Management of Neutropenic Cancer Patients

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152 Management of Neutropenic Cancer Patients

Among patients with chemotherapy-induced neutropenia, 1% to 5% experience toxic side effects or infections and benefit from intensive care unit (ICU) management.¹ The outlook for cancer patients requiring ICU admission has long been considered dismal. Several recent studies have shown improved ICU outcomes in the overall population of patients with hematologic malignancies,²^–⁶ highlighting that it is no longer relevant to deny ICU admission to patients with neutropenia or after autologous bone marrow transplantation.^7,⁸^–¹³

Several factors have contributed to improving the survival of neutropenic cancer patients admitted to the ICU:

• Better selection of patients likely to benefit from ICU admission has been achieved via close cooperation between oncologists and intensivists.² Selection is based on clinical status of the patient and available treatment options for the malignancy. By working together, oncologists and intensivists can arrange for early ICU admission, before multiple organ failure develops.

• Overall survival has improved in recent years in patients with hematologic or solid malignancies. The reasons include the introduction of new treatments,¹⁴^–¹⁶ advances in the management of treatment side effects,^17,¹⁸ and development of new ways to use existing treatments.

• Advances have been made in the life-supporting treatments used to manage cancer patients in the ICU. Two studies have established the benefits of noninvasive mechanical ventilation, which was independently associated with better survival in patients requiring respiratory support.^3,¹⁹ Survival rates in patients with septic shock have climbed steadily over the years.²⁰ The diagnostic benefits provided by widespread use of bronchoalveolar lavage or noninvasive diagnostic strategies in ICU patients with acute respiratory failure²¹ have improved survival of cancer patients in this setting.²²^–²⁴

The prognosis of these neutropenic patients is determined by the number of organ failures at ICU admission. The proliferative potential and other characteristics of the underlying malignancy seem to have a far smaller impact on survival.²⁵^–²⁷ The general severity scores (Simplified Acute Physiology Score II and Acute Physiology and Chronic Health Evaluation II)²⁸ are of limited assistance for several reasons:

1 They are intended for evaluating patient groups and do not perform well in the individual patient.

2 Although they have been validated in cancer patients, their calibration and discrimination for predicting survival are poor in this subset of patients.

3 The prognosis in cancer patients admitted to the ICU is not related to physiologic variables, but rather to organ failures and organ support therapies that may be best described by organ failure scores. The number of organ failures at ICU admission and, to an even greater extent, the time course of organ failures during the first few ICU days govern the chances for survival.^7,²⁹

Finally, although bone marrow transplantation has been associated with a poor prognosis in many studies,^10,^30,³¹ these studies failed to separate autologous from allogeneic bone marrow transplant recipients or bone marrow transplant recipients from patients given “peripheral” hematopoietic stem cells (i.e., cells collected after mobilization out of the marrow). Allogeneic bone marrow transplant recipients who require ICU management have extremely high mortality rates,^32,³³ and mortality is highest when the need for life-supporting treatment arises late after the transplantation procedure.³¹ Allogeneic bone marrow transplantation differs from autologous bone marrow transplantation in important ways, including the risk of graft-versus-host disease and the intensity of the immunosuppressive treatment required for this complication.

Management of Neutropenic Cancer Patients in the Intensive Care Unit

Immunodeficiency

Vulnerability to infections occurs in cancer patients for several reasons. Neutropenia diminishes the ability to fight against infectious agents. Neutrophil counts less than 1000/mm³ are associated with a significant risk of infection, and the lower the count, the greater the risk.³⁴ Infections are far more likely to occur when counts fall below 500/mm³, and risk is even greater at neutrophil counts less than 100/mm³. The duration of neutropenia also influences the rate and the severity of infections.³⁵

Qualitative abnormalities in the functions of neutrophils, phagocytes, and lymphocytes contribute to the susceptibility of cancer patients to infection. An increased risk of infection by intracellular agents occurs in patients with hairy cell leukemia or T-cell acute lymphoblastic leukemia and in association with specific treatment agents.

Fever

Probabilistic antibiotic therapy should be given routinely if a fever develops. The antibiotics should be active against gram-positive cocci (e.g., streptococci infecting mucositis lesions or staphylococci in intravascular catheters) and gram-negative rods (enterobacteria or Pseudomonas aeruginosa) (Table 152-1). The Infectious Diseases Society of America (IDSA) has updated its recommendations.³⁶ A good first-line regimen in an ICU patient with prolonged neutropenia (as often occurs in hematologic malignancies) is a penicillin that is active against P. aeruginosa and gram-positive cocci, given either alone or in combination with an aminoglycoside or a fluoroquinolone active against P. aeruginosa. Although not given routinely, vancomycin is usually added. Indeed, many neutropenic ICU patients meet IDSA criteria for introducing a glycopeptide, including suspected catheter-associated infection, methicillin-resistant Staphylococcus aureus colonization, gram-positive cocci in blood cultures before identification of the organism, shock, and two situations associated with infection by gram-positive cocci—grade III or IV mucositis and abrupt body temperature elevation to greater than 40°C.³⁶ Fluconazole, 400 mg/d, as prophylactic treatment of fungal infections has been found to be beneficial only in allogeneic bone marrow transplant recipients.¹⁸ After 5 to 7 days with febrile neutropenia, the risk of fungal infection (not only with Candida but also with Aspergillus) is sufficiently high to warrant routine antifungal therapy in combination with antibacterial agents. In our ICU, we use amphotericin B as the first-line drug. Finally, the need for antiviral agents or trimethoprim-sulfamethoxazole should be evaluated on a case-by-case basis according to patient-related factors and the clinical picture.³⁶ Initiation of treatment for herpesvirus infection should be considered in all patients with grade III or IV mucositis.

TABLE 152-1 Clinical Sepsis with Bacterial Identification in the Saint-Louis Hospital Cohort*

When the organism is recovered and identified, antimicrobial therapy should be adjusted accordingly. ICU patients whose body temperature returns to normal on the third treatment day but who have negative tests for causative organisms should continue to receive antibiotics until their blood cell counts return to normal.³⁶

The source of infection should be looked for on chest radiographs, blood cultures, urine sediment and cultures, and stool cultures with tests for Clostridium difficile in patients with diarrhea or a high risk of infection with this agent (including patients with hematologic disease). The Herpes Consensus PCR (polymerase chain reaction) test and a serum Aspergillus antigen assay should be done once or twice a week in patients who have been neutropenic for longer than 1 week.

Hematopoietic Growth Factors

Among available hematopoietic growth factors, granulocyte colony-stimulating factor (G-CSF) is the most widely used in patients with hematologic or solid malignancies. G-CSF increases neutrophil counts and enhances neutrophil functions. In non-ICU patients, G-CSF has been shown to decrease the duration of neutropenia, reducing the rate of serious infections.^37,³⁸ G-CSF also decreased mortality related to bone marrow transplantation complications³⁹ or dose-intensive chemotherapy.⁴⁰

Intensivists and hematologists place considerable emphasis on correcting neutropenia. However, neutropenia recovery during the ICU stay was not associated with better survival in a study conducted at our institution.¹³ For instance, G-CSF therapy that was associated with more rapid recovery from neutropenia did not contribute to increased survival. Nevertheless, using a statistical model appropriate for the time dependency of neutropenia recovery contradicted two earlier studies in which G-CSF provided no benefit in ICU patients (Table 152-2).^41,⁴² G-CSF should be given to all neutropenic ICU patients in whom neutropenia recovery can be expected within 7 days.⁴³ Examination of a bone marrow smear may be more accurate for predicting the time to neutropenia recovery but is not performed routinely in patients given standard chemotherapy regimens. A bone marrow smear may be useful, however, after dose-intensive chemotherapy with bone marrow transplantation or after the first induction course for leukemia. G-CSF can stimulate the leukemic clone in patients receiving induction chemotherapy for acute leukemia and is contraindicated in this setting.

TABLE 152-2 Comparison of Studies Evaluating Impact of Colony-Stimulating Factors on Outcome of Neutropenic Patients in the ICU

In contrast, G-CSF is given to nearly every patient with Hodgkin’s or non-Hodgkin’s lymphoma. Close monitoring is needed in patients with respiratory symptoms or lung infiltrates, as respiratory failure may get worse at time of recovery from leukopenia. It is imperative that G-CSF be discontinued as soon as bone marrow function improves (neutrophils > 500/mm³).⁴⁴ G-CSF can be given intravenously or subcutaneously; in the ICU, the intravenous route is simplest. Dosages recommended for adults are 10 µg/kg/d for filgrastim and 150 µg/m²/d for lenograstim; however, the optimal dosages in ICU patients have not been determined. The drug is given as a single injection daily. No dosage adjustment is required in patients with kidney dysfunction. Blood cell counts should be obtained daily, and the G-CSF should be stopped as soon as the leukocyte count increases to greater than 1000/mm³ or the neutrophil count increases to greater than 500/mm³.

Isolation Modalities

Protective isolation involves reducing the patient’s exposure to potentially infective microorganisms via geographic and technical measures (routine use of nonsterile gloves, gown, head covering, mask, and in some cases, overshoes). Because the gut lumen is a reservoir for bacteria that can cause bacteremia, selective digestive decontamination (SDD) is often added to isolation measures. In our ICU, we use oral colimycin capsules and oral amphotericin B. Efficacy data on these regimens come from old and methodologically flawed studies that often produced conflicting results. No data are available on neutropenic ICU patients. Finally, there is a paucity of studies comparing isolation measures. A combination of geographic isolation with air filtering (laminar flow or high-efficiency particulate-arresting filters), technical isolation (usually involving use of a mask, head covering, and gown, although variations exist across studies), and SDD have been found to decrease the mortality rate or the infection rate in many prospective and retrospective studies.⁴⁵ Although the optimal modalities for protective isolation and their usefulness in the ICU have not been determined, a reasonable approach to the management of neutropenic ICU patients is maximal protective isolation, including geographic isolation with air filtration, technical isolation with at least a mask and gown, and SDD.

Specific Organ Failures

Acute Respiratory Failure

Together with circulatory shock, acute respiratory failure is the most common organ failure leading to ICU admission of neutropenic patients.²⁰ In these patients, acute respiratory failure often stems from a combination of factors that may be closely intertwined, such as infection and cardiogenic edema or alveolar hemorrhage. The causes of acute respiratory failure in cancer patients can be divided into infectious and noninfectious categories. At least three distinctive features characterize them:

1 In contradistinction to patients with human immunodeficiency virus-related conditions, only 50% of cancer patients derive diagnostic benefit from bronchoscopy with bronchoalveolar lavage (BAL), and the proportion is even smaller in case of neutropenia, bone marrow transplant, or mechanical ventilation.

2 Chances of survival are better when the cause is identified (allowing adjustments in management), a finding that has prompted BAL studies in patients managed with noninvasive mechanical ventilation or a laryngeal mask.²⁴

3 Noninvasive diagnostic tools are being developed (e.g., antigen assays in serum and urine and PCR testing for viruses) and, when incorporated into current diagnostic strategies, should enable the noninvasive diagnosis of opportunistic pneumonia,²¹ obviating the need for bronchoscopy and protecting the patient from the morbidity associated with this procedure.

Septic Shock

Survival rates in cancer patients with septic shock have increased over the years.⁷ Earlier treatment is one component. There is a need for studies evaluating the impact of new management strategies in these patients, who were excluded from large multicenter randomized studies.⁴⁶^–⁴⁸

Macrophage Activation Syndrome

Lymphohistiocytic activation syndrome is another name for macrophage activation syndrome, which may develop in a neutropenic patient or cause neutropenia. Multiple organ failure with vasoplegic shock may occur.⁴⁹ Fever, thrombocytopenia, and hepatosplenomegaly are almost universally present. Other manifestations include low counts of other cell lines, cholestasis with jaundice, high serum levels of ferritin and triglycerides, and low serum albumin and fibrinogen. Bone marrow smear findings are typical, with activated macrophages phagocytizing platelets, erythrocytes, and leukocytes, although false-positive results are encountered occasionally. Corticosteroids and etoposide are the mainstays of treatment and should be considered on an emergency basis.⁵⁰

Typhlitis or Neutropenia-Associated Enterocolitis

Typhlitis occurs chiefly after intensive chemotherapy and manifests as any combination of abdominal pain, fever, and diarrhea.^34,⁵¹ The protean nature of the manifestations raises diagnostic challenges. Typhlitis is probably a multifactorial condition related to chemotherapy-induced colonic mucosal damage, thrombopenia-related bleeding within the colonic wall, and bowel colonization by pathogenic microorganisms.⁵¹ Complications include bacteremia (28%-82% of cases), gastrointestinal bleeding (65% of cases), and gastrointestinal perforation (5%-10%).⁵² Ultrasonography or computed tomography (CT) of the gastrointestinal tract confirms the diagnosis and evaluates the severity of the disease. CT may show pneumoperitoneum or colonic pneumatosis, indicating severe parietal damage with imminent perforation. Bowel-wall thickening on ultrasound scan confirms the diagnosis.⁵³ In a retrospective study, bowel-wall thickening was significantly associated with a high mortality rate (29% versus 0%), especially when the bowel wall was thicker than 10 mm.⁵⁴ Conservative treatment should be used if possible, but surgery is required in patients with life-threatening gastrointestinal bleeding, perforation, or uncontrolled sepsis.⁵² A diagnosis of typhlitis requires prior elimination of other abdominal conditions, most notably classic surgical conditions and pseudomembranous colitis.⁵²