Hematology and Oncology in Children

Published on 22/03/2015 by admin

Last modified 22/04/2025

Print this page

This article have been viewed 1253 times

157 Hematology and Oncology in Children

This chapter is an overview of the main hematologic and oncologic problems that can be observed in the pediatric intensive care unit (PICU). Differences between critically ill children and adults are emphasized.

Hematology

Anemia

A normal decrease in the hemoglobin (Hb) level is observed during the first weeks of life because of a limited release of erythropoietin. For this reason, the normal range of Hb concentration changes with age: 18.5 ± 2.0 g/dL (mean ± 2 standard deviations) during the first week of life, 11.5 ± 1.2 g/dL at 2 months, 12.0 ± 0.7 g/dL at 12 months, 13.5 ± 1.0 g/dL at 9 years, and 14.0 ± 1.0 g/dL after 12 years of age.¹ Based on these ranges, anemia is observed in 33% of patients on admission to PICU, and an additional 41% become anemic during their PICU stay.²

The small total blood volume of neonates and children (e.g., about 240 mL in a 3-kg patient) makes blood loss from phlebotomy or procedures a major cause of anemia in PICU.² Other causes include hemorrhage, hemolysis (immunologic, infectious, microangiopathic, or toxic), and decreased production (invasion of the bone marrow, side effect of therapy, nutritional deficiency, blunted production of erythropoietin in response to hypoxia).³ Causes quite specific to pediatric practice include congenital anemias (e.g., sickle cell disease, thalassemia, Blackfan-Diamond disease), glucose-6-phosphate dehydrogenase deficiency, and metabolic disorders. Sickle cell disease merits specific comment.

Sickle Cell Disease

Many types of abnormal Hb are observed in sickle cell disease. However, only Hb SS (homozygous sickle cell Hb), Hb SC, and Hb S-β-thalassemia can cause severe clinical problems. Hypoxemia, acidosis, polycythemia, infection, and a high proportion of abnormal Hb concentration are the main risk factors for sickle cell disease complications. The following sickle cell crises can be life threatening: acute chest syndrome, stroke, acute splenic sequestration, aplastic crisis, and infection. General management always includes optimization of oxygenation, adequate analgesia, and treatment of the precipitating cause of the crisis.⁴ Hyperhydration is also recommended in most instances, but fluid requirements must be adapted with caution in patients with respiratory symptoms or pulmonary hypertension. Red blood cell (RBC) transfusion is a cornerstone of therapy, aiming to decrease abnormal Hb while maintaining hematocrit below 35%. An exchange transfusion should be considered in severe cases, especially in acute chest syndrome or stroke.

Acute chest syndrome is a leading cause of morbidity and mortality in sickle cell disease.^5,⁶ It is defined by the development of a new pulmonary alveolar infiltrate involving at least one complete lung segment, accompanied by fever, chest pain, tachypnea, cough, and hypoxia. Severe forms are analogous to acute respiratory distress syndrome. Acute chest syndrome results from intricate mechanisms including pulmonary infection (mostly by atypical bacteria and virus), fat embolization, and local vaso-occlusion.⁶ Perturbation of nitric oxide metabolism⁷ and hypercoagulability have also been demonstrated.⁶ Growing evidence suggests that pulmonary hypertension play a crucial role during sickle cell disease evolution, which may lead to abrupt severe right heart failure.⁶ Besides general management and empirical antibiotic therapy, covering atypical bacteria and Streptococcus pneumoniae, incentive spirometry is encouraged. Mechanical ventilation may be required to improve oxygenation; noninvasive ventilation can be successful.⁸ Owing to disturbance of nitric oxide metabolism, inhaled nitric oxide has been used in small trials or case reports, but its efficacy remains to be validated.⁹

Stroke must be considered in patients with sudden onset of neurologic symptoms. Specific management includes an urgent exchange transfusion and careful attention to neurologic worsening. Intracranial pressure monitoring can be helpful in severe stroke.

During acute splenic sequestration crisis, the blood volume retained in the spleen may lead to severe hypovolemic shock. An acute reduction of Hb concentration of 2 g/dL or more, with no other cause of blood loss, is considered diagnostic. Aplastic crisis can also cause an acute and severe anemia, usually during a viral infection, particularly with parvovirus B19. The half-life of RBCs is severely shortened in patients with sickle cell diseases, and a compensatory increase of RBC production occurs. During aplastic crisis, the reticulocyte count falls, causing rapid development of severe anemia. Mortality rates associated with both sequestration and aplastic crises are significant, and these conditions must be treated aggressively with volume administration and RBC transfusion.

Sickle cell disease can cause a functional asplenia with increased susceptibility to severe bacterial infections, especially with encapsulated organisms. An infection should therefore be suspected early and treated aggressively in patients with sickle cell disease.

Preventive measures must also be used if possible. In particular, patients with sickle cell disease should be monitored in the PICU after significant surgery—the goals being to prevent dehydration and hypoxemia, provide optimal analgesia, and maintain the hematocrit between 30% and 35%.

Red Blood Cell Transfusion

The management of anemia in critically ill patients is discussed in Chapters 19 and 150; this includes prevention of blood loss, transfusion of blood products, and administration of folic acid and iron. Prophylactic erythropoietin use has not been evaluated in large pediatric trials, but its utility appears questionable insofar as most RBC transfusions are received during the first few days after admission.^2,¹⁰

The risks and benefits of RBC transfusion are not similar in adults and children. Necrotizing enterocolitis in neonates ¹¹ or erythrocyte alloimmunization in young girls (up to 8% of patients)¹² are significant problems in pediatric patients. RBC transfusion to neonates increases the ratio of adult to fetal Hb, which decreases the affinity of blood for oxygen.¹³ Nevertheless, RBCs improve oxygen transport in critically ill children,¹⁴^–¹⁷ although the improvement in clinically significant outcomes remains to be determined. Large variation in transfusion practice was observed among pediatric intensivists,^18,¹⁹ reflecting the unidentified Hb threshold with the best risk/benefit ratio in critically ill children. Maintaining Hb above 5.0 g/dL in hospitalized pediatric patients decreases the risk of death.^20,²¹ In a large randomized clinical trial enrolling 637 patients in 19 PICUs, Lacroix et al.²² demonstrated that a transfusion strategy to maintain Hb above 7 g/dL was as safe as a strategy to maintain Hb above 9.5 g/dL in stable critically ill children. While the number of transfusions was much lower in the restrictive transfusion group, no difference was observed in mortality rate or occurrence of new organ dysfunction.²² These findings were not different in three planned a priori subgroup analyses of patients in sepsis,²³ in postsurgical patients,²⁴ or in patients admitted following cardiac surgery.²⁵ These data and the cohesiveness of all subgroup analyses strongly support limiting RBC transfusion to patients with Hb below 7.0 g/dL in stable conditions. More data are required to identify a threshold in patients with cardiorespiratory instability.

In pediatric patients, packed RBCs should be administered on a unit-by-unit basis to limit exposure to multiple donors. Packed RBCs are available in half-units (standard division) or in small units of 75 mL (Pedipak) for young children. Packed RBC units must be warmed to 37°C for infants or if the transfused volume exceeds 30% of blood volume.

Transfusion in the neonatal period, in children with immunodeficiency, or transfusion using blood donated by family members are situations at higher risk of transfusion-associated graft-versus-host disease ²⁶; irradiated packed RBCs should be used in these conditions.

Hemorrhagic Disorders

Disseminated intravascular coagulation (DIC) is the most frequent hemorrhagic disorder observed in the PICU. Its causes, pathophysiology, and treatment are similar to those in adults (see Chapter 21), even though purpura fulminans is more frequent in the PICU.

Severe hemorrhage can be caused by congenital deficiencies of coagulation factors, as in hemophilia A (factor VIII), hemophilia B (factor IX), or factor VII deficiency. Massive RBC transfusion is a frequent cause of coagulation factor deficiency, which should be anticipated and prevented. Acquired (dietary, antibiotics) vitamin K deficiency can also cause severe bleeding, especially in the neonatal period.

Thrombocytopenia in critically ill patients is related most often to sepsis, DIC, multiple organ dysfunction syndrome, or is drug-induced (see Chapter 20). Heparin-induced thrombocytopenia must also be considered. Immune-mediated thrombocytopenia in newborns can be secondary to alloimmunization or maternal disease (e.g., maternal lupus erythematosus). Idiopathic thrombocytopenic purpura is frequent in children, but it rarely causes severe bleeding. Patients with hemolytic uremic syndrome and thrombotic thrombocytopenic purpura mostly require PICU admission because of renal failure or central nervous system involvement, but significant hemorrhage can occur. In these conditions, platelet transfusion can accelerate microangiopathy and should therefore be avoided unless a significant bleeding is present.

Thrombosis and Emboli

Elsewhere in this book, there are chapters on pulmonary emboli (Chapter 62), thromboembolic diseases (Chapter 153), and their prophylaxis. Most thromboses observed in pediatric critically ill patients are acquired during the PICU stay. Catheter-related thrombosis is common, appearing rapidly after catheter insertion.²⁷ Heparin-coated catheters may prevent catheter-related thrombosis,²⁸ but their cost/benefit ratio and the risk of heparin-induced thrombopenia remains to be determined. DIC, allergy to heparin, prothrombic states (e.g., G20210A prothrombin gene mutation, factor V Leiden, anticardiolipin antibody, antithrombin III, or protein C deficiency), and blood flow stasis are common risk factors for thrombosis in children. The incidence of deep vein thrombosis is lower with peripherally inserted central catheters (PICC lines) than with centrally inserted catheters.²⁹

Cerebral venous sinus thrombosis and renal vein thrombosis are more frequent in children than in adults. Symptoms of cerebral venous sinus thrombosis include seizures, headache, coma, paresis, cranial nerve palsies, and increased intracranial pressure. Head and neck infections, connective tissue disorders, or prothrombic states are frequently associated.³⁰ Symptoms of neonatal renal vein thrombosis are acute renal insufficiency, hematuria, and hypernephrosis.

Immunodeficiency

A significant proportion of critically ill children are immunodeficient. Most cases of acquired immunodeficiency are caused by chemotherapy and immunosuppressive drugs, but any severe condition such as severe head trauma, sepsis, or burns can induce immunodeficiency. Congenital immunodeficiencies are also frequent in PICU. For example, a high prevalence of DiGeorge syndrome is observed among patients with congenital heart disease. As in adults, immunocompromised patients have an increased risk of contracting infections with unusual pathogens, in unusual sites, and with increased severity.

Oncology

The initial presentation of an undiagnosed cancer can occasionally represent an acute emergency requiring critical care, but in most cases, children with cancer are admitted to PICU owing to a complication of the malignancy or its treatment. Any organ or system can be involved. This section gives a brief overview of the most frequent cancers seen in critically ill children and describes the most frequent causes of system dysfunction encountered in such patients. Finally, some ethical considerations specific to these patients are presented.

Cancer in Children

The most frequent cancers in children are leukemias, lymphomas, neuroblastoma, Wilms’ tumor, central nervous system solid tumors, bone tumors, and soft-tissue cancers. Cancer patients may need a stay in a PICU for the following reasons: (1) need for close monitoring during or after a high-risk procedure, (2) life-threatening complications of a cancer (e.g., compression of airways), or (3) therapy-related complications. The prognosis of the patients in the first group is usually good. Most of the discussion in the subsequent sections involves the two other presentations.

Respiratory System

Causes of respiratory dysfunction in cancer patients include those observed in patients without cancer (see Chapters 58 and 72). However, many specific diseases merit comments.

Primary lung malignancy is rare in children (histiocytosis), but leukemia, lymphoma, and metastases (neuroblastoma, bone cancer, Wilms’ tumor) can invade the lungs. Airways can be obstructed, particularly by anterior mediastinal masses. In this situation, mostly observed in lymphomas, a rapid cardiorespiratory failure can be precipitated by a sedation or anesthesia. Such maneuvers should therefore be strictly avoided until the treatment induces regression of the compression.

Pediatric cancer patients frequently develop acute respiratory failure resulting from infections due to unusual pathogens and from noninfectious mechanisms: pulmonary edema, local treatment toxicity, graft-versus-host disease, bronchiolitis obliterans, alveolar hemorrhage. Invasive investigations should be discussed, such as bronchoalveolar lavage or lung biopsy, because identification of an atypical pathogen or a noninfectious cause can facilitate management. However, the risk of severe complications (death, barotrauma, hemorrhage) is high in the most severe patients,^31,³² and empirical treatment is frequently considered in the absence of diagnostic maneuvers.

Noninvasive mechanical ventilation is an effective means of preventing endotracheal intubation in pediatric immunocompromised patients with acute respiratory failure.³³ Patients who require intubation and invasive ventilation have a higher risk of death^33,³⁴; a lung-protective strategy should be applied (see Chapter 58).

Cardiovascular System

All types of shock can be observed in patients with malignancy, but sepsis is the leading cause of shock in pediatric cancer patients (see Chapter 130). Hemodynamic failure can also result from heart obstruction (e.g., mass in the auricula), extrinsic compression, pericardial effusion (inflammatory, hemorrhagic, or septic), infection or inflammation of cardiac structures (endocarditis, myocarditis, pericarditis), fibrotic restrictive myocarditis, or dysrhythmia induced by cardiac electrical system inflammation. Congestive heart failure may also be caused by chemotherapy, especially anthracycline and cyclophosphamide.

Arterial hypertension is a frequent side effect of cancer treatment. Severe hypertensive crisis can also result from malignant synthesis of sympathic mediators (neuroblastoma, Wilms’ tumor, and pheochromocytoma).

Neurologic System

Causes of seizures include mass effect, metastasis, infection, vasculitis, thrombosis, hemorrhage, adverse reaction to therapy, hyponatremia, hypocalcemia, and hypertensive crisis.

Intracranial hypertension can be caused by infection, hemorrhage, a volume-expanding tumor, or hydrocephalus due to an infratentorial tumor blocking spinal fluid flux.

Meningitis can be caused by the cancer itself or by an infectious process. Unusual organisms may be involved, such as Cryptococcus neoformans, Toxoplasma gondii, Listeria monocytogenes, and gram-negative rods.

Coma or paralysis can result from cerebral or spinal cord compression, ischemia, hemorrhage, or radiotherapy side effects. Opsoclonus, raccoon eyes, and Horner’s syndrome are suggestive of a neuroblastoma.

Digestive System

Stress gastritis, peptic ulcer, and upper gastrointestinal bleeding are frequent in the PICU in children with cancer. Bleeding from a digestive cancer is rare in children. Epstein-Barr virus, herpes simplex virus, or cytomegalovirus can cause hemorrhagic necrosis of the gastrointestinal tract and severe bleeding. Candida esophagitis is another cause of bleeding.

Typhlitis is an inflammation of the caecum and surrounding tissue, reported in 10% of leukemic patients at postmortem examination.³⁵ Usual clinical signs of abdominal inflammation can be absent in neutropenic patients; therefore, typhlitis must be feared in all patients with suspicion of infection. Abdominal computed tomography is a good diagnostic test for this condition. Secondary sepsis or bleeding is the usual cause of death.

Diarrhea is also frequent in this population. Clostridium difficile colitis must be suspected in patients who have recently received antibiotics (see Chapter 146). Gastroenteritis may be caused by unusual organisms such as Cryptosporidium.

Hepatic dysfunction can be caused by viral infection, drug toxicity (methotrexate), or veno-occlusive disease resulting from chemotherapy or radiation therapy. Severe hepatic veno-occlusive disease has a high mortality rate and should be aggressively managed. Treatment includes reduction of weight gain (diuretics, close fluid and electrolytes monitoring) and appropriate nutrition. Thrombolytic therapy or anticoagulation (antithrombin III) have been proposed but need to be evaluated.³⁶ Defibrotide also seems to be a promising adjunctive therapy which is under evaluation.^37,³⁸

Most cases of pancreatitis result from cytotoxic reactions to chemotherapy.

Renal System

Metabolic Problems

Electrolyte disorders are frequently observed. These disorders are discussed in Parts 1 and 6 of the text.

Lactic acidosis in critically ill patients is usually a consequence of cardiovascular dysfunction, sepsis, or multiple organ dysfunction. However, cancer with rapid and large turnover of malignant cells (e.g., leukemia, lymphoma) can be associated with lactic acidosis.^39,⁴⁰

Craniopharyngioma, some types of histiocytosis, and intracranial metastases can cause panhypopituitarism.

Anorexia, nausea, and vomiting are extremely frequent in this population, and malnutrition must be aggressively prevented. Enteral feeding should be attempted, but it is frequently limited by intolerance or abdominal complications. Therefore, parenteral nutrition is frequently required.

Fasting hypoglycemia is relatively frequent in this population. Severe hypoglycemia can also be the consequence of an insulinoma. Hyperglycemia is also frequent, and insulin therapy may be indicated to avoid limitation of caloric intake.

Steroids are part of many therapeutic protocols. Secondary adrenal insufficiency may appear if steroid treatment is inadvertently suspended.

Hematologic Problems

The proportion of cancer patients receiving chemotherapy who present with a significant hemorrhage is about 10%.⁴¹ Hemorrhagic risk is the consequence of multiple mechanisms: coagulopathy, thrombocytopenia, and treatment-induced tissue fragility.

Thrombosis is also a concern. Many cancers are associated with a hypercoagulable state. DIC, heparin-induced thrombocytopenia, and catheter-related thrombosis are frequent.

Bone marrow failure is extremely frequent in patients with cancer. It is an expected side effect of cytotoxic and radiation therapies, but it can also result from the cancer itself, infection, and many other causes. A reactive hemophagocytic syndrome can also occur in patients with severe multiple organ dysfunction syndrome.⁴²

The risk of infections particularly increases if the neutrophil count is lower than 1000/mm³. Various colony-stimulating factors (CSFs) such as granulocyte-macrophage CSF, granulocyte CSF, and macrophage-granulocyte inducer are frequently used to shorten neutropenia. However, the usefulness of these treatments on the number of transfusions required, incidence of infection, and survival rate remains to be established.^43,⁴⁴

Infectious Problems

Children with cancer must always be considered immunodeficient. Community-acquired pneumonia (Chapter 66), nosocomial pneumonia (Chapter 67), infections in the immunocompromised patient (Chapters 68 and 137), vascular catheter–related infections (Chapter 128), and prevention as well as control of nosocomial infection (Chapter 126) are of considerable importance in these patients.

Many symptoms anticipated in normal patients are attenuated in immunocompromised patients; an infection should therefore always be suspected early and checked for carefully. Aggressive empirical antibiotic treatment must be initiated as soon as an infection is suspected, and association with antifungal or antiviral agents should be discussed promptly.

Outcome and Ethical Considerations

The current consensus among PICU caregivers is that intensive care is inappropriate if the chance of short-term survival is poor because the patient is in the late stage of a chronic disease.^45,⁴⁶ However, over the last 2 decades, the outcomes of cancer patients requiring intensive care has largely improved (Table 157-1).⁴⁷ Oncologic patients admitted to PICU for severe sepsis have a survival rate similar to patients without cancer.^48,⁴⁹ The mortality rate remains high when the admission cause is acute respiratory failure, but more than half of patients will survive. The mortality risk is higher in patients with a history of hematopoietic stem cell transplant.⁴⁷ Various scores or indicators of severity at admission have been correlated with mortality, but no index is powerful enough to permit a decision on the futility of a PICU admission if the oncologic disease itself is controlled. Usually these patients should be admitted to PICU, and full efforts should be made in support of a curative goal. However, it is important to reevaluate the survival possibility after a few days of this “ICU trial,”⁵⁰ because mortality is highly correlated with the number of persistent organ dysfunctions after several days,⁵⁰^–⁵³ and the goal of care may sometimes be redirected to comfort care.

TABLE 157-1 Outcomes of Patients Admitted to the Pediatric Intensive Care Unit with Malignancy or Hematopoietic Stem Cell Transplant

End-of-life decisions (see Chapter 217) about patients with cancer or bone marrow transplant must be addressed by a multidisciplinary team including the patient when capable, family members, nurses, oncologists, and intensivists. It must be based on the chance of recovery from the acute disease, chance of survival from the underlying disease, quality of life before the acute problem, and the wishes of the patient and parents.⁵⁴