Faculty Bibliography

Background: Transfusion is very common in the intensive care unit (ICU), but practice is highly variable, as has recently been shown in non-bleeding critically ill patients practices survey. Bleeding patients in ICU require different blood products across a range of specific patient categories. We hypothesize that a large variety in transfusion practice exists in bleeding patients. Study design and methods: An international online survey was performed among physicians working in the ICU. Transfusion practice in massively and non-massively bleeding patients was examined, including transfusion ratios, thresholds, and the presence of transfusion guidelines.
Result(s): Six hundred eleven respondents filled in the survey of which 401 could be analyzed, representing 64 countries. Among the respondents, 52% had a massive transfusion protocol (MTP) available at their ICU. In massively bleeding patients, 46% of the respondents used fixed transfusion component ratios. Of those who used fixed blood ratios, the 1:1:1 ratio (red blood cell [RBC] concentrates: plasma: platelet concentrates) was most commonly used (33%). The presence of an MTP was associated with a more frequent use of fixed ratios (p <.001). For RBC transfusion in the general non-massively bleeding ICU population, a hemoglobin (Hb) threshold of 7.0[7.0-7.3] g/dl was reported. In the general ICU population, a platelet count threshold of 50[26-50] x 10⁹/L was applied.
Discussion(s): Half of the centers had no massive transfusion protocol available. Transfusion practice in massively bleeding critically ill patients is highly variable and driven by the presence of an MTP. In the general non-massively bleeding ICU population restrictive transfusion triggers were chosen.
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INTRODUCTION/BACKGROUND:Given clinicians' frequent concerns about unfavourable outcomes, Intensive Care Unit (ICU) triage decisions in acutely ill cancer patients can be difficult, as clinicians may have doubts about the appropriateness of an ICU admission. To aid to this decision making, we studied the survival and performance status of cancer patients 2 years following an unplanned ICU admission. MATERIALS AND METHODS/METHODS:This was a retrospective cohort study in a large tertiary referral university hospital in the Netherlands. We categorized all adult patients with an unplanned ICU admission in 2017 into two groups: patients with or without an active malignancy. Descriptive statistics, Pearson's Chi-square tests and the Mann-Whitney U tests were used to evaluate the primary objective 2-year mortality and performance status. A good performance status was defined as ECOG performance status 0 (fully active) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out light work). A multivariable binary logistic regression analysis was used to identify factors associated with 2-year mortality within cancer patients. RESULTS:Of the 1046 unplanned ICU admissions, 125 (12%) patients had cancer. The 2-year mortality in patients with cancer was significantly higher than in patients without cancer (72% and 42.5%, P <0.001). The median performance status at 2 years in cancer patients was 1 (IQR 0-2). Only an ECOG performance status of 2 (OR 8.94; 95% CI 1.21-65.89) was independently associated with 2-year mortality. CONCLUSIONS:In our study, the majority of the survivors have a good performance status 2 years after ICU admission. However, at that point, three-quarter of these cancer patients had died, and mortality in cancer patients was significantly higher than in patients without cancer. ICU admission decisions in acutely ill cancer patients should be based on performance status, severity of illness and long-term prognosis, and this should be communicated in the shared decision making. An ICU admission decision should not solely be based on the presence of a malignancy.

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

Background: Transfusion practice on the intensive care unit (ICU) shifted from a liberal towards a more restrictive transfusion strategy during the last decades. However, current practice is still highly variable, as recently has been shown in non-bleeding critically ill patients. Bleeding patients are more complex and receive more and different blood products. Currently, no transfusion guideline for bleeding critically ill patients is available. Therefore, we hypothesized to find a great variety in transfusion practice in this patient population.
Aim(s): The aim of this survey was to study current transfusion practice in different bleeding subpopulations in the ICU and assess the availability and influence of transfusion guidelines.
Method(s): An online survey was performed among physicians working in the ICU only. The survey questioned transfusion practice in massively and non-massively bleeding ICU patients, including transfusion ratios of blood components and transfusion thresholds. Different relevant subpopulations were included. Also, the presence of transfusion guidelines was asked.
Result(s): A total of 611 physicians responded, of which 401 completed the survey, representing 64 countries. The majority of respondents work in high-income countries (72%) and 45% reports having a hospital wide transfusion protocol, 40% an ICU specific transfusion protocol, and 52% have a massive transfusion protocol available in their centre. In massively bleeding patients 67% of the respondents used conventional lab-based testing to guide their transfusion practice, 46% used fixed transfusion ratios and 41% used point of care visco-elastic tests. Of those who use fixed blood component ratio's, the 1:1:1 (red blood cell concentrates: plasma: platelet concentrates) was most commonly used (33%) followed by a 3:3:1 ratio (24%). In non-massively bleeding patients, different threshold were applied for different patient populations. In the general ICU population, a haemoglobin threshold of 7.0 [7.0-7.3] g/dl was used to transfuse red blood cells (RBCs). The highest variance in haemoglobin threshold was observed in patients treated with extracorporeal membrane oxygenation (ECMO) and in patients with haemorrhagic stroke or traumatic brain injury, with a haemoglobin threshold of 8.0 [7.0-9.0] g/dl each. In the general ICU population a platelet count threshold of 50 [26-50] x109 cells/l was applied. The highest threshold was observed in patients with haemorrhagic stroke or traumatic brain injury: 75 [50-100] cells/l. The presence of a hospital wide or an ICU specific transfusion guideline did not influence the applied transfusion thresholds in the non-massively bleeding patients. Summary/Conclusions: The majority of the respondents do not have an ICU specific transfusion guideline available in their centre. There is a high variance in the approach of both non-massive and massively bleeding ICU patients. In the general ICU population restrictive transfusion triggers are used. However, in ECMO and brain injury patients, physicians tend to transfuse more liberally

Despite the high number of intensive care beds in German hospitals compared to other European countries, intensive care medical shortages are common in daily clinical practice. This is due to a hardly established cross-departmental discharge and transfer management with missing objective discharge criteria, lack of personnel and bed closures. Aboveaverage lengths of stays and increased readmission rates to the intensive care unit also indicate an inefficient use of resources in German hospitals. Against this background, a systematic literature search was carried out on the current state of research on discharge criteria from the intensive care unit and transfer processes to follow-up wards. Between 1983 and 2020, 1,917 sources were found, 286 were selected as full text, 104 of which were considered relevant and used as the basis for this work. Approaches, such as a root cause analy- sis of bottleneck situations including the entire hospital system with its interdependent admission, transfer and discharge processes, and the use of electronic decision support in conjunction with standardised discharge criteria can improve the use of existing intensive care capacities and lead to safer and better patient flow. For better use of resources, the therapeutic outcome must be viewed along the entire clinical pathway in order to care for the right patient at the right place and at the right time. A standardised care transition management using objective discharge criteria could help to include the various stakeholders in the discharge decision and patient-transfer process to reflect patient-, caregiver-, process, and institution-specific factors, and ultimately to manage, proactively and efficiently, the available intensive care resources. Decision support in the discharge process using self-learning systems based on available data from patient data management systems is forward-looking, but must be validated more widely in clinical practice.
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BACKGROUND:Persistent hyperlactatemia has been considered as a signal of tissue hypoperfusion in septic shock patients, but multiple non-hypoperfusion-related pathogenic mechanisms could be involved. Therefore, pursuing lactate normalization may lead to the risk of fluid overload. Peripheral perfusion, assessed by the capillary refill time (CRT), could be an effective alternative resuscitation target as recently demonstrated by the ANDROMEDA-SHOCK trial. We designed the present randomized controlled trial to address the impact of a CRT-targeted (CRT-T) vs. a lactate-targeted (LAC-T) fluid resuscitation strategy on fluid balances within 24 h of septic shock diagnosis. In addition, we compared the effects of both strategies on organ dysfunction, regional and microcirculatory flow, and tissue hypoxia surrogates. RESULTS:content difference ratio; and lactate/pyruvate ratio. There was no difference between CRT-T vs. LAC-T in 6 h-fluid boluses (875 [375-2625] vs. 1500 [1000-2000], p = 0.3), or balances (982[249-2833] vs. 15,800 [740-6587, p = 0.2]). CRT-T was associated with a higher achievement of the predefined perfusion target (62 vs. 24, p = 0.03). No significant differences in perfusion-related variables or hypoxia surrogates were observed. CONCLUSIONS:CRT-targeted fluid resuscitation was not superior to a lactate-targeted one on fluid administration or balances. However, it was associated with comparable effects on regional and microcirculatory flow parameters and hypoxia surrogates, and a faster achievement of the predefined resuscitation target. Our data suggest that stopping fluids in patients with CRT ≤ 3 s appears as safe in terms of tissue perfusion. Clinical Trials: ClinicalTrials.gov Identifier: NCT03762005 (Retrospectively registered on December 3rd 2018).

Objectives/UNASSIGNED:Mortality rates in intubated coronavirus disease 2019 patients remain markedly elevated. Some patients develop sudden refractory hypercapnia and hypoxemia not explained by worsening pulmonary parenchymal disease. This case series highlights clinical findings and management of coronavirus disease 2019 patients with refractory hypercapnia despite maximal/optimal ventilatory support. Hypercapnia could not be explained by worsening lung disease or other common factors, and thus, a pulmonary vascular etiology was suggested. The pillars of management were targeted to improve pulmonary vascular patency via aggressive anticoagulation and support right ventricular function. Data Sources/UNASSIGNED:Four consecutive patients with confirmed coronavirus disease 2019 infection with sudden hypercapnia and hypoxemia were included. Data Synthesis/UNASSIGNED:removal was discontinued in three patients over the ensuing 3 weeks, and one patient was discharged home. Conclusions/UNASSIGNED:We speculate that thromboinflammation with pulmonary microvasculature occlusion leads to a sudden increase in dead space and shunt resulting in severe hypercapnia and hypoxemia in coronavirus disease 2019 patients. Early identification of these physiologic and clinical biomarkers could trigger the institution of therapies aiming to reverse the hypercoagulable state and support right ventricular function.

OBJECTIVE:We aimed to explore: the exposure of healthcare workers to a delirium guidelines implementation programme; effects on guideline adherence at intensive care unit (ICU) level; impact on knowledge and barriers, and experiences with the implementation. DESIGN/METHODS:A mixed-methods process evaluation of a prospective multicentre implementation study. SETTING/METHODS:Six ICUs. PARTICIPANTS/METHODS:4449 adult ICU patients and 500 ICU professionals approximately. INTERVENTION/METHODS:A tailored implementation programme. MAIN OUTCOME MEASURE/METHODS:Adherence to delirium guidelines recommendations at ICU level before, during and after implementation; knowledge and perceived barriers; and experiences with the implementation. RESULTS:Five of six ICUs were exposed to all implementation strategies as planned. More than 85% followed the required e-learnings; 92% of the nurses attended the clinical classroom lessons; five ICUs used all available implementation strategies and perceived to have implemented all guideline recommendations (>90%). Adherence to predefined performance indicators (PIs) at ICU level was only above the preset target (>85%) for delirium screening. For all other PIs, the inter-ICU variability was between 34% and 72%. The implementation of delirium guidelines was feasible and successful in resolving the majority of barriers found before the implementation. The improvement was well sustained 6 months after full guideline implementation. Knowledge about delirium was improved (from 61% to 65%). The implementation programme was experienced as very successful. CONCLUSIONS:Multifaceted implementation can improve and sustain adherence to delirium guidelines, is feasible and can largely be performed as planned. However, variability in delirium guideline adherence at individual ICUs remains a challenge, indicating the need for more tailoring at centre level.

BACKGROUND:Capillary refill time (CRT) may improve more rapidly than lactate in response to increments in systemic flow. Therefore, it can be assessed more frequently during septic shock (SS) resuscitation. Hyperlactatemia, in contrast, exhibits a slower recovery in SS survivors, probably explained by the delayed resolution of non-hypoperfusion-related sources. Thus, targeting lactate normalization may be associated with impaired outcomes. The ANDROMEDA-SHOCK trial compared CRT- versus lactate-targeted resuscitation in early SS. CRT-targeted resuscitation associated with lower mortality and organ dysfunction; mechanisms were not investigated. CRT was assessed every 30 min and lactate every 2 h during the 8-h intervention period, allowing a first comparison between groups at 2 h (T2). Our primary aim was to determine if SS patients evolving with normal CRT at T2 after randomization (T0) exhibited a higher mortality and organ dysfunction when allocated to the LT arm than when randomized to the CRT arm. Our secondary aim was to determine if those patients with normal CRT at T2 had received more therapeutic interventions when randomized to the LT arm. To address these issues, we performed a post hoc analysis of the ANDROMEDA-SHOCK dataset. RESULTS:Patients randomized to the lactate arm at T0, evolving with normal CRT at T2 exhibited significantly higher mortality than patients with normal CRT at T2 initially allocated to CRT (40 vs 23%, p = 0.009). These results replicated at T8 and T24. LT arm received significantly more resuscitative interventions (fluid boluses: 1000[500-2000] vs. 500[0-1500], p = 0.004; norepinephrine test in previously hypertensive patients: 43 (35) vs. 19 (19), p = 0.001; and inodilators: 16 (13) vs. 3 (3), p = 0.003). A multivariate logistic regression of patients with normal CRT at T2, including APACHE-II, baseline lactate, cumulative fluids administered since emergency admission, source of infection, and randomization group) confirmed that allocation to LT group was a statistically significant determinant of 28-day mortality (OR 3.3; 95%CI[1.5-7.1]); p = 0.003). CONCLUSIONS:Septic shock patients with normal CRT at baseline received more therapeutic interventions and presented more organ dysfunction when allocated to the lactate group. This could associate with worse outcomes.