section ≥ 37 GA, ≥ 2000 g with diagnosis of TTN and with a transcutaneous saturation < 90% at 20 minutes after birth were eligible. Infants were randomized to either NHFPV or NCPAP. The primary endpoint was a reduction of the duration of TTN. Secondary endpoints were the duration of oxygen therapy and the minimal level required to obtain a saturation between 90% and 96% integrated into an index which included a time factor : [(FiO 2 -21)/time of O 2 therapy].

  patients with cystic fibrosis

A

  prospective, unblinded, randomized controlled trial of NCPAP versus nasal high frequency percussive ventilation (NHFPV) (Percussionaire Corp., USA) in transient tachypnea of the newborn (TTN) was initiated in 2007 in consecutive eligible newborn infants in the maternity intensive care nursery at Pellegrin University Hospital of Bordeaux in France. BetweenNovember 2007 and September 2009, 46 newborns infants were assigned using a table of random numbers and sealed opaque envelopes to either NCPAP or NHFPV. Randomization occurred after written informed consent had been obtained from the infant's parent or legal guardian. The primary endpoint was the duration of respiratory distress. Secondary endpoints were the duration and level of oxygen supplementation, and the incidence of pneumothorax, and pulmonary infections. Study entry criteria were infant newborns born by caesarian section ≥ 37 wk gestational age (GA) and of ≥ 2000 g birth weight, transcutaneous oxygen saturation < 90% on room air, simplified Silverman score: (chest movement, expiratory grunt and nares dilation) ≥ 5, neonates managed within 20 minutes of birth. Before randomization infants were filmed and the inclusion criteria were checked by an independent observer. Prior to cesarean section parents were informed of the protocol and when necessary the consent and the randomization were obtained between birth and initiation of respiratory support.Exclusion criteria included major congenital malformation or pulmonary malformation; neonatal infection with hemodynamic alteration; neonatal asphyxia (pH < 7.1); clinical signs of chest wall retraction (that could be a differential diagnosis of TTN such as a hyaline membrane disease (HMD)). Newborn infants with secondary diagnosis of HMD were discontinuated from the study. The clinical symptoms of the neonates included

2 therapy

 2 2 adjusted to keep saturations at 90% to 96% (FiO 2 -0.21) related to time: [(FiO 2 -0.21)/time of O In order to identify respiratory distress but not RDS, we used the Silverman score without chest wall rectraction items («simplified Silverman score») defined by: chest mouvement, expiratory grunting and nasal flaring (21). RDS Deleted: positive Deleted: % Deleted: Each neonate included was evaluated every 5 minutes by an independent observer.

6

 6 High frequ-ency percussive ventilation (HFPV)The high frequency percussive ventilator (VDR3, Percussionaire, Bird technologies, Sandpoint, ID) is a pneumatically powered, time cycled, and pressure limited ventilator (Fig2A). It is a ventilatory technique that delivers small bursts of high flow respiratory gas into the lung at high rates. Unique to the HFPV is the presence of a sliding venturi system (phasitron, Fig 2B, Fig 2C), powered by compressed gas that generates the oscillations in the range of 80-650 cycles/min

9 Deleted

 9 infection, local intolerance) in infants studied. The two modes of ventilation were clinically well tolerated without need for sedation. All infants improved clinically on the given form of support, without necessitating formal mechanical ventilation. The respiratory distress duration was significantly decreased in the NHFPV group (105 min ± 20) compared with the NCPAP Deleted: of infant newborns treated with HFPV Deleted: reduction of 10 minutes Deleted: min ± 150) (p < 0.001) (Fig 3). The duration of oxygen supplementation was significantly decreased in the NHFPV group (6.3 min ± 3.3) compared with the NCPAP group (19.1 min ± 8.1) (p < 0.001) (Fig 4). The level of oxygen administrated during the treatment was significantly decreased in the NHFPV group (0.29 min -1 ± 0.16) compared with the NCPAP group (0.46 min -1 ± 0.50) (p < 0.001) (Fig 5).

11 Table 1 :

 111 of respiratory distress. The results of this preliminary study done on a mostly benign kind of respiratory distress show a potential interest of this mode of ventilation in the treatment of more severe deseases .In conclusion, we have shown that NHFPV is more effective than NCPAP in treatment of TTN. NHFPV may be a novel and safe tool to take care TTN. Additional studies are needed evaluating NHFPV in larger number of neonates with TTN and other respiratory distress conditions.Aknowledgments: The author would like to thank Pr Michael Fayon for the correction of the manuscript. Maternal baseline characteristics. Table 2: Infants baseline characteristics. SEM indicates standard error of the mean.

Figure 1 :

 1 Figure 1: Flow diagram of infants who were screened and randomly assigned to the NHFPV and NCPAP groups. Three infants in the NHFPV group were excluded because of secondary diagnosis of HMD. Two infants in the NCPAP group were excluded because of diagnosis of neonatal asphyxia and one infant because of secondary diagnosis of HMD.

Figure 2 :

 2 Figure 2 : Intrapulmonary percussive ventilation device (Percussionaire IPV-3, Percussionaire Corp.) (Fig 2A). Image (Fig 2B) and schematic (Fig 2C) of the phasitron : the sliding ventury body moves back and forth to open and close the phasitron exhalation gate by an orificed diaphragm. Burst of air are delivered to the patient during forward movement of the phasitron.

Figure 3 :

 3 Figure 3: Duration of TTN between the NHFPV and NCPAP groups. The duration of TTN was significantly reduced in the NHFPV group compared with the NCPAP group (p < 0.001).Error bars represent standard error of the mean.

Figure 4 :

 4 Figure 4: Duration of oxygen therapy between the NHFPV and NCPAP groups. The duration of oxygen therapy was significantly reduced in the NHFPV group compared with the NCPAP group (p < 0.001). Error bars represent standard error of the mean.

Figure 5 :

 5 Figure 5: Level of oxygen supplementation between the NHFPV and NCPAP groups. The level of oxygen supplementation was significantly reduced in the HFPV group compared with the NCPAP group (p < 0.001). Error bars represent standard error of the mean.

  Kasaoka S, Okabayashi K, Maekawa T. Efficacy and safety of intrapulmonary percussive ventilation superimposed on conventional ventilation in obese patients with compression atelectasis. J Crit Care. 2006 Dec;21(4):328-32. 37. Lelong-Tissier MC, Chiotasso D, Boudieres G, Doston C, Trinchero JF, Daussac E, et al. [Intrapulmonary percussive ventilation (IPV) as a post operative routine following pediatric scoliosis surgery]. Arch Pediatr. 2009 Jun;16(6):752-4. To determine whether nasal high frequency percussive ventilation (NHFPV) would decrease duration of transient tachypnea of the newborn (TTN) compared to nasal continuous positive airway pressure (NCPAP) in newborn infants. Methods. A prospective, unmasked, randomized, controlled clinical trial was conducted in 46 eligible newborn infants who were hospitalized for TTN in the University Hospital of Bordeaux (France) between 2007 and 2009. Infants born by caesarian section ≥ 37 GA, ≥ 2000 g with diagnosis of TTN and with a transcutaneous saturation < 90% at 20 minutes after birth were eligible. Infants were randomized to either NHFPV or NCPAP. The primary endpoint was a reduction of the duration of TTN. Secondary endpoints were the duration of oxygen therapy and the minimal level required to obtain a saturation between 90% and 96% integrated into an index which included a time factor : [(FiO 2 -21)/time of O 2 therapy].Results. In the NHFPV group the duration of TTN was half the time of NCPAP group (105 min ± 20 and 377 min ± 150 respectively) (p < 0.0001). There was a significant decrease in duration of oxygen supplementation in the NHFPV group (6.3 min ± 3.3) compared to the NCPAP group (19.1 min ± 8.1) (p < 0.001), and a significant decrease in level of oxygen supplementation [(FiO 2 -0.21)/time of O 2 therapy] in the NHFPV group (0.29 min -1 ± 0.16) compared to the NCPAP group (0.46 min -1 ± 0.50) (p < 0.001). There was no complication and NHFPV was as well tolerated as NCPAP.Conclusion.NHFPV is well tolerated and more effective than NCPAP in treatment of TTN. NHFPV might be a novel and safe tool to manage TTN.

  the newborn (TTN) is, with more than 40 percent of cases, the most common cause of neonatal respiratory distress (1, 2). TTN occurs when residual pulmonary fluid remains in lungs after delivery. Prostaglandins and catecholamines released during and after delivery induce lung fluid clearance as pulmonary circulation increases with the first breath. The persistence of lung fluid despite these mechanisms can induce TTN. The pathophysiology involves a lack of appropriate cathecholamine release and/or the inability of fetal lung to switch from fluid secretion to fluid absorption and this is related to insufficiency and or dysfunction of the epithelial Na + channel

  patients with cystic fibrosis

  A prospective, unblinded, randomized controlled trial of NCPAP versus nasal high frequency percussive ventilation (NHFPV) (Percussionaire Corp., USA) in transient tachypnea of the newborn (TTN) was initiated in 2007 in consecutive eligible newborn infants in the maternity intensive care nursery at Pellegrin University Hospital of Bordeaux in France. Between November 2007 and September 2009, 46 newborns infants were assigned using a table of random numbers and sealed opaque envelopes to either NCPAP or NHFPV. Randomization occurred after written informed consent had been obtained from the infant's parent or legal guardian. The primary endpoint was the duration of respiratory distress. Secondary endpoints were the duration and level of oxygen supplementation, and the incidence of pneumothorax, and pulmonary infections. Study entry criteria were infant newborns born by caesarian section ≥ 37 wk gestational age (GA) and of ≥ 2000 g birth weight, transcutaneous oxygen saturation < 90% on room air, simplified Silverman score: (chest movement, expiratory grunt and nares dilation) ≥ 5, neonates managed within 20 minutes of birth. Before randomization infants were filmed and the inclusion criteria were checked by an independent observer. Prior to cesarean section parents were informed of the protocol and when necessary the consent and the randomization were obtained between birth and initiation of respiratory support.Exclusion criteria included major congenital malformation or pulmonary malformation;

  2 adjusted to keep saturations at 90% to 96% (FiO 2 -0.21) related to time: [(FiO 2 -0.21)/time of O 2 therapy] (25).

  High frequ-ency percussive ventilation (HFPV)The high frequency percussive ventilator (VDR3, Percussionaire, Bird technologies, Sandpoint, ID) is a pneumatically powered, time cycled, and pressure limited ventilator (Fig2A). It is a ventilatory technique that delivers small bursts of high flow respiratory gas into the lung at high rates. Unique to the HFPV is the presence of a sliding venturi system (phasitron, Fig 2B, Fig 2C), powered by compressed gas that generates the oscillations in the range of 80-650 cycles/min (8, 22). Airway pressures oscillates between 2 to 35 cmH 2 O and the airway walls vibrate in synchrony with these oscillations. In non endotracheal mode, HFPV can be delivered via a facial mask or a nasal probe (9, 10)(Fig 2B).

  November 2007 and September 2009, 46 infants were enrolled in the study. 4 infants were excluded after randomization because of secondary diagnosis of HMD and 2 because of diagnosis of neonatal asphyxia associated with TTN (Fig 1). There were no statistical differences between the 2 groups with regard to any of the baseline maternal and infant characteristics (table 1). There was no complication (pneumothorax, pulmonary infection, local intolerance) in infants studied. The two modes of ventilation were clinically well tolerated without need for sedation. All infants improved clinically on the given form of support, without necessitating formal mechanical ventilation. The respiratory distress duration was significantly decreased in the NHFPV group (105 min ± 20) compared with the NCPAP min ± 150) (p < 0.001) (Fig 3). The duration of oxygen supplementation was significantly decreased in the NHFPV group (6.3 min ± 3.3) compared with the NCPAP group (19.1 min ± 8.1) (p < 0.001) (Fig 4). The level of oxygen administrated during the treatment was significantly decreased in the NHFPV group (0.29 min -1 ± 0.16) compared with the NCPAP group (0.46 min -1 ± 0.50) (p < 0.001) (Fig 5).

11 Table 1 :

 111 of respiratory distress. The results of this preliminary study done on a mostly benign kind of respiratory distress show a potential interest of this mode of ventilation in the treatment of more severe deseases .In conclusion, we have shown that NHFPV is more effective than NCPAP in treatment of TTN. NHFPV may be a novel and safe tool to take care TTN. Additional studies are needed evaluating NHFPV in larger number of neonates with TTN and other respiratory distress conditions.Aknowledgments: The author would like to thank Pr Michael Fayon for the correction of the manuscript. Maternal baseline characteristics. Table 2: Infants baseline characteristics. SEM indicates standard error of the mean.

Figure 1 :

 1 Figure 1: Flow diagram of infants who were screened and randomly assigned to the NHFPV

Figure 2 :

 2 Figure 2 : Intrapulmonary percussive ventilation device (Percussionaire IPV-3,

Figure 3 :

 3 Figure 3: Duration of TTN between the NHFPV and NCPAP groups. The duration of TTN

Figure 4 :

 4 Figure 4: Duration of oxygen therapy between the NHFPV and NCPAP groups. The duration

Figure 5 :

 5 Figure 5: Level of oxygen supplementation between the NHFPV and NCPAP groups. The

John Wiley & Sons, Inc.Pediatric Pulmonology

Author for correspondence


Pekka Leo

Lauri Malmberg

Anne Von Wright

Kristiina Kotaniemi-Syrjänen

Anna Malmström

Mika Pelkonen

Mäkelä

MD L Pekka Malmberg
email: pekka.malmberg@hus.fi

PhD Lauri Von Wright

BM Anne Kotaniemi-Syrjänen

PhD Kristiina Malmström

PhD Anna S Pelkonen

PhD Mika J Mäkelä

METHACHOLINE INDUCED LUNG FUNCTION CHANGES MEASURED WITH INFANT BODY PLETHYSMOGRAPHY

Keywords: Bronchial provocation tests, Forced expiratory flow, Body plethysmography, Infant

des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

We examined 94 infants with recurrent airway symptoms using methacholine airway challenge test including RTC and plethysmographic measurements. A significant association between changes in V' maxFRC and sG aw (r=0.30; p=0.004) was observed, but after adjustments with baseline variability the changes in V' maxFRC were greater and showed a closer association with changes in oxygen saturation. At the point of maximal airway obstruction, there was a poor agreement between V' maxFRC and sG aw to indicate a significant methacholine induced bronchoconstriction. Airway challenge was also associated with a significant increase in FRC (p<0.001), with decreasing V' maxFRC .

We conclude that in infants undergoing airway challenge with methacholine, plethysmographic measurements of sG aw correlate with the changes in V maxFRC , but the agreement is poor and the methods cannot be used interchangeably. V maxFRC is also more sensitive to detect airway obstruction than sG aw . However, methacholine induced bronchoconstriction was associated with significant increases in FRC, which may affect the validity of V maxFRC measurements during the test.

KEYWORDS

Bronchial provocation tests, forced expiratory flow, body plethysmography, infants INTRODUCTION Increased airway responsiveness (AR) is considered one of the basic pathophysiological manifestations of asthma. In infants, the relationship between wheezing lower respiratory tract illnesses and AR is more complex. While associated with clinical features such as atopy, current airway symptoms and the viral aetiology of wheeze, 1 the predictive value of AR in infancy is still unclear. Two longitudinal studies of randomly ascertained birth cohorts have suggested an association with abnormal airway function, persistence of lower respiratory symptoms and emergence of asthma later in life, 2,3 but in a four-year prospective study of wheezy children, the level of AR showed no predictive value. 4 While the contribution of AR measurements in the clinical assessment of infants with recurrent airway symptoms may be questioned, 5 they afford an important tool for research of the pathophysiology, outcome and interventions of wheezing disorders in infancy.

The measurement of AR in infants requires a method to administer bronchoconstrictive agents (such as methacholine or histamine) and lung function tests to measure response to the test agonist. Rapid thoracoabdominal compression (RTC) is one of the lung function techniques which is standardized 6 and can be applied in the measurement of AR in infants. It enables the assessment of maximal flow at functional residual capacity (V' maxFRC ) and requires several squeeze maneuvers to be conducted. During airway challenge tests, however, it is unclear whether repeated forceful compression of the thoracic cage affects infant bronchial tone as such, and whether induced bronchoconstriction may cause changes in the functional residual capacity (FRC) that could affect the validity of serial V' maxFRC measurements.

Plethysmographic method for measuring FRC and airway resistance (R aw ) was introduced in the late 1950s and has been later modified and standardized for use in young children and infants. 7 Theoretically, plethysmography can be used to monitor infant lung function during bronchial provocation testing by measuring changes in Raw, with the advantage of following simultaneous changes in FRC and conducting measurements during tidal breathing, without forced manouvres. However, so far there have been no attempts to compare lung function measurements by body plethysmography with those of RTC during airway challenge testing in infants.

METHODS

Study subjects

The study consists of data of 94 infants, who had been referred to a tertiary center (Dept of Allergology, Helsinki University Central Hospital, Helsinki, Finland) due to recurrent airway symptoms and underwent a complete and successful airway challenge test between May 12, 2004 and June 20, 2007. These infants constituted part of the recruitment cohort of a prospective intervention study into infant asthma.

The design of the current study was observational, and the number of infants undergoing the challenge test was powered only for the prospective study. The intervention study, including the performance of the baseline lung function and airway challenge tests during the recruitment phase, was approved by the local ethics committee. The tests were conducted after informed consent to conduct these tests had been received from the parents. The parents gave also their consent for the use of the lung function and airway challenge test results for research purposes. The demographic data of the study infants have been shown in Table 1. The mean (SD) duration of the infants' respiratory symptoms (cough, dyspnea or wheeze) was 7.5 (3.8) months, and 79 % of the infants had a history of physician confirmed wheeze. 42 % had atopic dermatitis, and a family history of asthma or allergy was found in 85 %.

Five of the infants had born preterm (gestational age <36 weeks), and one of them (gestational age 28.4 weeks) needed ventilatory support and continuous oxygen supply for 2 weeks after birth due to respiratory distress syndrome (RDS).

Lung function tests

Before lung function measurements, the infants were clinically examined to exclude current respiratory infection or clinical obstruction. β 2 -agonists were withheld for 12 h prior to testing. The infants were sedated with orally administered chloralhydrate (50 -100 mg / kg; maximum dose 1000 mg). Oxygen saturation (SaO2) and heart rate were continuously monitored during lung function tests and airway challenge with a pulse oximeter (Biox 3700e; Ohmeda, Louisville, KY, USA). All measurements were recorded and calculations performed with a commercial paediatric pulmonary function equipment (Babybody Masterscreen, Jaeger GmbH, Würzburg, Germany). The functional residual capacity (FRC) and specific airway conductance (sG aw ) were measured by whole body plethysmography employing an electronic algorithm to compensate for differences of temperature and humidity between inspired and expired air. 8 FRC was measured by selecting artifact free mouth vs. box pressure tracings during endinspiratory occlusion which were not preceded by pressure drift within the box, and did not show signs of leakage (such as change in endexpiratory level after occlusion). Accordingly, pressure-flow tracings were recorded during stable tidal breathing. Airway resistance was measured from the linear portion of the pressure-flow curve between 50 % of the maximum inspiratory and expiratory tidal flow, respectively. Loops without distortion due to artifacts and with minimal thermal drift were chosen. At the baseline, two sets of measurements including 3-5 occlusions and pressure-flow tracings were recorded to calculate the mean FRC and sG aw and their baseline within-subject variation (SD ws ). 9 The baseline measurements with body plethysmography were followed by the assessment of partial expiratory flow volume curves. 6 The maximum flow at FRC (V' maxFRC ) was determined using the RTC technique. The jacket was wrapped around the infant's chest and abdomen with the arms extended outside the jacket. Flow was measured at the infant's nose and mouth with a pneumotachometer attached to a face mask. A rim of silicone putty was applied around the mouth and nose and to the face mask to provide an airtight seal. The compression pressure was progressively increased until there was no further increase in V' maxFRC . The flow volume curves were considered acceptable when the peak flow occurred prior to expiring 50% of the tidal volume, there were no transients in the tracings in the region of FRC, and forced expiration lasted long enough to allow recording of flow at FRC. According to our protocol, which is similar to that used in the study of the reference values for V' maxFRC , 10 three acceptable maximal partial expiratory flow volume curves were recorded to calculate the mean V' maxFRC and its baseline within-subject variation (SD ws ).

Methacholine airway challenge

The details of the methacholine airway challenge have been described earlier. 1 After baseline measurements of V' maxFRC , increasing doses of methacholine chloride were administered by using an inhalation-synchonized dosimeter (Spira Electro 2, Spira Respiratory Care Centre Ltd, Hämeenlinna, Finland). The dosimeter was set to be triggered by an inhaled volume of 20 ml, after which a methacholine chloride dose of 50 µg was nebulised within 0.2 seconds in an air volume of 25 ml, in each breath. The dosimeter incorporates an indicator for inspiratory flows and volumes, which were carefully monitored during the administration of methacholine to ensure sufficient tidal flows (>100 ml/s) and volumes (>50 ml). By calculating the number of breaths with nebulised methacholine, a rapid dosage scheme with four non-cumulative dose steps was applied (0.1, 0.3, 0.9 and 1.8 mg), with V' max,FRC being recorded after each dose (mean of 2-3 acceptable curves). The procedure was continued until a 40% decrease in V' maxFRC was observed or the maximum dose of methacholine had been administered. At each phase, the applied compression pressure was the same as that which achieved the highest flows at baseline. After the final measurement of V' maxFRC , a plethysmographic measurement was performed to determine methacholine induced changes in FRC and sG aw . A similar set of measurements were recorded as in the baseline, to assess postchallenge mean FRC and sG aw . The lowest postchallenge value for SaO2 was also recorded. Only infants with a complete, uninterrupted methacholine challenge test including successful baseline and post challenge measurements of FRC, sG aw and V' maxFRC were included in the study.

The provocative dose of methacholine causing a 40% fall in V' maxFRC (PD 40 V' macFRC ) was determined from the dose-response curves. In addition, the degree of AR was estimated by calculating the dose response slope (DRS), 11 by dividing the maximum percentage change in lung function with the maximum dose of methacholine administered.

Following the challenge test, the infants received inhaled salbutamol (0.6 mg, 0.1 mg•dose -1 ; Ventoline Evohaler ® ; GlaxoSmithKline, Middlesex, UK) via nebunette ® (AstraZeneca, Södertälje, Sweden), and the measurement of V' maxFRC was repeated 15 min after the salbutamol inhalation. Scatter plots of the change in FRC, sG aw and SaO 2 were formed as a function of the change in V' maxFRC and the corresponding relationships were determined using linear regression analysis. The response data were divided into binomial classes according to the cutoff which was considered as a significant change indicating methacholine induced bronchoconstriction. For V' maxFRC , a decrease of 40% or more was considered significant. Regression analysis was used to define a corresponding cutoff value for the change in sG aw and the data was classified accordingly. Kappa-analysis was applied to assess agreement between these new binomial class variables of V' maxFRC and sG aw .

DRSs were calculated for each infant, based on the maximum dose of methacholine, and pre-and postchallenge results of V' maxFRC and sG aw . Due to distribution of DRS data, log10-based transformation was used, and the degree of airway responsiveness thereby assessed by using V' maxFRC and sG aw data, were compared with regression analysis. 2 presents a summary of the baseline and post-challenge measurements and the changes in FRC, sG aw , V' maxFRC and SaO 2 during methacholine challenge. The median within subject CVs in baseline FRC, V maxFRC and sG aw were 3.3, 4.4 and 10.1 %, respectively. As a response to methacholine, sGaw, V maxFRC and SaO 2 decreased, and FRC increased significantly. The post-challenge percentage changes in sGaw and V' maxFRC were similar, but expressed as multiples of the baseline within-subject variation, V' maxFRC showed a greater change, indicating better sensitivity to assess methacholine induced bronchoconstriction.

Figure 1 shows the scatter plot between postchallenge changes in sG aw and V' maxFRC , indicating a loose assocition. V' maxFRC showed also an correlation of similar degree with postchallenge changes in airway resistance (Raw) (r=-0.23; p=0.025). Almost all of the studied infants responded to methacholine challenge with decreases in both V' maxFRC and sG aw . The correlation coefficients between postchallenge changes in FRC, sG aw , SaO 2 and FRC have been presented in Table 3. The changes in V' maxFRC were significantly associated with changes in FRC and SaO 2 , but sG aw showed a weaker relationship with SaO 2 and no correlation to FRC.

Based on regression analysis between V' maxFRC and sG aw , a 40% decrease in V' maxFRC was approximately comparable to a 35% decrease in sG aw . Accordingly the changes in V' maxFRC and sG aw were divided into two classes (significant or non-significant), indicated in Figure 1 as horizontal and vertical lines. Crosstabulation and kappaanalysis of these binomial classes gave the к-value of 0.057 (p=0.56) indicating poor agreement between the V' maxFRC and sG aw as measures of methacholine induced bronchoconstriction.

In the current study group of infants with recurrent airway symptoms, the median (range) PD 40 V' maxFRC was 0.54 (0.05 ->1.8) mg of methacholine. Figure 2 shows a significant association of the estimated AR in terms of the logDRS using Vm axFRC and sG aw data, the value of 0 indicating no response, and higher values increasing responsiveness. In infants undergoing airway challenge with methacholine, an expected association between V' maxFRC and plethysmographic measurements of sG aw , both indices of airway patency, was observed. However, this relationship was rather weak and there was a poor agreement between these variables to indicate a significant methacholine induced bronchoconstriction. Interestingly, challenging infants with methacholine have also significant effects to their FRC levels, determined by body plethysmography. This may have implications to the validity of V maxFRC measurements during the test.

Difficulties in standardizing the bronchial challenge tests in infants have been acknowledged previously. 12 In particular, the dose of the test agonist is difficult to adjust for children of different size. We have chosen a direct-acting bronchoconstrictor methacholine, which was administered using a rapid dosimetric method found safe and well tolerated by infants. 1 Furthermore, different lung function methods are available to assess the response to the bronchoconstricting agent. The original approaches to evaluate airway responsiveness to histamine or methacholine in infants applied partial expiratory flow volume curves by using the RTC technique. [13][14][15] Subsequently, a methodology using the raised volume forced expiration technique was reported, which enables measurements of forced expiratory volumes as indices of airway patency. 16 There are a limited number of studies evaluating other lung function techniques to assess histamine or methacholine induced bronchoconstriction, than forced expiration. Benoist et al. 17 compared the ability of V maxFRC , tidal breathing parameters and measures of passive respiratory mechanics to assess a response to methacholine determined by a decrease in transcutaneous oxygen tension. They concluded that all these noninvasive lung function tests could be used to detect minor or moderate airway obstruction. Springer et al. 18 studied thoracoabdominal asynchrony in 17 infants by using respiratory inductance plethysmography during a methacholine challenge, and found the method sensitive enough to measure bronchial reactivity in most (82 %) of the children. In a large sample of infants, measurements of transcutaneous oxygen tension and forced expiratory volume in 0.5 second by raised volume RTC technique were superior in sensitivity during induced airway obstruction, compared to auscultation or tidal breathing indexes. 19 By using low 11 frequency forced oscillation it has been also shown that inhaled methacholine alters both airway and respiratory tissue mechanics in infants. 20 Only a few studies have applied infant whole body plethysmography during airway challenge testing. [21][22][23] In principle, this method allows rapid assessment of changes in airway resistance with simultaneous measurements of lung volumes (FRC). The potential advantage over forced expirations is that the measurements take place during normal tidal breathing, without interfering the breathing pattern, bronchial tone or resting lung volumes levels. 24 Although some comparative studies have been published in awake preschool children, 25,26 so far, there have been no attempts to compare whole body plethysmography and RTC technique in assessing airway responsiveness in sedated infants.

The present results in infants during airway challenge demonstrate that plethysmographic measurements of sG aw result in an estimate of airway responsiveness that closely correlates with that based on the response in V' maxFRC .

However, at the point of maximal and similar degree of airway obstruction, there seems to be a poor agreement between the two lung function methods, indicating that their physiological determinants are different. Little is known of the structure/function relationships of infants' airways, but it is assumed that measures of airway resistance reflect mainly changes in the larger airways, and forced expiratory flows at the end expiratory level are more sensitive to peripheral airway obstruction. 5 As the precise target of the test agonist in the bronchial tree is largely unknown and possibly varies between individual infants, the significance of these physiological mechanisms remain hypothetical. Factors associated with the infant's status (such as posture, changing breathing pattern, sleep state, glottis closure) as well as method-specific sources of error increase the inherent variability and probably also contribute to the disagreement between the two estimates of airway obstruction. 6,7 In the current settings, the within-subject variation of V maxFRC was significantly lower than that of sG aw . This resulted in a more pronounced postchallenge change in V maxFRC than in sG aw , when expressed as multiples of baseline SD ws , suggesting that the former is a more sensitive measure of methacholine induced bronchoconstriction. Closer association of SaO 2 with V maxFRC also favours its use over sG aw in the assessment of response during airway challenge. In the present study infants, methacholine induced airway obstruction was associated with a significant increase in FRC level, determined by body plethysmography. The prior repeated forced expirations should not significantly alter FRC, 27 therefore methacholine induced dynamic changes in breathing pattern or air trapping are more likely mechanisms. The finding is important, since the measurements of V maxFRC are dependent on the actual end expiratory lung volume, and an increase in FRC may result in an underestimation of the decrease in V maxFRC during the challenge test. The observation is also a strong argument to favor raised volume RTC technique in bronchial challenge testing of infants, since forced expiratory volumes after full lung inflation are not effected by changes in FRC level. Dynamic instability of FRC in infants is a major source of variability of V maxFRC measurements. 28 However, in a study of infants comparing tidal and raised volume RTC measurements during methacholine airway challenge, the agreement between the two methods was good and neither showed any obvious advantages over the other. 16 Changes in lung function were induced by methacholine, which has a limited time of action. The postchallenge measurements of lung function were assessed in a fixed sequence, as the decrease of V' maxFRC was followed as an endpoint criterion of the challenge test. Time dependent alleviation of airway obstruction would thus favour sensitivity of the RTC method over that of sGaw, and affect the association between them as well as with SaO2. However, studies on the time course of the methacholine induced bronchoconstriction have shown that, even though the peak action usually occurs within 4 minutes, it is followed by a plateau phase where significant bronchoconstriction is sustained for over 15 minutes. 29 In a similar comparative study of four different lung function methods in preschool children, Klug and Bisgaard 25 found relatively stable airway obstruction for at least 10 minutes after methacholine inhalation. This time frame was found to be sufficient in the current study to make all the postchallenge measurements (V' maxFRC , FRC and sGaw). Accordingly, they should not be severely affected by time dependent changes of airway obstruction.

We conclude that in infants undergoing airway challenge with methacholine, plethysmographic measurements of sG aw correlate with the changes in V maxFRC , but the agreement is poor and the methods cannot be used interchangeably. V maxFRC is also more sensitive to detect airway obstruction than sG aw . However, methacholine We examined 94 infants with recurrent airway symptoms using methacholine airway challenge test including RTC and plethysmographic measurements. A significant association between changes in V' maxFRC and sG aw (r=0.30; p=0.004) was observed, but after adjustments with baseline variability the changes in V' maxFRC were greater and showed a closer association with changes in oxygen saturation. At the point of maximal airway obstruction, there was a poor agreement between V' maxFRC and sG aw to indicate a significant methacholine induced bronchoconstriction. Airway challenge was also associated with a significant increase in FRC (p<0.001), with decreasing V' maxFRC .

We conclude that in infants undergoing airway challenge with methacholine, plethysmographic measurements of sG aw correlate with the changes in V maxFRC , but the agreement is poor and the methods cannot be used interchangeably. V maxFRC is also more sensitive to detect airway obstruction than sG aw . However, methacholine induced bronchoconstriction was associated with significant increases in FRC, which may affect the validity of V maxFRC measurements during the test.

INTRODUCTION

Increased airway responsiveness (AR) is considered one of the basic pathophysiological manifestations of asthma. In infants, the relationship between wheezing lower respiratory tract illnesses and AR is more complex. While associated with clinical features such as atopy, current airway symptoms and the viral aetiology of wheeze, 1 the predictive value of AR in infancy is still unclear. Two longitudinal studies of randomly ascertained birth cohorts have suggested an association with abnormal airway function, persistence of lower respiratory symptoms and emergence of asthma later in life, 2,3 but in a four-year prospective study of wheezy children, the level of AR showed no predictive value. 4 While the contribution of AR measurements in the clinical assessment of infants with recurrent airway symptoms may be questioned, 5 they afford an important tool for research of the pathophysiology, outcome and interventions of wheezing disorders in infancy.

The measurement of AR in infants requires a method to administer bronchoconstrictive agents (such as methacholine or histamine) and lung function tests to measure response to the test agonist. Rapid thoracoabdominal compression (RTC) is one of the lung function techniques which is standardized 6 and can be applied in the measurement of AR in infants. It enables the assessment of maximal flow at functional residual capacity (V' maxFRC ) and requires several squeeze maneuvers to be conducted. During airway challenge tests, however, it is unclear whether repeated forceful compression of the thoracic cage affects infant bronchial tone as such, and whether induced bronchoconstriction may cause changes in the functional residual capacity (FRC) that could affect the validity of serial V' maxFRC measurements.

Plethysmographic method for measuring FRC and airway resistance (R aw ) was introduced in the late 1950s and has been later modified and standardized for use in young children and infants. 7 Theoretically, plethysmography can be used to monitor infant lung function during bronchial provocation testing by measuring changes in Raw, with the advantage of following simultaneous changes in FRC and conducting measurements during tidal breathing, without forced manouvres. However, so far there have been no attempts to compare lung function measurements by body plethysmography with those of RTC during airway challenge testing in infants.

METHODS

Study subjects

The study consists of data of 94 infants, who had been referred to a tertiary center (Dept of Allergology, Helsinki University Central Hospital, Helsinki, Finland) due to recurrent airway symptoms and underwent a complete and successful airway challenge test between May 12, 2004 and June 20, 2007. These infants constituted part of the recruitment cohort of a prospective intervention study into infant asthma.

The design of the current study was observational, and the number of infants undergoing the challenge test was powered only for the prospective study. The intervention study, including the performance of the baseline lung function and airway challenge tests during the recruitment phase, was approved by the local ethics committee. The tests were conducted after informed consent to conduct these tests had been received from the parents. The parents gave also their consent for the use of the lung function and airway challenge test results for research purposes. The demographic data of the study infants have been shown in Table 1. The mean (SD) duration of the infants' respiratory symptoms (cough, dyspnea or wheeze) was 7.5 (3.8) months, and 79 % of the infants had a history of physician confirmed wheeze. 42 % had atopic dermatitis, and a family history of asthma or allergy was found in 85 %.

Five of the infants had born preterm (gestational age <36 weeks), and one of them (gestational age 28.4 weeks) needed ventilatory support and continuous oxygen supply for 2 weeks after birth due to respiratory distress syndrome (RDS).

Lung function tests

Before lung function measurements, the infants were clinically examined to exclude current respiratory infection or clinical obstruction. β 2 -agonists were withheld for 12 h prior to testing. The infants were sedated with orally administered chloralhydrate (50 -100 mg / kg; maximum dose 1000 mg). Oxygen saturation (SaO2) and heart rate were continuously monitored during lung function tests and airway challenge with a pulse oximeter (Biox 3700e; Ohmeda, Louisville, KY, USA). All measurements were recorded and calculations performed with a commercial paediatric pulmonary function equipment (Babybody Masterscreen, Jaeger GmbH, Würzburg, Germany). The functional residual capacity (FRC) and specific airway conductance (sG aw ) were measured by whole body plethysmography employing an electronic algorithm to compensate for differences of temperature and humidity between inspired and expired air. 8 FRC was measured by selecting artifact free mouth vs. box pressure tracings during endinspiratory occlusion which were not preceded by pressure drift within the box, and did not show signs of leakage (such as change in endexpiratory level after occlusion). Accordingly, pressure-flow tracings were recorded during stable tidal breathing. Airway resistance was measured from the linear portion of the pressure-flow curve between 50 % of the maximum inspiratory and expiratory tidal flow, respectively. Loops without distortion due to artifacts and with minimal thermal drift were chosen. At the baseline, two sets of measurements including 3-5 occlusions and pressure-flow tracings were recorded to calculate the mean FRC and sG aw and their baseline within-subject variation (SD ws ). 9 The baseline measurements with body plethysmography were followed by the assessment of partial expiratory flow volume curves. 6 The maximum flow at FRC (V' maxFRC ) was determined using the RTC technique. The jacket was wrapped around the infant's chest and abdomen with the arms extended outside the jacket. Flow was measured at the infant's nose and mouth with a pneumotachometer attached to a face mask. A rim of silicone putty was applied around the mouth and nose and to the face mask to provide an airtight seal. The compression pressure was progressively increased until there was no further increase in V' maxFRC . The flow volume curves were considered acceptable when the peak flow occurred prior to expiring 50% of the tidal volume, there were no transients in the tracings in the region of FRC, and forced expiration lasted long enough to allow recording of flow at FRC. According to our protocol, which is similar to that used in the study of the reference values for V' maxFRC , 10 three acceptable maximal partial expiratory flow volume curves were recorded to calculate the mean V' maxFRC and its baseline within-subject variation (SD ws ).

Methacholine airway challenge

The details of the methacholine airway challenge have been described earlier. 1 After baseline measurements of V' maxFRC , increasing doses of methacholine chloride were administered by using an inhalation-synchonized dosimeter (Spira Electro 2, Spira Respiratory Care Centre Ltd, Hämeenlinna, Finland). The dosimeter was set to be triggered by an inhaled volume of 20 ml, after which a methacholine chloride dose of 50 µg was nebulised within 0.2 seconds in an air volume of 25 ml, in each breath. The dosimeter incorporates an indicator for inspiratory flows and volumes, which were carefully monitored during the administration of methacholine to ensure sufficient tidal flows (>100 ml/s) and volumes (>50 ml). By calculating the number of breaths with nebulised methacholine, a rapid dosage scheme with four non-cumulative dose steps was applied (0.1, 0.3, 0.9 and 1.8 mg), with V' max,FRC being recorded after each dose (mean of 2-3 acceptable curves). The procedure was continued until a 40% decrease in V' maxFRC was observed or the maximum dose of methacholine had been administered. At each phase, the applied compression pressure was the same as that which achieved the highest flows at baseline. After the final measurement of V' maxFRC , a plethysmographic measurement was performed to determine methacholine induced changes in FRC and sG aw . A similar set of measurements were recorded as in the baseline, to assess postchallenge mean FRC and sG aw . The lowest postchallenge value for SaO2 was also recorded. Only infants with a complete, uninterrupted methacholine challenge test including successful baseline and post challenge measurements of FRC, sG aw and V' maxFRC were included in the study.

The provocative dose of methacholine causing a 40% fall in V' maxFRC (PD 40 V' macFRC ) was determined from the dose-response curves. In addition, the degree of AR was estimated by calculating the dose response slope (DRS), 11 by dividing the maximum percentage change in lung function with the maximum dose of methacholine administered.

Following the challenge test, the infants received inhaled salbutamol (0.6 mg, 0.1 mg•dose -1 ; Ventoline Evohaler ® ; GlaxoSmithKline, Middlesex, UK) via nebunette ® (AstraZeneca, Södertälje, Sweden), and the measurement of V' maxFRC was repeated 15 min after the salbutamol inhalation. Scatter plots of the change in FRC, sG aw and SaO 2 were formed as a function of the change in V' maxFRC and the corresponding relationships were determined using linear regression analysis. The response data were divided into binomial classes according to the cutoff which was considered as a significant change indicating methacholine induced bronchoconstriction. For V' maxFRC , a decrease of 40% or more was considered significant. Regression analysis was used to define a corresponding cutoff value for the change in sG aw and the data was classified accordingly. Kappa-analysis was applied to assess agreement between these new binomial class variables of V' maxFRC and sG aw .

DRSs were calculated for each infant, based on the maximum dose of methacholine, and pre-and postchallenge results of V' maxFRC and sG aw . Due to distribution of DRS data, log10-based transformation was used, and the degree of airway responsiveness thereby assessed by using V' maxFRC and sG aw data, were compared with regression analysis. 2 presents a summary of the baseline and post-challenge measurements and the changes in FRC, sG aw , V' maxFRC and SaO 2 during methacholine challenge. The median within subject CVs in baseline FRC, V maxFRC and sG aw were 3.3, 4.4 and 10.1 %, respectively. As a response to methacholine, sGaw, V maxFRC and SaO 2 decreased, and FRC increased significantly. The post-challenge percentage changes in sGaw and V' maxFRC were similar, but expressed as multiples of the baseline within-subject variation, V' maxFRC showed a greater change, indicating better sensitivity to assess methacholine induced bronchoconstriction.

Figure 1 shows the scatter plot between postchallenge changes in sG aw and V' maxFRC , indicating a loose assocition. V' maxFRC showed also an correlation of similar degree with postchallenge changes in airway resistance (Raw) (r=-0.23; p=0.025). Almost all of the studied infants responded to methacholine challenge with decreases in both V' maxFRC and sG aw . The correlation coefficients between postchallenge changes in FRC, sG aw , SaO 2 and FRC have been presented in Table 3. The changes in V' maxFRC were significantly associated with changes in FRC and SaO 2 , but sG aw showed a weaker relationship with SaO 2 and no correlation to FRC.

Based on regression analysis between V' maxFRC and sG aw , a 40% decrease in V' maxFRC was approximately comparable to a 35% decrease in sG aw . Accordingly the changes in V' maxFRC and sG aw were divided into two classes (significant or non-significant), indicated in Figure 1 as horizontal and vertical lines. Crosstabulation and kappaanalysis of these binomial classes gave the к-value of 0.057 (p=0.56) indicating poor agreement between the V' maxFRC and sG aw as measures of methacholine induced bronchoconstriction.

In the current study group of infants with recurrent airway symptoms, the median (range) PD 40 V' maxFRC was 0.54 (0.05 ->1.8) mg of methacholine. Figure 2 shows a significant association of the estimated AR in terms of the logDRS using Vm axFRC and sG aw data, the value of 0 indicating no response, and higher values increasing responsiveness. In infants undergoing airway challenge with methacholine, an expected association between V' maxFRC and plethysmographic measurements of sG aw , both indices of airway patency, was observed. However, this relationship was rather weak and there was a poor agreement between these variables to indicate a significant methacholine induced bronchoconstriction. Interestingly, challenging infants with methacholine have also significant effects to their FRC levels, determined by body plethysmography. This may have implications to the validity of V maxFRC measurements during the test.

Difficulties in standardizing the bronchial challenge tests in infants have been acknowledged previously. 12 In particular, the dose of the test agonist is difficult to adjust for children of different size. We have chosen a direct-acting bronchoconstrictor methacholine, which was administered using a rapid dosimetric method found safe and well tolerated by infants. 1 Furthermore, different lung function methods are available to assess the response to the bronchoconstricting agent. The original approaches to evaluate airway responsiveness to histamine or methacholine in infants applied partial expiratory flow volume curves by using the RTC technique. [13][14][15] Subsequently, a methodology using the raised volume forced expiration technique was reported, which enables measurements of forced expiratory volumes as indices of airway patency. 16 There are a limited number of studies evaluating other lung function techniques to assess histamine or methacholine induced bronchoconstriction, than forced expiration. Benoist et al. 17 compared the ability of V maxFRC , tidal breathing parameters and measures of passive respiratory mechanics to assess a response to methacholine determined by a decrease in transcutaneous oxygen tension. They concluded that all these noninvasive lung function tests could be used to detect minor or moderate airway obstruction. Springer et al. 18 studied thoracoabdominal asynchrony in 17 infants by using respiratory inductance plethysmography during a methacholine challenge, and found the method sensitive enough to measure bronchial reactivity in most (82 %) of the children. In a large sample of infants, measurements of transcutaneous oxygen tension and forced expiratory volume in 0.5 second by raised volume RTC technique were superior in sensitivity during induced airway obstruction, compared to auscultation or tidal breathing indexes. 19 By using low 11 frequency forced oscillation it has been also shown that inhaled methacholine alters both airway and respiratory tissue mechanics in infants. 20 Only a few studies have applied infant whole body plethysmography during airway challenge testing. [21][22][23] In principle, this method allows rapid assessment of changes in airway resistance with simultaneous measurements of lung volumes (FRC). The potential advantage over forced expirations is that the measurements take place during normal tidal breathing, without interfering the breathing pattern, bronchial tone or resting lung volumes levels. 24 Although some comparative studies have been published in awake preschool children, 25,26 so far, there have been no attempts to compare whole body plethysmography and RTC technique in assessing airway responsiveness in sedated infants.

The present results in infants during airway challenge demonstrate that plethysmographic measurements of sG aw result in an estimate of airway responsiveness that closely correlates with that based on the response in V' maxFRC .

However, at the point of maximal and similar degree of airway obstruction, there seems to be a poor agreement between the two lung function methods, indicating that their physiological determinants are different. Little is known of the structure/function relationships of infants' airways, but it is assumed that measures of airway resistance reflect mainly changes in the larger airways, and forced expiratory flows at the end expiratory level are more sensitive to peripheral airway obstruction. 5 As the precise target of the test agonist in the bronchial tree is largely unknown and possibly varies between individual infants, the significance of these physiological mechanisms remain hypothetical. Factors associated with the infant's status (such as posture, changing breathing pattern, sleep state, glottis closure) as well as method-specific sources of error increase the inherent variability and probably also contribute to the disagreement between the two estimates of airway obstruction. 6,7 In the current settings, the within-subject variation of V maxFRC was significantly lower than that of sG aw . This resulted in a more pronounced postchallenge change in V maxFRC than in sG aw , when expressed as multiples of baseline SD ws , suggesting that the former is a more sensitive measure of methacholine induced bronchoconstriction. Closer association of SaO 2 with V maxFRC also favours its use over sG aw in the assessment of response during airway challenge. In the present study infants, methacholine induced airway obstruction was associated with a significant increase in FRC level, determined by body plethysmography. The prior repeated forced expirations should not significantly alter FRC, 27 therefore methacholine induced dynamic changes in breathing pattern or air trapping are more likely mechanisms. The finding is important, since the measurements of V maxFRC are dependent on the actual end expiratory lung volume, and an increase in FRC may result in an underestimation of the decrease in V maxFRC during the challenge test. The observation is also a strong argument to favor raised volume RTC technique in bronchial challenge testing of infants, since forced expiratory volumes after full lung inflation are not effected by changes in FRC level. Dynamic instability of FRC in infants is a major source of variability of V maxFRC measurements. 28 However, in a study of infants comparing tidal and raised volume RTC measurements during methacholine airway challenge, the agreement between the two methods was good and neither showed any obvious advantages over the other. 16 Changes in lung function were induced by methacholine, which has a limited time of action. The postchallenge measurements of lung function were assessed in a fixed sequence, as the decrease of V' maxFRC was followed as an endpoint criterion of the challenge test. Time dependent alleviation of airway obstruction would thus favour sensitivity of the RTC method over that of sGaw, and affect the association between them as well as with SaO2. However, studies on the time course of the methacholine induced bronchoconstriction have shown that, even though the peak action usually occurs within 4 minutes, it is followed by a plateau phase where significant bronchoconstriction is sustained for over 15 minutes. 29 In a similar comparative study of four different lung function methods in preschool children, Klug and Bisgaard 25 found relatively stable airway obstruction for at least 10 minutes after methacholine inhalation. This time frame was found to be sufficient in the current study to make all the postchallenge measurements (V' maxFRC , FRC and sGaw). Accordingly, they should not be severely affected by time dependent changes of airway obstruction.

We conclude that in infants undergoing airway challenge with methacholine, plethysmographic measurements of sG aw correlate with the changes in V maxFRC , but the agreement is poor and the methods cannot be used interchangeably. V maxFRC is also more sensitive to detect airway obstruction than sG aw . However, methacholine

Figure 2 .

 2 Figure 2. The relationship between dose response slopes (DRS) by sGaw and VmaxFRC during methacholine airway challenge. 73x60mm (600 x 600 DPI)

  been applied to measure airway responsiveness (AR) in infants, but there are limited data on lung function changes measured by body plethysmography during induced bronchoconstriction. The aim of this study was to compare changes in maximum forced expiratory flow measured at functional residual capacity (V' maxFRC ) by rapid thoracoabdominal compression (RTC) technique with plethysmographic measurements of specific airway conductance (sG aw ), and to investigate whether changes in FRC occur during methacholine induced bronchoconstriction in infants.

  the study was to compare methacholine induced changes in lung function by body plethysmography, with those measured by more conventional RTCtechnique.1 Specifically, we aimed to test the agreement between the changes in V' maxFRC and the change in plethysmographic measurements of specific airway conductance (sG aw ), both indexes of airway patency, and additionally to investigate whether changes in FRC occur during methacholine induced bronchoconstriction.Therefore, in a series of 94 infants undergoing airway challenge testing with the RTC technique, baseline and post-challenge measurements with infant body plethysmography were included.

  testing, the infant was lying supine with the head supported in the midline and the neck slightly extended to minimise airway or glottic obstruction.

  analysis, SPSS 17.0 for Windows (SPSS Inc. Chicago, IL, USA) was used. Mean values, within subject standard deviation (SD ws ) and coefficient of variation (CV) were calculated for each of the baseline variables. Post-challenge changes in lung function were expressed as absolute units, percentage changes and as multiples of SD ws -units, the latter indicating the change in absolute units divided by the within subject SD at baseline.

  associated with significant increases in FRC, which may affect the validity of V maxFRC measurements during the test.

Figure 1 .

 1 Figure 1. The relationship between methacholine induced post-challenge changes in sGaw and VmaxFRC. The vertical and horizontal lines represent corresponding cutoffs of significant change.

Figure 2 .

 2 Figure 2. The relationship between dose response slopes (DRS) by sGaw and VmaxFRC during methacholine airway challenge.

  been applied to measure airway responsiveness (AR) in infants, but there are limited data on lung function changes measured by body plethysmography during induced bronchoconstriction. The aim of this study was to compare changes in maximum forced expiratory flow measured at functional residual capacity (V' maxFRC ) by rapid thoracoabdominal compression (RTC) technique with plethysmographic measurements of specific airway conductance (sG aw ), and to investigate whether changes in FRC occur during methacholine induced bronchoconstriction in infants.

KEYWORDS

  Bronchial provocation tests, forced expiratory flow, body plethysmography, infants

  the study was to compare methacholine induced changes in lung function by body plethysmography, with those measured by more conventional RTCtechnique.1 Specifically, we aimed to test the agreement between the changes in V' maxFRC and the change in plethysmographic measurements of specific airway conductance (sG aw ), both indexes of airway patency, and additionally to investigate whether changes in FRC occur during methacholine induced bronchoconstriction.Therefore, in a series of 94 infants undergoing airway challenge testing with the RTC technique, baseline and post-challenge measurements with infant body plethysmography were included.

  testing, the infant was lying supine with the head supported in the midline and the neck slightly extended to minimise airway or glottic obstruction.

  analysis, SPSS 17.0 for Windows (SPSS Inc. Chicago, IL, USA) was used. Mean values, within subject standard deviation (SD ws ) and coefficient of variation (CV) were calculated for each of the baseline variables. Post-challenge changes in lung function were expressed as absolute units, percentage changes and as multiples of SD ws -units, the latter indicating the change in absolute units divided by the within subject SD at baseline.

  associated with significant increases in FRC, which may affect the validity of V maxFRC measurements during the test.

Figure 1 .

 1 Figure 1. The relationship between methacholine induced post-challenge changes in sGaw and VmaxFRC. The vertical and horizontal lines represent corresponding cutoffs of significant change.

Figure 2 .

 2 Figure 2. The relationship between dose response slopes (DRS) by sGaw and VmaxFRC during methacholine airway challenge.

Table 2 .

 2 Mean (SD) baseline and postchallenge lung function, and change from baseline expressed as absolute units (abs), percentage change (%) and as multiples of within subject variation (standard deviation) at baseline (SD ws ).

	______________________________________________________________________________
		Baseline	Postchallenge Change (abs) Change (%) Change (SD ws )
	______________________________________________________________________________
	FRC, ml	240 (55)	279 (69)*	39 (36) #	17 (17) #	5.6 (7.4) #
	sGaw, kPa -1 s -1	3.3 (2.8)	1.4 (1.0)*	-1.9 (2.4) #	-48 (27) #	-5.0 (4.1) #
	V max FRC, ml/s SaO 2 , %	237 (124) 116 (88)* 96 (1) 93 (2)*	-121 (92) # -3 (2) #	-51 (21) # -3 (2) #	-23.0 (43.3) #
	______________________________________________________________________________
	*p<0.001 compared to baseline; # p<0.001, one sample t-test

ACKNOWLEDGEMENTS

We wish to thank Tuija Rito, RN, and Helena Punkari, RN, for their skill and care with the infants and their parents. The personnel of Spira Respiratory Care Center Ltd, is acknowledged for their help in the development of the inhalation-synchronized dosimetric equipment used in the methacholine challenge.

CONFLICTS OF INTEREST

None of the authors has any competing interests to declare.

ACKNOWLEDGEMENTS

We wish to thank Tuija Rito, RN, and Helena Punkari, RN, for their skill and care with the infants and their parents. The personnel of Spira Respiratory Care Center Ltd, is acknowledged for their help in the development of the inhalation-synchronized dosimetric equipment used in the methacholine challenge.

CONFLICTS OF INTEREST

None of the authors has any competing interests to declare.

The study was financially supported by Helsinki University Central Hospital Research Fund, Sigrid Juselius Foundation, Foundation for Paediatric Research in Finland, Nummela Sanatorium Foundation, and Finska Läkaresällskapet. An unrestricted research grant was received from Merck Sharp & Dohme Ltd. The study was financially supported by Helsinki University Central Hospital Research Fund, Sigrid Juselius Foundation, Foundation for Paediatric Research in Finland, Nummela Sanatorium Foundation, and Finska Läkaresällskapet. An unrestricted research grant was received from Merck Sharp & Dohme Ltd.