The scientific rationale and study protocol for the DPP3, Angiotensin II, and Renin Kinetics in Sepsis (DARK-Sepsis) randomized controlled trial: serum biomarkers to predict response to angiotensin II versus standard-of-care vasopressor therapy in the treatment of septic shock.

BACKGROUND: Data to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin-angiotensin-aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock. METHODS: The DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events. DISCUSSION: With an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05824767. Registered on April 24, 2023.

When to Stop Antibiotics in the Critically Ill?

Over the past century, antibiotic usage has skyrocketed in the treatment of critically ill patients. There have been increasing calls to establish guidelines for appropriate treatment and durations of antibiosis. Antibiotic treatment, even when appropriately tailored to the patient and infection, is not without cost. Short term risks-hepatic/renal dysfunction, intermediate effects-concomitant superinfections, and long-term risks-potentiating antimicrobial resistance (AMR), are all possible consequences of antimicrobial administration. These risks are increased by longer periods of treatment and unnecessarily broad treatment courses. Recently, the literature has focused on multiple strategies to determine the appropriate duration of antimicrobial therapy. Further, there is a clinical shift to multi-modal approaches to determine the most suitable timepoint at which to end an antibiotic course. An approach utilising biomarker assays and an inter-disciplinary team of pharmacists, nurses, physicians, and microbiologists appears to be the way forward to develop sound clinical decision-making surrounding antibiotic treatment.

Angiotensin ii therapy in refractory septic shock: which patient can benefit most? A narrative review.

Patients with septic shock who experience refractory hypotension despite adequate fluid resuscitation and high-dose noradrenaline have high mortality rates. To improve outcomes, evidence-based guidelines recommend starting a second vasopressor, such as vasopressin, if noradrenaline doses exceed 0.5 µg/kg/min. Recently, promising results have been observed in treating refractory hypotension with angiotensin II, which has been shown to increase mean arterial pressure and has been associated with improved outcomes. This narrative review aims to provide an overview of the pathophysiology of the renin-angiotensin system and the role of endogenous angiotensin II in vasodilatory shock with a focus on how angiotensin II treatment impacts clinical outcomes and on identifying the population that may benefit most from its use.

Red Blood Cell Transfusion in the Intensive Care Unit.

Importance: Red blood cell (RBC) transfusion is common among patients admitted to the intensive care unit (ICU). Despite multiple randomized clinical trials of hemoglobin (Hb) thresholds for transfusion, little is known about how these thresholds are incorporated into current practice. Objective: To evaluate and describe ICU RBC transfusion practices worldwide. Design, Setting, and Participants: International, prospective, cohort study that involved 3643 adult patients from 233 ICUs in 30 countries on 6 continents from March 2019 to October 2022 with data collection in prespecified weeks. Exposure: ICU stay. Main Outcomes and Measures: The primary outcome was the occurrence of RBC transfusion during ICU stay. Additional outcomes included the indication(s) for RBC transfusion (consisting of clinical reasons and physiological triggers), the stated Hb threshold and actual measured Hb values before and after an RBC transfusion, and the number of units transfused. Results: Among 3908 potentially eligible patients, 3643 were included across 233 ICUs (median of 11 patients per ICU [IQR, 5-20]) in 30 countries on 6 continents. Among the participants, the mean (SD) age was 61 (16) years, 62% were male (2267/3643), and the median Sequential Organ Failure Assessment score was 3.2 (IQR, 1.5-6.0). A total of 894 patients (25%) received 1 or more RBC transfusions during their ICU stay, with a median total of 2 units per patient (IQR, 1-4). The proportion of patients who received a transfusion ranged from 0% to 100% across centers, from 0% to 80% across countries, and from 19% to 45% across continents. Among the patients who received a transfusion, a total of 1727 RBC transfusions were administered, wherein the most common clinical indications were low Hb value (n = 1412 [81.8%]; mean [SD] lowest Hb before transfusion, 7.4 [1.2] g/dL), active bleeding (n = 479; 27.7%), and hemodynamic instability (n = 406 [23.5%]). Among the events with a stated physiological trigger, the most frequently stated triggers were hypotension (n = 728 [42.2%]), tachycardia (n = 474 [27.4%]), and increased lactate levels (n = 308 [17.8%]). The median lowest Hb level on days with an RBC transfusion ranged from 5.2 g/dL to 13.1 g/dL across centers, from 5.3 g/dL to 9.1 g/dL across countries, and from 7.2 g/dL to 8.7 g/dL across continents. Approximately 84% of ICUs administered transfusions to patients at a median Hb level greater than 7 g/dL. Conclusions and Relevance: RBC transfusion was common in patients admitted to ICUs worldwide between 2019 and 2022, with high variability across centers in transfusion practices.

Research priorities for therapeutic plasma exchange in critically ill patients.

Therapeutic plasma exchange (TPE) is a therapeutic intervention that separates plasma from blood cells to remove pathological factors or to replenish deficient factors. The use of TPE is increasing over the last decades. However, despite a good theoretical rationale and biological plausibility for TPE as a therapy for numerous diseases or syndromes associated with critical illness, TPE in the intensive care unit (ICU) setting has not been studied extensively. A group of eighteen experts around the globe from different clinical backgrounds used a modified Delphi method to phrase key research questions related to "TPE in the critically ill patient". These questions focused on: (1) the pathophysiological role of the removal and replacement process, (2) optimal timing of treatment, (3) dosing and treatment regimes, (4) risk-benefit assumptions and (5) novel indications in need of exploration. For all five topics, the current understanding as well as gaps in knowledge and future directions were assessed. The content should stimulate future research in the field and novel clinical applications.

Refractory septic shock and alternative wordings: A systematic review of literature.

BACKGROUND: We reviewed the different studies using the terms "refractory septic shock" and/or "catecholamine resistance" and/or "high dose norepinephrine" so as to highlight the heterogeneity of the definitions used by authors addressing such concepts. METHOD: A systematic review was conducted assessing the papers reporting data on refractory septic shock. We used keywords as exact phrases and subject headings according to database syntax. RESULTS: Of 276 papers initially reviewed, we included 8 studies - 3 randomized controlled trials, 3 prospective studies and 2 retrospective studies, representing a total of 562 patients with septic shock. Catecholamine resistance was generally defined as "a decreased vascular responsiveness to catecholamine independently of the administered norepinephrine dose". Refractory septic shock was broadly defined as "a clinical condition characterized by persistent hyperdynamic shock even though adequate fluid resuscitation (individualized doses) and high doses of norepinephrine (≥ 1 µg/kg/min)". Reported "high doses" of norepinephrine were often ≥1 µg/kg/min. However, wide variability was found throughout the literature on the use of these terms. DISCUSSION: Marked inconsistencies were identified in the usage of the terms for refractory septic shock. There is a pressing need to determine consensus definitions so as to establish a common language in the medical literature and to harmonize future studies.

Critical Care Pandemic Preparation: Considerations and Lessons Learned from COVID-19.

Pandemics, increases in disease incidence that affect multiple regions of the world, present huge challenges to health care systems and in particular to policymakers, public health authorities, clinicians, and all health care workers (HCWs). The recent COVID-19 pandemic has resulted in millions of severely ill patients, many of whom who have required hospital and intensive care unit (ICU) admission. The discipline of critical care is a vital and integral component of pandemic preparedness. Safe and effective critical care has the potential to improve outcomes, motivate individuals to seek timely medical attention, and attenuate the devastating sequelae of a severe pandemic. To achieve this, suitable critical care planning and preparation are essential.

Rotational thromboelastometry in critically ill COVID-19 patients does not predict thrombosis.

Background: Critically ill COVID-19 patients are in a hypercoagulable state with increased risk of thrombotic complications. Rotational thromboelastometry (ROTEM) is a viscoelastic test with the potential to reflect COVID-19-associated hypercoagulability and may therefore be useful to predict thrombotic complications. Objective: To investigate the potential of ROTEM profiles to predict thrombotic complications in critically ill COVID-19 patients. Patients/Methods: Retrospective multicenter cohort study in 113 adult patients with confirmed COVID-19 infection admitted to the intensive care unit (ICU) of two large teaching hospitals in the United States and in the Netherlands. ROTEM profiles of the EXTEM, INTEM, and FIBTEM tracings were measured within 72 h of ICU admission. Thrombotic complications encompass both arterial and venous thromboembolic complications, diagnosed with electrocardiogram, ultrasound, or computed tomography. ROTEM profiles were compared between patients with and without thrombosis. Univariable logistic regression followed by receiver operating characteristic (ROC) curves analysis was performed to identify ROTEM parameters associated with thrombosis. Results and Conclusions: Of 113 patients, 27 (23.9%) developed a thrombotic event. In the univariable analysis, EXTEM clot amplitude at 10 min (CA10) and EXTEM maximum clot formation (MCF) were associated with thrombosis with a p < 0.2 (p = 0.07 and p = 0.05, respectively). In ROC curve analysis, EXTEM CA10 had an area under the curve (AUC) of 0.58 (95% CI 0.47-0.70) and EXTEM MCF had an AUC of 0.60 (95% CI 0.49-0.71). Thereby, ROTEM profiles at ICU admission did not have the potential to differentiate between patients with a high and low risk for thrombotic complications.

Transfusion strategies in bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine.

PURPOSE: To develop evidence-based clinical practice recommendations regarding transfusion practices and transfusion in bleeding critically ill adults. METHODS: A taskforce involving 15 international experts and 2 methodologists used the GRADE approach to guideline development. The taskforce addressed three main topics: transfusion support in massively and non-massively bleeding critically ill patients (transfusion ratios, blood products, and point of care testing) and the use of tranexamic acid. The panel developed and answered structured guideline questions using population, intervention, comparison, and outcomes (PICO) format. RESULTS: The taskforce generated 26 clinical practice recommendations (2 strong recommendations, 13 conditional recommendations, 11 no recommendation), and identified 10 PICOs with insufficient evidence to make a recommendation. CONCLUSIONS: This clinical practice guideline provides evidence-based recommendations for the management of massively and non-massively bleeding critically ill adult patients and identifies areas where further research is needed.

Mean arterial pressure and mortality in patients with distributive shock: a retrospective analysis of the MIMIC-III database.

BACKGROUND: Maintenance of mean arterial pressure (MAP) at levels sufficient to avoid tissue hypoperfusion is a key tenet in the management of distributive shock. We hypothesized that patients with distributive shock sometimes have a MAP below that typically recommended and that such hypotension is associated with increased mortality. METHODS: In this retrospective analysis of the Medical Information Mart for Intensive Care (MIMIC-III) database from Beth Israel Deaconess Medical Center, Boston, USA, we included all intensive care unit (ICU) admissions between 2001 and 2012 with distributive shock, defined as continuous vasopressor support for ≥ 6 h and no evidence of low cardiac output shock. Hypotension was evaluated using five MAP thresholds: 80, 75, 65, 60 and 55 mmHg. We evaluated the longest continuous episode below each threshold during vasopressor therapy. The primary outcome was ICU mortality. RESULTS: Of 5347 patients with distributive shock, 95.7%, 91.0%, 62.0%, 36.0% and 17.2%, respectively, had MAP < 80, < 75, < 65, < 60 and < 55 mmHg for more than two consecutive hours. On average, ICU mortality increased by 1.3, 1.8, 5.1, 7.9 and 14.4 percentage points for each additional 2 h with MAP < 80, < 75, < 65, < 60 and < 55 mmHg, respectively. Multivariable logistic modeling showed that, compared to patients in whom MAP was never < 65 mmHg, ICU mortality increased as duration of hypotension < 65 mmHg increased [for > 0 to < 2 h, odds ratio (OR) 1.76, p = 0.005; ≥ 6 to < 8 h, OR 2.90, p < 0.0001; ≥ 20 h, OR 7.10, p < 0.0001]. When hypotension was defined as MAP < 60 or < 55 mmHg, the associations between duration and mortality were generally stronger than when hypotension was defined as MAP < 65 mmHg. There was no association between hypotension and mortality when hypotension was defined as MAP < 80 mmHg. CONCLUSIONS: Within the limitations due to the nature of the study, most patients with distributive shock experienced at least one episode with MAP < 65 mmHg lasting > 2 h. Episodes of prolonged hypotension were associated with higher mortality.

The Effects of red Blood Cell Transfusion on Tissue Oxygenation and the Microcirculation in the Intensive Care Unit: A Systematic Review.

The transfusion of red blood cells (RBCs) is a common intervention in intensive care unit (ICU) patients, yet the benefits are far from clear in patients with moderate anemia (eg, hemoglobin (Hb) levels of 7-10 g/dL). Determining which of these patients benefit, and how to even define benefit, from transfusion is challenging. As the intended physiological benefit underpinning RBC transfusion is to improve tissue oxygenation, several studies utilizing a wide range of assessment techniques have attempted to study the effects of transfusion on tissue oxygenation and microcirculatory function. The objective of this systematic review was to determine whether RBC transfusion improves tissue oxygenation/microcirculatory indices in the ICU population, and to provide an introduction to the techniques used in these studies. Eligible studies published between January 1996 and February 2017 were identified from searches of PubMed, Embase, Cinahl, ScienceDirect, Web of Science, and The Cochrane Library. Seventeen studies met inclusion criteria, though there was significant heterogeneity in study design, patient population, assessment techniques and outcomes reported. Overall, the majority of studies (11 of 17) concluded that transfusion did not generally improve tissue oxygenation or microcirculation. Inter-individual effects were highly variable, however, and closer review of sub-groups available in 9 studies revealed that patients with abnormal tissue oxygenation or microcirculatory indices prior to transfusion had improvement in these indices with transfusion, irrespective of assessment method. This finding suggests a new strategy for future trials in the ICU: utilizing tissue oxygenation/microcirculatory parameters to determine the need for transfusion rather than largely arbitrary hemoglobin concentrations.

Restrictive versus liberal red blood cell transfusion strategy after hip surgery: a decision model analysis of healthcare costs.

BACKGROUND: Red blood cell transfusion related to select surgical procedures accounts for approximately 2.8 million transfusions in the United States yearly and occurs commonly after hip fracture surgeries. Randomized controlled trials have demonstrated lack of clinical benefit with higher versus lower transfusion thresholds in postoperative hip fracture repair patients with cardiac disease or risk factors for cardiac disease. The economic implications of a higher versus lower hemoglobin (Hb) threshold have not yet been investigated. STUDY DESIGN AND METHODS: A decision tree analysis was constructed to estimate differences in healthcare costs and charges between a Hb transfusion threshold strategy of 8 g/dL versus 10 g/dL from the perspective of both Centers for Medicare and Medicaid Services (CMS) as well as hospitals. Secondary outcome measures included differences in transfusion-related adverse events. RESULTS: Among the 133,697 Medicare beneficiaries undergoing hip fracture repair in 2012, we estimated that 45,457 patients would be anemic and at risk for transfusion. CMS would save an estimated $11.3 million to $24.3 million in payments, while hospitals would reduce charges by an estimated $52.7 million to $93.6 million if the restrictive transfusion strategy were to be implemented nationally. Additionally, rates of transfusion-associated circulatory overload, transfusion-related acute lung injury, acute transfusion reactions, length of stay, and mortality would be reduced. CONCLUSIONS: This model suggests that the uniform adoption of a restrictive transfusion strategy among patients with cardiac disease and risk factors for cardiac disease undergoing hip fracture repair would result in significant reductions in clinically important outcomes with significant cost savings.

Assessing productive efficiency and operating scale of community blood centers.

BACKGROUND: In recent years demand for blood products has decreased, and as a result, the blood product marketplace has become much more competitive. Reducing inefficiency in the procurement and processing of blood products at blood centers can reduce costs while assuring that demand for blood products is met. STUDY DESIGN AND METHODS: This study uses data envelopment analysis to compare the productive efficiency of 65 community blood centers to determine to what extent efficiency can be improved, what cost savings and increases in platelet (PLT) production may be obtained by eliminating inefficiency, and what scales of operation are the most efficient from a budgetary and staffing standpoint. Data were collected from the 2012 to 2013 AABB Directory of Community Blood Centers and Hospital Blood Banks. RESULTS: The study found that 27 of 65 blood centers are efficient. The remaining 38 blood centers can reduce budget and staff levels and may be able to expand output. If inefficient centers were to eliminate all inefficiency, the total savings would be $671 million, approximately 20% of the aggregated budget ($3.45 billion) of all centers in the study. In addition, the centers would also see a 36% increase in PLT production. Inefficiency of some large blood centers stems from operating at too large a scale, while inefficiency of most small blood centers is scale independent. CONCLUSION: The results suggest that reducing inefficiency in blood procurement may be a good strategy to maximize competitiveness in the blood product marketplace. These findings further suggest that the trend of blood center consolidation may be ill advised from a cost containment perspective.