review Annals of Oncology 22: 1019–1029, 2011

doi:10.1093/annonc/mdq442
Published online 1 November 2010

Management of sepsis in neutropenic patients:

guidelines from the infectious diseases working party of
the German Society of Hematology and Oncology
O. Penack1*, D. Buchheidt2, M. Christopeit3, M. von Lilienfeld-Toal4, G. Massenkeil5,
M. Hentrich6, H. Salwender7, H.-H. Wolf3 & H. Ostermann8
1
Department of Hematology and Oncology, Charité Campus Benjamin Franklin, Berlin; 2Third Department of Internal Medicine, University Medical Centre Mannheim,
University of Heidelberg, Heidelberg; 3Department of Internal Medicine IV, Oncology and Hematology, University Hospital of Martin-Luther-University, Halle (Saale);
4
Department of Haematology and Oncology, University of Bonn, Bonn; 5Second Department of Internal Medicine, Hospital Gütersloh, Gütersloh; 6Department of
Hematology, Oncology and Palliative Care, Harlaching Hospital, Munich; 7Department of Haematology and Oncology, Asklepios Hospital Altona, Hamburg; 8Third
Department of Internal Medicine, Ludwig-Maximilians University, Munich, Germany

Received 18 February 2010; revised 4 May 2010; accepted 9 July 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

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of adults with neutropenia and sepsis. The guidelines are written for clinicians involved in care of cancer patients and
focus on pathophysiology, diagnosis and treatment of sepsis during neutropenia.
Key words: guideline, management, neutropenia, sepsis

introduction reviewed by the review committee of the Infectious Diseases

Patients with hematologic malignancies or solid tumors
undergoing intensive cytotoxic chemotherapy causing long-
term granulocytopenia are at high risk of infectious
complications [1]. Sepsis is a frequent syndrome caused by
serious infections in this patient population and remains
a leading cause of nonrelapse mortality [2]. Therefore,
optimization of diagnosis and management of sepsis could
improve outcome of intensive cytotoxic therapies. These
guidelines were written to provide guidance on diagnosis and
management of sepsis in the neutropenic host. First, a panel of
eight experts in the field of infectious diseases in Hematology
and Oncology systematically searched Medline for English
language publications up to June 2009 using the key term
‘sepsis’ and one of the following: ‘neutropenia’, bloodstream
infection, pathophysiology, definition, epidemiology,
incidence, risk factors, prognosis, treatment, antibiotic,
antifungal, cardiovascular, pulmonary failure, ventilation, renal
dysfunction, renal failure, dialysis, hemofiltration, nutrition,
hyperglycemia, steroid, coagulation, growth factor,
immunoglobulin and transfusion. Meeting abstracts were not
included; however, references generated from published
guidelines and reviews were also investigated. The consensus
process was carried out as an e-mail and meeting based
discussion group. In a second step, the panelists draft was peer
*Correspondence to: Dr O. Penack, Department of Hematology and Oncology, Charité
Campus Benjamin Franklin, Hindenburgdamm 30/31, 12200 Berlin, Germany.
Tel: +49-8445-4504; Fax: +49-8445-4468; E-mail: olaf.penack@charite.de
Working Party of the German Society of Hematology and
Oncology on 2 October 2009. In a third step, the guideline was
approved by the assembly of the members on 22 January 2010.
Criteria used to quote levels and grades of evidence are as
outlined in Table 1 [3].
A number of prior guidelines on the management of sepsis
have been published [4–9]; however, none of these guidelines
specifically addresses diagnosis and management of sepsis in
neutropenic patients.
pathophysiology
Sepsis is a systemic inflammatory response syndrome (SIRS)
that is characterized by widespread tissue injury often due to
severe infection. Pathogens or microbial associated molecules
(pathogen-associated molecular patterns) cause tissue damage
and inflammatory reactions. Organ dysfunction results from
direct cytotoxic effects of inflammatory mediators and
microbial toxins as well as from dysregulation of
microcirculation and macrocirculation, oxygen transport and
tissue oxygenation. Recruitment of inflammatory cells,
endothelial damage and activation of endothelial cells leading
to increased permeability of the vessel wall appear to be
additional factors contributing to organ dysfunction [10, 11].
Interstitial edema, capillary microembolization or
microthrombi and loss of regulation of the microvascular blood
flow lead to perfusion mismatch with a decrease in peripheral
vascular resistance. The decrease in vascular resistance is
partially compensated by an increase in heart frequency but

ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
review Annals of Oncology

potentially reversible myocardial depression often prevents an
adequate increase of cardiac output. This is thought to be
caused by myocardial depressant factors, such as toxins,
cytokines, metabolic defects of myocytes and down-regulation
of beta-receptors (septic cardiomyopathy). Additional factors
are a decrease in preload induced by a change in ventricular
compliance and a decrease in right ventricular venous retour
(venous pooling, volume deficiency by fluid sequestration).
Another important pathophysiological factor is a decrease in
tissue oxygenation. Besides a restriction of global oxygen
transport (respiratory failure, decrease in cardiac output and
anemia), inadequate regional oxygen supply due to perfusion
mismatch is possibly a critical factor [12].
definition
A formal definition of sepsis has long been tried by several
researchers and must lack specificity given the broad spectrum of
reactions to pathogens. The definition of sepsis suggested by the
consensus conference of the American College of Chest
Physicians and the Society of Critical Care Medicine (ACCP/
SCCM) in 1992 [13] has been revisited in 2001 by several North
American and European intensive care societies [SCCM,
 These definitions do not allow precise staging or
prognostication of the host response to infection.
 While SIRS remains a useful concept, the diagnostic criteria for
SIRS published in 1992 are overly sensitive and nonspecific.
 An expanded list of signs and symptoms of sepsis may better
reflect the clinical response to infection (Table 2) [14, 15].
We suggest to use the diagnostic criteria for sepsis proposed by
the SCCM, ESICM, ACCP, ATS and SIS adapted to
neutropenic patients (Table 2) [14, 15]. In neutropenic
patients, the white blood cell count (numbers of leukocytes)
cannot be used as criterion to define sepsis.
The definitions of severe sepsis and septic shock remain
unchanged and refer to sepsis-induced organ dysfunction
(Table 3).
incidence
Prospective studies using the SCCM/ESICM/ACCP/ATS/SIS
consensus definition in neutropenic patients are not available
[14, 15]. However, it can be assumed that in >90% of febrile
neutropenic episodes sepsis may be diagnosed using the
consensus definition according to SCCM/ESICM/ACCP/ATS/

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European Society of Intensive Care Medicine (ESICM), ACCP,
American Thoracic Society (ATS) and Surgical Infection Society Table 2. Diagnostic criteria for sepsis [14, 15]
(SIS)] with the following conclusions [14]:

 Current concepts of sepsis, severe sepsis and septic shock
remain useful to clinicians and researchers.
Table 1. Categories of evidence used in this guideline [3]
Category Grade Definition
Strength of A Good evidence to support
recommendation a recommendation for use
B Moderate evidence to support
a recommendation for use
C Poor evidence to support
a recommendation
D Moderate evidence to support
a recommendation against use
E Good evidence to support
a recommendation against use
Quality of evidence I Evidence from greater than or equal
to one properly randomized
controlled trial
II Evidence from greater than or equal
to one well-designed clinical trial,
without randomization; from
cohort or case-controlled analytic
studies (preferably from greater
than or equal to one center); from
multiple time-series or from
dramatic results from
uncontrolled experiments
III Evidence from opinions of respected
authorities, based on clinical
experience, descriptive studies or
reports of expert committees
General parameters
Fever (core temperature > 38.3
C)
Hypothermia (core temperature < 36
C)
Heart rate > 90 b.p.m. or > 2 SD above the normal value for age
Tachypnea: > 30 b.p.m.
Altered mental status
Significant edema or positive fluid balance (>20 ml/kg over 24 h)
Hyperglycemia (plasma glucose > 110 mg/dl or 7.7 mM/l) in the absence
of diabetes
Inflammatory parameters
Plasma C-reactive protein or plasma procalcitonin > 2 SD above the
normal value
Hemodynamic parameters
Arterial hypotension (systolic blood pressure < 90 mmHg, mean arterial
pressure < 70 or a systolic blood pressure decrease > 40 mmHg in
adults or < 2 SD below normal for age)
Mixed venous oxygen saturation > 70%
Cardiac index > 3.5 l/min/m2
Organ dysfunction parameters
Arterial hypoxemia (PaO2/FIO2 < 300)
Acute oliguria (urine output < 0.5 ml/kg/h or 45 mM/l for at least 2 h)
Creatinine increase ‡ 0.5 mg/dl
Coagulation abnormalities (international normalized ratio > 1.5 or
activated partial thromboplastin time > 60 s)
Ileus (absent bowel sounds)
Thrombocytopenia (platelet count < 100 000/ll)
Hyperbilirubinemia (plasma total bilirubin > 4 mg/dl or 70 mmol/l)
Tissue perfusion parameters
Hyperlactatemia (>3 mmol/l)
Decreased capillary refill or mottling
In neutropenic patients the white blood cell count (numbers of leukocytes)
cannot be used as criterion to define sepsis.
SD, standard deviation.

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Annals of Oncology
Table 3. Definitions of severe sepsis and septic shock
Severe sepsis Sepsis with new signs of organ dysfunction or
a decrease in organ perfusion [lactate acidosis,
oliguria (<30 ml/h or <0.5 ml/kg/h), hypotension
(<90 mmHg or decrease of >40mm Hg) and
mental alteration]
Septic shock Severe sepsis and hypotension persistent despite
adequate fluid substitution and exclusion for
other reasons for hypotension
SIS [14, 15]. The incidence of febrile episodes and consequently
of sepsis during the neutropenic phase after intensive
myelosuppressive chemotherapy lies 70%–100% [16–18] and
depends on the intensity of chemotherapy and the degree and
duration of neutropenia as well as the overall performance
status and pretreatment of the patient. In the majority of
studies, bacteremic infections could be detected in 10%–30% of
febrile neutropenic episodes [2, 19]. The incidence of septic
shock and severe sepsis has not been reported from the
majority of trials but in some studies, 40% of the patients
treated with intensive chemotherapy developed severe sepsis or
septic shock. As in the general population, an overall increase in
number and severity of septic episodes can be assumed [17].
risk factors and prognosis
Main risk factors following cytotoxic chemotherapy are the
severity and duration of granulocytopenia [1, 19]. In addition,
skin and mucosal barriers can be disrupted by chemotherapy,
insertion of catheters (staphylococci and fungi) and invasive
diagnostic procedures or by invasive tumor growth (colon
cancer) [2]. Decreased production of saliva or retention of
secretion due to tumor obstruction (particularly in patients
with lung cancer) facilitates the growth of pathogenic
microorganisms. Furthermore, the incidence of infection is
increased in malnourished tumor patients. In 2000, the
Multinational Association for Supportive Care in Cancer
(MASCC) proposed a score to identify febrile neutropenic
patients at low risk [20]. In addition to providing a useful tool
to aid the decision whether to admit a febrile patient, a recent
study has also identified the MASCC risk score as an
independent prognostic factor to predict complications during
the febrile episode [21].
The presence and degree of multiple organ dysfunction and
development of septic shock defined by volume-refractory
hypotension are prognostic factors [22]. The criteria of
leukocytosis, leukocytopenia or shift to the left in the
differential white blood cell count cannot be used in patients
with sepsis in neutropenia. Any neutropenic patient with signs
of a systemic inflammatory reaction without an obvious cause
other than infection (like blood transfusion or high-dose
cytarabine) has a high probability of sepsis. Thus, the use of the
consensus criteria [14] is also recommended for
leukocytopenic/neutropenic patients as no specific criteria for
this patient group have been specified as yet.
The prognosis of patients treated on the intensive care unit
(ICU) is determined by the physiological changes induced by
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review
the underlying infection, reflected by scoring systems such as
Acute Physiology and Chronic Health Evaluation II (APACHE
II) and Simplified Acute Physiology Score II (SAPS II).
However, long-term prognosis of these patients often depends on
the underlying malignant disease, rendering the SAPS II score in
leukocytopenic/neutropenic patients less useful than in
nonneutropenic patients (CII) [23]. With regard to scores
predicting outcome in respiratory failure requiring ventilatory
support a high APACHE II score was significantly correlated with
high in-ICU mortality but not with long-term outcome [24]. In
a retrospective study, a high SOFA score at ICU admission,
pulmonary site of infection and fungal infection were variables
independently associated with a higher 28-day mortality [25]. In
general, it has to be kept in mind that prognostic scoring systems
do not yield adequately reliable information to be used exclusively
for end-of-life decisions in individual patients [26]. Increased
levels of proinflammatory [tumor necrosis factor (TNF)-a,
nterleukin (IL)-6 and IL-8] as well as anti-inflammatory cytokines
(IL-10, IL-1RA) are found in neutropenic and nonneutropenic
patients with sepsis [27]. This is also the case for procalcitonin
levels, which can be useful in the early diagnostic phase before rise
of C-reactive protein in serum [28, 29].
Septic shock and multiple organ failure syndrome are often
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associated with systemic activation of coagulation and
fibrinolysis, disseminated fibrin deposition and consumption of
coagulation and fibrinolysis inhibitors. Disturbances of
hemostasis are of prognostic relevance in sepsis. For
antithrombin and PAI 1, prognostic relevance in neutropenic
sepsis could be shown [30].
microbiology
Blood cultures as part of the usual microbiological work-up as
per local protocol (including for instance urine cultures, stool
cultures etc.) remain the gold standard for the diagnosis of
bacteremia. Detailed recommendations regarding the
application of microbiological tests in this situation are given
elsewhere [31–33]. However, although most episodes of febrile
neutropenia are assumed to be caused by an infection, the
incidence of proven bloodstream infections in febrile
neutropenia is only 30% based on results of blood cultures
[34, 35]. Recent studies reporting a higher yield of positive
results by various PCR-based methods to detect bacterial and
fungal DNA have yet to be validated in larger cohorts [36, 37].
Particularly in the detection of bacteria at the beginning of
febrile neutropenia, PCR-based methods may add little further
information compared with blood cultures [38]. In contrast,
PCR-based methods play a definitive role in the diagnosis of
specific pathogens like combination chemotherapy with
methotrexate, vinblastine and cisplatin (CMV), which can be the
cause of neutropenic fever regardless of prior allogeneic stem cell
transplantation requiring early detection and treatment [39].
treatment
antimicrobial treatment
Empirical antimicrobial treatment using broad-spectrum
antibiotics must be started immediately in neutropenic patients
with sepsis. A large retrospective study including >2000 patients
doi:10.1093/annonc/mdq442 | 1021
review
showed that during severe sepsis effective antimicrobial
administration within the first hour of documented
hypotension is associated with increased survival [40]. In this
study, each hour of delay in antimicrobial administration over
the ensuing 6 h was associated with an average decrease in
survival of 7.6% [40].
Recommendations on antimicrobial treatment of infections
during neutropenia are given elsewhere [31, 32, 41]. Briefly, we
recommend initial treatment with meropenem or with
imipenem/cilastin or with piperacillin/tazobactam
monotherapy. Treatment with ceftazidim is an alternative
option. A combination treatment with an aminoglycoside has
not improved efficacy but increased renal toxicity [42, 43].
However, in case of severe sepsis, a combination treatment with
aminoglycoside is carried out in many centers and is
recommended by the European Organization for Research and
Treatment of Cancer infectious disease group. If infection due
to bacteria with frequent resistance to carbapenem or
piperacillin/tazobactam is suspected, a specific antibiotic
should be added (e.g. a glycopeptide in sepsis suspected to be
central venous catheter related). Recommendations on
antifungal therapy during neutropenia were recently published
by the infectious disease working party of the German Society
for Hematology and Oncology [44]. Knowledge of local
microbiology data is crucial for the choice of antimicrobial
agents. Typical organisms causing sepsis during neutropenia
are summarized in Table 4.
treatment of cardiovascular insufficiency
Aggressive and early goal-directed treatment aiming at
restoration of cardiovascular function has the potential to
increase survival of patients with sepsis if it is successful within
the first 6 h [45, 46]. Sepsis-induced hypotension or lactic
acidosis in patients at risk is primarily treated by volume
substitution. To restore adequate cardiac filling pressures and
to maintain adequate organ perfusion (goal: mean arterial
pressure ‡ 65 mmHg, central venous pressure 8–12 mmHg,
pulmonary wedge pressure 12–15 mmHg, urinary output ‡ 0.5
ml/kg/h and central venous or mixed venous oxygen saturation
Table 4. Typical pathogens during bacterial sepsis in neutropenic
patients
Origin Frequent pathogens
Unknown Coagulase negative staphylococci, Escherichia
coli, Enterococcus species
Lung Pseudomonas aeruginosa, Pneumococci,
Alpha-hemolytic streptococci, Acinetobacter species
Abdomen E. coli, Pseudomonas aeruginosa, Clostridium
species, Enterococcus species, Klebsiella species
Urogenital E. coli, Klebsiella species, P. aeruginosa
Soft tissue Staphylococcus aureus, Alpha-hemolytic streptococci
CVC Coagulase negative staphylococci, Corynebacteriae,
Propionibacterium species, Candida albicans,
Candida tropicalis
All pathogens can cause bloodstream infections in neutropenic hosts.
Specimens should be obtained from a normally sterile site.
CVC, central venous catheter.
1022 | Penack et al.
Annals of Oncology
‡ 70%), crystalloid fluids or colloids can be useful (AI) [46, 47].
Resuscitation with crystalloids requires more fluid volume
because of the larger volume of distribution. However, there is
no evidence-based support for the preferred use of colloids over
crystalloids. A meta-analysis and a large multicenter trial
revealed a small absolute increase in the risk of renal failure and
mortality with the use of colloids over crystalloids [46, 47].
Human albumin should not be used because in meta-analyses
of randomized trials, the application of human albumin was
not associated with a favorable outcome even if administered in
patients with burns and hypoalbuminemia (DII) [48].
Treatment with volume substitution should be done under
hemodynamic monitoring (central venous pressure, blood
pressure, heart rate, cardiac output, pulmonary wedge pressure
and lactate levels).
If a sufficient mean arterial pressure (>65 mmHg) cannot be
achieved by volume substitution in a reasonable time frame,
treatment with vasopressors is indicated. The drug of choice to
elevate the vasotonus is norepinephrine in a dose of 0.1–1.3 lg/
kg/min (BII) [49]. This may also lead to an improvement in
renal function [50]. There is no evidence that increasing the
mean arterial pressure to >85 mmHg by using high doses of
vasopressors, such as norepinephrine, has a positive impact on
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oxygen delivery and renal function (EI) [51]. Another
vasopressor that has been investigated in smaller studies is
vasopressin. Vasopressin (0.01–0.04 U/min) increased urinary
output and creatinine clearance in comparison to
norepinephrine [52–54]. However, in the large VASST trial, no
reduction in 28-day mortality was found in the vasopressin
group and there is currently poor evidence to support the use
of vasopressin in septic shock (CI) [55].
In case of sepsis-related myocardial depression leading to low
cardiac output despite adequate volume substitution,
vasopressor treatment with dobutamine should be instituted
(AII) [56]. Because of their toxicity profile and due to lack of
evidence of a beneficial effect, epinephrine and dopamine are
not recommended.
Bicarbonate therapy is not recommended for the purpose of
improving hemodynamics or reducing vasopressor
requirements in the presence of lactic acidosis and pH >7.15.
treatment of pulmonary failure
Nearly 15% of cancer patients experience acute respiratory
failure requiring admission to the ICU, where their mortality is
50% [57]. Nearly 50% of patients with severe sepsis will
develop acute lung injury/acute respiratory distress syndrome
(ARDS) [58].
In the awake, cooperative patient with a minor disturbance
of gas exchange (PaO2/FiO2 > 200), an augmentation of
spontaneous breathing with intermittent continuous positive
airway pressure (CPAP) can be attempted. In moderate-to-
severe respiratory insufficiency, endotracheal intubation and
controlled mechanical ventilation are necessary. However,
noninvasive positive pressure ventilation (CPAP or bilevel
positive airway pressure) should be preferred if possible in
patients without hypotension or altered mental status [58–61].
Both noninvasive treatment options led to a significant
reduction of intubation compared with the control group in
selected neutropenic and cancer patients (AII) [62]. An early
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Annals of Oncology
start of noninvasive ventilation, before development of severe
hypoxemia, is favorable (BIII), and predictors of noninvasive
ventilation failure might be used to guide decisions
regarding intubation. These include respiratory rate under
noninvasive ventilation (longer), delay between admission and
noninvasive ventilation first use [63], need for vasopressors or
renal replacement therapy (RRT) and the development of
ARDS [64].
Failure of noninvasive ventilation occurs in half the critically
ill hematologic patients and is associated with an increased
mortality [63]. In a retrospective multicenter study of
allogeneic hematopoietic stem cell transplantation recipients
admitted to the ICU, mechanical ventilation led to a dramatic
decrease in survival rates [41].
Regarding diagnostic procedures in the work-up of lung
infiltrates, fiberoptic bronchoscopy with bronchoalveolar lavage
(FO-BAL) is considered a cornerstone of the causal diagnosis
[41]. The diagnostic yield of at most 50% is related to the
widespread use of broad-spectrum antimicrobial therapy in
these patients [65, 66]. However, in patients with hypoxemia,
bronchoscopy and BAL may trigger a need for invasive
mechanical ventilation, thus considerably decreasing the
chances of survival [57, 67]. Respiratory status deterioration
after FO-BAL occurred in up to 50% of nonintubated patients,
including 35.5% patients who required ventilatory support
[67]. Life-threatening complications were noticed in up to 10%
of FO-BAL procedures [66].
In patients with pulmonary infiltrates during neutropenia,
granulocyte colony-stimulating factor (G-CSF)-induced
neutropenia recovery carries a risk of respiratory status
deterioration with acute lung injury or ARDS [68].
management of renal dysfunction
Acute renal failure (ARNF) develops in 23% of patients with
severe sepsis and 51% with septic shock. The combination of
ARNF and sepsis is associated with a 70% mortality [69]. The
pathophysiology of septic ARNF remains incompletely
understood but renal hypoperfusion and ischemia followed by
acute tubular necrosis are considered to be central. Hyperemia,
vasodilatation and nonhemodynamic mechanisms may also
play a role in the pathogenesis of septic ARNF [70].
ARNF in patients with sepsis necessitates the replacement of
renal function to balance fluids, remove uremic toxins and
control electrolytes. Currently, no clear guidelines on the
timing of the initiation of RRT can be given, and decisions
should be made on an individual basis [71]. The only
randomized trial, carried out in mainly surgical patients with
ARNF, did not show a benefit for the early initiation of
hemofiltration [72]. However, given the increased risk of severe
extrarenal complications, the initiation of RRT should not be
delayed in patients with rapidly developing oliguric forms of
ARNF (BIII) [71].
Regarding the mode of replacement therapy intermittent
hemodialysis (IHD) and continuous renal replacement
therapies (CRRT) are equivalent in patients with sepsis and
ARNF (BI). Three meta-analyses did not show a significant
difference in hospital mortality between patients who receive
intermittent or continuous RRT [73–75]. Moreover, two
additional randomized controlled trials, which were not
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review
included in the meta-analyses, also found intermittent or CRRT
equally effective with similar rates of survival [76, 77]. In
hemodynamically unstable patients, control of fluid balance
may be facilitated by the use of CRRT (BII) [45, 71], although
there is no strong evidence for a better hemodynamic tolerance
with continuous therapies as compared with IHD. In terms of
hemodynamic stability four of six prospective randomized
studies did not show a significant difference between either
method [45, 71].
Increasing the dose of RRT is thought to reduce the rate of
uremic complications and improve outcome in patients with
ARNF. However, randomized controlled studies showed
conflicting results [45, 71, 78]. A recent study indicates that
a strategy of intensive renal support in critically ill patients with
ARNF does not decrease mortality, accelerate recovery of
kidney function or alter the rate of nonrenal organ failure as
compared with less-intensive regimens [79]. Thus, no firm
recommendations can be given for the use of increased doses of
RRT (CI).
In patients undergoing RRT, the dosage of antimicrobial
substances should be carefully checked and adjusted. The use of
low-dose dopamine for protection of renal function is not
recommended (EI) [80, 81].
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nutrition and control of metabolic functions
An oral diet is preferred over parenteral nutrition unless
contraindicated or impossible, e.g. due to mucositis induced by
chemotherapy and radiation. Enteral caloric intake should be
calculated according to the phase of sepsis: during the initial
phase of sepsis, the supply of >20–25 kcal/kg ideal body weight
(IBW) has been associated with inferior outcome in one
observational study (DIII) [82]. During recovery, 25–30 kcal/kg
IBW should be provided (BIII) [83, 84]. Peptide-based
formulae are not superior to whole protein formulae [83, 84].
Patients with mild sepsis (APACHE II 10–15) might benefit
from receiving a formulation enriched with arginine, nucleotides
and x́-3-fatty acids (BI) [83, 85]. In one randomized controlled
trial, mortality of these patients was reduced, whereas the
mortality of patients with an APACHE II score of 16–25 was not
affected [85]. This formulation is also superior to standard
enteral formulae in patients with ARDS, with burns or with
trauma. In contrast, the formulation is discouraged in patients
with severe sepsis and an APACHE II score of >25 because their
mortality may be increased (EII) [85].
Hyperglycemia in patients requiring intensive care is
associated with inferior outcome [86, 87], Yet, results of
recently published clinical trials [88–90] do not support aiming
at a strictly normal blood glucose level of 4.4–6.6 mmol/l (80–
120 mg/dl) (EI). Two randomized controlled trials, one
including patients with severe sepsis [89] and the other
including both medical and surgical patients requiring
treatment on an ICU [90], had failed to repeat the results of the
initial trials by van den Berghe et al. [91, 92] suggesting
a benefit of a tight blood glucose control. Mortality, the rates of
severe hypoglycemia and serious adverse events were increased
in patients subjected to intensified blood glucose control
[89, 90]. In a meta-analysis including 26 trials, the pooled
relative risk (RR) of death with intensive insulin therapy
when compared with conventional insulin therapy was
doi:10.1093/annonc/mdq442 | 1023
review
0.93 [95% confidence interval (CI) 0.93–1.04] [88]. The pooled
RR for hypoglycemia with intensive insulin therapy was 6.0
(95% CI 4.5–8.0). In addition, a recently published trial showed
that intensive insulin therapy did not improve in hospital
mortality, compared with conventional insulin therapy, among
patients who were treated with hydrocortisone for septic
shock [93]. Based on these data, we recommend to maintain
blood glucose levels £8.3 mmol/l (150 mg/dl) in septic patients
(BIII). We do not recommend, however, intensive insulin
therapy aiming at a strictly normal blood glucose level of 4.4–
6.6 mmol/l (80–120 mg/dl) (EI).
Selenium exerts antioxidative effects. It has been proposed
that the substitution of selenium might positively influence the
outcome of patients suffering from sepsis. The per protocol
analysis of one small, randomized, placebo controlled clinical
trial [94] showed a reduction in the 28-day mortality rate by
the administration of high-dose selenium (1000 lg daily over
15 days, 42.4% in the treatment arm of the trial compared with
56.7% in the placebo group, P = 0.049, odds ratio, 0.56; 95% CI
0.32–1.00). Further clinical trials are needed before treatment
with selenium can be recommended (CI).
Replacement of an impaired adrenal reserve and anti-
inflammatory properties has been the rationale for studying
corticosteroids as an adjunctive to sepsis therapy. The use of
corticosteroids in sepsis has not been studied in a prospective
fashion in neutropenic patients. Meta-analyses reported on
increased overall mortality and increased mortality from
secondary infections in nonneutropenic patients with sepsis
receiving high-dose steroids [95, 96]. Thus, high-dose
corticosteroids should not be used in neutropenic or
nonneutropenic septic patients (EI). However, in patients
requiring corticosteroids or mineralocorticoids for treatment of
diseases other than sepsis (e.g. graft versus host disease), steroid
treatment should not be discontinued.
Interestingly, low doses of hydrocortisone might enhance
immune responses [97, 98]. Substitutive doses of
hydrocortisone during sepsis remain controversial [99–101] as
two recent meta-analyses support the use of low doses of
hydrocortisone [102, 103] but the CORTICUS trial [99] did not
reveal a difference in 28-day mortality between treatment and
placebo. A higher incidence of secondary infections was
recorded in the treatment group. Thus, we do not recommend
the use of substitutive doses of hydrocortisone in neutropenic
patients with sepsis (DI).
treatment with coagulation inhibitors
Disseminated activation of the coagulation cascade is an early
event, resulting in fibrin deposition in the microcirculation
thus contributing to multiorgan dysfunction in sepsis. Various
attempts have been made to reverse or avoid disseminated
coagulation. However, since neutropenia is usually
accompanied by thrombocytopenia, any manipulation of the
coagulation system has to be exerted with caution to avoid an
excessive risk of bleeding.
The prospective, randomized controlled HETRASE study
investigated treatment with low-dose heparin (500 IU/h for 7
days) in 319 patients [104]. No influence on 28-day all-cause
mortality was found [104]. Inclusion criteria were very liberal,
1024 | Penack et al.
Annals of Oncology
explaining the low mortality in this trial, and treatment was
discontinued immediately in case the partial thromboplastin
time rose >60 s. Under these conditions, the administration of
low-dose heparin was safe. Further trials including more
patients and better-defined subgroups, e.g. on the base of the
APACHE II score, are needed before recommendations can be
made (CI).
Antithrombin III (ATIII) exerts antithrombotic and anti-
inflammatory properties. The negative data from the KyberSept
trial [105] have recently been confirmed by a Cochrane analysis
[106]. Subgroup analyses have shown that concomitant
administration of heparin impairs beneficial effects of
antithrombin, especially in patients with disseminated
intravascular coagulation [107–109]. No evidence-based
recommendation on the use of ATIII in severe sepsis can be
made (CI).
In patients without thrombocytopenia, the use of
recombinant human activated protein C (APC) is
recommended in patients with severe sepsis and septic shock
who have an APACHE II score of >25 or a minimum of two
organs failing (AI) [110]. It is not recommended in patients
with an APACHE II score of <25 or one organ failure (EI)
[111]. The PROWESS trial was prematurely stopped because
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a reduction in absolute mortality at day 28 by 6% was achieved
[110]. Subgroup analyses of the PROWESS trial and the
following ADDRESS trial did not manage to prove a benefit for
lower risk groups (i.e. with an APACHE II score <25 or one
organ failure) but increased the risk of bleeding [111]. Because
APC increases the risk of bleeding, it is not recommended if
thrombocytopenia <30 000 platelets/ll is present and within 30
days after larger surgery or spinal puncture/anesthesia. It is
feasible to administer APC together with heparin [112]. The
PROWESS trial [110] reported antagonizing interactions
between the respective intervention and low-dose heparin.
Those were not found in the XPRESS trial [113]. At present, no
recommendation on the concomitant use of APC and low-dose
heparin can be made.
cytokines and hematopoietic growth factors
(G-CSF and granulocyte–macrophage colony-
stimulating factor)
The central role of cytokines during the hyperinflammatory
and anti-inflammatory phases of sepsis prompted clinical
studies on the use of cytokines and cytokine inhibitors as
therapeutic agents. However, studies on the therapeutic efficacy
of IL-1 receptor antagonist, TNF inhibitors and interferon
gamma did not show a clinical benefit (EI) [114–116].
The known effect of G-CSF and granulocyte–macrophage
colony-stimulating factor (GM-CSF) in increasing the number of
circulating neutrophil granulocytes was the rationale for clinical
studies assessing their role as additional therapy to antibiotics in
febrile patients with chemotherapy-induced neutropenia. A
meta-analysis of 13 randomized controlled trials including a total
of 1518 individuals showed that CSF effectively reduces the time
to neutrophil recovery and the length of hospitalization [117].
However, despite a marginally significant benefit for the use of
CSF in reducing infection-related mortality, overall mortality
appeared not to be influenced. Even though studies enrolled in
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Annals of Oncology
this meta-analysis report only mild side-effects associated with
CSF treatment (bone pain, joint pain and flu-like symptoms),
there is an accumulating number of studies reporting respiratory
deterioration with ARDS during CSF-induced neutropenia
recovery [68, 118]. In nonneutropenic patients with pneumonia
or sepsis CSF appeared to be safe but ineffective in reducing
mortality rates or complications from infection [119, 120]. On
the basis of the current studies and reports, the
Arbeitsgemeinschaft Infektionen in der Hämatologie und
review
Onkologie (AGIHO) does not recommend the routine
additional use of G-CSF or GM-CSF to standard treatment of
sepsis in neutropenia (DI).
immunoglobulins
The treatment of sepsis in neutropenia with i.v.
immunoglobulin’s (i.v. Ig) did not show a significant difference
in survival in a randomized controlled trial [121]. A meta-
analysis on trials of i.v. Ig in patients with sepsis identified 20

Table 5. Summary of treatment recommendations given by the Infectious Diseases Working Party of the German Society of Hematology and Oncology

Recommendation Evidence level

Cardiovascular insufficiency
Volume substitution can be carried out with crystalloid fluids or colloids AI
Human albumin should not be used for volume substitution DII
The drug of choice to elevate the vasotonus is norepinephrine BII
In case of sepsis-related myocardial depression leading to low cardiac output despite adequate volume AII
substitution, treatment with dobutamine should be instituted
Treatment of pulmonary failure
Noninvasive positive pressure ventilation (CPAP or bilevel positive airway pressure) should be AII
preferred if possible in patients without hypotension or altered mental status
An early start of noninvasive ventilation, before development of severe hypoxemia, is favorable BIII

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Management of renal dysfunction
Intermittent hemodialysis and continuous renal replacement therapies are equivalent BI
No firm recommendations can be given for the use of increased doses of renal replacement therapy CI
Low-dose dopamine for protection of renal function is not recommended. EI
Nutrition and control of metabolic functions
Oral diet is preferred over parenteral nutrition AIII
During initial phase of sepsis, energy supply should not exceed 20–25 kcal/kg IBW DIII
During recovery, 25–30 kcal/kg IBW should be provided BIII
Patients with an APACHE II score of 10–15 might benefit from receiving a formulation enriched with BI
arginine, nucleotides and x́-3-fatty acids
Mortality of patients with an APACHE II score of >25 might be increased when receiving EII
a formulation enriched with arginine, nucleotides and x́-3-fatty acids
Aiming at strictly normal blood glucose level of 4.4–6.6 mmol/l (80–120 mg/dl) is not recommended EI
Blood glucose levels should be kept £8.3 mmol/l (150 mg/dl) in septic neutropenic patients BIII
Further clinical trials are needed before treatment with selenium can be recommended CI
High-dose corticosteroids should not be used in neutropenic or nonneutropenic septic patients EI
The use of substitutive doses of hydrocortisone in neutropenic patients with sepsis is not DI
recommended
Treatment with coagulation inhibitors
Further trials on the use of low-dose heparin (500 IU/h for 7 days) are needed before CI
recommendations can be made
No evidence-based recommendations on the use of ATIII in neutropenic patients with sepsis can CI
be made
If contraindications are thoroughly ruled out, the use of APC is recommended in patients with an AI
APACHE II score >25 or a minimum of two organs failing
The use of APC is not recommended in patients with an APACHE II score <25 EI
Growth factors and immunoglobulins
The AGIHO does not recommend the routine additional use of G-CSF or GM-CSF to standard DI
treatment of sepsis in neutropenia
There is moderate degree of evidence to support the use of i.v. immunoglobulins in sepsis BII
Transfusion management
The cut-off for substitution of platelets is often set to a higher value (platelets 20 000/ll instead of BIII
10 000/ll) during sepsis
Although there are no prospective randomized studies showing a clinical benefit, hemoglobin levels BIII
should be kept >9 g/dl to optimize tissue oxygenation

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.

Volume 22 | No. 5 | May 2011 doi:10.1093/annonc/mdq442 | 1025

review
trials eligible for evaluation [122]. Compared with placebo or
no intervention, the use of polyclonal i.v. Ig was associated with
a survival benefit (RR 0.74 with a 95% CI 0.62–0.84). The
number needed to treat to save one life was 9. Interestingly,
more severely ill patients, those receiving treatment of >2 days
and those receiving at least 1 g/kg, seemed to benefit most. As
most of the individual trials analyzed had flaws in design, were
rather small or carried out during a time when the standard of
care for septic patients was different from today, the authors
conclude that a large, randomized controlled trial should be
carried out [122]. Two additional meta-analyses investigated
the use of i.v. Ig during sepsis and had similar outcomes [123,
124]. In conclusion, there is moderate degree of evidence to
support the use of i.v. Ig in sepsis (BII).
granulocyte transfusions
Several case reports and phase I/II studies have shown some
efficacy of granulocyte transfusions in patients with infections
during severe neutropenia including patients with invasive
fungal infections. However, complications have been reported
as well, e.g. fatal CMV infection, allo-immunization and the
transfusion-related acute lung injury (TRALI) syndrome.
Recently, a randomized controlled trial has been published
[125]. It failed to show any beneficial effect, but it was small
and the authors discussed several problems associated with the
design of the trial. Therefore, no recommendation can be given
on the use of granulocyte transfusions outside of clinical trials.
transfusion management in sepsis
The recommendations for substituting platelets or packed red
blood cell in neutropenic patients can be applied to those
patients developing sepsis as well. However, the cut-off for
substitution is often set to a higher value (platelets 20 000/ll
instead of 10 000/ll) (BIII). Although there are no prospective
randomized studies showing a clinical benefit, hemoglobin levels
should be kept >9 g/dl to optimize tissue oxygenation (BIII).
conclusions
Early start of effective antimicrobial treatment as well as
intensive adjunctive therapy is mandatory to improve outcome
of neutropenic patients with sepsis. Table 5 summarizes
treatment recommendations given by the Infectious Diseases
Working Party of the German Society of Hematology and
Oncology.
disclosure
The authors declare no conflict of interest.
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