Clinical research in febrile neutropenia in cancer patients: Past achievements and perspectives for the future

Febrile neutropenia (FN) is responsible for significant morbidity and mortality. It can also be the reason for delaying or changing potentially effective treatments and generates substantial costs. It has been recognized for more than 50 years that empirical administration of broad spectrum antibiotics to patients with FN was associated with much improved outcomes; that has become a paradigm of management. Increase in the incidence of microorganisms resistant to many antibiotics represents a challenge for the empirical antimicrobial treatment and is a reason why antibiotics should not be used for the prevention of neutropenia. Prevention of neutropenia is best performed with the use of granulocyte colony-stimulating factors (G-CSFs). Prophylactic administration of G-CSFs significantly reduces the risk of developing FN and consequently the complications linked to that condition; moreover, the administration of G-CSF is associated with few complications, most of which are not severe. The most common reason for not using G-CSF as a prophylaxis of FN is the relatively high cost. If FN occurs, in spite of prophylaxis, empirical therapy with broad spectrum antibiotics is mandatory. However it should be adjusted to the risk of complications as established by reliable predictive instruments such as the Multinational Association for Supportive Care in Cancer. Patients predicted at a low level of risk of serious complications, can generally be treated with orally administered antibiotics and as out-patients. Patients with a high risk of complications should be hospitalized and treated intravenously. A short period of time between the onset of FN and beginning of empirical therapy is crucial in those patients. Persisting fever in spite of antimicrobial therapy in neutropenic patients requires a special diagnostic attention, since invasive fungal infection is a possible cause for it and might require the use of empirical antifungal therapy.     

Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review

Neutropenia with fever (febrile neutropenia [FN]) is a serious consequence of myelosuppressive chemotherapy that usually results in hospitalization and the need for intravenous antibiotics. FN may result in dose reductions, delays, or even discontinuation of chemotherapy, which, in turn, may compromise patient outcomes. It is important to identify which patients are at high risk for developing FN so that patients can receive optimal chemotherapy while their risk for FN is appropriately managed. A systematic review of the literature was performed to gain a comprehensive and updated understanding of FN risk factors. Older age, poor performance status, advanced disease, certain comorbidities, low baseline blood cell counts, low body surface area/body mass index, treatment with myelosuppressive chemotherapies, and specific genetic polymorphisms correlated with the risk of developing FN. Albeit many studies have analyzed FN risk factors, there are several limitations, including the retrospective nature and small sample sizes of most studies.     

Arrhythmogene rechtsventrikuläre Kardiomyopathie

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically determined heart muscle disease and a major cause of sudden cardiac death and ventricular tachyarrhythmia in young, apparently healthy individuals and athletes. Patients affected by ARVC should be excluded from competitive sports and vigorous training. To provide optimal treatment, early diagnosis and risk stratification are mandatory and genetic counseling of families is recommended. Tailored treatment strategies aim at the prevention of ventricular tachyarrhythmia and sudden death as well as the preclusion of disease progression and symptomatic heart failure. Patients with a low risk of sudden death need either no specific treatment or can be treated with beta blockers or antiarrhythmic drugs, depending on the clinical manifestation of the arrhythmia. Catheter ablation in ARVC constitutes a symptom-oriented and palliative approach for frequently relapsing ventricular tachycardia refractory to antiarrhythmic medication. However, despite good acute results of catheter ablation, there is a high incidence of recurrence during long-term follow-up. In patients with ARVC at high risk of sudden death, implantation of an implantable cardioverter defibrillator (ICD) improves long-term survival by detection and termination of life-threatening ventricular arrhythmias. In the long term, however, the cumulative incidence of mainly lead-related complications of ICD therapy must be considered in the young population with ARVC, particularly when the indications are for primary prevention of sudden death or life-threatening arrhythmias. The proposed algorithm of therapeutic management in ARVC is under constant validation, development and refinement.     

Management of critically-ill cirrhotic patients

Cirrhotic patients are prone to develop life-threatening complications that require emergency care and ICU admission. They can present specific decompensations related to cirrhosis such as variceal bleeding and hepatorenal syndrome (HRS) or other critical events also observed in the general population such as severe sepsis or septic shock. Clinical management of all these entities requires a specific approach in cirrhosis. Cirrhotic patients have a hyperdynamic circulation with high cardiac output and low systemic vascular resistance in the absence of infection. Circulatory dysfunction increases the susceptibility of critically-ill cirrhotic patients to develop multiple organ failure and attenuates vascular reactivity to vasopressor drugs. HRS, a severe functional renal failure occurring in patients with advanced cirrhosis and ascites, is also secondary to this circulatory dysfunction that leads to an extreme renal vasoconstriction. Moreover, hypotensive cirrhotic patients require a carefully balanced replacement of volemia, since overtransfusion increases portal hypertension and the risk of variceal bleeding and undertransfusion causes tissue hypoperfusion which increases the risk of multiple organ failure. Cirrhotic patients are also at a high risk for development of other bleeding complications and are more susceptible to nosocomial infections. This extreme complexity of critically-ill cirrhotic patients requires a specific medical approach that should be known by general intensivists since it has a negative impact on patient prognosis. This review will focus on the diagnostic approach and treatment strategies currently recommended in the critical care management of patients with cirrhosis.     

Carotid Artery Stent Placement Prior to Coronary Angioplasty or Coronary Bypass Graft Surgery

Patients with concomitant carotid and coronary artery disease are at high risk of both cardiac and cerebrovascular complications when they undergo revascularization procedures. The best management strategies for patients with concomitant disease have not been determined for certain. Staged surgical procedures with either coronary artery bypass grafting prior to carotid endarterectomy or vice versa appear to be associated with an increased risk of ischemic complications compared to separate procedures. Until recently, there were no convincing data favoring a simultaneous or combined revascularization approach. Carotid artery stenting has emerged as a treatment option in patients with cerebrovascular disease, even in the presence of a high cardiac risk. Recent results in patients with severe concomitant coronary artery disease are encouraging. This report focuses on the treatment of severe carotid artery stenosis by stent implantation in patients with life-threatening comorbidity to emphasize the possibility of this endovascular approach as an alternative treatment option.     

Novel approaches for the treatment of ventricular tachycardia

Ventricular tachycardia(VT) is a crucial cause of sudden cardiac death(SCD) and a primary cause of mortality and morbidity in patients with structural cardiac disease. VT includes clinical disorders varying from benign to lifethreatening. Most life-threatening episodes are correlated with coronary artery disease, but the risk of SCD varies in certain populations, with various underlying heart conditions, specific family history, and genetic variants. The targets of VT management are symptom alleviation, improved quality of life, reduced implantable cardioverter defibrillator shocks, prevention of reduction of left ventricular function, reduced risk of SCD, and improved overall survival. Antiarrhythmic drug therapy and endocardial catheter ablation remains the cornerstone of guideline-endorsed VT treatment strategies in patients with structural cardiac abnormalities. Novel strategies such as epicardial ablation, surgical cryoablation, transcoronary alcohol ablation, pre-procedural imaging, and stereotactic ablative radiotherapy are an appealing area of res-earch. In this review, we gathered all recent advances in innovative therapies as well as experimental evidence focusing on different aspects of VT treatment that could be significant for future favorable clinical applications.     

„Standard operating procedures“ zur Diagnostik und Therapie des akuten Aortensyndroms

Acute aortic syndrome (AAS) describes a life threatening condition. Mortality rates in the initial phase remain high. Early diagnosis and therapy are essential to improving prognosis in these patients. Based on an advanced event-driven process chain (EPC) which addresses the diagnostic process as well as the therapy strategies for patients with AAS, standard operating procedures (SOPs) were developed. An estimation of pre-test risk of thoracic aortic dissection (AoD) is done by determination of risk factors that are associated with an AoD. Expedited aortic imaging is recommended to identify or exclude AoD in patients at high risk for the disease. For patients in the non-high risk group further diagnostic evaluation is necessary. In these patients a second risk-evaluation is done to indicate the need for urgent aortic imaging. After the diagnosis of an AoD could be made therapeutic strategies are based on the Stanford classification. AoD involving the ascending aorta (Stanford A) should be urgently evaluated for emergent surgical repair whereas AoD involving the descending aorta (Stanford B) should be managed medically unless life-threatening complications develop.     

Management of Acute Renal Dysfunction in Sepsis

Acute kidney injury (AKI) often complicates sepsis, leading to greater complexity and a worsening prognosis. Advances in the clinical management of sepsis may have secondary benefits with respect to renal outcomes. In critically ill patients, this disorder typically produces multiple organ dysfunction. Among the several disorders encountered in sepsis, AKI is one of the most important because it is a life-threatening condition, increases the complexity and cost of care, and is an independent risk factor for mortality. The potential interventions in sepsis-related AKI consist of effective prevention/protection strategies for the kidney in patients at risk, early recognition and attenuation of renal damage, pathophysiology-driven pharmacologic support, efficient extracorporeal blood purification therapy, and strategies that promote recovery of renal function. Existing and hybrid extracorporeal therapies are being investigated not only as means to replace lost kidney function, but also to modulate the immune response to sepsis.     

Effets indésirables métaboliques et cardiovasculaires des corticothérapies systémiques

Diabetes, dyslipidemia, hypertension, weight gain, lipodystrophy and cardiovascular events are well-known adverse events of systemic glucocorticoid therapy. Despite their frequency and their life-threatening consequences, there are few, and sometimes discordant, available data. Incidence of and risk factors for dyslipidemia, weight gain and lipodystrophy are for instance imperfectly known. The optimal pharmacological management of patients with glucocorticoid-induced diabetes or hypertension is uncertain. Lastly, the strategies for screening and prevention of these adverse events depend on physicians’ habits since no consensus is available. Some of these questions can be answered by looking at available data in patients with endogenous hypercorticism.     

Triaging in pulmonary embolism

Risk stratification of patients with pulmonary embolism represents an important step and may help to guide initial therapeutic management. Pulmonary embolism can be stratified into several groups, with different risk of early death or complications based on the presence of several risk factors. High-risk pulmonary embolism is defined by shock or peripheral signs of hypoperfusion. It is a life-threatening emergency with high short-term mortality (>25%) requiring specific therapeutic strategy with inotropic agents and fibrinolysis. In normotensive patients with pulmonary embolism, the presence of right ventricular dysfunction assessed by echocardiography or myocardial injury based on elevated levels of biomarkers, is associated with an intermediate risk of early death. These patients require close monitoring, and the role of thrombolytic treatment is currently assessed in a large trial. Lastly, patients with normotensive pulmonary embolism and without right ventricular dysfunction or myocardial injury have a low risk of death and complications. These patients may be candidates for home treatment. Several scores combining these risk factors have been described.     

Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study

Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0–3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required.     

Targeting treatment for optimal outcome

Rapid assessment of patients presenting with acute chest pain is essential, in order to distinguish between those who have a life-threatening condition, such as myocardial infarction or unstable angina, and the substantial proportion who do not have an acute coronary syndrome. It is thus of vital importance that reliable techniques are available to facilitate rapid risk stratification, as an aid to both clinical diagnosis and management strategy decisions. Assessments based on clinical findings, electrocardiographic monitoring, symptom-limited exercise testing, and biochemical marker measurements, used either singly or in various combinations, can fulfill this role. The present paper reviews some of the recent data that demonstrate the value of these techniques. Very few studies allow conclusions to be drawn about optimal treatment strategies in relation to groups stratified according to prognostic markers, and the question of whether intense medical treatment or early invasive intervention is most beneficial is one that clinical trials have yet to address adequately. In the recently completed Fragmin and Fast Revascularization during InStability in Coronary artery disease (FRISC II) study, comparisons were made of clinical outcomes achieved with early invasive versus noninvasive (i.e., medical) management strategies, and with short-term versus prolonged anticoagulation with dalteparin sodium (Fragmin), in patients with unstable coronary artery disease. All study participants underwent symptom-limited exercise testing and provided blood sample for measurements of biochemical markers; continuous electrocardiography monitoring and echocardiography were also performed in a high proportion of patients. Data from the FRISC II trial thus shed further light on the issue of risk stratification and its use to determine optimal treatment strategies.     

Use of risk stratification to identify patients with unstable angina likeliest to benefit from an invasive versus conservative management strategy

OBJECTIVES: This study was designed to determine whether patient characteristics collected at presentation can identify which patients benefit from immediate coronary angiography and revascularization. BACKGROUND: Risk stratification may offer a method for identifying which patients with unstable angina or non-Q-wave myocardial infarction (NQMI) are likeliest to benefit from invasive management strategies. METHODS: The analysis was based on data from a randomized controlled trial that enrolled 1,473 patients presenting with unstable angina or NQMI who were randomly assigned to an early invasive or early conservative (medical) management strategy. We constructed a risk-stratification score for each patient based on adjusted odds ratios for clinical variables likely to predict adverse outcomes. We stratified all trial subjects by their risk scores and studied the rates of death or myocardial infarction (MI) of the early invasive management strategy in each stratum. RESULTS: The final multivariate model included older age, ST segment depression on presentation, history of complicated angina before presentation, and elevation in baseline creatine kinase-MB fraction. Although patients with a higher risk score had an increased rate of death or MI within 42 days and 365 days (p < 0.001) in both management strategies, early invasive management for patients in the high and very high risk categories was associated with a lower rate of death or MI within 42 days compared with conservative management. No such benefit was seen in patients in the larger group of patients in the very low, low or moderate risk categories (p = 0.03 for the interaction between risk category and management assignment). CONCLUSIONS: Risk stratification may be an effective method for identifying those patients with unstable angina or NQMI most likely to benefit from early invasive management. Selective use of early invasive management can have a substantial impact in reducing morbidity and mortality in higher risk patients, but may not be warranted in lower risk patients.     

Canadian clinical practice guidelines for invasive candidiasis in adults

Candidemia and invasive candidiasis (C/IC) are life-threatening opportunistic infections that add excess morbidity, mortality and cost to the management of patients with a range of potentially curable underlying conditions. The Association of Medical Microbiology and Infectious Disease Canada developed evidence-based guidelines for the approach to the diagnosis and management of these infections in the ever-increasing population of at-risk adult patients in the health care system. Over the past few years, a new and broader understanding of the epidemiology and pathogenesis of C/IC has emerged and has been coupled with the availability of new antifungal agents and defined strategies for targeting groups at risk including, but not limited to, acute leukemia patients, hematopoietic stem cell transplants and solid organ transplants, and critical care unit patients. Accordingly, these guidelines have focused on patients at risk for C/IC, and on approaches of prevention, early therapy for suspected but unproven infection, and targeted therapy for probable and proven infection.     

Diagnostic performance of serum high-sensitivity procalcitonin and serum C-reactive protein tests for detecting bacterial infection in febrile neutropenia

Purpose

Although a few prospective studies have addressed the question as to which biomarker of infection in adult patients with febrile neutropenia (FN) is superior, procalcitonin (PCT) or C-reactive protein (CRP), the results have been inconsistent and inconclusive. This was possibly due to the poor sensitivity of previous PCT tests that have a functional sensitivity of 0.5 ng/ml.

Methods

Between November 2010 and February 2012, we prospectively compared the diagnostic utility of serum high-sensitivity (hs) PCT (lower limit of detection, 0.02 ng/ml) and CRP levels for detecting bacterial infection in patients with FN. Serum was collected within 72 h after the onset of FN in patients with hematological disorders.

Results

Seventy-five febrile episodes were evaluable. The areas under the receiver operating characteristic curves for life-threatening infection defined as septic shock and bacteremia caused by non-coagulase negative staphylococcus were 0.824 (95 % CI 0.711–0.937; P = 0.001) for hsPCT and 0.673 (0.505–0.842; P = 0.068) for CRP, respectively. In contrast, CRP, but not hsPCT, tended to increase significantly with the clinical severity, as indicated by the diagnostic classification (P = 0.002 for trend).

Conclusions

The serum hsPCT test may be more useful than the serum CRP test in the detection of life-threatening infection at an early phase after the onset of FN. In contrast, the serum CRP test may be more useful in diagnosing the severity of infection. However, neither of these tests was able to differentiate the cause of FN with a low probability of fatal outcome.     

Bronchoscopy-guided topical hemostatic tamponade therapy for the management of life-threatening hemoptysis

STUDY OBJECTIVES: Massive hemoptysis is a life-threatening condition. Therapeutic strategies such as interventional angiography, surgery, and/or bronchoscopy have been applied in the clinical setting with variable results. We investigated the efficacy of bronchoscopy-guided topical hemostatic tamponade therapy (THT) using oxidized regenerated cellulose (ORC) mesh in the management of life-threatening hemoptysis. DESIGN: Seventy-six consecutive patients underwent emergency bronchoscopy for massive hemoptysis. Fifty-seven patients (75%) had persistent endobronchial bleeding despite bronchoscopic wedging technique, cold saline solution lavage, and instillation of regional vasoconstrictors. These patients subsequently underwent THT according to the same procedure. SETTING: Teaching hospital, bronchoscopy unit of a 300-bed tertiary pulmonary referral center. RESULTS: THT with ORC was successfully performed on 56 of 57 patients (98%) with an immediate arrest of hemoptysis. All patients successfully treated with THT remained free of hemoptysis for the first 48 h. None required intensive care support or immediate surgery. Mean procedure time (+/- SD) of THT was 11.5 +/- 4.2 min. Recurrence of hemoptysis that was characterized as being mild (< 30 mL) to moderate (30 to 100 mL) developed in six patients (10.5%) 3 to 6 days after THT. Post-obstructive pneumonia developed in five subjects (9%) after endoscopic THT. A subgroup of patients (n = 14) underwent bronchoscopic follow-up 4 weeks after discharge. The ORC mesh was absorbed in all of these patients without signs of foreign body reaction. CONCLUSIONS: Endobronchial THT using ORC is a safe and practicable technique in the management of life-threatening hemoptysis with a high success and a relatively low complication rate.     

The role of budesonide/formoterol for maintenance and relief in the management of asthma

The aim of asthma management is to gain and maintain asthma control and reduce the risk of future exacerbations. However, despite the availability of effective therapies and national and international guidelines for their use, many patients remain inadequately controlled and continue to endure and accept a reduced quality of life. This review discusses current challenges in asthma management facing primary care physicians and provides insight into new treatment strategies developed to improve asthma control. A web-based literature review was undertaken with a focus on studies and reviews discussing asthma control and management with traditional therapies and new therapies, including a novel treatment approach using budesonide/formoterol maintenance and reliever therapy.One of the most common problems in long-term asthma control is poor adherence to inhaled corticosteroid (ICS) maintenance therapy, resulting in under-treatment of inflammation. Many patients tend to over-rely on short-acting β₂-agonist medication for quick relief of symptoms at the expense of ICS therapy, thus lowering anti-inflammatory protection and increasing the propensity for the development of severe and potentially life-threatening exacerbations. New simplified treatment strategies have been investigated with the aim of overcoming many of these primary care challenges, ultimately improving asthma control and reducing the future risk of exacerbations.     

Early infection in bone marrow transplantation: quantitative study of clinical factors that affect risk.

Infections remain common life-threatening complications of bone marrow transplantation. To examine clinical factors that affect infection risk, we retrospectively studied patients who received bone marrow transplants (53 autologous and 51 allogeneic). Over a median of 27 hospital days, 44 patients developed documented infections. Both autologous transplantation and hematopoietic growth factor use were associated with less prolonged neutropenia and decreased occurrence of infection (P < or = .05). In a survival regression model, variables independently associated with infection risk were the log10 of the neutrophil count (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.32-0.75), ciprofloxacin prophylaxis (HR, 0.42; 95% CI, 0.19-0.95), empirical intravenous antibiotic use (HR, 0.09; 95% CI, 0.03-0.32), and an interaction between neutrophil count and intravenous antibiotic use (HR, 1.86; 95% CI, 1.06-3.29). In this model, infection risk increases steeply at low neutrophil counts for patients receiving no antibiotic therapy. Ciprofloxacin prophylaxis and particularly intravenous antibiotic therapy provide substantial protection at low neutrophil counts. These results can be used to model management strategies for transplant recipients.     

Unterbrechung antithrombotischer Behandlung (Bridging) bei kardialen Erkrankungen

In patients who need antithrombotic therapy for cardiovascular diseases (anticoagulants or antiplatelet therapy) perioperative consideration of the bridging strategy is mandatory. The risks of thromboembolism and bleeding have to be taken into account. Periprocedural management depends on the urgency of the procedure. In emergency cases the operation has to be done in spite of antithrombotic therapy. In patients who need antithrombotics only for a limited period of time, an elective procedure could be performed after the time of anticoagulation or dual antiplatelet therapy. If heart valve replacement or coronary stenting is performed in a patient with known future need of an elective procedure, devices should be preferred for implantation which need antithrombotics only for a short time post implantation. In all other cases the risk of bleeding and the risk of thromboembolism should be balanced: In patients at low risk for a thromboembolic event, cessation of effective antithrombotic therapy is reasonable. However, patients with intermediate to high risk for thromboembolic events need specific bridging treatment depending on the risk of bleeding. Continuation of antithrombotics often increases just the risk of mild to intermediate bleeding, but it prevents occurrence of life-threatening thromboembolic events. For optimal periprocedural treatment of patients on anticoagulants or antiplatelet therapy cooperation of the medical disciplines involved is mandatory.     

Management of the patient with the Wolff-Parkinson-White syndrome

Patients with ventricular preexcitation may have symptomatic arrhythmias (Wolff-Parkinson-White syndrome) which can range from life-threatening, to disabling symptoms or minimal symptoms. Individuals may also be entirely asymptomatic. A rational approach to the management of these individuals is therefore dependent on the clinical circumstances. This review discusses the value and limitations of some of the available noninvasive and invasive investigations which may contribute to the successful management of these patients. In general, investigations are useful for establishing the diagnosis, identifying those patients at risk from life-threatening arrhythmias and providing a rational basis for therapy. The available pharmacologic and nonpharmacologic therapeutic options are discussed.