At the time of birth, a neonate is considered to be fundamentally immunocompromised for several reasons.¹⁴ First, although infants born at term have passively acquired immunity from maternal antibodies that were transferred transplacentally before birth, the titers of these antibodies quickly wane, leaving the infant without immunity to most specific pathogens. Until exposure to common pathogens by natural infection or immunization, infants lack durable organism-specific immunity. In addition, the function of specific components of the immune system does not mature until approximately 2 years of age. Until that time, infants are unable to make a robust antibody response to pathogens that have polysaccharide molecules on their surface. This developmental defect explains why the incidence of invasive pneumococcal infection, an organism with a polysaccharide coat, is relatively high in young children.

The transfer of maternal antibodies during fetal life occurs chiefly in the last trimester of gestation. The premature infant, born before the last trimester, lacks those transfused maternal antibodies, and therefore has a higher risk of infection, especially during the first months of life.

Infectious Disease Overview

Infection is a common cause and can be a common complication of critical illness in hospitalized children.⁴⁵ Common community-acquired infections such as bacterial pneumonia and viral infections can lead to life-threatening illnesses in both immunocompetent and immunocompromised children. Local and systemic complications of community-acquired infections include respiratory failure, shock, and renal insufficiency. Critically ill children are also at high risk of healthcare-acquired infections including catheter-associated bloodstream infections, ventilator-associated pneumonia, and surgical site infections. These infections can be caused by viruses, bacteria, or fungal organisms.

Colonization and Infection

At birth, a neonate is normally essentially sterile. Within hours, however, bacteria from both the environment and people who handle the infant are transferred onto and begin to grow on the baby’s skin and mucous membranes.²⁰ These bacteria are typically referred to as colonizing flora. The predominant colonizing organisms vary with anatomic site. For example, skin organisms such as Staphylococcus epidermidis can be found on almost all keratinized skin. In contrast, anaerobic and gram-negative organisms are typically found only in the intestinal tract. Colonizing flora typically do not cause inflammation or invasive infection. Many infections, however, do arise from the patient’s colonizing flora, often when a medical device breaches the integrity of skin or mucous membranes or when skin or mucous membranes become inflamed.

Common clinical conditions

Immunodeficiency Versus Immunosuppression

Immunodeficiency is a permanent state of impaired immune function. It is typically genetic or congenital in nature. Immunosuppression is typically a temporary state of impaired immune function. It may be intentional (e.g., pharmacologic suppression in the transplant population) or unintentional (e.g., retroviral infections). Immunocompromise (or impaired immune function) results from both immunodeficiency and immunosuppression.

Allergic Reactions and Anaphylaxis

Etiology

Allergic or “hypersensitivity” reactions occur when the body mounts an exaggerated or inappropriate immune response to a substance perceived as foreign, resulting in local or general tissue damage. Such reactions are usually classified by severity and involvement,¹ as in types I to IV (Table 16-1).

Table 16-1 Hypersensitivity Reactions

Type	Description	Example
Type I (anaphylactic reaction)	Triggered in response to an exposure to an environmental antigen Mediated by IgE antibodies that bind to specific receptors on the surface of mast cells and basophils Results in the release of a host of mediators to produce a classic anaphylactic response	Anaphylaxis Asthma Allergic rhinitis, hay fever
Type II (tissue specific hypersensitivity)	Triggered by the presence of an antigen found only on a cell or tissue Mediated by antibody (usually IgM, but also IgG) through two different mechanisms (complement and Fc receptors on phagocytes) Results in the destruction of the antibody-coated cell with consequences dependent on the cell or body that is destroyed (e.g., RBC, WBC, or platelet)	ABO incompatibility Rh incompatibility Drug-induced thrombocytopenia
Type III (immune complex reaction)	Triggered by the formation of antigen-antibody complexes that activate the complement cascade Immune complexes are formed in the circulation and are later deposited in blood vessels or healthy tissue. Multiple forms of the response exist depending on the type and location of the antigen Results in local edema and neutrophil attraction, and thus degradative lysosomal enzymes resulting in tissue injury	Serum sickness Glomerulonephritis
Type IV (delayed hypersensitivity)	Triggered by the recognition of an antigen mediated by activated T lymphocytes and release of lymphokines, which then stimulate the macrophage to phagocytize foreign invaders and some normal tissue Results in a delayed onset. Does not have an antibody component; this response is strictly a cellular reaction	Contact sensitivities such as poison ivy and dermatitis Tuberculin reactions Graft rejection

RBC, Red blood cell; WBC, white blood cell.

From Roberts KE, Brinker D, Murante B. Hematology and immunology. In Slota M, editor: Core curriculum for pediatric critical care nursing, ed 2. Philadelphia, 2006, Saunders Elsevier, p. 597.

Anaphylaxis is an allergic hypersensitivity reaction to a foreign protein or drug that causes a systemic response. Exposure to the antigen may be oral or intravenous, or through inhalation or via direct contact. The anaphylactic reaction can occur within seconds or minutes after exposure.⁴²

Reactions can range from mild itching and hives to life-threatening airway obstruction, hypotension, and cardiovascular collapse. Generally, the more the rapid the development of the reaction, the more severe will be the adverse reaction.

Pathophysiology

Clinical signs and symptoms usually appear within seconds to minutes of exposure to an antigen. They are caused by the action of numerous inflammatory mediators, including histamine and histamine-like substances on surrounding tissues and blood vessels. These mediators cause significant changes in capillary permeability that lead to facial edema, airway edema, and bronchoconstriction as well as vasodilation, hypotension, and possible circulatory collapse. Constriction of airway smooth muscle tissues results in wheezing, crackles, stridor, and progressive respiratory distress. Erythema and pruritus may also be seen as the result of an influx of eosinophils. Mortality from anaphylaxis results from complications of bronchospasm and airway compromise or profound hypotension.

Any medication has the potential to cause an allergic reaction, although some agents are more commonly associated with anaphylaxis than others. Agents with a higher potential for causing anaphylactic reactions include antibiotics (e.g., penicillin or sulfa drugs), chemotherapy agents (e.g., Asparaginase or Etoposide), antifungal agents, biotherapy agents (e.g., monoclonal antibodies), blood products, immunoglobins, radiologic contrast media, latex products, and food.

Clinical Signs and Symptoms

Signs and symptoms of hypersensitivity or anaphylaxis can develop within seconds or minutes after exposure. Patients often initially describe a sense of impending doom, accompanied by pruritus and flushing. This can evolve rapidly into other clinical manifestations of hypersensitivity (Table 16-2).

Table 16-2 Clinical Manifestations of Hypersensitivity Reactions

Organ System	Clinical Manifestation(s)
Cutaneous/ocular	Flushing, urticaria, angioedema, cutaneous and/or conjunctival pruritus, warmth, and swelling
Respiratory	Nasal congestion, rhinorrhea, throat tightness, wheezing, shortness of breath, cough, hoarseness
Cardiovascular	Dizziness, weakness, syncope, chest pain, palpitations
Gastrointestinal	Dysphagia, nausea, vomiting, diarrhea, bloating, cramps
Neurologic	Headache, dizziness, blurred vision, and seizure (very rare and often associated with hypotension)
Other	Metallic taste, feeling of impending doom

Data from Linzer JF: Pediatrics, anaphylaxis. 2008. Emedicine, http://emedicine.medscape.com/article/799744-overview.

Once the clinical manifestations of the reaction become systemic, anaphylaxis is present. Mild symptoms include irritability, coughing, anxiety, disorientation, erythema, hives, and itching. Severe symptoms include dyspnea; cyanosis; difficulty speaking; swelling of the tongue, face, and airways; intense coughing; chest tightness; wheezing; stridor; laryngospasm; seizures; sense of impending doom; hypotension; and cardiorespiratory arrest.²³

Management

When a patient develops signs of a severe hypersensitivity reaction or anaphylaxis, immediately stop the causative infusion or remove the offending agent (if known) and call for assistance (i.e., activate emergency response and notify a physician). Support the patient’s airway, oxygenation, and ventilation and circulation as necessary and initiate cardiopulmonary resuscitation if needed. Healthcare providers should always be prepared for further patient deterioration, particularly if symptoms develop soon after the exposure.

Evaluation of airway and breathing includes assessment of oxygenation and ventilation. Administer supplementary oxygen as needed. In extreme cases, intubation and mechanical ventilation will be required. In patients with laryngeal or tracheal edema, an emergent tracheostomy may be needed.

Establish vascular access, ideally with two large-bore vascular catheters and be prepared to administer fluid boluses (to treat relative hypovolemia resulting from vasodilation and increased capillary permeability) and vasoactive support (e.g., an epinephrine infusion) to restore and maintain adequate blood pressure and systemic perfusion. (For further information, please refer to Chapter 6.)

Epinephrine 1:1000 is administered intramuscularly in the prehospital setting, but is administered intravenously (if arrest has occurred or is imminent, it can be administered by intraosseous route) in the hospital setting. Additional vasoactive medications such as norepinephrine may also be required to maintain blood pressure and systemic perfusion.

Medications typically used to treat anaphylactic reactions include oxygen, IM epinephrine (an infusion may be needed for refractory hypotension), diphenhydramine (and possibly an H₂-blocker antihistamine), albuterol nebulizer, and methylprednisolone.^10,²³ Antihistamines are administered to antagonize the effects of histamine. Bronchodilators relax bronchial smooth muscles. Corticosteroids are antiinflammatory agents to enhance the effects of bronchodilators. (For further information, please refer to Chapter 6.)

Skin testing may help identify patients who may experience a hypersensitivity reaction with a known high-risk agent. Patients are given a small intradermal test dose of the agent and are monitored for at least 20 minutes.¹⁷ Emergency equipment and medications should be readily available. Patients receiving medications or agents with a higher risk of producing anaphylactic reaction and those with a history of anaphylaxis should be identified and monitored appropriately.

When a patient has a known allergy or hypersensitivity reaction to a drug, premedications may be prescribed before the agent is administered. Medications commonly used for pretreatment are corticosteroids, antihistamines, and antipyretics.¹⁷ Patients with known hypersensitivity responses should wear medical alert jewelry and should have an anaphylaxis kit (epinephrine autoinjector pen) readily available.

Systemic Inflammatory Response Syndrome (SIRS)

Etiology

In 1992, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) introduced definitions ³ for systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, and multiple organ dysfunction syndrome (MODS).

SIRS is a state of inflammatory/immune activation. SIRS is present when the adult patient demonstrates two or more of the following variables ³^,^8a:

• Altered temperature: fever of more than 38° C rectal or less than 36° C rectal

• Tachycardia (age related)

• Tachypnea (age related) or a PaCO₂ less than 32 mm Hg

• Abnormal white blood cell count: greater than 12,000/mm³ or less than 4000/mm³ or greater than 10% bands

SIRS is nonspecific and can be caused by a number of diverse clinical conditions (Table 16-3), including ischemia, inflammation, trauma, infection, or a combination of several insults. SIRS does not always occur as a result of infection. A number of underlying conditions may predispose patients to infections with specific pathogens and the development of SIRS (Table 16-4).

Table 16-3 Infectious and Noninfectious Causes of SIRS

Infectious Causes	Noninfectious Causes
Bacterial sepsis Burn wound infections Candidiasis Cellulitis Cholecystitis Community-acquired pneumonia Infective endocarditis Influenza Intraabdominal infections Meningitis Healthcare-acquired pneumonia Pyelonephritis Toxic shock syndrome Urinary tract infections	Autoimmune disorders Burns Chemical aspiration Dehydration Erythema multiforme (Stevens-Johnson syndrome) Hemorrhagic shock Intestinal perforation Pancreatitis Surgical procedures Transfusion reactions Upper gastrointestinal bleeding Vasculitis

From Burdette SD, et al: Systemic inflammatory response syndrome. Emedicine, http://emedicine.medscape.com/article/168943-overview. Updated July 20, 2010. Accessed April 27, 2011.

Table 16-4 Predisposing Conditions/Risk Factors for Development of SIRS

Acquired immunodeficiency syndrome (AIDS)	Predisposes to SIRS from both typical and unusual pathogens, particularly pneumococcus
Hemoglobin SS (Sickle Cell) disease	400-Fold increased risk of sepsis caused by pneumococcus and Salmonella, among other pathogens
Congenital heart disease (with few exceptions)	Risk for endocarditis (see Endocarditis in Chapter 8) and SIRS
Genitourinary anomalies	May increase the risk of urosepsis
Significant burns	Risk of SIRS, caused by skin flora and nosocomial gram-negative pathogens in particular
Splenic dysfunction or absence, as well as complement, immunoglobulin, and properdin deficiency	Predispose to infection from encapsulated organisms and resulting sepsis
Hematologic and solid-organ malignancies (before or during treatment)	Increased risk for SIRS from many organisms
Hospitalization (particularly if prolonged, in the critical care unit, or with invasive devices)	Increased risk of SIRS; prolonged stay and invasive devices increase risk of infection
Indwelling devices or prosthetic material and other breaches in barrier protective function	Increased risk of SIRS

Modified from Burdette SD, et al: Systemic inflammatory response syndrome. Emedicine, http://emedicine.medscape.com/article/168943-overview. Updated July 20, 2010. Accessed April 27, 2011.

Pathophysiology

Inflammation is the body’s response to nonspecific insults that arise from chemical, traumatic, or infectious stimuli. The inflammatory cascade is a complex process that involves humoral and cellular responses and complement, and cytokine cascades. This inflammatory response, regardless of cause, generally has the same pathophysiologic properties; minor differences are caused by the inciting factor.

Trauma, inflammation, or infection leads to the activation of the inflammatory cascade. The proinflammatory interleukins either function directly on tissue or work via secondary mediators to activate the coagulation cascade, the complement cascade, and the release of nitric oxide, platelet-activating factor, prostaglandins, and leukotrienes. Activation of the white blood cells leads to secretion of tumor necrosis factor-alpha (TNF-α), a proinflammatory mediator (TNF derived its name from the fact that it causes hemorrhagic necrosis of tumors). Messenger RNA for TNF is normally present in tissues throughout the body, and levels of TNF rise early in the inflammatory process, leading to further vasodilation, capillary leak, and release or activation of additional cytokines (vasoactive peptides), including platelet-activating factor and many interleukins. The complement cascade is designed to coat invading organisms, making them vulnerable to phagocytosis. Activation of the complement cascade includes activation of the coagulation cascade (described further in the following paragraphs and later section, Sepsis and Septic Shock).

Numerous proinflammatory polypeptides are found within the complement cascade. Two of these, protein complements C3a and C5a, contribute directly to the release of additional cytokines, causing vasodilatation and increasing vascular permeability. Prostaglandins and leukotrienes incite endothelial damage, leading to multiorgan system failure (MOSF).

More than 15 years ago, Bone ⁴ described the relationship between these complex inflammatory interactions. He described SIRS and MOSF as a five-stage process (Table 16-5). His definitions remain very helpful today.

Table 16-5 Bone’s Five Stages of SIRS and Multiple Organ System Failure (MOSF)

Stage 1

• Begins at a site of local injury or infection

• Proinflammatory mediators are released locally to promote wound healing and combat foreign organisms or antigens

• Antiinflammatory mediators are released to downregulate this process if the original insult is small and the patient is healthy, homeostasis will be quickly restored

Stage 2

• Occurs if local defense mechanisms are insufficient to correct the local injury or eliminate the local infection

• Proinflammatory mediators are released into the systemic circulation and recruit additional cells to the local area of injury

• Systemic release of antiinflammatory mediators follows under normal circumstances, these mediators ameliorate the proinflammatory reaction and restore homeostasis

Stage 3

• Occurs if the systemic release of proinflammatory mediators is massive or if the antiinflammatory reaction is insufficient to permit downregulation

• Most patients have symptoms of the systemic inflammatory response syndrome (SIRS) and evidence of the multiple organ system failure (MOSF)

• Excessive systemic levels of antiinflammatory mediators develop as a response to a massive proinflammatory response

Stage 4

• Compensatory antiinflammatory response syndrome (CARS)

• Marked immunosuppression; at increased risk for infection

• If the body can reestablish homeostasis after stage 3 or 4, the patient may survive

Stage 5

• Final stage of MOSF

• The balance between proinflammatory and antiinflammatory mediators has been lost

• Some patients may have persistent, massive inflammation

• Others may have ongoing immunosuppression and secondary infections

• Others may oscillate between periods of inflammation and immunosuppression

From Bone RC: Immunologic dissonance: a continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 125(8):680-687, 1998.

The relationship between inflammation and coagulation directly affects the potential clinical progression of SIRS. Interleukin-1 (IL-1) and TNF-α directly affect endothelial surfaces, leading to the expression of tissue factor. Tissue factor initiates the production of thrombin, thereby promoting coagulation; tissue factor is also a proinflammatory mediator. Fibrinolysis is impaired by IL-1 and TNF-α through production of plasminogen activator inhibitor-1.

Proinflammatory cytokines also disrupt the naturally occurring antiinflammatory mediators, antithrombin, and activated protein-C (APC). If unchecked, this coagulation cascade leads to complications of microvascular thrombosis, including organ dysfunction. The complement system also plays a role in the coagulation cascade. Infection-related procoagulant activity is generally more severe than that produced by trauma.

The cumulative effect of this inflammatory cascade is an unbalanced state with inflammation and coagulation. To counteract the acute inflammatory response, the body is equipped to reverse this process via a counter-inflammatory response syndrome (CARS). Co-morbidities and other factors can influence a patient’s ability to respond appropriately. The balance of SIRS and CARS determines a patient’s prognosis after an insult. Some researchers believe that, because of CARS, many of the new medications meant to inhibit the proinflammatory mediators may lead to deleterious immunosuppression.⁴

If SIRS is identified and reversed early, the subsequent inflammatory cascade can often be avoided or mitigated. However, in some situations, the cascade continues because the insult or the resultant host inflammatory response is too great. This damage can trigger cardiovascular dysfunction (increased cardiac output, peripheral vasodilation, maldistribution of blood flow, and impaired oxygen utilization), with resultant shock and a hypermetabolic state (i.e., warm shock).

If SIRS continues to progress, cardiac output may fall, peripheral vascular resistance may increase, and shunting of blood may ensue (i.e., cold shock). This results in development of tissue hypoxia, end-organ dysfunction, metabolic acidosis, end-organ injury and/or failure, and can be fatal.³⁵

Clinical Signs and Symptoms

Fever is the most common presenting symptom of children with SIRS. Fever is one component of the triad of hyperthermia (or hypothermia), tachypnea, and tachycardia that typifies the earliest, mildest manifestation of SIRS. The international consensus terminology defines SIRS in children as present when the patient demonstrates two or more of the following (see details in Box 16-1)¹⁸:

• Alteration in temperature: fever of more than 38° C rectal or temperature less than 36° C rectal

• Alteration in heart rate (age related): tachycardia or bradycardia (in infants)

• Tachypnea (age related) or a PaCO₂ less than 32 mm Hg

• Abnormal white blood cell count (greater than 12,000/mm³ or less than 4000/mm³ or greater than 10% bands)

Box 16-1 Pediatric Signs of Sepsis/Systemic Inflammatory Response Syndrome

Manifested by two or more of the following four criteria:

Alteration in temperature (fever above 38.5° C or less than 36° C)

Requires 0.5° C elevation higher fever than adult level of 38° C

Consider support required by warming device

Tachycardia OR bradycardia in infant less than 1 year old

Tachycardia:

Mean heart rate more than 2 standard deviations (SD) above normal for age in absence of external stimulus, chronic drugs, or painful stimuli OR

Otherwise unexplained persistent elevation over a 0.5- to 4-h time period

Bradycardia:

Mean heart rate less than the 10th percentile for age in absence of external vagal stimulus, ß-blocker drugs, or congenital heart disease

Persistent depression over a 0.5-h time period

Tachypnea

Mean respiratory rate more than 2 SD above normal for age OR

Mechanical ventilation for an acute process not related to underlying neuromuscular disease or the receipt of general anesthesia

Leukocyte count elevated or depressed for age (not secondary to chemotherapy-induced leukopenia) or more than 10% immature neutrophils

SD, Standard deviations.

Modified from Goldstein B, et al: International pediatric sepsis consensus conference. Pediatr Crit Care Med 6(1):5, 2005.

Management

Treatment of SIRS is focused on treating the inciting cause. Empiric antibiotics are not administered routinely to all patients. Indications for empiric antimicrobial therapy include suspected or diagnosed infectious etiology, hemodynamic instability, neutropenia, and asplenia.^8a Broad spectrum antibiotics are initiated when there is concern for an infectious cause but no definitive infection has been diagnosed.

Drotrecogin alpha, a recombinant form of human recombinant activated protein C (APC), reduces microvascular dysfunction by reducing inflammation and coagulation and increasing fibrinolysis. It has been hypothesized that APC may be beneficial in the management of SIRS. However, the supporting evidence to date is limited. In the prospective, randomized multicenter controlled PROWESS trial,² mortality was reduced by 28% in adult patients with severe sepsis who received APC. Patients who received APC also demonstrated significantly more bleeding than control patients. However, a Cochrane meta-analysis of adult trials²⁵ involving over 4000 patients (including some children who were not randomized) did not find overall evidence of improved survival when APC was administered; a multicenter pediatric study was halted because excessive bleeding occurred when children received APC.

APC currently has no role in the routine management of SIRS unless the presentation is consistent with septic shock. Although APC may be considered in the management of severe septic shock in adolescents and adults (see section, Sepsis and Septic Shock), it is not routinely used in pediatric patients.

Fluid resuscitation should be initiated in those patients who exhibit signs of hypovolemia and hypovolemic shock (see section, Sepsis and Septic Shock and Chapter 6). All patients require establishment of adequate intravenous access. Administer isotonic fluids boluses (typically 20 mL/kg boluses; smaller volumes may be used in children with poor myocardial function) as needed to treat shock and monitor hemodynamic status closely.²²^,³³ If signs of shock are present, antibiotics, aggressive fluid resuscitation and vasoactive support should be provided within the first hour after the onset of symptoms (see section, Sepsis and Septic Shock and Chapter 6).⁵

Assess and support adequate oxygenation and ventilation. The oxyhemoglobin saturation in the superior vena cava (S_CVO₂) allows tracking of the balance between oxygen delivery and oxygen use; therapy should be titrated to maintain this S_CVO₂

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