Consensus statement for cancer patients requiring intensive care support

Consensus statement for cancer patients requiring intensive care support This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients. . . . . Keywords Hematological malignancy Oncological malignancy Critical illness Intensive care treatment Mechanical . . ventilation ICU ICU admission Introduction and background Appropriate allocation of resources for cancer prevention, ear- ly diagnosis, as well as curative and palliative care remain of Cancer is the second leading cause of death worldwide. particular importance. This requires a detailed knowledge of According to recent publications, the incidence of neoplasms the local burden of cancer [1]. is expected to increase requiring more health care resources. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00277-018-3312-y) contains supplementary material, which is available to authorized users. * M. G. Kiehl Clinic for Intensive Care Medicine, University Hamburg, Martinistr. michael.kiehl@klinikumffo.de 52, 20246 Hamburg, Germany Department of Medicine I, Medical University of Vienna, 1 Waehringer Guertel 18-20, 1090 Vienna, Austria Department of Internal Medicine I, Clinic Frankfurt/Oder GmbH, Müllroser Chaussee 7, 15236 Frankfurt (Oder), Germany Department of Internal Medicine I, University Hospital, Fetschertstr. 74, 01307 Dresden, Germany Hannover Medical School (MHH) Clinic for Hematology, Department of Internal Medicine III, Schwarzwald-Baar-Klinikum, Coagulation, Oncology and Stem Cell Transplantation, Klinikstr. 11, 78052 Villingen-Schwenningen, Germany Carl-Neuberg-Straße 1, 30625 Hannover, Germany 3 Clinic for Stem Cell Transplantation, University Hospital Essen, Department of Internal Medicine I, University Hospital, Kerpener Hufelandstr. 55, 45147 Essen, Germany Str. 62, 50937 Cologne, Germany Department of Cardiology and Pulmonary Medicine, University III. Medical Clinic, Medical Faculty Mannheim, Hospital, Robert-Koch-Str. 40, 37075 Göttingen, Germany Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany Department of Hematology and Oncology, University Hospital, Johanniter-Hospital, Johanniterstr. 3-5, 53113 Bonn, Germany Leipziger Str. 44, 39120 Magdeburg, Germany 1272 Ann Hematol (2018) 97:1271–1282 In patients with hematological or oncological malignan- and manuscript wording underwent voting of the consensus cies, the disease itself or intensive therapy may result in crit- assembly. ical illness in a substantial number of patients. In 1999, the This guideline follows the structure and definitions of American College of Critical Care Medicine stated that pa- the ESCMID Guideline on Candida diseases [4–6]. It is in tients with hematological or metastasized oncological malig- accordance with the GRADE and AGREE [7, 8](Table 1). nancies are poor candidates for ICU admission with a mortal- All recommendations are given in boldface type. ity rate of up to 90%. Thus, refusal of ICU admission of these patients was the common procedure (Task Force of the American College of Critical Care Medicine, Society of Prognosis and ICU admission criteria Critical Care Medicine, 1999 [2]). However, within the last 25 years, cancer and ICU treatment clearly improved. As Whom to admit to the ICU/eligibility and goals shown in recent reports, hospital mortality decreased to less of therapy than 40% in these critically ill patients with hematologic ma- lignancies [3]. Thus, criteria for ICU admission have to be Full-code ICU management (without limitations of ICU adjusted. Aim of this consensus statement is to provide a re- resources) should be offered to all critically ill cancer patients view of the recent literature and the development of practical if long-term survival may be compatible with the general recommendations to hematologists, oncologists, and intensive prognosis of the underlying malignancy (A-IIu) care specialists. Due to a series of practice-changing investi- gations on proper ventilation techniques in cancer patients This statement, of course, presumes that the acute condi- with acute respiratory failure, we put a special emphasis on tion may be reversed by ICU measures, and that age and discussing this topic. comorbidities of patients do not contradict such an ap- proach. Typically, full-code management applies to pa- tients with curative therapeutic options, those in remission of their malignancy, as well as to patients in whom cure is Methods not likely but the expected life-span is substantial [3, 9]. It has been suggested in an earlier consensus that an assumed The consensus group was selected to represent the expertise in the field of critical care in cancer patients in Germany and Austria. Experts were sent by the German Society of Hematology and Medical Oncology (DGHO), the Austrian Table 1 Strength of the recommendation and quality of evidence Society of Hematology and Oncology (OeGHO), the Strength Recommendation German Society of Internal Intensive and Emergency A Strong recommendation for use Medicine (DGIIN), and the Austrian Society of Medical and B Moderate recommendation for use General Intensive Care and Emergency Medicine (ÖGIAIN). C Marginal recommendation for use All authors are actively supporting the “Intensive Care D Recommendation against use Medicine in Hematologic and Oncologic Patients (iCHOP)” Quality of evidence Initiative (info@ichop.eu). I Evidence from at least 1 properly designed Consensus statements are based on an in-depth PubMed lit- randomized, controlled trial erature retrieval of English as well as German language literature II Evidence from at least 1 well-designed clinical with last access February 01, 2017. For medical heading terms trial, without randomization; from cohort or (MeSH) identifying potential relevant literature, please see case-controlled analytic studies (preferably from > 1 center); from multiple time series; Appendix. Seven working groups (a: ICU transfer criteria and or from dramatic results of uncontrolled goals of therapy, b: respiratory failure, c: end of live decisions, d: experiments stem cell transplant patients, e: infections, f: coagulation, and g: III Evidence from opinions of respected authorities, miscellaneous) prepared the draft proposals in a first round of based on clinical experience, descriptive case consensus development. Working groups decided on references studies with relevant impact on guideline development, and every group Added index: : meta-analysis (or systematic review of RCT); :trans- r t member had to approve the draft guideline subchapter. Finally, ferred evidence, i.e., results from different patients Bcohorts^ or similar the consensus statements were approved by the assembly of the immune status situation; : comparator group: historical control; :un- h u members on March 2nd and 3rd 2017 in Vienna, Austria, a controlled trials; : published abstract (presented at an international sym- meetinghostedand sponsoredbytheOeGHO. Allstatements posium or meeting) Ann Hematol (2018) 97:1271–1282 1273 prognosis of 1 year may be used as cutoff for clinical de- Cancer patients should be considered for ICU admission cision making with regard to full-code status [10]. The in case of manifest or incipient acute organ dysfunction(s) authors of this manuscript believe this number is arbitrary (A-IIu) and may be regarded as basis for individual considerations only. Cancer ward patients at risk should be screened for the presence of sepsis daily (A-IIt) Patients with poor performance status not eligible for further Cancer ward patients at risk should be screened anti-cancer therapy, dying patients, as well as those rejecting for the presence of acute organ dysfunction(s) daily (A-IIu) critical care treatment should not be admitted to the ICU in general (A-III) Recommendations for local structures and educational matters For patients not fulfilling the above-described criteria for full-code ICU management or ICU refusal, time-limited ICU Mortality of ICU cancer patients has markedly dropped over trials or pre-defined do-not-escalate decisions (e.g., the last decades, presumably due to improved general ICU do-not-intubate or do-not-attempt-resuscitation) may be management, improved diagnostic and therapeutic strategies adequate options (B-IIu) for several cancer-specific situations, as well as refined admis- sion criteria [10, 17, 18]. Yet, prognostication of cancer patients In a prospective trial on patients with intermediary and adequate patient selection remain far from perfect [19]. prognosis (non-palliative, non-bedridden, non-full-code patients), those with worsening organ failure scores after Centers should establish local admission criteria for critically days 5ofICU therapyhad ahighriskofdying.The ill cancer patients as well as standardized admission authors suggested to offer these patients a full-code ICU procedures, such as joint assessment by cancer specialists trial with re-evaluation of the goals of therapy after at and intensivists, if available (A-III) least 6 days [9]. We would like to point out that almost all patients who died after day 5 had treatment- A recent Brazilian investigation showed an independent correla- limitation decisions. Therefore, it remains unknown tion between daily joint rounds of cancer specialists and what their course would have been in case of further intensivists as well as the number of protocols with lower mor- full-code management. Furthermore, data on cancer pa- tality and more efficient resource use [20]. This is supported by tients with poor prognosis suggest that the optimal du- Nassar and coworker stating that regular meetings may reduce ration of time-limited ICU trials seems to differ largely possible conflicts between intensivists and oncologists [21]. between patients with solid tumors and hematologic ma- lignancies [11]. Thus, proposing a fixed interval from Centers should establish daily joint rounds of cancer admission to re-evaluation of the goals of ICU therapy specialists and intensivists as well as standard-operating in patients undergoing time-limited ICU trials may not procedures for the management of frequent medical be generally appropriate. conditions of critically ill cancer patients (A-IIu) Although a recent study by Soares and colleagues failed to When to admit to the ICU, indications and screening identify ICU volume as a prognostic marker for ICU survival for organ dysfunction [20], the majority of available studies demonstrate a signifi- cant association of case volume and ICU mortality in cancer Several observational investigations on cancer patients patients with septic shock or acute respiratory failure [22–24]. with septic complications and respiratory failure indicate This effect might be linked to expertise and specific processes that early ICU admissions and early interventions, re- of care. However, some of the available observational studies spectively, are associated with improved survival [3, may not have accounted for potential confounders related to 12–16]. Thus, early identification of patients at risk for ICU organization, structure, and process of care. Ultimately critical deterioration seems crucial. Severity of illness recognizing and developing Bcritical care of cancer patients^ scores can only be used for describing groups of pa- as a medical subspecialty may optimally serve the needs of tients and should, therefore, not be used in individual affected patients [25]. Nevertheless, due to the fast-growing clinical decision making with regard to ICU admissions demand for critical care for cancer patients, the major practical or prognostication. challenge is how to provide high-quality and affordable care 1274 Ann Hematol (2018) 97:1271–1282 for all patients. Treating all critically ill cancer patients regard- lead to a (high-probability) diagnosis in approximately less of the underlying condition in specialized centers may not 70–80% of patients with ARF [31, 32]. However, diag- be feasible after all. Therefore, managing some of the rather nostic procedures should not cause a delay in the start of common cancer-specific ICU problems, such as neutropenic adequate ARF therapy including prompt antibiotic treat- sepsis, should become part of routine expertise for all inten- ment (modification) in the case of a (suspected) infection sive care specialists. However, in more specific situations, (A-III). such as chemotherapy administration in critically ill patients The diagnostic strategy should encompass a compre- with aggressive hematologic malignancies or caring for ICU hensive analysis of the clinical course of the underlying patients after allogeneic stem cell transplant, transfer to spe- malignancy, including data on mechanisms of immuno- cialized centers should be discussed. suppression, antineoplastic and antimicrobial treatment, and prophylaxis [31, 33]. Centers should establish joint continuous medical education of cancer specialists and intensivists (A-III) Independent of the clinical presentation, chest computed tomography is recommended (A-IIt) Basic concepts of the care of critically ill cancer patients should be included into the curricula of both cancer Bronchoscopy and a BAL-based diagnostic work-up including specialists and intensivists (A-III) a broad range of both culture- and non-culture-based diagnostic methods should be added to noninvasive tests All previous statements are summarized in Table 2. depending on pretest probabilities of clinical etiologies (if clinically feasible early after ICU admission and without causing clinical worsening) (A-I) Acute respiratory failure (ARF) Table 3 provides a summary of diagnostic procedures in can- cer patients with ARF. Diagnostic work-up With respect to the critical prognosis of ARF in cancer Ventilatory strategies patients, especially in patients with ARF of unknown origin [29, 30], diagnostic procedures are of major clin- Noninvasive ventilation (NIV) remains the first-line stan- ical importance. A systematic diagnostic work-up may dard of care in acute exacerbate chronic pulmonary Table 2 Admission to ICU, eligibility, and aims of therapy Intention Clinical situation/intervention SoR/QoE Reference I. Defining ICU eligibility criteria and Full-code ICU management in all critically ill cancer patients A-IIu [3] goals of therapy with prospect of long-term survival II. Defining ICU eligibility criteria and ICU refusal in patients with poor performance status not A-III goals of therapy eligible for further anti-cancer therapy, dying patients, as well as those rejecting critical care III. Defining ICU eligibility criteria and Time-limited ICU trial and/or do-not-escalate decisions in B-IIu [9, 11] goals of therapy patients neither fulfilling full code nor refusal criteria IV. Reducing mortality; indications for Early admission of patients with manifest or incipient acute A-IIu [3, 12–16] ICU admission organ dysfunction(s) to the ICU V. Reducing mortality; early Daily sepsis screening in cancer ward patients at risk A-IIt [26, 27, 28] identification of ICU candidates VI. Reducing mortality; early Daily screening for acute organ dysfunctions in cancer ward A-IIu identification of ICU candidates patients at risk VII. Facilitating ICU admission decisions Local ICU admission criteria and joint assessment by cancer A-III specialists and intensivists VIII. Reducing mortality; local structures Establish daily rounds of cancer specialists and intensivists A-IIu [20] IX. Reducing mortality; local structures Establish standard-operating procedures for frequent medical A-IIu [20] conditions of critically ill ICU cancer patients X. Reducing mortality; local structures Admit critically ill cancer patients to experienced ICUs A-IIu [19, 20] XI. Continuous medical education Establish joint continuous medical education of cancer A-III specialist and intensivists XII. Basic medical education/training Include basic concepts on critically ill cancer patients into A-III cancer specialists’ and intensivists’ curricula Ann Hematol (2018) 97:1271–1282 1275 Table 3 Invasive and Blood cultures noninvasive diagnostic procedures in ARF Multislice or high-resolution computed tomography (CT) scan of the lungs (in most cases without contrast media), (MRI of the lungs, if a pulmonary CT scan is not feasible) Echocardiography (cardiac status) Sputum examination for Bacteria Fungi Mycobacteria Induced sputum Pneumocystis jiroveci Nasopharyngeal aspirates RSV, influenza Polymerase chain reaction blood test for Herpesviridae Cytomegalovirus Epstein-Barr virus Circulating Aspergillus galactomannan Serologic tests for Chlamydia pneumoniae Mycoplasma pneumoniae Legionella pneumophila Urine antigen for Legionella pneumophila Streptococcus pneumoniae BAL (samples should include by default) � Cytospin preparation including Giemsa stain for cytological diagnostics and Gram stain � Bacteriological cultures (quantitative or semi-quantitative) including culture media to detect Legionella spp., mycobacteria and fungi � Calcofluor white or equivalent stain (assessment of fungi) � (quantitative, if possible) PCR for Pneumocystis jirovecii � direct immunofluorescence test for Pneumocystis jirovecii � Aspergillus antigen (Galactomannan ELISA) � Mycobacterium tuberculosis PCR, atypical mycobacteria BAL (optional) � PCR for cytomegalovirus, respiratory syncytial virus, influenza A/B virus, parainfluenza virus, human metapneumovirus, adenovirus, varicella zoster virus, and Pneumocystis jirovecii (quantitative) [34] � Aspergillus antigen (Galactomannan ELISA; ODI (optical density index): 1.0) Panfungal or Aspergillus/mucormycetes PCR Transbronchial biopsies Not recommended in general in febrile neutropenic and/or thrombocytopenic patients as a first line procedure. Adapted and modified from Azoulay et al., Am J Respir Crit Care Med 2010 [31] disease (AECOPD) or acute cardiogenic pulmonary ede- Society of Pneumology and Ventilatory Medicine ac- ma [35]. However, the role of NIV in hypoxic ARF is far knowledge that NIV can be attempted to avoid intubation less well documented. While a historic single-center ran- in immunosuppressed (including hemato-oncologic) pa- domized controlled trial (RCT) suggested superiority of tients. In this regard, it is of particular importance to NIV over conventional oxygen therapy in immunocom- respect common contraindications and termination, i.e., promised (mainly hematologic) patients with regard to intubation criteria [35]. However, the respective guide- intubation and survival rates [36], successive (mainly ob- line could not account for several meanwhile published servational) studies have led to conflicting results. The investigations: First, a meta-analysis on 2380 mainly he- 2015 BClinical Practice Guidelines on noninvasive me- matologic patients revealed that NIV as initial ventilator chanical ventilation in ARF^ on behalf of the German strategy was associated with lower mortality, whereas 1276 Ann Hematol (2018) 97:1271–1282 this finding is a mere association and cannot be patients, and specifically in those presenting with other interpreted as proof of principle. Importantly, 61% (range etiologies than pneumonia, remains to be demonstrated 40 to 78) of patients experienced NIV failure with sec- [43, 44]. ondary intubation, which itself was associated with in- creased mortality [37]. Second, in a large multicenter observational investigation in 1004 cancer patients with In case a NIV or HFNO trial is initiated in cancer patients ARDS, NIV failure occurred in 71% of patients and with hypoxic ARF, common contraindications and/or was, again, independently associated with mortality, the occurrence of pre-specified intubation criteria should while mortality of ARDS patients undergoing IMV per lead to intubation and invasive mechanical ventilation se had decreased to 52% in recent years [38]. Finally, a without delay (A-IIu) recent large multicenter landmark RCT compared the use of NIV to conventional oxygen in immunocompro- Given the considerable failure rates of NIV and HFNO mised (mainly hematologic) patients with hypoxic ARF in hypoxic ARF and the lack of sufficient data on the safety (acute cardiogenic pulmonary edema or hypercapnia, of such therapies in regular wards, NIV and HFNO should not i.e., PaCO > 50 mmHg excluded, pre-specified intuba- be attempted in this indication on a regular ward (B-III) tion criteria [39]). The trial did not show any clinical benefits or increased harms associated with NIV. End-of-life, palliative care However, the lower than expected mortality rate in the oxygen only group limited the power to detect signifi- Principles in palliative care and end-of-life (EOL) man- cant differences, and a higher proportion of patients in agement are not different in cancer patients compared to the NIV group received high flow nasal oxygen inter- critically ill patients without a malignancy as underlying mittently, which may have limited the demonstrable ef- disease (A-IIt). However, (i) patient’s wish, (ii) progres- fects of NIV. Risk factors for NIV failure in cancer sive (multi-) organ failure despite full-code ICU manage- patients are depicted in Table 4. ment and no chance of reversibility, or (iii) rapid prog- High flow nasal oxygen (HFNO) has recently been ress of cancer disease without further treatment options shown to be associated with reduced intubation (PaO have to be kept in mind and could change the treatment /FiO <200) and mortality (PaO /FiO < 300) rates in decision or treatment goals [45]. These issues have to be 2 2 2 elderly patients with pneumonia and hypoxic ARF when discussed between oncologists and the intensive care compared to conventional oxygen therapy or NIV [41]. team in an interdisciplinary manner. In cancer patients This effect was also observed in the subset of immuno- admitted to an ICU, current treatment state and estimated compromised patients [42]. However, given conflicting prognosis may be unknown to the ICU team. Therefore, data, the applicability of these findings in cancer consultation of an oncologist is highly recommended to provide valid prognostic information (A-III). Intensive care admissions often represent an addition- al burden for patients and families in situations without Table 4 Risk factors for NIV failure in cancer patients with acute option for cure. Good communication is essential to respiratory failure allow patients and families to meet their preferences regarding EOL. According to the literature, too many Prior to NIV Vasopressor need Multiple organ failure EOL decisions are made too late [46]. Early integration Airway involvement by malignancy of an interdisciplinary palliative care team for hospital- Acute respiratory distress syndrome ized patients with life-limiting disease leads to fewer Unknown etiology of ARF ICU admissions (A-I) [47]. Furthermore, integration of Delayed onset of ARF pro-active palliative care on ICUs, including palliative During NIV Patient not tolerating NIV No improvement of ABG within 6 h care rounds, leads to a shorter length of stay on ICU Respiratory rate > 30/min or in the hospital (A-IIt) [48, 49]. NIV dependency ≥ 3days To improve quality of EOL care in critically ill pa- Clinical or respiratory deterioration tients regarding important clinical questions, i.e., prepar- Unknown etiology of ARF ing for withdrawal, assessment and drug management of Adopted and modified from Soares et al., Critical Care Clinics 2010 [40] distress, discontinuation of treatment and monitoring, or NIV, noninvasive ventilation; ARF, acute respiratory failure; ABG, arterial dignity conserving care [50], the authors refer to pub- blood gas lished consensus recommendations [51, 52]. Ann Hematol (2018) 97:1271–1282 1277 Special situations & Unexplained fever in neutropenic patients [60](new ver- sion in progress) Anticancer therapy during ICU & Diagnosis of invasive fungal infections [70](new version in progress) In some cases, for example pulmonary involvement due to high & Treatment of invasive fungal infections [61]and grade non-Hodgkin lymphoma, hyperleukocytosis, etc., despite Pneumocystis jirovecii pneumonia [62] ICU treatment initiation or completion of anticancer chemother- & Diagnosis and antimicrobial therapy of lung infiltrates in apy, immunochemotherapy or radiotherapy is necessary to im- febrile neutropenic patients [63] prove patient’s clinical situation. Such some decision needs in- & Prophylaxis and treatment of infections in recipients of tensive discussions between the responsible hemato-oncologist autologous [71] (new version in progress) and allogeneic and intensivist. Again, we recommend joint assessments by can- stem cell transplant [26] cer specialists and intensivists and that basic concepts of the care & Community-acquired respiratory viral infections [72] of critically ill cancer patients should be included into the curric- & Management of central venous catheter-related infec- ula of both cancer specialists and intensivists. tions [73] & Gastrointestinal complications including neutropenic en- Prevention and treatment of infections in critically ill terocolitis [74] (new version in progress). cancer patients & Infections of the central nervous system in patients with hematological disorders [75] Published guidelines on prevention, diagnosis, and treatment of & The Surviving Sepsis Campaign (SSC) Guidelines for infections in cancer patients do not specifically address critically Management of Sepsis and Septic Shock recently pub- ill cancer patients. In addition, few studies and current guidelines lished [76]. The guidelines published in 2014 on sepsis on infections in critically ill patients specifically address the par- in neutropenic patients might be less appropriate since ticular requirements in the treatment of cancer patients (Table 5). they are based on the 2012-ssc-guidelines [59]. Resources on prevention and treatment of infections in & IDSA guidelines on immunization in patients with cancer cancer patients, which might be largely applicable to critically [58]; guidelines on immunization by the Infectious ill cancer patients, are guidelines on: Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) & Management of neutropenic patients in the intensive care are under progress. unit [69] & Prophylaxis of infectious complications with colony- & Prophylaxis of viral [57], bacterial [55], and fungal [56] stimulating factors in adult cancer patients undergoing chemotherapy [68 infections including Pneumocystis jirovecii pneumonia [55] ]. Table 5 Recommendations on prevention, diagnosis, and treatment of infections in cancer patients Intention Clinical situation/Intervention SoR/QoE Reference I. Reducing mortality Treatment in close collaboration of intensivist AIIt [53, 54] with cancer specialist and ID specialist II. Prevention of infections Continuation of prophylactic antiviral, antibacterial AIIt [55, 56, 57] and antifungal treatment upon ICU-admission, unless switch to therapeutic treatment or excessive organ toxicity III. Prevention of infections Immunization only according to specific guidelines BIII [58] for patients with cancer IV. Treatment Treatment of critically ill patients with infections AIIt [59] including neutropenic sepsis according to current guidelines for the treatment of sepsis and septic shock V. Anti-infective treatment Anti-infective treatment according to recommendations AIIr [60–64] for treatment of bacterial, fungal and viral infections in cancer patients VI. Reducing mortality Recommendation against routine use of GCSF in AIIr [65–67] neutropenic patients with pulmonary infiltrates VII Reducing mortality Use of GCSF only in selected cancer patients according AIIt [68] to current recommendations. 1278 Ann Hematol (2018) 97:1271–1282 Allogeneic stem cell transplant setting VAIA Criteria for ICU admission Transfusions The prognosis of allogeneic hematopoietic stem cell transplant In order to prevent the transfusion-associated graft versus host (HSCT) patients admitted to an ICU has been significantly reaction (GvHR), all cellular blood products have to be irradi- improved in the last years [77]. It is important to note that ated with ≥ 30 Gy for patients with lymphatic diseases, physicians of the primary hospital have to contact the patient’s autologous/allogeneic stem cell transplantation, and all pa- transplant center immediately in case of critical illness. tients treated with nucleoside analogues (fludarabine, Allogeneic HSCT patients with early ICU admission or single cladribine) [83]. Generally, to prevent acute hemolysis, AB0- organ dysfunction benefit from intensive care. However, pa- identic transfusions should be carried out. However, after al- tients with uncontrolled or refractory graft-versus-host disease logeneic HSCT, in exceptional cases, it is possible to transfuse (GvHD) should not be intubated for acute respiratory failure major or minor incompatible blood products according to the (A-III) [10, 78]. Thus, it is important to contact immediately AB0 blood group of the patient and the donor as stated in patient’stransplant center. Supplement Table S1 [84, 85]. Pooled platelet concentrates For further information regarding isolation procedures, have a higher risk of immunization. Therefore, we recommend specific monitoring, as well as typical complications, please the transfusion of apheresis platelet concentrates [84]. see supplement. Cytokine storm disease/Sepsis-like syndromes Coagulation Cancer patients are at risk to suffer from rare sepsis-like syndromes such as hemophagocytic lymphohistiocytosis Venous thromboembolism (VTE), including deep-vein throm- (HLH), cytokine release syndrome (CRS), drug reaction bosis and pulmonary embolism, represents a major cause of with eosinophilia and systemic syndromes (DRESS), or morbidity and mortality in cancer patients. An increased tu- capillary leak syndrome (CLS) [86–89]. Infections, ma- mor burden results in a higher risk for VTE with the highest lignancy itself, and drugs are major triggers for these risk in patients receiving systemic chemotherapy or being sepsis-mimicking syndromes. Diagnostic vigilance for hospitalized on surgical and medical floors. early recognition is essential to reduce mortality. To val- Although there are no validated data on the risk assessment idate diagnosis, we recommend to include blood differ- in cancer patients on the ICU, according to the American ential (cytopenia, eosinophilia), ferritin, soluble IL2R, Society of Clinical Oncology guidelines, risk scores (Khorana fibrinogen, and triglycerides in addition to the routine Score, revised Khorana score, Vienna score and Protecht score) ICU lab admission panel in cancer patients with sepsis are helpful tools to identify patients at highest risk for VTE or sepsis-like syndromes in whom there is no apparent [79–81]. For further information on thromboprophylaxis in focus of sepsis [90, 91](seeTable 6 for HLH diagnostic hospitalized patients with cancer, thromboprophylaxis in surgi- criteria). Withholding the assumed trigger drug and im- cal patients with cancer, and treatment of thrombosis, please see mediate search for an underlying malignancy or infection Supplement Table S3 and accompanying text. are pivotal. HLH patients require immediate immunosup- pression with corticosteroids to prevent further progres- sion of organ failure [92]. Early consultation with an Complications after new cancer drugs or cellular HLH expert to stratify treatment according to the most immunotherapy likely trigger is recommended (www.hlh-registry.org). Pharmacological and cellular treatment of cancer is changing dramatically not only with benefits for patient’s outcome and Summary comfort, but also with new toxicity profiles. The vast majority of adverse events can be classified as mild or moderate but During the last years, outcome of patients with malignant there are also some cases of severe and life-threatening com- hematological or oncological diseases requiring intensive care plications requiring ICU admission. Diagnosis and manage- treatment has clearly improved. From recently published data, ment of severe side effects after (monoclonal or bispecific) we conclude that the severity of the acute illness is more antibody treatment, tyrosine kinase inhibitors, immune check- important with regard to short-term survival than the underly- point inhibitors, and chimeric antigen receptor-modified ing type and stage of malignancy. Patients receiving intensive (CAR-) T cells were summarized recently in a concise review treatment of their malignancy should be considered for ICU by the iCHOP group [82]. treatment as other severely ill patients without cancer. Centers Ann Hematol (2018) 97:1271–1282 1279 Table 6 HLH diagnostic criteria [91] References HLH-2004 diagnostic criteria: ≥ 5 must be fulfilled 1. Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H et al (2017) Global, regional, and national cancer incidence, mortal- -Fever(≥ 38.3 °C) ity, years of life lost, years lived with disability, and disability-adjusted - Splenomegaly life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for - Cytopenias in ≥2lines (hb <9g/dL, plt <100/nL,neutrophils the global burden of disease study. JAMA Oncol 3(4):524–548 <1.0/nL) 2. Medicine TFotACoCC (1999) Guidelines for intensive care unit -Ferritin ≥ 500 μg/L admission, discharge, and triage. Task force of the American College of Critical Care Medicine, Society of Critical Care - Hypertriglyceridemia and/or hypofibrinogenemia (fasting Medicine. Crit Care Med 27(3):633–638 triglycerides ≥ 265 mg/dL, fibrinogen < 1.5 g/L) 3. Azoulay E, Mokart D, Pene F, Lambert J, Kouatchet A, Mayaux J - Hemophagocytosis in bone marrow or spleen or lymph nodes et al (2013) Outcomes of critically ill patients with hematologic - Low or absent NK activity malignancies: prospective multicenter data from France and Belgium—agroupederechercherespiratoireenreanimation - Soluble CD25 (soluble IL-2 receptor) ≥ 2400 U/mL onco-hematologique study. J Clin Oncol 31(22):2810–2818 4. Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, Meersseman W, Akova M, Arendrup MC, Arikan-Akdagli S, Bille J, Castagnola E, Cuenca-Estrella M, Donnelly JP, Groll AH, Herbrecht R, Hope WW,JensenHE, Lass-FlörlC,PetrikkosG,RichardsonMD, should establish local admission criteria for critically ill cancer Roilides E, Verweij PE, Viscoli C, Ullmann AJ, ESCMID Fungal patients as well as standardized admission procedures, such as Infection Study Group (2012) ESCMID* guideline for the diagnosis joint assessment by cancer specialists and intensivists, and management of Candida diseases 2012: non-neutropenic adult pa- tients. Clin Microbiol Infect 18:19–37 allowing identification of patients and standardized transfer 5. Cuenca-Estrella M, Verweij PE, Arendrup MC, Arikan-Akdagli S, to the ICU. In some patients, time-limited ICU trials with Bille J, Donnelly JP, Jensen HE, Lass-Flörl C, Richardson MD, pre-defined do-not-escalate decisions (e.g., do-not-intubate Akova M, Bassetti M, Calandra T, Castagnola E, Cornely OA, or do-not-attempt-resuscitation) may be an adequate option Garbino J, Groll AH, Herbrecht R, Hope WW, Kullberg BJ, Lortholary O, Meersseman W, Petrikkos G, Roilides E, Viscoli C, until final decision. This implements that critically ill cancer Ullmann AJ, ESCMID Fungal Infection Study Group (2012) patients should be referred to experienced intensive care units. ESCMID* guideline for the diagnosis and management of Candida We strongly recommend establishing a local structure with diseases 2012: diagnostic procedures. Clin Microbiol Infect 18:9–18 daily joint rounds of cancer specialists and intensivists as well 6. UllmannAJ,AkovaM,Herbrecht R,ViscoliC,ArendrupMC,Arikan- Akdagli S,BassettiM,BilleJ,Calandra T,CastagnolaE,Cornely OA, as standard-operating procedures for the management of fre- Donnelly JP, Garbino J, Groll AH, Hope WW, Jensen HE, Kullberg BJ, quent medical conditions in critically ill cancer patients. Lass-Flörl C, Lortholary O, Meersseman W, Petrikkos G, Richardson Furthermore, centers should organize continuous medical MD, Roilides E, Verweij PE, Cuenca-Estrella M, ESCMID Fungal education of cancer specialists and intensivists. Finally, basic Infection Study Group (2012) ESCMID* guideline for the diagnosis concepts of the care of critically ill cancer patients should be and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT). included into the curricula of both cancer specialists and Clin Microbiol Infect 18:53–67 intensivists. 7. 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Medicine & Public Health; Hematology; Oncology
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Abstract

This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients. . . . . Keywords Hematological malignancy Oncological malignancy Critical illness Intensive care treatment Mechanical . . ventilation ICU ICU admission Introduction and background Appropriate allocation of resources for cancer prevention, ear- ly diagnosis, as well as curative and palliative care remain of Cancer is the second leading cause of death worldwide. particular importance. This requires a detailed knowledge of According to recent publications, the incidence of neoplasms the local burden of cancer [1]. is expected to increase requiring more health care resources. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00277-018-3312-y) contains supplementary material, which is available to authorized users. * M. G. Kiehl Clinic for Intensive Care Medicine, University Hamburg, Martinistr. michael.kiehl@klinikumffo.de 52, 20246 Hamburg, Germany Department of Medicine I, Medical University of Vienna, 1 Waehringer Guertel 18-20, 1090 Vienna, Austria Department of Internal Medicine I, Clinic Frankfurt/Oder GmbH, Müllroser Chaussee 7, 15236 Frankfurt (Oder), Germany Department of Internal Medicine I, University Hospital, Fetschertstr. 74, 01307 Dresden, Germany Hannover Medical School (MHH) Clinic for Hematology, Department of Internal Medicine III, Schwarzwald-Baar-Klinikum, Coagulation, Oncology and Stem Cell Transplantation, Klinikstr. 11, 78052 Villingen-Schwenningen, Germany Carl-Neuberg-Straße 1, 30625 Hannover, Germany 3 Clinic for Stem Cell Transplantation, University Hospital Essen, Department of Internal Medicine I, University Hospital, Kerpener Hufelandstr. 55, 45147 Essen, Germany Str. 62, 50937 Cologne, Germany Department of Cardiology and Pulmonary Medicine, University III. Medical Clinic, Medical Faculty Mannheim, Hospital, Robert-Koch-Str. 40, 37075 Göttingen, Germany Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany Department of Hematology and Oncology, University Hospital, Johanniter-Hospital, Johanniterstr. 3-5, 53113 Bonn, Germany Leipziger Str. 44, 39120 Magdeburg, Germany 1272 Ann Hematol (2018) 97:1271–1282 In patients with hematological or oncological malignan- and manuscript wording underwent voting of the consensus cies, the disease itself or intensive therapy may result in crit- assembly. ical illness in a substantial number of patients. In 1999, the This guideline follows the structure and definitions of American College of Critical Care Medicine stated that pa- the ESCMID Guideline on Candida diseases [4–6]. It is in tients with hematological or metastasized oncological malig- accordance with the GRADE and AGREE [7, 8](Table 1). nancies are poor candidates for ICU admission with a mortal- All recommendations are given in boldface type. ity rate of up to 90%. Thus, refusal of ICU admission of these patients was the common procedure (Task Force of the American College of Critical Care Medicine, Society of Prognosis and ICU admission criteria Critical Care Medicine, 1999 [2]). However, within the last 25 years, cancer and ICU treatment clearly improved. As Whom to admit to the ICU/eligibility and goals shown in recent reports, hospital mortality decreased to less of therapy than 40% in these critically ill patients with hematologic ma- lignancies [3]. Thus, criteria for ICU admission have to be Full-code ICU management (without limitations of ICU adjusted. Aim of this consensus statement is to provide a re- resources) should be offered to all critically ill cancer patients view of the recent literature and the development of practical if long-term survival may be compatible with the general recommendations to hematologists, oncologists, and intensive prognosis of the underlying malignancy (A-IIu) care specialists. Due to a series of practice-changing investi- gations on proper ventilation techniques in cancer patients This statement, of course, presumes that the acute condi- with acute respiratory failure, we put a special emphasis on tion may be reversed by ICU measures, and that age and discussing this topic. comorbidities of patients do not contradict such an ap- proach. Typically, full-code management applies to pa- tients with curative therapeutic options, those in remission of their malignancy, as well as to patients in whom cure is Methods not likely but the expected life-span is substantial [3, 9]. It has been suggested in an earlier consensus that an assumed The consensus group was selected to represent the expertise in the field of critical care in cancer patients in Germany and Austria. Experts were sent by the German Society of Hematology and Medical Oncology (DGHO), the Austrian Table 1 Strength of the recommendation and quality of evidence Society of Hematology and Oncology (OeGHO), the Strength Recommendation German Society of Internal Intensive and Emergency A Strong recommendation for use Medicine (DGIIN), and the Austrian Society of Medical and B Moderate recommendation for use General Intensive Care and Emergency Medicine (ÖGIAIN). C Marginal recommendation for use All authors are actively supporting the “Intensive Care D Recommendation against use Medicine in Hematologic and Oncologic Patients (iCHOP)” Quality of evidence Initiative (info@ichop.eu). I Evidence from at least 1 properly designed Consensus statements are based on an in-depth PubMed lit- randomized, controlled trial erature retrieval of English as well as German language literature II Evidence from at least 1 well-designed clinical with last access February 01, 2017. For medical heading terms trial, without randomization; from cohort or (MeSH) identifying potential relevant literature, please see case-controlled analytic studies (preferably from > 1 center); from multiple time series; Appendix. Seven working groups (a: ICU transfer criteria and or from dramatic results of uncontrolled goals of therapy, b: respiratory failure, c: end of live decisions, d: experiments stem cell transplant patients, e: infections, f: coagulation, and g: III Evidence from opinions of respected authorities, miscellaneous) prepared the draft proposals in a first round of based on clinical experience, descriptive case consensus development. Working groups decided on references studies with relevant impact on guideline development, and every group Added index: : meta-analysis (or systematic review of RCT); :trans- r t member had to approve the draft guideline subchapter. Finally, ferred evidence, i.e., results from different patients Bcohorts^ or similar the consensus statements were approved by the assembly of the immune status situation; : comparator group: historical control; :un- h u members on March 2nd and 3rd 2017 in Vienna, Austria, a controlled trials; : published abstract (presented at an international sym- meetinghostedand sponsoredbytheOeGHO. Allstatements posium or meeting) Ann Hematol (2018) 97:1271–1282 1273 prognosis of 1 year may be used as cutoff for clinical de- Cancer patients should be considered for ICU admission cision making with regard to full-code status [10]. The in case of manifest or incipient acute organ dysfunction(s) authors of this manuscript believe this number is arbitrary (A-IIu) and may be regarded as basis for individual considerations only. Cancer ward patients at risk should be screened for the presence of sepsis daily (A-IIt) Patients with poor performance status not eligible for further Cancer ward patients at risk should be screened anti-cancer therapy, dying patients, as well as those rejecting for the presence of acute organ dysfunction(s) daily (A-IIu) critical care treatment should not be admitted to the ICU in general (A-III) Recommendations for local structures and educational matters For patients not fulfilling the above-described criteria for full-code ICU management or ICU refusal, time-limited ICU Mortality of ICU cancer patients has markedly dropped over trials or pre-defined do-not-escalate decisions (e.g., the last decades, presumably due to improved general ICU do-not-intubate or do-not-attempt-resuscitation) may be management, improved diagnostic and therapeutic strategies adequate options (B-IIu) for several cancer-specific situations, as well as refined admis- sion criteria [10, 17, 18]. Yet, prognostication of cancer patients In a prospective trial on patients with intermediary and adequate patient selection remain far from perfect [19]. prognosis (non-palliative, non-bedridden, non-full-code patients), those with worsening organ failure scores after Centers should establish local admission criteria for critically days 5ofICU therapyhad ahighriskofdying.The ill cancer patients as well as standardized admission authors suggested to offer these patients a full-code ICU procedures, such as joint assessment by cancer specialists trial with re-evaluation of the goals of therapy after at and intensivists, if available (A-III) least 6 days [9]. We would like to point out that almost all patients who died after day 5 had treatment- A recent Brazilian investigation showed an independent correla- limitation decisions. Therefore, it remains unknown tion between daily joint rounds of cancer specialists and what their course would have been in case of further intensivists as well as the number of protocols with lower mor- full-code management. Furthermore, data on cancer pa- tality and more efficient resource use [20]. This is supported by tients with poor prognosis suggest that the optimal du- Nassar and coworker stating that regular meetings may reduce ration of time-limited ICU trials seems to differ largely possible conflicts between intensivists and oncologists [21]. between patients with solid tumors and hematologic ma- lignancies [11]. Thus, proposing a fixed interval from Centers should establish daily joint rounds of cancer admission to re-evaluation of the goals of ICU therapy specialists and intensivists as well as standard-operating in patients undergoing time-limited ICU trials may not procedures for the management of frequent medical be generally appropriate. conditions of critically ill cancer patients (A-IIu) Although a recent study by Soares and colleagues failed to When to admit to the ICU, indications and screening identify ICU volume as a prognostic marker for ICU survival for organ dysfunction [20], the majority of available studies demonstrate a signifi- cant association of case volume and ICU mortality in cancer Several observational investigations on cancer patients patients with septic shock or acute respiratory failure [22–24]. with septic complications and respiratory failure indicate This effect might be linked to expertise and specific processes that early ICU admissions and early interventions, re- of care. However, some of the available observational studies spectively, are associated with improved survival [3, may not have accounted for potential confounders related to 12–16]. Thus, early identification of patients at risk for ICU organization, structure, and process of care. Ultimately critical deterioration seems crucial. Severity of illness recognizing and developing Bcritical care of cancer patients^ scores can only be used for describing groups of pa- as a medical subspecialty may optimally serve the needs of tients and should, therefore, not be used in individual affected patients [25]. Nevertheless, due to the fast-growing clinical decision making with regard to ICU admissions demand for critical care for cancer patients, the major practical or prognostication. challenge is how to provide high-quality and affordable care 1274 Ann Hematol (2018) 97:1271–1282 for all patients. Treating all critically ill cancer patients regard- lead to a (high-probability) diagnosis in approximately less of the underlying condition in specialized centers may not 70–80% of patients with ARF [31, 32]. However, diag- be feasible after all. Therefore, managing some of the rather nostic procedures should not cause a delay in the start of common cancer-specific ICU problems, such as neutropenic adequate ARF therapy including prompt antibiotic treat- sepsis, should become part of routine expertise for all inten- ment (modification) in the case of a (suspected) infection sive care specialists. However, in more specific situations, (A-III). such as chemotherapy administration in critically ill patients The diagnostic strategy should encompass a compre- with aggressive hematologic malignancies or caring for ICU hensive analysis of the clinical course of the underlying patients after allogeneic stem cell transplant, transfer to spe- malignancy, including data on mechanisms of immuno- cialized centers should be discussed. suppression, antineoplastic and antimicrobial treatment, and prophylaxis [31, 33]. Centers should establish joint continuous medical education of cancer specialists and intensivists (A-III) Independent of the clinical presentation, chest computed tomography is recommended (A-IIt) Basic concepts of the care of critically ill cancer patients should be included into the curricula of both cancer Bronchoscopy and a BAL-based diagnostic work-up including specialists and intensivists (A-III) a broad range of both culture- and non-culture-based diagnostic methods should be added to noninvasive tests All previous statements are summarized in Table 2. depending on pretest probabilities of clinical etiologies (if clinically feasible early after ICU admission and without causing clinical worsening) (A-I) Acute respiratory failure (ARF) Table 3 provides a summary of diagnostic procedures in can- cer patients with ARF. Diagnostic work-up With respect to the critical prognosis of ARF in cancer Ventilatory strategies patients, especially in patients with ARF of unknown origin [29, 30], diagnostic procedures are of major clin- Noninvasive ventilation (NIV) remains the first-line stan- ical importance. A systematic diagnostic work-up may dard of care in acute exacerbate chronic pulmonary Table 2 Admission to ICU, eligibility, and aims of therapy Intention Clinical situation/intervention SoR/QoE Reference I. Defining ICU eligibility criteria and Full-code ICU management in all critically ill cancer patients A-IIu [3] goals of therapy with prospect of long-term survival II. Defining ICU eligibility criteria and ICU refusal in patients with poor performance status not A-III goals of therapy eligible for further anti-cancer therapy, dying patients, as well as those rejecting critical care III. Defining ICU eligibility criteria and Time-limited ICU trial and/or do-not-escalate decisions in B-IIu [9, 11] goals of therapy patients neither fulfilling full code nor refusal criteria IV. Reducing mortality; indications for Early admission of patients with manifest or incipient acute A-IIu [3, 12–16] ICU admission organ dysfunction(s) to the ICU V. Reducing mortality; early Daily sepsis screening in cancer ward patients at risk A-IIt [26, 27, 28] identification of ICU candidates VI. Reducing mortality; early Daily screening for acute organ dysfunctions in cancer ward A-IIu identification of ICU candidates patients at risk VII. Facilitating ICU admission decisions Local ICU admission criteria and joint assessment by cancer A-III specialists and intensivists VIII. Reducing mortality; local structures Establish daily rounds of cancer specialists and intensivists A-IIu [20] IX. Reducing mortality; local structures Establish standard-operating procedures for frequent medical A-IIu [20] conditions of critically ill ICU cancer patients X. Reducing mortality; local structures Admit critically ill cancer patients to experienced ICUs A-IIu [19, 20] XI. Continuous medical education Establish joint continuous medical education of cancer A-III specialist and intensivists XII. Basic medical education/training Include basic concepts on critically ill cancer patients into A-III cancer specialists’ and intensivists’ curricula Ann Hematol (2018) 97:1271–1282 1275 Table 3 Invasive and Blood cultures noninvasive diagnostic procedures in ARF Multislice or high-resolution computed tomography (CT) scan of the lungs (in most cases without contrast media), (MRI of the lungs, if a pulmonary CT scan is not feasible) Echocardiography (cardiac status) Sputum examination for Bacteria Fungi Mycobacteria Induced sputum Pneumocystis jiroveci Nasopharyngeal aspirates RSV, influenza Polymerase chain reaction blood test for Herpesviridae Cytomegalovirus Epstein-Barr virus Circulating Aspergillus galactomannan Serologic tests for Chlamydia pneumoniae Mycoplasma pneumoniae Legionella pneumophila Urine antigen for Legionella pneumophila Streptococcus pneumoniae BAL (samples should include by default) � Cytospin preparation including Giemsa stain for cytological diagnostics and Gram stain � Bacteriological cultures (quantitative or semi-quantitative) including culture media to detect Legionella spp., mycobacteria and fungi � Calcofluor white or equivalent stain (assessment of fungi) � (quantitative, if possible) PCR for Pneumocystis jirovecii � direct immunofluorescence test for Pneumocystis jirovecii � Aspergillus antigen (Galactomannan ELISA) � Mycobacterium tuberculosis PCR, atypical mycobacteria BAL (optional) � PCR for cytomegalovirus, respiratory syncytial virus, influenza A/B virus, parainfluenza virus, human metapneumovirus, adenovirus, varicella zoster virus, and Pneumocystis jirovecii (quantitative) [34] � Aspergillus antigen (Galactomannan ELISA; ODI (optical density index): 1.0) Panfungal or Aspergillus/mucormycetes PCR Transbronchial biopsies Not recommended in general in febrile neutropenic and/or thrombocytopenic patients as a first line procedure. Adapted and modified from Azoulay et al., Am J Respir Crit Care Med 2010 [31] disease (AECOPD) or acute cardiogenic pulmonary ede- Society of Pneumology and Ventilatory Medicine ac- ma [35]. However, the role of NIV in hypoxic ARF is far knowledge that NIV can be attempted to avoid intubation less well documented. While a historic single-center ran- in immunosuppressed (including hemato-oncologic) pa- domized controlled trial (RCT) suggested superiority of tients. In this regard, it is of particular importance to NIV over conventional oxygen therapy in immunocom- respect common contraindications and termination, i.e., promised (mainly hematologic) patients with regard to intubation criteria [35]. However, the respective guide- intubation and survival rates [36], successive (mainly ob- line could not account for several meanwhile published servational) studies have led to conflicting results. The investigations: First, a meta-analysis on 2380 mainly he- 2015 BClinical Practice Guidelines on noninvasive me- matologic patients revealed that NIV as initial ventilator chanical ventilation in ARF^ on behalf of the German strategy was associated with lower mortality, whereas 1276 Ann Hematol (2018) 97:1271–1282 this finding is a mere association and cannot be patients, and specifically in those presenting with other interpreted as proof of principle. Importantly, 61% (range etiologies than pneumonia, remains to be demonstrated 40 to 78) of patients experienced NIV failure with sec- [43, 44]. ondary intubation, which itself was associated with in- creased mortality [37]. Second, in a large multicenter observational investigation in 1004 cancer patients with In case a NIV or HFNO trial is initiated in cancer patients ARDS, NIV failure occurred in 71% of patients and with hypoxic ARF, common contraindications and/or was, again, independently associated with mortality, the occurrence of pre-specified intubation criteria should while mortality of ARDS patients undergoing IMV per lead to intubation and invasive mechanical ventilation se had decreased to 52% in recent years [38]. Finally, a without delay (A-IIu) recent large multicenter landmark RCT compared the use of NIV to conventional oxygen in immunocompro- Given the considerable failure rates of NIV and HFNO mised (mainly hematologic) patients with hypoxic ARF in hypoxic ARF and the lack of sufficient data on the safety (acute cardiogenic pulmonary edema or hypercapnia, of such therapies in regular wards, NIV and HFNO should not i.e., PaCO > 50 mmHg excluded, pre-specified intuba- be attempted in this indication on a regular ward (B-III) tion criteria [39]). The trial did not show any clinical benefits or increased harms associated with NIV. End-of-life, palliative care However, the lower than expected mortality rate in the oxygen only group limited the power to detect signifi- Principles in palliative care and end-of-life (EOL) man- cant differences, and a higher proportion of patients in agement are not different in cancer patients compared to the NIV group received high flow nasal oxygen inter- critically ill patients without a malignancy as underlying mittently, which may have limited the demonstrable ef- disease (A-IIt). However, (i) patient’s wish, (ii) progres- fects of NIV. Risk factors for NIV failure in cancer sive (multi-) organ failure despite full-code ICU manage- patients are depicted in Table 4. ment and no chance of reversibility, or (iii) rapid prog- High flow nasal oxygen (HFNO) has recently been ress of cancer disease without further treatment options shown to be associated with reduced intubation (PaO have to be kept in mind and could change the treatment /FiO <200) and mortality (PaO /FiO < 300) rates in decision or treatment goals [45]. These issues have to be 2 2 2 elderly patients with pneumonia and hypoxic ARF when discussed between oncologists and the intensive care compared to conventional oxygen therapy or NIV [41]. team in an interdisciplinary manner. In cancer patients This effect was also observed in the subset of immuno- admitted to an ICU, current treatment state and estimated compromised patients [42]. However, given conflicting prognosis may be unknown to the ICU team. Therefore, data, the applicability of these findings in cancer consultation of an oncologist is highly recommended to provide valid prognostic information (A-III). Intensive care admissions often represent an addition- al burden for patients and families in situations without Table 4 Risk factors for NIV failure in cancer patients with acute option for cure. Good communication is essential to respiratory failure allow patients and families to meet their preferences regarding EOL. According to the literature, too many Prior to NIV Vasopressor need Multiple organ failure EOL decisions are made too late [46]. Early integration Airway involvement by malignancy of an interdisciplinary palliative care team for hospital- Acute respiratory distress syndrome ized patients with life-limiting disease leads to fewer Unknown etiology of ARF ICU admissions (A-I) [47]. Furthermore, integration of Delayed onset of ARF pro-active palliative care on ICUs, including palliative During NIV Patient not tolerating NIV No improvement of ABG within 6 h care rounds, leads to a shorter length of stay on ICU Respiratory rate > 30/min or in the hospital (A-IIt) [48, 49]. NIV dependency ≥ 3days To improve quality of EOL care in critically ill pa- Clinical or respiratory deterioration tients regarding important clinical questions, i.e., prepar- Unknown etiology of ARF ing for withdrawal, assessment and drug management of Adopted and modified from Soares et al., Critical Care Clinics 2010 [40] distress, discontinuation of treatment and monitoring, or NIV, noninvasive ventilation; ARF, acute respiratory failure; ABG, arterial dignity conserving care [50], the authors refer to pub- blood gas lished consensus recommendations [51, 52]. Ann Hematol (2018) 97:1271–1282 1277 Special situations & Unexplained fever in neutropenic patients [60](new ver- sion in progress) Anticancer therapy during ICU & Diagnosis of invasive fungal infections [70](new version in progress) In some cases, for example pulmonary involvement due to high & Treatment of invasive fungal infections [61]and grade non-Hodgkin lymphoma, hyperleukocytosis, etc., despite Pneumocystis jirovecii pneumonia [62] ICU treatment initiation or completion of anticancer chemother- & Diagnosis and antimicrobial therapy of lung infiltrates in apy, immunochemotherapy or radiotherapy is necessary to im- febrile neutropenic patients [63] prove patient’s clinical situation. Such some decision needs in- & Prophylaxis and treatment of infections in recipients of tensive discussions between the responsible hemato-oncologist autologous [71] (new version in progress) and allogeneic and intensivist. Again, we recommend joint assessments by can- stem cell transplant [26] cer specialists and intensivists and that basic concepts of the care & Community-acquired respiratory viral infections [72] of critically ill cancer patients should be included into the curric- & Management of central venous catheter-related infec- ula of both cancer specialists and intensivists. tions [73] & Gastrointestinal complications including neutropenic en- Prevention and treatment of infections in critically ill terocolitis [74] (new version in progress). cancer patients & Infections of the central nervous system in patients with hematological disorders [75] Published guidelines on prevention, diagnosis, and treatment of & The Surviving Sepsis Campaign (SSC) Guidelines for infections in cancer patients do not specifically address critically Management of Sepsis and Septic Shock recently pub- ill cancer patients. In addition, few studies and current guidelines lished [76]. The guidelines published in 2014 on sepsis on infections in critically ill patients specifically address the par- in neutropenic patients might be less appropriate since ticular requirements in the treatment of cancer patients (Table 5). they are based on the 2012-ssc-guidelines [59]. Resources on prevention and treatment of infections in & IDSA guidelines on immunization in patients with cancer cancer patients, which might be largely applicable to critically [58]; guidelines on immunization by the Infectious ill cancer patients, are guidelines on: Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) & Management of neutropenic patients in the intensive care are under progress. unit [69] & Prophylaxis of infectious complications with colony- & Prophylaxis of viral [57], bacterial [55], and fungal [56] stimulating factors in adult cancer patients undergoing chemotherapy [68 infections including Pneumocystis jirovecii pneumonia [55] ]. Table 5 Recommendations on prevention, diagnosis, and treatment of infections in cancer patients Intention Clinical situation/Intervention SoR/QoE Reference I. Reducing mortality Treatment in close collaboration of intensivist AIIt [53, 54] with cancer specialist and ID specialist II. Prevention of infections Continuation of prophylactic antiviral, antibacterial AIIt [55, 56, 57] and antifungal treatment upon ICU-admission, unless switch to therapeutic treatment or excessive organ toxicity III. Prevention of infections Immunization only according to specific guidelines BIII [58] for patients with cancer IV. Treatment Treatment of critically ill patients with infections AIIt [59] including neutropenic sepsis according to current guidelines for the treatment of sepsis and septic shock V. Anti-infective treatment Anti-infective treatment according to recommendations AIIr [60–64] for treatment of bacterial, fungal and viral infections in cancer patients VI. Reducing mortality Recommendation against routine use of GCSF in AIIr [65–67] neutropenic patients with pulmonary infiltrates VII Reducing mortality Use of GCSF only in selected cancer patients according AIIt [68] to current recommendations. 1278 Ann Hematol (2018) 97:1271–1282 Allogeneic stem cell transplant setting VAIA Criteria for ICU admission Transfusions The prognosis of allogeneic hematopoietic stem cell transplant In order to prevent the transfusion-associated graft versus host (HSCT) patients admitted to an ICU has been significantly reaction (GvHR), all cellular blood products have to be irradi- improved in the last years [77]. It is important to note that ated with ≥ 30 Gy for patients with lymphatic diseases, physicians of the primary hospital have to contact the patient’s autologous/allogeneic stem cell transplantation, and all pa- transplant center immediately in case of critical illness. tients treated with nucleoside analogues (fludarabine, Allogeneic HSCT patients with early ICU admission or single cladribine) [83]. Generally, to prevent acute hemolysis, AB0- organ dysfunction benefit from intensive care. However, pa- identic transfusions should be carried out. However, after al- tients with uncontrolled or refractory graft-versus-host disease logeneic HSCT, in exceptional cases, it is possible to transfuse (GvHD) should not be intubated for acute respiratory failure major or minor incompatible blood products according to the (A-III) [10, 78]. Thus, it is important to contact immediately AB0 blood group of the patient and the donor as stated in patient’stransplant center. Supplement Table S1 [84, 85]. Pooled platelet concentrates For further information regarding isolation procedures, have a higher risk of immunization. Therefore, we recommend specific monitoring, as well as typical complications, please the transfusion of apheresis platelet concentrates [84]. see supplement. Cytokine storm disease/Sepsis-like syndromes Coagulation Cancer patients are at risk to suffer from rare sepsis-like syndromes such as hemophagocytic lymphohistiocytosis Venous thromboembolism (VTE), including deep-vein throm- (HLH), cytokine release syndrome (CRS), drug reaction bosis and pulmonary embolism, represents a major cause of with eosinophilia and systemic syndromes (DRESS), or morbidity and mortality in cancer patients. An increased tu- capillary leak syndrome (CLS) [86–89]. Infections, ma- mor burden results in a higher risk for VTE with the highest lignancy itself, and drugs are major triggers for these risk in patients receiving systemic chemotherapy or being sepsis-mimicking syndromes. Diagnostic vigilance for hospitalized on surgical and medical floors. early recognition is essential to reduce mortality. To val- Although there are no validated data on the risk assessment idate diagnosis, we recommend to include blood differ- in cancer patients on the ICU, according to the American ential (cytopenia, eosinophilia), ferritin, soluble IL2R, Society of Clinical Oncology guidelines, risk scores (Khorana fibrinogen, and triglycerides in addition to the routine Score, revised Khorana score, Vienna score and Protecht score) ICU lab admission panel in cancer patients with sepsis are helpful tools to identify patients at highest risk for VTE or sepsis-like syndromes in whom there is no apparent [79–81]. For further information on thromboprophylaxis in focus of sepsis [90, 91](seeTable 6 for HLH diagnostic hospitalized patients with cancer, thromboprophylaxis in surgi- criteria). Withholding the assumed trigger drug and im- cal patients with cancer, and treatment of thrombosis, please see mediate search for an underlying malignancy or infection Supplement Table S3 and accompanying text. are pivotal. HLH patients require immediate immunosup- pression with corticosteroids to prevent further progres- sion of organ failure [92]. Early consultation with an Complications after new cancer drugs or cellular HLH expert to stratify treatment according to the most immunotherapy likely trigger is recommended (www.hlh-registry.org). Pharmacological and cellular treatment of cancer is changing dramatically not only with benefits for patient’s outcome and Summary comfort, but also with new toxicity profiles. The vast majority of adverse events can be classified as mild or moderate but During the last years, outcome of patients with malignant there are also some cases of severe and life-threatening com- hematological or oncological diseases requiring intensive care plications requiring ICU admission. Diagnosis and manage- treatment has clearly improved. From recently published data, ment of severe side effects after (monoclonal or bispecific) we conclude that the severity of the acute illness is more antibody treatment, tyrosine kinase inhibitors, immune check- important with regard to short-term survival than the underly- point inhibitors, and chimeric antigen receptor-modified ing type and stage of malignancy. Patients receiving intensive (CAR-) T cells were summarized recently in a concise review treatment of their malignancy should be considered for ICU by the iCHOP group [82]. treatment as other severely ill patients without cancer. Centers Ann Hematol (2018) 97:1271–1282 1279 Table 6 HLH diagnostic criteria [91] References HLH-2004 diagnostic criteria: ≥ 5 must be fulfilled 1. Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H et al (2017) Global, regional, and national cancer incidence, mortal- -Fever(≥ 38.3 °C) ity, years of life lost, years lived with disability, and disability-adjusted - Splenomegaly life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for - Cytopenias in ≥2lines (hb <9g/dL, plt <100/nL,neutrophils the global burden of disease study. JAMA Oncol 3(4):524–548 <1.0/nL) 2. Medicine TFotACoCC (1999) Guidelines for intensive care unit -Ferritin ≥ 500 μg/L admission, discharge, and triage. Task force of the American College of Critical Care Medicine, Society of Critical Care - Hypertriglyceridemia and/or hypofibrinogenemia (fasting Medicine. Crit Care Med 27(3):633–638 triglycerides ≥ 265 mg/dL, fibrinogen < 1.5 g/L) 3. Azoulay E, Mokart D, Pene F, Lambert J, Kouatchet A, Mayaux J - Hemophagocytosis in bone marrow or spleen or lymph nodes et al (2013) Outcomes of critically ill patients with hematologic - Low or absent NK activity malignancies: prospective multicenter data from France and Belgium—agroupederechercherespiratoireenreanimation - Soluble CD25 (soluble IL-2 receptor) ≥ 2400 U/mL onco-hematologique study. J Clin Oncol 31(22):2810–2818 4. Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, Meersseman W, Akova M, Arendrup MC, Arikan-Akdagli S, Bille J, Castagnola E, Cuenca-Estrella M, Donnelly JP, Groll AH, Herbrecht R, Hope WW,JensenHE, Lass-FlörlC,PetrikkosG,RichardsonMD, should establish local admission criteria for critically ill cancer Roilides E, Verweij PE, Viscoli C, Ullmann AJ, ESCMID Fungal patients as well as standardized admission procedures, such as Infection Study Group (2012) ESCMID* guideline for the diagnosis joint assessment by cancer specialists and intensivists, and management of Candida diseases 2012: non-neutropenic adult pa- tients. Clin Microbiol Infect 18:19–37 allowing identification of patients and standardized transfer 5. Cuenca-Estrella M, Verweij PE, Arendrup MC, Arikan-Akdagli S, to the ICU. In some patients, time-limited ICU trials with Bille J, Donnelly JP, Jensen HE, Lass-Flörl C, Richardson MD, pre-defined do-not-escalate decisions (e.g., do-not-intubate Akova M, Bassetti M, Calandra T, Castagnola E, Cornely OA, or do-not-attempt-resuscitation) may be an adequate option Garbino J, Groll AH, Herbrecht R, Hope WW, Kullberg BJ, Lortholary O, Meersseman W, Petrikkos G, Roilides E, Viscoli C, until final decision. This implements that critically ill cancer Ullmann AJ, ESCMID Fungal Infection Study Group (2012) patients should be referred to experienced intensive care units. ESCMID* guideline for the diagnosis and management of Candida We strongly recommend establishing a local structure with diseases 2012: diagnostic procedures. Clin Microbiol Infect 18:9–18 daily joint rounds of cancer specialists and intensivists as well 6. UllmannAJ,AkovaM,Herbrecht R,ViscoliC,ArendrupMC,Arikan- Akdagli S,BassettiM,BilleJ,Calandra T,CastagnolaE,Cornely OA, as standard-operating procedures for the management of fre- Donnelly JP, Garbino J, Groll AH, Hope WW, Jensen HE, Kullberg BJ, quent medical conditions in critically ill cancer patients. Lass-Flörl C, Lortholary O, Meersseman W, Petrikkos G, Richardson Furthermore, centers should organize continuous medical MD, Roilides E, Verweij PE, Cuenca-Estrella M, ESCMID Fungal education of cancer specialists and intensivists. Finally, basic Infection Study Group (2012) ESCMID* guideline for the diagnosis concepts of the care of critically ill cancer patients should be and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT). included into the curricula of both cancer specialists and Clin Microbiol Infect 18:53–67 intensivists. 7. 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Annals of HematologySpringer Journals

Published: Apr 27, 2018

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