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High-value care for critically ill oncohematological patients: what do we know thus far?

ABSTRACT

The number of patients with cancer requiring intensive care unit admission is increasing around the world. The improvement in the pathophysiological understanding of this group of patients, as well as the increasingly better and more targeted treatment options for their underlying disease, has led to a significant increase in their survival over the past three decades. Within the organizational concepts, it is necessary to know what adds value in the care of critical oncohematological patients. Practices in medicine that do not benefit patients and possibly cause harm are called low-value practices, while high-value practices are defined as high-quality care at relatively low cost. In this article, we discuss ten domains with high-value evidence in the care of cancer patients: (1) intensive care unit admission policies; (2) intensive care unit organization; (3) etiological investigation of hypoxemia; (4) management of acute respiratory failure; (5) management of febrile neutropenia; (6) urgent chemotherapy treatment in critically ill patients; (7) patient and family experience; (8) palliative care; (9) care of intensive care unit staff; and (10) long-term impact of critical disease on the cancer population. The disclosure of such policies is expected to have the potential to change health care standards. We understand that it is a lengthy process, and initiatives such as this paper are one of the first steps in raising awareness and beginning a discussion about high-value care in various health scenarios.

Keywords:
Neoplasms; Low-value care; Cost of illness; Hospital costs; Critical illness; Patient care management; Intensive care units

RESUMO

O número de pacientes oncológicos com necessidade de internação em unidades de terapia intensiva está aumentando em todo o mundo. A maior compreensão fisiopatológica desse grupo de pacientes, bem como opções de tratamento cada vez melhores e mais direcionadas à doença subjacente, tem levado a um aumento significativo da sobrevida nas últimas três décadas. Dentro dos conceitos organizacionais é necessário saber o que agrega valor ao cuidado de pacientes onco-hematológicos graves. As práticas terapêuticas não benéficas aos pacientes e possivelmente causadoras de danos são chamadas práticas de baixo valor, enquanto as práticas de alto valor são definidas como cuidados de alta qualidade a um custo relativamente baixo. Neste artigo discutimos dez domínios com evidências de alto valor no cuidado de pacientes com câncer: (1) políticas de internação na unidade de terapia intensiva; (2) organização da unidade de terapia intensiva; (3) investigação etiológica da hipoxemia; (4) manejo da insuficiência respiratória aguda; (5) manejo da neutropenia febril; (6) tratamento quimioterápico de urgência em pacientes graves; (7) experiência do paciente e da família; (8) cuidados paliativos; (9) cuidados com a equipe da unidade de terapia intensiva; e (10) impacto a longo prazo da doença grave na população oncológica. Esperase que a divulgação dessas políticas traga mudanças aos padrões atuais do cuidado em saúde. Entendemos que é um processo longo, e iniciativas como o presente artigo são um dos primeiros passos para aumentar a conscientização e possibilitar discussão sobre cuidados de alto valor em vários cenários de saúde.

Descritores:
Neoplasias; Cuidados de baixo valor; Custo da doença; Custos hospitalares; Estado terminal; Administração dos cuidados do paciente; Unidades de terapia intensiva

INTRODUCTION

Cancer mortality has decreased in the past three decades;(11 Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, CA Cancer J Clin. 2016;66(4):271-89.) however, the number of cancer patients requiring intensive care unit (ICU) admission is increasing. Data suggest that 25% to 30% of the beds in ICUs are occupied by cancer patients and that cancer characteristics are not associated with worse outcomes in the short term.(22 Schellongowski P, Staudinger T, Kundi M, Laczika K, Locker GJ, Bojic A, et al. Prognostic factors for intensive care unit admission, intensive care outcome, and post-intensive care survival in patients with de novo acute myeloid leukemia: a single center experience. Haematologica. 2011;96(2):231-7.)

The evolving knowledge of critically ill patients with cancer has introduced new concepts in patient management and ICU admission policies.(33 Azoulay E, Pène F, Darmon M, Lengliné E, Benoit D, Soares M, Vincent F, Bruneel F, Perez P, Lemiale V, Mokart D; Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique (Grrr-OH). Managing critically III hematology patients: iime to think differently. Blood Rev. 2015;29(6):359-67.,44 Azoulay E, Mokart D, Lambert J, Lemiale V, Rabbat A, Kouatchet A, et al. Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial. Am J Respir Crit Care Med. 2010;182(8):1038-46.) Within organizational concepts, it is necessary to know what adds value in caring for critical oncohematological patients; thus, the term “high-value care” was coined.

High-value care practices are defined as high quality of care at relatively low cost.(55 Blayney DW, Simon MK, Podtschaske B, Ramsey S, Shyu M, Lindquist C, et al. Critical lessons from high-value oncology practices. JAMA Oncol. 2018;4(2):164-71.) To identify what these practices are, researchers examine “positive deviants” (i.e., practices with good results associated with better outcomes;(66 Bradley EH, Curry LA, Ramanadhan S, Rowe L, Nembhard IM, Krumholz HM. Research in action: using positive deviance to improve quality of health care. Implement Sci. 2009;4:25.) practices that already exist; and practices that health care providers with expertise can generalize).(77 Marsh DR, Schroeder DG, Dearden KA, Sternin J, Sternin M. The power of positive deviance. BMJ. 2004;329(7475):1177-9.,88 Walker LO, Sterling BS, Hoke MM, Dearden KA. Applying the concept of positive deviance to public health data: a tool for reducing health disparities. Public Health Nurs. 2007;24(6):571-6.) The application of these practices has already been successfully applied in child nutrition and gestational care.(99 Marsh DR, Pachón H, Schroeder DG, Ha TT, Dearden K, Lang TT, et al. Design of a prospective, randomized evaluation of an integrated nutrition program in rural Viet Nam. Food Nutr Bull. 2002;23(4 Suppl):36-47.,1010 Ahrari M, Kuttab A, Khamis S, Farahat AA, Darmstadt GL, Marsh DR, et al. Factors associated with successful pregnancy outcomes in upper Egypt: a positive deviance inquiry. Food Nutr Bull. 2002;23(1):83-8.)

It is known, however, that the mere publication of items with scientific evidence of low-value care reduction alone will not be effective. Change will come from a broader discussion of culture, the benefit of economic savings in cutting low-value care, and the involvement of sectors of society so that knowledge of these topics will not be limited to the medical community.(1111 Rourke EJ. Ten years of choosing wisely to reduce low-value care. N Engl J Med. 2022;386(14):1293-5.) Cliff et al. demonstrated that the disclosure of such items has the potential to change patterns of health activity.(1212 Cliff BQ, Avancena AL, Hirth RA, Lee SD. The impact of choosing wisely interventions on low-value medical services: a systematic review. Milbank Q. 2021;99(4):1024-58.)

Decreasing low-value care has the potential for cost savings; therefore, discussion of the best payment models is of paramount importance. It is logical to think that the fee-for-service model, in which payment is based on the procedure executed, stimulates low-value care practices when compared to other models such as fee-for-performance.(1313 Park S, Jung J, Burke RE, Larson EB. Trends in use of low-value care in traditional fee-for-service medicare and medicare advantage. JAMA Netw Open. 2021;4(3):e211762.,1414 Mafi JN, Reid RO, Baseman LH, Hickey S, Totten M, Agniel D, et al. Trends in Low-Value Health Service Use and Spending in the US Medicare Fee-for-Service Program, 2014-JAMA Netw Open. 2021;4(2):e2037328.) The above statement has a rationale, but although a cross-sectional study by Park et al. found that 13 low-value services were similarly present in two different models, practices such as unnecessary cancer screening and antibiotics for upper respiratory infection were as prevalent in a fee-for-service model as in a fee-for performance model.(1313 Park S, Jung J, Burke RE, Larson EB. Trends in use of low-value care in traditional fee-for-service medicare and medicare advantage. JAMA Netw Open. 2021;4(3):e211762.) This suggests that the model is one of the topics that should be addressed to cut low-value care costs, along with health service costs, education, protocol development and better career plans for health care workers.(1414 Mafi JN, Reid RO, Baseman LH, Hickey S, Totten M, Agniel D, et al. Trends in Low-Value Health Service Use and Spending in the US Medicare Fee-for-Service Program, 2014-JAMA Netw Open. 2021;4(2):e2037328.)

We know that it is a lengthy process, and in this article, through the collaboration of seven experts on oncologic critical care, we list 10 domains with evidence of high value in the care of patients with cancer (Figure 1).

Figure 1
High-value care in the oncological intensive care unit

1. Intensive care unit admission policies

Intensive care unit admission of patients with cancer is frequently delayed,(1515 Azoulay E, Mokart D, Pène F, Lambert J, Kouatchet A, Mayaux J, et al. Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium-a groupe de recherche respiratoire en reanimation onco-hematologique study. J Clin Oncol. 2013;31(22):2810-8.,1616 Escher M, Perneger TV, Chevrolet JC. National questionnaire survey on what influences doctors’ decisions about admission to intensive care. BMJ. 2004;329(7463):425.) but it is known that delayed admission and oxygen therapy use are associated with higher mortality,(1717 Mokart D, Lambert J, Schnell D, Fouché L, Rabbat A, Kouatchet A, et al. Delayed intensive care unit admission is associated with increased mortality in patients with cancer with acute respiratory failure. Leuk Lymphoma. 2013;54(8): 1724-9.) while rapid ICU transfer is associated with better outcomes.(1818 Song JU, Suh GY, Park HY, Lim SY, Han SG, Kang YR, et al. Early intervention on the outcomes in critically ill cancer patients admitted to intensive care units. Intensive Care Med. 2012;38(9):1505-13.) Therefore, timely ICU admission is a measure of high-value care. Lengline et al. demonstrated that in patients with acute myeloid leukemia and a high risk of tumor lysis, direct admission to the ICU, even if there was no organ dysfunction, was associated with better outcomes.(1919 Lengliné E, Raffoux E, Lemiale V, Darmon M, Canet E, Boissel N, et al. Intensive care unit management of patients with newly diagnosed acute myeloid leukemia with no organ failure. Leuk Lymphoma. 2012;53(7):1352-9.) Applying objective criteria, such as the modified early warning score (MEWS), can be a strategy to improve ICU admission at the right time.(2020 Young RS, Gobel BH, Schumacher M, Lee J, Weaver C, Weitzman S. Use of the modified early warning score and serum lactate to prevent cardiopulmonary arrest in hematology-oncology patients: a quality improvement study. Am J Med Qual. 2014;29(6):530-7.)

It is of paramount importance to realize that cancer-related characteristics do not predict short-term outcomes. Actually, the severity of organ dysfunction at ICU admission and performance status are more sensitive prognostic predictors. (1515 Azoulay E, Mokart D, Pène F, Lambert J, Kouatchet A, Mayaux J, et al. Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium-a groupe de recherche respiratoire en reanimation onco-hematologique study. J Clin Oncol. 2013;31(22):2810-8.,2121 Soares M, Lobo SM, Torelly AR Mello PV, Silva U, Teles JM, Silva E, Caruso P, Friedman G, Souza PC, Réa-Neto A, Vianna AO, Azevedo JR, Vale E, Rezegue L, Godoy M, Maia MO, Salluh Jl; Rede Brasileira de Pesquisa em Terapia Intensiva. Outcomes of cancer patients admitted to Brazilian intensive care units with severe acute kidney injury. Rev Bras Ter Intensiva. 2010;22(3):236-44.,2222 Zampieri FG, Bozza FA, Moralez GM, Mazza DD, Scotti AV, Santino MS, et al. The effects of performance status one week before hospital admission on the outcomes of critically ill patients. Intensive Care Med. 2017;43(1 ):39-47.)

In cases of uncertainties related to the benefit of ICU “full code care”, a time-limited trial (TLT) is a high-value care practice.(2323 Azoulay E, Pochard F, Garrouste-Orgeas M, Moreau D, Montesino L, Adrie C, de Lassence A, Cohen Y Timsit JF; Outcomerea Study Group. Decisions to forgo life-sustaining therapy in ICU patients independently predict hospital death. Intensive Care Med. 2003;29(11):1895-901.,2424 Rocker G, Cook D, Sjokvist P, Weaver B, Finfer S, McDonald E, Marshall J, Kirby A, Levy M, Dodek |P, Heyland D, Guyatt G; Level of Care Study Investigators; Canadian Critical Care Trials Group. Clinician predictions of intensive care unit mortality. Crit Care Med. 2004;32(5):1149-54.) Lecuyer et al., in a pioneering study about TLT, demonstrated that the behavior of organ dysfunction up to the fifth day of ICU admission accurately predicted ICU mortality in nonbedridden patients with cancer. In patients requiring mechanical ventilation, vasopressors or renal replacement therapy, 3 days of treatment was enough to predict ICU mortality.(2525 Lecuyer L, Chevret S, Thiery G, Darmon M, Schlemmer B, Azoulay E. The ICU trial: a new admission policy for cancer patients requiring mechanical ventilation. Crit Care Med. 2007;35(3):808-14.)

The question of the TLT duration may have some peculiarities. Shrime et al. showed that a TLT of up to 4 days for patients with solid tumors and more severe organ dysfunction could discriminate 30-day survival. However, Shrime et al. concluded that for patients with hematological malignancies or with lower levels of organ dysfunction, a longer TLT duration, up to 2 weeks, is recommended.(2626 Shrime MG, Ferket BS, Scott DJ, Lee J, Barragan-Bradford D, Pollard T, et al. Time-limited trials of intensive care for critically ill patients with cancer: how long is long enough? JAMA Oncol. 2016;2(1):76-83.)

Regardless of the nuances of the evolution of each patient, it is important that we have a clear objective for admitting patients with cancer to the ICU. We know that some symptom control conditions require resources that the ward cannot provide; therefore, some patients can be admitted for symptom care.(2727 Merceron S, Canet E, Lemiale V, Azoulay E. Palliative vasoactive therapy in patients with septic shock. Chest. 2014;146(3):e107-8.)

In conclusion, points of ICU admission high-value care are as follows: admission as soon as organ dysfunction is identified; breaking the paradigm that cancer characteristics alone are prognostic factors; and TLT use in cases with uncertainties about the short-term evolution.

2. Intensive care unit organization

Intensive care unit practices and team organization have an impact on the outcome of patients with cancer. Hawari et al. demonstrated that implementing a high-intensity ICU staffing model was associated with a decrease in mortality by 15% to 60% in critically ill patients with cancer.(2828 Hawari Fl, AI Najjar Tl, Zaru L, AI Fayoumee W, Salah SH, Mukhaimar MZ. The effect of implementing high-intensity intensive care unit staffing model on outcome of critically ill oncology patients. Crit Care Med. 2009;37(6):1967-71.) Additionally, Soares et al. showed that the presence of clinical pharmacists in ICUs was associated with increased odds of survival in critically ill patients with cancer.(2929 Soares M, Bozza FA, Azevedo LC, Silva UV, Corrêa TD, Colombari F, et al. Effects of organizational characteristics on outcomes and resource use in patients with cancer admitted to intensive care units. J Clin Oncol. 2016;34(27):3315-24.)

Effective communication and therapeutic planning are essential in an oncological ICU because there may be points of care that are unknown by the ICU team, such as chemotherapy support, particularities of cancer care and alignment of patient and family expectations. However, oncologists and intensivists have different knowledge, and conflicts may arise about the proper management of these patients. A survey was conducted in Brazil among oncologists and intensivists at 2 academic cancer centers on the management of hypothetical patients with different types of cancer (metastatic pancreatic cancer and metastatic breast cancer) who developed septic shock and multiple organ failure.(3030 Nassar AP Jr, Dettino AL, Amendola CR Santos RA, Forte DN, Caruso P. Oncologists’ and intensivists’ attitudes toward the care of critically ill patients with cancer. J Intensive Care Med. 2019;34(10):811-17.) The results showed that although most oncologists and intensivists were in agreement about the goals of treatment, there were significant differences in how they approached the management of these two hypothetical cases. Intensivists favored the withdrawal of life support measures for patients with breast cancer more than oncologists did (54% versus 21%; p < 0.001). The results of this study suggested that oncologists tend to focus on cancer characteristics, while intensivists focus on multiple organ failure. Regular meetings between oncologists and intensivists can reduce potential conflicts regarding the intensive care of patients with cancer.(3030 Nassar AP Jr, Dettino AL, Amendola CR Santos RA, Forte DN, Caruso P. Oncologists’ and intensivists’ attitudes toward the care of critically ill patients with cancer. J Intensive Care Med. 2019;34(10):811-17.) Therefore, this integration is very important and is the rationale behind why daily rounds are associated with reduced hospital mortality and a more efficient use of resources in critically ill patients with cancer.(3131 Soares M, Bozza FA, Angus DC, Japiassú AM, Viana WN, Costa R, et al. Organizational characteristics, outcomes, and resource use in 78 Brazilian intensive care units: the ORCHESTRA study. Intensive Care Med. 2015;41(12):2149-60.)

In a retrospective analysis of 129,680 admissions in 93 ICUs, Zampieri et al. characterized the ICUs into three “phenotypes” based on three organizational characteristics: degree of nursing autonomy (measured by a score of autonomy in domains such as drug-drug titration, sedation and nutrition, active mobilization, weaning from mechanical ventilation and medication to control symptoms), presence of a dedicated clinical pharmacist, and presence of intensivists with certification 24 hours/7 days a week.(3232 Zampieri FG, Salluh Jl, Azevedo LC, Kahn JM, Damiani LR Borges LR Viana WN, Costa R, Corrêa TD, Araya DES, Maia MO, Ferez MA, Carvalho AGR, Knibel MF, Melo UO, Santino MS, Lisboa T, Caser EB, Besen BAMR Bozza FA, Angus DC, Soares M; ORCHESTRA Study Investigators. ICU staffing feature phenotypes and their relationship with patients’ outcomes: an unsupervised machine learning analysis. Intensive Care Med. 2019;45(11):1599-607.) Their study suggested that patients treated in ICUs combining expert intensivist coverage, a dedicated pharmacist and nurses with greater autonomy had the best outcomes.(3232 Zampieri FG, Salluh Jl, Azevedo LC, Kahn JM, Damiani LR Borges LR Viana WN, Costa R, Corrêa TD, Araya DES, Maia MO, Ferez MA, Carvalho AGR, Knibel MF, Melo UO, Santino MS, Lisboa T, Caser EB, Besen BAMR Bozza FA, Angus DC, Soares M; ORCHESTRA Study Investigators. ICU staffing feature phenotypes and their relationship with patients’ outcomes: an unsupervised machine learning analysis. Intensive Care Med. 2019;45(11):1599-607.)

Notably, the number of available protocols for the prevention of care-related infections was also significantly different in ICUs with better performance, with a higher average in ICUs with better performance.(3232 Zampieri FG, Salluh Jl, Azevedo LC, Kahn JM, Damiani LR Borges LR Viana WN, Costa R, Corrêa TD, Araya DES, Maia MO, Ferez MA, Carvalho AGR, Knibel MF, Melo UO, Santino MS, Lisboa T, Caser EB, Besen BAMR Bozza FA, Angus DC, Soares M; ORCHESTRA Study Investigators. ICU staffing feature phenotypes and their relationship with patients’ outcomes: an unsupervised machine learning analysis. Intensive Care Med. 2019;45(11):1599-607.)

In conclusion, high-intensity ICU staffing models, with the presence of board-certified intensivists 24 hours/7 days a week, a dedicated clinical pharmacist, daily rounds in the ICU with the presence of an oncologist, and a higher degree of nursing autonomy in domains preestablished by protocols, are part of what we currently interpret as positive deviants of high-value care.

3. Etiological investigation of hypoxemia

The main cause of ICU admission of patients with cancer is hypoxemic respiratory failure.(3333 Azoulay E, Thiéry G, Chevret S, Moreau D, Darmon M, Bergeron A, et al. The prognosis of acute respiratory failure in critically ill cancer patients. Medicine (Baltimore). 2004;83(6):360-70.) Cancer patients with hypoxemic respiratory failure require immediate empirical treatment, but it is also of paramount importance to reach the cause of respiratory failure, since patients without an etiological diagnosis have a higher mortality.(3434 Contejean A, Lemiale V, Resche-Rigon M, Mokart D, Pène F, Kouatchet A, et al. Increased mortality in hematological malignancy patients with acute respiratory failure from undetermined etiology: a Groupe de Recherche en Reanimation Respiratoire en Onco-Hematologique (Grrr-OH) study. Ann Intensive Care. 2016;6(1):102.)

The etiological investigation of hypoxemic respiratory failure depends on the arsenal of complementary tests available and the care team’s expertise. The most striking change in the investigation was the introduction of molecular biology techniques and biomarkers that allow etiological diagnosis in approximately 80% of patients with or without cancer.(44 Azoulay E, Mokart D, Lambert J, Lemiale V, Rabbat A, Kouatchet A, et al. Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial. Am J Respir Crit Care Med. 2010;182(8):1038-46.,3535 Wohlfarth P, Turki AT, Steinmann J, Fiedler M, Steckel NK, Beelen DW, et al. Microbiologic Diagnostic Workup of Acute Respiratory Failure with Pulmonary Infiltrates after Allogeneic Hematopoietic Stem Cell Transplantation: Findings in the Era of Molecular- and Biomarker-Based Assays. Biol Blood Marrow Transplant. 2018;24(8):1707-14.) Studies using a systematic approach and a robust diagnostic arsenal have shown that approximately two-thirds of the causes of hypoxemia are infectious, while one-third are divided between noninfectious or indeterminable causes (Table 1).(3636 Yoo H, Suh GY, Jeong BH, Lim SY, Chung MR Kwon OJ, et al. Etiologies, diagnostic strategies, and outcomes of diffuse pulmonary infiltrates causing acute respiratory failure in cancer patients: a retrospective observational study. Crit Care. 2013;17(4):R150.)

Table 1
Etiological diagnoses most frequently reported in studies of patients with cancer and hypoxemic respiratory failure

The systematic approach begins with clinical investigation, and the Direct mnemonic described in the study by Schnell et al. is a relevant aid.(3737 Schnell D, Mayaux J, Lambert J, Roux A, Moreau AS, Zafrani L, et al. Clinical assessment for identifying causes of acute respiratory failure in cancer patients. Eur Respir J. 2013;42(2):435-43.) Imaging tests are indispensable because they narrow the diagnostic hypotheses but are insufficient because they usually do not allow etiological diagnosis. To collect samples of lower airway secretions, it is possible to use an invasive approach, via bronchoscopy, or a noninvasive approach. Although the invasive approach seems more productive, there is at least one randomized study showing that the noninvasive strategy is equally effective when compared to the use of bronchoscopy with bronchoalveolar lavage.(44 Azoulay E, Mokart D, Lambert J, Lemiale V, Rabbat A, Kouatchet A, et al. Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial. Am J Respir Crit Care Med. 2010;182(8):1038-46.)

Finally, when empirical treatment does not yield a positive result and a noninvasive or minimally invasive approach does not allow etiological diagnosis, an invasive approach, which consists of transbronchial or open lung biopsy, should be considered. Due to the high risk of pneumothorax or bleeding, transbronchial biopsy is usually contraindicated in patients with thrombocytopenia or with positive pressure ventilation.(3838 Pincus PS, Kallenbach JM, Hurwitz MD, Clinton C, Feldman C, Abramowitz JA, et al. Transbronchial biopsy during mechanical ventilation. Crit Care Med. 1987;15(12):1136-9.,3939 O’Brien JD, Ettinger NA, Shevlin D, Kollef MH. Safety and yield of transbronchial biopsy in mechanically ventilated patients. Crit Care Med. 1997;25(3):440-6.) In patients without thrombocytopenia and outside positive pressure ventilation, the safety of transbronchial biopsy is greater, and the diagnostic gain is high for diseases with peribronchial involvement. As the diagnostic gain for infectious diseases is greater for bronchoalveolar lavage than for lung biopsy, there is no point in replacing bronchoalveolar lavage with transbronchial biopsy, but they can be considered complementary.(3939 O’Brien JD, Ettinger NA, Shevlin D, Kollef MH. Safety and yield of transbronchial biopsy in mechanically ventilated patients. Crit Care Med. 1997;25(3):440-6.) In a study with non-HIV immunocompromised patients, the combined diagnostic gain of bronchoalveolar lavage with transbronchial biopsy was greater than the gain of bronchoalveolar lavage alone.(4040 Chellapandian D, Lehrnbecher T, Phillips B, Fisher BT, Zaoutis TE, Steinbach WJ, et al. Bronchoalveolar lavage and lung biopsy in patients with cancer and hematopoietic stem-cell transplantation recipients: a systematic review and meta-analysis. J Clin Oncol. 2015;33(5):501-9.)

Open lung biopsy is an exception for etiological diagnosis. The ideal time to indicate an open biopsy is uncertain, but biopsies performed immediately after the onset of hypoxemia are not superior to noninvasive or minimally invasive methods, while biopsies performed more than 10 days after recognition of the pulmonary infiltrate do not decrease in-hospital mortality.(4141 Flabouris A, Myburgh J. The utility of open lung biopsy in patients requiring mechanical ventilation. Chest. 1999;115(3):811-7.) The mortality of an open lung biopsy is not higher than that of most elective surgeries, occurs in approximately 2% of cases, and is almost exclusively caused by bleeding and hemothorax. The incidence and occurrence of severe bleeding are associated with coagulation disorders, especially thrombocytopenia.(4242 White DA, Wong PW, Downey R. The utility of open lung biopsy in patients with hematologic malignancies. Am J Respir Crit Care Med. 2000;161 (3 Pt 1):723-9.) Compared to bronchoalveolar lavage, open lung biopsy has a higher gain for noninfectious diagnoses but a lower gain for infectious diagnoses with a higher probability of complications.(4040 Chellapandian D, Lehrnbecher T, Phillips B, Fisher BT, Zaoutis TE, Steinbach WJ, et al. Bronchoalveolar lavage and lung biopsy in patients with cancer and hematopoietic stem-cell transplantation recipients: a systematic review and meta-analysis. J Clin Oncol. 2015;33(5):501-9.)

4. Management of acute respiratory failure

Acute respiratory failure (ARF) is the main cause of unplanned ICU admission among patients with cancer. (4343 Pastores SM, Voigt LP. Acute respiratory failure in the patient with cancer: diagnostic and management strategies. Crit Care Clin. 2010;26(1):21-40.,4444 Soares M, Depuydt PO, Salluh Jl. Mechanical ventilation in cancer patients: clinical characteristics and outcomes. Crit Care Clin. 2010;26(1):41-58.) The most common etiology of ARF in these patients is lung infection, which represents approximately 65% of patients with acute respiratory distress syndrome (ARDS).(4545 Azoulay E, Lemiale V, Mokart D, Pène F, Kouatchet A, Perez P. et al. Acute respiratory distress syndrome in patients with malignancies. Intensive Care Med. 2014;40(8):1106-14.) The risk of ARF is higher in patients with hematological malignancies than in those with solid tumors, especially in patients with neutropenia and those undergoing bone marrow transplantation.(4646 Benz R, Schanz U, Maggiorini M, Seebach JD, Stussi G. Risk factors for ICU admission and ICU survival after allogeneic hematopoietic SCT Bone Marrow Transplant. 2014;49(1):62-5.,4747 Chi AK, Soubani AO, White AC, Miller KB. An update on pulmonary complications of hematopoietic stem cell transplantation. Chest. 2013; 144(6): 1913-22.) Patients with cancer and febrile neutropenia may develop a distinct form of ARDS that occurs during the neutrophil recovery phase in association with the administration of granulocyte colony stimulating factor (G-CSF).(4848 Todeschini G, Murari C, Bonesi R, Pizzolo G, Verlato G, Tecchio C, et al. Invasive aspergillosis in neutropenic patients: rapid neutrophil recovery is a risk factor for severe pulmonary complications. Eur J Clin Invest. 1999;29(5):453-7.,4949 Balsat M, Xhaard A, Lengline E, Tavernier E, Cornillon J, Guyotat D, et al. Worsening of respiratory status during neutropenia recovery in noncritically ill hematological patients: results of a prospective multicenter study. Respiration. 2015;90(3):229-34.) Lung cancer is the most frequent tumor associated with respiratory complications among patients with solid tumors.(5050 Cupp J, Culakova E, Poniewierski MS, Dale DC, Lyman GH, Crawford J. Analysis of factors associated with in-hospital mortality in lung cancer chemotherapy patients with neutropenia. Clin Lung Cancer. 2018;19(2):e163-9.) Other frequent causes of ARF are drug-related pulmonary toxicity, radiation and clinical situations frequently presented in patients with cancer, such as chronic obstructive pulmonary disease, cardiogenic pulmonary edema, diffuse alveolar hemorrhage and acute lung injury associated with transfusion (TRALI). In patients affected by acute leukemia, ARF may be caused by leukemic pulmonary infiltration, leukostasis and pneumopathy secondary to tumor lysis.(5151 Moreau AS, Lengline E, Seguin A, Lemiale V, Canet E, Raffoux E, et al. Respiratory events at the earliest phase of acute myeloid leukemia. Leuk Lymphoma. 2014;55(11):2556-63.)

The hospital mortality of patients with cancer and ARF is approximately 50%, depending on the etiology, severity, need for invasive mechanical ventilation (IMV) and associated organ dysfunction.(5252 Azoulay E, Pickkers P, Soares M, Perner A, Rello J, Bauer PR, van de Louw A, Hemelaar P, Lemiale V, Taccone FS, Martin Loeches I, Meyhoff TS, Salluh J, Schellongowski P, Rusinova K, Terzi N, Mehta S, Antonelli M, Kouatchet A, Barratt-Due A, Valkonen M, Landburg PR Bruneel F, Bukan RB, Pène F, Metaxa V, Moreau AS, Souppart V, Burghi G, Girault C, Silva UVA, Montini L, Barbier F, Nielsen LB, Gaborit B, Mokart D, Chevret S; Efraim investigators and the Nine-I study group. Acute hypoxemic respiratory failure in immunocompromised patients: the Efraim multinational prospective cohort study. Intensive Care Med. 2017;43(12):1808-19.) A multicenter, prospective, observational study evaluated 1,611 immunosuppressed patients (52% oncohematological and 35% with solid tumors) with ARF admitted to 68 ICUs between 2015 and 2016. Among the 1,611 patients analyzed, 596 patients (37%) were intubated at ICU admission or in the emergency room, and of these, 52% died. A total of 915 (56.8%) patients received noninvasive support first, such as standard oxygen therapy, high-flow nasal cannula (HFNC), noninvasive ventilation (NIV) or combination NIV plus HFNC. Approximately 40% of these patients required tracheal intubation during hospitalization. Approximately 85% of patients who failed noninvasive strategies and required IMV died.(5252 Azoulay E, Pickkers P, Soares M, Perner A, Rello J, Bauer PR, van de Louw A, Hemelaar P, Lemiale V, Taccone FS, Martin Loeches I, Meyhoff TS, Salluh J, Schellongowski P, Rusinova K, Terzi N, Mehta S, Antonelli M, Kouatchet A, Barratt-Due A, Valkonen M, Landburg PR Bruneel F, Bukan RB, Pène F, Metaxa V, Moreau AS, Souppart V, Burghi G, Girault C, Silva UVA, Montini L, Barbier F, Nielsen LB, Gaborit B, Mokart D, Chevret S; Efraim investigators and the Nine-I study group. Acute hypoxemic respiratory failure in immunocompromised patients: the Efraim multinational prospective cohort study. Intensive Care Med. 2017;43(12):1808-19.)

The best initial strategy for the ventilatory management of oncological patients with ARF still raises doubts and uncertainties. Previous studies have suggested that early NIV could improve survival and reduce the incidence of intubation and IMV.(5353 Azoulay E, Alberti C, Bornstain C, Leleu G, Moreau D, Recher C, et al. Improved survival in cancer patients requiring mechanical ventilatory support: impact of noninvasive mechanical ventilatory support. Crit Care Med. 2001;29(3):519-25.,5454 Hilbert G, Gruson D, Vargas F, Valentino R, Gbikpi-Benissan G, Dupon M, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001;344(7):481-7.,5555 Meert AR Close L, Hardy M, Berghmans T, Markiewicz E, Sculier JR Noninvasive ventilation: application to the cancer patient admitted in the intensive care unit. Support Care Cancer. 2003; 11(1):56-9.,5656 Squadrone V, Massaia M, Bruno B, Marmont F, Falda M, Bagna C, et al. Early CPAP prevents evolution of acute lung injury in patients with hematologic malignancy. Intensive Care Med. 2010;36(10):1666-74.) In 2001, Hilbert et al. compared the use of NIV with standard oxygen therapy in a randomized controlled trial that included 54 immunosuppressed patients (58% oncohematological) with fever, pulmonary infiltrate and hypoxemic ARF. Patients in the NIV group had a lower intubation rate (46% versus 77%) and hospital mortality compared to the group with standard oxygen therapy (50% versus 81%).(5454 Hilbert G, Gruson D, Vargas F, Valentino R, Gbikpi-Benissan G, Dupon M, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001;344(7):481-7.) Recent studies did not confirm previous reports of early NIV benefits compared to oxygen therapy. (5757 Lemiale V, Resche-Rigon M, Mokart D, Pène F, Rabbat A, Kouatchet A, et al. Acute respiratory failure in patients with hematological malignancies: outcomes according to initial ventilation strategy. A groupe de recherche respiratoire en reanimation onco-hematologique (Grrr-OH) study. Ann Intensive Care. 2015;5(1):28.,5858 Lemiale V, Mokart D, Resche-Rigon M, Pene F, Mayaux J, Faucher E, Nyunga M, Girault C, Perez P, Guitton C, Ekpe K, Kouatchet A, Théodose I, Benoit D, Canet E, Barbier F, Rabbat A, Bruneel F, Vincent F, Klouche K, Loay K, Mariotte E, Bouadma L, Moreau AS, Seguin A, Meert AR Reignier J, Papazian L, Mehzari I, Cohen Y, Schenck M, Hamidfar R, Darmon M, Demoule A, Chevret S, Azoulay E; Groupe de Recherche en Réanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH). Effect of noninvasive ventilation vs oxygen therapy on mortality among immunocompromised patients with acute respiratory failure: a randomized clinical trial. JAMA. 2015;314(16):1711-9.) A multicenter, randomized, prospective study conducted in 28 hospitals in France and Belgium evaluated the best ventilatory strategy (NIV versus oxygen mask) in 374 immunosuppressed patients with hypoxemic ARF. Neither 28-day mortality nor the intubation rate differed between the groups.(5858 Lemiale V, Mokart D, Resche-Rigon M, Pene F, Mayaux J, Faucher E, Nyunga M, Girault C, Perez P, Guitton C, Ekpe K, Kouatchet A, Théodose I, Benoit D, Canet E, Barbier F, Rabbat A, Bruneel F, Vincent F, Klouche K, Loay K, Mariotte E, Bouadma L, Moreau AS, Seguin A, Meert AR Reignier J, Papazian L, Mehzari I, Cohen Y, Schenck M, Hamidfar R, Darmon M, Demoule A, Chevret S, Azoulay E; Groupe de Recherche en Réanimation Respiratoire du patient d’Onco-Hématologie (GRRR-OH). Effect of noninvasive ventilation vs oxygen therapy on mortality among immunocompromised patients with acute respiratory failure: a randomized clinical trial. JAMA. 2015;314(16):1711-9.)

Noninvasive ventilation failure is more frequent in patients with cancer than in the general population and is associated with more complications related to intubation and worse outcomes.(5959 Ferreira JC, Medeiros P Jr, Rego FM, Caruso P. Risk factors for noninvasive ventilation failure in cancer patients in the intensive care unit: a retrospective cohort study. J Crit Care. 2015;30(5):1003-7.,6060 Meert AR Berghmans T, Markiewicz E, Hardy M, Nayer N, Paesmans M, et al. Invasive mechanical ventilation in cancer patients. Prior non invasive ventilation is a poor prognostic factor. J BUON. 2011 ;16(1):160-5.,6161 Molina R, Bernai T, Borges M, Zaragoza R, Bonastre J, Granada RM, Rodriguez-Borregán JC, Núñez K, Seijas I, Ayestaran I, Albaiceta GM; EMEHU study investigators. Ventilatory support in critically ill hematology patients with respiratory failure. Crit Care. 2012;16(4):R133.,6262 Mosier JM, Sakles JC, Whitmore SR Hypes CD, Hallett DK, Hawbaker KE, et al. Failed noninvasive positive-pressure ventilation is associated with an increased risk of intubation-related complications. Ann Intensive Care. 2015;5:4.,6363 Price KJ, Cardenas-Turanzas M, Lin H, Roden L, Nigam R, Nates JL. Prognostic indicators of mortality of mechanically ventilated patients with acute leukemia in a comprehensive cancer center. Minerva Anestesiol. 2013;79(2):147-55.,6464 Schnell D, Lemiale V, Azoulay E. Non-invasive mechanical ventilation in hematology patients: let’s agree on several things first. Crit Care. 2012;16(6):175.) Some identified factors associated with NIV failure in previous studies are a high respiratory rate, the time interval between ICU admission and NIV initiation, the need for vasopressor or renal replacement therapy and the ratio of partial pressure of oxygen and fraction of inspired oxygen (PaO2/FiO2) < 200.(5959 Ferreira JC, Medeiros P Jr, Rego FM, Caruso P. Risk factors for noninvasive ventilation failure in cancer patients in the intensive care unit: a retrospective cohort study. J Crit Care. 2015;30(5):1003-7.,6262 Mosier JM, Sakles JC, Whitmore SR Hypes CD, Hallett DK, Hawbaker KE, et al. Failed noninvasive positive-pressure ventilation is associated with an increased risk of intubation-related complications. Ann Intensive Care. 2015;5:4.,6565 Adda M, Coquet I, Darmon M, Thiery G, Schlemmer B, Azoulay E. Predictors of noninvasive ventilation failure in patients with hematologic malignancy and acute respiratory failure. Crit Care Med. 2008;36(10):2766-72.) Although there are no specific data available on patients with cancer, NIV can be considered in patients with cardiogenic pulmonary edema or exacerbation of chronic obstructive pulmonary disease with respiratory acidosis.(6666 Meert AR Wittnebel S, Holbrechts S, Mart AC, Lafitte JJ, Piagnerelli M, Lemaitre F, Peyrony O, Calvel L, Lemaitre J, Canet E, Demoule A, Darmon M, Sculier JR Voigt L, Lemiale V, Pène F, Schnell D, Lengline E, Berghmans T, Fiévet L, Jungels C, Wang X, Bold I, Pistone A, Salaroli A, Grigoriu B, Benoit D; Critically ill cancer patients consensus conference group. Critically ill cancer patient’s resuscitation: a Belgian/French societies’ consensus conference. Intensive Care Med. 2021;47(10):1063-77.) However, intubation should not be delayed if NIV does not provide immediate improvement of ARF.(6666 Meert AR Wittnebel S, Holbrechts S, Mart AC, Lafitte JJ, Piagnerelli M, Lemaitre F, Peyrony O, Calvel L, Lemaitre J, Canet E, Demoule A, Darmon M, Sculier JR Voigt L, Lemiale V, Pène F, Schnell D, Lengline E, Berghmans T, Fiévet L, Jungels C, Wang X, Bold I, Pistone A, Salaroli A, Grigoriu B, Benoit D; Critically ill cancer patients consensus conference group. Critically ill cancer patient’s resuscitation: a Belgian/French societies’ consensus conference. Intensive Care Med. 2021;47(10):1063-77.)

High-flow nasal cannula appears to be a promising therapy for patients with cancer. In a retrospective cohort of 178 patients with ARF, 76 (43%) received NIV plus HFNC, 74 (42%) received NIV plus standard oxygen therapy, 20 (11%) received only HFNC and 8 (4%) received only standard oxygen therapy. The combination of NIV and HFNC was associated with lower mortality rates (37% versus 52%, p = 0.04) and higher survival at 28 days.(6767 Harada K, Kurosawa S, Hino Y, Yamamoto K, Sakaguchi M, Ikegawa S, et al. Clinical utility of high-flow nasal cannula oxygen therapy for acute respiratory failure in patients with hematological disease. Springerplus. 2016;5:512.) Two randomized studies that evaluated HFNC in immunosuppressed patients were recently published.(6868 Azoulay E, Lemiale V, Mokart D, Nseir S, Argaud L, Pène F, et al. Effect of high-flow nasal oxygen vs standard oxygen on 28-day mortality in immunocompromised patients with acute respiratory failure: the HIGH randomized clinical trial. JAMA. 2018;320(20):2099-107.,6969 Coudroy R, Frat JR Ehrmann S, Pène F, Decavéle M, Terzi N, Prat G, Garret C, Contou D, Gacouin A, Bourenne J, Girault C, Vinsonneau C, Dellamonica J, Labro G, Jochmans S, Herbland A, Quenot JR Devaquet J, Benzekri D, Vivier E, Nseir S, Colin G, Thevenin D, Grasselli G, Bougon D, Assefi M, Guérin C, Lherm T, Kouatchet A, Ragot S, Thille AW; FLORAU-IM study group and the REVA Research Network. High-flow nasal oxygen alone or alternating with non-invasive ventilation in critically ill immunocompromised patients with acute respiratory failure: a randomised controlled trial. Lancet Respir Med. 2022;10(7):641-9.) The HIGH study was a multicenter, prospective study that randomized 778 immunosuppressed patients with ARF into two groups: HFNC and oxygen therapy. The primary outcome was 28-day mortality. Mortality between groups was similar (35.6% versus 36.1%), as was the percentage of patients who required IMV (38.1% versus 43.8%).(6868 Azoulay E, Lemiale V, Mokart D, Nseir S, Argaud L, Pène F, et al. Effect of high-flow nasal oxygen vs standard oxygen on 28-day mortality in immunocompromised patients with acute respiratory failure: the HIGH randomized clinical trial. JAMA. 2018;320(20):2099-107.) The FLORALI-IM study published in 2022 evaluated the use of HFNC versus NIV intercalated with HFNC in 299 immunosuppressed patients with ARF. There was no difference in 28-day mortality, intubation or IMV use.(6969 Coudroy R, Frat JR Ehrmann S, Pène F, Decavéle M, Terzi N, Prat G, Garret C, Contou D, Gacouin A, Bourenne J, Girault C, Vinsonneau C, Dellamonica J, Labro G, Jochmans S, Herbland A, Quenot JR Devaquet J, Benzekri D, Vivier E, Nseir S, Colin G, Thevenin D, Grasselli G, Bougon D, Assefi M, Guérin C, Lherm T, Kouatchet A, Ragot S, Thille AW; FLORAU-IM study group and the REVA Research Network. High-flow nasal oxygen alone or alternating with non-invasive ventilation in critically ill immunocompromised patients with acute respiratory failure: a randomised controlled trial. Lancet Respir Med. 2022;10(7):641-9.) There are no studies demonstrating the superiority of HFNC therapy over NIV or standard oxygen therapy in patients with cancer and ARF. However, hospital mortality in patients with cancer has been decreasing over the years, probably due to better ARF approaches, including etiological investigation, early ICU admission and protective ventilation.

5. Management of febrile neutropenia

In febrile neutropenic patients, the first dose of antibiotic should be administered within the first hour after blood culture collection.(7070 Flowers CR, Seidenfeld J, Bow EJ, Karten C, Gleason C, Hawley DK, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31(6):794-810.) Fever in neutropenic patients should be considered a medical emergency.

Empirical antimicrobial therapy must broadly cover the most likely pathogens, either guided by suspected infections or epidemiological features. Gram-negative bacteria are the main cause of infections in sites outside of the bloodstream; therefore, gram-negative pathogens are the first target of antimicrobial coverage.(7171 Viscoli C, Varnier O, Machetti M. Infections in patients with febrile neutropenia: epidemiology, microbiology, and risk stratification. Clin Infect Dis. 2005;40 Suppl 4:S240-5.)

Treatment for Gram-positive bacteria, which are the most frequent pathogens identified in neutropenic patients with fever, can be performed using vancomycin (or teicoplanin) in cases of suspected intravascular catheter infection, blood culture with gram-positive bacteria in identification, hemodynamic instability, soft tissue or skin infections or mucositis grade > l.(7272 Rolston KV. Challenges in the treatment of infections caused by gram-positive and gram-negative bacteria in patients with cancer and neutropenia. Clin Infect Dis. 2005;40 Suppl 4:S246-52.)

In patients without gram-positive bacteria, empirical antibiotic therapy should be discontinued within 48 to 72 hours. In patients colonized or suspected with vancomycin-resistant enterococcus, empirical treatment should be guided by the following criteria: hematological or solid tumors colonized by vancomycin-resistant enterococcus associated with clinical stability; persistence of fever and neutropenia with the use of carbapenem plus vancomycin for more than 72 hours; or clinical instability.(7373 Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, Gyssens IC, Kern WV, Klyasova G, Marchetti O, Engelhard D, Akova M; ECIL4, a joint venture of EBMT, EORTC, ICHS, ESGICH/ESCMID and ELN. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013;98(12):1826-35.,7474 Paul M, Dickstein Y, Borok S, Vidal L, Leibovici L. Empirical antibiotics targeting Gram-positive bacteria for the treatment of febrile neutropenic patients with cancer. Cochrane Database Syst Rev. 2014(1):CD003914.)

Usually, fungi are not the initial cause of fever in neutropenic patients, and initial empirical coverage is indicated only in patients with invasive fungal disease (histological or microbiological findings); after ≥ 4 days of persistent fever, if the radiological pattern is compatible with fungal disease; or if febrile neutropenia persists for more than 7 days. (7373 Averbuch D, Orasch C, Cordonnier C, Livermore DM, Mikulska M, Viscoli C, Gyssens IC, Kern WV, Klyasova G, Marchetti O, Engelhard D, Akova M; ECIL4, a joint venture of EBMT, EORTC, ICHS, ESGICH/ESCMID and ELN. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica. 2013;98(12):1826-35.) The recommendations of the guidelines of the International Disease Society of America (IDSA) suggest the use of caspofungin (70mg on the first day followed by 50mg/day),) and amphotericin B liposomal as the second choice (3 - 5mg/kg/day). The third option in stable patients without prior imidazole use is fluconazole (800mg of attack, followed by 400mg/day).(7575 Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50.) If aspergillosis is a strong clinical hypothesis or the patient is using echinocandins for prophylaxis, liposomal amphotericin B should be the first choice.(7575 Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50.) Micafungin and anidulafungin have not been adequately tested in patients with febrile neutropenia; however, they can be used as an alternative in the absence of caspofungin since the spectrum and antifungal activity of the two agents are similar.(7676 Walsh TJ, Gamaletsou MN. Treatment of fungal disease in the setting of neutropenia. Hematology Am Soc Hematol Educ Program. 2013;2013:423-7.)

The decision on antimicrobial maintenance should be reviewed within 72 and 96 hours (Table 2).

Table 2
Duration of antibiotic treatment

Granulocytic stimulating agents can be used in patients without response to antimicrobial treatment in the presence of sepsis or septic shock; outside this situation, the use should be individualized.(7777 Smith TJ, Bohlke K, Armitage JO. Recommendations for the Use of White Blood Cell Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Oncol Pract. 2015;11(6):511-3.)

Regarding prevention, the most effective measure is hand hygiene, especially during the management of neutropenic patients.(7878 Boyce JM, Pittet D; Healthcare Infection Control Practices Advisory Committee. Society for Healthcare Epidemiology of America. Association for Professionals in Infection Control. Infectious Diseases Society of America. Hand Hygiene Task Force. Guideline for Hand Hygiene in Health-Care Settings: recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Infect Control Hosp Epidemiol. 2002;23(12 Suppl):S3-40.) There is no benefit of specific protective measures to neutropenic patients, such as masks, gloves or aprons, but all patients should be subjected to standard precautions, such as hand hygiene (washing hands with soap and water for 2 minutes); appropriate use of personal protective equipment; respiratory hygiene; careful handling of materials, equipment, clothing and food utensils; environmental hygiene; prevention of accidents with sharps and biological materials; safe practice in the preparation and administration of medications; exclusion of plants and flowers in rooms or units of neutropenic patients; and contraindication of rectal manipulation in neutropenic patients (anal swab, thermometers, enemas, etc.).(7979 Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito Jl, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011;52(4):e56-93.) Three meta-analyses did not recommend the use of specific diets for neutropenic patients as a measure for the prevention of infection; however, a well-cooked diet without raw food was suggested for all neutropenic patients.(8080 van Dalen EC, Mank A, Leclercq E, Mulder RL, Davies M, Kersten MJ, et al. Low bacterial diet versus control diet to prevent infection in cancer patients treated with chemotherapy causing episodes of neutropenia. Cochrane Database Syst Rev. 2016;4(4):CD006247.)

6. Urgent chemotherapy treatment in critically ill patients

The use of chemotherapy in patients admitted to the ICU is an exception. Few tumors have a rapid response to chemotherapy to the point of reversal of organ dysfunction caused by the cancer itself. The studies that have evaluated the use of chemotherapy in the ICU were small, observational, retrospective, and single center. In general, chemotherapy in the ICU is acceptable in patients with hematological malignancies with complications leading to organ dysfunction, such as hyperviscosity syndrome, leukostasis and blast crisis.(8181 Benoit DD, Depuydt PO, Vandewoude KH, Offner FC, Boterberg T, De Cock CA, et al. Outcome in severely ill patients with hematological malignancies who received intravenous chemotherapy in the intensive care unit. Intensive Care Med. 2006;32(1):93-9.) In patients with solid tumors, chemotherapy in the ICU is often indicated in involvement, such as acute liver failure secondary to liver metastases, malignant tumor obstructions caused by tumors of the gastrointestinal tract and acute respiratory failure secondary to bronchial obstruction in lung tumors. However, with the exception of patients with small cell lung carcinomas and some germ-cell tumors associated with complications, the use of emergency chemotherapy in the ICU for solid tumors is associated with higher mortality.(8282 Zerbib Y, Rabbat A, Fartoukh M, Bigé N, Andréjak C, Mayaux J, De Prost N, Misset B, Lemiale V, Bruneel F, Maizel J, Ricome S, Jacobs F, Bornstain C, Dupont H, Baudin F, Azoulay E, Pène F; Graupe de Recherche sur la Réanimation Respiratoire en Onco-Hématologie (GRRR-OH). Urgent Chemotherapy for life-threatening complications related to solid neoplasms. Crit Care Med. 2017;45(7):e640-8.,8383 Chan Wah Hak C, Coyle C, Kocache A, Short D, Sarwar N, Seckl MJ, et al. Emergency Etoposide-Cisplatin (Em-EP) for patients with germ cell tumours (GCT) and trophoblastic neoplasia (TN). BMC Cancer. 2019;19(1 ):770.,8484 Moran-Ribon A, Droz JR Kattan J, Leclercq B, Ghosn M, Couanet D, et al. Super-high-risk germ-cell tumors: a clinical entity. Report of eleven cases. Support Care Cancer. 1994;2(4):253-8.,8585 de Oliveira MC, Ferreira JC, Nassar Junior AR Dettino AL, Caruso P. Impact of urgent chemotherapy in critically ill patients. J Intensive Care Med. 2020;35(4):347-53.)

7. Patient and family experience

The World Health Organization (WHO) considers that patient experience involves the perspectives of patients, families, and communities, considering them as participants and beneficiaries.

Relatives of patients who experience a critical illness have more symptoms associated with anxiety, depression and posttraumatic stress than patients themselves,(8686 Fumis RR, Ranzani OT, Martins PS, Schettino G. Emotional disorders in pairs of patients and their family members during and after ICU stay. PLoS One. 2015;10(1):e0115332.) and simple measures such as time devoted to communication, with proactive end-of-life conferences and a printed copy of the unit’s guidelines, can help reduce such symptoms.(8787 Lautrette A, Darmon M, Megarbane B, Joly LM, Chevret S, Adrie C, et al. A communication strategy and brochure for relatives of patients dying in the ICU. N Engl J Med. 2007;356(5):469-78.) Interactions between intensivists, other physicians and family members are other means of caring for such symptoms, with minimal costs but significant impact. Family meetings are the cornerstone of facilitating open communication, adhering to the care plan and minimizing distress between family members and health care providers.(8888 Fumis RR, Nishimoto IN, Deheinzelin D. Families’ interactions with physicians in the intensive care unit: the impact on family’s satisfaction. J Crit Care.2008;23(3):281-6.,8989 Ekberg S, Parry R, Land V, Ekberg K, Pino M, Antaki C, et al. Communicating with patients and families about illness progression and end of life: a review of studies using direct observation of clinical practice. BMC Palliat Care. 2021 ;20(1 ): 186.)

Although the time of interaction is an important factor, with a rationale for better disease understanding, participation in the decision-making process and interaction with the ICU staff, extending visiting hours remains controversial in the literature. The ICU Visits Group Investigators showed that an extended visiting hours policy compared to a more restrictive one (4.8 versus 1.4 hours) did not reduce delirium; however, there was a decrease in anxiety and depression among family members.(9090 Rosa RG, Falavigna M, da Silva DB, Sganzerla D, Santos MM, Kochhann R, de Moura RM, Eugênio CS, Haack TD, Barbosa MG, Robinson CC, Schneider D, de Oliveira DM, Jeffman RW, Cavalcanti AB, Machado FR, Azevedo LC, Salluh JIF, Pellegrini JAS, Moraes RB, Foernges RB, Torelly AR Ayres LO, Duarte PA, Lovato WJ, Sampaio PH, de Oliveira Júnior LC, Paranhos JL, Dantas AD, de Brito PI, Paulo EAR Gallindo MAC, Pilau J, Valentim HM, Meira Teles JM, Nobre V, Birriel DC, Corrêa E Castro L, Specht AM, Medeiros GS, Tonietto TF, Mesquita EC, da Silva NB, Korte JE, Hammes LS, Giannini A, Bozza FA, Teixeira C; ICU Visits Study Group Investigators and the Brazilian Research in Intensive Care Network (BRICNet). Effect of flexible family visitation on delirium among patients in the intensive care unit: the ICU visits randomized clinical trial. JAMA. 2019;322(3):216-28.) Regardless of the outcome, the preparation of the multidisciplinary team to treat these families is imperative.

8. Palliative care

According to the WHO, in a concept defined in 1990 and updated in 2002, “Palliative Care consists of assistance provided by a multidisciplinary team, which aims to improve the quality of life of patients and their families, in the face of a disease that threatens life, through the prevention and relief of suffering, through early identification, impeccable assessment and treatment of pain and other physical, social, psychological and spiritual symptoms”.

The role of palliative care for patients with cancer in the ICU is extremely important. These patients frequently present physical, psychosocial and spiritual suffering. Thus, the integration of palliative care in this scenario is associated with better quality of life for patients and families, more occurrence of advance directives and decreased use of nonbeneficial interventions to prolong life.

The symptoms most commonly presented by patients with cancer are pain, delirium, dyspnea and thirst, and palliative care support, particularly in pain management, has been proven to have a positive impact.(9191 Nelson JE, Meier DE, Oei EJ, Nierman DM, Senzel RS, Manfredi PL, et al. Self-reported symptom experience of critically ill cancer patients receiving intensive care. Crit Care Med. 2001;29(2):277-82.,9292 Delgado-Guay MO, Parsons HA, Li Z, Palmer LJ, Bruera E. Symptom distress, interventions, and outcomes of intensive care unit cancer patients referred to a palliative care consult team. Cancer. 2009;115(2):437-45.) A retrospective study evaluated 1,383 admissions to an oncological ICU, where 88 patients were evaluated by the palliative care team, and several opportunities for care improvement were identified. Additionally, the palliative care team made numerous pharmacological and nonpharmacological recommendations alleviating distressing symptoms and increasing do not resuscitate orders and withdrawal of IMV and noninvasive mechanical ventilation.(9292 Delgado-Guay MO, Parsons HA, Li Z, Palmer LJ, Bruera E. Symptom distress, interventions, and outcomes of intensive care unit cancer patients referred to a palliative care consult team. Cancer. 2009;115(2):437-45.) The provision of spiritual care and effective communication also contribute to reducing patient and family stress, leading to less aggressive interventions and more appropriate hospice indications. Finally, evidence suggests that proactive palliative care in the ICU, using consultative or integrative palliative care interventions, shortens hospital and ICU length of stay(9393 Aslakson R, Cheng J, Vollenweider D, Galusca D, Smith TJ, Pronovost PJ. Evidence-based palliative care in the intensive care unit: a systematic review of interventions. J Palliat Med. 2014;17(2):219-35.)

In conclusion, there is no doubt that palliative care in the ICU has numerous benefits to patients with cancer; however, challenges remain in terms of greater integration, additional training of intensivists in skills such as communication and symptom control of end-of-life patients, and earlier initiation of palliative care within the ICU.

9. Care of intensive care unit staff

One crucial point in the evaluation of the ICU employee experience is the development of burnout. Fumis et al. demonstrated that moral distress due to therapeutic obstinacy and futility in treatment are the main risk factors for moral distress.(9494 Fumis RR, Junqueira Amarante GA, de Fatima Nascimento A, Vieira Junior JM. Moral distress and its contribution to the development of burnout syndrome among critical care providers. Ann Intensive Care. 2017;7(1):71.)

The priority of ICU managers should be ICU efficiency in achieving its clinical goals while maintaining a humanized environment. Despite the excessive emphasis on the technological aspects of intensive care, it is the “human factor” that mediates the results of an ICU.(9595 Pattison N, Droney J, Gruber P. Burnout: caring for critically ill and end-of-life patients with cancer. Nurs Crit Care. 2020;25(2):93-101.) Additionally, organizational aspects such as ICU strain, suboptimal staffing patterns and lack of ICU resources have a significant burden on the ICU team.(9696 Duggal A, Mathews KS. Impact of ICU strain on outcomes. Curr Opin Crit Care. 2022;28(6):667-73.) In this sense, the COVID-19 pandemic was a scenario where all the abovementioned factors were simultaneously present for a long period of time, and studies have demonstrated that this adversely affected the well-being of health care personnel.(9797 Lobo SM, Creutzfeldt CJ, Maia IS, Town JA, Amorim E, Kross EK, et al. Perceptions of critical care shortages, resource use, and provider well-being during the COVID-19 pandemic: a survey of 1,985 health care providers in Brazil. Chest. 2022;161(6):1526-42.)

The volume and timing of work, particularly the number of nights and consecutive days worked, appear to be significant factors determining the chance of burnout among intensivists, which is associated with a desire to quit their jobs.(9898 Pastores SM, Kvetan V, Coopersmith CM, Farmer JC, Sessler C, Christman JW, D’Agostino R, Diaz-Gomez J, Gregg SR, Khan RA, Kapu AN, Masur H, Mehta G, Moore J, Oropello JM, Price K; Academic Leaders in Critical Care Medicine (ALCCM) Task Force of the Society of the Critical Care Medicine. Workforce, workload, and burnout among intensivists and advanced practice providers: a narrative review. Crit Care Med. 2019;47(4):550-7.) Strategies to reduce the ICU workload and decrease the burnout rate in multidisciplinary ICU teams are needed. Reducing the workload, avoiding shifts longer than 12 hours, and restricting the maximum number of consecutive days worked, including paid vacations, psychological support, and well-compensated pay, are viable approaches for preventing burnout in professionals.(9999 Moss M, Good VS, Gozal D, Kleinpell R, Sessler CN. An Official Critical Care Societies Collaborative Statement: Burnout Syndrome in Critical Care Healthcare Professionals: A Call for Action. Crit Care Med. 2016;44(7):1414-21.)

Oncologic critical care is a highly complex scenario where a combination of frequent discussions around end-of-life care, a high workload, and inadequate communication (as well as inter- and intrateam conflicts) generates stress and burnout in up to half of the professionals.(100100 Azoulay E, Timsit JF, Sprung CL, Soares M, Rusinová K, Lafabrie A, Abizanda R, Svantesson M, Rubulotta F, Ricou B, Benoit D, Heyland D, Joynt G, Français A, Azeivedo-Maia P, Owczuk R, Benbenishty J, de Vita M, Valentin A, Ksomos A, Cohen S, Kompan L, Ho K, Abroug F, Kaarlola A, Gerlach H, Kyprianou T, Michalsen A, Chevret S, Schlemmer B; Conflicus Study Investigators and for the Ethics Section of the European Society of Intensive Care Medicine. Prevalence and factors of intensive care unit conflicts: the conflicus study. Am J Respir Crit Care Med. 2009;180(9):853-60.) Therefore, we propose the use of known risk factors for moral distress and burnout as targets for quality improvement, aiming to reduce their prevalence and therefore burnout.

From the organizational perspective, it is vital to guarantee that an ICU is well staffed and resourced but also that it is a resilient ICU and therefore capable of adequately responding to daily challenges as well as unexpected situations (i.e., catastrophes, pandemics).(101101 Salluh Jl, Kurtz P, Bastos LS, Quintairos A, Zampieri FG, Bozza FA. The resilient intensive care unit. Ann Intensive Care. 2022;12(1):37.)

10. Long-term impact of critical disease on the cancer population

Post-intensive care syndrome as well as other long-term debilitating conditions are often described in survivors of severe and prolonged critical illness.(102102 Voiriot G, Oualha M, Pierre A, Salmon-Gandonnière C, Gaudet A, Jouan Y, Kallel H, Radermacher P, Vodovar D, Sarton B, Stiel L, Bréchot N, Préau S, Joffre J; la CRT de la SRLF. Chronic critical illness and post-intensive care syndrome: from pathophysiology to clinical challenges. Ann Intensive Care. 2022;12(1):58.,103103 Rousseau AF, Prescott HC, Brett SJ, Weiss B, Azoulay E, Creteur J, et al. Long-term outcomes after critical illness: recent insights. Crit Care. 2021;25(1):108.) Although the short-term mortality of ICU patients with cancer has substantially improved over the last few decades,(104104 Azoulay E, Schellongowski P, Darmon M, Bauer PR, Benoit D, Depuydt P, et al. The Intensive Care Medicine research agenda on critically ill oncology and hematology patients. Intensive Care Med. 2017;43(9):1366-82.,105105 Zampieri FG, Romano TG, Salluh Jl, Taniguchi LU, Mendes PV, Nassar AP Jr, et al. Trends in clinical profiles, organ support use and outcomes of patients with cancer requiring unplanned ICU admission: a multicenter cohort study. Intensive Care Med. 2021;47(2):170-9.) patient-centered outcomes and long-term survival remain suboptimal.(106106 Normilio-Silva K, de Figueiredo AC, Pedroso-de-Lima AC, Tunes-da-Silva G, Nunes da Silva A, Delgado Dias Levites A, et al. Long-term survival, quality of life, and quality-adjusted survival in critically ill patients with cancer. Crit Care Med. 2016;44(7):1327-37.) Patients with leukemia requiring ICU admission, relapsed or refractory disease, secondary leukemia, or multiorgan failure therapy were independently associated with 1-year mortality.(107107 Tavares M, Lemiale V, Mokart D, Pène F, Lengliné E, Kouatchet A, et al. Determinants of 1-year survival in critically ill acute leukemia patients: a GRRR-OH study. Leuk Lymphoma. 2018;59(6):1323-31.) These factors associated with adverse long-term outcomes are similar to those observed in patients with solid tumors.

Regarding the quality of life of survivors, a study demonstrated that among the baseline poor quality of life risk factors, previous health-related quality of life and performance status were associated with better outcomes at the 18-month follow-up.(106106 Normilio-Silva K, de Figueiredo AC, Pedroso-de-Lima AC, Tunes-da-Silva G, Nunes da Silva A, Delgado Dias Levites A, et al. Long-term survival, quality of life, and quality-adjusted survival in critically ill patients with cancer. Crit Care Med. 2016;44(7):1327-37.) In patients with hematologic malignancies, poor quality of life associated with impaired physical and mental health issues was observed at the 3-and 12-month follow-ups.(108108 Ehooman F, Biard L, Lemiale V, Contou D, de Prost N, Mokart D, et al. Long-term health-related quality of life of critically ill patients with haematological malignancies: a prospective observational multicenter study. Ann Intensive Care. 2019;9(1):2.) Additionally, the challenges of ICU survivors are not restricted to their quality of life but also to the impact on the potential continuity of cancer treatment. Loss of functional capacity is often described in ICU survivors, especially those who experience prolonged ICU stays and mechanical ventilation. The fact that up to 80% of cancer patients discharged from the ICU may not receive optimal chemotherapy should alert clinicians and oncologists and guide them to engage early in the discussion of the goals of care, considering that ICU discharge will not guarantee cancer survival. (15) In a study of patients with lung cancer treated in the ICU, 38% of survivors had to change their initially planned treatment regimen.(109109 Azevedo LC, Caruso P, Silva UV, Torelly AR Silva E, Rezende E, Netto JJ, Piras C, Lobo SM, Knibel MF, Teles JM, Lima RA, Ferreira BS, Friedman G, Rea-Neto A, Dal-Pizzol F, Bozza FA, Salluh Jl, Soares M; Brazilian Research in Intensive Care Network (BRICNet). Outcomes for patients with cancer admitted to the ICU requiring ventilatory support: results from a prospective multicenter study. Chest. 2014;146(2):257-66.)

Among the priorities to ensure high-value care for ICU cancer patients, intensivists and oncologists should consider the expected quality of life of survivors as well as their ability to remain eligible for highly effective anticancer therapies. In addition, patients with cancer should be considered for rehabilitation after critical illness. Although specific evidence related to cancer patients is missing, physical and nutritional rehabilitation has been successfully tested in general ICU survivors.(110110 Moisey LL, Merriweather JL, Drover JW. The role of nutrition rehabilitation in the recovery of survivors of critical illness: underrecognized and underappreciated. Crit Care. 2022;26(1):270.)

A combination of strategies aiming to improve muscle strength and endurance, respiratory function, nutrition and cognitive status is currently proposed to counteract the effects of postintensive care syndrome (PICS).(111111 Mikkelsen ME, Still M, Anderson BJ, Bienvenu OJ, Brodsky MB, Brummel N, et al. Society of Critical Care Medicine’s International Consensus Conference on Prediction and Identification of Long-Term Impairments After Critical Illness. Crit Care Med. 2020;48(11):1670-9.,112112 Azoulay E, Vincent JL, Angus DC, Arabi YM, Brochard L, Brett SJ, et al. Recovery after critical illness: putting the puzzle together-a consensus of Crit Care. 2017;21,113113 Cagino LM, Seagly KS, McSparron Jl. Survivorship after critical illness and post-intensive care syndrome. Clin Chest Med. 2022;43(3):551-61.) This is of utmost importance in ICU survivors and may be even more relevant for patients with cancer, as the loss of functional capacity after ICU admission may be a determining factor for eligibility for anticancer therapies.

CONCLUSION

There are “positive deviances” in the care of critically ill patients with cancer that have the potential to generate high-value care from patient admission to end-of-life care considering the experiences of patients and their families.

The implementation of such policies is feasible for most centers that care for this population. Even for facilities with scarce resources, applying resources that add value is imperative.

Initiatives such as this paper are one of the first steps in raising awareness and beginning a discussion about high-value care in various health scenarios.

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Edited by

Responsible editor: Felipe Dal-Pizzol

Publication Dates

  • Publication in this collection
    05 June 2023
  • Date of issue
    2023

History

  • Received
    09 Dec 2022
  • Accepted
    26 Feb 2023
Associação de Medicina Intensiva Brasileira - AMIB Rua Arminda, 93 - 7º andar - Vila Olímpia, CEP: 04545-100, Tel.: +55 (11) 5089-2642 - São Paulo - SP - Brazil
E-mail: ccs@amib.org.br