The general features of sepsis and septic shock, as well as their management, are discussed at length in Chapters 28 and 87. The development of sepsis or septic shock in the children with cancer presents special challenges because they are immunocompromised. They are commonly profoundly neutropenic, have impaired mucosal barriers, and may have preexisting end-organ dysfunction, making them more vulnerable to multiple organ system failure (MOSF). Their care should be meticulously directed to avoid organ failure, as they have substantially greater mortality from MOSF than do other patients (9). Cardiac function may deteriorate rapidly in these children, who frequently have subclinical myocardial dysfunction (10). Prompt recognition and the institution of goal-directed interventions are of paramount importance to mitigate end-organ injury (Table 115.1). Critical interventions include the timely normalization of the heart rate, the cardiac index, the perfusion pressures, and targeting a central venous oxygen saturation (Scvo₂) of ≥70% (8).

Aggressive fluid resuscitation (traditionally considered to be at least 60 mL/kg in the first hour) with isotonic crystalloid, colloid, or indicated blood products is the cornerstone of septic shock therapy, in the absence of preexisting volume overload or congestive heart failure. Patients with subclinical chemotherapy-induced myocardial dysfunction require extremely close monitoring during fluid resuscitation because congestive heart failure may develop suddenly (see below). Additionally, these patients usually require vasoactive agents to help achieve hemodynamic goals. Serial physical examinations, noninvasive, and in most cases invasive hemodynamic monitoring and echocardiography are useful in determining the status of intravascular volume, cardiac contractility, and systemic vascular resistance. Care should be taken to avoid exacerbating tachycardia that accompanies the systemic inflammatory response. Severe tachycardia may cause coronary insufficiency in children with marginal diastolic pressures, triggering life-threatening dysrhythmias. Careful review and frequent reassessment of clinical and hemodynamic data should be used to guide treatment decisions to optimize myocardial oxygen consumption while improving end-organ perfusion pressures. Brierley and colleagues (10) noted that chronically ill children with chronic venous catheters complicated by septic shock tended to present with a low systemic vascular resistance and high cardiac output, “warm shock,” while previously healthy children with community-acquired septic shock displayed more variability in their hemodynamic profiles, with a trend toward higher systemic vascular resistance and lower cardiac output, “cold shock.” These findings endorse the need to individualize the use of an inotrope versus a vasoactive agent as a first-line treatment in hypotensive cancer patients. Dopamine or the more potent vasopressor, norepinephrine, are often required in hypotensive children with evidence of decreased systemic vascular resistance unresponsive to fluid administration. Vasopressin may be effective in patients refractory to catecholamines due to its effect through distinct V₁ receptors. Terlipressin, a vasopressin analogue with a longer half-life, is utilized in some countries but is currently not available in the United States.

Calcium administration or infusion may improve refractory cardiomyocyte function in children with ionized hypocalcemia. Children with myocardial dysfunction and evidence of high systemic vascular resistance may respond to afterload reduction with inodilator agents such as milrinone. Milrinone loading doses may be avoided when there are concerns that resultant hypotension may be significant and prolonged. The calcium-sensitizing agent levosimendan is available outside the United States and appears to be useful in the stabilization of children with severe myocardial dysfunction, although its role in the management of pediatric septic shock is unclear.

Ventilator strategies designed to reduce work of breathing, optimize oxygenation, and minimize lung injury are critical. Renal replacement therapies should be applied early if indicated to maintain fluid balance as a means of mitigating injury and breakdown of integument that are associated with fluid overload. Analgesia and sedation may help minimize oxygen consumption and facilitate patient care. Neuromuscular blockade is becoming sparingly used given the concern for prolonged myopathy and neuropathy; the 2008 Surviving Sepsis Campaign recommends they be avoided in adults with sepsis (11).

Corticosteroids are used frequently in pediatric oncology patients as part of their chemotherapy and for control of complications, such as vomiting and graft-versus-host disease (GVHD). The American College of Critical Care Medicine guidelines suggest that the use of corticosteroids should be limited to patients with catecholamine-resistant shock and proven or suspected adrenal insufficiency (8). Other risk factors for adrenal insufficiency in pediatric cancer patients include catastrophic neurologic injury, profound shock with watershed injury to the adrenal glands, and exposure to megestrol acetate or etomidate. The administration of hydrocortisone to children who have absolute or relative adrenal dysfunction may promote rapid improvement in hemodynamic function and decreased requirement for vasoactive agents (12). Corticosteroids, therefore, should be implemented as indicated early and withdrawn as soon as practical. Extracorporeal support techniques and devices may be appropriate for selected patients with underlying malignancies suffering from refractory shock (13,14).

The importance of timely antibiotic administration cannot be overemphasized. Appropriate antibiotic therapy must be implemented within the first hour of contact. This intervention has measurable effects on patient outcome. Most tertiary pediatric cancer centers have protocols in place to ensure that children presenting to the hospital, emergency center, or clinic receive broad-spectrum antibiotics within the first hour of contact. Cultures should be obtained prior to antibiotic administration if possible, with care taken not to delay antibiotic administration. Cultures should be frequently reviewed and antibiotics tailored appropriately to culture results. Source control must be implemented if a focus of infection is identified. Consultation with an infectious disease specialist is often very helpful.

Cardiogenic shock is not uncommon in children with cancer and may be multifactorial. Myocardial dysfunction may evolve very rapidly, regardless of its cause, with corresponding changes in the physical exam. Persistent tachycardia is very common but may be missed, particularly in younger children. A narrow pulse pressure and changes in capillary refill and other indicators of perfusion are important clues. An intermittent or continuous gallop may be noted, along with systemic congestion (anasarca), pulmonary edema, and organ dysfunction. Physicians who care for cancer patients should be mindful that children exposed to chemotherapeutic agents may have acute, transient alterations in cardiac function or may experience a lifelong cardiac disability. Specialized echocardiographic protocols that evaluate diastolic function or provide indicators of myocardial performance under nonload conditions, such as speckle tracking imaging, may be more sensitive than measurements of ejection or shortening fractions (15). Measurement of biomarkers such as troponins and natriuretic peptides may be useful for monitoring children at risk for myocardial dysfunction. Carvedilol and enalapril may be beneficial in the chronic care of such patients. Long-term cardiology follow-up is indicated for these children, given their lifelong increased risk of myocardial dysfunction.

Chemotherapy, particularly anthracyclines may produce subclinical myocardial dysfunction, which may rapidly evolve into florid cardiac failure with stress such as sepsis. Although the anthracyclines (primarily doxorubicin and daunorubicin) are the agents most commonly implicated in myocardial dysfunction, other agents such as cytarabine, cyclophosphamide, 5-fluorouracil, and ifosfamide are capable of causing acute dysrhythmias or cardiac failure, particularly in the presence of electrolyte abnormalities. Clinically significant cardiac dysfunction may also occur in chemotherapy-naïve children. The systemic inflammatory response that accompanies sepsis, other causes of critical illness, or resection of large tumors may precipitate life-threatening, reversible myocardial dysfunction in a pattern reminiscent of takotsubo cardiomyopathy (a transient, stress-related, sympatheticmediated cardiomyopathy) seen in adults. Although survivors of pediatric cancer have a lifelong risk of cardiovascular dysfunction, much is now understood regarding mitigation of cardiovascular toxicity from anthracyclines and other agents (16).

Cardiac tumors are rare but may cause severe dysfunction in children of all ages. Most of the primary tumors such as rhabdomyomas seen in patients with tuberous sclerosis, while benign in histology, may cause significant hemodynamic compromise or dysrhythmias requiring intervention (17

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