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doi:10.1093/annonc/mdq442
Published online 1 November 2010
review
Sepsis is a leading cause of mortality in neutropenic cancer patients. Early initiation of effective causative therapy as
well as intensive adjunctive therapy is mandatory to improve outcome. We give recommendations for the management
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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review Annals of Oncology
potentially reversible myocardial depression often prevents an These definitions do not allow precise staging or
adequate increase of cardiac output. This is thought to be prognostication of the host response to infection.
caused by myocardial depressant factors, such as toxins, While SIRS remains a useful concept, the diagnostic criteria for
cytokines, metabolic defects of myocytes and down-regulation SIRS published in 1992 are overly sensitive and nonspecific.
of beta-receptors (septic cardiomyopathy). Additional factors An expanded list of signs and symptoms of sepsis may better
are a decrease in preload induced by a change in ventricular reflect the clinical response to infection (Table 2) [14, 15].
compliance and a decrease in right ventricular venous retour
(venous pooling, volume deficiency by fluid sequestration). We suggest to use the diagnostic criteria for sepsis proposed by
Another important pathophysiological factor is a decrease in the SCCM, ESICM, ACCP, ATS and SIS adapted to
tissue oxygenation. Besides a restriction of global oxygen neutropenic patients (Table 2) [14, 15]. In neutropenic
transport (respiratory failure, decrease in cardiac output and patients, the white blood cell count (numbers of leukocytes)
anemia), inadequate regional oxygen supply due to perfusion cannot be used as criterion to define sepsis.
mismatch is possibly a critical factor [12]. The definitions of severe sepsis and septic shock remain
unchanged and refer to sepsis-induced organ dysfunction
(Table 3).
definition
A formal definition of sepsis has long been tried by several incidence
researchers and must lack specificity given the broad spectrum of
reactions to pathogens. The definition of sepsis suggested by the Prospective studies using the SCCM/ESICM/ACCP/ATS/SIS
consensus conference of the American College of Chest consensus definition in neutropenic patients are not available
Physicians and the Society of Critical Care Medicine (ACCP/ [14, 15]. However, it can be assumed that in >90% of febrile
SCCM) in 1992 [13] has been revisited in 2001 by several North neutropenic episodes sepsis may be diagnosed using the
American and European intensive care societies [SCCM, consensus definition according to SCCM/ESICM/ACCP/ATS/
Current concepts of sepsis, severe sepsis and septic shock General parameters
remain useful to clinicians and researchers. Fever (core temperature > 38.3C)
Hypothermia (core temperature < 36C)
Heart rate > 90 b.p.m. or > 2 SD above the normal value for age
Table 1. Categories of evidence used in this guideline [3] Tachypnea: > 30 b.p.m.
Altered mental status
Category Grade Definition Significant edema or positive fluid balance (>20 ml/kg over 24 h)
Strength of A Good evidence to support Hyperglycemia (plasma glucose > 110 mg/dl or 7.7 mM/l) in the absence
recommendation a recommendation for use of diabetes
B Moderate evidence to support Inflammatory parameters
a recommendation for use Plasma C-reactive protein or plasma procalcitonin > 2 SD above the
C Poor evidence to support normal value
a recommendation Hemodynamic parameters
D Moderate evidence to support Arterial hypotension (systolic blood pressure < 90 mmHg, mean arterial
a recommendation against use pressure < 70 or a systolic blood pressure decrease > 40 mmHg in
E Good evidence to support adults or < 2 SD below normal for age)
a recommendation against use Mixed venous oxygen saturation > 70%
Quality of evidence I Evidence from greater than or equal Cardiac index > 3.5 l/min/m2
to one properly randomized Organ dysfunction parameters
controlled trial Arterial hypoxemia (PaO2/FIO2 < 300)
II Evidence from greater than or equal Acute oliguria (urine output < 0.5 ml/kg/h or 45 mM/l for at least 2 h)
to one well-designed clinical trial, Creatinine increase ‡ 0.5 mg/dl
without randomization; from Coagulation abnormalities (international normalized ratio > 1.5 or
cohort or case-controlled analytic activated partial thromboplastin time > 60 s)
studies (preferably from greater Ileus (absent bowel sounds)
than or equal to one center); from Thrombocytopenia (platelet count < 100 000/ll)
multiple time-series or from Hyperbilirubinemia (plasma total bilirubin > 4 mg/dl or 70 mmol/l)
dramatic results from Tissue perfusion parameters
uncontrolled experiments Hyperlactatemia (>3 mmol/l)
III Evidence from opinions of respected Decreased capillary refill or mottling
authorities, based on clinical
In neutropenic patients the white blood cell count (numbers of leukocytes)
experience, descriptive studies or
cannot be used as criterion to define sepsis.
reports of expert committees
SD, standard deviation.
showed that during severe sepsis effective antimicrobial ‡ 70%), crystalloid fluids or colloids can be useful (AI) [46, 47].
administration within the first hour of documented Resuscitation with crystalloids requires more fluid volume
hypotension is associated with increased survival [40]. In this because of the larger volume of distribution. However, there is
study, each hour of delay in antimicrobial administration over no evidence-based support for the preferred use of colloids over
the ensuing 6 h was associated with an average decrease in crystalloids. A meta-analysis and a large multicenter trial
survival of 7.6% [40]. revealed a small absolute increase in the risk of renal failure and
Recommendations on antimicrobial treatment of infections mortality with the use of colloids over crystalloids [46, 47].
during neutropenia are given elsewhere [31, 32, 41]. Briefly, we Human albumin should not be used because in meta-analyses
recommend initial treatment with meropenem or with of randomized trials, the application of human albumin was
imipenem/cilastin or with piperacillin/tazobactam not associated with a favorable outcome even if administered in
monotherapy. Treatment with ceftazidim is an alternative patients with burns and hypoalbuminemia (DII) [48].
option. A combination treatment with an aminoglycoside has Treatment with volume substitution should be done under
not improved efficacy but increased renal toxicity [42, 43]. hemodynamic monitoring (central venous pressure, blood
However, in case of severe sepsis, a combination treatment with pressure, heart rate, cardiac output, pulmonary wedge pressure
aminoglycoside is carried out in many centers and is and lactate levels).
recommended by the European Organization for Research and If a sufficient mean arterial pressure (>65 mmHg) cannot be
Treatment of Cancer infectious disease group. If infection due achieved by volume substitution in a reasonable time frame,
to bacteria with frequent resistance to carbapenem or treatment with vasopressors is indicated. The drug of choice to
piperacillin/tazobactam is suspected, a specific antibiotic elevate the vasotonus is norepinephrine in a dose of 0.1–1.3 lg/
should be added (e.g. a glycopeptide in sepsis suspected to be kg/min (BII) [49]. This may also lead to an improvement in
central venous catheter related). Recommendations on renal function [50]. There is no evidence that increasing the
antifungal therapy during neutropenia were recently published mean arterial pressure to >85 mmHg by using high doses of
by the infectious disease working party of the German Society vasopressors, such as norepinephrine, has a positive impact on
0.93 [95% confidence interval (CI) 0.93–1.04] [88]. The pooled explaining the low mortality in this trial, and treatment was
RR for hypoglycemia with intensive insulin therapy was 6.0 discontinued immediately in case the partial thromboplastin
(95% CI 4.5–8.0). In addition, a recently published trial showed time rose >60 s. Under these conditions, the administration of
that intensive insulin therapy did not improve in hospital low-dose heparin was safe. Further trials including more
mortality, compared with conventional insulin therapy, among patients and better-defined subgroups, e.g. on the base of the
patients who were treated with hydrocortisone for septic APACHE II score, are needed before recommendations can be
shock [93]. Based on these data, we recommend to maintain made (CI).
blood glucose levels £8.3 mmol/l (150 mg/dl) in septic patients Antithrombin III (ATIII) exerts antithrombotic and anti-
(BIII). We do not recommend, however, intensive insulin inflammatory properties. The negative data from the KyberSept
therapy aiming at a strictly normal blood glucose level of 4.4– trial [105] have recently been confirmed by a Cochrane analysis
6.6 mmol/l (80–120 mg/dl) (EI). [106]. Subgroup analyses have shown that concomitant
Selenium exerts antioxidative effects. It has been proposed administration of heparin impairs beneficial effects of
that the substitution of selenium might positively influence the antithrombin, especially in patients with disseminated
outcome of patients suffering from sepsis. The per protocol intravascular coagulation [107–109]. No evidence-based
analysis of one small, randomized, placebo controlled clinical recommendation on the use of ATIII in severe sepsis can be
trial [94] showed a reduction in the 28-day mortality rate by made (CI).
the administration of high-dose selenium (1000 lg daily over In patients without thrombocytopenia, the use of
15 days, 42.4% in the treatment arm of the trial compared with recombinant human activated protein C (APC) is
56.7% in the placebo group, P = 0.049, odds ratio, 0.56; 95% CI recommended in patients with severe sepsis and septic shock
0.32–1.00). Further clinical trials are needed before treatment who have an APACHE II score of >25 or a minimum of two
with selenium can be recommended (CI). organs failing (AI) [110]. It is not recommended in patients
Replacement of an impaired adrenal reserve and anti- with an APACHE II score of <25 or one organ failure (EI)
inflammatory properties has been the rationale for studying [111]. The PROWESS trial was prematurely stopped because
Table 5. Summary of treatment recommendations given by the Infectious Diseases Working Party of the German Society of Hematology and Oncology
AGIHO, Arbeitsgemeinschaft Infektionen in der Hämatologie und Onkologie; APACHE II, Acute Physiology and Chronic Health Evaluation II; APC,
activated protein C; CPAP, continuous positive airway pressure; IBW, ideal bodyweight.
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