Should We Nebulize Hypertonic Saline Prophylactically in Our Pediatric Intubated Patients? - PDF Document

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  1. Should We Nebulize Hypertonic Saline Prophylactically in Our Pediatric Intubated Patients? Mucoactive agents improve airway clearance by differ- ent mechanisms. According to their mode of action, they can be classified as mucolytics, expectorants, mucokinet- ics, and ion-transport modifiers. Whereas mucolytic agents disrupt the structure of the mucus gel, thereby reducing its viscosity and elasticity, expectorants promote osmotic pas- sage of water to the airway surface. Mucokinetic drugs improve cough-mediated clearance by reducing mucus ad- hesivity or by increasing air flow.1 Hypertonic saline enhances mucociliary clearance in pa- tients with obstructive lung diseases as well as normal individuals.2It is also considered a safe and effective ther- apy for neonatal and pediatric conditions requiring muco- ciliary clearance, such as viral bronchiolitis,3atelectasis,4 and cystic fibrosis.5Although hypertonic saline has been traditionally classified as a mucokinetic drug, it has mu- colytic properties. Hypertonic saline is capable of disrupt- ing ionic bonds within the mucus gel, changing the rheo- logical properties of the mucus and ultimately reducing its viscosity.1Furthermore,hypertonicsalinedissociatesDNA fromthemucoprotein,allowingnaturalproteolyticenzymes to digest the mucoprotein.6As a mucokinetic, hypertonic saline increases the liquid on the epithelial surface by os- motically drawing additional water from the mucosa and submucosa into the airway, which hence accumulates in the mucus layer.7The release of prostaglandins observed with the use of hypertonic saline appears to enhance cili- ary motility and water absorption from the airway mucosa and submucosa.8Radioaerosol studies in vitro have con- firmed the positive effect of hypertonic saline on muco- ciliarytransportandimprovementofclearancewithcough.9 Murray9reported that hypertonic saline was associated with an in vitro reduction of biofilm formation by Pseu- domonas aeruginosa and the production of associated vir- ulence factors. In addition to the well-known effects of hypertonic saline, it has been found that it may increase the levels of 2 thiols that are considered protective against oxidative injury, glutathione and thiocyanate, in the air- way surface liquid10and may also attenuate lung injury by exerting an anti-inflammatory effect on the pulmonary ep- ithelium.11In the clinical setting, nebulized hypertonic sa- line, alone or in combination, has been associated with decreased hospital stay and improvement of respiratory severity scores.12Although the use of a bronchodilator takes into account the potential for hypertonic saline to cause irritation of the airway and even bronchospasm in selected patients, a low rate of adverse events has been reported, suggesting that such a combination may be unnecessary.13 SEE THE ORIGINAL STUDY ON PAGE 586 In light of the efficacy that has been credited to hyper- tonic saline as a mucoactive agent, it seems logical to believethatitsuseinmechanicallyventilatedpatientscould provide an additional benefit in the critical care setting. Patients undergoing mechanical ventilation are often at risk for impairment of mucociliary function. Ineffective cough, muscle weakness, suboptimal heat and humidifica- tion of medical gases, and a negative fluid balance are some of the contributing factors that lead to inspissation of secretions. In children, the smaller airway size exponen- tially increases airway resistance and the risk for obstruc- tion and undesired clinical outcomes. Airway obstruction in the mechanically ventilated patient increases the rate of atelectasis and abnormalities in gas exchange, thus in- creasing the risk for extended stays in the ICU. A considerably large number of clinical trials and meta- analyses have published the efficacy of mucoactive agents in clinical conditions associated with mucus clearance im- pairment.14,15,18Nevertheless, the most recent meta-anal- ysis evaluating the therapeutic and prophylactic nebuliza- tion of mucoactive agents in adult critically ill patients found very low quantity and quality of evidence to support their use.14Little evidence exists of their prophylactic use in the pediatric critical care setting to decrease the duration of mechanically ventilation, and no prospective blinded studies in children undergoing mechanical ventilation have been reported. The authors have disclosed no conflicts of interest. Correspondence: Ruben D Restrepo MD RRT FAARC, Department of Respiratory Care, University of Texas Health Science Center at San Antonio, MSC 6248, San Antonio, TX 78229. E-mail: DOI: 10.4187/respcare.04812 RESPIRATORY CARE • MAY 2016 VOL 61 NO 5 716

  2. NEBULIZED HYPERTONIC SALINE FOR PEDIATRICS In this issue of RESPIRATORY CARE, Shein et al15con- ducted a blind randomized pilot study on the use of hy- pertonic saline in mechanically ventilated subjects. They investigated the use of nebulized hypertonic saline to im- prove airway clearance and shorten the duration of me- chanical ventilation. They studied 18 children ?18 y old who had been intubated for ?12 h and had an expected duration of mechanical ventilation of ?48 additional h. They were prophylactically given 3 mL of either nebulized hypertonic saline or placebo (0.9% saline) 4 times/d. The primary outcome was duration of mechanical ventilation. Ventilator parameters and the presence of wheezing were recorded before and after study drug administration. They found that the duration of mechanical ventilation was sig- nificantly longer in children treated with hypertonic saline (208.1 [interquartile range 136.3–319.8] h) versus those treatedwithplacebo(129.5[interquartilerange74.4–146.1] h) (P ? .03). After adjusting for baseline levels of PEEP, the duration of mechanical ventilation did not differ be- tween groups. Mechanical ventilation parameters, includ- ing dead space and dynamic compliance, did not differ between measurements taken before study drug adminis- tration and measurements taken after. New onset wheezing following study drug administration was rare (1.0% with hypertonic saline [3.0%] vs placebo, P ? .36). They con- cluded that prophylactic administration of nebulized hy- pertonic saline to mechanically ventilated children did not improve clinically relevant outcomes, including duration of mechanical ventilation. In fact, children treated with hypertonic saline had a significantly longer duration of mechanical ventilation. Wheezing after hypertonic saline treatment was rare. As mentioned by the authors, the study was underpow- ered, and any generalization of their findings will have to be taken with extreme caution. In addition, children given hypertonic saline had significantly more unfavorable ra- diographic findings and pulmonary mechanics at enroll- ment. Having those baseline differences can seriously change the intended outcomes of any therapeutic or pro- phylactic strategy. An in vitro study by Ari et al16found that inhaled drug mass can be significantly higher when a manual resuscitation bag is used to administer bronchodi- latorsthroughanadultartificialairway.However,Schleufe et al17did not find any advantage of using Ambu bags to improve aerosol deposition when compared with conven- tional methods. Assuming that disconnecting patients who have unfavorable radiographic findings, compromised pul- monary mechanics, and high PEEP requirement for the purpose of administering aerosol therapy would not sig- nificantly affect clinical outcomes is not easily supported. The disconnection of the patients to bag the treatment should not be considered the standard-of-care method to deliver nebulized hypertonic saline to pediatric patients. Routine disconnection of patients from mechanical venti- lation could increase cross-contamination and may ad- versely affect duration of ventilation. In addition, the group of subjects with higher PEEP levels in the present study could have experienced alveolar de-recruitment with ven- tilator disconnection. Although a small group of subjects may not allow generalization of findings, the possibility that those subjects could have been adversely affected by disconnection while receiving hypertonic saline cannot be ruled out. Despite some obvious limitations of the study by Shein et al15, their results are consistent with a few trials where nebulized hypertonic saline did not significantly improve any of the clinical outcomes measured.14,18,19 The evidence supporting the prophylactic use of nebu- lized hypertonic saline for patients undergoing mechanical ventilation as a mucoactive agent and its impact on clinical outcomes is lacking. This study invites clinicians to take a closer look at the potential prophylactic role of mucoactive agents to improve mucociliary clearance and possibly im- pact important clinical outcomes, such as ventilator length of stay. Only adequately powered clinical studies will re- veal the potential role of prophylactic nebulized hyper- tonic saline in mechanically ventilated pediatric patients. Ruben D Restrepo MD RRT FAARC Department of Respiratory Care University of Texas Health Science Center at San Antonio San Antonio, Texas Diana M Serrato MSc CRT Department of Respiratory Care Universidad Santiago de Cali Cali, Colombia and Department of Respiratory Care University of Texas Health Science Center at San Antonio San Antonio, Texas REFERENCES 1. Elkins MR, Bye PT. Mechanisms and applications of hypertonic saline. J R Soc Med 2011;104(Suppl 1):S2-S5. 2. Kellett F, Redfern J, Niven RM. Evaluation of nebulised hypertonic saline (7%) as an adjunct to physiotherapy in patients with stable bronchiectasis. Respir Med 2005;99(1):27-31. 3. Badgett RG, Vindhyal M, Stirnaman JT, Gibson CM, Halaby R. A Living systematic review of nebulized hypertonic saline for acute bronchiolitis in infants. JAMA Pediatr 2015;169(8):788-789. 4. Dilmen U, Karagol BS, Oguz SS. Nebulized hypertonic saline and recombinant human DNase in the treatment of pulmonary atelectasis in newborns. Pediatr Int 2011;53(3):328-331. 5. Robinson M, Hemming AL, Regnis JA, Wong AG, Bailey DL, Bautovich GJ, et al. Effect of increasing doses of hypertonic saline on mucociliary clearance in patients with cystic fibrosis. Thorax 1997;52(10):900-903. 6. Lieberman J, Kurnick NB. Influence of deoxyribonucleic acid con- tent on the proteolysis of sputum and pus. Nature 1962;196:988-990. RESPIRATORY CARE • MAY 2016 VOL 61 NO 5 717

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