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Inhaled Β2-Agonist Therapy Increases Functional Residual Capacity In Online Clinical Investigations Kumaraswamy Pediatric Critical Care Medicine Inhaled β2-Agonist Therapy Increases Functional 10.1097/PCC.0000000000000448 Residual Capacity in Mechanically Ventilated 1529-7535 Children With Respiratory Failure* Pediatr Crit Care Med Musaab A. Ramsi, MD1; Michael Henry, RRT2; Carlos E. Milla, MD3; David N. Cornfield, MD1,4 Objectives: To test the hypothesis that in mechanically ventilated However, in patients with an endotracheal tube size of more than Ramsi children with respiratory failure, aerosolized albuterol modifies or equal to 4.0 mm, resistance decreased from 33 ± 3 to 25 ± 3 functional residual capacity, lung mechanics, oxygen consump- (p < 0.02). Inhaled albuterol administration had no effect on tion, and hemodynamics. oxygen consumption despite an increase in heart rate from Design: Prospective, self-control clinical trial. 116 ± 2 to 128 ± 2 beats/min (p < 0.0001). Setting: A 24-bed PICU in a quaternary care, academic children’s Conclusions: In pediatric patients with respiratory failure, aero- hospital. solized albuterol increases functional residual capacity without a Patients: 25 children (age range, 1–18 yr) undergoing mechani- decrease in resistance. In infants and children, aerosolized alb- cal ventilation to treat respiratory failure. Entry criteria included uterol might favorably enhance pulmonary mechanics and thereby previously prescribed inhaled β2 agonists. Physiologic measure- represent a novel strategy for lung recruitment in children with ments were performed prior to and 20 minutes after adminis- respiratory failure. (Pediatr Crit Care Med 2015; 16:e189–e193) tration of aerosolized albuterol solution. Functional residual Key Words: agonist; children; functional residual capacity; inhaled capacity was determined via nitrogen washout. β2 agonist; respiratory failure Interventions: Functional residual capacity, oxygen consumption, respiratory mechanics, and vital signs were measured were mea- sured prior to and 20 minutes after administration of aerosolized albuterol solution. Functional residual capacity was determined via n children, a wide array of insults can result in respiratory nitrogen washout. failure. When lung injury is particularly severe, lung com- Measurement and Main Results: At baseline, functional residual Ipliance and gas exchange worsen, intrapulmonary shunt- capacity is only 53% of predicted. After aerosolized albuterol, ing becomes pronounced, and severe hypoxemia results. In the functional residual capacity increased by 18.3% (p = 0.008). absence of therapy, this leads to progressive hypoxemia, marked Overall, aerosolized albuterol had no effect on airway resistance. increase in work of breathing and respiratory failure (1). Severe diffuse lung injury, characterized by compromise in diffusion of *See also p. 678. oxygen from the alveoli into the bloodstream where the ratio of xxx 1Division of Pediatric Critical Care Medicine, Sheikh Khalifa Medical City arteriolar to alveolar oxygen is less than 200, constitutes acute (SKMC) in affiliation with Cleveland Clinic, Abu Dhabi, United Arab Emirates. respiratory distress syndrome (ARDS) (2). 2 Respiratory Therapy Department, Lucile Packard Children’s Hospital at Positive pressure ventilation with supplemental oxygen is the September Stanford University, Palo Alto, CA. cornerstone of therapy for either respiratory failure or ARDS. 3Division of Pulmonary Medicine, Center for Excellence in Pulmonary Biol- ogy, Stanford University School of Medicine, Stanford, CA. Over the past several decades, consensus surrounding ventilatory 2015 4Department of Pediatrics, Center for Excellence in Pulmonary Biology, strategies that optimize end-organ function, even while minimiz- Stanford University School of Medicine, Stanford, CA. ing lung injury has emerged. The fundamental principles include 16 Supplemental digital content is available for this article. Direct URL citations provision of sufficient positive end-expiratory pressure (PEEP) appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/pccmjournal). to maintain functional residual capacity (FRC) above closing 7 Dr. Milla lectured for Clinical Viewpoints, Inc. and Advanced Health Media, volumes throughout the ventilator cycle, limiting tidal volume Inc. and consulted for Gilead Sciences, Inc. His institution received grant to prevent overdistention, minimizing repeated alveolar collapse 2015 support from Kalobios Pharmaceuticals, Vertex Pharmaceuticals, and Cys- and reexpansion, and limiting radical-related injury due to high tic Fibrosis Foundation Therapeutics Inc. The remaining authors have dis- closed that they do not have any potential conflicts of interest. concentrations of inspired oxygen. The lung-protective strategy e189 For information regarding this article, E-mail: [email protected] entails use of relatively high PEEP, low tidal volumes, and permis- Copyright © 2015 by the Society of Critical Care Medicine and the World sive hypercarbia. Studies have consistently demonstrated that low e193 Federation of Pediatric Intensive and Critical Care Societies tidal volumes strategies, superimposed on an open lung strategy, DOI: 10.1097/PCC.0000000000000448 decrease both mortality and lung injury (3, 4). Pediatric Critical Care Medicine www.pccmjournal.org e189 Copyright © 2015 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. Unauthorized reproduction of this article is prohibited Ramsi et al Despite clarity surrounding the benefits of open lung strat- FRC Measurement Procedure egies, optimal lung recruitment often does not occur owing, FRC was measured using an automated procedure available arguably, to insufficient levels of PEEP. Strategies that pro- on the ventilator using wash in/wash out methodology (Care- mote lung recruitment and act synergistically with PEEP may station, E-COVX, General Electric, Madison, WI). The method yield meaningful clinical benefit in the context of acute lung is based on multibreath nitrogen washout, with an incremental injury. In Pediatrics, in particular, optimal levels of PEEP may IO change in F 2 of 0.1. Initially described by Olegard et al (13), be underutilized. Thus, we explored strategies that might opti- subsequent studies have further validated the method both in mize lung recruitment even without increasing PEEP. vivo and in vitro and down to small infants (14, 15). Measure- Inhaled β2 agonists have been long used by clinicians ment of FRC required between 3 and 5 minutes. Ventilation in hypoxemic, mechanically ventilated patients even in the and lung mechanics were not altered by measurement of FRC. absence of obstructive lung disease (5). Despite the ongoing The FRC values obtained were compared with predicted values clinical use of β2 agonists in mechanically ventilated patients, based on length, age, and gender according to published studies clear evidence surrounding either a mechanism or clinical based on multiple breath washout (16). benefit is lacking. Theoretical benefits of β2 agonist treatment include enhanced mucociliary clearance (6), optimization of Study Measurements lung mechanics (7), decrease work of breathing (8), and clear- The primary outcome measure was FRC change after inhala- ance of pulmonary edema (9). In vitro studies demonstrate that tion of nebulized albuterol. Additional measurements of lung stimulation of the β2 receptors regulates, via cyclic adenosine mechanics included airway resistance, measured as the differ- monophosphate-dependent pathways, several of the key pro- ence between peak and plateau airway pressures by the mean teins and ion channels, such as epithelial sodium channels, the inspiratory flow rate, and expressed as cm H2O/L/s. Further vali- cystic fibrosis transmembrane conductance regulator, and the dation of the airway resistance measurements was conducted in basolateral Na, K-ATPase pump, that stimulate pulmonary three patients using a NICO2 mainstream sensor (Model 7300, fluid clearance (10). Philips-Respironics, Wallingford, CT). Secondary outcome We reasoned that aerosolized albuterol in pediatric patients measures included heart rate and oxygen consumption as sec- with acute respiratory failure increases FRC and improves lung ondary outcomes. Oxygen consumption was measured using mechanics. To test this hypothesis, we measured the effect of indirect calorimetry by the calorimeter module on the ventilator aerosolized albuterol on FRC and pulmonary mechanics in 25 (Engström Carestation, GE Healthcare, Wauwatosa, WI) (17). critically ill children with respiratory failure. Statistical Analysis PATIENTS AND METHODS The data were expressed as mean ± SE. A paired t test was used to compare values obtained prior to and following administra- Study Design tion of inhaled albuterol. A p value of less than 0.05 was con- This is a prospective study of intubated, mechanically venti- sidered statistically significant. Data analysis was undertaken lated children with respiratory failure at Lucile Packard Chil- with Prism, version 5.0a (GraphPad Software, La Jolla, CA). dren’s Hospital at Stanford from August 15, 2013, to April 15, 2014. Inclusion criteria include: acute respiratory failure requiring mechanical ventilation, children 0–18 years admit- RESULTS ted to the pediatric intensive care with an active prescription A total of 25 pediatric patients with acute respiratory failure for a b2-agonist therapy delivered via an
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