Pediatric Critical Care Medicine Clerkship Readings Table of Contents Acute Respiratory Failure................................................................................................. 1-17 Acute Lung Injury............................................................................................................. 18-36 Acute Respiratory Distress Syndrome (ARDS).................................................................. 37-44 Asthma............................................................................................................................ 45-61 Obstructive Sleep Apnea (OSA)....................................................................................... 62-75 Shock.............................................................................................................................. 76-89 Sepsis and Septic Shock.................................................................................................. 90-101 Hemodynamic Support of Septic Shock............................................................................ 102-124 Hypertension....................................................................................................................125-139 Renal Complications........................................................................................................ 140-160 Acute Kidney Injury.......................................................................................................... 161-180 Traumatic Brain Injury (TBI)..............................................................................................181-196 Status Epilepticus............................................................................................................ 197-217 Acute Encephalitis............................................................................................................218-236 Pediatric Delirium............................................................................................................. 237-256 Brain Death..................................................................................................................... 257-273 Endocrine Issues............................................................................................................. 274-297 Anemia and Transfusion...................................................................................................298-314 Sedation.......................................................................................................................... 315-325 Ethics.............................................................................................................................. 326-342 End of Life Care............................................................................................................... 343-357

A c u t e R e s p i r a t o r y F a i l u re James Schneider,

MD*,

Todd Sweberg,

MD

KEYWORDS  Acute respiratory failure  Pediatrics  Acute lung injury  Monitoring  Respiratory physiology KEY POINTS  Acute respiratory failure is common in critically ill children.  Monitoring for respiratory failure includes commonly used invasive tests, such as blood gas analysis, but noninvasive monitoring has recently grown in importance and proven reliable.  Recent advancements in therapeutic options for respiratory failure have improved the overall outcome of critically ill children, but much more rigorous investigation is still needed.

INTRODUCTION

Acute respiratory failure is a common dilemma faced by pediatric critical care practitioners. As many as two-thirds of pediatric intensive care unit (PICU) patients will be admitted with a diagnosis of respiratory failure,1 which represents a common end point to multiple pathologic processes, categorized as hypoxemic, hypercapnic, or mixed. Common causes are listed in Table 1. In 2012, primary infections of the lung were responsible for 2% of all mortalities in children younger than 5 years in the United States and 18% worldwide.2 Developmental variations contribute to the diverse etiologies and higher incidence of acute respiratory failure in children compared with adults. Infants have more compliant chest walls than adults, making it more difficult to generate the negative intrathoracic pressure required to inspire sufficient tidal volumes in conditions of decreased lung compliance (ie, pneumonia, hyaline membrane disease). The infant chest wall also has less elastic recoil. Further, collateral ventilation through pores of Kohn or Lambert are not well developed in early life. These characteristics make young children more susceptible to alveolar collapse. Childhood airways lack the more rigid cartilaginous supports that strengthen into

The authors do not have any financial conflict of interest to disclose. Division of Critical Care Medicine, Hofstra North Shore-LIJ School of Medicine, Cohen Children’s Medical Center of New York, North Shore Long Island Jewish Health System, 269-01 76th Avenue, New Hyde Park, NY 11040, USA * Corresponding author. E-mail address: [email protected] Crit Care Clin 29 (2013) 167–183 http://dx.doi.org/10.1016/j.ccc.2012.12.004 criticalcare.theclinics.com 0749-0704/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

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Table 1 Etiologies of acute respiratory failure in children Location

Example

Upper airway obstruction

   

Lower airway obstruction

 Asthma  Bronchiolitis  Cystic fibrosis

Restrictive lung disease

    

Central nervous system disorder

 Intracranial injury (hemorrhage, ischemia)  Medication (sedatives)  Metabolic encephalopathy

Peripheral nervous system and muscle disorders

     

Infection (croup, epiglottitis, bacterial tracheitis) Laryngotracheomalacia Foreign body Anaphylaxis

Acute respiratory distress syndrome Pleural effusion Pneumonia Pulmonary edema Abdominal compartment syndrome

Guillian Barre´ syndrome Muscular dystrophy Scoliosis Spinal cord injury Botulism Intoxications (ie, organophosphates)

Adapted from Ghuman AK, Newth CJ, Khemani RG. Respiratory support in children. Paediatr Child Health 2011;21(4):163–9; with permission.

adulthood, making them more susceptible to dynamic compression and subsequent airway obstruction in disease states associated with increased airway resistance (ie, bronchiolitis, asthma). Last, the pediatric airways are naturally smaller in diameter than in adults. Because the resistance to airflow is inversely proportional to the fourth power of the radius (R 5 8NL/pr4), any narrowing of the pediatric airway will have a much greater impact on the resistance. This will lead to a more profound decrease in airflow, as laminar flow transitions to turbulent flow, as described by Reynolds number (Re 5 2 rVr/N, where r is the radius of the airway, V is the velocity of the gas flow, r is the density of the gas, and N is the viscosity of the gas). In the adult, the peripheral airways contribute about 20% of the total airway resistance. In infants and young children, they contribute about 50%, explaining why diseases affecting the peripheral airways (ie, bronchiolitis) have such a profound clinical impact. It is clear that the management of acute respiratory failure in children requires a thorough understanding of these physiologic differences, reminding the clinician that children are, in fact, not little adults. Acute respiratory failure occurs when embarrassment of the respiratory system results in the inability to properly transfer oxygen (O2) from the atmosphere to the blood or remove carbon dioxide (CO2) from the blood and eliminate it to the atmosphere. Hypoxic respiratory failure is defined by a partial pressure of arterial O2 (PaO2) that is less than 60 mm Hg on room air at sea level, and hypercapnic respiratory failure occurs when the partial pressure of CO2 (PaCO2) is greater than 50 mm Hg (with a concomitant respiratory acidosis) under the same conditions. To better understand these, it is first important to examine the mechanisms of oxygenation and ventilation. PEDIATRIC CRITICAL CARE MEDICINE

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Oxygenation

Ideally, oxygen that is contained within the alveolus at inspiration will equilibrate with arterial blood, as described by the alveolar gas equation: PAO2 5 PIO2 – (PACO2/R), then PAO2 5 FiO2 (PB – PH2O) – PACO2/R, where PAO2 5 partial pressure of alveolar oxygen; PIO2 5 partial pressure of inspired oxygen; PACO2 5 partial pressure of alveolar CO2 (substituted by arterial [PaCO2] due to the highly efficient manner that CO2 crosses cell membranes); R 5 respiratory quotient: ratio of CO2 production (VCO2) to O2 consumption (VO2) (R 5 VCO2/VO2), averages 0.8 on a normal, mixed adult diet; PB 5 barometric pressure; and PH2O 5 water vapor pressure. Adequate gas exchange also requires that the inspired alveolar gas matches blood distribution in the pulmonary capillaries. There is a normal gradient between alveolar and arterial PO2, known as the A-a gradient, which is less than 10 mm Hg. The alveolar gas equation also helps to understand some of the mechanisms behind hypoxemia (Box 1).3 Nonpulmonary causes, such as decreased cardiac output, increased extraction of O2, and abnormal hemoglobin, can also contribute to abnormal gas exchange.4 The most common etiology for hypoxemia in critically ill children is inequality in the relationship between ventilation and perfusion (V/Q). Regional differences in ventilation and blood flow, owing to regional differences in intrapleural pressures and gravitational forces, cause ventilation and perfusion to decrease from the base to the apex of the lung, although perfusion does so much more rapidly. This leads to an abnormally high V/Q ratio at the apex of the lung (in an upright position) and a much lower one at the base.3 Atelectasis from various pathologic states (ie, pneumonia, mucous plug) exaggerates the mismatching of V/Q, causing well-oxygenated blood from high V/Q regions to mix with poorly oxygenated blood from low V/Q regions, leading to worsening hypoxia with an increased A-a gradient. Pulmonary edema (ie, cardiac failure, systemic inflammatory response syndrome, acute respiratory distress syndrome [ARDS]) will lead to worsening V/Q mismatching, compromised diffusion, and atelectasis. Hypoxemia caused by V/Q inequality can be corrected by inspiring a higher concentration of oxygen, as well as the provision of positive pressure ventilation, which may recruit consolidated or collapsed lung units and improve V/Q matching. When alveolar ventilation is decreased, insufficiently replenishing alveolar oxygen, the alveolar PO2 falls as the PCO2 rises, not altering the normal A-a gradient. Elevation of PaCO2 that occurs with airway obstruction will not result in hypoxemia until severe obstruction is present, with forced expiratory volume in 1 second less than Box 1 Causes of hypoxemia Hypoventilation Shunt Ventilation-perfusion inequality Diffusion limitation Low inspired fraction of oxygen

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approximately 15% predicted.5 The hypoxia that results from CO2 retention is easily overcome with the addition of increased inspired oxygen. Shunting describes the direct mixing of deoxygenated venous blood that has not undergone gas exchange in the lungs with arterial blood. Normal anatomic shunting occurs as venous blood from the bronchial veins and Thebesian veins collects in the left-sided circulation. Pathologically, patients may have abnormal vascular connections (ie, arterial-venous fistula) or intracardiac communications allowing blood to traverse the heart from the right to the left without undergoing gas exchange at the level of the lungs. Intrapulmonary shunting most commonly occurs as blood perfuses regions of the lung that are not well ventilated. The addition of mixed venous blood (with depressed PO2) to oxygenated capillary blood results in decreased PaO2, increasing the A-a gradient. The amount of shunted blood that would need to be mixed with arterial blood to account for the A-a gradient can be calculated by the shunt equation: QS/QT 5 (CcO2 – CaO2)/(CcO2 – CvO2), where QS is shunt flow to unventilated lung units; QT is total pulmonary blood flow; and CaO2, CcO2, and CvO2 is the content of oxygen in arterial, end-capillary, and mixed venous blood, respectively.3 In healthy individuals, normal physiologic shunting accounts for less than 5% of cardiac output.6 The addition of supplemental oxygen, increasing the PAO2, has minimal effect on improving the hypoxemia, as the shunted blood is not exposed to the high alveolar PO2. Diffusion of oxygen between the alveolus and capillary blood can be altered by thickening of the alveolar-capillary barrier, by decreased alveolar capillary volume, or increased oxygen extraction. Further, decreasing the PAO2 at high altitude decreases the alveolar-capillary PO2 pressure gradient, limiting diffusion. Diffusion impairment is a rare primary cause of hypoxemia in children, although it can contribute to the hypoxemia associated with shunt and V/Q mismatching. More than 50% of the diffusion capacity of the lung must be compromised to develop hypoxemia from primary diffusion limitation. Supplemental oxygen can rapidly overcome hypoxemia associated with diffusion limitations. Ventilation

Exchange of CO2 follows similar physiologic principles to O2. Because of differences in the solubility, dissociation curves of CO2 and O2, as well as the way each gas effects central ventilatory control, CO2 exchange (and invariably PaCO2) is ultimately determined by alveolar minute ventilation and the degree of dead space present. PaCO2 is related to the balance between the production of CO2 (VCO2), which is a function of the metabolic conditions of the patient, and the alveolar minute ventilation (VA), as described by the equation: PACO2 5 VCO2 * K/VA Minute ventilation is determined by the product of the respiratory frequency (f) and the tidal volume (Vt). Dead space gas, both anatomic (in the conducting airways) and physiologic (areas of ventilation lung units that are poorly perfused; V>Q), does not participate in CO2 elimination. Therefore, total alveolar ventilation is determined by the difference between total minute ventilation (VE) and the degree of dead space ventilation (VD): VA 5 VE – VD PEDIATRIC CRITICAL CARE MEDICINE

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As a result, elevations in PaCO2 will result from conditions of decreased tidal volume or increased physiologic dead space (Table 2). Ventilatory muscles generally can maintain adequate tidal volumes with only 50% of normal strength.7 Hyperinflation further compromises respiratory muscle function. Diseases associated with airway obstruction increase the end expiratory lung volume greater than functional residual capacity (FRC), decreasing muscle fiber length below what is optimal. Muscle fibers generate less force at these shorter lengths.8 Similarly, hyperinflation causes a flattening of the diaphragm, putting it at a mechanical disadvantage. V/Q mismatching generally does not cause a direct increase in PCO2 because elevated CO2 from low V/Q units is a potent stimulator of the central respiratory centers, increasing alveolar minute ventilation.3 EPIDEMIOLOGY

As a common end point to multiple clinical conditions, the incidence of respiratory failure in the pediatric population is difficult to ascertain. In one study, 17.1% of patients admitted to a PICU at several large children’s hospitals required mechanical ventilation, with acute respiratory conditions as the culprit in 62.4% of these patients. In this cohort of patients, bronchiolitis (26.7%) and pneumonia (15.8%) were the leading etiologies for respiratory failure.9 Acute lung injury (ALI) accounts for 12.8 cases per 100,000 person years, with an in-hospital mortality rate of 18% to 22%10,11; 10% of intubated children admitted to a European PICU had ALI, with a mortality rate of 27%. Of the patients with ALI, 54% had ARDS at presentation and 80% progressed to ARDS at some point during their hospitalization.12 Bronchiolitis, both respiratory syncytial virus (RSV) and non-RSV, accounts for up to 16% of all hospital admissions, with RSV bearing responsibility for 1 of every 334 hospitalizations.13,14 From 7.4% to 28.0% of children with bronchiolitis require mechanical ventilation. The burden of RSV is more severe at younger age and in patients with chronic disease. Of all RSV admissions, for both bronchiolitis and pneumonia, 4% require intubation and mechanical ventilation.15

Table 2 Causes of hypercarbia Decreased Tidal Volume

Increased Dead Space

Sedative overdose:  Opioid  Benzodiazepine

Hyperinflation  Obstructive airway disease  Asthma  Bronchiolitis  Cystic fibrosis  Excessive PEEP on mechanical ventilator

Neuromuscular weakness  Central nervous system disease  Spinal cord injury/inflammation  Peripheral nerve disorder  Neuromuscular junction disease  Myopathy  Metabolic derangements

Decreased cardiac output  Dehydration  Dysrhythmia  Myocarditis/cardiomyopathy  Post cardiopulmonary bypass

Flail chest (post trauma)

Increased pulmonary vascular resistance Pulmonary embolism

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Respiratory failure in asthmatic individuals has declined over time, as novel therapies have emerged. Current intubation rates vary widely for asthmatic patients, from 5% to 17% based on presentation to a community hospital or tertiary care center, with a higher rate for those presenting to community hospitals.16 MONITORING

Monitoring respiratory function appropriately will help identify the development of respiratory failure as well as guide therapy based on response, and can predict outcome.17 The fundamental and most important assessment of respiratory function is the clinical examination. Respiratory rate and pattern are indicative of the physiologic status of the respiratory system. Tachypnea is often the first sign of respiratory compromise.18,19 Dys-coordinate, paradoxic movement of the chest during breathing is evidence of impending respiratory failure and requires immediate attention.20 Infants and young children may present with grunting in an attempt to increase their positive end-expiratory pressure and maintain functional residual capacity, indicating the presence of restrictive lung disease.21 Cyanosis is evident when greater than 3 to 5 g/dL of deoxygenated hemoglobin is present in arterial blood. This correlates with an arterial saturation of 80% in healthy individuals, but is unreliable in conditions of anemia, or in the presence of abnormal forms of hemoglobin, such as methemoglobin or carboxyhemoglobin. Traditionally, adequacy of gas exchange has been monitored by invasive means, in particular blood gas analysis. The arterial blood gas (ABG) is the gold standard for PO2 determination, as it reliably measures PO2 directly. The percent oxyhemoglobin saturation from a blood gas is highly unreliable, as it is a calculated value based on temperature, PaCO2, pH, and PaO2. Free-flowing capillary blood can accurately assess pH and PaCO2.22–25 Peripheral venous samples are unreliable for estimating pH or PaCO2,22,26,27 and should be avoided for clinical decisions regarding ventilation. Since the 1980s, noninvasive monitoring of oxygenation has been available in the form of pulse oximetry (SpO2). Pulse oximeters are accurate when oxyhemoglobin concentrations are greater than 60%, but may not be reliable in conditions of poor perfusion (ie, septic shock), peripheral vasoconstriction (ie, norepinephrine), hypothermia, peripheral edema, significant extremity movement, or in the presence of methemoglobin or carboxyhemoglobin. Other important clinical data can be interpreted by the pulse oximeter as well, such as heart rate, rhythm, and peripheral perfusion.28,29 The presence of pulsus paradoxus, indicated by respiratory variability in the pulse oximeter plethysmography tracing, correlates with important upper airway obstruction (eg, croup), as well as degree of lower airway obstruction (eg, asthma), and offers a continuous and accurate evaluation of response to therapy (Fig. 1).30,31 Pediatric intensivists frequently substitute pulse oximetry for arterial catheters while caring for critically ill children with respiratory failure, with management decisions and outcomes remaining equal.32 Similarly, ventilation can be monitored continuously and noninvasively. Capnography monitors detect CO2 levels, determined by its unique infrared light absorption characteristics. Capnography can be used at the end of the endotracheal tube in intubated patients or in nonintubated patients by nasal cannula during procedural sedation to assess the quality of ventilation.33–35 Table 3 lists the many clinical uses of capnography waveforms (Fig. 2). Generally, end-tidal CO2 (ETCO2) is about 1 to 3 mm Hg lower than PaCO2 in healthy individuals owing to physiologic dead space ventilation. In fact, the difference between the ETCO2 and PaCO2 directly correlates PEDIATRIC CRITICAL CARE MEDICINE

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Fig. 1. Pulse oximeter waveforms. Solid line: normal. Broken line: evidence of pulsus paradoxus. Arrow indicates inspiration and concordant decrease in peak of plethysmography tracing, indicating cardiovascular consequence of increased work of breathing, generating a more negative intrapleural pressure. This can be seen in upper airway obstruction (ie, infectious croup, postextubation) or lower airway obstruction (ie, asthma) and improves with appropriate therapy.

with the degree of dead space present, and can be used to estimate dead space ventilation according to the Bohr equation: VD/VT 5 (PACO2 – PECO2)/PACO2 Therefore, continuous capnography can be used to detect alterations in dead space ventilation and response to therapeutic interventions. Severe respiratory illness, such as ALI or ARDS, has traditionally been monitored and defined based on the severity of hypoxemia according to invasive measurements of PaO2.36 See Box 2 for diagnostic criteria for ALI/ARDS. The severity of hypoxemia has been determined by the ratio of PaO2 to the fraction of inspired oxygen (PaO2/FiO2). The oxygenation index (OI) is commonly used as a superior indication of oxygenation impairment, as it takes into account the level of ventilatory support provided ([OI 5 FiO2 * mean airway pressure]/PaO2). Unlike in adults, the degree of hypoxemia in children is associated with mortality,1,11,37–40 length of mechanical ventilation,38,39 and the

Table 3 Clinical conditions determined by use of capnography Increase in ETCO2

Decrease in ETCO2

Hypoventilation

Unplanned extubation

Administration of sodium bicarbonate

Endotracheal tube obstruction

Increase in cardiac output

Ventilator disconnection Increased dead space Pulmonary embolism Decreased cardiac output

Continuous capnography also allows for accurate evaluation of respiratory rate, rhythm, and patient-ventilator asynchrony. Abbreviation: ETCO2, end-tidal carbon dioxide.

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Fig. 2. Capnograph (time-based). Solid line: normal. Phase I: dead space (anatomic) gas exhaled from conducing airways; CO2 content near zero. Phase II: mixing of alveolar gas, which contains CO2. Phase III: plateau phase corresponds to pure alveolar gas. Phase IV: rapid fall due to inspiration, with negligible CO2. x and x’: ETCO2. Dotted line: obstructed airway disease. Phase III slopes upward because of delay in emptying of alveolar gas from different lung units owing to increased airway resistance. The upsloping directly correlates with degree of obstruction, and improves with response to bronchodilator therapy. (Data from Krauss B, Deykin A, Lam A, et al. Capnogram shape in obstructive lung disease. Anesth Analg 2005;100(3):884–8; and Yaron M, Padyk P, Hutsinpiller M, et al. Utility of the expiratory capnogram in the assessment of bronchospasm. Ann Emerg Med 1996;28(4):403–7.)

development of chronic lung disease in neonates.41 A significant proportion of children with acute hypoxemic respiratory failure are managed without arterial lines, and therefore cannot be classified as ALI/ARDS.32 Noninvasive correlates of severity of hypoxemia have now been established, as the definition of ALI/ARDS is being reconsidered. The SpO2/FiO2 ratio (substituting SpO2 for PaO2), as well as the OSI (oxygen saturation index, substituting SpO2 for PaO2) are gaining specific attention as validated measures of hypoxemia.42–44 Further, with the use of noninvasive measures, up to 35% more patients could be captured for pediatric studies of ALI.32 THERAPY

Specific aspects of the therapy for respiratory failure vary depending on the underlying cause. In all cases, however, the goal of therapy is to supplement the patient’s Box 2 Consensus criteria for definition of acute lung injury or acute respiratory distress syndrome Acute onset Bilateral infiltrates on chest radiograph Severe hypoxemia resistant to oxygen therapy  PaO2/FiO2 ratio 200 torr (26.6 kPa) for ARDS  PaO2/FiO2 ratio 300 torr (40 kPa) for ALI No evidence of left atrial hypertension  Pulmonary artery occlusion pressure 12 h daily. Chest 2003; 124(1):269–74. 56. Curley MA, Hibberd PL, Fineman LD, et al. Effect of prone positioning on clinical outcomes in children with acute lung injury. JAMA 2005;294(2):229–37. 57. Gattinoni L, Tognoni G, Pesenti A, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001;345(8):568–73. 58. Sud S, Friedrich JO, Taccone P, et al. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med 2010;36(4):585–99. PEDIATRIC CRITICAL CARE MEDICINE

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59. Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute hypoxic respiratory failure in children and adults: a meta-analysis. Anesth Analg 2003;97(4):989–98. 60. Willson DF, Thomas NJ, Markovitz BP, et al. Effect of exogenous surfactant (calfactant) in pediatric acute lung injury. JAMA 2005;293(4):470–6. 61. Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev 2009;(2):CD007836. 62. Duffett M, Choong K, Ng V, et al. Surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis. Crit Care 2007;11(3):R66. 63. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome. JAMA 1998;280(2): 159–65. 64. Meduri GU, Marik PE, Chrousos GP, et al. Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature. Intensive Care Med 2008;34(1):61–9. 65. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 2006;354(24):2564–75. 66. Foland JA, Fortenberry JD, Warshaw BL, et al. Fluid overload before continuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med 2004;32(8):1771. 67. Upadya A, Tilluckdharry L, Muralidharan V, et al. Fluid balance and weaning outcomes. Intensive Care Med 2005;31(12):1643–7. 68. Papazian L, Forel J, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363(12):1107–16. 69. Thill PJ, McGuire JK, Baden HP, et al. Noninvasive positive-pressure ventilation in children with lower airway obstruction. Pediatr Crit Care Med 2004;5(4):337. 70. Beers SL, Abramo TJ, Bracken A, et al. Bilevel positive airway pressure in the treatment of status asthmaticus in pediatrics. Am J Emerg Med 2007;25(1):6–9. 71. Levine DA. Novel therapies for children with severe asthma. Curr Opin Pediatr 2008;20(3):261–5. 72. Piva JP, Menna Barreto SS, Zelmanovitz F, et al. Heliox versus oxygen for nebulized aerosol therapy in children with lower airway obstruction. Pediatr Crit Care Med 2002;3(1):6. 73. Rodrigo G, Pollack C, Rodrigo C, et al. Heliox for nonintubated acute asthma patients. Cochrane Database Syst Rev 2006;(4):CD002884. 74. Leatherman JW, McArthur C, Shapiro RS. Effect of prolongation of expiratory time on dynamic hyperinflation in mechanically ventilated patients with severe asthma. Crit Care Med 2004;32(7):1542–5. 75. Stather DR, Stewart TE. Clinical review: mechanical ventilation in severe asthma. Crit Care 2005;9(6):581. 76. Oddo M, Feihl F, Schaller MD, et al. Management of mechanical ventilation in acute severe asthma: practical aspects. Intensive Care Med 2006;32(4):501–10. 77. Wetzel RC. Pressure-support ventilation in children with severe asthma. Crit Care Med 1996;24(9):1603. 78. Nagakumar P, Doull I. Current therapy for bronchiolitis. Arch Dis Child 2012;97(9): 827–30. 79. McKiernan C, Chua LC, Visintainer PF, et al. High flow nasal cannulae therapy in infants with bronchiolitis. J Pediatr 2010;156(4):634–8. 80. Hammer J, Numa A, Newth C. Acute respiratory distress syndrome caused by respiratory syncytial virus. Pediatr Pulmonol 1997;23(3):176–83. PEDIATRIC CRITICAL CARE MEDICINE

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81. Zabrocki LA, Brogan TV, Statler KD, et al. Extracorporeal membrane oxygenation for pediatric respiratory failure: survival and predictors of mortality. Crit Care Med 2011;39(2):364. 82. Domico MB, Ridout DA, Bronicki R, et al. The impact of mechanical ventilation time before initiation of extracorporeal life support on survival in pediatric respiratory failure: a review of the extracorporeal life support registry. Pediatr Crit Care Med 2012;13(1):16. 83. Ghuman AK, Newth CJL, Khemani RG. The association between the end tidal alveolar dead space fraction and mortality in pediatric acute hypoxemic respiratory failure. Pediatr Crit Care Med 2012;13(1):11. 84. DiCarlo JV, Alexander SR, Agarwal R, et al. Continuous veno-venous hemofiltration may improve survival from acute respiratory distress syndrome after bone marrow transplantation or chemotherapy. J Pediatr Hematol Oncol 2003;25(10):801. 85. Roberts JS, Bratton SL, Brogan TV. Acute severe asthma: differences in therapies and outcomes among pediatric intensive care units. Crit Care Med 2002;30(3): 581. 86. Bratton SL, Newth CJL, Zuppa AF, et al. Critical care for pediatric asthma: wide care variability and challenges for study. Pediatr Crit Care Med 2012;13(4): 407–14. 87. Knoester H, Grootenhuis MA, Bos AP. Outcome of paediatric intensive care survivors. Eur J Pediatr 2007;166(11):1119–28. 88. Weiss I, Ushay HM, DeBruin W, et al. Respiratory and cardiac function in children after acute hypoxemic respiratory failure. Crit Care Med 1996;24(1):148. 89. Golder N, Lane R, Tasker R. Timing of recovery of lung function after severe hypoxemic respiratory failure in children. Intensive Care Med 1998;24(5):530–3. 90. Fanconi S, Kraemer R, Weber J, et al. Long-term sequelae in children surviving adult respiratory distress syndrome. J Pediatr 1985;106(2):218–22. 91. Ben-Abraham R, Weinbroum AA, Roizin H, et al. Long-term assessment of pulmonary function tests in pediatric survivors of acute respiratory distress syndrome. Med Sci Monit 2002;8(3):CR153–7. 92. Ghio AJ, Elliott CG, Crapo RO, et al. Impairment after adult respiratory distress syndrome: an evaluation based on American Thoracic Society recommendations. Am J Respir Crit Care Med 1989;139(5):1158–62. 93. Hudson LD. What happens to survivors of the adult respiratory distress syndrome? Chest 1994;105(Suppl 3):123S–6S. 94. Dahlem P, Van Aalderen W, Bos A. Pediatric acute lung injury. Paediatr Respir Rev 2007;8(4):348–62.

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Advances in Monitoring and Management of Pediatric Acute Lung Injury Ira M. Cheifetz,

MD, FCCM

a,b,c,

*

KEYWORDS  Mechanical ventilation  Acute lung injury  Acute respiratory distress syndrome  Gas exchange  Pediatric  Hypoxia  Hypercapnia  Capnography KEY POINTS  Infants and young children are particularly prone to acute respiratory failure because of multiple physiologic factors including small airways (both natural and artificial), weak and ineffective cough clearance, high chest wall compliance, and low diaphragmatic efficiency.  A key point in the management of the patient with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is that increased oxygenation does not correlate with improved outcome, which has been shown in studies with low tidal volume ventilation, inhaled nitric oxide, and prone positioning.  Low tidal volume ventilation in the adult population with 6 mL/kg ideal body weight is the only approach for ALI that has been shown to reduce mortality.  Although various modes of ventilation are currently used in clinical practice, to date, no data exist to determine the mode that provides the greatest benefit and the least risk to an individual patient, including those with ALI/ARDS.  Airway graphic analysis and capnography may be useful monitoring tools to assist with optimal ventilatory management, including optimizing patient-ventilator interactions.

INTRODUCTION

Acute respiratory failure accounts for more than half of the admissions to pediatric critical care units and is a major cause of morbidity and mortality.1 Because the causes of acute respiratory failure in the pediatric population are diverse, this article focuses on the respiratory management and monitoring of pediatric acute lung injury (ALI) as a specific cause for respiratory failure. It should be noted from the start that definitive, randomized, controlled trials in pediatrics to guide the intensivist in the optimal a

Pediatric Critical Care Medicine, Duke University Medical Center, Box 3046, Durham, NC 27710, USA; b Pediatric Intensive Care Unit, Pediatric Respiratory Care and ECMO, Duke Children’s Hospital, Box 3046, Durham, NC 27710, USA; c Pediatric Critical Care Services, Duke University Health System, Box 3046, Durham, NC 27710, USA * Pediatric Critical Care Medicine, Duke Children’s Hospital, Box 3046, Durham, NC 27710. E-mail address: [email protected]

Pediatr Clin N Am 60 (2013) 621–639 http://dx.doi.org/10.1016/j.pcl.2013.02.015 pediatric.theclinics.com 0031-3955/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

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Cheifetz

ventilatory approach for an individual infant or child with acute respiratory failure and ALI are lacking. Because much of the respiratory management for this critically ill pediatric population is influenced by data from adult patients, it must be stressed that children are not simply small adults, and, similarly, infants are not simply small adolescents. It is important to stress the basic physiologic differences between these populations. Infants and young children are particularly prone to develop acute respiratory failure because of multiple physiologic factors. Overall, from a respiratory perspective, younger children have smaller airways (both natural and artificial), weaker and less effective cough clearance, greater chest wall compliance, decreased diaphragmatic efficiency, and thus are at a higher risk for airway occlusion. More specifically, younger patients have reduced elastic alveolar recoil, which can result in increased collapse, especially in the presence of decreased pulmonary compliance. In addition, they have fewer alveoli and collateral ventilation channels to allow ventilation distal to obstructed airways.2 An infant’s chest wall has greater compliance, making it more difficult to generate a significant negative intrathoracic pressure in the presence of decreased lung compliance. The weaker cartilaginous airway support in infants and young children may lead to dynamic compression (and subsequent airway obstruction) in conditions associated with high expiratory flow rates and increased airway resistance, such as bronchiolitis and asthma. The pediatric airway is also significantly narrower than the adult airway, thus contributing to the development of increased airway resistance and, potentially, secretion-induced obstruction. Despite these potential disadvantages of the pediatric pulmonary system, the progression of acute respiratory failure to acute respiratory distress syndrome (ARDS) is less likely to occur than in adults.3,4 In contrast with the 1994 American-European Consensus Conference definition of ALI and ARDS,5 the 2011 Berlin Definition (Table 1) specifies the timeframe for the development of ARDS, better defines the nature of infiltrates on chest radiographs,

Table 1 Berlin definition of ARDS Time of onset of respiratory symptoms

Known clinical cause within prior week or new/worsening respiratory symptoms

Radiological findings

Bilateral opacities (chest radiograph or CT scan) not explained by lobar collapse, pleural effusion, or nodules

Degree of hypoxemia

PEEP  5 cm H2O: Mild ARDS: PaO2/FiO2 201–300 torr (maybe CPAP >5 cm H2O if noninvasively ventilated) Moderate ARDS: PaO2/FiO2  200 torr Severe ARDS: PaO2/FiO2  100 torr

Risk factors

Risk factors for ARDS must be present. Respiratory failure cannot be fully explained by cardiac failure or fluid overload. If no ARDS risk factors are present, objective assessment of cardiac function (eg, echocardiography) is required to exclude cardiac causes

Abbreviations: CPAP, continuous positive airway pressure; CT, computed tomography; FiO2, fraction of inspired oxygen; PEEP, positive end-expiratory pressure. Data from Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526–33; and Ferguson ND, Fan E, Camporota L, et al. The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med 2012;38(10):1573–82.

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incorporates positive end-expiratory pressure (PEEP) in the definition of the severity of hypoxemia, minimizes the need for invasive pulmonary artery measurements in the presence of cardiac risk factors, and integrates ALI into a subgroup of mild ARDS.6,7 A comprehensive pediatric ALI consensus initiative is in progress under the leadership of the Pediatric Acute Lung Injury and Sepsis Investigator (PALISI) Network. GAS EXCHANGE

The overall goal of the management of ALI/ARDS is to treat the underlying disease process whenever possible, achieve adequate (but not necessarily maximal) tissue and organ oxygenation, and avoid pulmonary and nonpulmonary complications. Every patient with ALI is hypoxemic by definition and thus requires supplemental oxygen and often noninvasive or invasive mechanical ventilation. An appropriate level of tissue and organ oxygen delivery is provided by ensuring adequate cardiac output and arterial oxygen content, while avoiding excessive oxygen consumption. A key point in the management of the patient with ALI/ARDS is that increased oxygenation does not correlate with improved outcome, which is shown by the ARDS Network low tidal volume clinical investigation in which the intervention group (6 mL/kg) showed improved survival despite decreased oxygenation compared with the control group (12 mL/kg) for the initial 72 hours of ventilation.8 This lack of association between increased oxygenation and survival has been shown in other clinical studies as well.9–12 Timmons and colleagues12 showed no correlation between oxygenation and survival for pediatric ALI. Dobyns and colleagues9,10 showed that inhaled nitric oxide (iNO) improved oxygenation but did not affect mortality for pediatric acute respiratory failure during conventional or high-frequency oscillatory ventilation (HFOV). In addition, Curley and colleagues11 showed no survival benefit with prone positioning despite improved gas exchange. Permissive Hypoxemia

In contrast with maximizing arterial oxygenation, the concept of permissive hypoxemia accepts lower arterial oxygenation saturation (SaO2) in an attempt to avoid toxic ventilator support.13 Although the acceptable SaO2 target remains controversial, most agree with the concept that ventilatory approaches should target adequate tissue and organ oxygenation, while minimizing O2 toxicity and ventilator-induced lung injury. Definitive data to determine the optimal oxygenation level for pediatric patients are not available. The minimally acceptable oxygenation level likely varies throughout the range of the pediatric population, with neonates and adolescents potentially being more vulnerable to hypoxia than others. Because long-term neurologic effects of permissive hypoxemia have not been studied, clinicians should weigh the potential benefits and risks of this approach for each individual clinical situation. Permissive Hypercapnia

A logical consequence of low tidal volume ventilation (as described later) is hypercapnia. The degree of respiratory acidosis that can be safely tolerated remains controversial and likely varies between patients. However, most adverse effects associated with respiratory acidosis are minor and reversible when pH is maintained greater than approximately 7.20.14 Laboratory data from an ischemia-reperfusion model of ALI indicate that hypercapnic acidosis may be protective and that buffering attenuates its protective effects.15 Limited evidence suggests that low-volume ventilation allowing for permissive hypercapnia may improve outcomes in adult ARDS.16–18 However, PEDIATRIC CRITICAL CARE MEDICINE

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a Cochrane Review of the multicenter ARDS low tidal volume studies was unable to conclusively determine the clinical implications of permissive hypercapnia.19 Because these studies were not designed to answer the specific question of hypercapnia, the review stressed the many confounding variables in ALI management. Despite the lack of definitive data, permissive hypercapnia is used for the management of severe ARDS in many intensive care units (ICUs). However, permissive hypercapnia is generally not recommended for those with intracranial disorders in which increased cerebral blood flow related to hypercapnia may be detrimental, or significant pulmonary hypertension in which an increased carbon dioxide level may further increase pulmonary vascular resistance. MECHANICAL VENTILATION Noninvasive Ventilation

Pediatric noninvasive ventilation (NIV), mechanical respiratory support without an endotracheal tube (ETT), is being increasingly used for acute hypoxemic respiratory failure in an attempt to avoid the negative aspects of intubation and invasive ventilation. Unlike the adult and neonatal populations, definitive data on the success of NIV in pediatrics remain limited. NIV for adults with acute respiratory failure secondary to pneumonia has been reported to be unsuccessful.20 However, several nonrandomized reports have suggested that NIV may improve symptoms, augment gas exchange, and reduce the need for intubation without significant adverse events for pediatric acute respiratory failure.21–26 A high forced inspiratory oxygen (FiO2) requirement or an increased PaCO2 early in the course of NIV seem to be the best independent predictors for failure of this approach.27 In pediatrics, much of the available NIV data are in relation to acute asthma exacerbations. Among children with asthma exacerbations who required mechanical respiratory support, significantly more (41% vs 25%) were treated with noninvasive than invasive ventilation.28 Other small clinical studies have reported the successful use of NIV in children with asthma exacerbations.29–32 These reports note that NIV was generally well tolerated without major complications and was associated with improvement in gas exchange and respiratory effort. Martinon-Torres33 described the use of helium-oxygen (heliox) in children with increased airways resistance.33 Other pediatric subgroups that have benefited from NIV include those with compromised immune systems,21,22,34–37 acute chest syndrome,22,38 and postoperative respiratory failure.22–24,39–41 In a more limited population, NIV after liver transplantation decreased the need for reintubation and may have led to shorter ICU length of stay.42 One of the biggest challenges to the effective use of NIV for infants and small children is the lack of a sufficient choice of interfaces.43 The choice of interface and the available options are largely determined by patient age and underlying pathophysiology. Patient discomfort is the most common reason for changing the interface used.43 With recent improvements in technology and interfaces, it can be anticipated that an increased use of NIV for pediatric acute hypoxemic respiratory failure, including ALI, will occur. With this anticipated trend, it is hoped that a concomitant increase in clinical outcome data will occur as well. Invasive Ventilation Low tidal volume ventilation

ALI is a heterogeneous entity with regions of lung that are collapsed and others that are overdistended. Thus, large tidal volume ventilation can result in regional pulmonary overdistention and progressive secondary lung injury. Preclinical studies provided PEDIATRIC CRITICAL CARE MEDICINE

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initial insight into the pathophysiology of ventilation-induced lung injury by showing that large tidal volume ventilation caused rapid pulmonary changes despite normal lungs at baseline.44,45 Ventilator settings that resulted in excessive pulmonary stretch led to diffuse alveolar damage with resultant pulmonary edema, an inflammatory response, and leakage of immune modulators into the systemic circulation with subsequent multiorgan dysfunction.46–50 Many argue that the only ventilatory approach to conclusively reduce mortality for adult ALI/ARDS is low tidal volume ventilation,8 and that the current adult ALI/ARDS strategy should be focused on a 6 mL/kg (predicted body weight) tidal volume. Although the ARDS Network study showed that 6 mL/kg improved mortality compared with 12 mL/kg, the tidal volume associated with the least mortality may be between 6 and 12 mL/kg, or possibly lower than 6 mL/kg. The plateau pressure (Pplat) in the ARDS Network study was significantly lower in the low tidal volume intervention group.8 Debate continues as to whether the key variable is tidal volume or Pplat, or possibly both. Based on the medical literature, it seems optimal to maintain tidal volume at 6 mL/kg and Pplat less than 30 to 32 cm H2O for adults with ALI/ARDS.8,51–53 The lower safe limit for plateau pressure in pediatrics may be even less. Gajic and colleagues54 further showed the benefits of low tidal volume ventilation. The risk of an adult with previously normal lungs developing ALI while mechanically ventilated is directly proportional to the size of the delivered breath. Adults with previously normal lungs ventilated with tidal volumes less than or equal to 9 mL/kg were less likely to develop ALI while ventilated than those with larger volumes. It is not known whether the less injurious effects of lower tidal volumes are linear at less than 9 mL/kg or whether a plateau effect occurs. These investigators suggest that most (and possibly all) mechanically ventilated adults should be managed with a low tidal volume strategy to avoid excessive pulmonary stretch. Until a definitive randomized, controlled pediatric trial occurs, it is reasonable to ventilate infants and children with ALI/ARDS with 6 mL/kg predicted body weight. This approach is supported by some pediatric data55 because mortality for pediatric ALI decreased by 40% with lower tidal volumes, although this conclusion is weakened by the retrospective study design. Two mechanically ventilated cohorts were studied based on year: 1988 to 1992 versus 2000 to 2004. Patients from the earlier period were ventilated with larger tidal volume, lower PEEP, and higher peak inspiratory pressure (PIP) than in the more recent period. Mortality was lower (21% vs 35%, P 5 .04) and ventilator-free days increased (16.0  9.0 vs 12.6  9.9 days, P 5 .03) in the more recent time period. Significant study limitations include the retrospective design, tidal volume measurement at the expiratory valve without consideration of the volume lost because of the distensibility of the circuit, and tidal volume calculations as measured per actual (rather than predicted) body weight. Beyond the tidal volume differences, PEEP and PIP management varied between the two cohorts of patients. As previously noted, definitive low tidal volume ventilation data are lacking for pediatric patients with injured, or normal, lungs. Thus, the pediatric clinician can extrapolate from adult data and/or rely on clinical experience plus the limited, nondefinitive pediatric data. Some may argue that infants and children are different than adults, and, thus, the available tidal volume data do not apply. However, the counter argument is that the potential benefits of low tidal volume ventilation for infants and children seem real and the risks, if any, are theoretic. Thus, many intensivists have adopted a low tidal volume ventilation approach for pediatric ALI/ARDS. For infants and children with normal lungs, extrapolation of the adult data suggests ventilation with a tidal volume less than or equal to 9 mL/kg; whereas the tidal volume should PEDIATRIC CRITICAL CARE MEDICINE

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likely be 6 mL/kg for injured lungs. It seems that the critical limit for Pplat in pediatrics is less than 30 to 32 cm H2O and may vary with patient age and size. An important issue directly related to low tidal volume ventilation is the increasing incidence of pediatric obesity. When determining the appropriate tidal volume, the clinician must use predicted (ideal) body weight. Several Internet programs provide calculators for pediatric ideal body weight for children as young as 12 months old. As an alternative, the predicted body weight for a child can be calculated by using the 50th percentile weight for height on the appropriate growth chart based on gender and age. Modes of mechanical ventilation

Various modes of ventilation are currently used in clinical practice. Most patients in pediatric ICUs (PICUs) who require conventional mechanical ventilation are managed with a traditional volume-limited or pressure-limited mode with a synchronized intermittent mechanical ventilation (SIMV) or an assist control approach. To date, no data exist to determine the mode that provides the greatest benefit and the least risk to an individual patient, including those with ALI/ARDS.56–62 The lack of definitive evidence to support a single ventilatory approach in combination with efforts to improve clinical outcome have led to the development of several innovative modes of ventilation. One important area of emphasis for many of these novel modes is the maintenance of spontaneous respiration and improved patient-ventilator synchrony. Neurally adjusted ventilatory assist (NAVA), proportional assist ventilation (PAV), and airway pressure release ventilation (APRV) represent nontraditional modes that are the subject of investigation and much discussion. However, the impact of these novel approaches on clinical outcome remains uncertain.63–68 It remains unclear whether these new ventilatory modes provide an outcome advantage compared with the more traditional approaches. Until definitive data become available, practitioners must carefully consider the clinical circumstances of each clinical situation as well as the potential advantages and disadvantages of the available ventilatory methodologies and use their best clinical judgment. In most pediatric ICUs, the mode of ventilation chosen for a patient is often determined by institutional purchasing decisions and individual clinician preference. As ventilator technology advances, pediatric clinicians will continue to see the development of novel modes and ventilatory techniques. Despite considerable advancements in technology, no mode of ventilation has been shown to be superior to any other. Despite the lack of convincing evidence, there are likely circumstances in which a specific mode may be assumed to be optimal based on evaluation of airway graphic analysis and assessment of the pathophysiology. The challenge becomes one of matching a patient’s pathophysiology to the presumed optimal approach to ventilation. Additional clinical investigation is needed to determine the impact of novel techniques and ventilatory modes but, until additional data are available, practitioners must carefully consider individual clinical circumstances and the potential implementation of the available ventilatory methodologies while using their best clinical judgment. Regardless of the ventilator strategy/modality used, airway graphic analysis should be remembered in an attempt to optimize patient and ventilator interactions and minimize ventilator-induced lung injury while promoting patient comfort. HFOV When toxic’ conventional mechanical ventilation support is required to achieve the desired gas exchange goals, HFOV is often considered. In 1994, a randomized, controlled pediatric HFOV clinical trial showed improved oxygenation and reduced PEDIATRIC CRITICAL CARE MEDICINE

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supplementation oxygen requirements at 30 days with HFOV.69 However, the control group used a high tidal volume approach, and, thus, the application of these results in the current era of low tidal volume ventilation remains uncertain. Despite the paucity of definitive data, the use HFOV for pediatric ALI/ARDS remains common.70–73 In the adult population, HFOV has been shown to be equivalent to lung-protective, low tidal volume conventional ventilation.74–78 The use of HFOV in the adult population has steadily increased but remains controversial. A meta-analysis concluded that HFOV might improve survival and is unlikely to cause harm.78 This may be the best conclusion for HFOV in the pediatric and adult populations until new outcome data become available. It should be noted that an adult HFOV clinical trial has recently been completed. PEEP Determining optimal PEEP remains an essential component of ALI/ARDS ventilator management. PEEP maintains alveolar patency, restores functional residual capacity, and maintains transthoracic pressure at greater than the level at which additional alveoli collapse during expiration. During the initial phase of inspiration, reexpansion of collapsed alveoli (if present) occurs. In alveolar collapse, airway pressure must substantially increase before a volume of gas is delivered (ie, the recruitment interval). Poor pulmonary compliance with alveolar collapse results an increased risk of barotrauma and secondary lung injury caused by the resultant increased PIP for the same tidal volume delivery and inspiratory time. Although multicenter, randomized studies of adult ALI/ARDS have addressed this important clinical issue of PEEP titration, definitive data in pediatrics are limited.79–82 A randomized, multicenter study by the ARDS Network,79 in follow-up to the low tidal volume investigation, showed that an aggressive PEEP strategy resulted in similar survival compared with a more conservative approach, although arterial oxygenation and pulmonary compliance were improved with higher PEEP. The conservative PEEP group was not a low-PEEP approach but one of adequate PEEP. In addition, all patients were ventilated with 6 mL/kg and an end-inspiratory pressure limit of 30 cm H2O. Safety concerns were not raised regardless of PEEP group assignment. Follow-up studies have revealed similar findings.80,81 The implication of these data is that, once appropriate PEEP is applied to maintain the lungs at an ideal lung volume, further increases in PEEP do not improve outcome. Briel and colleagues82 subsequently analyzed data from the 2299 patients enrolled in the PEEP trials by Brower and colleagues,79 Meade and colleagues,80 and Mercat and colleagues.81 A higher PEEP strategy benefited those with more severe lung injury.82 The study also concluded that higher PEEP may be associated with a shorter length of ventilation and lower hospital mortality in adults with ARDS. This improvement was not seen in those who did not meet the accepted criteria for ARDS.82 Furthermore, this study suggests that increased PEEP may be associated with a longer duration of ventilation in those with less severe lung injury. Without definitive pediatric data, PEEP is generally increased to a level that allows adequate oxygenation at an acceptable FiO2 (generally defined as 12 y

≤23

24-27

≥28

Respiratory rate

O2 requirement

>95% on room air

90%-95% on room air

Retractions

None or intercostal

Intercostal and substernal Intercostal, substernal, and supraclavicular

Work of breathing (count to 10)

Speaks in sentences, coos and babbles

Speaks in partial sentences, short cry

Speaks in single words/short phrases, grunting

Auscultation

Normal breath sounds to end-expiratory wheezes only

Expiratory wheezing

Inspiratory and expiratory wheezing to diminished breath sounds

in children with severe asthma associated with large fluctuations in intrathoracic pressures. The use of half normal saline or isotonic solution in dextrose is preferred in the pediatric population. Steroids Corticosteroids are the first line of treatment for severe acute asthma, because of the inflammatory process.65 Steroids control airway inflammation through a number of mechanisms,66 such as reducing the number and activation of lymphocytes, eosinophils, mast cells, and macrophages; suppressing the production of cytokines, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, adhesion molecules, and inducible enzymes, including nitric oxide synthase and cyclooxygenase-2.67 Mucous production is decreased, and inflammatory cell infiltration and activation are reduced. 68,69 In children with severe acute asthma, systemic corticosteroids are indicated and in the intensive care unit (ICU) setting the intravenous route is preferred.70 Methylprednisolone is a widely used agent because of its limited mineralocorticoid effect.71 The previous National Asthma Education and Prevention Program (NAEPP), still in use by some centers, recommended an initial methylprednisolone loading dose of 2 mg/kg followed by 0.5 to 1 mg/kg every 6 hours.72 Nevertheless, the new dose recommendation for asthma exacerbations by the current NAEPP (2007) review is 1 to 2 mg/kg/day (maximum 60 92

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30 kg give 15 -45 mg/hr

3

IV Magnesium

25 to 50 mg/kg/dose (max 2 g) infused over 20 to 30 min. Follow by continuous infusion of 15-25 mg/kg/hr. Mg level ≈ 4 mg/dL. Monitor for hypotension.

4

Heliox

Provide O using non-rebreathing mask. May combine O by nasal 2 2 cannula if necessary to keep SaO > 92%. 2

5

IV Terbutaline

Loading dose of 10 mcg/kg over 10 min followed by 0.4 mcg/kg/min. Increase by 0.4 mcg/kg/min every 15 min. Range 0.1 to 10 mcg/kg/ min (average dose is 4 mcg/kg/min)

6

IV Theophylline

Loading dose of 5 mg/kg over 20 min followed by continuous infusion of 0.5-1 mg/kg/hr. Check serum theophylline concentration 30 min after the end of the loading dose. Target theophylline concentration is 10-20 mg/L

7

Non-Invasive Ventilation

Consider BiPAP to unload WOB. IPAP:10 EPAP:5

8

IV Ketamine

1 mg/kg/hr for sedation. Bronchodilatory properties. Increase airway secretions.

9

Intubation

Ketamine + Midazolam + Rocuronium

10

Ventilation

Try to avoid neuromuscular blockade. Permissive hypercapnia. PC/ PRVC/PSV. Monitor peak to plateau pressure difference.

Figure. Severe acute asthma stepwise approach for escalating therapy. BiPAP, bilevel positive airway pressure; EPAP, Expiratory Positive Airway Pressure; IPAP, Inspiratory Positive Airway Pressure; Mg, Magnesium; O2, oxygen; PC, Pressure Controlled Ventilation; PRVC, Pressure Regulated Volume Control; PSV, Pressure Support Ventilation; SaO , saturation level of oxygen; WOB, work of breathing 2

of muscle tone. cAMP inhibits the release of calcium ion from intracellular stores and reduces the membrane calcium entry and its intracellular sequestration, leading to airway smooth muscle relaxation.80,81 Alternative, cAMP independent pathways involving the activation of membrane maxi-potassium channels through Gi to the MAP kinase system have also been described.82 The most reported adverse drug reactions with β-agonists are tachycardia, tremors, and nausea. Cardiovascular effects include diastolic hypotension,83 arrhythmias, and prolonged QTc interval with hypokalemia.84 Hypokalemia is the result of intracellular potassium shifting from an increased number of sodium-potassium pumps.85 Albuterol Albuterol is a 50:50 racemic mixture of R-albuterol and S-albuterol. The R-enantiomer is pharmacologically active, whereas the S-enantiomer is considered inactive and has a longer elimination J Pediatr Pharmacol Ther 2013 Vol. 18 No. 2 • www.jppt.org

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half-life. Levalbuterol is the pure R-enantiomer as a preservative-free solution. In comparison trials the use of equivalent doses of levalbuterol was not superior to albuterol.85,86 Albuterol remains the drug of choice for treatment of severe acute asthma in the ICU owing to its lower cost and similar efficacy. Continuous β2-agonist nebulization is considered to be superior87 or at least equivalent88 to intermittent treatment89 for severe asthma and was not associated with severe cardiotoxicity.90–93 Transient increase in creatinine phosphokinase without evidence of cardiotoxicity during continuous albuterol nebulization has been reported.94 Continuous nebulization offers more comfort to patients and is more cost-effective.95 From the amount of drug that can be delivered per hour of nebulized treatment, approximately 25% of the dose will reach the lungs.96 The usual dose for continuous albuterol nebulization ranges from 0.15 to 0.5 mg/kg/h. Larger doses of continuous albuterol nebulization for near-fatal asthma have 93

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JPPT been used,97 although we generally do not exceed maximum rates of 30 mg/h. In our institution we use conventional continuous-output nebulizer devices with oxygen. Terbutaline Intravenous β2-agonist should be considered in patients who are not improving with continuous albuterol nebulization,98 probably owing to decreased respiratory flow and tidal volume resulting in a reduction of drug delivery to the small airways. Terbutaline is considered the drug of choice in the United States, although intravenous albuterol and other β2-agonists are also available elsewhere. Subcutaneous terbutaline is preferred because there are fewer adverse drug reactions when compared to epinephrine.99 Subcutaneous terbutaline sulfate has been recommended for hospitalized children or adolescents older than 12 years with asthma exacerbation, at a dose of 0.25 mg every 20 minutes for a total of 3 doses,55 as well as for children 12 years of age or younger at a dose of 0.01 mg/kg (maximum dose, 0.25 mg) every 20 minutes for a total of 3 doses, repeated every 2 to 6 hours as needed.55 To accelerate the therapeutic effect, an intravenous loading dose of 2 to 10 mcg/kg infused for 10 minutes is recommended, followed by a continuous infusion of 0.1 to 10 mcg/kg/min.83 Because of differences in drug metabolism and clinical effect among patients, dose adjustment should be assessed at regular intervals. Usually the starting dose is 0.4 mcg/kg/min; it is titrated to achieve the desired clinical effect with increments of 0.2 to 0.4 mcg/ kg/min every 15 to 30 minutes depending on the patient’s clinical response and on adverse drug reactions.100 Monitoring the patient for the side effects of tachycardia, arrhythmias, diastolic hypotension, hypokalemia, or (rarely) myocardial ischemia is more important in patients receiving continuous infusions of β-adrenergic agonists. Ipratropium Ipratropium bromide is a quaternary ammonium atropine derivative that does not cross the blood-brain barrier, precluding the manifestation of central anticholinergic effects. Ipratropium can produce bronchodilatation by inhibition of cholinergic-mediated bronchospasm, occurring without the inhibition of mucociliary clearance.101 The parasympatholytic effect is produced by 94

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IFF Nievas, et al

blocking acetylcholine interaction with the muscarinic receptors on bronchial smooth muscle cells and reducing intracellular cyclic guanosine monophosphate concentrations that impair bronchoconstriction. Nebulized anticholinergic agents are considered an important adjunct in the treatment of moderate to severe asthma exacerbation in the ED setting.102–104 After 1 dose of steroids, the use of ipratropium with the second and third albuterol doses was associated with clinical improvement and decreased hospital admission rates,105 compared with albuterol and corticosteroids alone.106,107 Nebulized ipratropium, in 0.25 to 0.50 mg doses, can be used every 20 minutes during the first hour, followed by the same dose range every 6 hours.108–110 Systemic effects are usually minimal; nevertheless, mydriasis and blurred vision have been reported.111,112 Although there is no significant apparent benefit with the addition of multiple doses of ipratropium to an albuterol and steroid regimen in hospitalized pediatric patients,113,114 there is a need for specific data in the PICU population. With the high safety profile and documented beneficial effects in the ED setting,115 we recommend its use every 6 hours in the critically ill patient owing to its potential advantages, despite not being recommended by the current National Heart, Lung, and Blood Institute asthma guidelines, until further data are obtained.55 Magnesium Sulfate Magnesium is a calcium antagonist that causes smooth muscle relaxation as a result of the inhibition of calcium uptake.116 With respect to asthmatic patients, mechanisms such as the inhibitory action on smooth muscle contraction,117 histamine release from mast cells,118 acetylcholine release from nerve terminals,119 and sedative action65,120 may contribute to its therapeutic effects. From current data, magnesium sulfate is likely to improve bronchospasm and consequent clinical symptoms and reduce hospitalization in children with moderate to severe acute asthma when added to classic therapy.121 Some studies122–124 have shown clinical improvement in patients with severe asthma receiving intravenous magnesium infusion. The usual dose of magnesium sulfate in children with severe acute asthma is 25 to 50 mg/ kg/dose (maximum 2 g), infused for 20 to 30 minutes.125–127 A larger loading dose of magneJ Pediatr Pharmacol Ther 2013 Vol. 18 No. 2 • www.jppt.org

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Escalating Therapy for Acute Asthma in Children

sium sulfate has been recommended128 to achieve serum magnesium concentrations between 3 to 5 mg/dL. For the treatment of acute asthma exacerbation refractory to conventional therapies, an initial bolus dose of 50 mg/kg (maximum dose, 2 g) infused for 20 to 30 minutes is recommended, followed by continuous infusion dependent on the patient’s weight. Children weighing less than 30 kg may receive an infusion of 25 mg/kg/h and children weighing more than 30 kg may receive 20 mg/kg/h, although infusion rates must not exceed 2 g/h in any patient.129 Titration to the desired clinical effect should be based on serum magnesium concentrations and tolerability. Adverse drug reactions, such as nausea, flushing, somnolence, vision changes, muscle weakness, and hypotension, were reported with magnesium concentrations above 9 mg/dL.130 Severe adverse reactions such as respiratory depression and arrhythmias occurred with concentrations above 12 mg/dL.36 Methylxanthines Methylxanthines are formed by the methylation of xanthines, such as theophylline. The combination of theophylline and ethylenediamine generates a water-soluble salt, aminophylline. The proposed mechanism for bronchodilatation involves the non-selective inhibition of phosphodiesterase isoenzymes,131 in particular, the inhibition of phosphodiesterase-IV, which reduces the intracellular degradation of cAMP.132 Other mechanisms include increased respiratory drive and diaphragmatic contractility,133 stimulation of endogenous catecholamine release,134 prostaglandin antagonism,135 and inhibition of afferent neuronal activity.136 In addition, theophylline is known to have anti-inflammatory and immunomodulatory effects, although the contributions of these mechanisms to its therapeutic effects in children with asthma have not been studied.137,138 The therapeutic range for theophylline is narrow, 10 to 20 mcg/mL, and overlaps with toxicity concentrations, which occurs above 15 mcg/mL.139 We recommend titration of dosing to a peak concentration of 10 to 15 mcg/mL. However, at a concentration above 5 mcg/mL bronchodilatory and anti-inflammatory effects were detected.140 The theophylline dose is 80% of the aminophylline dose. A loading intravenous dose, 5mg/kg of theophylline or 6 mg/kg of aminophylline, given during 20 minutes is needed to J Pediatr Pharmacol Ther 2013 Vol. 18 No. 2 • www.jppt.org

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JPPT achieve a therapeutic concentration.97 Assuming an average volume of distribution, 1 mg/kg of theophylline or 1.25 mg/kg of aminophylline increases serum concentration by 2 mcg/mL. After the loading dose, a continuous infusion should be started. The drug clearance is decreased in neonates and infants, and, therefore, infusion rates are based on patient age. Recommended doses for infants younger than 6 months are 0.5 mg/kg/h; for infants 6 months to 1 year, 0.85 to 1 mg/kg/h; for children 1 to 9 years, 1 mg/ kg/h; and for children older than 9 years, 0.75 mg/kg/h.141 These recommended doses are for patients with normal cardiac and liver functions. Serum drug concentrations should be obtained 30 to 60 minutes after the loading dose is finished, and again at 12 hours after the beginning of the continuous infusion, to check for steady-state concentrations, and then every 12 to 24 hours or when toxicity is suspected. Theophylline clearance possibly will be decreased in patients with acute pulmonary edema, congestive heart failure, cor pulmonale, fever, hepatic disease, hypothyroidism, sepsis with multiorgan failure, neonates, infants younger than 3 months with decreased renal function, children younger than 1 year, and patients after cessation of smoking or substantial second-hand smoke exposure. Many drugs decrease theophylline clearance. The most common are erythromycin, cimetidine, and oral contraceptives. Azithromycin has no effect on theophylline clearance because of the absence of interactions with cytochrome P450.142 Theophylline should be used for children with severe acute asthma exacerbation with impeding respiratory failure, or those on mechanical ventilation who are already getting other bronchodilator or anti-inflammatory therapies.143,144 Helium-Oxygen Mixture (Heliox) Helium is a low-density gas that, when used in a mixture with oxygen, reduces turbulent airflow, enhancing laminar flow and in consequence reducing airflow resistance.145 Limited evidence exists for the efficacy of helium-oxygen mixtures (i.e., heliox), typically 70%:30% or 79%:21%, in children with severe acute asthma. It has been demonstrated that heliox promotes a greater delivery and percentage of particle retention from nebulized albuterol.146 Furthermore, a superior clinical improvement was associated with heliox use than with oxygen-driven continuous 95

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IFF Nievas, et al

Table 2. Albuterol Dosage (0.5% Albuterol, 5 mg/mL) and Mixing Proportions for Continuous Albuterol Q1

Q2

4 h* (mL)

8 h† (mL)

mL/h

mg

mL

mg

ALB

NS

ALB

NS

6 5 4 3 2

30 25 20 15 10

12 10 8 6 4

60 50 40 30 20

24 20 16 12 8

76 80 84 88 92

48 40 32 24 16

152 160 168 176 184

ALB, Albuterol; NS, Normal Saline (0.9%) * ALB + NS = 100 mL total † ALB + NS = 200 mL total

albuterol in children with moderate to severe asthma.147 Nevertheless, other studies148,149 failed to show a decrease in length of hospital stay or a significant clinical improvement. Heliox reduces peak airway pressures when used in patients who require mechanical ventilation, presumably by allowing hyperinflated alveoli to decompress during expiration and reducing the functional residual capacity of patients with asthma.150 The existing evidence does not provide support for the routine use of helium-oxygen mixtures to all ED patients with acute asthma. However, new evidence suggests certain beneficial effects in patients with more severe airway obstruction.151 Given the relatively small patient numbers and few studies, there is still a role for heliox trials in refractory severe acute asthma.152,153 Ketamine Ketamine, a non-competitive N-methyl-Daspartate receptor antagonist, is used routinely as an anesthetic, analgesic, and sedative owing to its wide therapeutic index and favorable hemodynamic effects. 154,155 The bronchodilatory effects of ketamine were noted with its early use,156 although a randomized, doubleblind, placebo-controlled trial of intravenous ketamine in acute asthma showed no beneficial effects in adult patients.157 Despite the current lack of high-level evidence, some studies have reported beneficial clinical effects from ketamine use in children presenting to the ED with acute asthma.158,159 In critically ill children with asthma, a loading dose of ketamine (2 mg/kg) followed by continuous infusions (20-60 mcg/kg/min) significantly improved the PaO2/FiO2 ratio in all patients, the dynamic compliance and PaCO2, and peak inspiratory pressures in mechanically ventilated patients.160 The mean duration of ketamine infusion in this study was 40 ± 31 96

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hours and no significant side effects were noted. Ketamine infusions have been used in patients with near-fatal asthma, in combination with other bronchodilator therapies.161 Bilevel Positive Airway Pressure Noninvasive positive pressure ventilation (NPPV) in addition to conventional therapy showed clinical improvement and correction of gas exchange abnormalities in children and adults with asthma.162–164 NPPV was well tolerated in children, including patients as young as 1 year.164,165 Utilization of NPPV in younger patients can be challenging. However, under strict monitoring, the use of a small dose of benzodiazepines or propofol with or without a low-dose ketamine infusion or dexmedetomidine may facilitate the tolerance for NPPV. Typically recommended settings include an inspiratory positive airway pressure of 10 cm H2O, an expiratory positive airway pressure of 5 cm H2O, with or without a low back-up ventilation rate. In patients with severe asthma, a low level of continuous positive airway pressure may reduce the premature airway closure point, reducing intrinsic end expiratory pressure and subsequently the inspiratory workload.166,167 In addition, the use of NPPV may well improve the delivery of aerosolized albuterol to poorly ventilated areas.168 In conclusion, acute asthma exacerbation treatment in the pediatric population continues to require our proficiency to promptly intervene with a systematic and aggressive methodology. A stepwise approach for the management of acute asthma exacerbation is shown in the Figure. The use of this progressive treatment guideline is suggested for patients admitted to the PICU who are not responding to steroids and β2-agonists and need further therapy, based on their clinical status and asthma score. J Pediatr Pharmacol Ther 2013 Vol. 18 No. 2 • www.jppt.org

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At Le Bonheur Children’s Hospital ICU, we use different doses of continuous albuterol per hour, based on the patient’s age and weight, keeping the dose per kilogram roughly the same in each group. The guidelines and clinical pathway for treatment with and weaning from continuous albuterol are described in the Figure and Appendix. Table 2 provides practical guidelines for the dosage and mixing concentrations of the albuterol solutions used at Le Bonheur Children’s Hospital. DISCLOSURE The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. ABBREVIATIONS cAMP, cyclic adenosine monophosphate; ED, emergency department; FiO 2, fraction of inspired oxygen; Heliox, helium-oxygen mixtures; ICU, intensive care unit; NAEPP, National Asthma Education and Prevention Program; NPPV, noninvasive positive pressure ventilation; PaCO2, partial pressure of carbon dioxide in the arterial blood; PaO2, partial pressure of oxygen in arterial blood; PAS, Pediatric Asthma Score; PICU, pediatric intensive care unit; PKA, protein kinase A; SpO2, oxygen saturation. CORRESPONDENCE I. Federico Fernandez Nievas, MD, University of Tennessee Health Science Center, Department of Pediatrics, Division of Critical Care Medicine, 50 N Dunlap St, CFRC, 3rd Floor, Memphis, TN 38103, email: [email protected]

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136. Barlinski J, Lockhart A, Frossard N. Modulation by theophylline and enprofylline of the excitatory non-cholinergic transmission in guinea-pig bronchi. Eur Respir J. 1992;5(10):1201-1205. 137. Kidney J, Dominguez M, Taylor PM, et al. Immunomodulation by theophylline in asthma: demonstration by withdrawal of therapy. Am J Rrespir Criti Care Med. 1995;151(6):1907-1914. 138. Spina D. Theophylline and PDE4 inhibitors in asthma. Curr Opin Pulm Med. 2003;9(1):57-64. 139. Weinberger M, Hendeles L. Theophylline in asthma. New Engl J Med. 1996;334(21):13801388. 140. Sullivan P, Bekir S, Jaffar Z, et al. Antiinflammatory effects of low-dose oral theophylline in atopic asthma. Lancet. 1994;343(8904):1006-1008. 141. Weinberger M, Hendeles L, Ahrens R. Clinical pharmacology of drugs used for asthma. Pediatr Clin North Am. 1981;28(1):47-75. 142. Nahata M. Drug interactions with azithromycin and the macrolides: an overview. J Antimicrobial Chemother. 1996;37(suppl C):133-142. 143. Ream RS, Loftis LL, Albers GM, et al. Efficacy of IV theophylline in children with severe status asthmaticus. Chest. 2001;119(5):1480-1488. 144. Wheeler DS, Jacobs BR, Kenreigh CA, et al. Theophylline versus terbutaline in treating critically ill children with status asthmaticus: a prospective, randomized, controlled trial. Pediatr Crit Care Med. 2005;6(2):142147. 145. Gupta VK, Cheifetz IM. Heliox administration in the pediatric intensive care unit: an evidence-based review. Pediatr Crit Care Med. 2005;6(2):204-211. 146. Hess DR, Acosta FL, Ritz RH, et al. The effect of heliox on nebulizer function using a beta-agonist bronchodilator. Chest. 1999;115(1):184-189. 147. Kim IK, Phrampus E, Venkataraman S, et al. Helium/oxygen-driven albuterol nebulization in the treatment of children with moderate to severe asthma exacerbations: a randomized, controlled trial. Pediatrics. 2005;116(5):1127-1133. J Pediatr Pharmacol Ther 2013 Vol. 18 No. 2 • www.jppt.org

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148. Bigham MT, Jacobs BR, Monaco MA, et al. Helium/oxygen-driven albuterol nebulization in the management of children with status asthmaticus: a randomized, placebo-controlled trial. Pediatr Crit Care Med. 2010;11(3):356-361. 149. Carter ER, Webb CR, Moffitt DR. Evaluation of heliox in children hospitalized with acute severe asthma: a randomized crossover trial. Chest. 1996;109(5):1256-1261. 150. Abd-Allah SA, Rogers MS, Terry M, et al. Helium-oxygen therapy for pediatric acute severe asthma requiring mechanical ventilation. Pediatr Crit Care Med. 2003;4(3):353357. 151. Rodrigo G, Pollack C, Rodrigo C, et al. Heliox for nonintubated acute asthma patients. Cochrane Database Syst Rev. 2006(4):CD002884. 152. Carroll CL. Heliox for children with acute asthma: has the sun set on this therapy? Pediatr Crit Care Med. 2010;11(3):428-429. 153. Tobias JD, Garrett JS. Therapeutic options for severe, refractory status asthmaticus: inhalational anaesthetic agents, extracorporeal membrane oxygenation and helium/oxygen ventilation. Paediatr Anaesth. 1997;7(1):47-57. 154. Cohen SP, Liao W, Gupta A, et al. Ketamine in pain management. Adv Psychosom Med. 2011;30:139-161. 155. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004;99(2):482-495. 156. Park GR, Manara AR, Mendel L, et al. Ketamine infusion: its use as a sedative, inotrope and bronchodilator in a critically ill patient. Anaesthesia. 1987;42(9):980-983. 157. Howton JC, Rose J, Duffy S, et al. Randomized, double-blind, placebo-controlled trial of intravenous ketamine in acute asthma. Ann Emerg Med. 1996;27(2):170-175. 158. Petrillo TM, Fortenberry JD, Linzer JF, et al. Emergency department use of ketamine in pediatric status asthmaticus. J Asthma. 2001;38(8):657-664.

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JPPT 159. Priestley SJ, Taylor J, McAdam CM, et al. Ketamine sedation for children in the emergency department. Emerg Med (Fremantle). 2001;13(1):82-90. 160. Youssef-Ahmed MZ, Silver P, Nimkoff L, et al. Continuous infusion of ketamine in mechanically ventilated children with refractory bronchospasm. Intensive Care Med. 1996;22(9):972-976. 161. Mazzeo AT, Spada A, Pratico C, et al. Hypercapnia: what is the limit in paediatric patients: a case of near-fatal asthma successfully treated by multipharmacological approach. Paediatr Anaesth. 2004;14(7):596603. 162. Meduri GU, Cook TR, Turner RE, et al. Noninvasive positive pressure ventilation in status asthmaticus. Chest. 1996;110(3):767774. 163. Soroksky A, Stav D, Shpirer I. A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack. Chest. 2003;123(4):1018-1025. 164. Thill PJ, McGuire JK, Baden HP, et al. Noninvasive positive-pressure ventilation in children with lower airway obstruction. Pediatr Crit Care Med. 2004;5(4):337-342. 165. Carroll CL, Schramm CM. Noninvasive positive pressure ventilation for the treatment of status asthmaticus in children. Ann Allergy Asthma Immunol. 2006;96(3):454-459. 166. Cassart M, Pettiaux N, Gevenois PA, et al. Effect of chronic hyperinflation on diaphragm length and surface area. Am J Resp Crit Care Med. 1997;156(2 Pt 1):504-508. 167. Smith TC, Marini JJ. Impact of PEEP on lung mechanics and work of breathing in severe airflow obstruction. J Appl Physiol. 1988;65(4):1488-1499. 168. Pollack CV Jr, Fleisch KB, Dowsey K. Treatment of acute bronchospasm with beta-adrenergic agonist aerosols delivered by a nasal bilevel positive airway pressure circuit. Ann Emerg Med. 1995;26(5):552-557.

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APPENDIX The Pediatric Asthma Score1 (PAS) has been adopted by Le Bonheur Children’s Hospital for the assessment of patients with asthma exacerbation (Table 1). A respiratory therapist documents the PAS every 2 hours while the patient is receiving continuous albuterol treatment. Weaning can be done every 2 hours by lowering the dose by 5 mg/h for PAS scores ≤8. Advancement can be made to the next level only when there is worsening of the PAS. Patients should remain on continuous albuterol therapy until terbutaline is discontinued. Atrovent 0.25 to 0.5 mg will be administered every 6 hours.115 Peak flow measurements will be instituted along with the PAS assessment for children older than 5 years. Guidelines for Patients 8. • Begin and continue to wean albuterol by 5 mg/h for PAS assessment scores ≤8. Guidelines for Patients 20-30 kg: • Begin continuous albuterol treatment at 25 mg/h or per physician order. Duration = 8 hours. • Mix subsequent continuous solutions for a duration of 4 hours. • Continue at 25 mg/h or at present strength of solution for PAS assessment scores >8. • Begin and continue to wean albuterol by 5 mg/h for PAS assessment scores ≤8. Guidelines for Patients >30 kg: • Begin continuous albuterol treatment at 30 mg/h or per physician order. Duration = 8 hours. • Mix subsequent continuous solutions for a duration of 4 hours. • Begin and continue to wean albuterol by 5 mg/h for PAS assessment scores ≤8. • Continue at 30 mg/h or present milligram per hour delivery for PAS assessment scores >8.

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P e d i a t r i c O b s t r u c t i v e Sl e e p A p n e a S y n d ro m e Nathan S. Alexander,

MD,

James W. Schroeder Jr,

MD*

KEYWORDS  Obstructive sleep apnea  Pediatric  Management  Clinical practice guidelines  OSAS KEY POINTS  Pediatric obstructive sleep apnea syndrome (OSAS) is a common health problem, which if left untreated, may have a deleterious impact on neurocognitive and behavioral outcomes, physical development, and cardiovascular health.  Nocturnal polysomnography (PSG) is the gold standard method for diagnosing pediatric OSAS, however its performance and interpretation in the pediatric population has not been well standardized.  The first-line treatment for pediatric OSAS is adenotonsillectomy. Reduced efficacy rates are seen in obese children. Persistent OSAS postoperatively must be investigated, and other levels of airway obstruction should be addressed.  Patients at high risk for respiratory complications after adenotonsillectomy should undergo preoperative PSG, and those less than 3 years of age and those with severe OSAS should be considered for postoperative admission.

INTRODUCTION

Pediatric obstructive sleep apnea syndrome (OSAS) is a common health problem diagnosed and managed by various medical specialists, including family practice physicians, pediatricians, pulmonologists, and general and pediatric otolaryngologists. If left untreated, the sequelae can be severe. In the last decade, significant advancements have been made in the evidence-based management of pediatric OSAS. This article focuses on the current understanding of this disease and its management, and related clinical practice guidelines. TERMINOLOGY

Sleep-disordered breathing (SDB) is characterized by an abnormal respiratory pattern during sleep and includes snoring, mouth breathing, and pauses in breathing.1 SDB is

Division of Pediatric Otolaryngology, Ann & Robert H. Lurie Children’s Hospital of Chicago, 225 East Chicago Avenue, Box 25, Chicago, IL 60611-2605, USA * Corresponding author. E-mail address: [email protected] Pediatr Clin N Am 60 (2013) 827–840 http://dx.doi.org/10.1016/j.pcl.2013.04.009 pediatric.theclinics.com 0031-3955/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

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the most common indication for tonsillectomy with or without adenoidectomy; 530,000 such procedures are performed annually in the United States on children younger than 15 years of age.1,2 SDB is a clinical diagnosis and encompasses the spectrum of disorders ranging in severity from primary snoring (PS) to upper airway resistance syndrome (UARS) to OSAS. It is estimated that 3% to 12% of children have PS, which is characterized by snoring without associated apneas, gas exchange abnormalities, or arousals on polysomnography (PSG).3–5 UARS is characterized by snoring associated with repetitive occurrences of respiratory effort-related arousals (RERAs) without oxygen desaturations. It is hypothesized that UARS can lead to daytime symptoms resembling OSAS.6 The diagnosis of UARS requires the use of an esophageal pressure monitor during overnight PSG. This is not routine in most centers, thus its prevalence is not well known in the pediatric population.4,7 There is some variability in the exact definition of the term OSAS. The American Academy of Pediatrics (AAP) clinical practice guideline on the diagnosis and management of childhood OSAS defines OSAS in children as a disorder of breathing during sleep characterized by prolonged partial upper airway obstruction and/or intermittent complete obstruction that disrupts normal ventilation during sleep and normal sleep patterns accompanied by associated signs and symptoms characteristic of the disorder.8 The American Academy of Otolaryngology Head and Neck Surgery (AAOHNS) clinical practice guideline on PSG for SDB before tonsillectomy in children states that OSAS is diagnosed when SDB (clinically) is accompanied by an abnormal PSG with obstructive events.1 The prevalence of OSAS in children is believed to range from 1% to 10%.3,9–11 MORBIDITY Signs/Symptoms

The signs and symptoms of pediatric OSAS are variable and are often dependent on age. Some daytime symptoms are more apparent in the older child. Nocturnal symptoms are often the most obvious to the parents of the child, and these often prompt the initial evaluation. Snoring is the most common associated symptom seen in children with SDB and OSAS. Some of the additional signs and symptoms are listed in Table 1. Excessive daytime sleepiness is seen more frequently in adolescents and/or obese children, but hyperactivity and inattention are more characteristic of pediatric OSAS. One way to measure sleepiness is by applying the Epworth Sleepiness Scale (ESS). Melendres and colleagues12 compared 108 children with suspected SDB with 72 controls using a modified ESS and the Conners Abbreviated Symptom Questionnaire. They demonstrated that the children with suspected SDB were both sleepier and more hyperactive than the control patients. They found only weak correlation with the ESS and the PSG data obtained on the children with suspected SDB. Attempts to correlate physical examination findings to sleep apnea severity have also been made. The tonsils are typically graded on a clinically subjective scale from 0 to 41, describing the amount of space occupied between the tonsillar pillars in the oropharynx (0, tonsils within fossa; 11, 50%; 31, >75%; 41, >75%), Nolan and Brietzke13 recently demonstrated in a systematic literature review that the association between subjective tonsil size and objective OSAS severity is weak at best.14 Academic/Behavioral

The association of SDB and OSAS with impaired neurocognitive and behavioral development has been well studied in the past decade. Untreated OSAS has been PEDIATRIC CRITICAL CARE MEDICINE

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Table 1 Symptoms and signs of pediatric OSAS Nocturnal Symptoms

Daytime Symptoms

Signs/Findings

Snoring Gasping Noisy breathing (typically inspiratory) Paradoxic breathing Retractions (cervical or costal) Witnessed apneas Restless sleep Neck hyperextension Mouth breathing Nocturnal sweating Enuresis (after 6 mo continence) Parasomnia (walking, talking, terrors) Bruxism Mouth breathing

Difficulty waking Unrefreshed on waking Excessive sleepiness Hyperactivity Aggression/moodiness Mouth breathing Poor appetite Dysphagia Difficulty in school

Tonsil hypertrophy High/large tongue position Growth disturbance Obesity Failure to thrive Pulmonary hypertension Systemic hypertension Craniofacial abnormalities Laryngomalacia Nasal airway obstruction Hypotonia Gastroesophageal reflux

associated with poor learning, lower achievement, and attention deficit/hyperactivity disorder. Recent studies further delineate the association. For example, Gottlieb and colleagues15 found significantly lower performance on measures of memory, executive function, and general intelligence in 5-year-old children with symptoms of SDB than in asymptomatic children.16 In addition, Gozal and colleagues17 demonstrated that children with lower academic performance in middle school (lower 25% of their class) were more likely to have snored during early childhood and to have required adenotonsillectomy (T&A) for snoring compared with their schoolmates in the top 25% of the class. Other studies have shown improved attention, executive functioning, analytical thinking, verbal functioning, memory, and academic progress at 6 to 12 months after T&A, suggesting a reversible effect of the neurocognitive morbidity incurred from SDB and obstructive sleep apnea (OSA).4,14–20 Gozal17 was the first to suggest that “learning debt” created by a delay in treatment or untreated SDB may only be partially reversible. Early sleep fragmentation may adversely affect future academic performance.17 These studies also suggest that snoring may not be as benign as once believed.18 Behavioral problems such as social withdrawal and aggression have also been described in children with OSAS.19 The prevalence of attention deficit/hyperactivity (ADHD) in the school-age population is 8% to 10%, whereas 20% to 30% of children with snoring and/or OSAS have significant problems with inattention and hyperactivity.19–21 This connection is theorized to be secondary to the effect of fragmented, nonrestorative sleep with intermittent hypoxia on the development of the prefrontal cortex, which is believed to be responsible for working memory, behavioral control, analysis, organization, and self-regulation of motivation.19,22,23 Medical

Failure to thrive and growth failure are believed to be slightly more common in children with OSAS.24,25 This may be a result of increased energy consumption from increased work of breathing, decreased oral intake, and alterations of nocturnal growth hormone secretion patterns.19,25 Growth spurt or some associated weight gain after T&A is often reported. A recent study by Smith and colleagues26 demonstrated that aged 6 years or younger at the time of T&A was significantly predictive of having postoperative weight gain. PEDIATRIC CRITICAL CARE MEDICINE

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Cardiovascular morbidity in children with OSAS includes systemic hypertension, pulmonary hypertension, and cor pulmonale with heart failure. Intermittent airway obstruction may lead to alterations in intrathoracic pressure, sustained changes in systemic blood pressure and endothelial function, associated oxidative stress, and increased sympathetic tone.19,27,28 Several studies have shown significant improvement of ambulatory blood pressure measurements, both systolic and diastolic, after treatment of OSAS with T&A. Tezer and colleagues29 conducted a prospective noncontrolled study on 21 children with OSA diagnosed clinically and with lateral neck radiography and no reported cardiovascular disease. Using transthoracic echocardiography, they demonstrated abnormal ventricular diastolic functions, and subsequent normalization 3 months after T&A. Tal and colleagues30 used radionucleotide vetriculography in 27 children clinically diagnosed with OSA, with no known preoperative cardiovascular disease. They demonstrated that 35% had a reduced right ventricular ejection fraction, and 67% had a wall motion abnormality preoperatively; both of these variables were markedly improved in 11 of the 27 children after T&A. Systemic inflammation, as assessed by C-reactive protein (CRP) is notably higher in children with OSAS, which may place them at risk for substantial end-organ damage. Recent studies have shown that T&A significantly reduced the CRP levels in these children.31 DIAGNOSIS

The AAP published clinical practice guidelines for the diagnosis and management of childhood OSAS in 2002, and updated the guidelines in 2012. PSG is the gold standard method for diagnosing OSAS.8 However, because of a shortage of sleep laboratories with pediatric expertise, alternative diagnostic tests, such as videotaping, nocturnal pulse oximetry, and daytime nap PSG, may be helpful adjuncts to the clinical history and physical examination. The drawback is that these alternative tests have weaker positive and negative predictive values than PSG.1,8 The action statements from the AAP are listed in Box 1, and those patients considered to be at high risk (and therefore require postoperative observation) are listed in Box 2.8 The designation of PSG as the gold standard method for diagnosing OSAS in children highlights that the subjective clinical history and physical examination have poor sensitivity in distinguishing OSAS from PS.4,32–34 Goldstein and colleagues33 prospectively evaluated 30 children with obstructive symptoms by standard history, physical examination, and tape-recorded breathing during sleep. Only 55% of patients predicted clinically to have definite OSAS had a positive nocturnal PSG. Sixteen percent of the patients thought to be unlikely to have OSAS had a positive nocturnal PSG. The diagnostic PSG parameters for pediatric OSAS are different from those for adult OSAS. OSAS in adults is defined as a respiratory pause lasting more than 10 seconds; the higher respiratory rate in children portends that shorter intervals of apnea are likely to be clinically significant.3 The parameters that are primarily used in evaluating OSAS are the apnea-hypopnea index (AHI), RERAs, respiratory disturbance index (RDI), lowest oxygen saturation, and percentage of time with an end tidal CO2 level greater than 50 mm Hg. In children, apnea is defined as a complete interruption of air flow lasting at least 2 breath periods, whereas hypopnea is defined as a reduction in air flow of 50% or more with associated arousal, awakening, or desaturation of 3% or more for the same duration using a nasal cannula pressure transducer.19,35 RERAs are defined as a sequence of at least 2 breath periods that does not meet the requirements for apnea or hypopnea but results in increased respiratory effort and subsequent arousal from sleep. The AHI and RERAs may be combined to give the RDI. PEDIATRIC CRITICAL CARE MEDICINE

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Box 1 Key action statements by the AAP for diagnosis and management of pediatric OSA As part of routine health maintenance, the clinician should inquire if the child snores. If yes, or if the child presents with signs/symptoms of OSAS, the clinician should perform a more focused examination. If the child snores on a regular basis and has signs/symptoms of OSAS, the clinician should either (1) obtain PSG or (2) refer the patient to a sleep specialist or otolaryngologist for more extensive evaluation. If PSG is not available, the clinician may order alternative diagnostic tests, such as nocturnal video recording, nocturnal pulse oximetry, daytime nap PSG, or ambulatory PSG. If the child has OSAS with adenotonsillar hypertrophy, adenotonsillectomy is recommended as first-line treatment. If the child has OSAS without adenotonsillar hypertrophy, other treatments should be considered. Clinicians should monitor high-risk (see Box 2) patients undergoing adenotonsillectomy as inpatients postoperatively. Clinicians should clinically reassess all patients with OSAS for persisting signs/symptoms after therapy to determine if further therapy is required. Clinicians should reevaluate high-risk patients for persistent OSAS after adenotonsillectomy, including those who had a significantly abnormal baseline PSG, have sequelae of OSAS, are obese or remain symptomatic after treatment, with an objective test or referral to a sleep specialist. Clinicians should refer patients for continuous positive airway pressure management if symptoms/signs or objective evidence of OSAS persists after adenotonsillectomy or if adenotonsillectomy is not performed. Clinicians should recommend weight loss in addition to other therapy if a child with OSAS is overweight or obese. Clinicians may prescribe topical intranasal corticosteroids for children with mild OSAS in whom adenotonsillectomy is contraindicated or for children with mild postoperative OSAS (apneahypopnea index 2 SD above the upper limit of the normal range for age) Tachypnea Altered mental status Substantial edema or positive fluid balance (>20 ml/kg of body weight over a 24-hr period) Hyperglycemia (plasma glucose, >120 mg/dl [6.7 mmol/liter]) in the absence of diabetes Inflammatory variables Leukocytosis (white-cell count, >12,000/mm3) Leukopenia (white-cell count, 10% immature forms Elevated plasma C-reactive protein (>2 SD above the upper limit of the normal range) Elevated plasma procalcitonin (>2 SD above the upper limit of the normal range) Hemodynamic variables Arterial hypotension (systolic pressure, 2 SD below the lower limit of the normal range for age) Elevated mixed venous oxygen saturation (>70%)‡ Elevated cardiac index (>3.5 liters/min/square meter of body-surface area)§ Organ-dysfunction variables Arterial hypoxemia (ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, 44 μmol/liter) Coagulation abnormalities (international normalized ratio, >1.5; or activated partial-thromboplastin time, >60 sec) Paralytic ileus (absence of bowel sounds) Thrombocytopenia (platelet count, 4 mg/dl [68 μmol/liter]) Tissue-perfusion variables Hyperlactatemia (lactate, >1 mmol/liter) Decreased capillary refill or mottling Severe sepsis (sepsis plus organ dysfunction) Septic shock (sepsis plus either hypotension [refractory to intravenous fluids] or hyperlactatemia)¶ * Data are adapted from Levy et al.5 † In children, diagnostic criteria for sepsis are signs and symptoms of inflammation plus infection with hyperthermia or hypothermia (rectal temperature, >38.5°C or 45 g/m2.7 in boys should be considered abnormal. In contrast, the 50th percentile values of LVMI in children