Page 872 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 68: Approach to Infection in Patients Receiving Cytotoxic Chemotherapy for Malignancy 603

intravenous bolus or as a continuous infusion at doses of 100 to 200 mg/m respectively, over the course of several cycles of treatment. Similarly,
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daily over 5 to 7 days (a “7 + 3” regimen). These regimens predictably between 15% and 26% of patients undergoing multiagent chemotherapy
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produce periods of profound myelosuppression, in which a median of for Hodgkin and non-Hodgkin lymphoma may develop a neutropenic
24 to 26 days passes until the circulating neutrophil count rises above fever over the course of therapy; however, the majority of such episodes
0.5 × 10 /L. 30-32 If more than one cycle of therapy is required to achieve occur within the first 1 to 2 cycles. Independent risk factors for neutro-
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a complete remission, then the median time until marrow recovery may penic fevers and for complications of neutropenic fevers (including pro-
be prolonged by as long as 40 days (range 33-60 days). This additional longed hospitalization, need for critical care services, and death) have
period of myelosuppression is associated with a significant increase in included advanced age (≥65 years), type of cancer, advanced cancer
infectious morbidity. 30,33 stage and large tumor burden, and increasing number of comorbid
Intensive regimens using high-dose cytarabine (HDARA-C) in doses conditions (including hypertension, chronic airflow obstruction, pneu-
15 to 30 times that for standard induction regimens have been successful monia, previous invasive fungal infection, and sepsis). 48,49
for salvage therapy of relapsed or resistant leukemia, for initial remis-
sion-induction therapy, and for post-remission consolidation therapy ■ NEUTROPENIC FEVER SYNDROMES PRESENTING
for acute leukemia. The median time until neutrophil recovery follow- TO THE EMERGENCY DEPARTMENT
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ing administration of HDARA-C (3.0 g/m infused over 1 hour every
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12 hours for 12 consecutive doses) is 28 days. Surprisingly, the overall The incidence of neutropenic fever presenting to the emergency depart-
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period of myelosuppression is not substantially longer than for standard ment (ED) is relatively uncommon. Even more uncommon is the
induction regimens. The time from day 1 of HDARA-C post-remission requirement for ICU services in this context. Among 777,876 ED visits in
consolidation until the development of severe neutropenia is a median 47 French hospitals over a 6-month period, only 198 (0.03%) satisfied the
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of 10 days (compared to a median of 4 days for primary induction with a case definition (ANC <0.5 × 10 /L and a core temperature >38.3°C) for
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“7 + 3” regimen). Accordingly, the overall duration of severe neutrope- neutropenic fever. Of these, patients with solid tumors accounted
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nia for patients receiving post-remission consolidation with HDARA-C for 56% and hematological malignancies for 44%. Severe sepsis or
may be shorter than for a “7 + 3” primary induction by 4 to 6 days. 30 septic shock was the presenting problem in the ED 89 of 198 patients
Patients undergoing hematopoietic stem cell transplantation are con- (45%). A total of 18 patients, 9% of the total group of febrile neutropenic
ditioned for the stem cell infusion through the administration of cyto- patients and 20% of the 89 presenting with severe sepsis or septic shock,
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toxic therapy alone or in conjunction with irradiation in an attempt to were admitted to the ICU. These observations suggest that almost half
reduce tumor burden and to suppress the host immune system in order (45%) of the cases of neutropenic fever present to the ED for care will
to permit stem cell engraftment. The intensities of the commonly used have potentially life-threatening severe neutropenic sepsis of which one
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conditioning regimens vary significantly and have differential impacts in five may require ICU admission.
upon the degree of tumor reduction, immunosuppression, toxicities, and The Multinational Association for Supportive Care in Cancer
treatment-related mortality. In the case of acute leukemia, increased con- (MASCC) developed and validated a scoring system to discriminate
ditioning intensity may reduce leukemia recurrence, but at the expense febrile neutropenic patients at high or low risk for medical complications
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of increased toxicity. In the case of allogeneic HSCT, a reduction that would either require hospitalization or prolong an admission. In
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in the intensity of the conditioning regimen not only reduces toxicities, one report, 85% of those patients defined by this scoring system as high
it reduces the anticancer cytoreductive effect; the anticancer effect must risk (score <21) also had medical complications sufficiently serious
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be derived from the graft-versus-tumor effect. Conventional myeloabla- to warrant ICU admission. The MASCC score is a useful tool for the
tive conditioning regimens are based on cyclophosphamide (Cy) plus identification of those febrile neutropenic patients who may be at greater
either busulfan (Bu) or total body irradiation (TBI), the so-called BuCy risk for complications that may require critical care services.
and CyTBI regimens. More recently, a reduced intensity approach based Hemodynamic instability during the evolution of the neutropenic
on fludarabine (Flu), an immunosuppressive antimetabolite, used with fever is one of the common reasons for ICU admission. Effective anti-
reduced doses of the alkylating agents Cy or Bu, or reduced doses of bacterial therapy within 1 hour of hypotension is associated with a
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TBI has become very widely used among transplant centers. The term, survival advantage among patients with septic shock. Among patients
myeloablative as applied to conditioning regimens in HSCT is defined with acute community-acquired pneumonia, initial antibacterial therapy
by the administration of cytotoxic agents in doses sufficient to preclude administered early in the ED (door-to-needle time, mean 3.5 ± 1.4 hours)
spontaneous autologous hematopoietic recovery. In contrast, the term rather than on an inpatient unit (door-to-needle time, 9.5 ± 3.0 hours)
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reduced intensity conditioning (RIC) is defined by the administration of was independently associated with a significantly shorter duration of
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cytotoxic agents in doses that produce prolonged but not irreversible hospitalization and a lower hospital-based all-cause mortality.
myelosuppression and cytopenia; however, stem cell support is required A wide range of times from triage in the ED to antimicrobial admin-
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in order to mitigate excess aplasia-related morbidity and mortality. In istration have been reported (102-254 minutes). Current guide-
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contrast to the classical myeloablative conditioning regimens, RIC con- lines recommend that antibacterial therapy be initiated early (within
46,51,65
ditioning regimens typically have dose reductions in the alkylating agent 60-120 minutes) in neutropenic patients presenting with severe sepsis.
with melphelan, busulfan, or thiotepa, or reduced dose TBI. The ■ OTHER IMMUNOSUPPRESSIVE EFFECTS OF CYTOTOXIC THERAPY
or the TBI of ≥30%. Examples of such regimens include Flu combined
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term nonmyeloablative conditioning is applied to a regimen that will The remission-induction regimens commonly used for acute leukemia
produce temporary hematopoietic suppression and minimal cytopenia have important immunosuppressive effects in addition to the myelo-
without the need for stem cell support. Examples of such regimens suppressive effects discussed above. Anthracyclines and similar agents
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include FluCy, TBI at a dose of 1 to 2 Gy, 42,43 antithymocyte globulin, (eg, doxorubicin, daunorubicin, idarubicin, epirubicin, amacrine,
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and total lymphoid irradiation (TLI). Basic understanding of the con- mitoxantrone, and rubidazone), antimetabolites (eg, cytarabine, meth-
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ditioning regimen can help predict the duration of myelosuppression otrexate, thioguanine, and mercaptopurine), and alkylating agents
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or the need for mechanical ventilation. 45 (eg, cyclophosphamide, ifosfamide, melphalan, busulfan, and platinum
Patients receiving less myelosuppressive treatments have a lower risk analogues) have profound suppressive effects on the numbers of circulat-
for severe neutropenia and neutropenic fever. Between 85% and 95% ing T- and B-lymphoid cells that parallel the acquired functional defects
of patients undergoing “7 + 3”-based AML treatments are expected in cell-mediated and humoral immune mechanisms. The consequences of
to develop neutropenic fever; whereas, approximately 1%, 4%, 5% to these effects are reflected by an increased susceptibility to pathogens nor-
6%, 10%, 12%, 23% of patients receiving standard cytotoxic regimens mally controlled by these mechanisms. The ultimate impact on immune
for prostate, breast, colorectal, lung, ovarian, and germ cell cancers, responsiveness appears to depend on the schedule of administration.
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