This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection.

/pdf/clinical-practice-guideline-for-the-use-of-antimicrobial-1cdrjevze2.pdf

Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Diseases Society of America

Disseminated intravascular coagulation is characterized by the widespread activation of coagulation, which results in the intravascular formation of fibrin and ultimately thrombotic occlusion of small and midsize vessels.1–3 Intravascular coagulation can also compromise the blood supply to organs and, in conjunction with hemodynamic and metabolic derangements, may contribute to the failure of multiple organs. At the same time, the use and subsequent depletion of platelets and coagulation proteins resulting from the ongoing coagulation may induce severe bleeding (Figure 1). Bleeding may be the presenting symptom in a patient with disseminated intravascular coagulation, a factor that can complicate decisions about . . .

Disseminated Intravascular Coagulation

ContextActivation of the coagulation system and depletion of endogenous anticoagulants
are frequently found in patients with severe sepsis and septic shock. Diffuse
microthrombus formation may induce organ dysfunction and lead to excess mortality
in septic shock. Antithrombin III may provide protection from multiorgan failure
and improve survival in severely ill patients.ObjectiveTo determine if high-dose antithrombin III (administered within 6 hours
of onset) would provide a survival advantage in patients with severe sepsis
and septic shock.Design and SettingDouble-blind, placebo-controlled, multicenter phase 3 clinical trial
in patients with severe sepsis (the KyberSept Trial) was conducted from March
1997 through January 2000.PatientsA total of 2314 adult patients were randomized into 2 equal groups of
1157 to receive either intravenous antithrombin III (30 000 IU in total
over 4 days) or a placebo (1% human albumin).Main Outcome MeasureAll-cause mortality 28 days after initiation of study medication.ResultsOverall mortality at 28 days in the antithrombin III treatment group
was 38.9% vs 38.7% in the placebo group (P = .94).
Secondary end points, including mortality at 56 and 90 days and survival time
in the intensive care unit, did not differ between the antithrombin III and
placebo groups. In the subgroup of patients who did not receive concomitant
heparin during the 4-day treatment phase (n = 698), the 28-day mortality was
nonsignificantly lower in the antithrombin III group (37.8%) than in the placebo
group (43.6%) (P = .08). This trend became significant
after 90 days (n = 686; 44.9% for antithrombin III group vs 52.5% for placebo
group; P = .03). In patients receiving antithrombin
III and concomitant heparin, a significantly increased bleeding incidence
was observed (23.8% for antithrombin III group vs 13.5% for placebo group; P<.001).ConclusionsHigh-dose antithrombin III therapy had no effect on 28-day all-cause
mortality in adult patients with severe sepsis and septic shock when administered
within 6 hours after the onset. High-dose antithrombin III was associated
with an increased risk of hemorrhage when administered with heparin. There
was some evidence to suggest a treatment benefit of antithrombin III in the
subgroup of patients not receiving concomitant heparin.

https://jamanetwork.com/journals/jama/articlepdf/194284/JCE10000.pdf

High-Dose Antithrombin III in Severe Sepsis: A Randomized Controlled Trial

https://journal.chestnet.org/article/S0012-3692(12)60137-8/pdf

Antithrombotic therapy in neonates and children: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

Statistical Methods in Medical Research.

Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients.

Variables of the fibrinolytic system were prospectively studied in patients with haematologic malignancies in chemotherapy-induced leukocytopenia at onset and during the course of septicemia to evaluate their prognostic value. This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective testing of fibrinolytic variables prior to and during evolving sepsis or septic shock. 62 patients with febrile infectious events were accrued to the study. Of these, 13 patients progressed to severe sepsis and an additional 13 patients to septic shock as defined according to standard diagnostic criteria. At onset of fever, plasminogen activator inhibitor (PAI) activity and PAI-1 antigen levels increased from normal baseline levels and were significantly higher in the group of patients who developed septic shock compared to those with severe sepsis (medians: 10.6 versus 1.3 U/ml, p = 0.0001; 50.0 versus 5.0 ng/ml, p = 0.0002). The increase in PAI activity and antigen in septic shock was accompanied by an increase in tissue-type plasminogen activator antigen and total fibrin(ogen) degradation products and a decrease in alpha(2)-antiplasmin activity (p 5 U/ml at onset of fever predicted a lethal outcome with a sensitivity of 92% and a specificity of 100%. Thus, septic shock in leukocytopenia is associated with significant activation of the fibrinolytic system presumably as a response of the vascular endothelium to inflammatory injury. Furthermore, PAI activity measurements are sensitive markers of an unfavourable prognosis.

Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis.

Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG—German Cancer Society)

Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using org 10172

Septic shock is the major cause of treatment-related death in patients with acute myelogenous leukaemia (AML) undergoing intensive chemotherapy. Interleukins (IL)-1 beta, -6, -8, and tumour necrosis factor alpha (TNF-alpha) have been implicated as mediators of septic shock, with circulating leucocytes being considered a major source for their release. However, plasma cytokine levels of leucocytopenic patients with evolving sepsis have not been studied. We have prospectively measured plasma cytokines during chemotherapy-induced leucocytopenia (< 1 x 10(9)/l) in 50 patients with AML. Cytokine levels in patients with severe sepsis (n = 5) or septic shock (n = 8) were compared to those measured in 13 matched patients with uncomplicated febrile infections. In evolving septic shock, IL-6, IL-8 and TNF-alpha peaked within 48 h of fever onset at levels reported for non-leucocytopenic patients and distinctively higher than during uncomplicated febrile episodes (P < 0.05). Peak concentrations measured within 48 h after onset of fever were related to fatal outcome. IL-1 beta was detected in less than 5% of all samples. Cytokine concentrations were unrelated to leucocyte counts and markers of neutrophil or monocyte activation (elastase and neopterin levels, respectively). We conclude that cytokine release associated with evolving septic shock in patients with AML does not depend on circulating leucocytes.

H. Ostermann

Papers

Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients.

Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis.

Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG—German Cancer Society)

Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using org 10172

Cytokine response to infection in patients with acute myelogenous leukaemia following intensive chemotherapy