Development and Validation of a Prediction Model for 1-Year Mortality in Patients With a Hematologic Malignancy Admitted to the ICU.

OBJECTIVES: To develop and validate a prediction model for 1-year mortality in patients with a hematologic malignancy acutely admitted to the ICU. DESIGN: A retrospective cohort study. SETTING: Five university hospitals in the Netherlands between 2002 and 2015. PATIENTS: A total of 1097 consecutive patients with a hematologic malignancy were acutely admitted to the ICU for at least 24 h. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We created a 13-variable model from 22 potential predictors. Key predictors included active disease, age, previous hematopoietic stem cell transplantation, mechanical ventilation, lowest platelet count, acute kidney injury, maximum heart rate, and type of malignancy. A bootstrap procedure reduced overfitting and improved the model's generalizability. This involved estimating the optimism in the initial model and shrinking the regression coefficients accordingly in the final model. We assessed performance using internal-external cross-validation by center and compared it with the Acute Physiology and Chronic Health Evaluation II model. Additionally, we evaluated clinical usefulness through decision curve analysis. The overall 1-year mortality rate observed in the study was 62% (95% CI, 59-65). Our 13-variable prediction model demonstrated acceptable calibration and discrimination at internal-external validation across centers (C-statistic 0.70; 95% CI, 0.63-0.77), outperforming the Acute Physiology and Chronic Health Evaluation II model (C-statistic 0.61; 95% CI, 0.57-0.65). Decision curve analysis indicated overall net benefit within a clinically relevant threshold probability range of 60-100% predicted 1-year mortality. CONCLUSIONS: Our newly developed 13-variable prediction model predicts 1-year mortality in hematologic malignancy patients admitted to the ICU more accurately than the Acute Physiology and Chronic Health Evaluation II model. This model may aid in shared decision-making regarding the continuation of ICU care and end-of-life considerations.

Tacrolimus Variability and Clinical Outcomes in the Early Post-lung Transplantation Period: Oral Versus Continuous Intravenous Administration.

BACKGROUND AND OBJECTIVE: High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx. METHODS: Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and  percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission. RESULTS: We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9-14.6; p < 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI - 11.3 to - 3.4; p < 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8-1.8; p = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0-2.3; p = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar. CONCLUSIONS: Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection.

Thrombosis pathways in COVID-19 vs. influenza-associated ARDS: A targeted proteomics approach.

BACKGROUND: Pulmonary embolism (PE) occurs in one-third of critically-ill COVID-19 patients. Although prior studies identified several pathways contributing to thrombogenicity, it is unknown whether this is COVID-19-specific or also occurs in ARDS patients with another infection. OBJECTIVE: To compare pathway activity among patients having COVID-19 with PE (C19PE+), COVID-19 without PE (C19PE-), and influenza-associated ARDS (IAA) using a targeted proteomics approach. METHODS: We exploited an existing biorepository containing daily plasma samples to carefully match C19PE+ cases to C19PE- and IAA controls on mechanical ventilation duration, PEEP, FiO2, and cardiovascular-SOFA (n = 15 per group). Biomarkers representing various thrombosis pathways were measured using proximity extension- and ELISA-assays. Summed z-scores of individual biomarkers were used to represent total pathway activity. RESULTS: We observed no relevant between-group differences among 22 biomarkers associated with activation of endothelium, platelets, complement, coagulation, fibrinolysis or inflammation, except sIL-1RT2 and sST2, which were lower in C19PE- than IAA (log2-Foldchange -0.67, p = .022 and -1.78, p = .022, respectively). However, total pathway analysis indicated increased activation of endothelium (z-score 0.2 [-0.3-1.03] vs. 0.98 [-2.5--0.3], p = .027), platelets (1.0 [-1.3-3.0] vs. -3.3 [-4.1--0.6], p = .023) and coagulation (0.8 [-0.5-2.0] vs. -1.0 [-1.6-1.0], p = .023) in COVID-19 patients (C19PE+/C19PE- groups combined) compared to IAA. CONCLUSION: We observed only minor differences between matched C19PE+, C19PE-, and IAA patients, which suggests individual biomarkers mostly reflect disease severity. However, analysis of total pathway activity suggested upregulation of some distinct processes in COVID-19 could be etiologically related to increased PE-risk.

Outcome of cancer patients considered for intensive care unit admission in two university hospitals in the Netherlands: the danger of delayed ICU admissions and off-hour triage decisions.

BACKGROUND: Very few studies assessed the association between Intensive Care Unit (ICU) triage decisions and mortality. The aim of this study was to assess whether an association could be found between 30-day mortality, and ICU admission consultation conditions and triage decisions. METHODS: We conducted a retrospective cohort study in two large referral university hospitals in the Netherlands. We identified all adult cancer patients for whom ICU admission was requested from 2016 to 2019. Via a multivariable logistic regression analysis, we assessed the association between 30-day mortality, and ICU admission consultation conditions and triage decisions. RESULTS: Of the 780 cancer patients for whom ICU admission was requested, 332 patients (42.6%) were considered 'too well to benefit' from ICU admission, 382 (49%) patients were immediately admitted to the ICU and 66 patients (8.4%) were considered 'too sick to benefit' according to the consulting intensivist(s). The 30-day mortality in these subgroups was 30.1%, 36.9% and 81.8%, respectively. In the patient group considered 'too well to benefit', 258 patients were never admitted to the ICU and 74 patients (9.5% of the overall study population, 22.3% of the patients 'too well to benefit') were admitted to the ICU after a second ICU admission request (delayed ICU admission). Thirty-day mortality in these groups was 25.6% and 45.9%. After adjustment for confounders, ICU consultations during off-hours (OR 1.61, 95% CI 1.09-2.38, p-value 0.02) and delayed ICU admission (OR 1.83, 95% CI 1.00-3.33, p-value 0.048 compared to "ICU admission") were independently associated with 30-day mortality. CONCLUSION: The ICU denial rate in our study was high (51%). Sixty percent of the ICU triage decisions in cancer patients were made during off-hours, and 22.3% of the patients initially considered "too well to benefit" from ICU admission were subsequently admitted to the ICU. Both decisions during off-hours and a delayed ICU admission were associated with an increased risk of death at 30 days. Our study suggests that in cancer patients, ICU triage decisions should be discussed during on-hours, and ICU admission policy should be broadened, with a lower admission threshold for critically ill cancer patients.

A Pathophysiological Perspective on the SARS-CoV-2 Coagulopathy.

Recent evidence is focusing on the presence of a hypercoagulable state with development of both venous and arterial thromboembolic complications in patients infected with SARS-CoV-2. The ongoing activation of coagulation related to the severity of the illness is further characterized by thrombotic microangiopathy and endotheliitis. These microangiopathic changes cannot be classified as classical disseminated intravascular coagulation (DIC). In this short review we describe the interaction between coagulation and inflammation with focus on the possible mechanisms that might be involved in SARS-CoV-2 infection associated coagulopathy in the critically ill.

Long-Term Outcome of Patients With a Hematologic Malignancy and Multiple Organ Failure Admitted at the Intensive Care.

OBJECTIVES: Historically, patients with a hematologic malignancy have one of the highest mortality rates among cancer patients admitted to the ICU. Therefore, physicians are often reluctant to admit these patients to the ICU. The aim of our study was to examine the survival of patients who have a hematologic malignancy and multiple organ failure admitted to the ICU. DESIGN: This retrospective cohort study, part of the HEMA-ICU study group, was designed to study the survival of patients with a hematologic malignancy and organ failure after admission to the ICU. Patients were followed for at least 1 year. SETTING: Five university hospitals in the Netherlands. PATIENTS: One-thousand ninety-seven patients with a hematologic malignancy who were admitted at the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was 1-year survival. Organ failure was categorized as acute kidney injury, respiratory failure, hepatic failure, and hemodynamic failure; multiple organ failure was defined as failure of two or more organs. The World Health Organization performance score measured 3 months after discharge from the ICU was used as a measure of functional outcome. The 1-year survival rate among these patients was 38%. Multiple organ failure was inversely associated with long-term survival, and an absence of respiratory failure was the strongest predictor of 1-year survival. The survival rate among patients with 2, 3, and 4 failing organs was 27%, 22%, and 8%, respectively. Among all surviving patients for which World Health Organization scores were available, 39% had a World Health Organization performance score of 0-1 3 months after ICU discharge. Functional outcome was not associated with the number of failing organs. CONCLUSIONS: Our results suggest that multiple organ failure should not be used as a criterion for excluding a patient with a hematologic malignancy from admission to the ICU.

Time trend analysis of long term outcome of patients with haematological malignancies admitted at dutch intensive care units.

A few decades ago, the chances of survival for patients with a haematological malignancy needing Intensive Care Unit (ICU) support were minimal. As a consequence, ICU admission policy was cautious. We hypothesized that the long-term outcome of patients with a haematological malignancy admitted to the ICU has improved in recent years. Furthermore, our objective was to evaluate the predictive value of the Acute Physiology and Chronic Health Evaluation (APACHE) II score. A total of 1095 patients from 5 Dutch university hospitals were included from 2003 until 2015. We studied the prevalence of patients' characteristics over time. By using annual odds ratios, we analysed which patients' characteristics could have had influenced possible trends in time. A approximated mortality rate was compared with the ICU mortality rate, to study the predictive value of the APACHE II score. Overall one-year mortality was 62%. The annual decrease in one-year mortality was 7%, whereas the APACHE II score increased over time. Decreased mortality rates were particularly observed in high-risk patients (acute myeloid leukaemia, old age, low platelet count, bleeding as admission reason and need for mechanical ventilation within 24 h of ICU admission). Furthermore, the APACHE II score overestimates mortality in this patient category.

Characteristics and outcomes of patients with a haematological malignancy admitted to the intensive care unit for a neurological event.

OBJECTIVES: Patients with haematological malignancies are at risk of concomitant critical neurological events warranting intensive care unit admission. We aimed to examine the characteristics and outcomes of this patient population, as more knowledge could facilitate decision making on ICU admission and treatment. DESIGN, SETTING AND PARTICIPANTS: A retrospective cohort study of 68 patients in adult ICUs of six Dutch university hospitals between 2003 and 2011. RESULTS: The median Acute Physiology and Chronic Health Evaluation (APACHE) II score was 23 (IQR, 16-27), and 77% of patients needed mechanical ventilation within the first 24 hours of admission. Forty percent of patients had received an allogeneic stem cell transplantation, and 22% were neutropenic on admission. The most frequent underlying haematological condition was non-Hodgkin lymphoma (27%). Seizures were the most common neurological event for ICU admission (29%). The median ICU length of stay was 5 days (IQR, 1-13 days). ICU mortality (28%), hospital mortality (37%) and 3-month mortality (50%) were comparable with other studies of ICU patients with haematological malignancies. Factors associated with 3-month survival were baseline platelet count (113×10(9)/L in survivors v 39×10(9)/L in non-survivors, P<0.01) and APACHE II score (20 in survivors v 25 in non-survivors, P=0.02). CONCLUSIONS: Patients with a history of haematological malignancy presenting with a critical neurological event have comparable survival rates with other patients with a haematologic malignancy admitted to the ICU. Our findings suggest that restrictions in ICU care are not justified for this patient population.

A perspective on mesenchymal stromal cell transplantation in the treatment of sepsis.

Although a variety of disease-modifying agents have been studied as potential sepsis treatments, no beneficial effects on the course of sepsis, in terms of survival, have been observed until now. Because of their plasticity, mesenchymal stromal cells (MSCs) have been implicated as an effective novel therapy modality for various diseases and are widely used for cellular therapies and tissue engineering. The existing knowledge supports the idea that MSCs might be beneficial in sepsis treatment. Our objective was to selectively address the evidence, based on multistep processes, supporting the potential of MSC-based therapies in clinical sepsis trials. In this study, we performed a stepwise approach to defend the evaluation of MSC treatments for sepsis from the bench to the bedside. Altogether, the reviewed data postulate that the signals produced by inflamed tissues might determine the functional effects of MSCs. These effects include bacterial clearance, suppression of inflammation, antiapoptosis, or stimulation of regenerative responses. We conclude that the clinical application of MSCs is a feasible and well-tolerated approach and therefore may have benefits for patients with sepsis.

Embryonal subregion-derived stromal cell lines from novel temperature-sensitive SV40 T antigen transgenic mice support hematopoiesis.

Throughout life, the hematopoietic system requires a supportive microenvironment that allows for the maintenance and differentiation of hematopoietic stem cells (HSC). To understand the cellular interactions and molecules that provide these functions, investigators have previously established stromal cell lines from the late gestational stage and adult murine hematopoietic microenvironments. However, the stromal cell microenvironment that supports the emergence, expansion and maintenance of HSCs during mid-gestational stages has been largely unexplored. Since several tissues within the mouse embryo are known to harbor HSCs (i.e. aortagonads-mesonephros, yolk sac, liver), we generated numerous stromal cell clones from these mid-gestational sites. Owing to the limited cell numbers, isolations were performed with tissues from transgenic embryos containing the ts SV40 Tag gene (tsA58) under the transcriptional control of constitutive and ubiquitously expressing promoters. We report here that the growth and cloning efficiency of embryonic cells (with the exception of the aorta) is increased in the presence of the tsA58 transgene. Furthermore, our results show that the large panel of stromal clones isolated from the different embryonal subregions exhibit heterogeneity in their ability to promote murine and human hematopoietic differentiation. Despite our findings of heterogeneity in hematopoietic growth factor gene expression profiles, high-level expression of some factors may influence hematopoietic differentiation. Interestingly, a few of these stromal clones express a recently described chordin-like protein, which is an inhibitor of bone morphogenic proteins and is preferentially expressed in cells of the mesenchymal lineage.

Stromal cell lines from mouse aorta-gonads-mesonephros subregions are potent supporters of hematopoietic stem cell activity.

The aorta-gonads-mesonephros (AGM) region autonomously generates the first adult repopulating hematopoietic stem cells (HSCs) in the mouse embryo. HSC activity is initially localized to the dorsal aorta and mesenchyme (AM) and vitelline and umbilical arteries. Thereafter, HSC activity is found in the urogenital ridges (UGs), yolk sac, and liver. As increasing numbers of HSCs are generated, it is thought that these sites provide supportive microenvironments in which HSCs are harbored until the bone marrow microenvironment is established. However, little is known about the supportive cells within these midgestational sites, and particularly which microenvironment is most supportive for HSC growth and maintenance. Thus, to better understand the cells and molecules involved in hematopoietic support in the midgestation embryo, more than 100 stromal cell lines and clones were established from these sites. Numerous stromal clones were found to maintain hematopoietic progenitors and HSCs to a similar degree as, or better than, previously described murine stromal lines. Both the AM and UG subregions of the AGM produced many supportive clones, with the most highly HSC-supportive clone being derived from the UGs. Interestingly, the liver at this stage yielded only few supportive stromal clones. These results strongly suggest that during midgestation, not only the AM but also the UG subregion provides a potent microenvironment for growth and maintenance of the first HSCs.