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Management of Sepsis in Neutropenic Patients

Date of document January 2012
This document is not the most recent version. Please view: Sepsis bei neutropenischen Patienten

1Basic Information

Sepsis is a frequent syndrome caused by serious infections in neutropenic patients and remains a leading cause of non-relapse mortality. Clinical symptoms are highly acute. Early treatment with causal and supporting measures may reduce mortality. This guideline on diagnostics and therapy of sepsis was developed by the AGIHO Infectious Diseases Working Party of the DGHO. The majority of recommendations is based on studies in non-neutropenic patients, validated on experience in the care of patients in hematology and oncology.

Categories are based on the evaluation of study results and the recommendations developed by the Infectious Diseases Society of America, ISDA, see Table 1.

Table 1: Categories of Evidence 

Category, grade Strength of Recommendation

Definition

A

Good evidence to support a recommendation for use

B

Moderate evidence to support a recommendation for use

C

Poor evidence to support a recommendation for use

D

Moderate evidence to support a recommendation against use

E

Good evidence to support a recommendation against use

Quality of Evidence

Definition

I

Evidence from ≥1 properly randomized, controlled trial

II

Evidence from ≥1 well-designed clinical trial, without randomization; from cohort or case-controlled analytic studies (preferable from >1 centre); from multiple time series; or from dramatic results of uncontrolled experiments

III

Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports from expert committees

2Definitions

2.1Sepsis

Definition is based on the consensus criteria of the Society of Critical Care Medicine (SCC), European Society of Intensive Care Medicine (ESICM), American College of Chest Physicians (ACCP), American Thoracis Society (ATS) and the Surgical Infection Society (SIS) [1, 2], see Table 2.

Table 2: Diagnostic Criteria of Sepsis 

Category

Parameter

General

  • Fever (core temperature > 38,3° C)

  • Hypothermia (core temperature < 36° C)

  • Heart Rate > 90 b.p.m. or 2SD above the normal value for age

  • Tachypnea > 30 breaths 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

  • C reactive protein > 2 SD above the normal value

  • Procalcitonin > 2 SD above the normal value

Hemodynamic

  • Arterial hypotension (systolic blood pressure < 90 mmHg, mean arterial pressure < 70 or a systolic blood pressure decrease > 40 mmHg in adults)

  • 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 for at least 2 h)

  • Creatinine increase ≥ 0,5 mg / dl

  • Coagulation abnormalities (INR > 1,5 or aPTT > 60 s)

  • Ileus (absent bowel sounds)

  • Hyperbilirubinemia (plasma total bilirubin > 4 mg / dl or 70 mmol / l)

Tissue perfusion

  • Hyperlactatemia (>3 mmol / l)

  • Decreased capillary refill or mottling

2.2Severe Sepsis and Septic Shock

Criteria of severe sepsis and septic shock are summarized in Table 3. [1, 2].

Table 3: Diagnostic Criteria 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

3Therapy

Recommendations for treatment of sepsis are summarized for cardiovascular insufficiency in Table 4, for respiratory failure in Table 5, for renal failure in Table 6, nutrition and control of metabolic functions in Table 7, for coagulation disorders in Table 8, for hematopoetic growth factors and immunoglobulins in Table 9, for transfusion in Table 10.

Table 4: Therapy of Sepsis – Cardiovascular Insufficiency 

Recommendations

Category of Evidence

Volume substitution can be carried out with crystalloid fluids or colloids.

A-I

Human albumin should not be used for volume substitution.

D-II

The drug of choice to elevate the vasotonus is norepinephrine.

B-II

In case of sepsis-related myocardial depression leading to low cardiac output despite adequate volume substitution, treatment with dobutamine should be instituted.

A-II

Table 5: Therapy of Sepsis – Respiratory Failure 

Recommendations

Category of Evidence

Noninvasive positive pressure ventilation (CPAP or bilevel positive airway pressure) should be preferred if possible in patients without hypotension or altered mental status.

A-II

An early start of noninvasive ventilation, before development of severe hypoxemia, is favorable.

B-III

Table 6: Therapy of Sepsis – Renal Dysfunction 

Recommendations

Category of Evidence

Intermittent hemodialysis and continuous renal replacement therapies are equivalent.

B-I

No firm recommendations can be given for the use of increased doses of renal replacement therapy.

C-I

Low-dose dopamine for protection of renal function is not recommended.

E-I

Table 7: Therapy of Sepsis – Nutrition and Control of Metabolic Functions 

Recommendations

Category of Evidence

Oral diet is preferred over parenteral nutrition.

A-III

During initial phase of sepsis, energy supply should not exceed 20–25 kcal/kg IBW.

D-III

During recovery, 25–30 kcal/kg IBW should be provided.

B-III

Patients with an APACHE II score of 10–15 might benefit from receiving a formulation enriched with arginine, nucleotides and ώ -3-fatty acids.

B-I

Mortality of patients with an APACHE II score of >25 might be increased when receiving a formulation enriched with arginine, nucleotides and ώ -3-fatty acids.

E-II

Aiming at strictly normal blood glucose level of 4.4–6.6 mmol/l (80–120 mg/dl) is not recommended.

E-I

Blood glucose levels should be kept ≤ 8.3 mmol/l (150 mg/dl) in septic neutropenic patients.

B-III

Further clinical trials are needed before treatment with selenium can be recommended.

C-I

High-dose corticosteroids should not be used in neutropenic or nonneutropenic septic patients.

E-I

The use of substitutive doses of hydrocortisone in neutropenic patients with sepsis is not recommended.

D-I

Table 8: Therapy of Sepsis – Coagulation 

Recommendations

Category of Evidence

Further trials on the use of low-dose heparin (500 IU/h for 7 days) are needed before

recommendations can be made.

C-I

No evidence-based recommendations on the use of ATIII in neutropenic patients with sepsis can be made.

C-I

If contraindications are thoroughly ruled out, the use of APC is recommended in patients with an APACHE II score >25 or a minimum of two organs failing.

A-I

The use of APC is not recommended in patients with an APACHE II score <25.

E-I

Table 9: Therapy of Sepsis – Hematopoetic Growth Factors and Immunoglobulins 

Recommendations

Category of Evidence

The routine additional use of G-CSF or GM-CSF to standard treatment of sepsis in neutropenia is not recommended.

D-I

There is moderate degree of evidence to support the use of i.v. immunoglobulins in sepsis.

B-II

Table 10: Therapy of Sepsis – Transfusion 

Recommendations

Category of Evidence

The cut-off for substitution of platelets is often set to a higher value (platelets 20 000/ll instead of 10,000/ll) during sepsis.

B-III

Although there are no prospective randomized studies showing a clinical benefit, hemoglobin levels should be kept >9 g/dl to optimize tissue oxygenation.

B-III

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9References

  1. Olaf Penack, Dieter Buchheidt, Maximilian Christopeit, Marie von Lilienfeld-Toal, Gero Massenkeil, Marcus Hentrich, Hans Salwender, Hans-Heinrich Wolf, Helmut Ostermann: Management of sepsis in neutropenic patients: Guidelines from the infectious diseases working party of the German Society of Haematology and Oncology. Ann Oncol 22:1019-1029, 2011. DOI:10.1093/annonc/mdq442

  2. Levy MM, Fink MP, Marshall JC et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Definitions Conference. Crit Care Med 2003; 31: 1250-1256. PMID:12682500

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16Authors’ Affiliations

Prof. Dr. med. Dieter Buchheidt
PD Dr. med. habil. Maximilian Christopeit
Universitätsklinikum Hamburg-Eppendorf
II. Medizinische Klinik und Poliklinik
Onkologie, Hämatologie,
Knochenmarktransplantation mit Abteilung für Pneumologie
Martinistr. 52
20246 Hamburg
Prof. Dr. med. Marcus Hentrich
Rotkreuzklinikum München gGmbH
III. Medizinische Abteilung -
Hämatologie und Onkologie
Nymphenburger Str. 163
80634 München
Prof. Dr. med. Helmut Ostermann
Klinikum der Universität München
Marchioninistr. 15
81377 München
Prof. Dr. med. Olaf Penack
Charité - Universitätsmedizin Berlin
CVK: Campus Virchow-Klinikum
CC 14: Tumormedizin
Augustenburger Platz 1
13353 Berlin
Dr. med. Hans-Jürgen Salwender
Asklepios Klinik Hamburg-Altona
II. Medizinische Abteilung
Hämatologie / Stammzelltransplantation
Paul-Ehrlich-Str. 1
22763 Hamburg
Prof. Dr. med. Marie von Lilienfeld-Toal
Ruhr-Universität Bochum
Medizinische Fakultät
Institut für Diversitätsmedizin
Universitätsstr. 105
44789 Bochum
Dr. med. Hans-Heinrich Wolf
Südharzklinikum
Klinik für Innere Medizin III
Hämatologie, Onkologie, Hämostaseologie
Dr.-Robert-Koch-Str. 39
99734 Nordhausen

17Disclosures

according to the rules of the responsible Medical Societies.

17Disclosure

according to the rules of the German Association of Hematology and Oncology (DGHO, Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie) and the recommendations of the AWMF (version dated April 23, 2010) and international recommendations.

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