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.

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.

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.

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.

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.

Plasma exchange in the intensive care unit: a narrative review.

In this narrative review, we discuss the relevant issues of therapeutic plasma exchange (TPE) in critically ill patients. For many conditions, the optimal indication, device type, frequency, duration, type of replacement fluid and criteria for stopping TPE are uncertain. TPE is a potentially lifesaving but also invasive procedure with risk of adverse events and complications and requires close monitoring by experienced teams. In the intensive care unit (ICU), the indications for TPE can be divided into (1) absolute, well-established, and evidence-based, for which TPE is recognized as first-line therapy, (2) relative, for which TPE is a recognized second-line treatment (alone or combined) and (3) rescue therapy, where TPE is used with a limited or theoretical evidence base. New indications are emerging and ongoing knowledge gaps, notably regarding the use of TPE during critical illness, support the establishment of a TPE registry dedicated to intensive care medicine.

Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set.

BACKGROUND: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients. METHODS: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method. RESULTS: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO. CONCLUSIONS: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021).

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.

Can Death Cafés resuscitate morale in hospitals?

Death Cafés are non-profit social franchises that arise spontaneously in communities to serve as informal forums for discussing death. There is a great need within the medical community for the kind of conversation that Death Cafés foster: open, unstructured, spontaneous, genuine and interdisciplinary dialogue. Burnout in healthcare, with symptoms of exhaustion, depersonalisation and decreased efficacy, is a global crisis, with alarming estimates suggesting one in three practicing physicians experience burnout. While open-forum community-based Death Cafés exist widely, there appears to be no evidence in the literature to suggest that healthcare settings have adapted this model for fostering debriefings among hospital employees. We have started hospital-based Death Cafés in a large, public, urban-centre, Level I Trauma centre in the Gulf South in an effort to study healthcare worker burnout. In this brief commentary, we introduce the concept of hospital-based Death Cafés as distinct from community-based Death Cafés. From our experience, hospital-based Death Cafés are easy to implement, inexpensive, require little planning and yet offer tremendous reward to participants. Should the phenomenon of Death Cafés take off in hospitals as it has in communities internationally, we propose that this intervention be studied for its effect on healthcare worker burnout.

Implementing an intensive care unit (ICU) diary program at a large academic medical center: Results from a randomized control trial evaluating psychological morbidity associated with critical illness.

BACKGROUND: Psychological morbidity in both patients and family members related to the intensive care unit (ICU) experience is an often overlooked, and potentially persistent, healthcare problem recognized by the Society of Critical Care Medicine as Post-intensive Care Syndrome (PICS). ICU diaries are an intervention increasingly under study with potential to mitigate ICU-related psychological morbidity, including ICU-related post-traumatic stress disorder (PTSD), depression and anxiety. As we encounter a growing number of ICU survivors, in particular in the wake of the coronavirus pandemic, clinicians must be equipped to understand the severity and prevalence of significant psychiatric complications of critical illness. METHODS: We compared the efficacy of the ICU diary, written by family and healthcare workers during the patient's intensive care course, versus education alone in reducing acute PTSD symptoms after discharge. Patients with an ICU stay >72 h, who were intubated and mechanically ventilated over 24 h, were recruited and randomized to either receive a diary at bedside with psychoeducation or psychoeducation alone. Intervention patients received their ICU diary within the first week of admission into the intensive care unit. Psychological symptom screening with IES-R, PHQ-8, HADS and GAD-7 was conducted at baseline within 1 week of ICU discharge and at weeks 4, 12, and 24 after ICU discharge. Change from baseline in these scores was assessed using Wilcoxon rank sum tests. RESULTS: From September 26, 2017 to September 25, 2018, our team screened 265 patients from the surgical and medical ICUs at a single large academic urban hospital. 60 patients were enrolled and randomized, of which 35 patients completed post-discharge follow-up, (n = 18) in the diary intervention group and (n = 17) in the education-only control group. The control group had a significantly greater decrease in PTSD, hyperarousal, and depression symptoms at week 4 compared to the intervention group. There were no significant differences in other measures, or at other follow-up intervals. Both study groups exhibited clinically significant PTSD symptoms at all timepoints after ICU discharge. Follow-up phone interviews with patients revealed that while many were interested in getting follow-up for their symptoms, there were many barriers to accessing appropriate therapy and clinical attention. CONCLUSIONS: Results from psychological screening tools demonstrate no benefit of ICU diaries versus bedside education-alone in reducing PTSD symptoms related to the intensive care stay. However, our study finds an important gap in clinical practice - patients at high risk for PICS are infrequently connected to appropriate follow-up care. Perhaps ICU diaries would prove beneficial if utilized to support the work within a program providing wrap-around services and close psychiatric follow up for PICS patients. This study demonstrates the high prevalence of ICU-related PTSD in our cohort of survivors, the high barrier to accessing care for appropriate treatment of PICS, and the consequence of that barrier-prolonged psychological morbidity. TRIAL REGISTRATION: NCT04305353. GRANT IDENTIFICATION: GH-17-022 (Arnold P. Gold Foundation).