Chapter 14: Critical Care

Critical care medicine is the discipline of caring for patients with acute life-threatening conditions or conditions likely to cause serious harm if not rapidly addressed. This work requires a detailed understanding of human physiology, the pathophysiology of severe illness and injury, the intricate interactions between organ systems and therapies, as well as an understanding of and experience with the rapidly changing technologies available in a modern pediatric intensive care unit (PICU). The science of caring for the critically ill patient continues to advance rapidly as the molecular mediators of illness have become better defined and new therapies are brought into clinical use. Critical care, then, is a highly complex, multidisciplinary field in which optimal patient outcomes require a team-oriented approach, including critical care physicians and nurses; respiratory therapists; pharmacists; consulting specialists; physical, occupational and recreational therapists; and social services specialists.

ACUTE RESPIRATORY FAILURE

Pathogenesis

Acute respiratory failure, defined as the inability of the respiratory system to adequately deliver oxygen or remove carbon dioxide, is a major cause of morbidity and mortality in infants and children. Anatomic and developmental differences place infants and young children at higher risk than older children or adults for respiratory failure. An infant’s thoracic cage is more compliant, allowing a greater tendency toward alveolar collapse. The intercostal muscles are poorly developed and unable to achieve the “bucket-handle” motion characteristic of adult breathing, and the diaphragm is shorter and relatively flat with fewer type I muscle fibers, making it less effective and more easily fatigued. The infant’s airways are also smaller in caliber resulting in greater resistance to airflow and greater susceptibility to occlusion by mucus plugging and mucosal edema, particularly in the setting of respiratory infections. Alveoli in children are smaller and have less collateral ventilation than adults, again resulting in a greater tendency to collapse and develop atelectasis. Finally, young infants may have a more reactive pulmonary vascular bed, impaired immune system, or residual effects from prematurity, all of which increase the risk of respiratory failure.

Respiratory failure can be due to inadequate oxygenation (hypoxemic respiratory failure) or inadequate ventilation (hypercapnic respiratory failure) or both. Hypoxemic respiratory failure occurs in three situations: (1) Ventilation-perfusion (V/Q) mismatch, when blood flows to inadequately ventilated lung or when ventilated areas of the lung are inadequately perfused; (2) diffusion defects, caused by thickened alveolar membranes or excessive interstitial fluid at the alveolar-capillary junction; and (3) intrapulmonary shunt, when structural anomalies in the lung allow blood to flow through the lung without participating in gas exchange. Hypercapnic respiratory failure results from impaired alveolar ventilation, due to conditions such as increased dead space ventilation, reduced respiratory drive due to CNS dysfunction or oversedation, or neuromuscular disorders (Table 14–1).

Clinical Findings

The clinical findings in respiratory failure are the result of hypoxemia, hypercapnia, and arterial pH changes. Common features of respiratory failure are summarized in Table 14–2. These features may not be clinically obvious and many are nonspecific. As a result, a strictly clinical assessment of respiratory failure is not always reliable, and clinical findings of respiratory failure should be supplemented by laboratory data such as blood gas analysis.

Noninvasive Monitoring & Blood Gas Analysis

The adequacy of oxygenation and ventilation can be measured noninvasively and/or through blood gas analysis. Pulse oximetry measures arterial oxygen saturation (SaO₂) continuously and noninvasively and is an important tool in the assessment and treatment of patients with potential or actual respiratory failure. However, pulse oximetry readings can be much less accurate in patients with saturations below 80%, poor skin perfusion, or significant movement. In addition, pulse oximetry can be dangerously inaccurate in certain clinical settings such as carbon monoxide poisoning or methemoglobinemia. End-tidal CO₂ (ETCO₂) monitoring measures exhaled carbon dioxide (CO₂) noninvasively, allowing for continuous assessment of ventilation. Normally, the ETCO₂ level closely approximates the alveolar CO₂ level (P_aCO₂), which should equal arterial CO₂ levels (PaCO₂) because carbon dioxide diffuses freely across the alveolar-capillary barrier. While most accurate in the intubated patient, this technique can also be used in extubated patients with the proper equipment. However, the ETCO₂ level may not accurately reflect the PaCO₂ in patients with increased dead space ventilation or rapid, shallow breathing.

Given the limitations of these noninvasive techniques, arterial blood gas (ABG) analysis remains the gold standard for assessment of acute respiratory failure. ABGs provide measurements of the patient’s acid-base status (with a measured pH and calculated bicarbonate level) as well as PaO₂ and PaCO₂ levels. Capillary or venous blood gases may provide some reassurance regarding the adequacy of ventilation and can be useful for following trends; however, they yield virtually no useful information regarding oxygenation and may generate highly misleading information about the ventilatory status of patients who have poor perfusion or who had difficult blood draws. As a result, ABG analysis is important for all patients with suspected respiratory failure, particularly those with abnormal venous or capillary gases.

Knowing the ABG values and the inspired oxygen concentration also enables one to calculate the alveolar-arterial oxygen difference (A–aDO₂, or A–a gradient). The A–a gradient is less than 15 mm Hg under normal conditions, widening with diffusion impairment, shunts, and V/Q mismatch. The degree of widening has prognostic value in severe hypoxemic respiratory failure, with A–a gradients over 400 mm Hg being strongly associated with mortality. Assessment of intrapulmonary shunting (the percentage of pulmonary blood flow that passes through nonventilated areas of the lung) may also be helpful. Normal individuals have less than a 5% physiologic shunt from bronchial, coronary, and thebesian (cardiac intramural) circulations. Shunt fractions greater than 15% usually indicate the need for aggressive respiratory support. However, calculation of the shunt fraction requires a pulmonary arterial catheter, the use of which has decline significantly over the past decade.

Modes of Respiratory Support

Patients with severe hypoxemia, hypoventilation, or apnea require immediate assistance with bag and mask ventilation. Although assisted ventilation can generally be maintained for some time with a properly sized mask, gastric distention, emesis leading to aspiration of gastric contents, and inadequate tidal volumes leading to atelectasis are possible complications. In patients not requiring immediate intubation, several modalities can be used to provide respiratory support, including supplemental oxygen, heated high-flow nasal cannula (HHFNC), and noninvasive ventilation (NIV).

Supplemental oxygen with a nasal cannula or oxygen mask may be adequate to treat patients with mild respiratory insufficiency (Table 14–3). Patients with hypoventilation and diffusion defects respond better to supplemental oxygen than patients with significant shunts or V/Q mismatch. For patients requiring more support, HHFNC can be considered. HHFNC devices deliver heated and humidified oxygen mixtures via nasal cannula at flow rates higher than possible with cooler dry air. Depending on the flow rate and size of patient, HHFNC can also generate some amount of positive pressure and potentially improve work of breathing without further escalation of support. Generally, flow rates of 1–2 L/kg/min are considered high flow in infants and children (up to a maximum of 25 L/min) although some studies have utilized up to 60 L/min in adults. HHFNC use has been studied in children with bronchiolitis and appears to be well tolerated, potentially decreasing the need for noninvasive ventilation or intubation. However, if the patient is not improving on HHFNC after 30–60 minutes, additional escalation of care may be warranted, including initiation of noninvasive ventilation that can deliver positive pressure more consistently.

Noninvasive ventilation (NIV) refers to the administration of positive pressure breathing through various interfaces (mouthpiece or nasal, face, or helmet mask) rather than an invasive artificial airway (endotracheal tube [ETT] or tracheostomy tube). NIV has become an integral tool in the management of both acute and chronic respiratory failure, reducing need for intubation in milder cases of respiratory failure or as a bridge after extubation in patients with marginal lung function and respiratory mechanics. Various modes of support can be used with NIV, such as continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), or average volume-assured pressure support (AVAPS).

CPAP refers to the constant application of airway pressure, usually in the range of 5–10 cm H₂O. BiPAP cycles between a higher inspiratory positive airway pressure (IPAP) and a lower expiratory positive airway pressure (EPAP). The additional inspiratory support in this mode improves tidal volume and ventilation in patients who are breathing shallowly and can improve oxygenation by providing a higher mean airway pressure (MAP). Common initial settings would place the IPAP at 12–14 cm H₂O and the EPAP at 6–8 cm H₂O. The IPAP can then be titrated upward to achieve adequate tidal volumes, usually in the range of 5–7 mL/kg, and based on the patient’s work of breathing and respiratory rate. EPAP and delivered oxygen concentration can be adjusted upward to achieve adequate oxygenation. AVAPS targets a tidal volume within an allowable inspiratory pressure range. Usually, a tidal volume of approximately 8 mL/kg is set with an IPAP max of 20–30 cm H₂O. EPAP is approached in a similar manner as BiPAP. With any mode of NIV, close respiratory monitoring is essential for assessing response to NIV therapy and guiding further adjustments.

Although NIV is generally well tolerated, successful application of NIV requires careful patient selection and close respiratory monitoring. The best candidates are patients with moderate lung disease, in the recovery phases of their illness, or those with primarily hypercapnic respiratory failure, such as patients with muscular dystrophies or other forms of neuromuscular weakness. These patients should be closely monitored, however, as NIV may mask symptoms of underlying disease progression, making eventual intubation more precarious. Patients suffering from coma, impaired respiratory drive, an inability to protect their airway, or cardiac or respiratory arrest are not candidates for NIV. In patients with severe respiratory failure or those who are not improving with NIV, endotracheal intubation should not be delayed.

For patients with acute respiratory failure, endotracheal intubation and the initiation of mechanical ventilation can be life-saving. Safe placement of an ETT in infants and children requires experienced personnel and appropriate equipment at the bedside, including a correctly sized mask, Ambu bag, oral airways, ETTs, and appropriate suction catheters. The patient should first be positioned properly to facilitate air exchange while supplemental oxygen is provided. The sniffing position is used in infants. Head extension with jaw thrust is used in older children without neck injuries. If obstructed by secretions or vomitus, the airway must be cleared by suction. When not obstructed and properly positioned, the airway should be patent and easily visualized, allowing the placement of an oral or nasopharyngeal ETT of the correct size. Patients with normal airway anatomy may be intubated under intravenous (IV) anesthesia by experienced personnel (Table 14–4). Endotracheal intubation of high-risk patients, such as those with significant upper airway obstruction (eg, patients with croup, epiglottitis, foreign bodies, or subglottic stenosis), mediastinal masses, or suspected or known difficult airways should be approached with extreme caution; minimal sedation should be used and paralytic agents should be strictly avoided unless trained airway specialists decide otherwise.

Appropriately sizing the ETT is important for reducing complications and providing adequate respiratory support. An inappropriately large ETT is a risk factor for subglottic pressure necrosis, potentially leading to scarring and stenosis requiring surgical repair. An inappropriately small ETT can result in excessive air leak around the ETT, making adequate ventilation and oxygenation difficult, or inability to clear secretions effectively. Two useful methods for calculating the correct size of ETT for a child are (1) measuring the child’s height with a Broselow tape and then reading the corresponding ETT size on the tape, or (2) in children older than 2 years, choosing a tube size using the formula ETT size = (16 + age in years) ÷ 4. Either cuffed or uncuffed tubes may be used, although a cuffed tube can ensure more effective provision of mechanical ventilation. Assessment of air leakage around the ETT is an important measure of appropriate ETT sizing. An audible leak (with the cuff deflated) noted at pressures of 15–20 cm H₂O generally indicates acceptable ETT size. If there is insufficient leak, the decision to change the ETT needs to be carefully considered, especially in those with severe lung disease. Approximate proper insertion depth (in cm) as measured at the teeth can be estimated by tripling the size of the ETT. Correct placement of the ETT should be confirmed by auscultation for equal bilateral breath sounds and by detecting carbon dioxide using either a colorimetric filter or quantitative capnography. A chest radiograph is necessary for final assessment of ETT placement. A correctly positioned ETT will terminate in the mid-trachea between the thoracic inlet and the carina, at approximately the level of the second thoracic vertebra.

CONVENTIONAL MECHANICAL VENTILATION

Indications

The principal indication for institution of mechanical ventilation is respiratory failure caused either by illness, injury, or treatment with sedating medications. The goals of mechanical ventilation are to facilitate the movement of gas into and out of the lungs (ventilation) and to improve oxygen uptake into the bloodstream (oxygenation). While lifesaving in many situations, positive pressure ventilation can also be harmful. As a result, mechanical ventilation strategies must be adapted to achieve these goals in a way that minimizes further injury to the lung. The overriding principles of this “lung-protective ventilation strategy” are to safely recruit underinflated lung, sustain lung volume, minimize phasic overdistention, and decrease lung inflammation. This strategy requires adjustment of ventilator settings with an understanding of the difference between the gas exchange that is permissible and that which is normal.

Modes of Mechanical Ventilation

The parameters used to control the delivery of mechanical ventilation breaths are known as the trigger, cycle, control, and limit variables. The trigger variable describes how breaths are initiated, either by the patient or by the ventilator. The most common triggers are patient effort, sensed as a drop in return pressure or gas flow to the ventilator, and time. A newer trigger method, neurally adjusted ventilatory assist (NAVA), measures the electrical activity of the diaphragm via an esophageal catheter in order to adjust the ventilator breaths to meet the patient’s neural activity. While NAVA holds promise for improving patient-ventilator synchrony and facilitating ventilator weaning, its ideal role in clinical practice remains to be determined. The cycle variable describes how the inspiratory phase is terminated, either by the patient or by the ventilator. Most ventilator modes cycle according to a set inspiratory time (I-time) although flow-cycled modes can be used in spontaneously breathing patients. The control variable determines whether the ventilator delivers a specific tidal volume (volume-controlled modes) or a specific pressure (pressure-controlled modes). Limit variables are parameters whose magnitude is constrained during inspiration in order to prevent excessive pressure or volume from being delivered by the ventilator.

Breathing during mechanical ventilation can be classified as spontaneous or mandatory. The patient controls the timing and size of spontaneous breaths. The ventilator controls the timing and/or size of mandatory breaths, independent of patient activity. In addition, the breathing pattern provided by the ventilator can be set to one of three configurations. In continuous mandatory ventilation (CMV), the ventilator determines the size and duration of all breaths. In intermittent mandatory ventilation (IMV), the ventilator delivers mandatory breaths, but additional spontaneous breaths between and during mandatory breaths are allowed. In continuous spontaneous ventilation (CSV), the patient initiates and controls all breaths, but the ventilator can assist those efforts.

A ventilator mode consists of a specific control variable (pressure or volume), a specific pattern of breathing (CMV, IMV, or CSV), and a specific set of phase variables (trigger, limit, and cycle). Initiation of breaths and the length of exhalation are controlled by setting the respiratory rate. In time-cycled modes of ventilation, the inspiratory time (I-time) determines the length of inspiration and when to allow exhalation. Most modern ventilators can deliver either a pressure-targeted or a volume-targeted breath in several manners. In synchronized IMV (SIMV), the ventilator delivers breaths in an IMV pattern, but the machine breaths are synchronized with the patient’s efforts. If the patient does not make adequate respiratory efforts to trigger the ventilator, the machine delivers a mandatory breath at a preset time interval. In pressure-support ventilation, the patient’s own efforts are assisted by the delivery of gas flow to achieve a targeted peak airway pressure. Pressure support ventilation allows the patient to determine the rate and pattern of breaths (CSV breathing pattern), thus improving patient comfort and decreasing the work of breathing. The most commonly used mode of ventilation in many PICUs is synchronized IMV with pressure support (SIMV + PS), a mixed mode allowing pressure-supported breaths between the synchronized machine breaths.

In pressure-controlled ventilation, air flow begins at the start of the inspiratory cycle and continues until a preset airway pressure is reached. That airway pressure is then maintained until the end of the set I-time, when the exhalation valve on the ventilator opens and gas exits into the machine. With this mode of ventilation, changes in the compliance of the respiratory system will lead to fluctuations in the actual tidal volume delivered to the patient. The advantage of pressure-targeted ventilation lies primarily in the avoidance of high airway pressures that might cause barotrauma or worsen lung injury. The main disadvantage of pressure-controlled ventilation is the possibility of delivering either inadequate or excessive tidal volumes during periods of changing lung compliance. In volume-controlled ventilation, the machine delivers a set tidal volume to the patient. Changes in lung compliance will lead to fluctuations in the peak airway pressure generated by the breath. The main advantage of volume ventilation is more reliable delivery of the desired tidal volume and thus better control of ventilation. More reliable tidal volume delivery may also help prevent atelectasis due to hypoventilation. Disadvantages of volume ventilation include the risk of barotrauma from excessive airway pressures and difficulties overcoming leaks in the ventilator circuit. In either pressure- or volume-controlled modes, alarm limits can be set in order to restrict changes in either tidal volume or airway pressure with changing lung compliance; interpreting those alarms and adjusting the ventilator require the ICU clinician to understand the ventilator mode in use.

Finally, in any mode of ventilation, the minimum distending pressure applied to the lung during the respiratory cycle is determined by setting the positive end-expiratory pressure (PEEP). PEEP helps prevent the end-expiratory collapse of open lung units, thus preventing atelectasis and shunting. In disease states such as pulmonary edema, pneumonia, or acute respiratory distress syndrome (ARDS), a higher PEEP (10–15 cm H₂O) may increase the patient’s functional residual capacity (FRC), helping to keep open previously collapsed alveoli and improve oxygenation. However, high levels of PEEP may also cause complications such as gas trapping and CO₂ retention, barotrauma with resultant air leaks, and decreased central venous return leading to reduced cardiac output or increased intracranial pressure (ICP).

Setting & Adjusting the Ventilator

When initiating either volume-controlled or pressure-controlled modes of ventilation, the ICU clinician sets a respiratory rate, an inspiratory time (I-time), and a level of PEEP. The respiratory rate will depend on multiple factors, including patient comfort and blood gas measurements. However, many patients will initially require full support with respiratory rates between 20-30 breaths/min. The minimum PEEP is usually 5 cm H₂O but can be titrated up to maintain adequate oxygenation at acceptable inspired oxygen concentrations (< 60%–65%), while monitoring for adverse effects of increased intrathoracic pressure. In volume-controlled ventilation, a reasonable initial tidal volume is 8 mL/kg, as long as that volume does not cause excessive airway pressures (> 30 cm H₂O) (see below for open-lung strategies in ARDS). In pressure-controlled ventilation, the amount of peak inspiratory pressure required will depend on the overall respiratory compliance. Patients without lung disease require peak inspiratory pressures of 15–20 cm H₂O, while patients with respiratory illnesses may require 20–30 cm H₂O pressure to provide adequate ventilation. Adequacy of the inspiratory pressure is assessed by observing the patient’s chest rise and by measuring the delivered tidal volume and gas exchange.

Ventilated patients require careful monitoring for the efficacy of mechanical ventilation, including respiratory rate and activity, chest wall movement, and quality of breath sounds. Gas exchange (oxygenation and ventilation) should be monitored using either noninvasive or invasive methods as described above. Frequent or continuous systemic blood pressure monitoring is also necessary for patients ventilated with high PEEP levels, given the risk of adverse hemodynamic effects.

Ventilator settings can be adjusted to optimize both ventilation (PaCO₂) and oxygenation (PaO₂). Ventilation is most closely associated with the delivered minute volume, or the tidal volume multiplied by the respiratory rate. As a result, abnormal PaCO₂ values can be most effectively addressed by changes in the respiratory rate or the tidal volume. Increased respiratory rate or tidal volume should increase minute volume and thus decrease PaCO₂ levels; decreases in respiratory rate or tidal volume should act in the opposite fashion. In some circumstances, additional adjustments may also be necessary. For example, for patients with disease characterized by extensive alveolar collapse, increasing PEEP may improve ventilation by helping to keep open previously collapsed lung units. Also, for patients with disease characterized by significant airway obstruction, decreases in respiratory rate may allow more time for exhalation and improve ventilation despite an apparent decrease in the minute volume provided.

The variables most closely associated with oxygenation are the inspired oxygen concentration and the MAP during the respiratory cycle. Increases in inspired oxygen concentration will generally increase arterial oxygenation, unless right-to-left intracardiac or intrapulmonary shunting is a significant component of the patient’s illness. Concentrations of inspired oxygen above 60%–65%, however, may lead to hyperoxic lung injury. For patients requiring those levels of oxygen or higher to maintain adequate arterial saturations, increases in MAP should be considered as a means to recruit underinflated lung units. MAP is affected by PEEP, peak inspiratory pressure, and I-time. Increases in any one of those factors will increase MAP and should improve arterial oxygenation. Importantly, increases in MAP may also lead to decreases in cardiac output, primarily by decreasing venous return to the heart. In this circumstance, raising MAP may increase arterial oxygenation but actually compromise oxygen delivery to the tissues. For patients with severe hypoxemic respiratory failure, these tradeoffs highlight the need for careful monitoring by experienced personnel.

Supportive Care of the Mechanically Ventilated Patient

Patients undergoing mechanical ventilation require meticulous supportive care. Mechanical ventilation is often frightening and uncomfortable for critically ill children. In order to reduce dyssynchrony with the ventilator and impaired gas exchange, careful attention must be directed toward optimizing patient comfort and decreasing anxiety. Sedative anxiolytics are typically provided as intermittent doses or continuous infusions. Since oversedation of the ventilated patient may lead to longer durations of ventilation and difficulty weaning from the ventilator, standardized assessments of sedation level and targeting treatment to the minimum sedation level necessary to maintain patient comfort and adequate gas exchange are important.

For patients with severe respiratory illness, even small physical movements can compromise gas exchange. In such cases, muscle paralysis may facilitate oxygenation and ventilation. Nondepolarizing neuromuscular blocking agents are most commonly used for this purpose, given as intermittent doses or as continuous infusions. When muscle relaxants are given, extra care must be taken to ensure that levels of sedation are adequate, as these medications will mask many of the usual signs of patient discomfort. In addition, ventilator support may need to be increased to compensate for the elimination of patient respiratory effort.

Mechanically ventilated patients can usually be fed enterally with the use of temporary or existing feeding tubes. In patients where reflux or emesis is a major concern, transpyloric feeding or parenteral nutrition should be considered. Ventilator-associated pneumonia (VAP) is a significant complication of mechanical ventilation, leading to longer ICU stays and increased hospital costs. As a result, many local and national quality improvement initiatives have focused on minimizing the risks of VAP. These preventative measures include proper hand washing, elevation of the head of the bed to 30 degrees to prevent reflux, frequent turning of the patient, proper oral care, the use of closed suction circuits on all ventilated patients and avoidance of breaking the closed suction system, sedation protocols to minimize sedation administration, and daily assessment of extubation readiness.

Mechanical ventilation should be weaned and discontinued as soon as safely possible. Extubation failure rates in mechanically ventilated children have been estimated between 4% and 20%. Considerable effort has been devoted to identifying predictors of extubation readiness and there is literature describing tests used to predict extubation success utilizing trials of spontaneous breathing on pressure support mode. Successful extubation requires adequate gas exchange, adequate respiratory muscle strength, and the ability to protect the airway. To assess extubation readiness, most intensivists will perform a trial of spontaneous breathing in which the patient, while remaining intubated, breathes either without assistance (through a T-piece) or with a low level of pressure support (through the ventilator) for a defined period of time, usually 1–2 hours. The patient is observed carefully for signs of rapid shallow breathing or worsened gas exchange during this trial, and if neither is observed, the patient can generally be safely extubated.

Troubleshooting

Troubleshooting a sudden deterioration in the mechanically ventilated patient should begin with examining the patient. Determine whether the ETT is patent and in the correct position by auscultating for bilateral breath sounds, attempting to pass a suction catheter, assessing for detectable ETCO₂, and direct laryngoscopy, if necessary. A chest x-ray may also be helpful for ensuring appropriate ETT positioning. If the ETT is patent and correctly positioned, the next step is to determine whether any changes in the physical examination—such as poor or unequal chest rise, or absent or unequal breath sounds—suggest atelectasis, bronchospasm, pneumothorax, or pneumonia. Next, determine whether hemodynamic deterioration could be underlying acute respiratory compromise (shock or sepsis). If the problem cannot be readily identified, take the patient off the ventilator and begin manual ventilation by hand-bagging. Hand-bagging can support the patient while the ventilator is checked for malfunction as well as assess for changes in compliance, informing necessary ventilator adjustments.

OTHER MODES OF RESPIRATORY SUPPORT

High-Frequency Oscillatory Ventilation

High-frequency oscillatory ventilation (HFOV) is an alternative mode of mechanical ventilation in which the ventilator provides very small, very rapid tidal volumes at high rates around a higher MAP. Respiratory rates used during oscillatory ventilation typically range from 5 to 10 Hz (rates of 300–600 breaths/min) in most PICU patients. This mode of ventilation has been used successfully in neonates, older pediatric patients, and adults, although recent work has suggested that HFOV use may be associated with worse outcomes in adults with ARDS. HFOV is most widely used in severe, diffuse lung diseases, such as ARDS, which require high MAP to maintain lung expansion and oxygenation. Diseases characterized by significant heterogeneity or extensive gas trapping often respond too poorly to HFOV, although reports do exist of successful HFOV use in asthma. The advantage of HFOV is that high levels of MAP can be achieved without high peak inspiratory pressures or large tidal volumes, thus theoretically protecting the lung from ventilator-induced lung injury. Disadvantages of HFOV include poor tolerance by patients who are not heavily sedated or paralyzed, the risk of cardiovascular compromise due to high MAP, and the risk of gas-trapping and barotrauma in patients with highly heterogeneous lung disease. Although HFOV can be useful as a rescue mode for selected patients, recent literature suggests that HFOV has a limited role in ARDS compared with carefully managed conventional modes of ventilation.

Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) has been used as a rescue therapy to support pediatric patients with severe respiratory failure who have not improved with mechanical ventilation. ECMO circuits generally consist of a membrane oxygenator, a heater, and a pump. Central venous blood from the patient is directed out of the body, oxygenated, warmed and returned back to the patient. ECMO can be provided in two major modes: venoarterial (VA) and venovenous (VV). VA ECMO bypasses the lungs and the heart, thus supporting both the cardiovascular and respiratory systems, and requires cannulation of a large central artery and vein. VV ECMO utilizes central venous cannulation to provide extracorporeal oxygenation and carbon dioxide removal, thus augmenting the function of the patient’s lungs, but the patient’s own cardiac output is required to provide systemic oxygen delivery. VV ECMO use has increased over the past 15 years and provides the advantage of a reduced risk of systemic and, particularly, cerebral emboli when compared to VA ECMO. Patients with moderate hemodynamic compromise prior to ECMO initiation can also experience improvements in circulatory status on VV ECMO, likely due to the improvements in acid base status, oxygenation, and decreased intrathoracic pressures achieved with ECMO. ECMO is indicated for patients with reversible cardiovascular and/or respiratory failure and is not recommended in patients with severe neurologic compromise or who is in the terminal stages of a lethal condition. Despite an increase in the complexity of patients placed on ECMO, survival has remained acceptable over the past two decades. According to recent registry data, 57% of pediatric respiratory failure patients who are supported with ECMO survive, and survival rates are even better for ECMO patients with a diagnosis of viral pneumonia (especially due to respiratory syncytial virus) and without significant co-morbidities. Of note, in both neonatal and adult randomized controlled trials, patients with severe respiratory failure who were referred to an ECMO center for consideration of ECMO had improved survival, even though not all patients were actually placed on ECMO. These results emphasize the importance of early referral to experienced centers if ECMO is to be considered.

Determining the optimal time to consider ECMO initiation is one of the most challenging aspects of using this technology. Survival appears equally good for most indications with mechanical ventilation for up to 14 days prior to ECMO initiation. Patients placed on ECMO later in the course of their illness or with prolonged ECMO runs (> 14 days) may have worse outcomes. Protocols to improve secretion clearance and lung recruitment have been described and should be considered to hasten lung recovery and shorten the ECMO course, although the optimal mechanical ventilation strategy has yet to be elucidated.

While ECMO remains a viable therapy for selected patients with severe respiratory failure, serious complications such as CNS injury, hemorrhage, renal insufficiency, infection, and complications of immobility do occur, and each patient should be carefully evaluated by experienced personnel in order to choose the optimal timing and mode of ECMO support.

ACUTE RESPIRATORY DISTRESS SYNDROME

ARDS is a syndrome of acute respiratory failure characterized by increased pulmonary capillary permeability resulting in bilateral diffuse alveolar infiltrates on chest radiography, decreased lung compliance, and hypoxemia that is refractory to supplemental oxygen. Mortality rates for pediatric ARDS have fluctuated over time, depending on the diagnostic criteria, the presence of important coexisting conditions, and the quality and consistency of supportive care provided in the ICU. Mortality rates as high as 60%–75% were reported in the 1980s and early 1990s. Since that time there has been a trend toward decreased mortality in pediatric ARDS, ranging from 8% to 40%, though mortality among immunocompromised patients still approaches 60%. Across all subpopulations of pediatric ARDS patients, nonpulmonary organ failure remains an important cause of mortality.

Current consensus diagnostic criteria for ARDS in adult patients include (1) acute onset; (2) bilateral pulmonary infiltrates on chest radiograph; (3) no clinical evidence of left atrial hypertension; and (4) severe hypoxemia in which the ratio of the arterial oxygen level (PaO₂) to inspired oxygen concentration (FIO₂) or P/F ratio is 300 or less while receiving a PEEP of at least 5 cm H₂O via mechanical ventilation. The P/F ratio defines the severity of ARDS, with a P/F ratio between 300 and 200 categorized as mild ARDS; 200–100, moderate ARDS; and less 100, severe ARDS. Pediatric criteria for diagnosing ARDS are similar, but with notable differences including allowing for pulmonary infiltrates to be unilateral, utilizing the oxygenation index (OI) as the marker of ARDS severity in mechanically ventilated patients, and broadening the oxygenation criteria to include measures based on pulse oximetry saturations.

Presentation & Pathophysiology

ARDS may be precipitated by a variety of insults (Table 14–5). Pneumonia and sepsis account for the majority of ARDS cases in children. Despite the diversity of potential causes, the clinical presentation is remarkably similar in most cases. ARDS can be divided roughly into four clinical phases (Table 14–6). In the earliest phase, the patient may have dyspnea and tachypnea with a relatively normal PaO₂ and hyperventilation-induced respiratory alkalosis. No significant abnormalities are noted on physical or radiologic examination of the chest. Experimental studies suggest that neutrophils accumulate in the lungs at this stage and that their products damage lung endothelium.

Over the next few hours, hypoxemia worsens and respiratory distress becomes clinically apparent, with cyanosis, tachycardia, irritability, and dyspnea. Early radiographic changes include the appearance of increasingly confluent alveolar infiltrates initially appearing in dependent lung fields, in a pattern suggestive of pulmonary edema. Proteinaceous exudates into the alveolar space and direct injury to type II alveolar pneumocytes cause surfactant inactivation and deficiency. As a result, the injured lung requires high inflation pressures to achieve lung opening, and increased PEEP to maintain end-expiratory volume.

Injury to the alveolar type II cell also reduces the capacity for alveolar fluid clearance. Under normal conditions, sodium is taken up from the alveolar space by channels on the apical surface of type II cells and then actively transported across the basolateral cell membrane into the interstitial space. This process creates a gradient for the passive movement of water across the alveolar epithelium and back into the interstitium. In ARDS, this mechanism becomes overwhelmed as direct lung injury depopulates the alveolar epithelium, creating conditions that favor alveolar fluid accumulation. Pulmonary hypertension, reduced lung compliance, and increased airways resistance are also commonly observed in ARDS.

Computed tomography (CT) studies of adult patients in the acute phases of ARDS demonstrate a heterogeneous pattern of lung involvement. The most dependent lung regions remain consolidated throughout the respiratory cycle and can only be recruited using exceedingly high inflation pressures. The most nondependent regions are overinflated throughout the respiratory cycle. Between these two zones lies a region that is either normally inflated or repetitively cycles between inflation and collapse. Attempts to improve oxygenation by recruiting the collapsed dependent lung regions occur at the expense of damaging nondependent regions by hyperinflation. This process, termed volutrauma, incites a potent inflammatory response that is capable of worsening non-pulmonary organ dysfunction. Even in normal lungs, ventilation with large tidal volumes and low PEEP levels can produce a lung injury that is indistinguishable from ARDS. This phenomenon is called ventilator-induced lung injury. Taken together, these findings suggest that mechanical injury from positive pressure ventilation is superimposed on the initial insult and is an integral part of the pathogenesis of ARDS. Appreciation of this phenomenon has prompted a shift toward ventilating ARDS patients with smaller tidal volumes and a tolerance for the relative hypercarbia that typically ensues. Published evidence currently supports using PEEP levels sufficient to stabilize those alveoli with tendency to collapse at end-expiration but below a threshold level that would overdistend nondependent lung regions at end-inspiration. Volutrauma is then mitigated by tidal volume reduction or plateau pressure limitation. This approach is termed the “open-lung strategy” of mechanical ventilation.

The subacute phase of ARDS (2–10 days after lung injury) is characterized by type II pneumocyte and fibroblast proliferation in the interstitium of the lung. This results in decreased lung volumes and signs of consolidation that are noted clinically and radiographically. Worsening of the hypoxemia with an increasing shunt fraction occurs, as well as a further decrease in lung compliance. Some patients develop an accelerated fibrosing alveolitis. The mechanisms responsible for these changes are unclear. Current investigation centers on the role of growth and differentiation factors, such as transforming growth factor-β and platelet-derived growth factor released by resident and nonresident lung cells, such as alveolar macrophages, mast cells, neutrophils, alveolar type II cells, and fibroblasts. During the chronic phase of ARDS (10–14 days after lung injury), fibrosis, emphysema, and pulmonary vascular obliteration occur. During this phase of the illness, oxygenation defects generally improve, and the lung becomes more fragile and susceptible to barotrauma. Air leak is common among patients ventilated with high airway pressures at this late stage. Also, patients have increased dead space and difficulties with ventilation are common. Airway compliance remains low because of ongoing pulmonary fibrosis and insufficient surfactant production.

Secondary infections are common in the subacute and chronic phases of ARDS and can impact clinical outcomes. The mechanisms responsible for increased host susceptibility to infection during this phase are not well understood. Mortality in the late phase of ARDS can exceed 80%. Death is usually caused by multiorgan failure and systemic hemodynamic instability rather than by hypoxemia.

Treatment

Contemporary ventilator management of ARDS is directed at protecting vulnerable lung regions from cyclic alveolar collapse at end expiration and protecting overinflated lung regions from hyperinflation at end inspiration. The actual mode of mechanical ventilation (eg, volume limited vs pressure limited) employed for ARDS is ultimately not as important as limiting phasic alveolar stretch and stabilizing lung units that are prone to repetitive end expiratory collapse. A landmark multicenter trial established that adult ARDS patients who were ventilated using a 6-mL/kg (ideal body weight) tidal volume had a 22% mortality reduction and fewer extrapulmonary organ failures relative to those randomized to receive tidal volumes of 12 mL/kg. Although this trial has never been replicated in pediatric patients, application of these same management principles has gained widespread acceptance among pediatric ICU clinicians.

Given the large body of evidence supporting the benefits of low tidal volume ventilation, we suggest that mechanical ventilation of pediatric ARDS patients be initiated using a tidal volume of 6–8 mL/kg (ideal body weight), combined with PEEP sufficient to produce target arterial saturations (≥ 88%–90%) using an FIO₂ of 0.6 or less. In general, this can be accomplished by incremental increases in PEEP until adequate oxygenation is achieved or until a limiting side effect of the PEEP is reached. Whenever escalating mechanical ventilator settings, clinicians should minimize the ETT cuff leak (if possible), ensure an appropriate plane of patient sedation, and optimize the ventilation to perfusion relationship by verifying that the patient’s intravascular volume status is appropriate. Permissive hypercapnia (ie, accepting elevated PaCO₂) should be used unless a clear contraindication exists (eg, increased ICP). Throughout the course, efforts should be made to limit the alveolar plateau pressure (pressure at end-inspiration) to 25–30 cm H₂O or less.

Fluid management is an important element of the care of patients with ARDS. Given the increased pulmonary capillary permeability in ARDS, further pulmonary edema accumulation is likely with any elevation in pulmonary hydrostatic pressures. Evidence in adults has shown that a “conservative” fluid strategy targeting lower cardiac filling pressures (CVP < 4 mm Hg) is associated with better oxygenation and a shorter duration of mechanical ventilation compared to a “liberal” fluid strategy targeting CVP 10–14 mm Hg. Fluid restriction should only be implemented after hemodynamic variables stabilize and volume resuscitation should not be denied to hemodynamically unstable patients with ARDS.

Patients with ARDS require careful monitoring. Given the risks of ventilator-induced lung injury and the inherent limitations of pulse oximetry and capnography, ABG analysis is preferred for accurate assessment of oxygenation and ventilation and careful titration of mechanical ventilation. Indwelling arterial catheters are useful for continuous blood pressure monitoring and frequent laboratory sampling. Since secondary infections are common and contribute to increased mortality rates, surveillance for infection is important by obtaining appropriate cultures and following the temperature curve and white blood cell count. Renal, hepatic, and GI function should be watched closely because of the prognostic implications of multiorgan dysfunction in ARDS.

For patients failing these standard approaches of mechanical ventilation and fluid restriction, several alternative or rescue therapies are available. Prone positioning is a technique of changing the patient’s position in bed from supine to prone, with the goal of improving ventilation of collapsed dependent lung units via postural drainage and improved V/Q matching. This technique can dramatically improve gas exchange in the short term, particularly for patients early in the course of ARDS, but the gains are often not sustained. Clinical trials examining the role of prone positioning in adults have shown a survival benefit in those with severe disease, but no study in children with ARDS has shown a clear improvement in mortality or in duration of mechanical ventilation. HFOV has been used successfully for many years in pediatric patients with ARDS; however, studies in adults have shown no benefit or an increase in mortality with HFOV. No pediatric studies to date have compared HFOV to a modern lung protective conventional ventilation strategy, and whether HFOV provides any advantage over conventional ventilation for pediatric ARDS remains unclear. In general, HFOV is considered a rescue therapy for patients with severe hypoxemia failing conventional ventilation. Based on the ability of inhaled nitric oxide (iNO) to reduce pulmonary artery pressure and to improve the matching of ventilation with perfusion without producing systemic vasodilation, iNO can be used as a therapy for refractory ARDS. Several multicenter trials of iNO in the treatment of ARDS, both in adults and in children, showed acute improvements in oxygenation in subsets of patients, but no significant improvement in overall survival. As a result, iNO cannot be recommended as a standard therapy for ARDS. Finally, ECMO has been used to support pediatric patients with severe ARDS. Recent registry data suggest the overall survival rate for children who require ECMO for ARDS is around 50%–60%. To date, the efficacy of ECMO has not been evaluated against lung protective ventilation strategies for pediatric ARDS in a prospective randomized trial. In addition, recent improvements in outcome for pediatric ARDS patients receiving “conventional” therapies have made the role of ECMO less clear and have made further prospective randomized studies of ECMO difficult to complete. For now, ECMO remains a viable rescue therapy for patients with severe ARDS that is unresponsive to other modalities.

Outcomes

Information regarding the long-term outcome of pediatric patients with ARDS remains limited. One report of 10 children followed 1–4 years after severe ARDS showed that three children were still symptomatic and seven had hypoxemia at rest. Until further information is available, all patients with a history of ARDS need close follow-up of pulmonary function.

STATUS ASTHMATICUS

Pathogenesis

Life-threatening asthma exacerbations are caused by severe bronchospasm, excessive mucus secretion, inflammation, and edema of the airways (see Chapter 38). Infants and children are at particular risk for respiratory failure from asthma due to several structural and mechanical features of their lungs. They have less elastic recoil than the adult lung, thicker airway walls leading to greater peripheral airway resistance for any degree of bronchoconstriction, increased airway reactivity to bronchoconstrictors, fewer collateral channels of ventilation, and a more compliant chest wall which can lead to increased work of breathing with airway obstruction. Additional risk factors for severe asthma exacerbation include obesity, lower socioeconomic status, non-Caucasian race, and a prior history of previous ICU admissions or intubations.

Clinical Findings

Patients admitted to the PICU with severe asthma exacerbations can have a variety of constitutional and cardiorespiratory findings. They often have tachypnea, increased use of accessory muscles, and variable aeration. Diffuse wheezing is usually present, but absence of wheeze may indicate severe obstruction impeding airflow. Dyspnea at rest that interferes with the ability to speak and cyanosis are also ominous signs of severe airflow obstruction. These children may also display signs of panic or exhaustion and an altered level of consciousness. Agitation, drowsiness, or confusion can be signs of elevated PaCO₂ levels and impending respiratory failure. Likewise, gasping respirations or frank apnea are indications of respiratory failure and need for intubation.

These patients generally have elevated heart rates (HRs) secondary to stress, dehydration, and β-agonist therapy, and may have systolic and/or diastolic hypotension. Diastolic pressures less than 40 mm Hg in conjunction with extreme tachycardia may impair coronary artery filling and predispose to cardiac ischemia, which can present with chest pain and ST changes on electrocardiogram. Pulsus paradoxus (ie, an exaggerated decrease in systolic blood pressure with inspiration) may be observed and can be used as a marker of disease severity and response to treatment.

Laboratory Findings

In addition to pulse oximetry, blood gas measurements should be considered in critically ill patients with status asthmaticus to evaluate gas exchange and acid-base balance. Although venous blood gas measurements may be acceptable for screening, ABG measurements provide the most accurate and complete information. Patients with severe asthma exacerbations typically have increased minute ventilation and should be expected to have a PaCO₂ less than 40 mm Hg. Normal to elevated PaCO₂ levels suggest respiratory failure. Desaturation or reduced PaO₂ on room air may indicate severely impaired gas exchange and impending respiratory failure but also may occur with initiation of β-agonist therapy and associated ventilation/perfusion mismatching. The presence of metabolic acidosis may signify relative dehydration, inadequate cardiac output, or underlying infection.

Other laboratory evaluations may include serum electrolytes, complete blood counts, and other inflammatory markers if clinically indicated. Patients may demonstrate decreased serum potassium, magnesium, and/or phosphate, especially with prolonged β-agonist use. Leukocytosis is commonly observed during asthma exacerbations and may be due to infection or to demargination of polymorphonuclear leukocytes as a result of stress or corticosteroid treatment. Differentiating between these two etiologies of leukocytosis can be difficult, and measurement of other inflammatory markers can be useful if there is concern for infection.

Chest x-rays should be obtained in patients presenting with severe asthma exacerbations to evaluate for treatable conditions such as pneumonia, foreign-body aspiration, air leak, or a chest mass. Pneumothorax and pneumomediastinum are common complications of severe exacerbations and may only be revealed with chest radiography. Severe wheezing without a prior history of asthma should raise suspicion for alternative diagnoses. Electrocardiograms are not routinely recommended but may be indicated to rule out cardiac ischemia, especially in patients with known cardiac disease, extreme tachycardia and low diastolic blood pressure, or complaints of chest pain.

Although measurements of pulmonary function such as forced expiratory volume in 1 second (FEV₁) or peak expiratory flow (PEF) are recommended in other clinical settings, their use in patients admitted to the PICU with severe asthma exacerbations is limited as those patients are often unable to cooperate with testing. When obtained, values of less than 40% of predicted indicate a severe exacerbation and values less than 25% of predicted indicate imminent respiratory arrest.

Treatment

The key treatment strategy for status asthmaticus is to reverse the underlying process swiftly and aggressively before respiratory failure requiring endotracheal intubation and mechanical ventilation ensues given the complications of providing mechanical ventilation in patients with severe airflow obstruction. Children with status asthmaticus require IV access, continuous pulse oximetry, and cardiorespiratory monitoring, as close monitoring of gas exchange, cardiovascular status, and mental status are crucial to assessing response to therapy and determining appropriate interventions.

Because of inadequate minute ventilation and V/Q mismatching, patients with severe asthma are almost always hypoxemic and should receive supplemental humidified oxygen immediately to maintain saturations more than 90%. The delivery method will depend on the child’s age, level of oxygen required, and institutional resources, as described earlier in this chapter. Children with clinical signs of dehydration should receive appropriate fluid resuscitation, while avoiding volume overload. Additionally, the hemodynamic effects of certain asthma therapy (peripheral dilation, diastolic hypotension) may also require further fluid resuscitation to maintain cardiac output and avoid metabolic acidosis. Antibiotics are generally not recommended for treatment of status asthmaticus unless a coexisting infection is identified or suspected.

The first-line treatment for rapidly reversing airflow obstruction is the repetitive or continuous administration of inhaled selective short-acting β₂-agonist therapy such as albuterol. The frequency of administration will vary based on the severity of symptoms and the occurrence of adverse side effects. Nebulized albuterol may be given intermittently at a dose of 2.5–5 mg every 10–15 minutes, or it can be administered continuously at a dose of 10 mg/h to a maximum of 20–30 mg/h, usually without serious side effects.

Patients with severe distress and poor inspiratory flow rates may have inadequate delivery of inhaled medications and may require subcutaneous or IV medication. Subcutaneous epinephrine or terbutaline, a relatively specific β₂-agonist, may be used for initial treatment with an acute exacerbation. Continuous IV therapy with terbutaline may also be used with an infusion of 0.5–5 mcg/kg/min after a loading dose of 10 mcg/kg. Because significant tachycardia and other arrhythmias as well as diastolic hypotension are recognized side effects of inhaled and IV β₂-agonist therapy, these children should have close cardiovascular monitoring. An indwelling arterial catheter may be useful for continuous hemodynamic and blood gas monitoring in the most severely ill patients on IV therapy. They may also require additional fluid resuscitation because of hypovolemia from dehydration compounded by the vasodilating effects of β₂-agonist therapies.

In addition to β₂-agonist therapy, immediate administration of systemic corticosteroids is critical to the early management of life-threatening status asthmaticus. Because enteral medications may not be tolerated in patients with severe exacerbations, administration of IV or IM steroids should be considered early in these children. Both methylprednisolone and dexamethasone have been used in the treatment of status asthmaticus.

For severe exacerbations unresponsive to the initial treatments listed previously, additional treatments may be considered despite limited clinical pediatric evidence. Ipratropium bromide, an inhaled anticholinergic bronchodilator, is commonly used in emergency medicine and is a reasonable intervention in the PICU, despite limited evidence of efficacy. Administration of magnesium sulfate may also be considered for patients who are unresponsive to early treatment or who have impending respiratory failure. The bronchodilatory properties of magnesium sulfate are thought to be caused by interference with calcium flux in the bronchial smooth muscle cell. Hypotension and flushing may occur with administration and should be anticipated with adequate fluid resuscitation. Heliox-driven albuterol nebulization can also be considered for patients refractory to conventional therapy. Heliox is a mixture of helium and oxygen that has a lower viscosity than ambient air and can improve airway delivery of albuterol and gas exchange. However, a mixture of at least 60%–70% helium is required to be effective, thus limiting its use in patients with severe hypoxia.

Methylxanthines, such as theophylline and aminophylline, may also be considered for the management of severe asthma, although their use remains controversial. The theoretical benefit of methylxanthines is relaxation of airway smooth muscle by preventing degradation of cyclic guanosine monophosphate, a mechanism of action distinct from that of β₂-agonists. In addition, mucociliary inflammatory mediators and microvascular permeability are reduced. Unfortunately, the pharmacokinetics of these agents are erratic, and the narrow therapeutic window can be difficult to manage, with serious side effects such as seizures and cardiac arrhythmias occurring with higher drug levels. These concerns, in addition to mixed evidence of benefit, have led to a general recommendation against the routine use of methylxanthines for asthma exacerbations. However, they may still have a role in individual cases of severe refractory asthma as a means to prevent intubation. When a methylxanthine is added to a patient’s care, close therapeutic drug monitoring is essential and consultation with a pharmacist recommended.

NIV may be used to support patients with severe asthma exacerbations and help avoid the need for intubation and mechanical ventilation. Positive-pressure ventilation may help avoid airway collapse during exhalation as well as to unload fatigued respiratory muscles by reducing the force required to initiate each breath. Because of its noninvasive interface, spontaneous breathing and upper airway function are preserved, allowing the patient to provide his/her own airway clearance. Data on the effectiveness of NIV for acute severe asthma in children are limited, but some small studies and case series have shown improvements in gas exchange and respiratory effort. Careful titration of inspiratory and expiratory pressures is essential, however, to avoid complications of positive pressure.

If aggressive management fails to result in significant improvement, endotracheal intubation and mechanical ventilation may be necessary. Patients who present with apnea or coma should be intubated immediately. If there is steady deterioration despite intensive therapy for asthma, intubation should occur before acute respiratory arrest. The intubation procedure can be dangerous for these patients, given the high risk of barotrauma and cardiovascular collapse, and should be performed by the most experienced provider available.

Mechanical ventilation for patients with asthma is difficult because the severe airflow obstruction often leads to very high airway pressures, air trapping, and resultant barotrauma. Therefore, the goal of mechanical ventilation in this setting is to maintain adequate oxygenation and ventilation with the least amount of barotrauma until other therapies become effective. This approach typically means accepting some degree of hypercarbia in order to avoid complications of aggressive ventilation. Because of the severe inspiratory and expiratory airflow obstruction, these patients will require long inspiratory times to deliver a breath and long expiratory times to avoid air trapping. Either volume- or pressure-targeted modes of ventilation can be used, although volume and pressure limits should be closely monitored and low (≤ 6 cc/kg) tidal volumes used initially. In general, the ventilator rate should be decreased until the expiratory time is long enough to allow emptying prior to the next machine breath. The level of PEEP should be titrated to minimize air trapping from either auto-PEEP or dynamic obstruction. If possible, and when a patient moves toward extubation, a support mode of ventilation is useful, as the patient can set his or her own I-time and flow rate.

These ventilator strategies and the resulting hypercarbia typically are uncomfortable, requiring that patients be heavily sedated. Ketamine is a dissociative anesthetic with bronchodilatory properties that can be used to facilitate intubation and also as a sedative infusion for intubated patients. Ketamine can also increase bronchial secretions, which may limit its use in certain patients or require administration of an anticholinergic agent. Barbiturates and morphine should be avoided, as both can increase histamine release and worsen bronchospasm. Many patients will also require neuromuscular blockade initially to optimize ventilation and minimize airway pressures. In intubated patients not responding to the preceding strategies, inhaled anesthetics, such as isoflurane, should be considered. These agents act not only as anesthetics but also cause airway smooth muscle relaxation. Inhalational anesthetics must be used with caution, however, as they can also cause significant hypotension due to vasodilation and myocardial depression. Finally, use of ECMO has been reported for severe cases of status asthmaticus and could be considered as a rescue therapy.

Prognosis

Status asthmaticus remains among the most common reasons for admission to the PICU, and it is associated with a surprisingly high mortality rate (1%–3%), especially in patients with a previous PICU admission. Careful but expedient management, however, can reduce the associated morbidities and mortality. As many as 75% of patients admitted to the PICU with life-threatening asthma flares will be readmitted with a future exacerbation, emphasizing the need for careful outpatient follow-up of this high-risk population.

SHOCK

Pathogenesis

Shock is a syndrome characterized by inadequate oxygen delivery to meet the body’s metabolic demands. Shock can complicate multiple different disease processes and can be categorized based on the primary physiologic disturbance (Table 14–7).

Shock, regardless of underlying etiology, can be best understood by examining the factors affecting the balance between delivery of oxygen to the tissues and consumption of oxygen by the tissues. Metabolic failure may occur as a result of reduced oxygen delivery (as in respiratory or cardiac failure or acute hemorrhage), increased tissue demand (as in infection, burns, or other major physiologic stresses), or impaired oxygen utilization (as in severe sepsis), or combinations of all three conditions. These may result in anaerobic cellular metabolism, hypoxia, lactic acidosis, and, ultimately, irreversible cellular damage if not reversed.

Oxygen delivery (DO₂) is defined as the product of the cardiac output and the oxygen content of arterial blood (CaO₂) delivered by the heart. Cardiac output, in turn, is determined by ventricular stroke volume (SV) and HR. SV is influenced by preload, afterload, contractility, and cardiac rhythm. Numerous conditions can disrupt one or more of these factors, leading to decreased cardiac output. Preload can be decreased as a result of hypovolemia due to hemorrhage or dehydration or as a result of vasodilation due to anaphylaxis, medications, or septic shock. Impaired contractility can occur with conditions such as cardiomyopathy, myocardial ischemia/reperfusion following a cardiac arrest, postcardiac surgery, and sepsis. Age-dependent differences in myocardial physiology can also affect systolic performance and contractility. For example, in the infant heart, the sarcolemma, sarcoplasmic reticulum, and T-tubules are less well developed than in older children, resulting in a greater dependency on extracellular serum calcium concentrations for contraction. Afterload can be increased, as seen in late septic shock and cardiac dysfunction, or decreased, as in “warm” septic shock. Cardiac dysrhythmias can also alter cardiac output and contribute to inadequate oxygen delivery. One common example is supraventricular tachycardia, in which reduced time for ventricular filling can lead to reduced SV and cardiac output.

The oxygen content of arterial blood consists of the oxygen bound to hemoglobin and the oxygen dissolved in the blood. The bound oxygen is determined by the hemoglobin concentration and the percent of the hemoglobin saturated by oxygen. The dissolved oxygen is calculated from the partial pressure of oxygen in the arterial blood (PaO₂). In general, the main determinant of arterial oxygen content is the bound oxygen. Illnesses that affect the oxygen saturation of hemoglobin or alter hemoglobin concentration can impair oxygen delivery. Low hemoglobin oxygen saturations most commonly occur as a result of impaired uptake of oxygen in the lungs. Low hemoglobin concentrations, as in hemorrhage or other causes of anemia, reduce oxygen delivery, as do abnormal hemoglobins such as carboxyhemoglobin (from carbon monoxide poisoning) and methemoglobin.

Clinical Findings

The clinical presentation of shock can be categorized into a series of recognizable stages: compensated, hypotensive or decompensated, and irreversible. Patients in compensated shock have relatively normal blood pressures, and compensatory mechanisms preserve oxygen delivery. In infants, a compensatory increase in cardiac output is achieved primarily by increases in HR, given the limited ability of infants to increase SV. In older patients, SV and HR both increase to improve cardiac output. Blood pressure remains normal initially because of peripheral vasoconstriction and increased systemic vascular resistance. Drops in blood pressure occur late, defining hypotensive shock. Patients in hypotensive shock are at risk of developing multiorgan system failure (MOSF), which carries a high risk of mortality. In extreme cases, organ damage can progress to the point that restoration of oxygen delivery will not improve organ function, a condition known as irreversible shock.

The symptoms and signs of shock result from end-organ dysfunction caused by inadequate oxygen delivery. Because this condition can progress rapidly to serious illness or death, rapid assessment of a child in shock is essential to determining the need for resuscitation. In patients with impaired cardiac output and peripheral vasoconstriction, the skin will be cool and pale with delayed capillary refill (> 3 seconds) and thready pulses. Additionally, the skin may appear gray or ashen, particularly in newborns, and mottled or cyanotic in patients with decreased cardiac output. In contrast, patients with “warm” or septic shock can present with warm skin with brisk capillary refill and bounding pulses. The detection of peripheral edema is a worrisome sign and can indicate severe vascular leak due to sepsis or poor cardiac output with fluid and sodium retention. The skin examination can also provide insight into the diagnosis (eg, the presence of rash such as purpura fulminans may indicate an infectious etiology) or reveal the site and extent of traumatic injury. Cracked, parched lips, and dry mucous membranes may indicate severe volume depletion.

Tachycardia is an important and early sign of shock and is typically apparent well before hypotension, which is a late feature in pediatric shock. Not all patients can mount an appropriate increase in HR, however, and the presence of bradycardia in a patient with shock is particularly ominous. Peripheral pulses will weaken first in shock as cardiac output is diverted to the body core. Shock in an infant associated with a discrepancy in pulses between lower extremities and upper extremities may indicate a critical coarctation of the aorta with closure of the ductus arteriosus. A gallop cardiac rhythm can indicate heart failure, while a pathologic murmur suggests the possibility of congenital heart disease or valvular dysfunction. A rub or faint, distant heart sounds may indicate a pericardial effusion. Rales, hypoxia, and increased work of breathing occur in patients with shock from heart failure or acute lung injury, and a patient with severe metabolic acidosis due to shock will have compensatory tachypnea and respiratory alkalosis. Urine output is directly proportionate to renal blood flow and the glomerular filtration rate and, therefore, is a good reflection of cardiac output. Normal urine output is greater than 1 mL/kg/h; output less than 0.5 mL/kg/h is considered significantly decreased. Hepatomegaly may suggest heart failure or fluid overload, while splenomegaly may suggest an oncologic process and abdominal distension may suggest obstruction or perforated viscus as the etiology of shock.

The level of consciousness reflects the adequacy of brain cortical perfusion. When brain perfusion is severely impaired, the infant or child first fails to respond to verbal stimuli, then to light touch, and finally to pain. Lack of motor response and failure to cry in response to venipuncture or lumbar puncture is ominous. In uncompensated shock with hypotension, brainstem perfusion may be decreased. Poor thalamic perfusion can result in loss of sympathetic tone. Finally, poor medullary flow produces irregular respirations followed by gasping, apnea, and respiratory arrest.

Monitoring

Laboratory studies in the patient with suspected shock should be directed at evaluating the etiology of shock, assessing the extent of impaired oxygen delivery, and identifying signs of end-organ dysfunction due to inadequate oxygen delivery (Table 14–8). Assessments of oxygen delivery require measurement of oxygen saturation and hemoglobin concentration. Pulse oximetry is adequate to measure oxygen saturation in patients with low oxygen requirements. ABG analyses provide more accurate oxygen measurements, which are important for optimizing mechanical ventilation in patients with significant hypoxemia, and provide measurements of arterial pH, which can reflect the adequacy of tissue perfusion. Measurements of central venous oxygen saturation can serve as a measure of the adequacy of overall oxygen delivery. If oxygen delivery is inadequate for the needs of the tissues, a greater portion of that oxygen will be consumed and the central venous saturation will be lower than normal (< 70% in a patient without cyanotic heart disease). In contrast, patients with septic shock may have an elevated central venous saturation due to impaired oxygen utilization by the tissues (> 80%).

Additional laboratory signs of organ dysfunction include evidence of anaerobic metabolism such as acidemia and elevated lactate, increased serum creatinine, or abnormal liver function tests such as elevated transaminases or reduced production of clotting factors. Blood chemistry measurements are also essential in patients with shock. Hypo- or hypernatremia are common, as are potentially life-threatening abnormalities in potassium levels, particularly hyperkalemia in patients with impaired renal function due to shock. Patients in shock may have decreased serum ionized calcium levels, which will adversely impact cardiac function, especially in infants. Calcium homeostasis also requires normal magnesium levels, and renal failure may disrupt phosphorus levels. Evaluation of a coagulation panel is required to detect disseminated intravascular coagulation (DIC), particularly in patients with purpura fulminans or petechiae, or in those at risk for thrombosis.

The selection of imaging studies, similar to laboratory studies, should be guided by the presumed etiology of shock. For patients presenting with shock secondary to trauma, standard trauma protocols to evaluate organ damage and potential sites of hemorrhage are indicated. Chest x-rays can evaluate the extent of airspace disease and presence of pleural effusions or pneumothorax and evaluate for pulmonary edema and cardiomegaly. CT of the chest or abdomen may be indicated to better evaluate sites of infection in septic shock, and echocardiography can provide important information about cardiac anatomy and function.

Patients with shock often need invasive hemodynamic monitoring for diagnostic and therapeutic reasons. Arterial catheters provide constant blood pressure readings, and to an experienced interpreter, the shape of the waveform is helpful in evaluating cardiac output. Central venous catheters allow monitoring of central venous pressure (CVP) and central venous oxygen saturation. CVP monitoring does not provide information about absolute volume status, but can provide useful information about relative changes in volume status as therapy is given. Pulmonary artery catheters can also provide valuable information on cardiac status and vascular resistance and enables calculations of oxygen delivery and consumption (Table 14–9), but these catheters are associated with a higher complication rate than CVP lines and are no longer commonly used in either adult or pediatric critical care. Principles of shock treatment are described in Sepsis section.

SEPSIS

Sepsis and septic shock require particular consideration because sepsis is one of the major illnesses leading to admission to the PICU. Worldwide, an estimated 18 million patients develop sepsis each year, with 750,000 of those cases in North America. Sepsis is the tenth leading cause of death in the United States and accounts for approximately 40% of intensive care unit (ICU) expenditures in the United States and Europe. Among children, an estimated 42,000 cases of severe sepsis occur annually in the United States, accompanied by a mortality rate of nearly 10%. The incidence of severe sepsis is highest in infancy, remains relatively low from age 1 to mid-life, then rises again in later life.

Published literature regarding sepsis uses a number of overlapping and sometimes confusing terminologies. In earlier definitions, systemic inflammatory response syndrome (SIRS) referred to a nonspecific syndrome of systemic inflammation typically associated with fever, tachycardia, tachypnea, and an abnormal white blood cell count. Sepsis was defined as documented or suspected infection accompanied by clinical and laboratory signs of systemic inflammation, and severe sepsis was defined as sepsis along with evidence of at least one sepsis-induced major organ dysfunction such as hypotension, hypoxemia, lactic acidosis, oliguria, renal failure, thrombocytopenia, coagulopathy, or hyperbilirubinemia. Septic shock was severe sepsis associated with impaired oxygen delivery, typically defined clinically as hypotension requiring either IV fluid boluses or pressor agents and a persistently elevated blood lactate level. A 2016 revision to the definitions effectively eliminated the terms SIRS and severe sepsis, and redefined sepsis as documented or suspected infection with at least one organ failure. Though the criteria used to define sepsis in adults and children differ in published guidelines (Table 14–10), the more specific adult criteria provide a useful framework for thinking about sepsis-related organ dysfunction. Of note, the number of organ systems affected by severe sepsis is an important prognostic factor. The risk of death from sepsis rises with the number of organ failures, with a mortality rate of 7%–10% with single-organ failure and up to 50% mortality with four-organ failures.

In addition to impaired oxygen delivery, sepsis and septic shock are also associated with impaired utilization of delivered oxygen. The etiology of this impaired oxygen utilization is not well understood but is likely multifactorial, including maldistribution of blood flow in the microcirculation as well as mitochondrial dysfunction. Recent work has also brought to light the critical role of the innate immune system in sepsis. Infectious agents release pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide or peptidoglycans, and damaged tissues release endogenous proteins and nucleic acids that act as molecular triggers, collectively referred to as damage-associated molecular patterns (DAMPs). These molecules are recognized by pattern recognition receptors of the innate immune system, most prominently the toll-like receptors, which then trigger inflammatory cascades throughout the body. Derangements of adaptive immunity also contribute to the pathogenesis of sepsis. Toll-like receptor signaling may activate subsets of regulatory T cells in septic patients, leading to either immune paralysis or uncontrolled inflammation depending on the pathophysiologic setting. Cytokine production and leukocyte activation lead to endothelial damage and activation of the clotting system. Microvascular thrombi lead to impaired tissue perfusion, which leads to further tissue damage, which in turn leads to further activation of the immune system. The end result of these processes is impaired oxygen delivery to the tissues, impaired oxygen utilization, and metabolic downregulation, leading to end-organ dysfunction and ultimately to death if the process is not reversed.

Treatment of Shock & Sepsis

Much attention has been directed in recent years to the role of standardized treatment guidelines in improving outcomes from shock and sepsis, and detailed guidelines are now available from several professional organizations, most prominently the American Heart Association Pediatric Advanced Life Support (PALS) guidelines for initial management of shock in children, and the Surviving Sepsis Campaign guidelines for management of sepsis in adults and children. A key principle of both guidelines is that early recognition and treatment of shock and sepsis, preferably stemming from a consistent organized clinical approach, improve outcomes in all age ranges.

Regardless of the etiology, the end result of shock is organ dysfunction, which if untreated can lead to irreversible MOSF. Therefore, early recognition of shock, coupled with early control of underlying cause and supportive care, is necessary to minimize end-organ injury and improve survival. Airway, breathing, and circulation should be rapidly assessed, with appropriate stabilization of the airway, support of breathing, and stabilization of circulation. Indications for intubation and mechanical ventilation include altered mental status, significant hemodynamic instability, inability to protect the airway, poor respiratory effort, high work of breathing, poor gas exchange, or need for procedural intervention. Because of low FRC, infants and neonates are more likely to require early initiation of NIV or endotracheal intubation. Use of etomidate for sedation during intubation should be avoided in patients suspected with sepsis due to its association with adrenal suppression and increased mortality. A temporary intraosseous line should be placed if IV access cannot be rapidly obtained for resuscitation fluids and medications. A central venous line should be considered in patients with hemodynamic instability, particularly if they require ongoing resuscitation and infusions of vasoactive medications. While femoral venous lines are simpler and safer to place, subclavian and internal jugular lines are preferred for more accurate and consistent central venous saturation and pressure monitoring, although they do carry the additional risk of pneumothorax. The rapidity and accuracy of placing central venous lines can be improved with the use of ultrasound guidance.

Empiric antimicrobials should be delivered promptly, ideally within 1 hour of presentation in patients with suspected sepsis. Antibiotics should be chosen according to the most likely cause of infection. While it is highly desirable to obtain cultures prior to initiation of antibiotics in order to guide the choice and duration of antibiotic coverage, the acquisition of cultures should never delay antibiotic administration in patients with suspected sepsis. Early and aggressive control of sources of infection is also essential for patients with sepsis and septic shock, including surgical drainage of abscesses or other infected spaces or removal of infected foreign bodies such as vascular catheters.

An important element of the treatment of shock is early aggressive fluid resuscitation targeted to measurable physiologic endpoints of organ perfusion, so-called “early goal directed therapy.” Fluid resuscitation should begin with 20 mL/kg increments administered over 5–10 minutes and repeated as necessary. Fluid administration should be titrated to reverse hypotension and achieve normal capillary refill, pulses, level of consciousness, and urine output. Trends in serum lactate measurements can also provide a useful marker of reversal of shock to guide fluid administration. If pulmonary edema or hepatomegaly develops, vasoactive medication infusions should be used in place of more fluid, and cardiac function evaluated for evidence of cardiogenic shock. Large volumes of fluid for acute stabilization in children with hypovolemic or septic shock may be necessary to restore adequate oxygen delivery and do not necessarily increase the incidence of ARDS or cerebral edema. Patients who do not respond rapidly to 40–60 mL/kg should be monitored in an intensive care setting and considered for inotropic therapy and invasive hemodynamic monitoring. Initial fluid resuscitation should consist of crystalloid (salt solution), which is readily available and inexpensive. Albumin has been shown to be safe in adults and children with septic shock and should be considered when patients have received large volumes of crystalloid and require ongoing resuscitation. Hydroxyethyl starches (HES) are not recommended as resuscitation fluids in septic shock based on adult studies, which showed no improvement in mortality with HES versus normal saline, but an increased risk of renal failure.

Inotropic and vasopressor agents should be considered for patients with refractory shock despite receiving 60 mL/kg of fluid resuscitation (Table 14–11). Inotropic medications improve cardiac contractility but can increase myocardial oxygen demand and arrhythmia risk; vasopressor medications increase vascular tone and resistance but can increase cardiac afterload. Inotropic or vasopressor therapy should be selected based on the hemodynamic state, that is, cardiac output and systemic vascular resistance, and reassessed with changes in clinical course. These medications can be delivered through an intraosseous or peripheral line until stable central access is secured to prevent a delay in initiation. Although dopamine (α- and β-adrenergic agonist) is no longer recommended for adults with septic shock due to arrhythmogenic effects in this population, dopamine remains an acceptable first-line vasopressor in the pediatric population. Either norepinephrine (α- and β₁-adrenergic agonist) or epinephrine (potent α- and β-adrenergic agonist) may be useful for dopamine-refractory shock; generally, epinephrine has a greater net effect on cardiac output and is preferred for cold shock states, while norepinephrine has a greater net effect on vascular tone and is preferred for warm shock states. Vasopressin may be considered for patients failing catecholamine infusions but has not been clearly shown to improve outcomes from severe sepsis in children. In patients with low cardiac output and high systemic vascular resistance, milrinone, a type III phosphodiesterase inhibitor with inotropic and vasodilator activity, can be added to other more potent inotropic agents. Alternatively, dobutamine (selective β-agonist) may be used to improve myocardial contractility and reduce afterload. As hypocalcemia also may contribute to cardiac dysfunction in shock, calcium replacement should be given to normalize ionized calcium levels.

If perfusion is still inadequate despite aggressive fluid and pressor support, the patient can be considered to have catecholamine-resistant septic shock. This condition may be related to critical illness-related corticosteroid insufficiency (CIRCI), which is a condition of impaired adrenal responsiveness that may occur in as many as 30%–50% of critically ill patients. Absolute adrenal insufficiency, characterized by impaired adrenal responsiveness, low-circulating cortisol concentrations, and often associated with adrenal hemorrhage, is less common and occurs in fewer than 25% of children with septic shock. Children with fulminant meningococcemia, congenital adrenal hyperplasia, or recent steroid exposure are at the highest risk of absolute adrenal insufficiency, while CIRCI can occur in any critically ill patient. Pediatric patients with fluid-refractory, catecholamine-resistant septic shock and suspected or proven adrenal insufficiency should receive hydrocortisone. The recommended dose of hydrocortisone is 50 mg/m²/day (up to 200 mg/day) either as a continuous infusion or divided doses; however, some children may require higher doses. Hydrocortisone is generally continued until catecholamine support can be successfully discontinued, and a taper should be considered in those children requiring longer than 7 days of therapy.

Cardiogenic shock is often associated with elevated ventricular filling pressures (> 20 mm Hg). Although increasing preload may augment cardiac output for some patients, volume should be administered cautiously in smaller increments as elevated pulmonary venous pressures from cardiac dysfunction may lead to, or worsen, pulmonary edema. In this setting, judicious administration of diuretics combined with inotropic support can reduce pulmonary edema and improve pulmonary compliance, the work of breathing, and oxygenation.

Blood products can be important supportive therapies in patients with shock. Red blood cells can be administered to patients with shock to improve oxygen-carrying capacity. In hemodynamically stable patients, hemoglobin levels are often maintained over 7 g/dL, while the transfusion threshold can be increased to 10 g/dL in unstable patients. DIC is common in shock, particularly septic shock, due to endothelial damage, formation of microvascular emboli, and consumptive coagulopathy. Thus, a process beginning as increased coagulation leads to a bleeding diathesis. Platelets are generally transfused when platelet counts are less than 20,000/μL, or less than 40,000–60,000/μL in a patient with bleeding or requiring surgical intervention. For severe coagulopathies associated with bleeding in the setting of shock, the standard treatment is fresh frozen plasma (FFP) or, for fibrinogen replacement, cryoprecipitate, with close monitoring of prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time (PTT).

Other supportive therapies for shock and sepsis include mechanical ventilation, sedation and analgesia, renal replacement therapy for renal insufficiency, deep vein thrombosis prophylaxis, stress ulcer prophylaxis, nutrition, and glucose control. Finally, ECMO can be considered as a life-saving measure in the treatment of severe shock in patients with recoverable cardiac and pulmonary function who have failed conventional management.

Pediatric neurocritical care is an emerging multidisciplinary field focused on critically ill pediatric patients with neurologic injury due to conditions such as traumatic brain injury (TBI), stroke, status epilepticus, and hypoxic-ischemic brain injury, as well as brain injury that is secondary to other types of critical illness. Neurointensivists work to better understand the distinct pathophysiological and clinical features of pediatric brain injury, develop and apply new diagnostic and monitoring strategies to better understand brain function and dysfunction in real time, and formulate pediatric-specific management guidelines for common neurocritical care problems. While the field is still relatively young, some basic tenets of support for the injured brain are beginning to emerge.

TRAUMATIC BRAIN INJURY

TBIs can be conceptualized as occurring in two phases. Primary injury occurs at the moment that injury disrupts bone, blood vessels, and brain tissue. Prevention through helmets, safety belts, and other injury prevention efforts is the only true means to reduce primary injury. Secondary injury is the indirect result of the primary injury and develops minutes to days after the initiating event. Reducing secondary injury is the focus of first responders, emergency medicine doctors, and intensivists. Management of the brain-injured child aims to optimize delivery of oxygen and nutrients (supply) while reducing hypermetabolic states (demand). Therapy, therefore, focuses on avoidance of factors such hypoxia, hypotension, hypoglycemia, hyperthermia, infection, and agitation.

Pathogenesis

The skull contains a fixed total volume composed of the brain, cerebrospinal fluid (CSF), and cerebral blood. Because of this physical constraint, an increase in volume of one component must be offset by a decrease in one of the other components to maintain a constant ICP (Monro-Kellie doctrine). As a result of a brain injury, the volume of any or all of these components may increase, resulting in increased ICP. Intracranial hypertension is defined as an ICP over 20 mm Hg (vs < 15 mm Hg in healthy children) and is associated with increased morbidity and mortality in brain-injured patients. Intracranial hypertension may occur due to other illnesses in addition to TBI (Table 14–12), but in all cases, the pathogenesis of intracranial hypertension can be understood by considering each of the intracranial components.

The uninjured brain occupies about 80% of the volume within the skull, but this volume can increase dramatically after brain injury as a result of cerebral edema. Vasogenic edema is frequently associated with trauma, tumors, abscesses, and infarct; breakdown of the tight endothelial junctions that make up the blood-brain barrier (BBB) is a hallmark component. As plasma constituents cross the BBB, extracellular water moves into the brain parenchyma. Cytotoxic edema is the most common form of cerebral edema seen in the PICU and is the least easily treated. Cytotoxic edema occurs as a result of direct injury to brain cells, often leading to irreversible cell swelling and death. This form of cerebral edema is typical of TBIs as well as hypoxic-ischemic injuries and metabolic disease. Hydrostatic edema, due to transudation of fluid from the capillaries into the parenchyma as a result of elevated cerebral vascular pressures, and interstitial edema, which results from obstructed CSF flow and appears in a typical periventricular distribution, are less common. Cerebral edema can be diagnosed by characteristic findings on either CT or magnetic resonance imaging (MRI) of the brain.

CSF occupies an estimated 10% of the intracranial space. Intracranial hypertension due primarily to obstructed CSF flow or increased CSF volume (eg, primary or secondary hydrocephalus) is generally easily diagnosed by CT scan and treated with appropriate drainage and shunting. CSF drainage can be of benefit in managing intracranial hypertension even in the absence of overt hydrocephalus.

Cerebral blood volume comprises the final 10% of the intracranial space and is affected by cerebral blood flow. Changes in cerebral blood flow occur by altering cerebral perfusion pressure or vascular resistance. Cerebral perfusion pressure (CPP), defined as mean systemic arterial pressure minus CVP or ICP, whichever is higher, is the driving pressure across the cerebral circulation. Hypotension, which may occur due to hemorrhage from comorbid injuries or as a part of a systemic inflammatory response following TBI, results in decreased CPP. Changes to vascular resistance generally result from alterations in vascular diameter in response to metabolic demands or vascular pressures, responses termed autoregulation. Metabolic autoregulation matches cerebral blood flow to tissue demands. High metabolic rates, such as those induced by fever or seizure activity, increase cerebral blood flow by causing vasodilation, which in turn increases cerebral blood volume; lower metabolic rates allow the vessels to constrict, reducing cerebral blood volume. Partial pressure of carbon dioxide is another important determinant, as elevations in blood PaCO₂ lead to cerebral vasodilation and decreases in PaCO₂ lead to vasoconstriction. Pressure autoregulation, which works to maintain a constant cerebral blood flow in spite of variable systemic blood pressures, links cerebral blood pressure to cerebral blood flow. Within the autoregulatory range of blood pressure, cerebral vessels dilate with low systemic blood pressures or constrict with high systemic blood pressures to maintain constant cerebral blood flow. Above the autoregulatory range, cerebral vessels are maximally constricted, and further increases in systemic pressure will result in increased cerebral blood flow and volume; the opposite is true below the autoregulatory range, and cerebral blood flow will fall with further decreases in systemic pressure. It is not unusual to see partial or complete loss of cerebral blood flow autoregulation following TBI. Cerebral blood flow then becomes dependent on systemic blood pressure (traditionally termed “pressure passive” blood flow).

In addition to direct damage from elevated ICP and cerebral edema, secondary injury following trauma may also occur due to ischemia and/or excitotoxicity. Ischemia results from decreased cerebral blood flow or hypoxemia. Excitotoxicity occurs via excessive glutamate exposure, sodium-dependent neuronal swelling, and calcium-dependent mitochondrial failure. Depletion of adenosine triphosphate (ATP), oxidative stress, calcium fluxes, hypomagnesemia, and hyponatremia may all contribute to these processes.

Clinical Findings

The clinical presentation of TBI is dependent on the nature, location, and size of affected areas in the brain, as well as the amount of edema and infringement of CSF pathways. Physical deformities such as skull fractures and exposure of the brain parenchyma may or may not be apparent. Clinical presentation can be subtle, such as a headache from a concussion, or more severe, such as manifestations of intracranial hypertension (Table 14–13) or complete unresponsiveness. Often, early signs and symptoms are nonspecific, particularly in young children. For these reasons, TBI should be included in the differential diagnosis for a wide range of clinical presentations.

Initial examination of the patient with TBI should include assessment of airway patency, breathing, and cardiovascular function. Mental status should be evaluated, and the Glasgow coma scale (GCS) score calculated. Once stabilized from a cardiac and respiratory standpoint, a more detailed neurologic examination including cranial nerves, spontaneous movement of extremities, strength, sensory perception, and presence or absence of deep tendon reflexes should be performed. Similar considerations apply in patients with suspected intracranial hypertension but no clinical history of trauma. In either setting, repeated neurologic examinations are needed. Head imaging (CT or MRI) is also beneficial to identify specific intracranial injuries, determine the need for surgical intervention, monitor the progression of injuries and cerebral edema, and to monitor for the development of complications.

Treatment

Initial stabilization should begin with support of the airway, breathing, and circulation, but prevention of further neurologic injury should be considered as these steps are completed. Cervical spine immobilization should be strongly considered prior to securing the airway to avoid worsening spinal cord injury. If the GCS is less than 8, or if the patient demonstrates apnea, irregular respirations, significant hypoxia, or other signs concerning for intracranial hypertension, the airway should be secured via endotracheal intubation. Care should be taken during this process to avoid hypercapnia, which will further increase ICP. Similarly, sedative agents used in the process of intubation should be chosen carefully, as adequate sedation is important to blunt further elevations in ICP with airway manipulation. Maintenance of systemic blood pressure is also critically important during this time.

Following intubation and support of systemic blood pressure, treatment strategies for TBI in children are largely focused on optimizing cerebral blood flow and reducing metabolic demand. Minimizing intracranial hypertension is a critical component of management, and current treatment guidelines for children with TBI recommend ICP monitoring for all patients with GCS of 8 or less. Elevated ICP (ICP > 20) can be treated with medical or mechanical interventions.

Medical treatment strategies to reduce ICP rely on osmotic therapies such as hypertonic (≥ 3%) saline and mannitol. Hypertonic saline, given in bolus doses of 2–5 mL/kg of 3% saline or as a continuous infusion, encourages intravascular volume expansion and increases serum osmolality, enhancing movement of excess water out of brain cells and interstitium and into blood vessels for removal by the kidneys. Serum sodium and osmolality should be followed closely to avoid severe hypernatremia or severe hypertonicity when this agent is used. Mannitol, given in doses of 0.25–1 g/kg, exerts a rapid rheologic effect, reducing blood viscosity which improves blood flow and subsequent autoregulatory vasoconstriction. Mannitol also exerts a potent osmotic and diuretic effect. While this may further reduce ICP, it can also result in hypovolemia and hypotension, which reduces CPP and exacerbates secondary injury. Volume status and systemic blood pressures should therefore be monitored closely following administration, and treatment should be prompt to reduce these side effects. Renal failure due to intravascular volume depletion and acute tubular necrosis is a rare side effect and is associated with serum osmolality greater than 320 mOsm/L.

Controlled ventilation is another important element of treating intracranial hypertension. Normocapnia, with a goal PaCO₂ between 35 and 40 mm Hg, is the current standard of care. Hypocapnia (hyperventilation), although acutely effective in causing cerebral vasoconstriction, leads to larger decreases in blood flow than in blood volume, such that hyperventilation may actually compromise CNS perfusion and exacerbate secondary injury. This concept was confirmed by studies showing worse outcomes in head-injured patients consistently hyperventilated to a PaCO₂ of 25 mm Hg or less. Hyperventilation to PaCO₂ levels less than 30 mm Hg—in the past a mainstay in the treatment of intracranial hypertension—is no longer recommended although could be considered for short periods in emergent situations in patients with refractory intracranial hypertension while awaiting more definitive therapy.

Mechanical therapies to reduce ICP are aimed at improved drainage of fluids. Midline positioning and head elevation to 30 degrees can aid in cerebral venous drainage. CSF drainage reduces ICP by reducing CSF volume and can be accomplished by placement of an external ventricular drain in the lateral ventricles of the brain. Timely surgical evacuation of hematomas and other pathologic masses is also a mainstay of TBI treatment.

In some cases, intracranial hypertension is refractory to initial medical and mechanical therapies. In these circumstances, 2019 guidelines suggest three additional measures to reduce ICP: decompressive craniectomy (removal of a portion of the skull and opening of the dura), moderate hypothermia (32–33°C), and high-dose barbiturates. Of note, barbiturates are potent cardiac depressants and their use often leads to hypotension, necessitating the use of vasopressor medications to maintain adequate cerebral and systemic perfusion pressures. Plasma barbiturate levels correlate poorly with effect on ICP, and monitoring of CNS electrical activity by electroencephalography (EEG) is necessary to accurately titrate their use.

In addition to reducing ICP, systemic hemodynamic support is a critical component of optimizing cerebral blood flow. Studies in both adult and pediatric patients with head injury show that even a single episode of hypotension is associated with a marked increase in mortality rates. Maintenance of systemic blood pressure can be accomplished using volume and/or vasopressor medication, and goal systemic pressures are often augmented to maintain CPP in the setting of refractory ICP. Although the ideal CPP in children is not definitively known, 2019 guidelines suggest a goal of 40–50 mmHg, acknowledging that a graded response based on age may be appropriate (eg, 40–55 in infants/toddlers, 50–60 in children, and > 60 in adolescents).

Prevention of ischemia and excitotoxicity are similarly important. Hypoxic episodes (PaO₂ < 60 mm Hg) after TBI are associated with increased morbidity and mortality, and should be prevented. Maintenance of normal ranges for glucose, calcium, magnesium, and phosphorus may be beneficial. Current guidelines also recommend enteral nutrition within 72 hours of injury.

Finally, optimizing oxygen and nutrient delivery to the injured brain should be facilitated by reducing metabolic demands. Aggressive control of fevers (controlled normothermia), using antipyretics and surface cooling devices, is warranted, and continuous temperature monitoring helps prevent over- or undercorrection. Induced hypothermia lowers cerebral metabolism, cerebral blood flow, and cerebral blood volume but has not been shown to improve overall outcome in the pediatric population. Adequate sedation to reduce episodes of agitation and/or pain can further reduce metabolic demands and ICP, although caution should be used, as bolus administration may contribute to systemic hypotension, and therefore cerebral hypoperfusion. Neuromuscular blockade can also be considered as an effective adjunctive therapy. Seizures occur in approximately 30% of patients with severe head injury and result in increased metabolic demand and secondary injury. Continuous EEG should be used in patients with persistent altered mental status or in those requiring heavy sedation. A short course (7 days) of empiric antiepileptic medication is suggested, and seizures noted on EEG should be treated rapidly. Corticosteroids may be of use in reducing vasogenic cerebral edema surrounding tumors and other inflammatory CNS lesions, but they are not recommended in the treatment of TBI.

Complications

Complications are frequent in patients with TBIs and should be anticipated. Nosocomial infections are more common in these patients than other critically ill populations and may lead to worse outcomes. Abnormalities of sodium handling such diabetes insipidus, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), or cerebral salt wasting are also relatively common following serious brain injuries and require careful monitoring and intervention. In more severe cases, cerebral infarctions may occur as a result of ischemia, thrombosis, and progressive edema compromising blood supply. Finally, cerebral herniation presenting with Cushing triad of bradycardia, hypertension, and altered respirations is an ominous and life-threatening medical emergency, often leading to death or serious disability in brain-injured patients.

Prognosis

Many factors will affect prognosis of patients with TBI, especially the inciting event and severity of injury. Experience has shown that it is difficult to predict overall outcome in the initial stabilization period, but lack of improvement in neurologic examination after 24–72 hours (the peak period for swelling) is associated with worse outcomes. Follow-up studies have also demonstrated that “recovery” occurs over time, even months to years.

Inflicted Traumatic Brain Injury

Inflicted traumatic brain injury (iTBI), also referred to as nonaccidental trauma (NAT), accounts for a significant portion of TBIs in infants and young children. Repetitive brain injuries prior to presentation and global hypoxic-ischemic brain damage (as a result of trauma-induced respiratory failure or cardiac arrest) may complicate the pathophysiology. Management of children with iTBI is similar to those with accidental TBI, but additional evaluations should include an ophthalmologic assessment for retinal hemorrhages and a radiologic skeletal survey to identify occult bone fractures. Child advocacy and law enforcement groups should be notified when abuse is suspected. Unfortunately, children with iTBI often have a worse neurologic outcome compared to accidentally injured children.

HYPOXIC-ISCHEMIC ENCEPHALOPATHY

HIE results from global brain hypoxia and ischemia produced by systemic hypoxemia and/or reduced blood flow to the brain. Pediatric HIE is commonly caused by cardiopulmonary arrest due to drowning, hanging or other strangulation, severe respiratory distress, shock, drug overdose/poisoning, lethal arrhythmia, and other insults. Pediatric HIE is associated with poor neurologic outcome. Like TBI, the extent of brain injury in HIE depends on the duration and severity of the initial inciting event and the development of secondary injury over the minutes to days following reestablishment of cerebral blood flow and oxygen delivery.

Clinical Findings

Signs and symptoms of brain injury secondary to hypoxic-ischemic injury are variable and depend on injury severity and affected brain regions. Manifestations of HIE can include cognitive dysfunction, seizures (clinical and subclinical), status epilepticus, stroke, coma, a persistent vegetative state, and irreversible cessation of neurologic function (“brain death”).

Treatment

The initial stabilization of a patient with HIE includes airway management, respiratory support, and maintenance of cardiovascular stability. As with TBIs, treatment strategies for victims of HIE are focused on optimizing cerebral blood flow and mitigating neuronal loss. Blood flow to the brain is dependent on cardiac output, which may be impaired following cardiac arrest and/or injury. Optimization of cardiac function and systemic hemodynamics with fluid resuscitation and inotropic and/or vasopressor agents is necessary to ensure adequate delivery of oxygen and nutrients to the injured brain. Cerebral pressure autoregulation may also be impaired in children who develop HIE as a result of cardiac arrest. Several studies in adult victims of cardiac arrest suggest that maintaining a higher mean blood pressure may better support the postischemic brain, but the degree of pressure dysregulation and blood pressure targets to optimize cerebral blood flow in the ischemic pediatric brain remain unclear. Intracranial hypertension may develop as a result of cerebral edema, but the utility of ICP monitoring and titration of therapies to a normal ICP in HIE patients has not been clearly defined. Use of therapies for ICP reduction varies across pediatric referral centers. Seizures should be aggressively treated, and continuous EEG monitoring is useful for identifying subclinical seizure activity. Similar to the case with TBIs, temperature regulation and maintenance of normothermia are also essential, since the risk of severe disability in patients with HIE increases with fevers. Therapeutic hypothermia (target body temperature 33–35°C) is a mainstay of treating postcardiac arrest HIE in adults and postanoxic HIE in newborns, but published data in the pediatric population do not demonstrate significant benefit.

Prognosis

Accurately predicting outcome in children with HIE is difficult. Out-of-hospital cardiac arrest and/or prolonged cardiopulmonary resuscitation (> 10–15 minutes) are significant risk factors for poor outcome. Other indicators of likely poor outcome include any of the following, 24 hours or more after the inciting event: (1) GCS score less than 3–5, (2) absent pupillary and motor responses, (3) absent spontaneous respiratory effort, (4) bilateral absence of median nerve somatosensory evoked potential (N20), (5) discontinuous, nonreactive, or silent EEG (in the absence of confounding drug administration), and (6) MRI demonstrating watershed, basal ganglia, and brainstem injury. Outcome prediction is enhanced when several assessment modalities are combined.

STATUS EPILEPTICUS

Pathogenesis

Status epilepticus can result from multiple etiologies (Chapter 25). In a patient with a prior diagnosis of epilepsy, common infections such as viral respiratory illnesses can lower the seizure threshold enough to result in prolonged seizure activity, as can nonadherence to antiepileptic medications. In patients without a prior diagnosis of epilepsy, the differential diagnosis is broad. Diagnoses to be considered include complex febrile seizure, CNS tumor, TBI, ischemic or hemorrhagic stroke, CNS infection, hypertensive encephalopathy, electrolyte abnormalities (hyponatremia or hypoglycemia), withdrawal to benzodiazepines or alcohol, acute demyelinating encephalomyelitis, previously unrecognized metabolic disorders, or autoimmune disorders.

Regardless of the etiology, the development of status epilepticus occurs due to an imbalance between excitatory and inhibitory neurotransmission, with rhythmic discharges of multiple neurons in a brain region. Left untreated, these discharges can ultimately result in energy failure and long-lasting changes in neurons, including cell death.

Clinical Findings

While seizures and status epilepticus may be focal in nature (involving only one area of the brain and manifesting in a single body part), classic status epilepticus in considered to be generalized tonic-clonic activity with altered mental status, lasting at least 30 minutes. Loss of bladder or bowel continence may occur. Status epilepticus may be associated with profound respiratory abnormalities, apnea, tachycardia, and/or hypertension or hypotension. Because it is a hypermetabolic state, a long post-ictal period of altered mental status and/or rhabdomyolysis may occur.

Treatment

As with all emergencies, resuscitation begins with attention to airway, breathing, and circulation. If a specific etiology for the seizure can be found (eg, hyponatremia), rapid correction of that abnormality (eg, hypertonic saline) usually results in seizure cessation. In the absence of a clear etiology, treatment generally begins with benzodiazepines, most commonly Ativan 0.1 mg/kg IV, given within the first 5 minutes. This can be repeated, or transition to an alternate agent may be considered. Fosphenytoin 20 mg/kg IV in the general pediatric population or phenobarbital 20 mg/kg IV in the neonatal period are common choices. For refractory status epilepticus that persists after these initial agents, selection of next-line therapies may include infusions of midazolam, propofol, ketamine, or phenobarbital. Close collaboration with neurology and pharmacy experts is encouraged. During treatment of refractory status epilepticus, hypoventilation and apnea may occur, and intubation and initiation of mechanical ventilation are often needed. Similarly, antiepileptic-induced hypotension may occur, and support of systemic blood pressure with volume and/or vasopressor medications is recommended.

Definitions

The kidney is important in maintaining homeostasis for a number of important physiologic processes, including fluid and electrolyte balance, acid-base status, erythropoiesis, and vascular tone. Acute kidney injury (AKI) is a frequent problem in critically ill children, with a range of manifestations from modest reductions in creatinine clearance with preserved urine output to anuria, and even life-threatening electrolyte derangements. Several staging systems have been developed, but the most commonly used are the pRIFLE and KDIGO criteria (Table 14–14).

Pathophysiology

The etiology of AKI in critically ill children is most often multifactorial and related to conditions commonly seen in the intensive care unit. Decreased renal perfusion can occur with systemic hypotension from a variety of etiologies or from elevated intra-abdominal pressures reducing local perfusion (eg, abdominal compartment syndrome). In addition to alterating hemodynamics, sepsis can lead to disturbances of the renal microvasculature from inflammatory mediators and activation of the coagulation system. Other conditions associated with AKI, either through direct or indirect mechanisms, include hypoxia, pulmonary-renal and hepatorenal syndromes, and toxic metabolic byproducts as in rhabdomyolysis or tumor lysis syndrome. Finally, nephrotoxic medications contribute to as much as 25% of cases of AKI, most commonly antibiotics (aminoglycosides, vancomycin) and immunosuppressive medications such as cytotoxic cancer chemotherapeutics and calcineurin inhibitors.

Clinical Findings

In general PICU populations, 10%–40% of patients have AKI at some point in their hospital course. Most cases of AKI develop within the first 24–48 hours of hospitalization, and nearly all within the first week. Irrespective of diagnostic criteria, studies consistently show an independent association between AKI and increased ICU length of stay and mortality. Critically ill patients with AKI can have complications such as electrolyte abnormalities, severe metabolic acidosis and fluid overload. Although the mechanisms are unclear and likely complex, fluid overload exceeding 10% of body weight has been shown to be an independent risk factor for worse outcomes, and patients overloaded by 20% of their body weight in fluid may have as much as an eightfold increased risk of death. The causal relationship between fluid overload and poor outcome is uncertain, but based on these findings, some authorities recommend consideration of renal replacement therapies for patients reaching 10%–20% fluid overload.

Treatment

The management of AKI is directed at alleviating potential contributing factors. Methods to improve renal perfusion include maintenance of adequate cardiac output and blood pressure with fluids and/or vasopressor medications and relief of excess intrathoracic and intra-abdominal pressures when feasible. For the latter, some experts recommend measurement of intra-abdominal pressures to guide therapy. Prospectively validated thresholds of adequate renal perfusion pressures to prevent or reverse AKI are lacking.

Diuretics are commonly used to address fluid overload associated with AKI, but these agents have not been shown to improve renal recovery in children and have been associated with an increased risk of death in adults with AKI. Fluid restriction can be helpful in managing fluid overload and may be of particular benefit in patients with concomitant lung injury.

Renal replacement therapies should be considered for serious electrolyte disturbances, drug or toxin overdoses, refractory acidosis, or when fluid overload associated with AKI is not responsive to fluid restriction and/or diuretic use. Renal replacement modalities include peritoneal dialysis, intermittent hemodialysis, and continuous renal replacement therapy (CRRT), also known as continuous VV hemofiltration with or without dialysis (CVVHF or CVVHD). CRRT involves sending patient venous blood through an extracorporeal filtration circuit and pump to provide slow, continuous fluid removal and/or dialysis. While the ideal renal replacement therapy depends on the individual clinical situation, CRRT is often the preferred modality for managing AKI in PICU patients. CRRT can be performed as ultrafiltration alone if control of intravascular volume is the primary goal, or CRRT can be performed with a dialysate to allow solute control as well. Advantages of CRRT include (1) in hemodynamically labile patients, a slower continuous rate of fluid removal may be better tolerated and can be more precisely controlled than intermittent dialysis; (2) solute and fluid removal can be regulated separately; and (3) CRRT may allow easing of fluid restrictions so that nutrition can be improved. Disadvantages include the technical complexity of the procedure, including anticoagulation of the circuit, and the need for central venous access. No prospective studies have compared CRRT with other modes of renal replacement or demonstrated that early initiation of CRRT improves outcomes in AKI, although retrospective studies have suggested that early initiation of CRRT may be associated with lower mortality. The decision to proceed with CRRT should involve a careful assessment of risks and possible benefits in each individual patient.

Fluid Management

The majority of critically ill children are unable to take oral fluids and food, and, as a result, the ICU provider must carefully consider the needs of the individual patient in prescribing a fluid and nutrition regimen. Perhaps the most important issue in prescribing fluids is the patient’s overall fluid balance. Standard maintenance IV fluid calculations are based on the assumption of a healthy, normotensive, spontaneously breathing patient. However, the “ideal” amount of fluid in a critically ill patient is variable, depending on the underlying condition, current physiologic state and ongoing fluid losses from urine, hemorrhage, or external drains. Insensible fluid losses may be elevated due to increased work of breathing or fever. In addition to common causes of hypovolemia, inflammatory states can lead to vasodilation and leakage from the vascular space into tissues, producing a “relative hypovolemic” state despite being total body fluid overloaded. Patients may be oliguric due to AKI or have reduced urine output due to excess antidiuretic hormone secretion associated with certain lung diseases and/or positive pressure ventilation. In addition, mechanically ventilated patients generally require less fluid than non-intubated patients because the ventilator delivers humidified gas and the insensible fluid loss that occurs with normal breathing is greatly reduced. Therefore, maintenance fluid requirements for these patients may be as little as two-thirds that of someone who is not mechanically ventilated. Because fluid overload has been associated with worse outcomes, if systemic hemodynamics allow, early consideration of fluid restriction and/or diuretic use may be warranted in these situations.

In addition to rate and volume, the tonicity of IV fluid is another important consideration. Hyponatremia has been associated with significant morbidity and mortality in neurocritical care patients, and even mild to moderate abnormalities in serum sodium are associated with worse outcomes in adult ICU patients. For these reasons, in children with acute brain injury (traumatic or hypoxic-ischemic), isotonic maintenance fluids are generally recommended to avoid worsening the risk of cerebral edema. For other children who are also at high risk for cerebral edema or hyponatremia, such as patients with diabetic ketoacidosis or meningitis, it may also be prudent to use isotonic fluid. When using isotonic fluid, close electrolyte monitoring is warranted to avoid the complications of undesired hypernatremia and hyperchloremic acidosis, particularly given recent literature describing chloride-rich fluids possibly affecting outcomes. No matter the choice of fluid, the critical care practitioner should closely monitor the patient’s fluid balance based on physical examination, weight, and laboratory values and modify the fluid management strategy accordingly.

Nutritional Support

When severely ill pediatric patients are admitted to the PICU, provision of adequate nutritional support is often overlooked early in the course of therapy. Malnutrition is, however, a major problem in hospitalized patients, associated with higher rates of infectious and noninfectious complications as well as longer hospital stays and increased hospital costs. In the pediatric ICU, as many as 20% of patients experience either acute or chronic malnutrition, a rate that is largely unchanged over the past 30 years. Malnutrition in PICU patients is typically multifactorial, related to increased demands due to the physiologic and metabolic stresses associated with critical illness (Table 14–15), inaccurate assessments of caloric needs, and/or inadequate delivery of nutrition at the bedside.

Nutritional Assessment

Early assessment by a pediatric dietitian or nutritionist can be helpful to establish nutritional requirements and goals in critically ill children and identify factors impeding adequate nutrition intake and tolerance. The initial caloric needs of the critically ill child can be estimated from calculations of the basal metabolic rate (BMR) or the resting energy expenditure (REE), and applying adjustments to those calculations based on the patient’s illness and level of support. BMR represents the energy requirements of a healthy, fasting person who recently awoke from sleep, with normal temperature, and no stress, while REE represents the energy requirements of a healthy person at rest, with normal temperature and not fasting (Table 14–16). These closely related parameters are for practical purposes used interchangeably, although the REE tends to be approximately 10% above the BMR. The estimated basal metabolic need can then be multiplied by a stress factor related to the severity of the patient’s illness to more accurately estimate overall energy requirements. Unfortunately, because these calculations are based on studies of healthy adults and children, they can be very inaccurate for use in critically ill children and lead to underfeeding or overfeeding. For example, studies have demonstrated significant metabolic instability and alterations in REEs with a predominance of hypometabolism in the PICU population, resulting in a higher risk of overfeeding when using calculations alone.

Indirect calorimetry (IC) is a more accurate means of directly measuring energy expenditure and determining caloric needs, but it is more difficult and expensive to perform and as a result is not always readily available. Identification of patients at highest risk for malnutrition (see Table 14–16) for targeted use of IC assessment has been suggested as one strategy for optimizing the cost-benefit ratio of IC. This technique requires collection of exhaled gases from the patient and can be inaccurate if a significant ETT leak is present, if the FIO₂ is more than 60%, and during hemodialysis or CRRT.

Delivery of Nutrition

In adult ICU patients, enteral nutrition is associated with fewer infectious complications than parenteral nutrition. No such comparisons in pediatric patients exist, but it is generally accepted that enteral nutrition is preferred in critically ill children as well. Enteral nutrition is generally well tolerated in hemodynamically stable children, with a goal protein intake of 2–3 g/kg/day. Patients with unstable hemodynamics or requiring vasopressor support may not tolerate full-volume enteral feeding, although low-volume continuous “trophic” feeding is generally safe and feasible in all but the most unstable patients and may reduce the incidence of nosocomial infections by protecting GI tract integrity. Use of an enteral feeding protocol and early transpyloric feeding may improve tolerance. Complications of enteral feeding include GI intolerance (vomiting, bleeding, diarrhea, and necrotizing enterocolitis), aspiration events/pneumonia, and mechanical issues (occlusion of tube, errors in tube placement).

Parenteral nutrition should be considered in critically ill children when enteral nutrition cannot be delivered or tolerated within 3–5 days. Although it is common practice to gradually increase the amino acid dose, evidence from preterm neonates shows that it is safe and efficacious to start parenteral amino acids at the target dose. Lipids should be included to decrease carbon dioxide production, minute ventilation, and fat storage, enhance lipid oxidation, augment protein retention, and prevent essential fatty acid deficiency. Hyperglycemia, hypertriglyceridemia, infection, and hepatobiliary abnormalities are all potential complications of parenteral nutrition. Metabolic evaluation (electrolytes, glucose, lipase, and liver function tests) should be performed regularly and the components of parenteral nutrition adjusted as needed.

Regardless of route of nutrition, monitoring should include routine physical examination, serial measures of growth (weight, skinfold thickness), serial monitoring of serum electrolyte and mineral concentrations, and repeated measurements of REE when available. Measurements of serum albumin provide limited information about nutritional status given the multiple other influences on albumin concentrations. Prealbumin and CRP measurements may be helpful, however. Prealbumin levels are a good marker of nutritional protein status; they drop during acute illness and return to normal during recovery. CRP levels are a marker of the acute phase response to illness and injury; they rise during acute illness and drop with recovery, typically in association with a return to anabolic metabolism and before increases in prealbumin.

Children admitted to the PICU often require anxiolytic and analgesic medications to minimize discomfort and keep them safe. Sedation and anxiolysis may also be needed to facilitate mechanical ventilation or the performance of procedures, and analgesia may be needed for postoperative pain or pain related to traumatic injuries. Thus, careful consideration of a patient’s sedative and analgesic needs is a vital part of ICU management.

When determining which anxiolytic and analgesic medications to initiate, it is important to distinguish between anxiety and pain, because pharmacologic therapy may be directed at either or both of these symptoms (Table 14–17). Additional considerations in sedative selection are the route of administration and the anticipated duration of treatment. Routes of administration may be limited by the patient’s IV access or ability to tolerate oral medications. Children who require more frequent dosing or tighter control of sedation level may benefit from a continuous infusion whereas patients undergoing a bedside procedure may only require a small number of discrete doses. Potential adverse effects in particular clinical circumstances are another important consideration in sedative and analgesic selection.

Sedation

Sedative (anxiolytic) medications may be indicated when the goals of treatment are to reduce anxiety, facilitate treatment or procedures, manage acute confusional states, and diminish physiologic responses to stress, such as tachycardia, hypertension, or increased ICP. The most commonly used agents in the PICU are the benzodiazepines and the opioids. These should be carefully titrated to effect to avoid oversedation and resultant respiratory depression and/or hemodynamic instability.

A. Benzodiazepines

Benzodiazepines work through the neuroinhibitory transmitter γ-aminobutyric acid (GABA) system, resulting in anxiolysis, sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant effects. Benzodiazepines provide little to no analgesia and thus need to be combined with other medications when pain control is required.

Most benzodiazepines are metabolized in the liver, with their metabolites subsequently excreted in the urine; thus, patients in liver failure are likely to have long elimination times. Benzodiazepines can cause respiratory depression if given rapidly in high doses, an important consideration for the nonintubated patient. They can also cause cardiovascular compromise in critically ill patients, making careful titration of doses essential.

In some children, benzodiazepines can cause a paradoxical effect, producing greater agitation than sedation. In those cases, selection of an alternative agent may be more appropriate than escalation in dose. When overdose is a concern, flumazenil may be used to reverse benzodiazepine effects. Flumazenil must be used with care, however, as its effects generally wear off faster than those of most benzodiazepines. Additionally, in tolerant patients rapid reversal may result in withdrawal symptoms, including seizures.

Commonly used benzodiazepines in the PICU include midazolam, lorazepam, and diazepam. Each has differing half-lives, resulting in varying durations of effect, and multiple possible routes of administration. Midazolam has the shortest half-life and produces excellent retrograde amnesia lasting for 20–40 minutes after a single IV dose. Therefore, it can be used for short-term procedural sedation and anxiolysis with single or intermittent doses or for prolonged sedation as a continuous infusion. Lorazepam has a longer half-life than midazolam (or diazepam) and can achieve sedation for as long as 6–8 hours. It has less effect on the cardiovascular and respiratory systems than other benzodiazepines and is commonly used for short-term sedation or initial treatment of seizures. Continuous infusions of lorazepam should be avoided because its preservative, polyethylene glycol, can accumulate in patients with renal insufficiency and produce a metabolic acidosis. Diazepam has a longer half-life than midazolam and is used most commonly to treat muscle spasticity and seizures. A disadvantage of diazepam in the PICU is the long half-life of its intermediary metabolite, nordazepam, which may accumulate and prolong sedation, making diazepam less ideal for short-term sedation.

B. Other Sedative Medications

Opioids are strong analgesics that also have sedative effects. They are commonly used as adjuncts in combination with other sedatives such as benzodiazepines. Specific medications are described further in the analgesic medication section.

Ketamine is a phencyclidine derivative that produces a trance-like state of immobility and amnesia known as dissociative anesthesia. Ketamine does not cause significant respiratory depression at nonanesthetic doses, an advantage for the nonintubated patient. Ketamine has direct negative inotropic effects, but these are countered by stimulation of the sympathetic nervous system resulting in an increase in HR, blood pressure, and cardiac output for most patients. These effects may make ketamine a good choice for hemodynamically unstable patients unless there is concern that the patient may be catecholamine depleted, such as in the setting of chronic heart failure. Additionally, ketamine has bronchodilatory properties and, thus, may be useful for children with status asthmaticus. Finally, it has strong analgesic effects and therefore may be used as a single agent for sedation for painful procedures. The main side effects seen with ketamine are increased salivary and tracheobronchial secretions and unpleasant dreams or hallucinations. Atropine or glycopyrrolate may be administered ahead of time to reduce secretions, and concurrent administration of benzodiazepines may reduce the hallucinatory effects. Although most frequently used for short-term sedation, low-dose continuous infusions may be used in selected patients.

Dexmedetomidine is a selective α₂-adrenoreceptor agonist that produces sedation, anxiolysis, and some analgesia with minimal respiratory depression. It allows for the ability to rouse the patient easily if necessary. These advantages have resulted in increasing use in critically ill children for procedural sedation as well as sedation to facilitate both invasive and non-invasive mechanical ventilation. The most frequent side effects observed are dose-related bradycardia and hypotension. Dexmedetomidine is primarily used as a short- or long-term continuous infusion. The use of dexmedetomidine may also mitigate the need for increasing doses of opioids and benzodiazepines in patients requiring multiple sedative medications.

Propofol is an anesthetic IV induction agent with strong sedative effects. Its main advantages are a rapid onset and recovery time resulting from its rapid hepatic metabolism. Because propofol has no analgesic properties, an analgesic agent should be concurrently administered for painful procedures. Propofol can cause significant vasodilation, resulting in dose-related hypotension, in addition to dose-dependent respiratory depression. Owing to concerns for propofol infusion syndrome, a sudden-onset, profound, and often fatal acidosis associated with prolonged infusions, propofol is now used in children mostly for procedural or short-term sedation.

Barbiturates (eg, phenobarbital) can cause direct myocardial and respiratory depression and are, in general, poor choices for standard sedation of critically ill patients.

Analgesia

Opioid and nonopioid analgesics are the mainstay of treatment for acute and chronic pain in the PICU. Although several other medications used for sedation also have analgesic properties, they are uncommonly used for primary treatment of pain.

A. Opioid Analgesics

All opioids provide analgesia and have dose-dependent sedative effects. A range of plasma concentrations produce analgesia without sedation; the dose required to produce adequate analgesia varies significantly between patients. Therefore, the best approach to dosing with opioids is to start with a low-end dose but then titrate to effect, monitoring for side effects. The most common side effects of these agents are nausea, pruritus, slowed intestinal motility, miosis, cough suppression, and urinary retention. Opioids can also cause respiratory depression, particularly in infants. Morphine can cause histamine release leading to pruritus and even hypotension; fentanyl generally has few hemodynamic effects in a volume-replete patient. Opioids are metabolized in the liver, with metabolites excreted in the urine. Thus, patients with hepatic or renal impairment may have prolonged responses to their administration.

The choice and mode of delivery of agents within this class depends on the physiologic state of the child and the etiology of pain. In an awake and developmentally capable patient, a patient-controlled analgesia (PCA) approach with an infusion pump may be appropriate. Each of these medications may also be administered intermittently, in which case half-life and tolerability of side effects may be the primary considerations. For many patients in the PICU, a continuous infusion may be the best option. Several IV medications are commonly used as a continuous infusion or by PCA, including fentanyl, morphine, and hydromorphone. For children who have more chronic, less severe pain and who can tolerate oral medications, there are many different options, including hydrocodone, hydromorphone, morphine, methadone, and oxycodone.

Naloxone may be used as an opioid reversal agent for narcotic overdoses. Because of its relatively short half-life compared to many opioids, symptoms may recur and repeat dosing or even a continuous infusion may be necessary. Caution should be used in patients with chronic opioid exposure to avoid precipitating severe withdrawal symptoms.

B. Nonopioid Analgesics

Nonopioid analgesics used to treat mild to moderate pain include acetaminophen, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs). Because the effects of these agents can be additive with opiates, a combination of opiate and nonopiate medications can be a very effective approach to pain management in the ICU.

Acetaminophen is the most commonly used analgesic in pediatrics in the United States and is the drug of choice for mild to moderate pain because of its low toxicity and minimal side-effect profile. With chronic use and higher doses, acetaminophen may cause liver and renal toxicity.

NSAIDs are reasonable alternatives for the treatment of pain, particularly those conditions associated with inflammation. All NSAIDs carry the risk of gastritis, renal compromise, and bleeding due to inhibition of platelet function, limiting their use in patients with thrombocytopenia, bleeding, and kidney disease. Ketorolac is the only IV NSAID currently available. It can be very effective for children who cannot take oral medication or require a faster onset of action. Because of the concerns for more serious renal toxicity with longer-term use, ketorolac is primarily used for shorter-term pain control. Ibuprofen and naproxen are options for patients who can tolerate oral medications. Ibuprofen has a shorter half-life and therefore requires more frequent dosing.

Titration of Sedative & Analgesic Dosing, Delirium, & Withdrawal Syndromes

Sedative analgesic and anxiolytic agents have a number of serious disadvantages, including short- and long-term cognitive deficits, an increased risk of delirium, and withdrawal syndromes. Daily interruption of all continuous sedation with titrated reintroduction as necessary has been shown in adult ICU patients to dramatically reduce the duration of mechanical ventilation and length of stay in the ICU. Similar data are not yet available for pediatric patients. Another proposed intervention to decrease sedation use in children is protocolized, nurse-driven sedation goals. A recent large multicenter, randomized study of this approach in pediatrics demonstrated decreased overall opioid exposure but failed to show a decreased length of mechanical ventilation. The untoward effects of sedation in critically ill children remain a concern and, in general, doses of these agents should be titrated downward daily to the minimum required doses.

Standardized scales have been developed to assist in the titration of sedatives and analgesics in children. In the awake and verbal patient, a pain scale can be used to determine the level of pain and need for treatment. In a nonverbal patient, this assessment can be more difficult, and the medical team may need to depend on changes in physiologic parameters such as HR and blood pressure to indicate pain and the effect of treatment. When using these measures, however, the provider should also exclude or address physiologic causes of agitation, such as hypoxemia, hypercapnia, or cerebral hypoperfusion caused by low cardiac output.

Several scoring systems are available to assess the level of sedation and help guide sedation management decisions. These include the COMFORT score and the State Behavioral Scale (SBS). Utilizing such a measurement tool allows for better communication among team members with regard to the goals of treatment and the effectiveness of any changes in sedation plan.

As with adult patients, critically ill children are at risk for developing delirium. Delirium may present with a wide variety of symptoms, commonly grouped as hypoactive, hyperactive or mixed. Hyperactive delirium is associated with restlessness, agitation, emotional lability and combativeness. Hypoactive delirium, on the other hand, may be more difficult to recognize; patients may be quiet, withdrawn, and apathetic with decreased responsiveness. Parents may notice their child’s personality is quite different from baseline. PICU delirium scales including the Pediatric Confusion Assessment Method for the ICU (pCAM-ICU) and Cornell Assessment of Pediatric Delirium (CAPD) may help better assess for delirium in the PICU population.

In critically ill children, as in adults, the risk of developing delirium appears to increase with severity of illness, administration of sedative medications such as benzodiazepines, and greater sleep disturbances. Suggested strategies for preventing and treating delirium include reducing sedative exposure, promoting normal circadian rhythms with greater activity during the day and quiet, dark rooms at night, and ensuring the presence of parents and objects familiar to the child. Finally, in more extreme situations, treatment with medications can be considered. Quetiapine is a newer antipsychotic agent that has shown promise in early studies for treating pediatric delirium. Older antipsychotics such as haloperidol are still used at times, but their side-effect profile demands caution. Benzodiazepines may calm the patient but also may induce a paradoxical reaction. Dexmedetomidine may also be an effective medication for treatment of delirium, but this use has not been well studied in the pediatric population.

Withdrawal syndromes are another important aspect of the use of sedative and analgesic agents in the ICU. Long-term administration and high doses of continuous infusions of opioids or benzodiazepines can lead to tolerance and physical dependence. Acute reductions or cessation of these medications can result in withdrawal symptoms such as agitation, tachypnea, tachycardia, sweating, and diarrhea. The risk of withdrawal varies among individuals, but the longer patients receive opiates or benzodiazepines, the more likely they are to have withdrawal symptoms. Gradual tapering of the medication dosage over 7–10 days often effectively prevents withdrawal symptoms. This gradual reduction may be facilitated by transitioning to intermittent dosing of longer half-life agents, such as methadone or lorazepam. While weaning opiates or benzodiazepines, providers should assess daily for symptoms of withdrawal. This assessment can be facilitated by symptom scores such as the Withdrawal Assessment Tool-1 (WAT-1). A higher WAT-1 score suggests greater withdrawal symptoms and may indicate a need to slow the weaning plan. Conversely, if the WAT-1 score is consistently low, the patient is likely to tolerate the current pace or, possibly, an accelerated dose reduction.

Death in the PICU

In-hospital pediatric deaths occur infrequently. A large proportion of pediatric deaths occur in the PICU, however, and pediatric intensivists may be called upon to help define the limits to care provided, assist in the withdrawal of life-sustaining medical therapies (LSMTs), and provide compassionate palliative care. End-of-life discussions may have occurred prior to PICU admission for some children with congenital or chronic diseases. For other children, their PICU stay may be the first time a child or family discusses end-of-life decisions. Regardless of the individual patient’s situation, the medical team has a responsibility to facilitate discussions regarding the goals of care in an honest and sensitive manner.

Deaths without any limitations on patient care comprise a small minority (10%–12%) of pediatric ICU deaths. In these circumstances, most recent studies have found greater family satisfaction with the care provided if family members are allowed to witness ongoing resuscitative efforts. The remainder of pediatric deaths is divided between brain death declarations (23%) and decisions to limit or withdraw LSMTs (65%).

Brain Death

Patients with severe neurologic injuries may meet the criteria for a diagnosis of brain death. The concept of brain death arose when advances in ICU technologies allowed heart and lung function to be supported even in the absence of any discernible brain activity. Brain death is diagnosed by a clinical examination (Table 14–18) based on published guidelines and is recognized as legally equivalent to somatic (cardiopulmonary) death in all 50 US states. The general approach to the diagnosis of brain death is similar in most medical centers, but subtle institutional variations make it imperative for PICU providers to be familiar with their own institutional policies on brain death declaration. Once a patient is declared legally brain dead, further medical support is no longer indicated, although the timing of discontinuation of mechanical life support should be discussed and agreed upon with the patient’s family.

Brain death is determined through a complete clinical assessment of the patient. First and foremost, the provider must be confident that the patient’s condition is irreversible and must exclude any potentially reversible conditions that may produce signs similar to brain death. These may include hypotension, hypothermia, or the presence of excessive doses of sedating medications. The brain death examination is a formal clinical examination directed at demonstrating the absence of cortical function (flaccid coma without evidence of response to stimuli) and brainstem function (cranial nerve testing). In order to meet the definition of brain death, guidelines require that qualified physicians document two separate clinical examinations consistent with brain death (ie, no evidence of brain function) separated by a period of observation. If a patient cannot tolerate some portion of the clinical examination (typically apnea testing) or is very young (especially < 1 year of age), an ancillary test such as EEG or cerebral perfusion scan may provide supporting evidence of brain death. Once a child has been declared brain dead, the time of death is noted as occurring at the completion of the second examination even if the child is still receiving cardiopulmonary support.

Limitation or Withdrawal of Medical Care

Most patients who die in the pediatric ICU will do so following a decision to limit or withdraw medical support. The discussions leading to these decisions should include the patient (to the extent possible given their medical condition and developmental age), family members, and members of the medical team. The primary goals of these discussions should be to (1) communicate information regarding the patient’s medical status and anticipated prognosis and (2) clarify the goals of ongoing medical care both in regard to the patient’s current status and in the event of an acute decompensation. If the opinion of the medical team is that the patient’s condition is likely irreversible, the options for care include (1) continuing current support with escalation as deemed medically reasonable by the health care team; (2) continuing current support but not adding any new therapies; (3) withdrawal of life-sustaining therapies such as mechanical ventilation and hemodynamic support. The first two options may include a decision to withhold cardiopulmonary resuscitation in the event of a respiratory or cardiac arrest (do-not-attempt resuscitation [DNAR]). The third option presumes a DNAR but this must be explicitly written in the medical record and communicated to team members.

Discussions with patients and families regarding the decision to limit resuscitation or to withdraw LSMT should be conducted by experienced personnel with the ability to communicate in a clear and compassionate manner and should occur at an appropriate time and place. Cultural needs should be considered prior to major discussions and may include the need for a translator or spiritual guidance. Discussions should begin with a clear statement that the goal is to make decisions in the best interest of the patient and that the health care team will support the patient and family in making reasonable decisions based on that goal. Potential options regarding limitations of care or withdrawal of care should be clearly explained for the decision makers. Withdrawal of LSMT can be considered when the pain and suffering inflicted by prolonging and supporting life outweighs the potential benefit for the individual. If there is no reasonable chance of recovery, the patient has the right to a natural death in a dignified and pain-free manner. The health care team should emphasize that decisions are not irrevocable and that if at any time the family or health care providers wish to reconsider the decision, full medical therapy can be reinstituted until the situation is clarified.

Prior to the withdrawal of LSMT, the patient’s family and care team should be prepared for the physiologic process of dying that the child will undergo. Key facets of the process to discuss include the possibility of agonal respirations, which can be disturbing to witness for family members and care providers, as well as the unpredictable length of time that the process may require. Additionally, the fact that the patient will ultimately have a cardiopulmonary arrest and a member of the medical team will declare the time of death should be discussed. The family should also be reassured that the patient will be given appropriate doses of medications to treat signs and symptoms of pain or discomfort and that neither they nor the patient will be abandoned by the medical team during this process.

Palliative Care & Bioethics Consultation

Palliative care teams and ethics consultation services are important resources to help the health care team and families address difficult end-of-life decision making. For families of children with congenital or chronic diseases, the palliative care team may have established relationships with the patient and family outside of the acute illness. For patients with new conditions or whose prognosis has changed, the palliative care team may be newly introduced in the PICU. In either case, the palliative care team can bring invaluable support and resources for families during end-of-life discussions. A more comprehensive discussion of palliative care can be found elsewhere in this book.

If conflict arises surrounding decisions about limiting medical care, an ethics consultation can aid the process by helping to identify, analyze, and resolve ethical problems. Ethics consultation can independently clarify views and allow the health care team, patient, and family to make decisions that respect patient autonomy and promote maximum benefit and minimal harm to the patient.

Tissue & Organ Donation

Organ transplantation is standard therapy for many pediatric conditions and many children die while awaiting a transplant due to short supply of organs. The gift of organ donation can be a positive outcome for a family from the otherwise tragic loss of their child’s life. The 1986 U.S. Federal Required Request Law mandates that all donor-eligible families be approached about potential organ donation. The decision to donate must be made free of coercion, with informed consent, and without financial incentive. The state organ-procurement agencies provide support and education to care providers and families to make informed decisions.

To be a solid-organ donor, the patient must be declared dead and have no conditions contraindicating donation. The most frequent type of solid-organ donor in the PICU is a brain-dead donor. The unmet demand for donor organs has, however, led to the emergence of protocols for procuring solid organs from non–heart-beating donors. Although this practice has been described by many terms including Donation after Cardiac Death, the most recent nomenclature is Donation after Circulatory Determination of Death (DCDD). In these cases, the patient does not meet brain death criteria but has an irreversible disease process and the family or patient has decided to withdraw life-sustaining therapy and consented to attempted organ donation. In the DCDD process, LSMT is withdrawn and comfort measures are provided as per usual care. The withdrawal of care may take place in the PICU or the operating room without any surgical staff present, depending on institutional policy. Once the declaring physician has determined cessation of cardiac function, the patient is observed for an additional short time period for auto-resuscitation (the return of cardiac activity without medical intervention). After this waiting period, the patient is declared dead and the organs are immediately harvested for donation. If the patient does not die within a predetermined time limit after discontinuation of LSMT, comfort measures continue but solid-organ donation is abandoned due to unacceptably long ischemic times.

Tissue (heart valves, corneas, skin, and bone) can be donated following a “traditional” cardiac death (no pulse or respirations), brain death, or DCDD.

Bereavement & Grief Support

After any pediatric death, bereavement and grief support for families and health care providers are essential components of comprehensive end-of-life care. Families may need information about care of the body after the death, funeral arrangements, and autopsy decisions as well as about educational, spiritual, and other supportive resources available. Members of the medical team may feel their own grief and sense of loss with the death of a patient. These emotions, if not appropriately addressed, can negatively affect their personal and professional lives. Therefore, similar supportive services should be available to health care workers caring for dying children.

Given the complexity of both the illnesses faced and the care provided in PICUs, these environments are among the most susceptible to medical error. As a result, critical care units also tend to be the areas that are likely to benefit from quality improvement and patient safety initiatives. National and local reporting requirements for a number of hospital-acquired conditions, such as central line-associated bloodstream infections, catheter-associated urinary tract infections, pressure injuries, and venous thromboembolisms, have led to the development of national collaboratives focused on data gathering and sharing of best practices for prevention of those conditions. Improving quality and safety practices relies on creating both a culture of awareness and safe reporting of adverse events and tools or workflows designed to help reduce the likelihood of error. As an example, multipronged efforts to reduce catheter-related bloodstream infections include checklists or tools to ensure strict adherence to sterile procedure during catheter insertion, sterile practice when accessing the catheter during care, reductions in the number of times the catheter is accessed, and removal of catheters at the earliest safe opportunity. More recent efforts have begun to focus on early identification and treatment of sepsis using defined diagnostic triggers and order sets. Most of the data supporting these interventions have been derived from adult ICU populations, and, to date, few large-scale studies have been published documenting efficacy of these measures in the pediatric ICU population. Data that are available suggest that these initiatives are beneficial, although additional studies will likely be needed to refine and optimize these approaches in the pediatric ICU setting.