Todd C. Carpenter, MD
Angela S. Czaja, MD, MSc
Jennifer Exo, DO
Eva N. Grayck, MD
Cameron F. Gunville, DO
Carleen Zebuhr, MD
The care of patients with life-threatening conditions requires a detailed understanding of human physiology and the pathophysiology of major illnesses, as well as an understanding of and experience with the rapidly changing technologies available in a modern intensive care unit (ICU). In addition, the science of caring for the critically ill patient has evolved rapidly in recent years as the molecular mediators of illness have become better defined and new therapies have been devised based on those advances. As a result, critical care is a multidisciplinary field and optimal outcomes for critically ill patients require a team-oriented approach, including critical care physicians and nurses, respiratory therapists, and pharmacists, as well as consulting specialists, physical, occupational and recreational therapists and social services specialists.
RESPIRATORY CRITICAL CARE
ACUTE RESPIRATORY FAILURE
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Inability to deliver oxygen or remove carbon dioxide.
Pao2 is low while Paco2 is normal in hypoxemic respiratory failure (V/Q mismatch, diffusion defects, and intrapulmonary shunt).
Pao2 is low and Paco2 is high in hypercapnic respiratory failure (alveolar hypoventilation seen in CNS dysfunction, over-sedation, neuromuscular disorders).
Noninvasive mechanical ventilation can be an effective treatment for hypercapnic respiratory failure and selected patients with hypoxemic failure.
Conventional mechanical ventilation should be accomplished within a strategy of “lung-protective” ventilation.
HFOV and ECMO are viable options for patients failing conventional mechanical ventilation.
Acute respiratory failure, defined as the inability of the respiratory system to adequately deliver oxygen or remove carbon dioxide, causes significant morbidity and mortality in critically ill children, accounting for approximately 50% of deaths in children younger than 1 year of age. Anatomic and developmental differences place infants at higher risk than adults for respiratory failure. An infant’s thoracic cage is more compliant than that of the adult or older child, 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 smaller in caliber than those in older children and adults, resulting in greater resistance to inspiratory and expiratory airflow and greater susceptibility to occlusion by mucus plugging and mucosal edema. Compared with adults, the alveoli of children are also smaller and have less collateral ventilation, again resulting in a greater tendency to collapse and develop atelectasis. Finally, young infants may have an especially 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) V/Q mismatch, which occurs when blood flows to parts of the lung that are inadequately ventilated, 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, which occurs 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 over-sedation, or neuromuscular disorders (Table 14–1).
Table 14–1. Types of respiratory failure.
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 are not consistently clinically obvious, and most of them have nonrespiratory causes as well. 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.
Table 14–2. Clinical features of respiratory failure.
Noninvasive Monitoring and Blood Gas Analysis
The adequacy of oxygenation and ventilation can be measured both noninvasively and through blood gas analysis. Arterial oxygen saturation (Sao2) can be measured continuously and noninvasively by pulse oximetry, a technique that should be used in the assessment and treatment of all patients with potential or actual respiratory failure. Pulse oximetry readings, however, become markedly less accurate in patients with saturations below approximately 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) monitoringprovides a continuous noninvasive means of assessing the adequacy of ventilation. The ETCO2 level closely approximates the alveolar CO2 level (Paco2), which should equal the arterial CO2 level (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. Though useful for following trends in ventilation, ETCO2 monitoring is also susceptible to significant error, particularly in patients with rapid, shallow breathing or increased dead space ventilation.
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. Although measurement of capillary or venous blood gases may provide some reassurance regarding the adequacy of ventilation and can be useful for following trends, 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, though it widens with increasing inspired oxygen concentrations to about 100 mm Hg in normal patients breathing 100% oxygen. This number has prognostic value in severe hypoxemic respiratory failure, with A–a gradients over 400 mm Hg being strongly associated with mortality. Diffusion impairment, shunts, and V/Q mismatch all increase the A–a gradient. In addition to the calculation of the A–a gradient, assessment of intrapulmonary shunting (the percentage of pulmonary blood flow that passes through nonventilated areas of the lung) may 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. When intrapulmonary shunt reaches 50% of pulmonary blood flow, Pao2 does not significantly increase regardless of the amount of supplemental oxygen used. Calculation of the shunt fraction requires a pulmonary arterial catheter for measurement of mixed venous blood gases; for patients without pulmonary artery catheters, the A–a gradient is a good surrogate measure of intrapulmonary shunting.
Modes of Respiratory Support
Patients with severe hypoxemia, hypoventilation, or apnea require immediate assistance with bag and mask ventilation until the airway is successfully intubated and controlled mechanical ventilation can be provided. Assisted ventilation with a bag and mask can generally be maintained for some time with a mask of the proper size, but gastric distention, emesis leading to aspiration of gastric contents, and inadequate tidal volumes leading to atelectasis are possible complications. In those patients not requiring immediate intubation, a variety of modalities can be used to provide respiratory support, including supplemental oxygen, heated high flow nasal cannula (HHFNC), and noninvasive ventilation (NIV) with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP).
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. Heated high-flow nasal cannula (HHFNC) devices utilize a nasal cannula for delivery of heated and humidified oxygen mixtures at high flow rates not normally tolerated with cooler drier air. This approach is increasingly being used in infants and young children but is also well tolerated in older patients. Generally, flow rates of greater than 2 L/min in infants and greater than 4 L/min in children are considered high flow. HHFNC use has been studied in children with bronchiolitis and appears to be well tolerated, potentially decreasing the need for intubation by providing some amount of airway positive pressure. HHFNC should be considered in patients who need more respiratory support than a simple low-flow nasal cannula, but if the patient is not improving on HHFNC after 60–90 minutes, additional escalation of care may be warranted. Furthermore, although HHFNC provides some amount of positive pressure, the exact amount of positive pressure cannot be accurately determined from the flow rate. If a patient needs further escalation of care, the device used should be capable of more reliably delivering a fixed amount of positive pressure, such as CPAP or BIPAP.
Table 14–3. Supplemental oxygen therapy.
Noninvasive ventilation (NIV) refers to the administration of mechanical ventilatory support without using an invasive artificial airway (endotracheal tube or tracheostomy tube). The use of NIV has become an integral tool in the management of both acute and chronic respiratory failure. NIV can be used to avoid endotracheal intubation for milder cases of respiratory failure and as a bridge to extubation in mechanically ventilated patients with marginal lung function and respiratory mechanics. NIV devices provide positive pressure breathing through a variety of interfaces (mouth piece or nasal, face, or helmet mask) and using a variety of ventilatory modes, including continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), volume ventilation, and pressure support. Ventilators dedicated to NIV exist, and many standard ventilators are capable of providing support through a mask with the appropriate adapters. Most current NIV ventilator models incorporate oxygen blenders for precise delivery of the fraction of inspired oxygen (Fio2).
Continuous positive airway pressure (CPAP) refers to the constant application of airway pressure, usually in the range of 5–8 cm H2O, and seeks to improve work of breathing, ventilation, and oxygenation by maintaining the functional residual capacity (FRC) of the lungs. Bilevel positive airway pressure (BIPAP) functions similarly but cycles between a higher inspiratory pressure (IPAP) and a lower expiratory 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. Typical initial settings would place the IPAP at 10–14 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 to reduce the patient’s work of breathing and respiratory rate toward the normal range. EPAP and delivered oxygen concentration can be adjusted upward on the basis of pulse oximetry to achieve adequate oxygenation. Serial blood gas measurements are essential to monitor the response to therapy and to guide further ventilator adjustments.
Successful application of NIV requires careful patient selection. The best candidates are patients 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. Patients suffering from coma, impaired respiratory drive, an inability to protect their airway, or cardiac or respiratory arrest are not candidates for NIV. Controversy still exists regarding the safety of NIV as an initial strategy in patients with acute hypoxemic respiratory failure, but in general NIV appears to be well tolerated in many children with this condition and it may decrease the risk for intubation. These patients should be closely monitored, however, as NIV may mask symptoms of underlying disease progression, making eventual intubation more precarious. In patients with severe respiratory failure or those who are worsening on NIV, endotracheal intubation should not be delayed.
For patients with respiratory failure not responding adequately to noninvasive support, endotracheal intubation and the initiation of mechanical ventilation can be life-saving. Safe placement of an endotracheal tube in infants and children requires experienced personnel and appropriate equipment at the bedside, including supplemental oxygen, correctly sized mask and bag oral airways, and endotracheal tubes, and suction catheters. The patient should first be positioned properly to facilitate air exchange while supplemental oxygen is given. 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 endotracheal tube 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 patients with significant upper airway obstruction (eg, patients with croup, epiglottitis, foreign bodies, or subglottic stenosis) or mediastinal masses should be approached with extreme caution; minimal sedation should be used and paralytic agents should be strictly avoided unless trained airway specialists decide otherwise.
Table 14–4. Drugs commonly used for controlled endotracheal intubation.
The size of the endotracheal tube (ETT) is of critical importance in pediatrics. An inappropriately large endotracheal tube can cause pressure necrosis in the subglottic region, potentially leading to scarring and stenosis requiring surgical repair. An inappropriately small endotracheal tube can result in inadequate pulmonary toilet and excessive air leak around the endotracheal tube, making adequate ventilation and oxygenation difficult. Two useful methods for calculating the correct size of endotracheal tube for a child are (1) measuring the child’s height with a Broselow Tape and then reading the corresponding endotracheal tube size on the tape, or (2) in children older than age 2 years, choosing a tube size using the formula ETT size = (16 + age in years) ÷ 4. Approximate proper insertion depth (in cm) as measured at the teeth can be estimated by tripling the size of the ETT. Either cuffed or uncuffed tubes are appropriate; preference should be given for a cuffed tube in patients with significant lung disease likely to have poor lung compliance. Correct placement of the endotracheal tube should be confirmed by auscultation for the presence of equal bilateral breath sounds and by the use of a colorimetric filter (pH-sensitive indicator that changes from purple to yellow when exposed to carbon dioxide) to detect carbon dioxide. An assessment of air leakage around the endotracheal tube is an important measure of the appropriateness of endotracheal tube size. An audible leak noted at pressures of 15–20 cm H2O indicates acceptable ETT size, though higher leak pressures are acceptable in patients who have poor lung compliance and as a result require higher airway pressures to effectively ventilate and oxygenate. A chest radiograph is necessary for final assessment of endotracheal tube 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 vertebrae.
CONVENTIONAL MECHANICAL VENTILATION
The principal indications for institution of mechanical ventilation are acute and chronic respiratory failure or an airway rendered unstable either by illness, injury, or treatment with sedating medications. Examples of these conditions include pneumonia, sepsis, trauma, neuromuscular disease, and procedural sedation. 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 life-saving 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 under-inflated 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 or optimal.
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 as a means to 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 assists 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 intermittent mandatory ventilation (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 most PICUs is synchronized intermittent mandatory ventilation with pressure support (SIMV + PS), a mixed mode allowing pressure-supported breaths between the synchronized machine breaths.
One of the ongoing controversies in critical care medicine surrounds the relative roles of volume- vs pressure-controlled modes of ventilation. 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). All mechanical ventilators open their expiratory limbs at the end of inspiration allowing gas release until a preset pressure is achieved; this is the PEEP value. PEEP helps to prevent the end-expiratory collapse of open lung units, thus preventing atelectasis and shunting. In disease states such as pulmonary edema, pneumonia, or ARDS, a higher PEEP (10–15 cm H2O) may increase the patient’s functional residual capacity, helping to keep open previously collapsed alveoli and improve oxygenation. 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 declines in cardiac output or increases in intracranial pressure (ICP).
Setting and Adjusting the Ventilator
When initiating volume-controlled modes of ventilation, the ICU clinician sets a tidal volume, I-time, rate, and level of PEEP. A typical initial tidal volume is 6–10 mL/kg, as long as that volume does not cause excessive airway pressures (> 30 cm H2O). The I-time is typically set at 1 second or 33% of the respiratory cycle, whichever is shorter. Rate can be adjusted to patient comfort and blood gas measurements, but generally patients starting on mechanical ventilation require full support at least initially with a rate of 20–30 breaths/min. Pressure-controlled ventilation is set in a similar fashion, although the adequacy of the inspiratory pressure is assessed by observing the patient’s chest rise and by measuring the delivered tidal volume. Typically, 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. In general, PEEP should be set at 5 cm H2O initially and titrated up to maintain adequate oxygenation at acceptable inspired oxygen concentrations (< 60%–65%) while watching carefully for adverse effects on systemic hemodynamics.
Ventilated patients require careful monitoring for the efficacy of gas exchange, including respiratory rate and activity, chest wall movement, and quality of breath sounds. Oxygenation should be measured by ABGs and by continuous pulse oximetry. Ventilation should be assessed by blood gas analysis and by noninvasive means, such as transcutaneous monitoring or ETCO2 sampling. Transcutaneous PO2 or PCO2 measurements are most useful with younger patients who have good skin perfusion, but they become problematic in patients with poorly perfusion, anasarca, or obesity. ETCO2 monitoring involves placing a gas-sampling port on the endotracheal tube and analyzing expired gas for CO2. This technique is more valuable for patients with large tidal volumes, lower respiratory rates, and without significant leaks around the endotracheal tube. In practice, ETCO2 values may differ significantly (usually lower) from measured Paco2 values and thus are most useful for following trends in ventilation, for early recognition of occluded or malpositioned endotracheal tubes, and for assessing the adequacy of chest compressions during CPR. Frequent, preferably 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 mean airway pressure (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. It is important to bear in mind, however, that 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 of benzodiazepines, with or without opioids. Some patients respond better to the steady state of sedation provided by continuous infusion of these agents, although oversedation of the ventilated patient may lead to longer duration of ventilation, difficulty with weaning from the ventilator, and other complications. It is beneficial to use standardized assessments of sedation level and target the minimum sedation level necessary to maintain patient comfort and adequate gas exchange.
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 paralytics 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 often be fed enterally with the use of nasogastric feeding tubes. However, reflux aspiration leading to ventilator-associated pneumonia can be a concern. 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 success. Unfortunately, the available literature does not clearly support any specific weaning protocol or extubation readiness test. Successful extubation requires adequate gas exchange, adequate respiratory muscle strength, and the ability to protect the airway. If those conditions can be met, most practitioners as a test of extubation readiness 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 a sudden deterioration in the mechanically ventilated patient should begin with determining whether the endotracheal tube is still in place using direct laryngoscopy and/or ETCO2 measurements. Determine whether the ETT is patent and in the correct position by attempting to pass a suction catheter and by obtaining a chest x-ray if necessary. 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 while the ventilator is checked for malfunction. Hand-bagging the patient can also determine the root of the problem if it lies within the patient and can help determine the next ventilator adjustments.
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. 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 general 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 clearly can be useful as a rescue mode for selected patients, it remains unclear whether HFOV provides any benefit 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 less invasive therapies. 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. 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 that can be 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 2 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 ECMO runs.
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.
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MAJOR RESPIRATORY DISEASES IN THE PEDIATRIC ICU
ACUTE RESPIRATORY DISTRESS SYNDROME
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
ARDS is a severe form of lung injury characterized by hypoxemia, bilateral pulmonary infiltrates, and no clinical evidence of left atrial hypertension.
ARDS can arise as a consequence of either direct pulmonary injury or systemic conditions that are nonpulmonary in origin, such as sepsis.
Lung protective mechanical ventilation and careful fluid management are crucial to good outcomes in ARDS patients.
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 usually refractory to supplemental oxygen alone. Mortality rates for pediatric ARDS have fluctuated over time, depending on the criteria used to diagnose the disease, 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 include (1) acute onset; (2) bilateral pulmonary infiltrates on chest radiograph; (3) pulmonary artery occlusion pressure (PAOP) ≤ 18 mm Hg or 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) is ≤ 300 while receiving a PEEP of at least five via mechanical ventilation. When the Pao2:Fio2ratio is between 200 and 300, the case is defined as mild ARDS, between 100 and 200 is moderate ARDS, and under 100 is severe ARDS. While these criteria remain controversial because of their lack of specificity, they helped to usher in a new era of clinical research that has contributed greatly to what we now know about the pathophysiology ARDS and factors influencing its outcomes in children.
Presentation and 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.
Table 14–5. ARDS risk factors.
Table 14–6. Pathophysiologic changes of acute respiratory distress syndrome.
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 positive end expiratory pressure (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. Clinical studies suggest that airways resistance may be increased in up to 50% of patients with ARDS, likely as a result of airway damage or inflammation-induced bronchospasm, although this increased resistance is only rarely clinically important.
Computer 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 nonpulmonary organ dysfunction. Even in normal lungs, ventilation with large tidal volumes and low positive end-expiratory pressure (PEEP) levels can produce a lung injury that is histologically 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 peak 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.
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 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. Over a decade ago, 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. The trial also demonstrated a greater reduction in plasma levels of pro-inflammatory cytokines among those in the lower tidal volume group, a finding suggesting that appropriate ventilator strategies can actually reduce the systemic inflammatory response. 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. 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 endotracheal tube 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 should be used unless a clear contraindication exists (eg, increased intracranial pressure). If adequate ventilation cannot be achieved (pH remains below 7.25 due to hypercapnia), the ventilator rate can then be increased, provided the patient has time to adequately exhale before the next breath. Subsequently, tidal volume can then be increased as necessary toward 8 mL/kg (ideal body weight), monitoring again for adequacy of expiratory time. Throughout the course, efforts should be made to limit the alveolar plateau pressure (pressure at end-inspiration) to 25 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, or, if a pulmonary artery catheter is used, pulmonary artery occlusion pressure < 8 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 (or PAOP 14–18 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.
Hemodynamic support is directed toward increasing perfusion and oxygen delivery. Patients should be given adequate intravascular volume resuscitation using either crystalloid or colloid solutions to restore adequate circulating volume, and inotropes or vasopressors should be titrated to achieve adequate end-organ perfusion and oxygen delivery. While blood transfusions are excellent volume expanders and should theoretically increase oxygen-carrying capacity, transfusion incurs the risks of volume overload and transfusion-related lung injury. There is no evidence to support transfusion above a normal hemoglobin level in ARDS patients.
Patients with ARDS require careful monitoring. Given the risks of ventilator-induced lung injury and the inherent limitations of pulse oximetry and capnography, arterial blood gas analysis is strongly 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. Many clinicians advocate the use of CVP measurements to help determine the level of cardiac preload, although it is important to emphasize that the CVP value must be interpreted in the context of intrathoracic pressure and myocardial compliance. For patients with severe disease or concurrent cardiac dysfunction, consideration can be given to pulmonary artery catheterization in order to guide fluid management and to allow assessment of mixed venous oxygen saturation as an index of overall tissue oxygenation. 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. High-frequency oscillatory ventilation (HFOV) has been used successfully for many years in pediatric patients with ARDS. No 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 unknown. Earlier studies have demonstrated that pediatric ARDS patients treated with HFOV can demonstrate rapid and sustained improvements in oxygenation without adverse effects on ventilation, and have suggested that HFOV patients showed a reduced incidence of chronic lung injury, as evidenced by a decreased need for supplemental oxygen at 30 days. At present, whether HFOV is best used as a first-line ventilator strategy or as a rescue therapy for patients failing conventional ventilation remains a matter of institutional and clinician preference. 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 ventilation-perfusion 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. To date, clinical trials examining the role of prone positioning in both adults and children with ARDS have not shown any improvement in mortality or in duration of mechanical 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. Surfactant-replacement therapy is also not routinely recommended for children with ARDS, as the data regarding its efficacy remain mixed. To date, it has been difficult to draw meaningful conclusions from the completed surfactant trials because they differ so greatly with respect to surfactant composition, dosing regimen, study population, and mechanical ventilation strategy. 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 40%–50%. 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.
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.
ARDS Definition Task Force: Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307(23):2526–2533 [PMID: 22797452].
Curley MA, Hibberd PL, Fineman LD et al: Effect of prone positioning on clinical outcomes in children with acute lung injury: a randomized controlled trial. JAMA 2005;294:229–237 [PMID: 16014597].
Duffett M et al: Surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis. Crit Care 2007;11:R66 [PMID: 17573963].
Randolph AG: Management of acute lung injury and acute respiratory distress syndrome in children. Crit Care Med 2009;37:2448–2454 [PMID: 19531940].
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Status asthmaticus is reversible small airway obstruction that is refractory to sympathomimetic and anti-inflammatory agents and that may progress to respiratory failure without prompt and aggressive intervention.
Dyspnea at rest that interferes with the ability to speak can be an ominous sign.
Absence of wheezing may be misleading because, in order to produce a wheezing sound, the patient must take in sufficient air.
Patients with severe respiratory distress, signs of exhaustion, alterations in consciousness, elevated Paco2, or acidosis should be admitted to the PICU.
Life-threatening asthma exacerbations are caused by severe bronchospasm, excessive mucus secretion, inflammation, and edema of the airways (see Chapter 38). Reversal of these mechanisms is key to successful treatment. Several structural and mechanical features of the lungs of infants and children place them at increased risk for respiratory failure from severe asthma exacerbations, including less elastic recoil than the adult lung, thicker airway walls which lead 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. In addition, some individual patients display a pattern of recurrent life-threatening asthma exacerbations. These patients will often have a history of previous ICU admissions or intubations; obesity, lower socioeconomic status, and non-Caucasian race are additional risk factors for severe asthma exacerbations.
Patients presenting in status asthmaticus are often tachypneic and may have trouble speaking. Dyspnea at rest that interferes with the ability to speak can be an ominous sign of severe airflow obstruction. Accessory muscle use correlates well with expiratory flow rates less than 50% of normal predicted values. Inspiratory and expiratory wheezing, paradoxical breathing, cyanosis, and a respiratory rate more than 60 breaths/min are all important signs of serious distress. Particular attention should be paid to the degree of aeration. Diffuse wheezing is typically appreciated, but if severe airway obstruction reduces airflow enough, wheezing may be absent. Pulse oximetry should be performed on presentation. Saturations less than 90% on room air can be indicative of severe airway obstruction, especially in infants.
Patients with severe asthma exacerbations may display signs of panic or exhaustion and alterations in level of consciousness. Agitation, drowsiness, and confusion can be signs of elevated Paco2 levels and may signify impending respiratory failure. Likewise, gasping respirations or frank apnea are indications of respiratory failure and need for intubation.
Patients are typically tachycardic secondary to stress, dehydration, and β-agonist therapy. A pulsus paradoxus of over 22 mm Hg correlates with elevated Paco2 levels. Diastolic blood pressure may be low secondary to dehydration and β-agonist use. Diastolic pressures less than 40 mm Hg in conjunction with extreme tachycardia may impair coronary artery filling and predispose to cardiac ischemia, especially in teenagers.
Blood gas measurements should be performed on all patients with severe asthma exacerbations. Venous blood gas measurements may serve as a screening test for acidosis and hypercapnia but cannot substitute for arterial blood gas measurements in critically ill asthmatics. 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. Metabolic acidosis may be due to relative dehydration, inadequate cardiac output, or underlying infection. Hypoxemia (Pao2 < 60 mm Hg) on room air may be a sign of impending respiratory failure or significant ventilation/perfusion mismatch caused by pneumonia or atelectasis. Ventilation/perfusion mismatching also can be exacerbated by β-agonist therapy due to effects on both the airway and vascular smooth muscle.
Monitoring of serum electrolytes may reveal decreased serum potassium, magnesium, and/or phosphate, especially in patients with prolonged β-agonist use. Blood count measurements are not required routinely. Leukocytosis is common in asthma exacerbations, and corticosteroid treatment causes demargination of polymorphonuclear leukocytes within a few hours of administration. Differentiating infection from stress demargination as causes of leukocytosis can be difficult; measurement of other inflammatory markers such as C-reactive protein (CRP) levels can be useful.
Measurement of forced expiratory volume in 1 second (FEV1) or peak expiratory flow (PEF) is recommended in the urgent or emergency care setting; however, patients with life-threatening asthma exacerbation are often unable to cooperate with testing. Values of less than 40% of predicted indicate a severe exacerbation and values less than 25% of predicted indicate imminent respiratory arrest. Repeated measures of pulmonary function in very severe exacerbations are of limited value. 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.
Chest x-rays should be obtained in severe asthma exacerbations to evaluate for treatable triggers such as pneumonia, foreign body aspiration, suspected air leak, or a chest mass. Particularly in patients with severe wheezing who lack a previous asthma history, alternative diagnoses such as foreign body aspiration, congestive heart failure, pulmonary infections, or mediastinal mass should be entertained. An expiratory chest film is particularly helpful in identifying foreign bodies. Pneumothorax and pneumomediastinum are common complications of severe asthma exacerbations and may occur in nonintubated patients.
Much of the morbidity associated with the treatment of severe asthma is related to the complications of providing mechanical ventilation in patients with severe airflow obstruction. As a result, the goal of initial treatment of patients with life-threatening status asthmaticus is to improve their ability to ventilate without resorting to endotracheal intubation and mechanical ventilation. The medical therapies described in the following discussion should be undertaken swiftly and aggressively with the goal of reversing the bronchospasm before respiratory failure necessitates invasive ventilation.
Close monitoring of gas exchange, cardiovascular status, and mental status are crucial to assessing response to therapy and determining the appropriate interventions. Children with status asthmaticus require IV access, continuous pulse oximetry and cardiorespiratory monitoring. Due to inadequate minute ventilation and V/Q mismatching, patients with severe asthma are almost always hypoxemic and should receive supplemental humidified oxygenimmediately to maintain saturations more than 90%.
The repetitive or continuous administration of a selective short-acting β2-agonist is the most effective means of rapidly reversing airflow obstruction. Treatment with agents such as albuterol remains the first-line therapy for these patients. If the patient is in severe distress and has poor inspiratory flow rates, thus preventing adequate delivery of nebulized medication, subcutaneous injection of epinephrine or terbutaline may be considered. The frequency of β2-agonist administration varies according to the severity of the patient’s symptoms and the occurrence of adverse side effects. Nebulized albuterol may be given intermittently at a dose of 0.1 mg/kg per nebulization up to 5.0 mg every 10–15 minutes, or it can be administered continuously at a dose of 0.5 mg/kg/h to a maximum of 20–30 mg/h, usually without serious side effects. IV β-agonists should be considered in patients with severe bronchospasm unresponsive to inhaled bronchodilators. The agent most commonly used in the United States is terbutaline, a relatively specific β2-agonist, which can be given as a bolus dose or as a continuous infusion. Owing to its relative specificity for β2-receptors, terbutaline has fewer cardiac side effects than previously available IV β-agonists such as isoproterenol. Terbutaline is given as a bolus or loading dose of 10 mcg/kg followed by a continuous infusion of 0.5–5 mcg/kg/min. The heart rate and blood pressure should be monitored closely, because excessive tachycardia, ventricular ectopy, and diastolic hypotension may occur in patients receiving either inhaled or IV β2-agonist therapy. In general, patients receiving IV therapy should have indwelling arterial lines for continuous blood pressure and blood gas monitoring.
Immediate administration of systemic corticosteroids is critical to the early management of life-threatening status asthmaticus. Although oral systemic corticosteroids are generally recommended, consideration should be given to IV steroid administration in critically ill patients secondary to frequent intolerance of enterally administered medications. A dose of 2 mg/kg/d of methylprednisolone is generally prescribed for the critical care setting.
Infants and children with status asthmaticus may become dehydrated as a result of increased respiratory rate and decreased oral intake. In these patients, clinicians should make an assessment of fluid status and provide appropriate corrections. Fluid replacement should be aimed toward restoration of euvolemia while avoiding overhydration. The hemodynamic effects of high dose β2-agonist therapy (peripheral dilation, diastolic hypotension) may require some 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.
For severe exacerbations unresponsive to the initial treatments listed above, additional treatments may be considered to avoid intubation. Ipratropium bromide, an inhaled anticholinergic bronchodilator, is a reasonable intervention given its low side-effect profile, though two controlled clinical trials failed to detect a significant benefit from its addition to standard therapy in preventing hospitalization due to asthma. Magnesium sulfate is reported to be an effective bronchodilator in adult patients with severe status asthmaticus when given in conjunction with steroids and β2-agonists and may be considered for patients with impending respiratory failure or who have life-threatening exacerbations that do not respond well to the first 1 hour of intensive conventional therapy. The mechanism of action of magnesium is unclear, but its smooth muscle relaxation properties are probably caused by interference with calcium flux in the bronchial smooth muscle cell. Magnesium sulfate is given IV at a dose of 25–50 mg/kg per dose. Although usually well tolerated, hypotension and flushing can be side effects of IV magnesium administration. Heliox-driven albuterol nebulization can also be considered for patients refractory to conventional therapy. Heliox is a mixture of helium and oxygen that is less viscous than ambient air and can improve airway delivery of albuterol and gas exchange. Clear evidence of clinical efficacy is lacking for young patients, and heliox requires a mixture containing at least 60%–70% helium to alter viscosity sufficiently to significantly improve air flow, limiting its use in patients requiring higher concentrations of supplemental oxygen.
Theophylline is a methylxanthine that remains controversial in the management of severe asthma. Clinical studies have yielded a mixed verdict on its benefit when given with steroids and β2-agonists for children with asthma. This uncertainty, together with its high side-effect profile, led to a general recommendation against the use of theophylline for asthma exacerbations, although it may still have a role in severe exacerbations as a means to prevent intubation. The theoretical benefit of theophylline is relaxation of airway smooth muscle by preventing degradation of cyclic guanosine monophosphate, a mechanism of action distinct from that of β2-agonists. Besides causing bronchodilation, this agent decreases mucociliary inflammatory mediators and reduces microvascular permeability. However, the pharmacokinetics of theophylline are erratic and therapeutic levels can be difficult to manage. It is also associated with serious side effects, such as seizures and cardiac arrhythmias that can occur with high drug levels. Theophylline is given IV as aminophylline. Each 1 mg/kg of aminophylline given as a loading dose will increase the serum level by approximately 2 mg/dL. For a patient who has not previously received aminophylline or oral theophylline preparations, load with 7–8 mg/kg of aminophylline in an attempt to achieve a level of 10–15 mg/dL; then start a continuous infusion of aminophylline at a dosage of 0.8–1 mg/kg/h. A postbolus level and steady-state level should be drawn with the initiation of the medication. Watch closely for toxicity (gastric upset, tachycardia, and seizures) and continue to monitor steady-state serum levels closely, trying to maintain steady-state levels of 12–14 mg/dL.
Noninvasive ventilation (NIV) is another approach for treatment of respiratory failure due to severe asthma exacerbation that may help avoid the need for intubation and mechanical ventilation. Positive pressure ventilation may help to 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 to small studies and case series but have shown an improvement in gas exchange and respiratory effort.
If aggressive management fails to result in significant improvement, mechanical ventilation may be necessary. Patients who present with apnea or coma should be intubated immediately. Otherwise, if there is steady deterioration despite intensive therapy for asthma, intubation should occur semi-electively before acute respiratory arrest, because the procedure can be dangerous in patients with severe asthma given the high risk of barotrauma and cardiovascular collapse. 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. The goal of mechanical ventilation for an intubated asthma patient is to maintain adequate oxygenation and ventilation with the least amount of barotrauma until other therapies become effective. Worsening hypercarbia following intubation is typical, and aggressive efforts to normalize blood gases may only lead to complications. Due to the severe airflow obstruction, these patients will require long inspiratory times to deliver a breath and long expiratory times to avoid air trapping. In general, the ventilator rate should be decreased until the expiratory time is long enough to allow emptying prior to the next machine breath. Ventilator rates of 8–12 breaths/min are typical initially. Either volume- or pressure-targeted modes of ventilation can be used effectively, although tidal volume and pressure limits should be closely monitored. As 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. Due to air trapping, patients can have significant auto-PEEP. The level of PEEP on the ventilator is usually set low (0–5 cm H2O) to minimize air trapping and high peak pressures. Isolated reports have noted patients who respond to greater PEEP, but these are exceptions.
These ventilator strategies and resulting hypercarbia typically are uncomfortable, requiring that patients be heavily sedated and often medically paralyzed. Fentanyl and midazolam are good choices for sedation. Ketamine is a dissociative anesthetic that can be used to facilitate intubation and also as a sedative infusion for intubated patients. Ketamine has bronchodilatory properties, although it also increases bronchial secretions. Barbiturates should be avoided as well as morphine, both of which can increase histamine release and worsen bronchospasm. Most patients, at least initially, will also require neuromuscular blockade 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; they must be used with caution, however, as they can also cause significant hypotension due to vasodilation and myocardial depression.
Status asthmaticus remains among the most common reasons for admission to the PICU. It is associated with a surprisingly high mortality rate (1%–3%), especially in patients with a previous PICU admission. 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.
Carroll CL et al: Identifying an at-risk population of children with recurrent near-fatal asthma exacerbations. J Asthma 2010 May;47(4):460–464 [PMID: 20528602].
National Asthma Education and Prevention Program: Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma—Summary Report 2007, Section 5, Managing Exacerbations of Asthma. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm.
Ram FS et al: Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Database Syst Rev 2005;(1):CD004360 [PMID: 15674944].
CARDIOVASCULAR CRITICAL CARE
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Shock is defined as the inadequate delivery of oxygen and nutrients to tissues to meet metabolic needs.
Shock can result from decreased delivery of oxygen, inadequate delivery of oxygen in the face of increased demands, or from impaired utilization of oxygen.
Shock can be categorized as compensated, uncompensated, and irreversible.
Early recognition and intervention are essential to improving patient outcomes from shock.
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), though many of these processes overlap in critically ill patients.
Table 14–7. Categories of shock.
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. The lack of adequate oxygen delivery to meet the metabolic demands of a tissue leads to anaerobic metabolism in cells and ultimately to irreversible cellular damage.
Since oxygen delivery (DO2) is defined as the product of the ability of the heart to pump blood to the organs, that is, cardiac output (CO), and the oxygen content of arterial blood (CaO2) delivered by the heart, it can be expressed mathematically as CO × CaO2. Cardiac output in turn is determined by ventricular stroke volume (SV) and heart rate (HR) and is calculated as SV × HR. Stroke volume is influenced by preload, afterload, contractility, and cardiac rhythm. Numerous conditions can disrupt one or more of these factors. 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 lead to shock in 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 transsarcolemma Ca2+ flux (ie, 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 stroke volume 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 amount of dissolved oxygen is much smaller than that of bound oxygen and the main determinant of arterial oxygen content is the bound oxygen. Both illnesses that affect the oxygen saturation of hemoglobin and illnesses that 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. Abnormal hemoglobins can also impair oxygen delivery, since carboxyhemoglobin (formed in carbon monoxide poisoning) or methemoglobin have different oxygen-carrying capacities than normal hemoglobin, resulting in impaired oxygen delivery.
Although shock from different critical illnesses can manifest similarly, the cellular pathophysiology will differ depending upon the underlying etiology. For example, in patients with cardiogenic shock, heart failure activates the renin-angiotensin-aldosterone and adrenergic sympathetic systems and decreases parasympathetic stimulation leading to sodium and water retention, increased afterload, increased energy expenditure, cardiomyocyte death, and progressive ventricular dysfunction. Persistent activation of the sympathetic nerves results in adrenergic receptor down-regulation, which is further complicated in the neonatal heart, which has less β-adrenergic receptor expression that limits the response to inotropic agents. Dissociative shock is a term referring to abnormalities of hemoglobin-oxygen dissociation that lead to impaired oxygen availability to the tissues, typically as a result of abnormal hemoglobin function due to poisoning. In all cases of shock, the defects in oxygen delivery and utilization lead to anaerobic metabolism, hypoxia, and lactic acidosis.
The clinical presentation of shock can be categorized into a series of recognizable stages: compensated, uncompensated, and irreversible. Patients in compensated shock have relatively normal cardiac output and normal blood pressures but have alterations in the microcirculation that increase flow to some organs and reduce flow to others. As shock progresses, cardiac output increases in order to meet the tissue demand for oxygen delivery. In infants, a compensatory increase in cardiac output is achieved primarily by tachycardia rather than by an increase in stroke volume. In older patients, cardiac contractility (stroke volume) and heart rate both increase to improve cardiac output. Blood pressure remains normal initially because of peripheral vasoconstriction and increased systemic vascular resistance. Thus, hypotension occurs late and is characteristic of uncompensated shock. In this stage, the oxygen and nutrient supply to the cells deteriorates further with subsequent cellular breakdown and release of toxic substances, causing further redistribution of flow. Patients in uncompensated 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 determine 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 the pulse thready. 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; in a patient with shock this may reflect severe vascular leak due to sepsis or poor cardiac output with fluid and sodium retention. The skin examination can 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 heart rate, 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. Also, a discrepancy in pulses between lower extremities and upper extremities may indicate a critical coarctation of the aorta leading to shock, particularly in an infant 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 can be seen 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 > 1 mL/kg/h; output < 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.
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. Arterial blood gas (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%).
Table 14–8. Laboratory studies in the case of shock.
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 are routinely performed for critically ill patients to check endotracheal tube or central line placement, evaluate the extent of airspace disease and presence of pleural effusions or pneumothorax, and evaluate for pulmonary edema and cardiomegaly. Computed tomography (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. The pulmonary artery catheter 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.
Table 14–9. Hemodynamic parameters.
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Sepsis and septic shock remain major causes of death in children worldwide.
Early recognition and intervention are key to improving patient outcome.
Organized systematic approaches to the treatment of sepsis within an institution can improve survival.
Sepsis and septic shock require particular consideration because sepsis is one of the major illnesses leading to admission to the pediatric intensive care unit. 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 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. The systemic inflammatory response syndrome (SIRS) refers to a nonspecific syndrome of systemic inflammation typically associated with fever, tachycardia, tachypnea, and an abnormal white blood cell count. Sepsis is defined as a clinical syndrome characterized by a documented or suspected infection, accompanied by clinical and laboratory signs of systemic inflammation (SIRS). 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. Severe sepsis is defined as sepsis along with evidence of at least 1 sepsis-induced major organ dysfunction such as hypotension, hypoxemia, lactic acidosis, oliguria, renal failure, thrombocytopenia, coagulopathy, or hyperbilirubinemia. 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. Septic shock is defined as severe sepsis associated with impaired oxygen delivery, often accompanied by hypotension unresponsive to fluids.
Table 14–10. Diagnostic criteria for sepsis.
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 and includes 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 down-regulation, leading to end-organ dysfunction and ultimately to death if the process is not reversed.
Treatment of Shock and 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 intervention, 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, or poor gas exchange. In addition, patients in shock who will require surgery or other interventions requiring general anesthesia will also require mechanical ventilation. Due to low functional residual capacity, infants and neonates are more likely to require early initiation of noninvasive ventilation or endotracheal intubation. In patients with septic shock, use of etomidate for sedation during intubation should be avoided 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 may 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. Adult guidelines recommend targeting fluid resuscitation to achieve a central venous oxygen saturation (ScvO2) of greater than 70% and CVP of 8–12 mm Hg in the emergency department, but due to the challenges of placing central venous lines in pediatric patients, this is often not feasible in young patients. If pulmonary edema or hepatomegaly develop, inotropes 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 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. Children with hemolytic anemia crises who are hemodynamically stable should receive red blood cell transfusions. 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 support can be delivered through an intraosseous or peripheral line until stable central access is secured to prevent a delay in initiation. Inotropes or vasopressor therapy should be selected based on the hemodynamic state, which may include high or low cardiac output and high or low systemic vascular resistance and which may also change during the clinical course. An inotropic agent may be required to maintain cardiac output when patients require vasopressors for refractory hypotension. Though 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 as a rescue therapy 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, dobutamine (selective β-agonist) may be used to improve myocardial contractility and reduce afterload. Alternatively, milrinone, a type III phosphodiesterase inhibitor with inotropic and vasodilator activity, can be added to other more potent inotropic agents. Hypocalcemia also often contributes to cardiac dysfunction in shock; calciumreplacement should be given to normalize ionized calcium levels.
Table 14–11. Pharmacologic support of the patient with shock.
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/d (up to 200 mg/d) 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 can also be associated with elevated ventricular filling pressures (> 20 mm Hg). Although increasing preload to patients in this condition may result in augmented cardiac output (to a degree), volume should be administered cautiously as improvement may occur at the expense of elevated pulmonary venous pressure with resultant 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 should be 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. The presence of antiplatelet antibodies may modify these transfusion criteria. For severe coagulopathies associated with bleeding in the setting of shock, the standard treatment is fresh frozen plasma 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 used as a life-saving measure in the treatment of severe shock in patients with recoverable cardiac and pulmonary function who have failed conventional management.
Dellinger RP et al: Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock. Crit Care Med 2013;41(2):580–637.
Monica E. Kleinman et al: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science. Part 14: Pediatric Advanced Life Support 2010. Circulation 2010;122:S876–S908.
Surviving Sepsis Campaign website (a good source for information on sepsis including protocols and order bundles for the care of patients with sepsis). http://www.survivingsepsis.org/Pages/default.aspx
Wong HR: Genome-wide expression profiling in pediatric septic shock. Pediatr Res 2013 Jan 17 [Epub ahead of print] [PMID: 23329198].
Pediatric neurocritical care is an emerging multidisciplinary practice whose participants share the common goal of improving outcomes in critically ill pediatric patients with neurologic injury. Pediatric neurocritical care providers focus on optimizing care delivery to support brain function, prevent additional injury, and maximize brain recovery. To this end, the field has focused on understanding the distinct pathophysiological and clinical features of pediatric brain injury, developing and applying new monitoring and diagnostic strategies, and formulating pediatric-specific management guidelines. Pediatric neurocritical care encompasses a variety of diagnoses, including traumatic brain injury, stroke, status epilepticus, and hypoxic-ischemic brain injury, and includes children whose neurologic injuries are the primary cause of or a secondary result of their critical illness.
TRAUMATIC BRAIN INJURY
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Hypotension, hypoxia, hypoglycemia, and hyperthermia are harmful to the injured brain and can exacerbate brain damage. Timely identification and correction of these factors is essential.
Early signs and symptoms of intracranial hypertension tend to be nonspecific. The classic Cushing triad of bradycardia, hypertension, and apnea occurs late and is often incomplete.
Trauma is the leading killer of children in the United States. Fifty percent of trauma-related deaths are due to traumatic brain injury, and many survivors endure lifelong disabilities. Prevention is the only true “therapy” for traumatic brain injury, and injury prevention strategies have helped reduce the incidence of this problem.
Traumatic brain injuries can be conceptualized as occurring in two phases. Primary injury occurs at the moment injury disrupts bone, blood vessels, and brain tissue. Secondary injury is the indirect result of the primary injury and develops within minutes to days after the initiating injury. Secondary injuries are potentially reversible and include (1) processes triggered by the primary injury, such as excitotoxicity (neuronal damage due to excitatory neurotransmitter release), oxidative stress, inflammation, and delayed neuronal death; and (2) additional insults to the vulnerable injured brain, including hypoxia, hypotension, hyperthermia, and hypoglycemia. Management of the head-injured child is directed at preventing and/or modifying the events contributing to secondary injury.
One of the key elements of managing children with traumatic brain injuries is the management of intracranial hypertension, in large part because intracranial hypertension can promote and worsen secondary brain injury. Intracranial pressure (ICP) is the pressure inside the skull, and is generally less than 15 mm Hg in healthy children. Prolonged periods of intracranial hypertension (defined as ICP greater than 20 mm Hg) are associated with increased morbidity and mortality. Table 14–12 lists common causes of intracranial hypertension in children. The skull, containing the brain, CSF, and cerebral blood, contains a fixed volume. Under normal circumstances, these three components are in balance, such that an increase in the volume of one component is offset by a decrease in one of the other components, maintaining a constant intracranial pressure (Monroe-Kellie doctrine). As a result of a traumatic brain injury, the volume of any or all of these components may increase, resulting in increased intracranial pressure (ICP). The factors contributing to intracranial hypertension can be understood by considering each of these three components.
Table 14–12. Pediatric illnesses commonly associated with intracranial hypertension.
The brain occupies about 80% of the volume within the skull. Apart from solid tumors, increases in the brain compartment are generally a result of cerebral edema. Cerebral edema can be divided into several forms: vasogenic, hydrostatic, interstitial, and cytotoxic. Vasogenic edema is frequently associated with trauma, tumors, abscesses, and infarct, and is due to breakdown of the tight endothelial junctions that make up the blood-brain barrier (BBB). As plasma constituents cross the BBB, extracellular water moves along fiber tracts into the brain parenchyma. This form of edema is thought to be at least partially responsive to corticosteroid therapy. Hydrostatic edema is due to transudation of fluid from the capillaries into the parenchyma as a result of elevated cerebral vascular pressures. This form of edema is frequently associated with malignant hypertension and is treated by judicious reduction of cerebral vascular pressures. Interstitial edema occurs primarily in lesions resulting in obstructed CSF flow and appears in a typical periventricular distribution; it is best treated by CSF drainage. Cytotoxic edema is the most common form of 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 traumatic brain injuries as well as hypoxic-ischemic injuries and metabolic disease.
CSF occupies an estimated 10% of the intracranial space. Intracranial hypertension due primarily to obstructed CSF flow or increased CSF volume (eg, hydrocephalus, primary or secondary) is generally easily diagnosed by CT scan and treated with appropriate drainage and shunting. CSF drainage can be of benefit in managing intracranial hypertension, however, even in the absence of overt hydrocephalus.
Cerebral blood volume comprises the final 10% of the intracranial space. Changes in cerebral blood volume generally result from alterations in vascular diameter in response to local metabolic demands or to local vascular pressures, responses termed auto-regulation. Several factors interact to control cerebral blood volume via the auto-regulatory responses of the cerebral vasculature. Metabolic auto-regulation 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 auto-regulation links cerebral blood pressure to cerebral blood flow. This response attempts to maintain a constant cerebral blood flow rate over a range of systemic blood pressures. Within the auto-regulatory range of blood pressure, the cerebral vessels dilate or constrict as appropriate to maintain constant cerebral blood flow. Once the cerebral vessels are maximally constricted, continued increases in systemic pressure may further increase cerebral blood flow and volume; conversely, once the vessels are maximally dilated, flow will fall as perfusing pressure falls. It is not unusual to see partial or complete loss of cerebral blood flow auto-regulation in the event of injury. Cerebral blood flow then becomes dependent on systemic blood pressure (traditionally termed “pressure passive” blood flow).
Initial examination of the patient with traumatic brain injury should include assessment of airway patency, breathing, and cardiovascular function. In addition, mental status should be evaluated, and the Glasgow Coma Scale (GCS) score calculated. Once stabilized from a cardiac and respiratory standpoint, a more detailed neurological examination including cranial nerves, spontaneous movement of extremities, strength, sensory perception, and presence or absence of deep tendon reflexes should be performed. Cervical spine injury and immobilization should also be considered. Similar considerations apply in patients with suspected intracranial hypertension but no clinical history of trauma. In either setting, repeated neurologic examinations are needed to monitor the progression of intracranial hypertension.
The clinical presentation of intracranial hypertension is dependent on the nature, location and size of the lesions in the brain, as well as the amount of edema and infringement of CSF pathways (Table 14–13). Early signs and symptoms are nonspecific, particularly in young children. Head CT or magnetic resonance imaging (MRI) is generally needed to identify intracranial injuries, to determine the need for surgical intervention, to monitor the progression of injuries and cerebral edema, and to monitor for the development of complications.
Table 14–13. Signs and symptoms of intracranial hypertension in children.
Continuous monitoring and correction of hemodynamic and respiratory abnormalities are essential for maintaining proper nutrient and oxygen supply to the brain after injury. Hypoxic episodes (Pao2 less than 60 mm Hg) after TBI are associated with increased morbidity and mortality, and current treatment guidelines recommend early endotracheal intubation and initiation of mechanical ventilation if elevated ICP is suspected. Episodes of agitation and/or pain can induce elevated ICP, and thus adequate sedation, either via intermittent dosing or continuous infusion, is also important. Several modalities may be used to monitor ICP, including placement of an external ventricular drain (EVD) in the lateral ventricle, and/or an intraparenchymal pressure monitor. Current treatment guidelines for children with severe traumatic brain injury recommend ICP monitoring for all patients with GCS ≤ 8. Little evidence exists to support the utility of ICP measurement and ICP-directed therapies in conditions associated with global CNS injuries (eg, anoxic brain injuries).
Mechanical treatments for TBI range from simple positioning to aggressive surgical decompression. Midline positioning and head elevation to 30 degrees can aid in cerebral venous drainage of blood from the head, thereby reducing cerebral blood volume and ICP. Timely surgical evacuation of hematomas and other pathologic masses remains a mainstay of TBI treatment, and decompressive craniectomy (removal of a portion of the skull and opening of the dura) can be of benefit in the treatment of refractory intracranial hypertension secondary to focal or diffuse injury. CSF drainage reduces ICP by reducing CSF volume, and can be accomplished by placement of an EVD in the lateral ventricles of the brain.
Medical treatment strategies for TBI in children are largely based on reducing ICP to normal levels. Studies in adult patients have demonstrated that more frequent and higher elevations in ICP predict worse outcomes, particularly when ICP rises over 20 mm Hg. As a result, treatment should be directed at reducing ICP to less than 20 mm Hg and preventing frequent spikes to higher levels. Another important concept for the treatment of intracranial hypertension is that of cerebral perfusion pressure (CPP), which is the driving pressure across the cerebral circulation and is defined as mean arterial pressure minus central venous pressure (CVP) or ICP, whichever is higher. Maintenance of CPP remains a second tier goal in most published guidelines for management of TBI. Though the ideal target value is not clear in children, most practitioners use 50–60 mm Hg. A suggested treatment algorithm for patients with documented intracranial hypertension based on best available evidence is presented in Figure 14–1. The information is largely drawn from experience with traumatic brain injuries, and the direct applicability of these concepts to other illnesses associated with intracranial hypertension remains unclear.
Figure 14–1. Proposed treatment algorithm for intracranial hypertension in head injury. CSF, cerebrospinal fluid; ICP, intracranial pressure; Pco2, partial pressure of arterial CO2.
Osmotic therapies such as mannitol and hypertonic (3% or greater) saline can be effective treatments for elevated ICP regardless of etiology. These agents exert a rheologic effect, decreasing blood viscosity, which allows for increased blood flow and subsequent auto-regulatory vasoconstriction, which reduces cerebral blood volume and therefore ICP. Osmotic agents also increase serum osmolarity and enhance movement of excess water out of brain cells and interstitium into blood vessels for removal by the kidney, an effect which enhances and prolongs the initial rheologic effects on ICP. Continuous infusion of hypertonic saline can be used to increase serum osmolarity, using the minimum dose to achieve an ICP of less than 20 mm Hg. Serum sodium and osmolarity should be followed closely to avoid severe hypernatremia or severe hypertonicity. Mannitol in doses of 0.25–1 g/kg can also be used for intracranial hypertension unresponsive to sedation. Treatment with mannitol may result in a brisk diuresis, leading to hypovolemia and hypotension that exacerbate secondary injuries, and should be promptly treated with fluid resuscitation and/or vasopressors. Renal failure due to intravascular volume depletion and acute tubular necrosis is a rare side effect and is associated with serum osmolarity greater than 320 mOsm/L.
Controlled ventilation is an important element of treating intracranial hypertension. Although acutely effective in causing cerebral vasoconstriction, hyperventilation leads to much larger decreases in blood flow than in blood volume, such that hyperventilation necessary to control ICP may actually compromise CNS perfusion to uninjured brain 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—should only be used in emergent situations involving patients with acute ICP elevations unresponsive to other measures, such as sedation, paralysis, ventricular drainage, and osmotic diuretics. Mild hyperventilation, to maintain Paco2 between 30 and 35 mm Hg, may be useful for managing intracranial hypertension in patients with severe brain injury. Due to the risks of worsening CNS ischemia, monitoring cerebral perfusion by blood flow studies or jugular bulb saturation is recommended for patients treated with extreme hyperventilation.
Current guidelines suggest the use of barbiturates for treating intracranial hypertension refractory to other measures. Barbiturates suppress cerebral metabolism and, through metabolic auto-regulatory effects, reduce cerebral blood volume and ICP. Although effective in many instances for ICP elevations, these agents are potent cardiac depressants, and their use often leads to hypotension, necessitating the use of a pressor to maintain adequate cerebral and systemic perfusion pressures. In addition, plasma barbiturate levels correlate poorly with effect on ICP, and monitoring of CNS electrical activity by EEG is necessary to accurately titrate their use.
Temperature regulation and in particular maintenance of normothermia is essential. Hyperthermia increases cerebral metabolic demand and worsens outcome, and should be promptly recognized and treated with antipyretics and/or surface cooling devices. Induced hypothermia lowers cerebral metabolism, cerebral blood flow, and cerebral blood volume, but has not been shown to improve overall outcome.
Hemodynamic support is also crucial in managing patients with traumatic brain injuries. Maintenance of adequate cardiac output and oxygen delivery to the CNS is necessary to optimize chances for recovery from significant brain injuries. Studies in both adult and pediatric head injury patients show that even a single episode of hypotension is associated with a marked increase in mortality rates. Although age-appropriate thresholds for blood pressure in the context of severe TBI have not been delineated, a rational starting point for therapy would be maintenance of an adequate circulating blood volume, and a blood pressure at least well within the normal range for age.
Corticosteroids may be of use in reducing vasogenic cerebral edema surrounding tumors and other inflammatory CNS lesions but in general they have no role in the treatment of traumatic brain injuries or diffuse cerebral edema due to traumatic, ischemic, or metabolic injuries.
Complications are frequent in patients with traumatic brain injuries and should be anticipated. Seizures occur in approximately 30% of patients with severe head injury, and therefore a short course of empiric antiepileptic medication is frequently used. Single early seizures do not require long-term treatment. Continuous electroencephalography (EEG) should be considered to determine if clinically unrecognized seizures or nonconvulsive status epilepticus are present in patients with persistent altered mental status or in those requiring heavy sedation. Cerebral herniation presenting with Cushing triad of bradycardia, hypertension, and altered respirations is a medical emergency requiring intubation, infusion of mannitol, and brief period of hyperventilation while more definitive therapies are implemented. Cerebral infarctions may occur as a result of ischemia, thrombosis, and progressive edema compromising blood supply.
Many factors will affect prognosis of traumatic brain injury patients, especially the inciting event and severity of injury. To date there are no clear methods for definitively predicting outcome, although several studies have shown that the initial GCS score (particularly the motor score), mechanism of injury, or radiologic findings may be useful. Global hypoxic-ischemic events and inflicted brain injury have a worse outcome than uncomplicated, accidental traumatic brain injuries. Lack of improvement in neurological examination at 24–72 hours is associated with poor outcome. Follow-up studies have also demonstrated that “recovery” occurs over time, even months to years.
Hypoxic-ischemic encephalopathy (HIE) is due to global brain hypoxia and ischemia produced by systemic hypoxemia and/or reduced blood flow to the brain. Pediatric HIE is commonly caused by cardiopulmonary arrests due to drowning, 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.
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 brain death.
The initial evaluation of a patient with HIE includes assessment of airway patency, breathing, and cardiovascular stability. The GCS score should be periodically calculated to assess injury progression. As with traumatic brain injuries, 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 auto-regulation 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 post-ischemic 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. The utility of intracranial pressure monitoring and titration of therapies to a normal ICP in HIE patients has not been clearly defined, and this remains an area of substantial variation in practice across pediatric referral centers. Seizures should be aggressively treated, and continuous EEG monitoring is useful for identifying subclinical seizure activity. Temperature regulation and maintenance of normothermia are also essential, since the risk of severe disability in patients with HIE increases with temperatures greater than 38°C. Therapeutic hypothermia (target body temperature 33–35°C) is a mainstay of treating postcardiac arrest HIE in adults and post-anoxic HIE in newborns. Application of therapeutic hypothermia to improve neurologic outcome can be considered in children with HIE following cardiac arrest. Currently, clinical data in children are controversial and research evaluating the efficacy of hypothermia in the pediatric population is underway.
Accurately predicting outcome in children with HIE is difficult. While practice parameters for prognosticating neurologic outcome after cardiac arrest in adult patients have been published, no clear roadmap for predicting outcome in pediatric HIE exists. There are, however, several event characteristics, physical examination findings, and tests that have been shown to have a high positive predictive value for poor outcome. A prolonged cardiopulmonary resuscitation (> 10–15 minutes) is a significant risk factor 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), (6) MRI imaging demonstrating watershed, basal ganglia, and brainstem injury. Outcome prediction is enhanced when several assessment modalities are combined.
Inflicted Traumatic Brain Injury
Inflicted traumatic brain injury (iTBI), also referred to as nonaccidental trauma (NAT), accounts for a significant portion of traumatic brain injuries in infants and young children. The pathophysiology underlying severe iTBI is often more complex than in accidental head trauma. This is the result of several factors, including (1) sustaining multiple, less severe brain injuries prior to presentation and (2) suffering additional acute global hypoxic-ischemic brain damage as a result of trauma-induced respiratory failure or cardiac arrest. The management of children with iTBI is similar to children with accidental TBI and includes therapies to mitigate secondary brain injuries. Additional evaluations that should be performed include an ophthalmologic assessment for retinal hemorrhages and a radiological skeletal survey to identify occult bone fractures should be performed. The appropriate child advocacy and law enforcement groups should also be notified when abuse is suspected. Unfortunately, children with inflicted traumatic brain injury often have a worse neurologic outcome compared to accidentally injured children.
Abend NS, Licht DJ: Predicting outcome in children with hypoxic ischemic encephalopathy. Pediatr Crit Care Med 2008;9:32–39 [PMID: 18477911].
Hutchison JS et al: Hypothermia therapy after traumatic brain injury in children. N Engl J Med 2008;358:2447–2456 [PMID: 18525042].
Jagannathan J et al: Long-term outcomes and prognostic factors in pediatric patients with severe traumatic injury and elevated intracranial pressure. J Neurosurg Pediatrics 2008;2:240–259 [PMID: 18831656].
Mehta A et al: Relationship of intracranial pressure and cerebral perfusion pressure with outcome in young children after severe traumatic brain injury. Dev Neurosci 2010;32:413–419 [PMID: 20805152].
ADDITIONAL THERAPEUTIC CONSIDERATIONS IN THE PEDIATRIC ICU
ACUTE KIDNEY INJURY AND RENAL REPLACEMENT THERAPY
The kidney is important in maintaining homeostasis for a number of important physiologic processes, including fluid balance, electrolyte balance, acid-base status, erythropoiesis, and vascular tone. Acute renal failure 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. In recent years, the recognition that renal injury is often undiagnosed led to efforts to develop more consistent diagnostic criteria. The term acute kidney injury (AKI) has been adopted to reflect the broad range of clinically important manifestations of renal failure, and a number of diagnostic scoring systems have been developed. The most widely accepted of these is the pRIFLE system (Table 14–14), which specifies thresholds for increasing degrees of renal injury.
Table 14–14. pRIFLE criteria for diagnosis of acute kidney injury in children.
The etiology of AKI in pediatric ICU patients is most often multifactorial. Altered renal perfusion is a common contributing factor, due to combinations of systemic hypotension, impaired venous return to the heart (as with heart failure or high intrathoracic pressure), or high intra-abdominal pressures (abdominal compartment syndrome). Sepsis is another common contributing factor to AKI. The renal effects of sepsis are thought to be due to disturbances of the renal microvasculature caused by inflammatory mediators and activation of the coagulation system, as well as to sepsis-related alterations in systemic hemodynamics. Nephrotoxic medications contribute to as much as 25% of cases of AKI, most commonly antibiotics (aminoglycosides, vancomycin), and immunosuppressives such as cytotoxic cancer chemotherapeutics and calcineurin inhibitors. Other contributing factors can include hypoxia, pulmonary-renal and hepatorenal syndromes, and toxic metabolic byproducts as in rhabdomyolysis or tumor lysis syndrome.
In general PICU populations, 10%–30% of patients are found to have or develop AKI, defined as “I” or worse on the pRIFLE scale. Of those who develop AKI, most do so within the first 24–48 hours of hospitalization and almost all within the first week. Importantly, the development of AKI is a strong independent risk factor for increased ICU length of stay and increased mortality. Even after adjusting for severity of illness, AKI is associated with a 2- to 6-fold increase in mortality risk.
One of the most important clinical consequences of AKI is fluid overload. Excess fluid over 10% of body weight is an independent risk factor for increased ICU length of stay and mortality, and patients overloaded by 20% of their body weight in fluid may have as much as an 8-fold increased risk of death. The mechanism behind this association remains unclear, but based on these findings some authorities recommend consideration of renal replacement therapies for patients reaching 10%–20% fluid overload. Other potential clinical consequences of AKI include electrolyte abnormalities, hypertension, and reduced clearance of medications.
The management of AKI is directed at alleviating potential contributing factors. Methods to improve renal perfusion include maintenance of adequate cardiac output and systemic blood pressure with fluids and/or pressors, and relief of excess intrathoracic and intraabdominal pressures when feasible. Unfortunately, prospectively validated thresholds of adequate renal perfusion pressures to prevent or reverse AKI do not exist. The use of direct renal vasodilators such as dopamine or fenoldopam to increase renal blood flow does not improve outcomes in AKI.
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, 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 venovenous hemofiltration (CVVH). This latter technique involves sending patient venous blood through an extracorporeal filtration circuit and pump to provide slow, continuous fluid removal and/or dialysis. While the ideal modality depends on the individual clinical situation, recent advances in technology have made CRRT the preferred modality of renal replacement for managing AKI in most pediatric ICU 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. Importantly, despite its growing popularity, no prospective studies have compared CRRT with other modes of renal replacement or demonstrated that early initiation of CRRT improves outcomes in AKI. As a result, the decision to proceed with CRRT should involve a careful assessment of risks and possible benefits in each individual patient.
Basu RK, Devarajan P, Wong H, Wheeler DS: An update and review of acute kidney injury in pediatrics. Pediatr Crit Care Med 2011;12:339–347 [PMID]: 21057358].
Goldstein SL: Continuous renal replacement therapy: mechanisms of clearance, fluid removal, indications, and outcomes. Curr Opin Pediatr 2011;23:181–185 [PMID: 21178623].
Soler YA et al: Pediatric risk, injury, failure, loss, end-stage renal disease score identifies acute kidney injury and predicts mortality in critically ill children: a prospective study. Pediatr Crit Care Med 2013;14:1–7 [PMID: 23439463].
FLUID MANAGEMENT AND NUTRITIONAL SUPPORT OF THE CRITICALLY ILL CHILD
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Fluid overload is an important predictor of poor outcome in critically ill children.
Hyponatremia is also common in the PICU and may be associated with worse outcomes.
Critically ill children are more susceptible to metabolic stress than adults due to lower muscle and fat mass and higher resting energy requirements.
Obese children are more likely to develop complications including sepsis, wound infection, and increased length of stay in the PICU.
Changes in nutritional status can persist for up to 6 months after discharge from a prolonged ICU stay.
Early enteral and parenteral feeding can improve nutrition deficits and may influence morbidity and mortality in critically ill infants and children.
The majority of critically ill children will be 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. Especially in the complex environment of the ICU, the prescription of a fluid and nutrition regimen is a decision that should be approached with the same care as prescription of antibiotics or vasopressors.
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 normotensive, spontaneously breathing patient. Patients presenting with hypovolemia or poor perfusion will usually benefit from an infusion rate greater than maintenance. Additional fluid losses may occur from increased urinary losses (eg, with glucosuria), hemorrhage, or externalized surgical drains. Insensible fluid losses may be elevated due to increased work of breathing or fever. Furthermore, any patient with evidence of hypovolemic shock should have appropriate fluid resuscitation regardless of the continuous fluid rate.
While some patients require administration of large volumes of IV fluid early in their course, PICU patients are more likely to develop fluid overload than hypovolemia. Patients may be oliguric due to AKI or have reduced urine output due to excess ADH secretion, as is seen 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 2/3 that of someone who is not mechanically ventilated. Fluid overload more than 10%–20% of body weight is an independent risk factor for increased length of stay and death in general ICU populations, and fluid overload has been associated with worse outcomes in many critically ill subpopulations, including patients with acute lung injury, traumatic brain injury, and acute renal failure. If systemic hemodynamics will allow, early consideration of fluid restriction and/or diuretic use may be warranted in these situations.
Another important parameter in prescribing fluids in the ICU is the tonicity of the fluid chosen. 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. 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.
When severely ill pediatric patients are admitted to the PICU, initial therapy is directed at the primary or underlying problem and at providing cardiorespiratory and hemodynamic support. Provision of adequate nutritional support is often overlooked early in the course of therapy. Malnutrition is, however, a major problem in hospitalized patients, leading to higher rates of infectious and noninfectious complications as well as longer hospital stays and increased hospital costs. In the pediatric ICU, it is estimated that as many as 20% of patients experience either acute or chronic malnutrition, a rate that is largely unchanged over the past 30 years. The etiology of 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), to inaccurate assessments of caloric needs, and to inadequate delivery of nutrition at the bedside.
Table 14–15. Physiologic and metabolic responses to severe illness.
Pediatric Registered Dietitians (RDs) are integral members of the PICU team. Early assessment by a pediatric RD can be helpful to establish nutritional requirements and goals and to identify factors impeding adequate nutrition intake and tolerance. The caloric needs of the critically ill child can be estimated beginning with calculations of the basal metabolic rate (BMR) or the resting energy expenditure (REE). 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 (BMR or REE) 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 resting energy expenditures with a predominance of hypometabolism in the PICU population, resulting in a higher risk of overfeeding when using calculations alone.
Table 14–16. Markers of high risk of malnutrition suggested as indications for targeted indirect calorimetry assessment of REE.
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 (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 endotracheal tube leak is present, if the Fio2 is more than 60%, and during hemodialysis or continuous renal replacement.
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/d. 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.
Supplementation in Critical Illness
Pharmaconutrition is an area of ongoing research interest, but little prospective data is available to guide the use of supplements in critically ill children. Glutamine levels decrease during critical illness, and glutaminesupplementation may improve GI, metabolic, antioxidant, and immune functions in a stressed state. Some subgroups of critically ill adults may have improved outcomes with glutamine supplementation; studies in critically ill infants and children have been conflicting. Glutamine supplementation in children with burns, trauma, and critical illness should be considered, since it may produce the same benefits as in adults. Arginine is important for immune function, protein synthesis, and tissue repair, and arginine supplementation may improve nitrogen intake and immune function in children with traumatic injuries, including burns.
Mehta NM, Duggan CP: Nutritional deficiencies during critical illness. Pediatr Clin North Am 2009 Oct;56(5):1143–1160 [PMID: 19931068].
Mehta NM et al: A.S.P.E.N. clinical guidelines: nutrition support of the critically ill child. J Parent Enteral Nutr 2009;33(3): 260–276 [PMID: 19398612.]
Soler YA et al: Pediatric risk, injury, failure, loss, end-stage renal disease score identifies acute kidney injury and predicts mortality in critically ill children: a prospective study. Pediatr Crit Care Med 2013; Epub ahead of print Feb 22 [PMID: 23439463].
Valentine SL et al: Fluid balance in critically ill children with acute lung injury. Crit Care Med 2012 Oct;40(10):2883–2889 [PMID: 22824936].
SEDATION & ANALGESIA IN THE PEDIATRIC ICU
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
Pain control and relief of anxiety are standard of care for all patients in the PICU.
Sedation and analgesia must be individualized for each patient and reassessed frequently to avoid inadequate or excessive medication.
Every medication has a unique set of physiologic effects and side effects, and should never be used without adequate monitoring and support to address potential adverse events.
Children admitted to the PICU often require anxiolytic and analgesic medications to minimize their 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 children suffering postoperative pain or pain related to traumatic injuries. Thus, careful consideration of a patient’s sedative and analgesic needs is a critical part of ICU management.
When determining which anxiolytic and analgesic medications to initiate, the PICU provider should consider the underlying problem and the goals of treatment. 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 intravenous access or ability to tolerate oral medications. Children who will require more frequent dosing or tighter control of sedation level may benefit from a continuous infusion rather than intermittent dosing. Patients undergoing a bedside procedure, on the other hand, may only require a small number of discrete doses. Potential adverse effects are another important consideration in sedative and analgesic selection. For example, a medication known to cause hypotension may not be an optimal choice in a hemodynamically unstable child. Because of the known potential for adverse effects, all children should be appropriately monitored, with resuscitation equipment readily available.
Table 14–17. Commonly used intravenous medications for pain and anxiety control.
Sedative (anxiolytic) medications may be indicated when the goals of treatment are to reduce anxiety, facilitate treatment or diagnostic procedures, manage acute confusional states, and diminish physiologic responses to stress, such as tachycardia, hypertension, or increased ICP. Although many classes of drugs cause sedation, the most commonly used classes in the PICU are the benzodiazepines and the opioids. These should be carefully titrated to effect to avoid over-sedation and resultant respiratory depression and/or hemodynamic instability.
The benzodiazepine class works 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 the critically ill patient, 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 benzodiazepine withdrawal symptoms, including seizures.
The three 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 (IV, oral, intranasal) or for prolonged sedation as a continuous IV infusion. Lorazepam (PO, IV, or intramuscular) 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 can be administered via IV, oral or rectal routes. It 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.
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 below.
Ketamine (IV or IM) 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 non-anesthetic doses, an advantage for the nonintubated patient. Although it does have negative inotropic effects, this is countered by stimulation of the sympathetic nervous system resulting in an increase in heart rate, blood pressure, and cardiac output for most patients. This effect may make ketamine a good choice for hemodynamically unstable patients. Additionally, ketamine has bronchodilatory properties and, thus, may be an agent of choice 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 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 an α2-adrenoreceptor agonist that produces sedation with minimal respiratory depression and maintains the ability to rouse the patient easily if necessary. Dexmedetomidine does have some analgesic properties as well. These advantages have resulted in increasing use in critically ill children for procedural sedation as well as sedation to facilitate 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.
Propofol is an anesthetic IV induction agent with strong sedative effects. Its main advantages are a rapid recovery time and no cumulative effects 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. Due to concerns for propofol infusion syndrome, a sudden-onset, profound, and often fatal acidosis associated with prolonged infusions, propofol is now used mostly for procedural or short-term sedation rather than prolonged sedation.
Barbiturates (phenobarbital and thiopental) can cause direct myocardial and respiratory depression and are, in general, poor choices for sedation of seriously ill patients. Phenobarbital has a very long half-life (up to 4 days), and recovery from thiopental, although it is a short-acting barbiturate, can be prolonged because remobilization from tissue stores occurs.
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 drugs within the opioid class provide analgesia and have the potential for sedation that is dose-dependent. 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, pruritis, 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 upon the physiologic state of the child and the etiology of pain. If the patient is awake and developmentally capable, 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 pediatric ICU, 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 codeine, hydrocodone, hydromorphone, morphine, 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 may be necessary. Furthermore, caution should be used in patients with chronic opioid exposure to avoid precipitating severe withdrawal symptoms.
B. Nonopioid Analgesics
Nonopioid analgesics used in the treatment of 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 lack of effect on bleeding time. With chronic use and higher doses, acetaminophen may cause liver and renal toxicity.
Nonsteroidal anti-inflammatory drugs (NSAID) 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. These side effects may limit 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 two oral NSAID options for patients who can tolerate oral medications. Ibuprofen has a shorter half-life and therefore requires more frequent dosing.
Titration of Sedative and Analgesic Dosing, Delirium, and Withdrawal Syndromes
Recently, there has been an increasing appreciation of the disadvantages of sedative agents, 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 but 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 upon changes in physiologic parameters such as heart rate 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 Ramsay scale, the COMFORT score, and the State Behavioral Scale (SBS). The SBS is the most recently developed and has been validated for infants and children who are mechanically ventilated. 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 while in the intensive care unit. Delirium may present with a wide variety of symptoms, commonly grouped as hypoactive or hyperactive. Hyperactive delirium is associated with restlessness, agitation, emotional lability and even combativeness. Hypoactive delirium, on the other hand, may be more difficult to recognize. With hypoactive delirium, patients may be quiet, withdrawn, and apathetic with decreased responsiveness. Parents may notice their child’s personality is quite different from baseline. A newly developed PICU delirium scale (Pediatric Confusion Assessment Method for the ICU, or, pCAM-ICU) may help to 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. Preventing delirium completely may be difficult, but suggested strategies include avoiding over-sedation, changing environmental cues between day and night, and ensuring presence of parents and objects familiar to the child. Once delirium is present, returning to as normal a schedule and environment as possible can be very helpful. This includes promoting normal circadian rhythms, for example, greater activity during the day and quiet, dark rooms at night. Maintaining close involvement of family members may also bring reassurance and consistency for the child. Finally, in more extreme situations, treatment with medications can be considered. Antipsychotics may be used intermittently but with caution given their potential side effects. Benzodiazepines may calm the patient but also may induce a paradoxical reaction. Dexmedetomidine has also been proposed as 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 a period of 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 course of dose reduction.
Anand KJ et al: Tolerance and withdrawal from prolonged opioid use in critically ill children. Eunice Kennedy Shriver National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network. Pediatrics 2010 May;125(5):e1208–e1225 [PMID: 20403936].
Franck LS et al: Validity and generalizability of the Withdrawal Assessment Tool-1 (WAT-1) for monitoring iatrogenic withdrawal syndrome in pediatric patients. Pain 2012 Jan;153(1):142–148 [PMID: 22093817].
Hartman ME, McCrory DC, Schulman SR: Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: a systematic review. Pediatr Crit Care Med 2009 Mar;10(2):246–255 [Review] [PMID: 19188867].
Smith HA et al: Delirium: an emerging frontier in the management of critically ill children. Anesthesiol Clin 2011 Dec; 29(4): 729–750 [PMID: 22078920].
END-OF-LIFE CARE AND DEATH IN THE PICU
ESSENTIALS OF DIAGNOSIS & TYPICAL FEATURES
End-of-life discussions in the PICU should include the patient, if possible, and family members as well as the medical team.
PICU providers may assist in defining the limits of care provided, facilitating withdrawal of life support, and providing compassionate palliative care.
The palliative care and ethics teams, if available, may facilitate end-of-life discussions in the PICU.
Withdrawal of life-sustaining therapies should include a plan to treat any pain and discomfort in the patient.
Brain death determination requires a systematic and age-appropriate evaluation consistent with institutional policies.
Tissue and organ donation must be considered with every death.
Grief/bereavement support for the family as well as medical team members should be provided following every death in the PICU.
Death in the PICU
In-hospital pediatric deaths occur infrequently. A large proportion of pediatric deaths occur in the PICU, however, and the PICU provider may be called upon to help define the limits to care provided, assist in the withdrawal of life-sustaining medical therapies (LSMT), 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 medical care (65%).
Severe neurologic injury can result in the irreversible loss of all brain functioning, or 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 brain activity. Brain death is diagnosed by a clinical examination (Table 14–18) and is based on published guidelines. The general approach in the diagnosis of brain death is similar in most medical centers, but there can be subtle institutional variations. Therefore, it is imperative for PICU providers performing the brain death examination to be familiar with their own institutional policies on brain death declaration. A patient declared brain dead is legally dead and further medical support is no longer indicated, though the timing of discontinuation of medical support should be discussed and agreed upon with the patient’s family.
Table 14–18. Brain death examination.
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 electroencephalography or cerebral perfusion scan may provide supporting evidence of brain death. Once a child has been declared brain dead, their time of death is noted as occurring at the completion of the second examination even if they are 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 rather than via a brain death declaration. 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 (1) to communicate information regarding the patient’s medical status and anticipated prognosis, and (2) to 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 healthcare 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 or 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 respect the following basic principles:
• Discussions 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.
• Deliberations should begin with a clear statement that the goal is to make decisions in the best interest of the patient, and that the healthcare team can 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 elucidated 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 healthcare team should emphasize that decisions are not irrevocable; if at any time the family or healthcare 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 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 essential resources to help the healthcare 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 during prior medical episodes. 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. If conflict arises, surrounding decisions about limiting medical care, an ethics consultation in the ICU setting can aid the process by helping to identify, analyze, and resolve ethical problems. Ethics consultation can independently clarify views and allow the healthcare team, patient, and family to make decisions that respect patient autonomy and promote maximum benefit and minimal harm to the patient.
A more comprehensive discussion of palliative care can be found elsewhere in this book. Briefly, palliative care medicine has developed as a specialized field of practice to address the needs of dying children or children with a shortened lifespan. Many centers have developed palliative care teams that include medical personnel, social workers, and spiritual leaders to help families navigate the difficult process of dying and end-of-life decision-making, including withdrawal of support. Once the decision is made to limit or withdraw LSMT, a palliative care plan should be agreed on by all decision-makers, clarified to other healthcare providers and instituted with the primary goal of optimizing the patient’s and family’s experience prior to and following death. The plan, at minimum, should address: (1) adequate pain control and sedation, (2) provision of warmth and cleanliness, and (3) ongoing patient and family support and dignity.
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. However, the need for new donor organs has 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 upon 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 re-initiation of cardiac activity without medical intervention). After this waiting period, the patient is declared dead and the organs are 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 and Grief Support
After any pediatric death, bereavement and grief support for families and healthcare 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 healthcare workers caring for dying children.
Lee KJ et al: Alterations in end-of-life support in the pediatric intensive care unit. Pediatrics 2010;126(4):e859–e864.
Nakagawa T et al: Guidelines for the determination of brain death in infants and children: an update of the 1987 task force recommendations. Pediatrics 2011;128(3):e720–e740.
Truog RD et al: Recommendations for end-of-life care in the intensive care unit: a consensus statement by the American College [corrected] of Critical Care Medicine. Crit Care Med 2008;36(3):953–963 [PMID: 18431285].
Truog RD et al: Toward interventions to improve end of life care in the pediatric intensive care unit. Crit Care Med 2006;34 (11 Suppl):S373–S379 [PMID: 17057601].
QUALITY IMPROVEMENT INITIATIVES IN THE PICU
There has been intense interest in quality improvement initiatives in adult and pediatric ICUs in recent years given the frequency and high cost of ICU-related complications. National collaboratives have identified six areas of focus for pediatric ICU quality and safety improvement efforts: risk adjustment (severity-adjusted mortality rates and length of stay measures), central venous catheter infection, mechanical ventilation, unplanned readmissions to the PICU, pain assessment, and medication safety. The two most widely applied quality initiatives are efforts to reduce central venous catheter-related infections and to reduce the incidence of ventilator-associated pneumonia. Efforts to reduce catheter-related infections have largely focused on implementation of procedure checklists to ensure strict adherence to sterile procedure during catheter insertion, including hand hygiene, barrier precautions and site preparation, as well as sterile practice when accessing the catheter during care. Efforts to reduce ventilator-associated pneumonias include defined order sets (“order bundles”) for mechanically ventilated patients specifying patient positioning, oral care, feeding, and endotracheal tube suctioning practices in an effort to reduce contamination of the airway and endotracheal tube with bacterial pathogens from the patient’s GI tract or caregivers. 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.