Pediatric patients undergoing treatment for cancer may require intensive care at any time during their diagnostic and treatment courses. Caring for pediatric cancer patients in the intensive care unit requires skilled, specially trained members of the medical team to provide around the clock care for this distinct patient population. This chapter will focus on critical care issues of pediatric cancer patients, including the need for intensive monitoring following procedural or oncologic treatments, as well as perioperative and postoperative management following tumor resection.
Neurologic Diagnoses in the Pediatric Oncologic Critical Care Patient
Children are commonly admitted to the pediatric intensive care unit (PICU) after neurologic surgery for brain tumor resection. For both primary and metastatic disease, children are monitored postoperatively for acute neurologic changes, acute hemorrhage, and acute neurohormonal changes, such as central diabetes insipidus (CDI) and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion. Furthermore, depending on the risk of increased intracranial pressure (ICP) following surgery, some patients will have an externalized ventricular drain (EVD) or lumbar drain (LD) for cerebral spinal fluid (CSF) diversion in place postoperatively, which demands close monitoring, typically only available in the PICU. In addition to the postoperative state, children with brain tumors may be admitted to the PICU preoperatively if they are at risk of acute increase in ICP, or if they need placement of an EVD for treatment of increased ICP.
In this section, two common circumstances that warrant PICU monitoring will be examined in greater detail: sodium balance and posterior reversible encephalopathy syndrome (PRES). Additionally, a relatively new surgical approach used for tumor-directed therapy convection-enhanced delivery (CED) will be discussed for its use in the treatment of pontine gliomas.
Disorders of Sodium Homeostasis Following Neurosurgery
Due to the location of many pituitary and suprasellar tumors, neurosurgery in these areas may lead to postoperative disorders under hormonal control from the pituitary stalk. These common disorders can occur in isolation or in combination. ,
Central Diabetes Insipidus
CDI can occur in more than 50% of patients after transsphenoidal surgery (TSS) to resect intrasellar or suprasellar tumors. The diagnosis of CDI is made on the basis of both clinical and biochemical findings. Polyuria (>4 mL/kg/h of urine output) and polydipsia, in combination with increased serum osmolality (>300 mOsm/L) and decreased urine osmolality with a urine/plasma osmolality ratio <1, is the hallmark of CDI in the postoperative period. Patients with an intact thirst mechanism and free access to oral fluids may not develop symptoms or hypernatremia. However, patients who are unable to maintain normal plasma osmolality and serum sodium levels need immediate intervention or they will develop symptoms of CDI, such as acute dehydration, nausea and vomiting, and alterations in mental status.
Monitoring of CDI includes following hourly urine output, hourly fluid intake, as well as measurements of serum and urine osmolality, serum electrolytes, and blood glucose levels every 6–8 h in the immediate postoperative period.
For patients who show laboratory and/or clinical evidence of CDI, management will depend on the patients’ thirst mechanism and access to oral fluids. For patients without an intact thirst mechanism or without free access to oral fluids, supplemental intravenous (IV) fluids are necessary. Institutional guidelines are very helpful in these circumstances, as a multidisciplinary approach to monitoring and treatment is warranted for consistency. A reasonable approach to IV fluids with either normal saline or ½ normal saline with dextrose at one-third of maintenance needs or 400 mL/m 2 /h, plus urine output replacement mL:mL with ½ normal saline or other balanced solution. If this fluid replacement method of CDI treatment is not successful, an alternative approach is to administer oral 1-desamino-8- d -arginine vasopressin (DDAVP) or vasopressin infusion for the hormonal replacement of endogenous vasopressin, which is often due to transient direct surgical injury or localized edema at the site of surgery. The course of CDI most typically lasts up to 48 h from the immediate postoperative period , , but may undergo what is termed a triphasic pattern of immediate postoperative CDI, followed by a period of SIADH for 5–7 days, followed once again by CDI, which may persist after discharge. , This triphasic pattern persists in more than 3% of patients undergoing TSS, and approximately 1% of patients experience the biphasic pattern of immediate postoperative CDI followed by SIADH. ,
Syndrome of Inappropriate Antidiuretic Hormone
SIADH can occur in the immediate postoperative phase following TSS, either in isolation or as part of the triphasic pattern discussed earlier. SIADH occurs in isolation following TSS in up to 20% of patients. , The mechanism is likely the uncontrolled release of ADH from either degenerating posterior pituitary or from magnocellular neurons with damaged axons. With this release of ADH, urine output decreases, and the patient remains in either a euvolemic or hypervolemic state with a subsequent drop in serum osmolality <270 mOsm/L. The most important therapeutic intervention is fluid restriction and cessation of IV fluids, as soon as the patient is able to drink. Sodium replacement is only required for prolonged SIADH or in cases of severe hyponatremia. Symptoms of severe hyponatremia from SIADH include visual changes, focal neurologic changes, respiratory depression, and seizures. These symptoms are consistent with cerebral edema and can be treated carefully with hypertonic saline until symptoms resolve. ,
Cerebral Salt Wasting
Cerebral salt wasting (CSW), characterized by polyuria and natriuresis, occurs in about 4% of children following neurosurgery. CSW is thought to be due to a tubular defect in sodium transport, leading to extracellular volume depletion. CSW and SIADH can be present in both surgical and nonsurgical settings. Making a distinction between the two is important, as the treatment of CSW is different from that of SIADH. The treatment of CSW involves water and sodium repletion. The fundamental difference between these two syndromes is the presence of polyuria, which leads to dehydration in CSW. Replacement of both free water and sodium is therefore necessary because of the significant urine sodium losses and high urine output. , Depending on the severity, sodium replacement needs can be met with oral sodium, or CSW may require aggressive fluid and sodium replacement in the PICU with central venous pressure monitoring of intravascular volume status. In severe CSW, the mineralocorticoid fludrocortisone may be used, although CSW typically resolves within a month of onset.
Posterior Reversible Encephalopathy Syndrome
PRES is a clinical syndrome consisting of headache, impaired consciousness, seizures, visual disturbances, nausea and vomiting, and occasionally focal seizures. These clinical features in the setting of specific cofactors often lead to its diagnosis. Cofactors, such as acute hypertension, , preeclampsia or eclampsia, chemotherapeutic agents, , posttransplant immunosuppression, and other diseases of inflammation, , , , have been associated with the development of PRES.
The best understanding of the etiology of PRES is that it is a disturbance in cerebral autoregulation, often in the face of severe hypertension, generating vasogenic edema. Clinical diagnosis is often confirmed by magnetic resonance imaging (MRI). Classically, PRES affects the parieto-occipital region of the brain, , although it can also be located in the temporal and frontal lobes and posterior fossa. , On T2 and fluid-attenuated inversion recovery MRI, white matter intensities are demonstrated in the affected areas, confirming the diagnosis ( Fig. 52.1 ). ,
Treatment of encephalopathy, headache, and other neurologic findings surrounds the treatment of the underlying cause, and removing the offending medicines that are related to the PRES. , , , , Hypertension requires timely intervention, including admission to a PICU, initiation of antihypertensive therapy, and close invasive blood pressure monitoring. Calcium-channel blockers or beta blocker infusions have been used in the acute treatment of hypertensive emergencies in children. Treatment of PRES-associated seizures with valproic acid has been advocated for its favorable mechanism of action. ,
Last, the removal of medications that are thought to contribute to the development of PRES should be strongly considered. Patients in whom the chemotherapy used to treat their underlying cancer diagnosis is thought to be the offending agent present difficult challenges to oncologists. The same is true for transplant physicians in managing immunosuppression following an episode of PRES, as cyclosporine and tacrolimus have both been implicated in the development of PRES and are staples of posttransplant immunosuppression. , ,
Convection-Enhanced Delivery
The delivery of chemotherapy to malignant gliomas has proven challenging. Systemic chemotherapy and more direct methods such as chemotherapy-infused wafers and intrathecal administration of chemotherapy have been ineffective at delivering tumor-directed therapy to deep gliomas. Developed in the 1990s, CED utilizes a syringe pump to generate a pressure gradient at the interstitium to enhance delivery of the therapy to the desired target.
Diffuse intrinsic pontine glioma (DIPG) is a rare but lethal brain tumor seen in children. DIPG accounts for 15%–20% of all CNS tumors in children, and more than 90% will die within 2 years of diagnosis, with conventional fractionated radiation as the primary means of treatment. In recent years, pediatric neurosurgeons have explored the use of CED in the delivery of tumor-directed therapy to children with DIPG ( Fig. 52.2 ).
In phase I, dose-escalation trial using the radiolabeled antibody monoclonal 124 I-8H9, the first 16 subjects received the entire infusion under general anesthesia in the operating room, while the remaining 12 subjects were observed while receiving the infusion in the PICU after cessation of anesthesia for more complete neurologic monitoring. In this cohort, the most common adverse event was the development of a transient facial palsy, which occurred in 9 of the 28 subjects. There was one grade 4 adverse reaction (respiratory failure requiring reintubation after the completion of the infusion) in the cohort. In a second phase I trial exploring the use of CED in the treatment of DIPG, investigators used the recombinant chimera of human interleukin 13 (IL-13) and the enzymatically active portion of Pseudomonas exotoxin A, which effectively targeted glioma cells in preclinical studies. In this cohort, all subjects received the infusion (up to 13 h) in the operating room under general anesthesia. Similarly, the adverse reaction profile was acceptable, suggesting that further studies are warranted to study clinical effectiveness, including the use of liposomal doxorubicin via CED in DIPG.
In all cases, admission to the PICU is necessary if patients are transferred from the operating room. Even small volumes delivered to the pons may cause acute neurologic changes that warrant close monitoring.
Anterior Mediastinal Masses
The anesthetic approach to mediastinal masses is described in detail in Chapter 47. Tumors located in the thoracic cavity can pose challenges to patients, as they can compress or obstruct vital structures. Anterior mediastinal masses in pediatric patients are primarily caused by lymphoma (Hodgkin’s and non-Hodgkin’s) with other causes, including leukemia, thymoma, histiocytosis, and neuroblastoma. Due to the wide range of possible etiologies, obtaining a tissue biopsy is needed to confirm the exact diagnosis, yet several risks are associated with obtaining such biopsies. The most significant risks include cardiovascular collapse and respiratory compromise; however, bleeding and other complications may also occur.
As described in Chapter 47, large anterior mediastinal masses can compress vital structures within the mediastinum, particularly affecting thin-walled structures, such as the right atrium, superior vena cava, and pulmonary artery. Preparing individualized plans for each patient’s unique case addresses the needs and potential risks associated with surgical biopsies and anesthesia. Prior to sedation, patients should have a thorough workup, including computed tomography (CT) and echocardiogram at the minimum. Patients with anterior mediastinal masses can be broadly classified into three categories defining the risk level associated with anesthesia ( Table 52.1 ).
| Risk Level | Symptoms | Percent Tracheal Compression |
|---|---|---|
| Low risk | None or mild | No radiographic evidence of compression |
| Intermediate risk | Mild-to-moderate postural symptoms | Less than 50% |
| High risk | Severe postural symptoms: orthopnea, stridor, cyanosis | 50% or more |
Preoperative management of pediatric patients with anterior mediastinal masses should be performed in an intensive care unit or unit in which close airway monitoring can be maintained. Should patients develop inadequate ventilation or oxygenation, immediate attention and intervention are needed. Escalation of noninvasive respiratory support, including the use of high-flow nasal cannula, continuous positive airway pressure (CPAP), or bilevel positive airway pressure (BIPAP) ventilation, can be useful in this patient population. BIPAP devices allow the delivery of adjustable levels of continuous positive pressure during inspiration and expiration. Inspiratory positive airway pressure helps to overcome upper airway resistance in cases of partial obstruction. However, CPAP alone provides expiratory positive airway pressure to open the upper airway, thereby preventing alveolar collapse.
A helium/oxygen mixture or heliox can be used in these patients, as helium is less dense than oxygen, thus enhancing laminar flow through a compressed airway. Heliox must be delivered as a mixed gas. It is imperative to use the lowest oxygen content (i.e., Fi o 2 ), thereby the highest concentration of helium in order to achieve the most beneficial clinical effects.
Corticosteroids can be used in cases of severe airway or cardiovascular compromise. With its use, patients are at risk of tumor lysis syndrome, and additional monitoring is needed. Corticosteroid use prior to tumor biopsy does not necessarily interfere with making a diagnosis, as one small cohort had a 95% clear histologic diagnosis made in patients who had received corticosteroids. Radiotherapy prior to diagnostic biopsy is uncommonly used in pediatric patients, as children may require anesthesia to tolerate the procedure.
Finally, pediatric patients with the highest risk of cardiovascular collapse may be prophylactically placed on cardiopulmonary bypass prior to the procedure. Despite thorough planning and careful preparation, patients may need to be urgently placed on cardiopulmonary bypass should the need arise. This may be particularly true in adult populations, as they are less responsive to changes in positioning compared to pediatric patients. In conclusion, advanced, experienced airway and critical care professionals should manage this high-risk patient cohort, having a variety of tools and cardiopulmonary support available.
Metastatic Lung Disease
Children with metastatic lung disease may require intensive care. One example of lung metastases in children is osteosarcoma, which is the most common bone tumor in children and young adults. Metastatic lung disease can occur within the first year after diagnosis and more than 30% of patients with osteosarcoma relapse. In order to maximize survival, complete metastatic tumor surgical resection is needed, as systemic antitumor therapies are not as reliable a treatment modality for improving survival. Patients undergoing surgical resection of pulmonary metastases often need management and monitoring in the PICU before and following their surgery.
The surgical approach for patients with metastatic lung disease depends on several factors. The majority of patients have bilateral lung involvement but the literature shows that 24%–40% of patients may have unilateral disease. The most common approach to surgical resection is thoracotomy; however, single-staged operations via median sternotomy are sometimes performed.
Pediatric patients who have undergone thoracotomy often recover in the PICU or a surgical step-down unit. Postoperative complications include bleeding, pain control, and respiratory failure. Anticipating these potential complications can mitigate harm and shorten the length of stay in the PICU. Monitoring for bleeding requires close monitoring of hemoglobin and platelet counts as well as coagulation factors, especially in patients who may have recently received chemotherapeutic agents, suppressing marrow production of blood cells. Pain control is the most common postoperative complication. The use of thoracic epidural patient-controlled analgesia (ePCA) has been proven to be safe and effective in controlling pain. , The use of ePCA can decrease the need for systemic analgesics, particularly opiates, in an effort to expedite mobility and reduce hospital length of stay. The care of patients with pulmonary metastatic disease requires a multidisciplinary team to achieve the best outcomes.
Intraabdominal Tumors
Pediatric tumors in the abdomen often require surgical management as a first-line or adjuvant therapy with antineoplastic medications .
Neuroblastoma
Neuroblastoma accounts for 8%–10% of all pediatric cancers and as high as 15% of all deaths in children with cancer, prognosis of which depends on the stage of the tumor, determined using several tumor-specific and histologic factors. Patients with high-risk neuroblastoma often undergo complete surgical resection. Thoracoabdominal resections for neuroblastoma are tedious, long surgeries, during which blood loss, fluid shifts, and respiratory failure give rise to the need for intensive care monitoring. This unique patient population differs from other postsurgical patients in that some patients require additional exogenous catecholamines. This has been hypothesized to be caused by underlying neuroblastoma cells secreting catecholamines, which once removed may cause hemodynamic instability.
Postoperative management of large thoracoabdominal resections in patients with neuroblastoma requires close attention from a team of providers, nurses, therapists, and other members of the care team. The development of a postoperative management protocol for patients undergoing any major surgical resection allows for a systematic approach, thereby ensuring that all aspects of care are met. Patients should have adequate blood pressures to ensure perfusion to all end organs, including adequate urine output (typically between 0.5 and 1 mL/kg/h for children), monitoring of central venous pressure, and trending of serum lactate. Administration of crystalloid fluid is recommended if any of these parameters are not met. The use of vasoactive medications, such as norepinephrine, should be considered if hypotension and hypoperfusion exist following fluid resuscitation or if there are signs of hypoperfusion in the setting of an elevated central venous pressure. The use of stress dose glucocorticoids should be considered if adrenal insufficiency is a concern.
Early extubation is the goal for postoperative patients in the PICU with stable hemodynamics, adequate ventilation and pulmonary compliance, and no major postoperative bleeding. Target respiratory goals include normal ventilation and oxygenation, while medical teams should anticipate the third spacing of fluid causing pulmonary edema, if large volumes of crystalloid or blood products are required perioperatively. Postoperative transfusion thresholds are discussed later. As with thoracotomies, ePCA is ideal for analgesia to minimize the systemic need for opiates or sedating medications. Maintenance of monitoring lines is imperative, including arterial lines and central venous catheters, along with assessing the daily need for any surgical drains, nasogastric tubes, and urinary catheters.
Immunotherapy for Neuroblastoma
Immunotherapy is a major component in the treatment of high-risk neuroblastoma. Several different antibodies target ganglioside GD2, which is expressed on the surface of neuroblastoma cells. These immunotherapies require close monitoring during and after infusions because of their poor side effect profile. Commercially available dinutuximab is a chimeric human-murine antibody to GD2, and a similar monoclonal antibody, Hu3F8, is used at Memorial Sloan Kettering Cancer Center (MSKCC).
Intensivists and oncologists should be aware of the side effects of such antibodies and be prepared for treatment in the inpatient or intensive care setting. Pain is the most common adverse event, as GD2 is also expressed in peripheral nerve cells. High-dose opioids may be needed to control pain, which can in turn lead to respiratory depression. Continuous opioid infusions should be administered with caution when combined with other sedating medications. Opioids with dexmedetomidine, an alpha-2 agonist, can lead to hypotension and bradycardia, whereas ketamine infusions are generally well tolerated without respiratory compromise but may lead to dysphoria. ,
Antibodies against GD2 can also cause anaphylactic-like hypersensitivity responses with symptoms, including bronchospasm, urticaria, hypotension, and capillary leak. Treatment with epinephrine, inhaled beta-2 agonists, fluid boluses, and antihistamines can improve many anaphylactic and anaphylactoid reactions. Hypertension can be a late side effect following immunotherapy infusion, and these patients should have close follow up as Hu3F8 has been associated with PRES as discussed earlier. These patients with hypertension and any signs of symptoms of neurologic involvement should be treated with antihypertensives and require neuroimaging.
Wilms Tumor
Childhood kidney cancers account for approximately 7% of all pediatric cancers. Wilms tumor is the primary type for all pediatric kidney cancers. CT or MRI of the abdomen is imperative to assess disease burden. Approximately 11% of Wilms tumor patients have renal vein involvement and 4% present with inferior vena cava or atrial involvement. Embolization of a caval thrombus to the pulmonary artery is a rare occurrence but can be fatal, necessitating precise surgical planning. Initial nephrectomy is recommended as the first-line treatment for stage I and II Wilms tumors by North American experts, and postoperative management often occurs in the intensive care unit or pediatric floor. Complications include the need for extensive resections, removal of addition organs, and intraoperative tumor contamination in stage III–V Wilms tumors.
Transfusion Medicine
Pediatric oncology patients are a special population who often require blood and platelet transfusions throughout their treatment course. There are limited evidence-based guidelines for transfusion thresholds for this population, yet recent experts have recommended restrictive transfusion strategies. Current guidelines recommend transfusing for hemoglobin <7–8 g/dL, platelets <10 × 10 9 /L, and INR >2.5 with clinically significant bleeding.
Postoperative pediatric oncology patients pose an even more unique challenge with regard to the timing of transfusion. Current management of postoperative oncologic patients not only recommends a restrictive transfusion strategy for anemia but also a higher threshold for platelets, transfusion of platelets to maintain a count greater than 50 × 10 9 /L. INR thresholds differ by clinician and surgeon in terms of when to transfuse plasma, most suggesting plasma transfusion if INR is prolonged and the patient has clinically significant bleeding. However, there is a lack of validated bleeding scales, and clinically relevant bleeding has not been universally defined. Additional evidence-based studies and guidelines are needed to standardize transfusion practices that can be used in all critically ill patients.
Enhanced Recovery After Surgery
The goal of caring for pediatric oncologic patients following surgery is to provide high-quality medical care, optimize hospital resources, and expedite their discharge from the intensive care unit and hospital, while providing patient and parent support. Enhanced Recovery After Surgery (ERAS) programs are designed to achieve these goals (see Fig. 52.3 ). From presurgical counseling in an outpatient setting, to intraoperative pain control and conservative fluid management, to follow up after discharge, the ERAS program highlights the full spectrum of a surgical experience. Derived from adult ERAS programs, these concepts have been applied to pediatric patients and retrospectively studied in several common childhood surgeries. Ideally, all elective surgeries would undergo screening for ERAS participation.
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