The role of microRNAs in muscle wasting and recovery during critical illness: a systematic review

Background: Intensive care patients commonly develop muscle wasting and functional impairment. However, the role of severe COVID-19 in the magnitude of muscle wasting and functionality in the acute critical disease is unknown.Objective: To perform a prospective characterization to evaluate the skeletal muscle mass and functional performance in intensive care patients with severe COVID-19.Methods: Thirty-two critically ill patients (93.8% male; age: 64.1 ± 12.6 years) with the diagnosis of the severe COVID-19 were prospectively recruited within 24 to 72 h following intensive care unit (ICU) admission, from April 2020 to October 2020, at Hospital Sírio-Libanês in Brazil. Patients were recruited if older than 18 years old, diagnosis of severe COVID-19 confirmed by RT-PCR, ICU stay and absence of limb amputation. Muscle wasting was determined through an ultrasound measurement of the rectus femoris cross-sectional area, the thickness of the anterior compartment of the quadriceps muscle (rectus femoris and vastus intermedius), and echogenicity. The peripheral muscle strength was assessed with a handgrip test. The functionality parameter was determined through the ICU mobility scale (IMS) and the International Classification of Functioning, Disability and Health (ICF). All evaluations were performed on days 1 and 10.Results: There were significant reductions in the rectus femoris cross-section area (−30.1% [95% IC, −26.0% to −34.1%]; P < 0.05), thickness of the anterior compartment of the quadriceps muscle (−18.6% [95% IC, −14.6% to 22.5%]; P < 0.05) and handgrip strength (−22.3% [95% IC, 4.7% to 39.9%]; P < 0.05) from days 1 to 10. Patients showed increased mobility (0 [0–5] vs 4.5 [0–8]; P < 0.05), improvement in respiratory function (3 [3–3] vs 2 [1–3]; P < 0.05) and structure respiratory system (3 [3–3] vs 2 [1–3]; P < 0.05), but none of the patients returned to normal levels.Conclusion: In intensive care patients with severe COVID-19, muscle wasting and decreased muscle strength occurred early and rapidly during 10 days of ICU stay with improved mobility and respiratory functions, although they remained below normal levels. These findings may provide insights into skeletal muscle wasting and function in patients with severe COVID-19.

To assess the impact of delay in emergency department (ED) on outcome of critically ill patients admitted to the medical intensive care unit (MICU). Outcome was defined as hospital mortality and as health-related quality of life (HRQoL) at 6 months after intensive care assessed by the 15D measure. The 15D is a generic, 15-dimensional, standardized measure of HRQoL. We hypothesized that prolonged stay in the ED is related to worse outcome. A prospective follow-up cohort study in university hospital. All consecutive 1675 patients admitted to the MICU between July 2002 and June 2004. The 15D questionnaire was mailed to all patients alive at 6 months after admission. Of all MICU patients, 64% were admitted from ED. The mean length of stay in the ED was 6.2 h (95%CI 5.9-6.5 h). The hospital mortality rate was 24.4% (20.0% in the ED vs. 33.0% in the non-ED cohort, P < 0.001) and it was associated with higher age and degree of physiological derangement at admission. Neither the length of ED stay was associated with hospital mortality (P = 0.82) nor with HRQoL at 6 months after MICU admission (P = 0.34). Altogether, HRQoL at 6 months was significantly lower compared with the age- and sex-matched general population (P < 0.001). In a university hospital, the length of ED stay was not associated with the outcome of critically ill medical patients. However, we feel that the effect of ED treatment and delay on outcome and outcome prediction in the critically ill patients deserves further evaluation.

At this time, we are unable to determine an overall effect on functional exercise capacity, or on health-related quality of life, of an exercise-based intervention initiated after ICU discharge for survivors of critical illness. Meta-analysis of findings was not appropriate because the number of studies and the quantity of data were insufficient. Individual study findings were inconsistent. Some studies reported a beneficial effect of the intervention on functional exercise capacity, and others did not. No effect on health-related quality of life was reported. Methodological rigour was lacking across several domains, influencing the quality of the evidence. Wide variability was noted in the characteristics of interventions, outcome measures and associated metrics and data reporting.If further trials are identified, we may be able to determine the effects of exercise-based intervention following ICU discharge on functional exercise capacity and health-related quality of life among survivors of critical illness.

Importance Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment. Objective To perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown. Design, Setting, and Participants Sixty-three critically ill patients (59% male; mean age: 54.7 years [95% CI, 50.0-59.6 years]) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were prospectively recruited within 24 hours following intensive care unit (ICU) admission from August 2009 to April 2011 at a university teaching and a community hospital in England. Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to spend more than 7 days in critical care, and to survive ICU stay. Main Outcomes and Measures Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized. Results There were significant reductions in the rectus femoris CSA observed at day 10 (−17.7% [95% CI, −20.9% to −4.8%]; P P P = .03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour) ( P = .57) and increased by day 7 (0.076% [95% CI, 0.032%-0.120%/hour]; P = .03) to rates associated with fed controls (0.065%/hour [95% CI, 0.049% to 0.080%/hour]; P = .30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5 [95% CI, 4.7 to 12.3] to 10.6 [95% CI, 6.8 to 14.4] μmol of phenylalanine/min/ideal body weight × 100; P = .40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = −0.83, P = .005) and decreased synthesis (n = 9, r = −0.69, P = .04). Conclusions and Relevance Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting in critical illness.

Long-term recovery of survivors of coronavirus disease (COVID-19) treated with extracorporeal membrane oxygenation: The next imperative

Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment. To perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown. Sixty-three critically ill patients (59% male; mean age: 54.7 years [95% CI, 50.0-59.6 years]) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were prospectively recruited within 24 hours following intensive care unit (ICU) admission from August 2009 to April 2011 at a university teaching and a community hospital in England. Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to spend more than 7 days in critical care, and to survive ICU stay. Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized. There were significant reductions in the rectus femoris CSA observed at day 10 (−17.7% [95% CI, −25.9% to 8.1%]; P < .001). In the 28 patients assessed by all 3 measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1% to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8% to 29.3%), and the ratio of protein to DNA by 29.5% (95% CI, 13.4% to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced multiorgan failure by day 7 (−15.7%; 95% CI, −27.7% to 11.4%) compared with single organ failure (−3.0%; 95% CI, −5.3% to 2.1%) (P < .001), even by day 3 (−8.7% [95% CI, −59.3% to 50.6%] vs −1.8% [95% CI, −12.3% to 10.5%], respectively; P = .03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour) (P = .57) and increased by day 7 (0.076% [95% CI, 0.032%-0.120%/hour]; P = .03) to rates associated with fed controls (0.065%/hour [95% CI, 0.049% to 0.080%/hour]; P = .30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5 [95% CI, 4.7 to 12.3] to 10.6 [95% CI, 6.8 to 14.4] μmol of phenylalanine/min/ideal body weight × 100; P = .40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = −0.83, P = .005) and decreased synthesis (n = 9, r = −0.69, P = .04). Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting in critical illness.

BackgroundAcute muscle wasting is common in critically ill patients, and this can lead to unfavorable clinical outcomes. The aim of this study was to identify factors associated with muscle wasting and to investigate the association between skeletal muscle wasting and prolonged hospital stay in critically ill patients with acute brain injury.MethodsThis single-center prospective observational study was conducted in critically ill patients with acute brain injury who stayed in the intensive care unit for at least 1 week. The rectus femoris cross-sectional area was measured via ultrasound at baseline and a week after the first assessment. Univariate and multivariate logistic regression analyses were performed to identify factors that predicted prolonged hospital stay.ResultsA total of 86 patients were included in the study. Their mean age was 49.4 ± 16.9 years, 57% were male, and 46.5% had an admission diagnosis of subarachnoid hemorrhage. The percentage change in the rectus femoris cross-sectional area was 15.8% (95% confidence interval [CI] − 19.8% to − 12.0%; p < 0.001), and 57% of all patients had acute muscle wasting. According to the univariate analysis, there was a significant association between prolonged hospital stay and acute muscle wasting (odds ratio [OR] 3.677; 95% CI 1.487–9.043; p = 0.005), mechanical ventilation status (OR 3.600; 95% CI 1.455–8.904; p = 0.006), and Glasgow Coma Scale score (OR 0.888; 95% CI 0.808–0.976; p = 0.014) at intensive care unit admission. The multivariate analysis demonstrated that acute muscle wasting (OR 3.449; 95% CI 1.344–8.853; p = 0.010) was an independent risk factor for prolonged hospital stay.ConclusionsThere was considerable muscle wasting in critically ill patients with brain injuries over a 1-week period. Acute muscle wasting was associated with prolonged hospital stay in critically ill patients with acute brain injury.

Long-Term Outcomes of Acute Kidney Injury

careful selection of the appropriate mode of feeding and monitoring the success of the feeding strategy. The use of specific nutrients, which possess a drug-like effect on the immune or inflammatory state during critical illness, continues to be an exciting area of investigation. The lack of systematic research and clinical trials on various aspects of nutrition support in the PICU is striking and makes it challenging to compile evidence based practice guidelines. There is an urgent need to conduct well-designed, multicenter trials in this area of clinical practice. The extrapolation of data from adult critical care literature is not desirable and many of the interventions proposed in adults will have to undergo systematic examination and careful study in critically ill children prior to their application in this population. In the following sections, we will discuss some of the key aspects of nutrition support therapy in the PICU; examine the literature and provide best practice guidelines based on evidence from PICU patients, where available. While some PICU popu lations include neonates, A.S.P.E.N. Clinical Guidelines for neonates will be published as a separate series.

Invited Commentary

BackgroundMuscular weakness and/or muscle wasting is recognized as a key medical problem in critically ill patients on intensive care units (ICUs) worldwide.Methods and ResultsIntensive care unit‐acquired weakness (ICUAW) results from various diseases leading to critical illness and is observed in about 40% [1080/2686 patients, 95% confidence interval (CI): 38–42%] of mixed (medical–surgical) ICU patients. Muscle strength at ICU discharge is directly associated with mortality 5 years after discharge [hazard ratio 0.946, 95% CI: 0.928–0.968 per point increase in Medical Research Council (MRC) scores, P = 0.001]. ICUAW serves as umbrella term for the subgroups ‘critical illness myopathy’, ‘critical illness polyneuropathy’, and ‘critical illness polyneuromyopathy’, the latter distinguished using electrophysiology and/or biopsy studies. Diagnosing, studying, and developing treatments for ICUAW among the critically ill seems challenging due to the acuity and severity of the underlying heterogeneous diseases. Ventilator‐induced diaphragmatic dysfunction occurs in up to 80% (n = 32/40) of ICUAW patients after mechanical ventilation and mostly results from distinct muscular pathologies, disuse, underlying critical illness, and/or effects imposed directly by mechanical ventilation. Swallowing disorders/dysphagia likely represent an additional (local) neuromuscular dysfunction/ICUAW sequelae and presents in 10.3% (n = 96/933) of mixed medical–surgical ICU survivors, with 60.4% (n = 58/96) of patients remaining dysphagia positive until hospital discharge. Key independent risk factors for dysphagia following mechanical ventilation are baseline neurological disease [odds ratio (OR) 4.45, 95% CI: 2.74–7.24, P &lt; 0.01], emergency admission (OR 2.04, 95% CI: 1.15–3.59, P &lt; 0.01), days on mechanical ventilation (OR 1.19, 95% CI: 1.06–1.34, P &lt; 0.01), days on renal replacement therapy (OR 1.1, 95% CI: 1–1.23, P = 0.03), and disease severity (Acute Physiology and Chronic Health Evaluation II score within first 24 h; OR 1.03, 95% CI: 0.99–1.07, P &lt; 0.01). Dysphagia positivity independently predicts 28‐day and 90‐day mortality (90‐day univariate hazard ratio: 3.74; 95% CI, 2.01–6.95; P &lt; 0.001) and is associated with a 9.2% excess (all‐cause) mortality rate.ConclusionsNeuromuscular weakness and muscle wasting is observed in many survivors of critical illness. ICUAW, ventilator‐induced diaphragmatic dysfunction, and dysphagia are associated with complicated and prolonged ICU stay, impaired weaning from mechanical ventilation, impeded rehabilitative measures, and a considerable impact on morbidity and mortality is noted. Future research strategies should further explore underlying pathomechanisms and lead to development of causal treatment strategies.

BackgroundPhysical rehabilitation interventions aim to ameliorate the effects of critical illness-associated muscle dysfunction in survivors. We conducted an overview of systematic reviews (SR) evaluating the effect of these interventions across the continuum of recovery.MethodsSix electronic databases (Cochrane Library, CENTRAL, DARE, Medline, Embase, and Cinahl) were searched. Two review authors independently screened articles for eligibility and conducted data extraction and quality appraisal. Reporting quality was assessed and the Grading of Recommendations Assessment, Development and Evaluation approach applied to summarise overall quality of evidence.ResultsFive eligible SR were included in this overview, of which three included meta-analyses. Reporting quality of the reviews was judged as medium to high. Two reviews reported moderate-to-high quality evidence of the beneficial effects of physical therapy commencing during intensive care unit (ICU) admission in improving critical illness polyneuropathy/myopathy, quality of life, mortality and healthcare utilisation. These interventions included early mobilisation, cycle ergometry and electrical muscle stimulation. Two reviews reported very low to low quality evidence of the beneficial effects of electrical muscle stimulation delivered in the ICU for improving muscle strength, muscle structure and critical illness polyneuropathy/myopathy. One review reported that due to a lack of good quality randomised controlled trials and inconsistency in measuring outcomes, there was insufficient evidence to support beneficial effects from physical rehabilitation delivered post-ICU discharge.ConclusionsPatients derive short-term benefits from physical rehabilitation delivered during ICU admission. Further robust trials of electrical muscle stimulation in the ICU and rehabilitation delivered following ICU discharge are needed to determine the long-term impact on patient care. This overview provides recommendations for design of future interventional trials and SR.Trial registration numberCRD42015001068.

Tyrosine Kinase Inhibitors for Acute Respiratory Failure Because of Non–small-Cell Lung Cancer Involvement in the ICU

Critical care or intensive care units (ICUs) began to emerge in major academic medical centres in the years following World War II (E. P. Didier, personal communication (see Acknowledgements below); Didier, 1970). At the same time, there was a parallel emergence of what might be described as high-tech surgery which included most notably the development of open heart surgery which is now routine. All of this required translation of basic physiological techniques including invasive monitoring of pressures throughout the cardiovascular system, measurement of arterial blood gases, and mechanical ventilation, along with administration of drugs in attempts to maintain some semblance of physiological homeostasis in the patients. As progress continued, these techniques were applied to patients with a wide variety of severe illnesses and facilitated additional impressive surgical interventions, permitting patients to survive illnesses like pneumonia and sepsis that were frequently fatal in earlier eras. So, by any stretch of the imagination, ICUs and the medical advances they have facilitated are clear demonstrations of how broad-based physiological principles, techniques and interventions can be translated into medical practice. Intensive care is also sometimes flippantly referred to as ‘expensive care’ inside the walls of academic medical centres (Halpern, 2009). This euphemism reflects the high cost of care for these patients because it requires significant equipment and around the clock attention and intervention by skilled teams of physicians, nurses, and other hospital personnel (Didier, 1970). While the cost of ICU care is a great challenge to policy makers, at another level the vast sums spent taking care of critically ill patients demonstrate the potential life-saving powers of the integrated use of expertise and technology in complex patients. Additionally, one unforeseen ‘side effect’ of ICUs has been what happens after the patient recovers from their acute condition or conditions. Finally, the complex nature of the critically ill patient is also a great challenge in the design of clinical trials to improve outcomes because generating a large pool of relatively homogeneous subjects who can participate in well-controlled standardized interventions is very difficult in these patients. These issues are amplified by the challenges associated with informed consent and just the unpredictable nature and ‘rollercoaster’ clinical course in many patients admitted to ICUs. With this information as a background, Constantin and colleagues have performed an outstanding study on the general syndrome of muscle wasting in the ICU, described in a recent issue of The Journal of Physiology (Constantin et al. 2011). As they point out, muscle wasting, and loss of muscle strength (especially respiratory muscle strength) is a major issue for patients in critical care units in the short term. In addition to general and respiratory muscle weakness, muscle wasting also leads to acute disruptions in metabolic control (diabetes) in many ICU patients. In the medium term it can also make weaning patients from mechanical ventilation problematic. In the longer term (especially in older patients) muscle wasting poses a significant challenge for the rehabilitation of these patients and resumption of the normal activities of daily living. Along these lines, the main findings from Constantin et al. are that a suite of molecular events occurs early on in the course of critical illness that promote muscle protein breakdown via activation of a number of catabolic pathways. Additionally, while there is an increase in the transcription of at least some anabolic pathways in skeletal muscle, this transcription does not appear to generate a major bump in the proteins that synthesize skeletal muscle and any anabolic changes are overwhelmed by a broad-based catabolic attack. From both basic science and clinical perspectives, these finding are important for the following reasons. First, the ten patients studied at some level are typical of ICU patients at teaching hospitals. They have a wide variety of conditions, multiple co-morbidities, and are unified primarily by the fact that they tend to be older. In this context, it is interesting to note that there appears to be a generic catabolic response irrespective of the clinical syndrome that lands the patient in the ICU. Second, the finding of a relatively generic set of defects in the catabolic/anabolic pathways and their regulation is important because this suggests that perhaps a common set of anti-catabolic strategies will have broad-based success in these patients. Third, is there a strategy of either anti-catabolic drugs (myostatin inhibitors?) that might be useful in these patients, and how would any pharmacological or physiological strategies interact with nutritional support in the ICU? As noted above, mechanistic clinical studies and clinical trials are especially difficult in ICU patients. However, over the last 10–20 years physiologically based strategies have been developed and tested in the ICU and led to improved outcomes in these complex patients. A key example relates to how mechanical ventilators have been used in the treatment of the adult respiratory distress syndrome (Gillette & Hess, 2001). The change towards less aggressive ventilator strategies was based on a number of studies and observations in small groups of patients that then led to larger trials. These trials and the parallel generation of ICU research networks have facilitated and improved outcomes in ICU patients. Thus, perhaps the data from Constantin et al. will ultimately lead to a comprehensive set of strategies and interventions in critically ill patients designed to preserve their muscle mass, quicken their recovery, and facilitate their rehabilitation. If this happens, it will be another demonstration of the link between understanding the physiology of complex medical conditions and treatment strategies that improve outcomes (Joyner, 2011). The late E. P. Didier (1925-2006) was a Consultant in Anesthesia at the Mayo Clinic for many years. He played a pioneering role in the development of the Mayo ICUs in the early 1960s. The impressions cited are from lectures he gave to departmental trainees and informal conversations over 20 years. The Author considers himself lucky to have worked with Dr Didier, who always questioned trainees about the value of high-tech or invasive interventions in patients.

Due to prolonged survival and increasing treatment costs per patient, cancer treatment imposes an increasing burden on total healthcare expenditures. Healthcare expenditures in cancer will approximately increase from 5.6 billion euros in 2015 to 61 billion in 2060 in the Netherlands, of which 49 billion will be hospital costs.1 Previous research showed that treatment costs in cancer patients are highest in the first and last year of life.2,3 Health economics research demonstrated that proximity to death is a better predictor of increasing health expenditures than age, especially in cancer.4,5 Furthermore, aggressive treatment and higher costs of treatment at the end of life are associated with worse quality of life.6–8 Therefore, critically reviewing the use of intensive treatment at the end of life may provide valuable insights to improve the quality of life while reducing costs. Although there is an increasing interest in end-of-life care in cancer patients, research on the costs of end-of-life care in hematological malignancies is limited. Patients with hematological malignancies, and multiple myeloma (MM) patients in particular, are more likely to undergo intensive hospital care compared with other cancer patients in the last month before death.9–13 Nevertheless, analyses addressing the burden and costs of end-of-life care in MM are lacking. Given the limited research on the use and costs of end-of-life care,14 we aimed to describe the hospital-related care in the last month before death in patients diagnosed with MM and to provide a comparison with other malignancies in our hospital. In this single-site study, anonymized data from electronic health records were used. All MM patients deceased between 2017 and 2021 were included in our analyses. Hospital care activities were defined as all clinical and outpatient diagnostic, treatment (anticancer treatments excluded), follow-up, and aftercare activities by medical professionals performed in the Dutch hospital setting and were obtained from claims data, which are standardized throughout the Netherlands. We used standardized cost estimates for the year 2021 of Amphia Hospital, which corresponded with costs in comparable nonacademic Dutch teaching hospitals (Suppl. Table S1). The costs of anticancer treatments, that is, medication treatments to stop the progression of cancer, were analyzed separately. Furthermore, subanalyses were performed by age, using the cutoff between old age and very old age of 80 years as is used by the World Health Organization,15 and by time since diagnosis, in which diagnosis could mean time of diagnosis or time of start of oncological treatment (after initial diagnosis by other medical departments). The total costs presented in this study are accumulated over 5 years (2017–2021) and mean costs per patient were calculated over the total group of deceased patients. To put the outcomes of the MM group in perspective, a cohort with reference data from patients with other malignancies (including 500 patients with hematological malignancies other than MM) was collected similarly. These patients were diagnosed and treated in Amphia Hospital with at least 1 hospital care activity in the last year before death (to only include patients who were recently actively treated or received follow-up for malignant disease) (Suppl. Table S2). Descriptive statistics for end-of-life care, defined as costs of hospital-related care in the last 30 days before death, were performed for the MM and the reference group. Because the comparison of groups was primarily intended to interpret the MM data, no inferential statistical analyses were performed.16 Between 2017 and 2021, a total of 131 deceased patients with MM were identified, with a median age at death of 76. In total 44 (33.6%) patients had anticancer treatments and 106 (81%) patients had hospital care activities in the last 30 days before death. In the reference group, 4841 deceased patients were identified with a median age at death of 73 years. In total 733 (15.1%) received anticancer treatments and 3582 (74%) patients had hospital care activities in the last 30 days before death (Suppl. Table S3). The mean costs per patient of anticancer treatment were €1614 per patient in MM in the last 30 days before death between 2017 and 2021, which was higher than in the reference group, €452 per patient (Figure 1A). Also, the proportion of MM patients receiving anticancer treatment was higher than in the reference group (33.6% versus 15.1%). The higher costs per patient of anticancer treatments in MM may be caused by the fact that MM treatments are more expensive. The higher proportion of patients treated with anticancer treatment may be caused by sudden health deteriorations leading to death in actively treated patients. The mean costs per patient of hospital care activities in MM patients were €8367 per patient, which was considerably higher than in the reference group (€5414/patient) (Figure 1) and also higher than the mean anticancer treatment costs per patient. The total accumulated costs of anticancer treatment and hospital care activities in the last 30 days of life of patients with MM were €1,307,546 in 2017–2021 (see Suppl. Table S4 for more details on total costs).Figure 1.: Costs per patients 30 days before death in MM (N=131) and the reference group (N=4841). (A) Cost per patient of ACT and hospital care. (B) Cost per patient of hospital and ICU admissions. (C) Cost per patient of treatment*, diagnostics, outpatient/ED visits. (D) Costs per patient by age group. (E) Cost per patient by time since diagnosis. *ACT excluded. The scales in figures (A)–(E) are different. MM = multiple myeloma; ACT = anticancer treatment; ICU = intensive care unit; ED = emergency department.Analyses by type of hospital activity showed that hospital admissions in the last 30 days before death were observed in 57% (N=75) of the MM patients and caused the highest total end-of-life costs and €3424 per patient. Intensive care unit (ICU) admissions caused €1666 per patient (N=17, 13.0%). In the reference cohort, the proportion of patients with hospital and ICU admissions was lower (49% and 6.9%, respectively), and also mean costs per patient were lower (€2678 and €628, respectively), which means that relatively more MM patients were admitted to the hospital and ICU, with longer length of stay, compared with the reference group (Figure 1B). Costs of treatments, which included (blood)transfusion therapy, dialysis, surgery, paramedical, and rehabilitation treatments (excluding anticancer treatments), in the last 30 days before death were observed in 65% (N=85) MM patients, with mean treatment costs per patient of €1696 per patient of which costs of blood transfusions and dialysis were the largest cost components (Suppl. Table S4). These (supportive) treatment costs were higher in MM than in the reference cohort and were equivalent to the costs of anticancer treatments in MM (Figure 1C). Furthermore, diagnostics costs (N=92), including radiology and laboratory tests, were €1111 per patient, and outpatient and emergency department consultations costs were €461 per patient (N=90), which were both higher than in the reference group (Figure 1C). Subanalysis by age groups showed that hospital care activities and anticancer treatment costs in the last 30 days before death were lower in MM patients ≥80 years (N=43) compared with younger MM patients (N=88). Hospital care activity costs and anticancer treatment costs were also considerably higher in MM patients <80 years compared with patients <80 in the reference group (Figure 1D). In the subanalysis by time since diagnosis, we found €10,276 per patient hospital care activity costs in the last 30 days before death in MM patients who died within 1 year after diagnosis (N=39) and €10,798 per patient in MM patients who died between 1 and 5 years after diagnosis (N=45). In MM patients who survived >5 years after diagnosis, the total costs of hospital care activities were considerably lower at €4456 per patient (N=47). End-of-life anticancer treatment costs in MM patients based on the time since diagnosis showed the following: €1377 per patient in patients who died within 1 year, €2336 per patient in patients who died between 1 and 5 years, and €1119 per patient in patients who lived >5 years after diagnosis. The median survival since diagnosis in the MM group was 1039 days (2.9 years). In the reference group, all costs per subgroup were lower except in patients with >5 years since diagnosis (hospital care activity costs €5080 per patient), and the median survival time was 432 days (1.2 years) (Figure 1E). The percentages of patients receiving intensive end-of-life treatment and costs per patient at the end of life are higher in MM compared with patients with other malignancies. This may be explained by the fact that more treatment lines are available in MM compared with other malignancies, which may explain the higher proportion of MM patients being treated near the end of life. Furthermore, unforeseen health deteriorations caused by infections or other adverse events leading to unexpected death are more common in MM. Also, MM patients are more often in need of (intensive) supportive treatments such as blood transfusions and dialysis treatments, compared with patients with other malignancies (Figure 2A and 2B).Figure 2.: Type of costs in the last 30 days before death in percentages of total costs including anticancer treatments. (A) MM. (B) Reference cohort. MM = multiple myeloma; ACT = anticancer treatment; ICU = intensive care unit.This study aimed to contribute to the scarce research on end-of-life costs of hematological malignancies and particularly in MM. However, the generalizability of the findings needs to be addressed with caution due to the small sample size. Data collection and analyses were relatively easy to perform and repeat with updated data. Nevertheless, hospital, hospice, or home care policies may differ between countries, which should be considered when comparing these outcomes to findings in other countries. Also, the high costs of new anticancer treatments versus off-patent medications need to be considered when monitoring end-of-life costs over time. Further research preferably in a larger population of MM patients, addressing the effect of end-of-life care on both quality of life and costs is necessary. In conclusion, costs per patient in the last 30 days of life were higher in MM patients compared with patients with other malignancies, predominantly caused by hospitalizations and high costs of ICU admissions, especially in patients deceased within 5 years from diagnosis. Supportive treatment costs, primarily caused by blood transfusions and dialysis, were equal to the costs of anticancer treatment in MM patients’ last 30 days of life. More awareness about the high intensity and potential burden of treatment at the end of life in MM may improve the quality and efficiency of care, although further research to validate our results in other settings is necessary. AUTHOR CONTRIBUTIONS CB, MK, and HW presented the idea. All authors actively participated in the study design. CB, DS, and FB executed the data capture. CB, DS, FB, MK, HW, and HB performed the analyses and drafted the article. All authors critically revised the article and approved the final version. DISCLOSURES PS: Received Research grants from Amgen, Celgene, Janssen, Skyline Dx. Honoraria from Amgen, Celgene, Janssen, Karyopharm, Seagen, Chairman of European Myeloma Network, Co-chairman of HOVON Myeloma Working Group. HW: travel expenses Astellas and Ipsen; Honoraria Astellas, Roche, Merck. HB: Reports consulting or advisory role for Pfizer (paid to institute) and research funding from BMS-Celgene (paid to institute). All the other authors have no conflicts of interest to disclose. SOURCES OF FUNDING The authors declare no sources of funding for this manuscript.