1109CHAPTER 92 Hematology and Oncology Problems Assess anesthetic risk Clinical assessment • CT scan • Echocardiogram • PEFR erect and supine • Stridor • Orthopnea • Wheeze • SVC obstruction • Collaps[.]
CHAPTER 92 Hematology and Oncology Problems Assess anesthetic risk Mandatory special investigations Clinical assessment • CT scan • Echocardiogram • PEFR erect and supine • • • • • Clinically high risk if following symptoms or signs present? Stridor Orthopnea Wheeze SVC obstruction Collapse/dizziness High risk? • • • • • • • • • • High risk if results of special investigations show any of: Tracheal cross-sectional area ≤70% and/or carinal or bronchial compression SVC obstruction Pericardial effusion/tamponade Pulmonary artery outflow obstruction Ventricular dysfunction Supine PEFR ≤50% predicted Low risk? Consider biopsy under LA if possible: BMA ± LP Pleural fluid aspirate Lymph node Other tissue? Not possible/no diagnosis? Consider steroids: • Prednisolone 60 mg · m–2 · day–1 with IV hydration and rasburicase • Monitor daily for improvement • Maximum 5-day course If GA required • Maintain spontaneous ventilation if possible • Fibreoptic bronchoscope available • Be prepared for obstruction distal to ETT; rigid bronchoscope or one lung ventilation may be needed • Consider changing patient position if condition deteriorates • Attempt “test” IPPV, if required, without relaxants or use suxamethonium first • PICU bed available postoperatively • Fig 92.2 Preoperative anesthetic guidelines for a child with a mediastinal mass BMA, bone marrow aspirate; CT, computed tomography; ETT, endotracheal tube; GA, general anesthesia; IPPV, intermittent positive-pressure ventilation; IV, intravenous; LA, left atrium; LP, lumbar puncture; PEFR, peak expiratory flow rate; PICU, pediatric intensive care unit; SVC, superior vena cava (From Hack HA, Wright NB, Wynn RF The anaesthetic management of children with anterior mediastinal masses Anaesthesia 2008;63:837–846.) 1109 1110 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology Superior Vena Cava Syndrome SVC syndrome encompasses the signs and symptoms related to compression or obstruction of the SVC In childhood, it most commonly results from anterior mediastinal mass, middle mediastinal lymph nodes, or occlusion of the SVC itself SVC obstruction may be accompanied by compression of other mediastinal structures, large airways, pulmonary vessels, and aorta SVC syndrome is most often caused by lymphoid malignancy, including non-Hodgkin lymphoma, acute lymphocytic leukemia, and Hodgkin disease In addition to malignancies, indwelling catheters, previous cardiac surgery, previous extracorporeal life support, right-sided congenital diaphragmatic hernia, and ventriculoperitoneal shunts are other causes of SVC syndrome in pediatric patients In children, respiratory symptoms usually predominate; air hunger, dyspnea, wheezing, and anxiety occur, particularly with position change The gradual development of SVC syndrome may manifest with periorbital edema, conjunctival suffusion, facial swelling, dizziness, syncope, and cough SVC syndrome may occur in conjunction with spinal cord compression (Rubin syndrome), in which significant venous obstruction usually develops before the spinal cord compression.51 Patients with SVC syndrome and back pain should be evaluated with MRI of the vertebral spine when their condition is stable Evaluation of an anterior mediastinal mass was described previously As in airway compression, SVC syndrome places a patient at significant risk for anesthetic complications during diagnostic procedures CT should be pursued without sedation and may require prone positioning because compression of the great vessels may occur despite a patent airway, resulting in profound hypoxia and reduced cardiac output In addition, echocardiography can evaluate cardiac motility and the degree of venous return Diagnosis should be established with the least invasive means available, but empiric anticancer therapy may be required if no histologic sample can be obtained safely Tissue for definitive diagnosis should be obtained as soon as the patient’s clinical status allows in order to decrease the likelihood that empiric therapy will permanently obscure the diagnosis Hemophagocytic Lymphohistiocytosis Hemophagocytic lymphohistiocytosis (HLH) describes a syndrome of conditions rather than a specific disease entity that is marked by hyperinflammation resulting from elevated circulating cytokines (see also Chapter 106).52 HLH represents an emergency because it shares many clinical features with the systemic inflammatory response syndrome (SIRS) or sepsis syndrome These similarities make the diagnosis difficult; however, identifying HLH results in a much different treatment algorithm.53 Inadequately treated HLH results in very poor outcomes Classically, HLH is thought to occur as a consequence of acquired or inherited defects in cytotoxic activity, but emerging data suggest that HLH should be viewed as a single syndrome with a continuum of risk factors.54 Generally, these defects diminish elimination of cellular targets and impair downregulation of the immune response HLH arises from abnormalities involving the process by which cytotoxic vesicles migrate to contact, attach, fuse, and release their contents with a target cell Familial or primary HLH is usually an autosomal recessive condition caused by one of several mutations in the natural killer/T-cell cytotoxic pathway.55 Mutations in four genes have been identified as disease causing, PRF1, UNC13D, STX11, and STXBP2 Perforin is a cytotoxic protein stored in secretory granules of cytotoxic cells; defects in this protein account for 50% of all familial HLH cases in North America.56 Primary HLH is associated with and can be the initial presentation of an immunodeficiency syndrome such as Chediak-Higashi syndrome, Griscelli syndrome, Hermansky-Pudlak syndrome, and X-linked lymphoproliferative syndrome Acquired or secondary HLH most frequently occurs in the setting of infections, malignancy, or rheumatologic conditions However, the mechanism of impairment of natural killer cells and cytotoxic lymphocytes in secondary HLH remains unclear but occurs in all age groups.52 Less common associations include Kawasaki disease, metabolic diseases such as lysinuria protein intolerance, multiple sulfatase deficiency, and Wolman disease Macrophage activation syndrome is a term commonly used to describe HLH in the setting of an underlying autoimmune disorder, most commonly rheumatoid arthritis Patients typically present with signs and symptoms of systemic infection or SIRS, including prolonged fever (usually unresponsive to antibiotics), hepatosplenomegaly, and cytopenias Primary and secondary HLH are frequently triggered by infection In some patients, neurologic symptoms, seizures, and cranial nerve palsies may occur Once HLH is strongly suspected, initial evaluation includes MRI of the brain and cerebrospinal fluid analysis Because HLH often mimics other conditions, a high index of suspicion remains paramount Fortunately, diagnostic guidelines exist (Box 92.3), but each clinical situation must be considered carefully because of the substantial overlap with severe sepsis, SIRS, and multiple-organ dysfunction syndromes Laboratory studies often aid in diagnosis but may not be routinely obtained in patients who may have provisional diagnoses such as severe sepsis Diagnostic criteria require a ferritin level higher than 500 ng/mL, but the levels are usually much higher, exceeding 10,000, unlike in sepsis, in which serum ferritin is elevated but appears to be generally below 2000 Serum triglycerides often are elevated Soluble IL-2 receptor (sCD 25) and soluble Fas (CD178) are elevated Although helpful in making the diagnosis of HLH, hemophagocytosis may be absent early in the disease, can be missed on bone marrow aspirates, and is a nonspecific finding Treatment depends on whether HLH is primary or secondary Initial treatment targets suppression of the hyperinflammation using immunosuppressive and cytostatic treatment with • BOX 92.3 Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis Familial Disease/Known Genetic Defect Clinical and Laboratory Criteria (Five of Eight Criteria) Fever Splenomegaly Cytopenia 2 cell lines Hemoglobin ,90 g/L (below weeks ,120 µg/L) Platelets ,100 109/L Neutrophils ,1 109/L Hypertriglyceridemia or hypofibrinogenemia a Fasting triglycerides mmol/L b Fibrinogen ,1.5 g/L Ferritin 500 pg/L sCD25 2400 U/mL 10 Decreased or absent natural killer cell activity 11 Hemophagocytosis in bone marrow, cerebrospinal fluid, or lymph nodes CHAPTER 92 Hematology and Oncology Problems corticosteroids, cyclosporine A, or etoposide.52,57 Identification of infection or malignancy should prompt immediate treatment of the underlying disease Evidence of macrophage activation syndrome should prompt rheumatologic consultation Patients with primary HLH or underlying immunodeficiency may ultimately require stem cell transplantation Anthracycline-Induced Cardiac Dysfunction The anthracyclines—daunorubicin, doxorubicin, epirubicin, mitoxantrone, and idarubicin—are used for chemotherapy in a wide variety of solid tumor and hematopoietic malignancies of childhood Unfortunately, 15% of all pediatric cardiomyopathies occur in patients treated for childhood or adolescent malignancies.58 In one prospective study, 5% of children developed heart failure after anthracycline treatment, and 19% presented with abnormal left ventricular function.59 Shortening fractions declined proportionately to cumulative doses Furthermore, differential susceptibility to cardiotoxicity became apparent early in treatment Hence, patients at high risk for important anthracycline cardiotoxicity may be identifiable early in treatment by regular echocardiography Pediatric age and female gender are known risk factors for anthracycline cardiotoxicity Anthracycline-induced early-onset cardiotoxocity injury is a form of cardiotoxicity that may occur immediately after a single dose or after a course of anthracycline therapy, with clinical symptoms usually occurring within year of treatment.60 Acute cardiotoxicity ranges from relatively benign arrhythmias to serious conditions, such as fatal ventricular arrhythmias, myocardial ischemia/infarction, congestive heart failure, and cardiomyopathy A study by Getz et al found that more than 70% of cardiotoxicity events occurred during on-protocol therapy during a specific acute myeloid treatment protocol.61 The pathophysiology of anthracycline-induced cardiotoxicity may include free radical–mediated myocyte damage, adrenergic dysfunction, intracellular calcium overload, and release of cardiotoxic cytokines The myocardium appears susceptible to free radical damage from low levels of superoxide dismutase, catalase, and glutathione peroxidase activity Cardiac mitochondria contain a unique enzyme (reduced nicotinamide adenine dinucleotide dehydrogenase) in their inner membrane that reduces anthracyclines to their semiquinones, producing severe oxidative damage to mitochondrial DNA, reductions in cellular energy production, and myocyte apoptosis Prevention of cardiotoxicity remains the ultimate goal There is evidence that dexrazoxane reduces the cardiotoxicity associated with some anthracyclines without affecting the efficacy of anthracycline therapy.62 The antioxidant CoQ10 is an integral component of the mitochondrial respiratory chain and has successfully been used in the treatment of cardiac failure The outcome of anthracycline-induced cardiogenic shock during chemotherapy remains poor The myocardium has limited regeneration ability The mortality rate related to anthracyclineassociated heart failure is substantial Supportive treatment, including mechanical support (e.g., extracorporeal life support or ventricular assist devices), may stabilize patients while decisions about longer-term care can be made.63 Posterior Reversible Encephalopathy Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiographic syndrome that classically presents with clinical signs 1111 and symptoms of headache, visual acuity disturbances, abrupt changes in mental status, and seizures, with neuroimaging showing posterior white matter edema The reversible posterior leukoencephalopathy syndrome was initially characterized by Hinchey and colleagues in 1996 in a case series that included patients aged 15 to 62 years and was closely associated with hypertensive encephalopathy, preeclampsia/eclampsia, cyclosporine A neurotoxicity, and uremic encephalopathy.64 As more cases were reported and neuroimaging improved, the name PRES was introduced in 1999 by Casey as a better description of the syndrome because the radiographic lesions were not felt to be consistent with a leukoencephalopathy.65 Since the 1990s, PRES has become more clinically recognized in pediatric populations, especially in those pediatric populations who are exposed to immunomodulatory or cytotoxic therapy.66 Although the exact incidence of PRES is unknown, in the context of tacrolimus or cyclosporine A used after solid-organ transplant, PRES developed in 1% to 6% of all recipients The exact precipitating factor for PRES is unknown, but it is believed that the syndrome is associated with a disorder of cerebrovascular autoregulation likely from multiple etiologies It is believed that the severe hypertension or other causes of PRES disrupt cerebrovascular autoregulation, with a resulting leakage of fluid into brain parenchyma Compared with the carotid system, the vertebrobasilar system has fewer adrenergic innervations, which may make it more prone to disruption of its autoregulation This may explain the predominance of lesions in the posterior cerebral area seen in PRES Although lesions can be seen in the cortex, the cortex is thought to be more “resistant” to edema because it is structurally more tightly packed and thus most PRES lesions are seen in the white matter There is also a proposed direct cytotoxic effect of various chemotherapeutic and immunomodulatory agents on the vascular endothelium PRES is a clinicoradiographic syndrome without specific diagnostic criteria A high index of suspicion is required to help guide appropriate neuroimaging in a suggestive clinical context Whereas abnormalities consistent with PRES can be seen on CT scans, MRI, especially fluid-attenuated inversion recovery (FLAIR) sequences, are most sensitive for PRES lesions.67 MRI is also helpful in distinguishing PRES from ischemia and guiding appropriate therapy The treatment for PRES is mostly supportive, consisting of reducing hypertension, treating seizures, and withdrawing or reducing the dose of the offending agent It is important to distinguish PRES lesions from ischemia because PRES requires aggressive treatment of hypertension, whereas ischemia is permissive of mild to moderate hypertension The seizures associated with PRES usually respond well to benzodiazepines, but most case series report using multiple doses and sometimes requiring loading doses of another antiepileptic medication (e.g., phenytoin, phenobarbital) in order to break the seizure.66,67 Most patients require admission to a pediatric ICU for continued monitoring and optimization of support for vital functions Rarely, seizures associated with PRES require more aggressive antiepileptic medication in the context of status epilepticus Chimeric Antigen Receptor T Cell–Mediated Toxicity Clinical trials using T cell–engaging immunotherapies have shown significant promise to improve the survival of relapsed leukemia and lymphoma For pediatrics, chimeric antigen receptor modified T cells (CAR T cells) with specificity against CD19 have especially improved survival in relapsed pre–B-cell ALL.68,69 1112 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology This led to the US Food and Drug Administration approval of tisagenlecleucel (Kymriah) for patients up to age 25 years with relapsed or refractory B-cell ALL.70 This unique therapy, however, has unique toxicities Patients treated with CAR T cells experience a sudden increase in multiple cytokines as the T cells engage the immune system and eliminate leukemic cells This cytokine release syndrome (CRS), or cytokine storm, is defined as a disorder characterized by fever, nausea, headache, tachycardia, hypotension, rash, and shortness of breath caused by the release of cytokines from cells CRS reflects part of the efficacy of the CAR T-cell treatment However, it can become severe, affecting nearly every organ system—including fluid refractory hypotension, tachycardia, cardiomyopathy, acute respiratory failure, neurologic toxicity, and disseminated intravascular coagulation.71 The timing of symptom onset and CRS severity is likely dependent on tumor burden, baseline cytokine levels, and the underlying genetic predisposition of each patient Onset of CRS usually occurs days to as late as to weeks after the initial infusion and coincides with the maximal in vivo T-cell expansion.72 The manifestation of CRS in pediatric patients can mimic the clinical presentation of HLH/macrophage activation syndrome (MAS) with highly elevated serum ferritin, D-dimer, aminotransferases, lactate dehydrogenase, triglycerides, hypofibrinogenemia, and hepatosplenomegaly CRS occurs in about two-thirds of patients treated with CAR T cells.73 When the syndrome becomes severe or life threatening, inhibition of the inflammatory cascade outweighs further expansion of CAR T cells Cytokine levels drawn during CAR T-cell therapy indicate IL-6 as a central mediator of toxicity in CRS and have been shown to be a possible target for downregulating the inflammatory cascade.74 Tocilizumab is a humanized immunoglobulin antihuman IL-6 receptor monoclonal antibody approved for the treatment of rheumatoid arthritis,75 juvenile idiopathic arthritis,76 and polyarticular juvenile rheumatoid arthritis Clinical experience at several institutions conducting CAR T-cell trials has indicated that tocilizumab is an effective treatment for severe or life-threatening CRS.77 Initial dosing is mg/kg, which is administered over hour This dose can be repeated in 24 to 48 hours if clinical improvement does not occur Clinical response is usually seen within a few hours, with resolution of hypotension and fever allowing for weaning of supportive measures and vasopressors If clinical response is not achieved 24 to 48 hours after the administration of tocilizumab, another immunosuppressive agent, such as corticosteroids, should be considered Corticosteroids are usually avoided as first-line therapy due to their potential adverse effect on the antitumor activity of the CAR T cells Dosing and choice of corticosteroid can vary among patients, but an initial dose of methylprednisolone of mg/kg per day can be considered and then weaned with symptom resolution, with a preference of dexamethasone in patients experiencing neurotoxicity As more children are treated with highly active T-cell engaging therapies, critical care providers will continue to gain clinical experience with managing the toxicities of this novel treatment There is suggestion that earlier, during or after T-cell expansion, intervention with immunomodulatory agents may aid in the reduction of CRS severity.78 This must be further studied, however, as the continued challenge will be to limit the toxicity without interfering with the therapy’s efficacy Neurotoxicity is a separate but potentially serious complication of CAR T cells for which the pathophysiology is not completely understood It typically manifests days after CRS Initial symptoms include tremor, speech difficulties, dysgraphia, and lethargy Severity may progress to obtundation or coma within hours or days of initial presentation Clinical or subclinical seizures may also develop and, in rare cases, cerebral edema Supportive care along with prophylactic antiepileptic drugs should be considered along with corticosteroids when symptoms are felt to be a result of CAR T cells.79 Key References George JN, Nester CM Syndromes of thrombotic microangiopathy N Engl J Med 2014;371:654-666 Lee DW, Santomasso BD, Locke FL, et al ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells Biol Blood Marrow Transplant 2019;25(4): 625-638 Bergsten E, Horne A, Aricó M, et al Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study Blood 2017;130(25):2728-2738 The full reference list for this chapter is available at ExpertConsult.com e1 References Noronha SA Aplastic and hypoplastic anemias Pediatr Rev 2018;39(12):601-608 Valentine SL, Bembea MM, Muszynski JA Consensus recommendations for 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of 70 pediatric patients Pediatr Hematol Oncol 2003;20:457 ... Hematology and Oncology This led to the US Food and Drug Administration approval of tisagenlecleucel (Kymriah) for patients up to age 25 years with relapsed or refractory B-cell ALL.70 This unique therapy,... mg/kg, which is administered over hour This dose can be repeated in 24 to 48 hours if clinical improvement does not occur Clinical response is usually seen within a few hours, with resolution of... toxicities of this novel treatment There is suggestion that earlier, during or after T-cell expansion, intervention with immunomodulatory agents may aid in the reduction of CRS severity.78 This must