Журнал «Медицина неотложных состояний» 1 (64) 2015

In this chapter identifies the main tactics of treatment of febrile neutropenia as the most formidable and frequent complication of chemotherapy conducted in patients with cancer.The lecture is addressed primarily to non-cancer experts institutions, which may be hospitalized patients with this complication, so the issues of prevention will not be considered.

Febrile neutropenia (FN), in the absence of therapy transformed into septic shock, starting usually with lightning speed and atypical. Febrile neutropenia is often a component of pancytopenia, where due to the cytotoxic effects of drugs inhibit all three germ bone marrow. According to the criteria of the American Society of infectious diseases IDSA - febrile neutropenia - a condition in which the level of granulocytes less than or equal to 0,5  10⁹, body temperature twice a day exceeds 38,0 ° C, or at least once 38,3 ° C. Characteristic is that microbial activity is a sign of fever, in the absence of classic symptoms (pain, hyperemia, edema). Virtually no physiological barriers throughout the intestinal tube, hypopharynx, the tracheobronchial tree. Massive translocation occurs in the pathogen initially sterile environment, developing bacteremia, sometimes - septicemia. Since the patient was in the hospital chemotherapy often repeatedly should expect a nosocomial infection.

Until recently, fever in neutropenic patients was an absolute indication for hospitalization. However, after the introduction of MASCC (prognostic index system the risk of complications, these readings have ceased to be so rigid. If MASCC - greater than or equal to 21 points, the risk of therapy in an outpatient setting is minimal.

A patient arrives at the maximum must be isolated.

The emergence of symptom FN is the direct basis for a series of diagnostic procedures and immediate (within 1 hour!) appointment of antimicrobial therapy. Diagnostic procedures should be performed before treatment, that is, almost immediately after the detection of FN. The diagnostic panel includes the following activities:

• inspection to identify hidden pockets of infection (skin puncture site, catheterization, perianal area, nails, visible mucous membranes);
• blood cultures, urine, discharge from the mouth, places catheterization; smears from the mucous mouth, throat, vagina;
• chest X-ray;
• abdominal ultrasound;
• clinical analysis of blood, urine;
• biochemical analysis of blood (protein, bilirubin, urea, creatinine, the activity of transaminases, alkaline phosphatase, LDH, C-reactive protein, electrolytes).

During the FN held gut decontamination.

Can be recommended:

• metronidazole - in terms more than 2 weeks from the start of the selective decontamination at a dose of 20-30 mg / kg / day. 2-3 divided doses for 7 days;
• gentamicin - per os the maximum daily doses throughout the period of agranulocytosis;
• kanamycin - per os the maximum daily doses throughout the period of agranulocytosis. Aminoglycosides per os no toxic systemic effects, acting in the intestinal tube;
• preparation nonabsorbent nitrofuran series in corresponding doses - (nifuroxazide - 2 tablets 4 twice a day);
• there are lymphopenia (lymphocyte levels <300 / mm3) is assigned to acyclovir per os 750 mg/m² per day in 4 receptions 5 days.

Started to combine antimicrobial therapy and conducting prevention of septic shock in patients with febrile neutropenia ARE urgent. They start at a time!

Preventing septic shock.

If possible (acceptable level of platelets, the lack of anticoagulation effects) must be installed a central venous catheter, with the control of CVP 4 times a day or more, with a negative clinical dynamics of the load is carried in the volume of crystalloid 2000-3000 ml/m²/day (but no more than 3 -x liters total adult.) with the addition of potassium 50 mmol/m²/day. It should be appreciated myocardial contractility. With reduced ejection fraction (EF) dose volemic load is reduced. The estimated dose is only round the clock continuously. On the introduction of antibiotics parallel infusion is interrupted (to prevent an increase in their clearance!). Deficiency diuresis thus should not exceed 200 ml/m² for 6 hours. If you exceed this figure - furosemide i.v. a dose of 0.1-0.5 mg/kg (maximum daily dose should not exceed 10 mg/kg) or 20-40 mg of torasemide. In the event of a threat of shock must focus on an hourly diuresis, which should be no lower than 100 ml/m² per hour. If the glomerular filtration rate is below this figure, furosemide administered hourly dose of 0.4 mg/kg per hour torasemide or 10-20 mg every hour - until the normalization of diuresis. Can be combined with osmodiuretikami without the threat of pulmonary edema. This involves hourly monitoring of body temperature, blood pressure, heart rate, respiratory rate. Under normal circumstances, the control of these parameters is necessary to carry out one every 6 hours. Sodium bicarbonate infusion in the program may be added if necessary only under the supervision of acid-base status of blood.

Infusion is terminated for at least 24 hours after the first administration of a combination of antibiotics and/or 24 hours after the temperature normalization.

Each new combination of antibiotics should be accompanied by a parallel infusion over at least 24 hours of the first injection.

It is very important to maintain body temperature at all times during the episode of febrile neutropenic patients have at below 38,5°C (≥ 38,5°C - a significant increase in the threat of shock) by intravenous injection of 50% solution metamizol and/or for each of paracetamol raising the temperature ≥ 38,5°C, without waiting under the control of blood pressure immediately before the administration of the antibiotic and at 30 and 60 minutes - after. This is due to the risk of developing the syndrome Jarisch - Herxheimer.

Antimicrobial therapy for febrile neutropenia.

Almost always for admissions at the start of antibiotic therapy is empirical, but holding her under the concept of de-escalation in the practice is not always possible.

Before the appointment of empirical antimicrobial therapy should:

• carry out all diagnostic measures;
• determine the degree of risk of infection;
• assess the need for inclusion in the first row of vancomycin, teicoplanin, linezolid.

Inclusion of one of these drugs in the initial empiric therapy of patients it is expedient in the following clinical situations:

• clinically suspected catheter-related infections;
• the availability of data on the colonization of penicillin and cephalosporin-resistant cocci or methicillin-resistant;
• hypotension or other signs of cardiovascular disorders.

In 10-15% of cases, the cause of infections in patients with FN may be a fungus. Bacterial and fungal infections can coexist, while another one may mask. Clinical signs of mycosis are consistently high fever with administration of antibiotics. The most common fungal pathogens fever are all kinds of Candida spp. or Aspergillus. Given the difficulty of diagnosis of mycosis administered antifungal agent to patients, febrile for 5 days in the antibacterial eradication background. Forecast fungal septitsiemii remains poor (30-40% mortality) and to a large extent depends on adequate treatment.

 In the case of clinical failure of the primary circuit of antibacterial full microbiological examination should be performed again in the enjoyment of all items regardless of the presence or absence of clear evidence. In this situation, besides the primary diagnostic methods must be:

• CT of the body (pay special attention to the lungs, liver, spleen, kidney);
• direct microscopic and bacteriological examination of the cerebrospinal fluid;
• fundus examination;
• CT scan of the skull - with indications (focal neurological symptoms and cerebral);
• remove the central catheter in the presence of at least minimal signs of inflammation of tissues in situ, with microbiological investigation of its parts, is under the skin.

Particular attention should be paid to the centers, which can be detected by clinical examination: mucositis, perianal infiltration, pulmonary infiltrates, respiratory failure, defects and infiltration of the mucous membranes and skin, lymphadenitis, focal neurological symptoms, abdominal problems, cardiac, renal activity, etc. . with their microbiological analysis possible.

In the presence of pseudomembranous enterocolitis vancomycin simultaneously with parenteral administration should be administered per os.

Appointment is necessary at an earlier date: amphotericin B - in the presence of deep fungal infections of the oral mucosa, skin, or a clearly defined focus in the lung parenchyma (CT).

Metronidazole - if there is heavy (with tissue defects) endotselyulita oral mucosa/esophagus and/or perianal infiltrate.

Biseptol — in the presence of diffuse pulmonary symptoms (interstitial/drain/basal pneumonia). In the presence of respiratory failure parenteral administration biseptolum is urgent, regardless of the conclusion of the radiologist (as occurs interstitial Pneumocystis pneumonia in patients with febrile neutropenia). Biseptolum high dose - 20 mg/kg trimethoprim.

Zovirax - in the presence of herpetic lesions of the skin/mucous membranes or suspected herpes infection at other sites (CNS, lungs, etc.).

In cases of suspected CMV infection (especially in cases of CMV serologic positivity): CMV pneumonia, CMV hepatitis, etc. - must be assigned to ganciclovir, valacyclovir or foscarnet. In the absence of these drugs is used zovirax, which can be effective in these cases, approximately 30% of patients. The presence of severe, in violation of vital functions, asperigileznoy invasion and/or invasion of Candida species resistant necessitates the appointment of amphotericin B, liposomal amphotericin B (ambisome), caspofungin (cancidas), voriconazole (vifend), anidulafungin (eraksisa).

Infectious hepatitis B and C (serologically documented process activity) should be treated recombinant interferon dose of 1-2 million IU 10-21 days and then 4 MIU 3 times a week for 2 to 6 months or pegirovannymi forms of interferon with added lipoic acid in high doses per os or intravenously.

TACTICS THAT CAN NOT BE STRONGLY RECOMMENDED.

1. Antibiotic monotherapy, which can be used in any other situation, is unacceptable in patients with febrile neutropenia in the background of intensive chemotherapy, even in cases where a specific identification of the pathogen, as always in such a situation, there is the potential for undetected mixed infection and the development of cross-resistance of pathogens.
2. Non-therapeutic use below the third-generation cephalosporins and penicillins, which have antibetalaktamaznoy activity since they are ineffective against opportunistic microflora.
3. Do not use for medicinal purposes per os drugs (except those for which the path is due specifically) and intramuscular and subcutaneous injections, except insulin (risk of abscess formation in the background immunosuppression and hematomas in thrombocytopenia). 
4. It can not be recommended single administration of the entire daily dose, which is permissible in other situations, as always there is a high clearance by maintaining a high rate of diuresis (prevention of septic shock), with the exception of amphotericin B.
5. It does not make sense to use two simultaneous cephalosporins or aminoglycosides, since in this case there is no synergistic increase in toxicity.
6. Unacceptable cessation of antibiotic therapy earlier than 3 days after the normalization of temperature because of the risk of forming resistant strains and reinfection.
7. It is unacceptable to start antimicrobial therapy without accompanying prophylactic infusion, given the significant risk of infectious-toxic shock.
8. Reduction of doses of medication is not permitted (unless renal or hepatic failure, when the dose may only be modified with a creatinine clearance or clearly indicated in the instructions, on the basis of the markers of hepatic dysfunction), as well as any change in the method and mode of administration, since it can lead to reduce therapeutic efficacy, formation of cross-resistance improving agents and the toxic load on the body of the patient.

Transfusion support.

Replacement of red blood cells.

Replacement of red blood cells is carried out at the level of hemoglobin less than 70 g/l eritrocontsentratom (er. mass). Patients with leukemia at initial hyperleykocytosis > 50,000/mm³; replacement of red blood cells to normal is strictly prohibited! In this situation, erythrocyte transfusions are carried out only in the presence of hypoxemia.

Replacement of platelets.

Levels thrombocytopenia and choice of treatment tactics:

1. at 50-100/l possible to carry out urgent operations, followed by the completion of the platelet count;
2. at 30-50/l may conduct minimally invasive operations, catheterizations, etc.;
3. at 20-30/l to carry out any surgical intervention is impossible, platelet transfusion is performed in hemorrhagic syndrome;
4. less than 20 cells / mm - shown transfusion even without hemorrhagic syndrome.

N.B.! Even in young patients, even in children, even with normal blood pressure at less than 20 platelets/ml should be prepared for hemorrhagic stroke!

Replacement of plasma factors.

Fresh frozen plasma is carried out, which is entered when the deficit (can be used as a reference level of plasma fibrinogen <2 g/l); at a dose of up to 30 ml/kg/day.) in 3 divided doses.

The use of growth factors for the elimination of neutropenia.

The use of recombinant hematopoietic factors (G-CSF, GM-CSF) (granocyte, neupogen, neulastim) to stimulate hematopoiesis germs and overcoming myelosuppression when FN was considered in several randomized trials. Today, on the basis of the published results of the joint can make the following conclusions and recommendations on the appointment CSF patients during febrile neutropenia:

1. the use of CSF significantly reduced the duration of neutropenia;
2. revealed no positive impact on the CSF for FN: (duration of fever, duration of antimicrobial therapy);
3. were found to reduce the cost of treating an episode of FN;
4. revealed no effect on CSF levels of mortality from infections;
5. is not justified by the routine use of CSF in patients with uncomplicated FN (FN uncomplicated fever is defined as lasting less than 10 days without signs of severe infections and organ dysfunction);
6. the use of CSF is justified in patients with a high risk of infectious complications life-threatening.
7. Growth factors absolutely indicated for mild neutropenia (absolute neutrophil count <0.1 to 1 mm), the absence of tumor remission, pneumonia, hypotension, sepsis with multiple organ failure, invasive fungal infections, age 65, early postcytostatics lymphopenia, tendency to hypotension.

An important point is fairly frequent deterioration of the patient after the level of granulocytes. After all, the role of neutrophils in the mechanisms of systemic inflammatory response syndrome, multiple organ failure and septic shock has been well studied.