Page 1287 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

894 PART 7: Hematologic and Oncologic Disorders

one might think, the risk of neutropenia is greatest earlier in treatment ■ PULMONARY TOXICITY
(7-14 days). In retrospective studies as well as clinical trials, in 63% to Due to the lack of definitive diagnostic testing, nonspecific clinical find-
65% and 75% of hospitalizations, febrile neutropenia occurred within
the first two cycles of treatment for NHL and advanced breast carcinoma ings (dyspnea, hypoxemia, infiltrates), and significant overlap, diagnosing
pulmonary toxicity due to anticancer agents is challenging as is determin-
respectively. Late onset (>3-4 weeks after the last treatment) neutrope-
11
nia (LON) has been described in case reports following use of the mono- ing the incidence of complications due to particular agents. The mecha-
nisms by which chemotherapies can cause pulmonary toxicity include
clonal antibody rituximab. Wolach and colleagues presented a series of six
patients treated with rituximab as part of a regimen for DLBCL or follicu- direct damage to pneumocytes or alveolar capillary endothelium, immu-
nologic-mediated toxicity, and capillary leak. Any one or combination of
lar lymphoma who developed neutropenia anywhere from 42 to 168 days
after the last treatment. All but one of these cases was associated with at these mechanisms can lead to clinical manifestations such as interstitial
12
pneumonitis, hypersensitivity pneumonitis, noncardiogenic pulmonary
least one episode of febrile neutropenia. In their review of the literature,
they found an incidence range of 3% to 27% of late onset neutropenia edema, alveolar hemorrhage, BOOP, pleural effusions, bronchospasm,
and pulmonary venoocclusive disease. Depending on the severity of
16
associated with rituximab with a median onset of 38 to 175 days and dura-
tion of 5 to 77 days. Mortality rates associated with febrile neutropenia are the clinical findings, a diagnosis of ALI/ARDS may be met. Many pul-
monary manifestations secondary to chemotherapy are beyond the scope
8.4% and up to 13.2% in patients with hematologic cancers. 4
Neutropenia is also associated with dose reductions and treatment of a critical care–oriented text and will not be addressed; rather the focus
delays, potentially compromising desired goals of long-term survival in will be on agents with potentially life-threatening pulmonary toxicities.
patients being treated with curative intent. This has been supported by Hypersensitivity reactions in response to many chemotherapeutic infu-
sions may result in respiratory symptomatology, and will be discussed
studies demonstrating a direct relationship between dose intensity and
disease-free as well as overall survival. 13 later. In addition, complications due to underlying malignancy such as
infection and metastatic disease may coexist and confound the diagnosis
Use of granulocyte colony-stimulating factor has been shown to
both decrease nadir and duration of neutropenia if administered prior of treatment-induced lung disease.
Acute respiratory distress and failure can be caused by a number of
to its development. Hartman et al performed a randomized controlled
clinical trial, which found no benefit (decreased rate of hospitalization, anticancer therapies, and can be secondary to direct toxic drug effects or
secondary to other complications caused by treatment side effects such
LOS, duration of antibiotics, or culture positive infections) to treating
neutropenia with granulocyte colony-stimulating factor compared to as pancytopenia resulting in pulmonary hemorrhage and pneumonia, or
pulmonary edema due to fluid overload. These entities are particularly
placebo once it developed even though the median time to achieve
ANC greater than 500 cells/mL was 2 days shorter. Current recom- notable for patients being treated for hematologic malignancies. Ameri
14
et al performed a retrospective analysis at MD Anderson including over
mendations for use of granulocyte colony-stimulating factor are based
on patient’s risk factors for developing neutropenia (age ≥65; poor 1500 patients undergoing induction chemotherapy for AML or high-
risk MDS (typically with an anthracycline plus cytarabine) and found
performance status; existing cytopenia due to marrow involvement of
malignancy; serious comorbidities; concurrent radiation therapy; exten- an 8% incidence of acute respiratory failure requiring ventilator support
within 2 weeks of initiation of treatment. Seventy-three percent of
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sive prior chemotherapy; previous episode of febrile neutropenia; and
planned dose intensity >80%). 13 those patients who experienced respiratory failure died with a median
survival of 3 weeks, indicating substantial mortality associated with
Clinical practice guidelines for the management of febrile neutropenia
were most recently updated by the Infectious Disease Society of America the need for ventilatory support in this patient population. Significant
predictors of developing respiratory failure were identified and included
in 2010 and are summarized in Table 95-2. In addition to standard
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laboratory testing (CBC with differential, electrolytes, BUN/creatinine, poor performance status, infiltrates on presentation, renal insufficiency,
and male sex.
and LFTs), at least two sets of blood cultures are recommended, includ-
Direct injury to pneumocytes as well as the alveolar capillary endo-
ing samples from each lumen of an indwelling catheter and chest x-ray thelium and the resultant release of inflammatory mediators can result
and culture from other sites of suspected infection. Monotherapy with
an antipseudomonal β-lactam (cefepime), carbapenem (meropenem or in leaky capillaries and development of noncardiogenic pulmonary
edema severe enough to require mechanical ventilation. This so-called
imipenem-cilastatin), or piperacillin-tazobactam is an A-I recommen-
dation. Empiric vancomycin is not recommended (A-I) unless a specific capillary leak may also result from systemic cytokine release and resul-
tant immunologic-mediated toxicity to alveolar capillary endothelium.
clinical indication (catheter-related blood stream infection, skin-soft
Cytarabine at moderate and high doses used in leukemic patients
tissue infection, pneumonia, hemodynamic instability) is present and is well known for resulting in respiratory failure via noncardiogenic
should be discontinued if after 2 days there is no evidence of gram-
positive infection (A-II). In instances of suspected bacterial resistance, pulmonary edema (NCPE). Haupt et al was the first to report “massive”
and “moderate” pulmonary edema in 24% and 33%, respectively, of
empiric coverage may be modified (B-III). If fever or hemodynamic 18
instability persists, empiric antifungal coverage should be considered 181 leukemic patients on autopsy who received cytosine arabinoside. In
a more recent report and review performed by Kopterides et al, there is
(A-II). In cases where there is a documented infection (clinically or
microbiologically), the duration of treatment should continue until ANC an approximate incidence of NCPE resulting in respiratory failure of 11%
to 28% in leukemic patients treated with either induction or consolida-
≥500 cells/mL or as long as clinically necessary (B-III). In instances 19
where fever remains unexplained, the course should be continued tion chemotherapy consisting of cytarabine. Clinical findings typically
include low-grade fever, severe dyspnea, hypoxemia, and crackles on
until evidence of marrow recovery (ANC ≥500 cells/mL) (B-II).
TABLE 95-2 IDSA Treatment Guidelines for Febrile Neutropenia
Criteria High Risk (Any One) Empiric Treatment (Any One) Specific Additions to Treatment
Fever ≥38.3°C Anticipated neutropenia >7 days Piperacillin/tazobactam Vancomycin or linezolid for CRBSI, cellulitis, pneumonia, or hemodynamic instability
ANC ≤500 cells/mL Clinically unstable Carbapenem Aminoglycoside + carbapenem for pneumonia or gram-negative bacteremia
Any medical comorbidities Ceftazidime Metronidazole for abdominal symptoms or suspected C difficile infection
Cefepime Antifungal therapy (echinocandin, voriconazole, or amphotericin B) if hemodynamic
instability or fever persists (>4-7 days)

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