Introduction
Neutropenic sepsis is a major cause of mortality in patients receiving intensive chemotherapy regime (1). Mortality rate can reach up to 18% in cases with proven bacteraemia (2)
Sepsis is a systemic inflammatory response syndrome leading to tissue injury due to severe infection. Therefore, prompt diagnosis and management of sepsis can improve the outcome.
In my review, I will be discussing how to assess, diagnose and manage Neutropenic sepsis in patients undergoing chemotherapy treatment for haematological and solid tumours.
Sepsis Criteria (3)
Fever >38.3C or < 36C, heart rate >90/min, tachypnea > 30/min, altered mental status, hyperglycaemia in absence of diabetes
Raised CRP or procalcitonin
Hypotension
Hypoxaemia
Acute oliguria (urine output < o.5ml/kg/hr), creatinine >0.5mg/dl
INR > 1.5
Thrombocytopenia
Hyperbilirubinaemia
Raised lactate > 3mmol/l
Decreased Capillary refill
WBC >12.000 or <4000
*In neutropenia patients would have low neutrophil count <1.0
*Severe sepsis is SIRS + organ dysfunction or tissue hypoperfusion ( hypotension, high lactate, low urine output)
*Septic shock is severe sepsis + persistent hypotension despite intravenous fluids
Incidence and Risk factors
Incidence of sepsis during neutropenia phase after intensive chemotherapy lies between 70-100%, it also depends on the overall performance status of patients and the duration of neutropenia(4)
Main risk factors for developing sepsis are the duration of neutropenia, catheters insertion, invasive diagnostic procedure and tumour invasion/obstruction e.g colon cancer, lung cancer(5) which facilitates pathogens growth. Moreover, malnourished patients are at increased risk.
In 2000, Multinational Association for Supportive Care in Cancer (MASCC) was implemented to identify high and low risk patients presenting with febrile neutropenia(6) it has been approved by NICE guideline.
Patients with a score of 21 or above are considered low risk for developing complications(6) whom can be safely treated with oral antibiotics rather than with aggressive treatments. See table below
Presentation
• Neutropenic patients with sepsis can present with vague symptoms e.g confusion or feeling unwell, not necessarily with the same features mentioned in Sepsis Criteria above, particularly in patients taking steroids which can dampen the SIRS. Thus, doctors must have a high index of suspicion for infection in every patient receiving chemotherapy who become unwell(7)
• Neutrophil count start plummeting 7 days post administration of chemotherapy and can last for up to 6 weeks in some cases(7), at which patients are more likely to develop severe sepsis.
Assessment
• ABC assessment with resuscitative measures as needed. Empiric antibiotics should not be delayed.
• Then take full history and examination which should include all systems: CNS, ENT, respiratory, cardiac, abdomen, skin for superficial infections/wounds/indwelling chest and abdominal drains and not to miss intravascular central access sites.
• Occult sources of infection could be(8): Endocarditis, enterocolitis, osteomyelitis, meningitis, intravascular access, skin, empyema.
• Blood sampling should include blood culture from peripheral site and central access if applicable. Other supportive tests like CRP, lactate, BM, U&E, LFTs and FBC are as important.
• CXR is not indicated routinely unless indicated(9)
• Samples from wounds/skin/urine/stool/throat swab should be obtained as appropriate to look for a source of infection.
• Confirm the diagnosis of neutropenic sepsis in patients with neutrophil count is 0.5 x 109 or lower with either: a) temperature higher than 38C or b) signs or symptoms consistent with clinically significant sepsis (10)
Management
Management of neutropenic sepsis patients is more or less similar to non-neutropenic patients through early goal directed therapy. Follow sepsis 6 protocol which includes:
1. Oxygen, aim to keep saturation above 94% (COPD patients can be adjusted according to patient condition)
2. Take blood cultures
3. IV antibiotics
4. IV fluids
5. Check lactate
6. Urine output
Patients in severe sepsis to sepsis shock ideally should have central venous access and Intensive care unit monitoring. However, uncomplicated patients can be managed at ward-based level
Antimicrobial treatment
Empirical antibiotics with broad spectrum cover must be given immediately within 1 hour from presentation in every suspected neutropenic sepsis patient as it’s associated with increased survival(11). Every one hour delay in administration of antibiotics over 6 hours decreased survival by 7.6%(11).. Piperacillin/Tazobactam is been used in my trust as 1st line treatment of sepsis with gentamicin or clarithromycin if suspecting renal or chest, respectively, as a source of infection.
In one study, the use of B-lactam antibiotic/aminoglycoside combinations showed superior outcome as compared to single agent antimicrobial in neutropenic patients with severe sepsis and septic shock(12).
Cardiovascular support
Cardiovascular support should be initiated using crystalloid or colloid fluids. To maintain adequate organ perfusion, the goal is: MAP≥65mmHg, CVP 8-12mmHg, PWP 12-15mmHg, urine output ≥ 0.5ml/kg/hr.
No evidence supports the use of human albumin even in patients with burns or hypoalbuminaemia (13).
Vassopressors are indicated if MAP can not be maintained above 65mmHg with drug of choice Norepinephrine. Dobutamine can be instituted in case of sepsis related myocardial depression leading to low cardiac output.
Pulmonary support
Acute respiratory failure in sepsis related situations has mortality rate reaching 50% (14). Fifty percent of patients with severe sepsis will develop acute lung injury(15)
In the cooperative patients with no altered mental status NIV with CPAP can be attempted. However, in severe respiratory insufficiency, endotracheal intubation is indicated. Early implementation of NIV lead to significant reduction of intubation(16)
Renal support
Acute kidney injury can occur in up to 1/4 of patients with severe sepsis and 1/2 of septic shock patients. Acute tubular necrosis due to renal hypoperfusion and ischaemia is thought to be the main reason.
Renal replacement therapy can be started when deemed appropriate as no current clear guideline on the timing of initiation.
Intermittent haemodialysis and continuous renal replacement showed no difference in survival in meta analysis studies(17-18)
Dosage of antibiotics should be adjusted according to kidney function.
Low-dose dopamine for protection of kidney function hasn’t been recommended (19)
(GCSF) Granulocyte-colony stimulating factor
The use of GCSF in neutropenic patient has been proven to reduce recovery time of neutrophil count and length of hospitalization (20) It has reduced infection related mortality but not overall mortality
Immunoglobulins
IVIG use in neutropenic sepsis didn’t show any significant difference in survival rate(21).
Blood products
Haemoglobin should be kept >9gm/dl, cut off for platelets transfusion should be 20.000 rather than 10.000.
Granulocytes transfusion has shown some benefit in several case reports in patients with severe fungal infections but randomized trial showed no beneficial effect. Hence, no recommendation for use of granulocyte transfusion.
References
1. Penack, O. et al. (2014) ‘Management of sepsis in neutropenic patients: 2014 Updated guidelines from the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO)’, Annals of Hematology. doi: 10.1007/s00277-014-2086-0.
2. Kuderer, N.M., Dale, D.C., Crawford, J., Cosler, L.E. and Lyman, G.H., 2006. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer, 106(10), pp.2258-2266
3. Levy, M.M., Fink, M.P., Marshall, J.C., Abraham, E., Angus, D., Cook, D., Cohen, J., Opal, S.M., Vincent, J.L. and Ramsay, G., 2003. 2001 sccm/esicm/accp/ats/sis international sepsis definitions conference. Intensive care medicine, 29(4), pp.530-538
4. Moerer, O. and Quintel, M., 2009. Sepsis in adult patients-definitions, epidemiology and economic aspects. Der Internist, 50(7), pp.788-790
5. Green, R.S., Djogovic, D., Gray, S., Howes, D., Brindley, P.G., Stenstrom, R., Patterson, E., Easton, D. and Davidow, J.S., 2008. Canadian Association of Emergency Physicians Sepsis Guidelines: the optimal management of severe sepsis in Canadian emergency departments. Canadian Journal of Emergency Medicine, 10(5), pp.443-459
6. Klastersky, J., Paesmans, M., Rubenstein, E.B., Boyer, M., Elting, L., Feld, R., Gallagher, J., Herrstedt, J., Rapoport, B., Rolston, K. and Talcott, J., 2000. The Multinational Association for Supportive Care in Cancer risk index: a multinational scoring system for identifying low-risk febrile neutropenic cancer patients. Journal of Clinical Oncology, 18(16), pp.3038-3051
7. Freifeld, A.G., Bow, E.J., Sepkowitz, K.A., Boeckh, M.J., Ito, J.I., Mullen, C.A., Raad, I.I., Rolston, K.V., Young, J.A.H. and Wingard, J.R., 2011. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clinical infectious diseases, 52(4), pp.e56-e93.
8. Holmes, F.A., Jones, S.E., O’shaughnessy, J., Vukelja, S., George, T., Savin, M., Richards, D., Glaspy, J., Meza, L., Cohen, G. and Dhami, M., 2002. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Annals of Oncology, 13(6), pp.903-909.
9. Cohen, J. and Drage, S., 2011. How I manage haematology patients with septic shock. British journal of haematology, 152(4), pp.380-391.
10. Bate, J., Gibson, F., Johnson, E., Selwood, K., Skinner, R. and Chisholm, J., 2013. Neutropenic sepsis: prevention and management of neutropenic sepsis in cancer patients (NICE Clinical Guideline CG151). Archives of Disease in Childhood-Education and Practice, 98(2), pp.73-75
11. Legrand, M., Max, A., Peigne, V., Mariotte, E., Canet, E., Debrumetz, A., Lemiale, V., Seguin, A., Darmon, M., Schlemmer, B. and Azoulay, E., 2012. Survival in neutropenic patients with severe sepsis or septic shock. Critical care medicine, 40(1), pp.43-49.
12. Legrand, M., Max, A., Peigne, V., Mariotte, E., Canet, E., Debrumetz, A., Lemiale, V., Seguin, A., Darmon, M., Schlemmer, B. and Azoulay, E., 2012. Survival in neutropenic patients with severe sepsis or septic shock. Critical care medicine, 40(1), pp.43-49
13. Alderson, P., Bunn, F., Lefebvre, C., Li, W.P., Li, L., Roberts, I. and Schierhout, G., 2002. Human albumin solution for resuscitation and volume expansion in critically ill patients. Cochrane Database Syst Rev, (1), p.CD001208
14. Azoulay, É. and Schlemmer, B., 2006. Diagnostic strategy in cancer patients with acute respiratory failure. Intensive care medicine, 32(6), pp.808-822.
15. Sevransky, J.E., Levy, M.M. and Marini, J.J., 2004. Mechanical ventilation in sepsis-induced acute lung injury/acute respiratory distress syndrome: an evidence-based review. Critical care medicine, 32(11), pp.S548-S553
16. Horn, D.L., Morrison, D.C., Opal, S.M., Silverstein, R., Visvanathan, K. and Zabriskie, J.B., 2000. What are the microbial components implicated in the pathogenesis of sepsis? Report on a symposium. Clinical infectious diseases, 31(4), pp.851-858.
17. Kellum, J.A., Angus, D.C., Johnson, J.P., Leblanc, M., Griffin, M., Ramakrishnan, N. and Linde-Zwirble, W.T., 2002. Continuous versus intermittent renal replacement therapy: a meta-analysis. Intensive care medicine, 28(1), pp.29-37
18. Tonelli, M., Manns, B. and Feller-Kopman, D., 2002. Acute renal failure in the intensive care unit: a systematic review of the impact of dialytic modality on mortality and renal recovery. American Journal of Kidney Diseases, 40(5), pp.875-885
19. Bellomo, R., Chapman, M., Finfer, S., Hickling, K. and Myburgh, J., 2000. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet (London, England), 356(9248), pp.2139-2143.
20. Clark, O.A., Lyman, G.H., Castro, A.A., Clark, L.G. and Djulbegovic, B., 2005. Colony-stimulating factors for chemotherapy-induced febrile neutropenia: a meta-analysis of randomized controlled trials. Journal of Clinical Oncology, 23(18), pp.4198-4214
21. Hentrich, M., Fehnle, K., Ostermann, H., Kienast, J., Cornely, O., Salat, C., Übelacker, R., Buchheidt, D., Behre, G., Hiddemann, W. and Schiel, X., 2006. IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: A randomized, controlled, multiple-center trial. Critical care medicine, 34(5), pp.1319-1325