Part 1: The Pathophysiology of Acute and Critical Illness

INTRODUCTION

Acute respiratory dysfunction in children warrants prompt diagnosis and management, particularly in neonates and infants, as decompensation can be fast and respiratory arrest is the most common cause of cardiac arrest in children. Their smaller airways, increased metabolic demands (relative to body mass), and decreased respiratory reserve may put children at a disadvantage compared to adults.

Severe respiratory dysfunction necessitates admission to the intensive care unit (ICU). Since the polio epidemic of the 1950s, ICUs have developed in parallel with our increasing understanding of respiration in health and disease. Respiratory support is now extensively used and has become progressively more sophisticated.

In this chapter, we will explore the approach to a child with acute respiratory dysfunction, the initial considerations about the differential diagnosis of those conditions, and the broad principles of management strategies. In order to provide perspective, we first review some essentials of normal respiratory function.

NORMAL RESPIRATION

The principal purposes of respiration are to provide oxygen and remove carbon dioxide, and this normal function involves the following elements.

Control of Respiration

Respiratory centers in the medulla receive stimulatory input from central respiratory pacer cells, central and peripheral chemoreceptors, upper airway receptors, and volitional pathways. These signals are integrated into a combined output to respiratory muscles in order to regulate breathing frequency, as well as the durations of inspiration and expiration.

Neuromuscular Function

Central signals are carried by the cervical and thoracic nerves to the neck, thoracic muscles, and diaphragm. These signals maintain patency of the upper airway and drive the thoracic bellows to provide ventilation. Downward movement of the diaphragm and outward movement of internal intercostal muscles lead to negative intrathoracic pressure and movement of air into the lungs (inhalation). The relaxation of these muscles leads to passive recoil of the lung and moves the air out (exhalation). The more negative the intrathoracic pressure, the greater the tidal volume generated.

Resting Lung Volume

At rest, elastic recoil tends to move the thoracic cage outward and the lung inward. The balance of these opposing forces, along with a surfactant in the alveoli that reduces the surface tension (ie, lessens the force required to distend the lung). Elastic recoil determines the resting volume of the lung at the end of expiration, also known as functional residual capacity (FRC). This is the effective volume available for gas exchange.

Airflow in the Large and Small Airways

Airflow generated by mechanical movements passes through the airways. The nasal passages, nasopharynx, larynx, trachea, and mainstem bronchi constitute the large airways. The bronchial tree, from segmental to subsegmental bronchi and down to each alveolar unit, comprise the lower airways. Large airways offer less resistance and airflow is mostly laminar except at bifurcations and in the upper trachea near the glottis, where it tends to be turbulent. The airways humidify and warm the air.

Alveoli

Air reaches the alveoli, which are small air-filled sacs covered with a surface-active agent called surfactant. Each alveolus is lined with epithelium and has an adjacent endothelial surface that lines the nearby capillaries. The interface is termed the alveolar-capillary membrane. Oxygen (O₂) and carbon dioxide (CO₂) are exchanged here along their respective concentration gradients. CO₂ moves from the pulmonary arterial blood (high concentration, endothelial) to the airspace (low concentration, epithelial), and oxygen moves in the reverse direction. Thus, adequate surfactant function and an intact alveolar-capillary membrane are keys to gas exchange.

Pulmonary Vessels

The pulmonary artery brings blood rich in CO₂ and low in O₂ into contact with the alveoli, and the pulmonary veins deliver blood rich in O₂ and lower in CO₂ to the left atrium, for systemic distribution. Movement of blood flow along the capillaries is necessary for effective gas exchange. At alveolar level, the microvessels are either in the alveoli (alveolar) or in the interstitial space (extra-alveolar). At FRC, alveoli and vessels are optimally open.

Ventricular Function

Normal ventricular function assures good pulmonary blood flow in the presence of enough preload. Low preload or suboptimal pump function leads to lower pulmonary blood flow and may affect gas exchange. The negative intrathoracic pressure also moves more blood into the lungs during inspiration and keeps it out of thorax during expiration, thus keeping a good balance throughout the respiratory cycle.

RESPIRATORY FAILURE

The respiratory system can fail if any of the above components of respiration is dysfunctional. Infants and children are at increased risk of developing airways obstruction when compared with adults. This is in part due to anatomic differences, particularly of the upper airways (see Fig. 96-1), but also due to conditions that more frequently affect younger patients. Large (or upper) airway obstruction usually occurs in children because of inhalation of a foreign body or airway inflammation such as croup or epiglottitis; rare causes include external compression from tumours or vascular malformations. Usually, large airway obstruction causes inspiratory stridor; in contrast, peripheral airway obstruction from asthma or bronchiolitis causes expiratory wheezing. Bronchiolitis is caused by small airway inflammation and narrowing, leading to expiratory obstruction. If severe, it can lead to trapping of air in the alveoli and hyperinflation. Alveolar damage mostly occurs from infection, edema, alveolar collapse, or contusion or alveolar hemorrhage. Such alveoli have diminished ventilation but are perfused; thus, shunting of deoxygenated blood occurs from the pulmonary artery to the pulmonary vein. Hypercapnia and hypoxemia increase respiratory drive, which coupled with reduced compliance from an injured lung, increases the work of breathing.

Chest wall restriction (eg, circumferential burn scars, kyphoscoliosis) limits tidal volume and necessitates rapid, shallow breathing. Diaphragm paralysis results in the diaphragm being pulled up (passively) by the inspiratory effort, creating a paradoxical pattern of breathing and mechanical disadvantage.

Neurological dysfunction, if severe or associated with elevated intracranial pressure, can depress respiration; in contrast, hyperventilation is characteristic of many congenital or acquired encephalopathies. Hyperventilation is also a typical finding as a compensation for metabolic acidosis (eg, ketoacidosis, salicylate ingestion). Sepsis increases utilization of oxygen, which elevates the work of breathing, and systemic inflammatory disorders (eg, systemic lupus erythematosus) can cause alveolar or pleural inflammation.

Finally, mechanical ventilation can damage the lungs; this is called ventilator-induced lung injury (VILI). Use of high tidal volume, suboptimal end-expiratory pressure, high driving pressure, and spontaneous breathing in injured lungs are some of the mechanisms that may contribute.

ACUTE RESPIRATORY FAILURE

Based on the underlying pathophysiology, acute respiratory failure can be either hypoxemic or hypercapnic.

• Hypoxemic. Alveolar airspace disease (eg, acute respiratory distress syndrome, or ARDS) and/or pulmonary vascular disease (eg, persistent pulmonary hypertension, pulmonary embolism) result primarily in oxygenation failure.

• Hypercapnic. Airway obstruction and disordered control of breathing lead to low tidal volume or reduced flow, resulting in primary ventilation failure with elevation of CO₂.

CHRONIC RESPIRATORY FAILURE

Chronic inflammation of alveoli, airways, or both (eg, cystic fibrosis, bronchopulmonary dysplasia), and chronic dysregulation of control of breathing (eg, central hypoventilation syndrome) can lead to long-term gas exchange failure, resulting in a baseline increase in CO₂ and ongoing O₂ dependence. Compensatory mechanisms of metabolic alkalosis to counter respiratory acidosis and re-establish a normal pH, and polycythemia to counter chronic hypoxemia become evident over time.

EPIDEMIOLOGY OF RESPIRATORY FAILURE

The epidemiology of respiratory failure in children is complex because of developmental issues, variable severity of illnesses in the pediatric ICU, and classification based on syndromes (eg, ARDS, sepsis) versus disease entities.

Croup

Croup is common in children aged 6 to 36 months, mostly in males. Family history is a risk factor, and it occurs most commonly in the fall and winter. Approximately 5% of children with croup in the emergency department (ED) are admitted to the hospital, and of those discharged home, approximately 5% return to the ED in 48 hours (see also Chapters 118 and 503).

Respiratory Syncytial Virus

Respiratory syncytial virus (RSV) is typically seasonal, with outbreaks usually occurring between October and April in the northern hemisphere and April and September in the southern hemisphere. It is the most common cause of lower respiratory tract infection in children less than 1 year of age, and hospitalization is most common in those aged less than 3 months. The mortality from RSV is about 1% in children less than 4 years of age. Risk factors include age less than 6 months, daycare, older siblings, underlying lung disease, gestational age less than 35 weeks, congenital heart disease, secondhand smoke, and Down syndrome.

Asthma Requiring ICU Admission

Sixty percent of asthmatic children have acute exacerbations, and the risk is greater in younger children or in those with inadequate interval asthma control. ICU admission is rare, but previous admission and exposure to multiple allergens are predictors (see also Chapter 505).

Pneumonia

Approximately 156 million children under 5 years of age develop pneumonia each year worldwide, and about 20 million cases require hospital admission. Mortality in the developed world is low (1/1000) but high in the developing world. Risk factors include winter months, malnutrition, crowding, and chronic pulmonary, cardiac or neurologic conditions.

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome in children is similar in its clinical, radiological, and pathological (see Fig. 96-2) characteristics to ARDS in adults. However, the incidence (8 vs 15/1000 ICU admissions) and the mortality (less than 20%) are lower in children than in adults. In addition, death due to pediatric ARDS is usually due to hypoxemia, whereas in adults it is more commonly from multiorgan failure.

INITIAL EVALUATION AND MANAGEMENT

A prompt evaluation can identify and facilitate the early stabilization of most sick children with respiratory failure. Hypopnea, severely increased work of breathing, dusky or mottled skin, pallor, and unresponsiveness can all herald imminent respiratory arrest.

Airway

Immediate airway assessment is essential for any patient presenting in actual or pending respiratory failure. The airway is patent if there are good chest movements and no obstructive sounds. If necessary, airway patency can be achieved with suction to clear airway contents and mechanical maneuvers such as a jaw thrust or chin lift, repositioning, placement of an oropharyngeal airway, or endotracheal intubation.

Breathing

Normal chest wall movement and breath sounds usually indicate adequate ventilation, although they cannot in themselves rule out hypercapnia or hypoxia. Respiratory distress is recognized by the use of accessory muscles, nasal flaring, subcostal and intercostal retraction. Severe distress is indicated by substernal, sternal, and suprasternal retraction. Auscultation may reveal crackles (airspace disease) or wheeze (airway disease), and the absence of cyanosis (confirmed by pulse oximetry) indicates adequate oxygenation. The unilateral absence of, or diminished, breath sounds indicates ipsilateral pneumothorax, major atelectasis, or pleural effusion.

UNDERLYING DIAGNOSIS

History

The history should include details of the course of the current symptoms, as well as any previous history of breathlessness, wheezing, cough or restricted activity, or failure to thrive. Access to or opportunities for ingestion of small objects, such as toys, or small pieces of food, should be specifically discussed with the caregivers, particularly if a foreign body is part of the differential diagnosis in a child with acute obstruction (see also Chapters 118 and 503).

Investigations

Multiple investigations are available to help establish the underlying diagnosis, but the key lies in narrowing down the selection to a definitive test. A chest radiograph can confirm hyperinflation, consolidation, asymmetry, collapse, and pleural collections. Blood gas analysis will provide arterial O₂ and CO₂ tensions, and the pH may be useful as a guide to chronicity of a respiratory acidosis, or may determine whether there is a metabolic acidosis driving the process. Ultrasound of the chest is a useful tool to characterize pleural collections (single or loculated), to assist with drainage, or in recent years to confirm atelectasis or consolidation. Fiber-optic bronchoscopy can be used in the evaluation of central airway obstruction and sampling of alveolar fluid using the technique of bronchial alveolar lavage (BAL), and in children is usually conducted under general anesthesia.

Diagnosis of Specific Conditions

• Croup. The acute onset of stridor, fever, barking cough, and hoarseness in older children strongly suggest a diagnosis of croup. Throat pain, drooling, or swallowing difficulty may suggest epiglottitis rather than croup. Differential diagnoses in which the patients are typically toxic, with high fevers on presentation, include acute epiglottitis, retro- and parapharyngeal abscesses, paratonsillar abscesses, and bacterial tracheitis (see also Chapter 118). Additional possibilities include foreign body aspiration, acute angioneurotic edema, and upper airway injury from burns.

• Bronchiolitis. A 1- to 3-day history of upper respiratory infection–like symptoms followed by fever, cough, and respiratory distress (eg, tachypnea, retractions, wheezing, and rales) in children younger than 2 years of age suggest bronchiolitis. Cyanosis, lethargy, dehydration, or apnea would indicate severe bronchiolitis, and children presenting in this way should be hospitalized.

• Asthma. Acute exacerbations of asthma can be characterized by a dry cough with or without specific exposure (eg, cold air, pollens, dust). A history of atopy, positive family history for asthma, and seasonal symptoms indicate the diagnosis. Expiratory wheezes and hyperinflation are common. When severe, air entry may be almost absent with severe fatigue and altered sensorium (see also Chapter 505).

• Pneumonia. High-grade fever, cough, breathlessness, chest pain with increased work of breathing, presence of crackles, and bronchial breathing make a clinical diagnosis of pneumonia very likely. The chest radiograph typically shows patchy or homogenous consolidation. Hypoxemia usually is present, and hypercapnia also may be present if the pneumonia is severe or if the patient becomes fatigued. Elevated white counts, high inflammatory marks (eg, C-reactive protein and/or procalcitonin) point toward a bacterial etiology over viral. Nasal swab, sputum cultures, or bronchoscopic cultures are the most specific tests to identify the microbial etiology.

• Pneumothorax. Respiratory distress with unilateral absent air entry, a resonant percussion note, and a shift of the mediastinum (trachea and heart sounds) make the diagnosis, and chest x-ray is confirmatory.

• Pleural effusion. Reduced air entry with a dull percussion note, and bronchial breath sounds at the upper levels with a shift of the mediastinum to the opposite side (if ipsilateral atalecatsis is not marked) indicate pleural effusion. Chest x-ray is diagnostic in most cases and chest ultrasound provides additional confirmation and permits image-guided aspiration.

RESPIRATORY SUPPORT

Supplemental Oxygen

Supplemental oxygen can be provided by nasal cannula or via a regular facemask or a nonrebreather mask. Oxygen flow is generally maintained at 3 to 4 times the minute ventilation so that all the inspiratory flow is provided by oxygen (100% O₂). Heated and humidified high-flow nasal cannula (HFNC) can also deliver high inspired O₂ with an additional component of positive pressure, which may assist with lung recruitment, though the level achieved is highly variable. The constant airflow displaces CO₂ from the anatomical dead space, thereby creating an oxygen reservoir. A HFNC also improves mucociliary function due to humidification and high flows.

Positive Pressure Ventilation

Noninvasive ventilation is routinely used to provide respiratory support in modern ICUs and can be applied in various ways. Continuous positive airway pressure (CPAP) opens the alveoli and increases FRC, thus improving oxygenation while the patient breathes spontaneously above this pressure to maintain ventilation. If efforts are inadequate, then bilevel positive airways pressure (BiPAP) can be applied. This provides an additional level of inspiratory support, as well as the option of providing mandatory breaths to further assist inspiratory effort and gas exchange. If problems persist or deteriorate, invasive ventilation should be instituted. In the case of a hypoxemic patient, an optimal positive end-expiratory pressure (PEEP) derived from a recruitment maneuver helps to open the alveoli and keep them open, thus increasing FRC. A tidal volume set at 6 mL/kg or adjusted to allow permissive hypercapnia (high CO₂ and pH > 7.2) reduces ongoing VILI. Adequate minute ventilation is achieved by adjusting the rate and providing good patient-ventilator synchrony. The inspiratory-to-expiratory time ratio is set such that it allows maximal oxygenation without reducing ventilation. High inspired O₂ concentrations are toxic to lung tissue and moderating the goals of oxygenation with a degree of permissive hypoxia might be beneficial.

Prone Positioning

Prone positioning has been used to improve oxygenation and ventilation in patients with ARDS. Prone positioning shifts the ventilation from nondependent to dependent parts of the lungs and moves abdominal contents away from the diaphragm, thus reducing impedance to ventilation in the injured area (Fig. 96-3).

High-Frequency Oscillatory Ventilation

High-frequency oscillatory ventilation (HFOV) was designed with the goal of keeping the lungs open and reducing tidal shear stress. It ventilates the lungs at the optimal compliance and moves air/oxygen flow continuously in a central column instead of in bulk flow. It achieves ventilation directly in relation to the amplitude of the percussions and inversely in relation to the frequency applied.

Inhaled Nitric Oxide

Inhaled nitric oxide (iNO) is a potent, selective pulmonary vasodilator. It is primarily indicated in pulmonary hypertension, especially in newborns. It is also used as an adjunct in hypoxic respiratory failure refractory to improve ventilation/perfusion matching, and therefore improve oxygenation. However, it is important to note that there is little evidence to support improved overall outcomes associated with the use of iNO in patients with ARDS. Inhaled nitric oxide delivery should be carefully monitored, as it can be toxic in high concentrations and may produce methemoglobinemia, though this is rare in the therapeutic dose range (usually up to 20 parts per million). It can also be cytotoxic to alveolar and vascular tissues.

Extracorporeal Membrane Oxygenation

Hypoxia unresponsive to all above therapies needs to be managed with extracorporeal life support. Use of venovenous extracorporeal membrane oxygenation (VV ECMO) helps the lungs rest and recover while oxygenation is achieved by an artificial membrane. Coexistent right heart failure or the presence of circulatory shock warrants the use of venoarterial (VA) ECMO. See also Chapter 108.

SPECIFIC THERAPIES

Antimicrobials

Specific choices of primary or adjunctive antimicrobial agents are largely dictated by the disease severity; factors relating to the underlying host (immunocompetent or otherwise); whether the infection may have been nosocomial or community acquired; and local pathogens and likely susceptibility. Optimal broad-spectrum antibiotics, started early and narrowed by sensitivity results from culture, are the standard of care for the treatment of pneumonia. This may be achieved with single agents, or if specific organisms such as Chlamydia, Mycoplasma, or methicillin-resistant Staphylococcus aureus (MRSA) are potential pathogens, or in severe cases requiring ICU admission, then 2 or more empiric antibiotics should be used. Antiinfluenza therapy using oseltamivir should be considered for severe pneumonia needing ICU admission until influenza is ruled out.

Surfactants

Ongoing surfactant replacement in primary surfactant deficiency in neonates should be instituted if transplantation is an ultimate goal. Outside of the newborn period, there is otherwise little evidence to support the use of surfactant in acute lung injury.

Bronchodilators

Rescue albuterol nebulization given continuously initially, and potentially followed by intravenous (IV) infusion in unresponsive cases of asthma, has become the standard of care. Magnesium sulphate and aminophylline are potential adjuncts to β₂-agonist therapy, and in the most severe cases, administration of inhalational anesthetic agents such as isoflurane or sevoflurane can be considered if appropriate delivery systems and monitoring exist.

Corticosteroids

Systemic steroids are strongly recommended in acute asthma exacerbations needing admission. Methylprednisolone 1 to 2 mg/kg/dose given every 6 to 8 hours either enterally or IV is the standard practice, though recent evidence suggests that a shorter course of dexamethasone may be a viable alternative. Steroids may also be useful to help reduce inflammation of the alveoli in cases of ARDS if given after a serious infection has been excluded.

PREVENTION

Prevention is the key to reduce the burden of morbidity and mortality from childhood respiratory illnesses, and to prevent hospitalization.

Asthma

Outpatient stabilization and well-controlled, long-term treatment and action plans may prevent acute exacerbations from requiring hospital admissions, and from reaching the ICU. Prompt use of inhalers, allergen identification and control, and patient education and follow-up become keys to the management of childhood asthma (see also Chapter 505).

Viral and Bacterial Infections

Timely vaccinations, avoiding overcrowding, minimizing travel during the peak season, and early visits for timely diagnosis and management are important to avoid progression to severe illness and ICU admission.

Hospital-Acquired Infection

Adherence to strict protocols of hand hygiene, ventilator-associated pneumonia (VAP) prevention bundles, and ongoing healthcare team education are imperative to reduce hospital-acquired infections.

Minimizing Ventilator-Induced Lung Injury

Use of lung protective strategy, minimizing repeated opening and closing of alveoli, and judicious use of PEEP are some of the measures to reduce VILI.

SUMMARY

Acute respiratory dysfunction is the most common cause for emergency and ICU visits in childhood. Preventive measures, prompt diagnosis, and early interventions with optimal respiratory support and diagnosis-driven therapies are all important mechanisms to reduce morbidity and mortality, in addition to potentially reducing healthcare costs.

SUGGESTED READINGS

INTRODUCTION AND EPIDEMIOLOGY

Sepsis continues to be the leading cause of death among children worldwide, accounting for more than 5.9 million deaths per year according to data from the World Health Organization and the United Nations Children’s Fund. In the United States, sepsis poses a significant healthcare burden with approximately 75,000 children admitted annually to hospitals with severe sepsis and an associated cost of $4.8 billion. Understanding the pathophysiology of systemic inflammatory response syndrome (SIRS) and sepsis syndrome is essential for recognition and management of this deadly disease.

PATHOGENESIS OF SIRS AND SEPSIS

In the 1990s, Bone and colleagues set forth the notion that systemic inflammation due to an infection can lead to SIRS, sepsis syndrome, multiple organ dysfunction syndrome (MODS), and multiple organ failure (MOF). Typically, after sensing an invading pathogen, the host’s innate immune system is locally activated in order to eradicate the infection. This immune activation is mediated by pathogen-associated molecular patterns (PAMPS), such as lipopolysaccharides from bacterial cell walls that interact with the pattern recognition receptors (PRRS) such as toll-like receptors (TLRs), which are present on local immune cells. This initial interaction between PAMPS and PRRS will lead to a signaling cascade, resulting in inflammatory cytokine and chemokine synthesis and release. Injured and dying cells caused by this inflammation go on to release damage-associated molecular patterns (DAMPS) such as the intracellular protein high-mobility group box 1. DAMPS released from tissue injury amplify the cytokine response to PAMPS that can progress into a vicious cycle of tissue and organ injuries (Fig. 97-1). The inflammatory mediators synthesized and released during sepsis syndrome are meant to help the host in combating the invading pathogen. However, if unregulated, these inflammatory mediators can induce a pathologic state of shock in the host. Shock is defined as a state of cellular and tissue hypoxia due to reduced oxygen delivery and/or increased oxygen consumption or inadequate oxygen utilization. For example, the inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1beta can both (1) depress myocardial function and (2) pathologically vasodilate blood vessels partly through mechanisms of nitric oxide generation, both of which cause low blood perfusion to tissues. TNF-α also causes vascular leak syndrome by triggering the shedding of glycocalyx, which disrupts the endothelial cell lining. Glycocalyx, a multicomponent layer consisting of proteoglycans and glycoprotein that lines the luminal membrane of the endothelium, is essential in regulating vascular permeability and barrier function, hemostasis, vasomotor control, and immunological function. Thus, sepsis can cause significant disturbance in all organs, which can result in cardiovascular collapse, respiratory failure, immune dysregulation, acute kidney injury, coagulopathy, thrombotic microangiopathy, ischemic hepatitis, endotheliopathy, and mitochondrial dysfunction. The severity of these disturbances depends on many factors, including the genetic and environmental factors of both the host and the pathogen.

It is important to note that pathogenic microbes double every 30 minutes. Therefore, early source control with appropriate antibiotics and nidus removal is the key to stopping the progression from sepsis to severe sepsis or septic shock to MODS or MOF to death.

DEFINITIONS

Bone and colleagues first proposed clinical definitions of SIRS, sepsis, severe sepsis, and septic shock. These definitions with modifications are still being used by pediatricians, though the term SIRS is no longer used in adults.

CLINICAL MANIFESTATIONS OF SEPSIS AND SEPTIC SHOCK

Responding to the request from the Institute of Medicine for establishment of best practice guidelines across medicine, in 2002, the American College of Critical Care Medicine (ACCM) published its first guidelines, “Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Patients in Septic Shock.” This document reported the best clinical practices for pediatric sepsis that were associated with the best outcomes. By then, sepsis mortality had already decreased from 97% to 9% over past decades due to early recognition and innovations. The ACCM/PALS guidelines, were updated in 2007 and again in 2014. Many studies have evaluated the outcomes associated with implementation of the 2002 and 2007 guidelines. In resource-rich settings with intensive care units available, studies have found adherence to these ACCM/PALS guidelines have resulted in improved outcomes. The ACCM/PALS guidelines stress the importance of early sepsis recognition in order to implement the time-sensitive and goal-directed recommendations of septic shock resuscitation. Thus, a clear and easy clinical definition of septic shock is essential.

Septic pediatric patients can present to the doctor’s office with a vague constellation of soft signs and symptoms including fever, runny nose, irritability, not eating well, not acting playful, and warm hands and feet. Others may present with overt septic shock with high fever, lethargy, and cold hands and feet, or with obvious vasodilatory shock with warm peripheries, bounding pulses and a high-output state. Table 97-1 lists the definition of clinical pediatric shock from the 2007 ACCM/PALS guidelines.

The ACCM/PALS guidelines suggest that septic shock should be diagnosed by clinical signs and symptoms including (1) hypothermia or hyperthermia; (2) altered mental status; and (3) peripheral vasodilation, bounding peripheral pulses, and wide pulse pressure (warm shock) or vasoconstriction with capillary refill > 2 seconds, diminished pulses, and mottled cool extremities (cold shock) before hypotension. Once the septic shock is recognized, shock resuscitation should be rapidly initiated with the goals of restoring normal (1) mental status, (2) threshold heart rates, (3) peripheral perfusion (capillary refill < 3 seconds), (4) palpable distal pulses, and (5) blood pressure for age. The ACCM/PALS guidelines recommend implementing 5 key elements during the first hour of managing pediatric septic shock: (1) recognition, (2) establishing intravenous access, (3) starting intravenous fluids and resuscitation as needed, (4) administering antibiotics, and (5) starting vasoactive agents as needed (see also Chapter 106).

WARM VERSUS COLD SHOCK

The majority (58%) of community-acquired fluid refractory pediatric septic shock presents as cold shock. On examination, the patient is difficult to arouse and exhibits cold hands and feet, weak peripheral pulses, and capillary refills delayed to > 2 seconds. In cold shock, the main defect is the significant reduction in oxygen delivery to tissues due to intravascular hypovolemia and/or myocardial dysfunction. The patient feels cold to the touch because the blood vessels vasoconstrict as a physiologic compensatory mechanism to maintain appropriate perfusion pressure and oxygen delivery to vital organs. If not appropriately resuscitated, the tissues will be starved of oxygen and energy substrates leading to tissue hypoxia, metabolic acidosis, and organ dysfunction. Thus, pediatric cold septic shock frequently responds well to volume resuscitation and to inotropic support, especially with peripheral epinephrine infusion being an excellent first choice for myocardial dysfunction. These patients commonly require mechanical ventilation to reduce cardiopulmonary work requirements.

In contrast, warm shock is the typical presentation in septic adults but only in 20% of septic children and is predominantly seen in older children or those with long-term central access. On examination, the patient again is difficult to arouse and has warm hands and feet, bounding peripheral pulses, and flash capillary refills. The main circulatory defect in warm shock is vasomotor paralysis (vasoplegia) with significant vasodilatation. Cardiac output is typically normal or increased though overall oxygen balance is deranged. Of note, adults with warm shock typically have a defect in oxygen extraction rather than oxygen delivery. Warm shock frequently responds to volume resuscitation and vasoconstrictor agents. Over time, a minority (10%) of patients may have a complete change in the hemodynamic state between warm and cold shock. In general, persistent pediatric septic shock will progress to cold shock with significant decrease in cardiac function.

SEPSIS-INDUCED MULTIPLE ORGAN DYSFUNCTION SYNDROME AND FAILURE

Even with the best efforts in septic shock resuscitation and early control of the infective source, a subset of patients still progresses to significant tissue injury and MODS. Individual patients respond very differently from each other to septic shock resuscitation, and their response depends on the time to source control first and foremost, but also to the genetic makeup and environmental factors of both the host and pathogen. Current clinical and experimental evidence suggests that these genetic and environmental factors can impede the resolution of systemic inflammation in sepsis-induced MODS. Investigators propose that there is a spectrum of MODS pathobiology phenotypes such as thrombocytopenia-associated multiple organ failure (TAMOF), immunoparalysis, sequential MODS, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and others. The common denominator in these MODS phenotypes is immune dysregulation. Thus, understanding and recognizing these MODS pathobiology phenotypes may lead to better therapeutic strategies for the leading reversible cause of late death in sepsis.

TAMOF is a clinical syndrome characterized by new onset thrombocytopenia in a setting of evolving MODS. TAMOF represents a spectrum of mixed thrombotic microangiopathies and coagulopathies including thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, and disseminated intravascular coagulation. The drop in platelet count in this syndrome suggests the pathologic involvement of platelets as they form disseminated microvascular thromboses in the vascular beds of tissues, which leads to ischemia and injury resulting in the observed MODS. Persistent SIRS in sepsis induces extensive endothelial and immunologic activation leading to a prothrombotic and antifibrinolytic state. In TAMOF, tissue factor, von Willebrand factor and platelets, and/or complement pathways are dysregulated. For example, patients with a genetic mutation in plasminogen activator inhibitor type 1, ADAMTS-13, or complement factors are at higher risk of developing TAMOF during sepsis.

Immunoparalysis is a state of impaired innate and/or adaptive immunity that occurs after the initial life-threatening proinflammatory insult in sepsis. The host immune system responds to the initial SIRS with a compensatory anti-inflammatory response syndrome (CARS) to prevent uncontrolled SIRS. If CARS persists, it will lead to a form of acquired immune deficiency. These patients are unable to clear the invading pathogens and will succumb to unresolved infection. Genetic predisposition such as an increase in anti-inflammatory cytokine production or other pathologic immune downregulation mechanisms places the patient at risk for immunoparalysis. Immunosuppressive medications such as steroids, antirejection drugs and chemotherapies can also induce a state of immunoparalysis.

Pathologic immune activation is an immune dysregulated state that leads to hyperinflammation. This occurs when the host immune system is unable to shut down the initial SIRS. The pathologic mechanism can be caused by a failure to shut down activated immune cells, such as a defect in the Fas/Fas ligand apoptotic pathway or in perforin or granzyme B-mediated cytolysis. Persistent presence of activated antigen presenting cells or persistent stimulation of TLR9 by pathogen can also lead to pathologic immune activation and hyperinflammation. Sequential MODS phenotypes have characteristic respiratory dysfunction followed by hepatic and renal failure evolving over the initial 3 days following sepsis presentation. These patients have an increased soluble Fas level, which inhibits apoptosis of activated immune cells after a viral infection. The clinical manifestations of this, HLH and MAS include a characteristic severe hepatitis and disseminated intravascular coagulation or TAMOF after an infection. HLH and MAS patients are typically found to have either an inherited or acquired defect in the ability of cytotoxic lymphocytes to induce cytolysis of target cells such as antigen presenting cells.

Currently, there is no single “magic bullet” agent to cure sepsis or abate the sequelae of septic shock. Nevertheless, in the United States, the overall sepsis mortality has significantly decreased over the past 4 decades thanks in part to early recognition and application of the best practice guidelines of septic shock resuscitation. However, sepsis-induced MODS is still the leading reversible cause of late death in pediatric sepsis with mortality increasing with each additional dysfunctional organ. Current active research is being directed at identifying common MODS pathobiology phenotypes and identifying therapeutic strategies for each pathologic mechanism. For example, anti–C5 monoclonal antibody and/or therapeutic plasma exchange are being studied to reverse TAMOF. Immune modulation therapies such as granulocyte-macrophage colony-stimulating factor are being studied to reverse immunoparalysis. Steroids, intravenous immunoglobulin, and interleukin-1 receptor antagonists are being studied to reverse MAS. Steroids, etoposide, and anti–interferon-gamma antibody therapies are agents that are currently being investigated in the treatment of HLH.

CONCLUSION

Sepsis remains a healthcare burden worldwide with enormous human and economic toll. Significant progress has been made with septic shock resuscitation in the resource-rich developing and developed settings. National sepsis initiatives are in place to improve septic shock outcomes. Research targeting a role for personalized medicine strategies in pediatric sepsis-induced MODS and MOF is underway.

SUGGESTED READINGS

ACUTE NEUROLOGICAL DYSFUNCTION

Altered consciousness can be a manifestation of a variety of disease processes. It is commonly indicative of life-threatening illness that requires urgent stabilization, diagnosis, and institution of disease-specific therapy to prevent ongoing neurologic injury and long-term neurodevelopmental disability. Although the anatomic structures related to consciousness have been defined, depressed consciousness is usually poorly localized to specific nervous system pathways, and often represents the consequence of a failed non-neurologic organ system.

The goals of this chapter are to review the pathophysiology and age-specific epidemiology of altered mental status, to delineate the current framework used to assess the presentation of depressed consciousness, to give a practical overview of its differential diagnosis, and finally to outline a strategy for stabilization, diagnostic evaluation, and emergent treatment options. A full discussion of the clinical approach to altered consciousness, including a comprehensive review of the interpretation of clinical signs, can be found in standard texts on coma.

PATHOPHYSIOLOGY AND EPIDEMIOLOGY

Consciousness has 2 components, wakefulness and awareness (of self and of the surrounding environment). Awareness cannot occur without wakefulness but wakefulness can occur without awareness. Consciousness is dependent on the function of the reticular activating system (RAS) that promotes widespread cortical activation. The core areas for maintaining wakefulness are thought to be ascending glutamatergic and cholinergic neurons in the dorsal tegmentum of the midbrain and pons. These activate the central thalamus and basal forebrain, which in turn activate the cortex.

The level of arousal is a function of the overall state of activity of the brain. Awareness is a more complex and integrated process involving the cerebral cortex and thalamus. Coma is a state in which a child has eyes closed and is unaware and unresponsive to any external stimuli, except for reflex responses. It results from either damage to the RAS or profound global cortical dysfunction. While lesions of the RAS can result in coma, detailed knowledge of this anatomic pathway is generally not required as global cortical dysfunction is by far the most common cause of altered consciousness. Focal lesions that affect the RAS do occur, especially those that produce pressure in the posterior fossa.

Regulation of Cerebral Blood Flow

Cerebral blood flow is tightly matched to the metabolic need of brain tissue, which is dependent on a continuous supply of oxygen and glucose for obligate-aerobic metabolism. Neither excessive nor inadequate cerebral blood flow can be tolerated for prolonged duration without causing brain injury. Multiple layers of adaptive mechanisms work simultaneously to adjust and constrain cerebral blood flow to an optimized level during disrupted physiological states such as shock or disturbed delivery of substrate.

Systemic Vasoconstriction

The first adaptive mechanism to preserve cerebral blood flow is the systemic vasoconstrictor response to shock or hypotensive states, which is characteristically associated with neurohormonal activation. However, vessels in the brain have diminished responses to this neurohormonal state, so the net effect is to maintain arterial blood pressure with preserved cerebral blood flow and diminished blood flow to other systemic organ beds. This mechanism of cardiac output redistribution is highly relevant to the child in shock from low cardiac output. Vasoactive agents that modulate systemic vascular resistance will preserve cerebral perfusion pressure and cerebral blood flow in this setting, but do so at the expense of visceral perfusion.

Pressure Autoregulation

When systemic vasoconstriction fails to maintain arterial blood pressure, vessels of the brain actively dilate to preserve cerebral blood flow. Modulation of cerebrovascular resistance in response to changes in arterial blood pressure is called pressure autoregulation, and is known to fail at a lower limit of arterial blood pressure. Although descriptions of autoregulation in hypertensive adults and women treated for pre-eclampsia suggested a lower limit of autoregulation at a mean arterial blood pressure of 50 mm Hg, lower limits of acceptable arterial blood pressure for pediatric patients are not known, but they are likely much lower and influenced by pathologic states, especially those that increase intracranial pressure.

Neurovascular Coupling

When the global control of cerebral blood flow is at undisturbed, regional control is also active to provide heterogeneous distribution of flow to areas of high metabolic activity. This mechanism is called metabolic autoregulation or neurovascular coupling and is mediated by neurovascular units with astrocyte projections connecting neuronal synapses and resistance arterioles. Neurovascular coupling is useful clinically when it is desirable to reduce cerebral blood flow (and therefore blood volume and intracranial pressure). The induction of electrical silence with barbiturate coma reduces cerebral metabolism and cerebral blood flow by as much as 60% without causing a deficit of oxygen delivery.

Carbon Dioxide Reactivity

Carbon dioxide diffuses freely into the cerebral spinal fluid, but bicarbonate buffers are unable to cross the blood-brain barrier. When minute ventilation and arterial carbon dioxide tension are normal, pH reactivity facilitates the regulation of constant carbon dioxide and pH levels in the spinal fluid. Acute hypercarbia lowers the pH of cerebrospinal fluid and this induces a profound vasodilatory effect on the resistance vessels of the brain. Acute hypocarbia raises the pH and induces a vasoconstrictive effect. These pathologic increases or reductions of cerebral blood flow are not necessarily matched to the metabolic activity of the brain and can cause significant injury. Hyperventilation to control intracranial pressure in children with traumatic brain injury is thought to cause ischemic injury and may be harmful outside of transient use to control acute spikes in intracranial pressure and impending herniation syndromes.

Hypoxic and Hypoglycemic Vasodilation

Cerebral blood flow is increased (secondary to vasodilation) when oxygen or glucose delivery is reduced below the normal physiologic range. In patients with coma or acute brain injury, it is important to maintain hematocrit, systemic oxygenation, and blood glucose levels in the normal range.

Herniation Syndromes

Brain herniation occurs if intracranial pressure is not controlled. There is displacement of part of the brain from 1 compartment in to another (see Chapter 105) and compression of adjacent structures. The syndromes of herniation include subfalcial, transtentorial, and tonsillar.

Subfalcial herniation is when unilateral hemisphere swelling leads to herniation of the cingulate gyrus under the falx. There is a direct relationship between the amount of midline shift and the degree of impaired consciousness. In adults, shift of 3 to 6 mm is associated with drowsiness, 6 to 9 mm with stupor, and > 9 mm with coma. This may lead to compression of branches of the anterior cerebral artery and infarction of the medial surface of the frontal lobes.

Transtentorial herniation occurs when there is downward displacement of the brain through the tentorial opening. It is classically divided into uncal herniation, in which the uncus of the temporal lobe herniates over the free edge of the tentorium compressing the 3rd cranial nerve, and central herniation, in which the diencephalon and brain stem are directly compressed. In earlier diencephalic stages, there is decorticate posturing with small, reactive pupils. As more rostral compression occurs, the midbrain–upper pons is compressed with decerebrate posturing and fixed mid-position pupils. As the lower pons and medulla are compressed, motor responses are lost and pupils become dilated and fixed.

Tonsillar herniation occurs when the cerebellar tonsils are forced into the upper spinal canal and there is compression of the caudal medulla. Respiratory and cardiovascular function may be impaired. Tonsillar herniation is commonly fatal.

Epidemiology of Neurological Dysfunction

Traumatic brain injury is thought to be the leading cause of altered mental status in pediatrics. While the majority of cases are mild and do not result in hospital admission, the incidence of hospitalization for moderate to severe traumatic brain injury is close to 40 per 100,000. Hospitalization or death for nontraumatic pediatric coma occurs at an annual incidence of 30 per 100,000, with a reported mortality of nearly 50%. The incidence of this varies significantly with age: Children under 1 year of age have the highest incidence of nontraumatic coma, 160 per 100,000 per year. The most common causes of coma in children resulting in hospital admission or death are infection (38%), intoxication (10%), seizure (10%), complications of congenital malformations (8%), accidental causes such as inhalation or drowning (7%), and metabolic disorders (5%) (Fig. 98-1). The cause of coma was unknown in 15% of cases.

Etiologies of Depressed Level of Consciousness

The full differential diagnosis of depressed consciousness in pediatrics is too large to list in this chapter, as neurologic dysfunction can be a common manifestation of any severe systemic illness, but key causes are listed in Table 98-1. They are commonly classified as those conditions with structural changes in the brain and those with a diffuse nonlocalizing etiology. In practice, the distinction is artificial because many of the pathologies may coexist in the same patient. For example, status epilepticus or electrolyte disorders may complicate most causes of coma. Trauma, stroke, poisoning, electrolyte (glucose, sodium, calcium, magnesium) disorders, and hypoxic ischemic encephalopathy will often have obvious features in the history, clinical presentation, or initial laboratory and head CT assessment, which lead promptly to the diagnosis. Some further considerations about less immediately obvious causes are discussed below.

Infective Causes

The range of organisms (eg, bacteria, virus, fungus, protozoa) that can cause central nervous system (CNS) infection vary with geographic region, age, immune status (eg, immunizations, immunocompromise), season, and underlying comorbidities. CNS infection can be difficult to diagnose, and in up to 60% a causative agent is not identified. Commonly identified causes in developed economies include Mycoplasma pneumonia, herpes simplex virus 1 (HSV1), enterovirus, varicella, and bacterial meningoencephalitis. Arboviruses (eg, West Nile, eastern and western equine encephalitis) have occurred in seasonal outbreaks in parts of North America. In developing countries, tuberculous meningitis and vaccine preventable causes (eg, hemophilus influenza, measles, varicella, mumps, rubella) remain a frequent and important cause. Cerebral malaria, dengue, and Japanese encephalitis occur especially when mosquito populations are high. Cerebral abscess is associated with chronic sinus and middle ear infections and cyanotic congenital heart disease and is suggested by fever, focal neurological signs, and signs of raised intracranial pressure (ICP).

Immune-Mediated and Demyelinating Causes

Acute demyelinating encephalomyelitis (ADEM) is 1 of the most common causes of encephalitis. It most commonly affects prepubertal children (mean age 5–8 years), is often preceded by infection, and typically involves the white matter tracts of the cerebral hemispheres, brain stem, optic nerves, and spinal cord. While ADEM typically has a monophasic course and a favorable prognosis, up to 20% to 25% of children have at least 1 relapse.

Immune-mediated encephalitides are increasingly being recognized in children. A now well-established example is anti- N-methyl-D-aspartate (NMDA) receptor encephalitis that is characterized by a mixture of psychiatric manifestations, seizures, hyperkinetic movement disorder, dysautonomia, and coma. In the California Encephalitis Project, anti-NMDA receptor encephalitis was more common than any single infectious cause. In about half of cases, it is associated with an ovarian teratoma. There is often an infectious prodrome, and an association with herpes virus as a trigger has been postulated.

Other conditions suspected of having an autoimmune basis are febrile infection-related epilepsy syndrome (FIRES) and acute necrotizing encephalopathy (ANE). Both typically follow a febrile illness. FIRES is an epileptic encephalopathy presenting with acute refractory status epilepticus, usually in previously well children. The seizures are commonly focal in onset and may have secondary generalization, and an EEG typically shows multiple bilateral frontal and temporal foci. ANE is characterized by altered consciousness and bilateral thalamic and external capsule lesions on MRI, which resolve between attacks. It is classically triggered by influenza A in children with an autosomal dominant mutation in RANBP2. The differential diagnosis includes Leigh Disease.

Inborn Errors of Metabolism

Coma is an important and sometimes presenting feature of a number of inborn errors of metabolism (IEM). These include maple syrup urine disease, urea cycle enzyme defects, disorders of fatty acid oxidation, nonketotic hyperglycinemia, mitochondrial cytopathies, congenital lactic acidosis, and certain leukodystrophies. Minor preceding infections may precipitate decompensation and coma.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

History

The initial history should be focused in nature, and a full history may be delayed by procedures to stabilize the patient. The goal of the initial history, therefore, is to efficiently gather sufficient preliminary information to direct immediate management, including rapid identification of elevated intracranial pressure or a structural lesion that requires urgent neurosurgical intervention. Knowledge of the timing of onset can be helpful: Sudden loss of consciousness is more likely with acute hemorrhage, seizure, and stroke, while a slower or fluctuating onset is more likely with hydrocephalus, an expanding intracranial mass, metabolic process, or infection. A history of vomiting, headache, fever, and seizures should be sought. Headache with positional changes or Valsalva maneuver suggest raised ICP. Fever suggests infection, although the absence of fever does not exclude it, especially in infants under 3 months of age or in immunocompromised children. A history of recent infectious illness is common in autoimmune and demyelinating conditions. A history of trauma may or may not be forthcoming if it was nonaccidental. Exposure to and availability of common toxins such as pesticides and prescription and recreational drugs can be rapidly assessed. Failure to thrive, developmental delay and parental consanguinity may each suggest an inborn error of metabolism in a young infant. Preexisting medical, conditions, such as cancer, epilepsy, congenital heart defects, or metabolic or endocrine abnormalities, may also direct the workup. Recurrent coma may suggest recurrent nonconvulsive status epilepticus, inborn error of metabolism, or nonaccidental poisoning. A history of travel may indicate exposure to infections prevalent in specific areas.

Examination

The goals of the physical examination are to (1) to identify, for immediate treatment, any compromise in airway, breathing, and circulation; (2) determine the level of consciousness; (3) assess for signs of raised intracranial pressure and/or localizing neurological signs; and (4) identify stigmata of any underlying cause.

The physical exam begins with basic vital signs to assess the status of oxygen delivery to the brain, including adequacy of ventilation and arterial oxygen saturation. Circulation is assessed with standard electrocardiogram (ECG) monitoring and findings should include an arterial blood pressure that is normal for age and extremities that are normothermic, without pallor or cyanosis, and without delayed capillary refill. Abnormalities of the basic vital assessment are addressed while further examination is performed, including a basic trauma survey.

Stereotypic patterns of spontaneous respiration may be observed while assessing vital signs, and these can help identify the etiology of the insult. A summary of stereotypic pathologic breathing patterns is given in Table 98-2.

Quantifying the Level of Consciousness

Full consciousness has 2 components: wakefulness and awareness of self and the surrounding environment. Coma is a state of loss of wakefulness and complete lack of awareness. Between arousal and coma, the following terms have been applied in an inconsistent gradation: lethargy, obtundation, and stupor. Lethargy is a pathologic state of mild sleepiness and confusion. Obtundation is blunted alertness with diminished sensation of pain and diminished interaction with the environment. Stupor is a state of unresponsiveness but vigorous stimulation can produce some limited arousal. Delirium is also a type of impaired consciousness, both in wakefulness and awareness. The main characteristics are impaired attention, altered alertness, disorganized thinking and an acute onset with a fluctuating course. Other features such as disordered sleep-wake cycles, memory impairment, and hallucinations may also be present.

The most well-known scale that is used to quantify the arousal to stimuli is the Glasgow Coma Scale (GCS; Table 98-3). The GCS records the best response achieved during assessment, which includes efforts to arouse the patient with verbal, tactile, and painful stimuli. The GCS is the sum of scores in 3 simple domains: eye opening, verbal response, and motor response. It has been adapted for pediatric use, requiring mostly modifications in the verbal scoring. The individual components as well as the total score should be recorded. The motor response is the most powerful predictive component, so that particular care should be taken with performing and recording this accurately. In traumatic brain injury (TBI) in children, the predictive power of the motor score alone was as good as the full GCS and had a linear relationship with mortality.

Presenting Neurological Signs Associated with Depressed Level of Consciousness

A targeted neurologic examination, focusing on cranial nerves and the motor system, can quickly identify signs of raised intracranial pressure and any focal signs. Core brain stem reflexes and the cranial nerves involved are the following: direct and consensual light reflex (II, III); oculocephalic (“doll’s eyes”) reflex (III, VI, VIII); oculovestibular (“caloric”) reflex (III, VI, VIII); corneal reflex (V, VII); cough and gag reflexes (IX, X). Completely normal pupillary function and eye movements suggest that the lesion causing coma is above the midbrain. Pupillary abnormalities with correlates of the associated anatomic abnormalities are listed in Table 98-4. To properly assess the pupils, baseline pupil size is established in dim light and activity is assessed with a bright light directed at the eye. In the case of asymmetric pupils, the abnormality (constriction or dilation) is assigned from the baseline dim light assessment. When the pupils are more asymmetric in the dark, the smaller pupil is usually abnormal (Horner syndrome), while when they are more asymmetric in the light, the larger pupil is usually abnormal (3rd cranial nerve).

Conjugate lateral deviation of the eyes occurs with an ipsilateral hemisphere lesion, a contralateral hemisphere seizure focus, or a lesion of the contralateral pontine region. Tonic downward eye deviation occurs with injury or compression of the thalamus or dorsal midbrain (eg hydrocephalus), while tonic upward gaze has been associated with bilateral hemispheric damage. Ocular bobbing suggests a pontine lesion and rapid horizontal eye movements usually suggest seizures. Spontaneous roving eye movements indicate that the brain stem is intact.

The motor response is assessed in the awake child with a verbal command in the verbal child and spontaneous observation in the preverbal child. When consciousness is impaired, it is assessed by a painful stimulus. A sternal rub can be applied and the response observed. If there is any sort of flexion response, pain should be applied in the cranial nerve distribution (eg squeezing ear lobes, supraorbital pressure) as otherwise it is difficult to clearly distinguish flexor posturing, withdrawal, and localization. Elevated intracranial pressure is strongly suspected when abnormal flexion or extension or flaccidity is present. Lack of a motor response to painful stimulus with either increased or decreased tone is concerning for a low brain stem or spinal cord lesion. Flexion of the arms with extension of the legs has been classically labeled decorticate posturing, implying pathology above the tentorium, leaving the posterior compartment reflexes unopposed. Extension and internal rotation of the arms with leg extension has been similarly labeled decerebrate posturing, implying disruption of the infratentorial (brain stem) reflexes. These anatomic localizations, however, are not as clear-cut; flexor arm responses suggest less severe dysfunction, while extensor arm responses suggest more severe dysfunction but may still be supratentorial. Arm extension with leg flexion suggests pontine injury, and generalized flaccidity implies injury below the pontomedullary junction. At initial presentation, the distinctions are largely academic, as the presence of any of these abnormalities suggests life-threatening severity and prompts rapid evaluation with brain imaging. Asymmetries of motor response suggest lateralization and make a structural cause of altered consciousness more likely.

Initial Management of a Child with Depressed Level of Consciousness

A depressed level of consciousness is a manifestation of either severe systemic disease or significant central nervous system disease and so requires urgent management. Coma is a medical emergency because of the potential for life-threatening complications and preventable secondary brain injury. Initial management must be rapid and systematic with immediate priorities being (1) resuscitation and maintenance of cardiorespiratory stability, (2) treatment of reversible causes (eg, hypoglycemia), (3) treatment of complications (eg, intracranial hypertension, seizures), and (4) investigation and treatment of underlying causes. In practice, many of these can be achieved concurrently.

Resuscitation and Immediate Treatment

Children with a depressed level of consciousness are at risk of airway obstruction and respiratory depression. Intubation and mechanical ventilation are indicated if any of the following is present (1) GCS < 9 or deteriorating, (2) signs of intracranial hypertension, (3) airway obstruction or loss of airway protection, (4) hypoxia (SpO₂ < 92% despite oxygen therapy), (4) hypoventilation, and (5) shock requiring ongoing fluid resuscitation and vasoactive therapy. The goals of mechanical ventilation are normal values for PaO₂ and PaCO₂. There is no indication for hyperventilation to reduce PaCO₂ below normal apart from the emergency management of life-threatening intracranial hypertension (until more definitive therapy is established). Immediate interventions should be aimed at correcting hypovolemia, hypoxemia, hypotension, hypoglycemia, and any other factors that may further exacerbate existing injury to the vulnerable brain. Hypotonic fluids can lead to hyponatremia and worsening of cerebral edema and should not be given; all intravenous fluids should be isotonic.

Early monitoring should include continuous ECG, oxygen saturation, and respiratory monitoring, and at least hourly measurement of blood pressure. If the child is critically ill, with shock or coma, an arterial line should be placed, for continuous blood pressure measurement and blood gas analysis.

Early Investigation

After initial stabilization, a head computed tomography (CT) scan will almost always be required, apart from children with known pre-existing conditions having typical presentations of their illness (eg, epilepsy). This scan can detect intracranial hemorrhage, space-occupying lesions (eg, tumor, abscess), hydrocephalus, cerebral edema, and in some cases focal hypodensities (eg, infarct, ADEM, herpes simplex encephalitis). Contrast is rarely needed in the acute setting. Signs of raised ICP on CT scan include compression of sulci and lateral ventricles, loss of gray/white differentiation, lateral midline shift, and effacement of basal and quadrigeminal cisterns. However, a normal CT scan does not exclude intracranial hypertension, particularly if early in the clinical course. It is also less sensitive than a magnetic resonance imaging (MRI) scan for many pathologies. Once a patient has been stabilized and had initial investigations, an MRI scan is indicated if the cause of coma is still unclear or if there is a cause for which the MRI will provide significantly more information, particularly for injuries involving subcortical structures, the brain stem, and the spinal cord and for detecting ischemia (eg, stroke, early hypoxic ischemic encephalopathy), demyelinating diseases (eg, ADEM), hypertensive encephalopathy, metabolic brain disease, diffuse axonal injury, and venous thrombosis.

TREATMENT OF COMPLICATIONS

Complications are discussed next as they may also need urgent management before further investigations and specific treatments are instigated.

Intracranial Hypertension

Intracranial hypertension may be caused by mass lesions (eg, hemorrhage, tumor, abscess), hydrocephalus, or cerebral edema. Cerebral edema is common in trauma, infection, hepatic encephalopathy, inborn errors of metabolism, status epilepticus, and strokes and tumors. Intracranial hypertension should be considered in all children with impaired consciousness and especially those with a GCS < 9. Other suggestive signs are a bulging or tense fontanelle, a “setting-sun” sign (a persistent downward gaze), dilated pupils, and papilledema. Severe intracranial hypertension with impending herniation is suggested clinically by (1) hypertension with bradycardia and abnormalities of breathing pattern (Cushing’s triad); (2) abnormalities of posture: decorticate, decerebrate, or flaccid (ie, motor response of the arms to pain is flexor posturing, extensor posturing, or absent, respectively); (3) abnormal pupils: unilateral or bilateral dilated or unreactive; (4) abnormal pattern of breathing; and (5) abnormal doll’s eye (oculocephalic) or caloric (oculovestibular) reflexes. In addition, there are features on the head CT scan that suggest raised intracranial pressure (see above).

Severe intracranial hypertension is a medical emergency. Immediate treatment to lower ICP includes hyperosmolar therapy (hypertonic saline, mannitol), intubation and mechanical ventilation (if not performed already), and acute hyperventilation, together with anesthesia (narcotic and benzodiazepine, barbiturate) to reduce cerebral oxygen demand and muscle relaxation. Urgent CT scan may reveal pathology amenable to neurosurgical intervention to reduce ICP, including evacuation of mass lesions and diversion of cerebrospinal fluid (CSF) in hydrocephalus. Other therapies and neurosurgical interventions will be dictated by the underlying cause.

Standard neuroprotective measures should be undertaken in all patients with coma. These include a neutral head position; head of the bed elevated to 30° above horizontal; sedation and analgesia; maintenance of normal PaO₂, PaCO₂, and blood pressure/cardiac output; maintenance of normothermia (36°C–37.5°C); maintenance of normal to slightly high sodium (140–150 mmol/L); and avoidance of hyper or hypoglycemia. When intracranial pressure is known to be raised, either clinically, radiologically, or based on direct measurement, a tiered approach to reduction is taken. Additional interventions that have been considered include CSF drainage, hyperosmolar therapy, barbiturate coma, and decompressive craniectomy. Full discussion of these therapies can be found in Chapter 105.

Seizures

Seizures are common in comatose children. They may be the cause of the coma or they may be a complication of the underlying condition. If coma is persistent 1 hour after a seizure, the seizure should not be assumed to be the cause of the coma and management should be that of an unknown cause of coma. In children presenting with status epilepticus, an underlying acute condition is present in 30% to 50% of cases. For example, almost half of children with encephalitis will have at least 1 seizure. Prolonged seizures (> 30 minutes) may cause or exacerbate brain injury and can also increase ICP. They should therefore be treated aggressively and metabolic derangements (eg, low glucose, sodium, calcium, magnesium) should be rapidly identified and treated. The longer a seizure lasts, the less likely it is to resolve spontaneously, the harder it is to control, and the greater the risk is of morbidity and mortality. Most (80–92%) seizures that stop spontaneously do so within 5 minutes. Seizures should be treated with first-line agents if they have not stopped spontaneously after a maximum of 5 minutes (sooner if they are occurring secondary to an underlying condition or in the presence of raised ICP), and the cycle should be repeated after a further 5 minutes if the seizure does not stop. Intravenous lorazepam and diazepam are equally efficacious in terminating seizures acutely. If seizures do not stop after a second dose of 1 of these agents, a second-line agent should be used. Second-line agents include phenytoin or fosphenytoin, levetiracetam, and sodium valproate. Fosphenytoin is better tolerated than phenytoin and is preferred where it is available. Intravenous (IV) phenobarbital may also be used if other agents are not available, but it is more likely to cause respiratory depression. If the seizure persists beyond 30 to 40 minutes, options include another second-line agent or anesthetic doses of midazolam, pentobarbital, or propofol. In this setting, intubation and mechanical ventilation are typically required as hypoventilation or apnea will typically ensue. Where there is a severe underlying condition, especially if the child is in an intensive care unit, the treatment algorithm may be delivered faster.

An electroencephalogram (EEG) is indicated for any refractory seizures or when the cause of coma is unclear. EEG is principally useful to confirm the presence or absence of seizures, to exclude nonconvulsive seizures as a cause of persistent coma, and to differentiate nonconvulsive motor phenomena from electrographic seizures. Electroencephalogram patterns may also suggest a cause (eg, HSV encephalitis). Continuous EEG, where available, is indicated in children with refractory clinical or electrographic seizures, especially if intracranial hypertension is present or if muscle relaxant drugs are being used.

Investigation and Treatment of Underlying Causes

A lumbar puncture (LP) to test for infection should be performed if the patient has a fever, if meningitis or encephalitis is suspected, or if there is no clear cause of impaired consciousness. Cerebrospinal fluid should be analyzed for cell count, protein and glucose levels, Gram stain, viral polymerase chain reaction (PCR), bacterial culture, and other stains/PCR/culture (eg, tuberculosis, fungal) as indicated. The interpretation of CSF results is shown in Table 98-5. Additional CSF may be collected and stored for later testing for metabolic and immune mediated conditions as clinically indicated. The Gram stain may be negative in up to 60% of cases of bacterial meningitis; neither a normal Gram stain nor lymphocytosis excludes a bacterial cause. An abnormal CSF, even if typical for a viral infection, should be treated with antibiotics until culture results are known.

An LP is contraindicated or should be deferred in the presence of (1) shock, (2) clinical diagnosis of meningococcemia, (3) respiratory compromise, (4) coagulopathy or thrombocytopenia (platelets < 50,000), (5) local infection at the site where LP would be performed, (6) papilledema or clinical or CT signs of raised ICP, (7) focal neurological signs, (8) GCS < 9 or deteriorating, and (9) prolonged seizure and GCS ≤ 12. Opinions differ as to whether the last 3 of these are absolute contraindications. Decisions as to whether to perform an LP should be made by the most experienced clinician, taking into account the risks of herniation and benefits (making a definite diagnosis, knowing the antimicrobial sensitivity of an identified bacteria). If an LP is deferred, antibiotics that reflect the local sensitivity pattern of likely bacteria, and antiviral agents should be given. Herpes simplex encephalitis may be suggested by the presence of focal neurological signs, a fluctuating GCS of greater than 6 hours duration, and the presence of or contact with herpetic lesions.

A toxicology screen should always be performed if the cause of coma is unclear. Standard urine screens differ in terms of the drugs covered, so that knowledge of the local test is required. Additional blood or urine testing will be dictated by the clinical toxidrome (see Chapter 114). Drugs present in the house (especially in cases involving toddlers) and possible drugs of abuse (especially in cases involving teenagers) should be specifically sought out in the history.

Hypertension is common in the setting of coma and can be difficult to interpret. Impaired consciousness may be caused by hypertensive encephalopathy or hypertension may be a protective physiological response to raised intracranial pressure. The former requires urgent treatment to reduce blood pressure, while in the latter, such treatment may cause cerebral ischemia and exacerbate intracranial hypertension. Hypertensive encephalopathy may be caused by renal, cardiovascular (eg, coarctation of the aorta), vasculitic, and endocrine conditions (eg, pheochromocytoma) and also drugs (recreational and prescribed). It is suggested by a history of hypertension, headaches, visual disturbance, and seizures. It may be associated with posterior reversible encephalopathy syndrome (PRES) that has a typical pattern on CT/MRI scan with edema typically affecting the parietal-occipital regions, has most commonly been reported in children after hematopoietic stem cell and solid organ transplantation. PRES is thought to be caused by loss of autoregulation to rapid changes in blood pressure in the areas affected. However, 20% to 30% of children with PRES have normal or only slightly high blood pressure and it is speculated that endothelial dysfunction and inflammation may play an important role in the pathogenesis. Hypertensive encephalopathy should be managed with intravenous vasodilators and/or β-blockers with the goal of initial reduction in blood pressure of approximately 25% and then further reduction more slowly over 24 to 48 hours.

Metabolic emergencies such as diabetic ketoacidosis or severe hyperammonemia associated with acute liver failure or inborn errors of metabolism should be managed according to established guidelines that are disease specific. Demyelinating and autoimmune encephalopathies may be treated with steroids, immunoglobulin, or plasmapheresis (see Chapter 548).

An extensive evidence-based guideline and an abbreviated algorithm for the investigation and management of a child with impaired consciousness have been published online by the Pediatric Accident and Emergency Research Group of the Royal College of Pediatrics and Child Health and the British Association of Emergency Medicine (http://www.nottingham.ac.uk/paediatric-guideline/index2.htm).

SUGGESTED READINGS