ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock.

BACKGROUND: Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) medications are widely prescribed. We sought to assess how pre-admission use of these medications might impact the response to angiotensin-II treatment during vasodilatory shock. METHODS: In a post-hoc subgroup analysis of the randomized, placebo-controlled, Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we compared patients with chronic angiotensin-converting enzyme inhibitor (ACEi) use, and patients with angiotensin receptor blocker (ARB) use, to patients without exposure to either ACEi or ARB. The primary outcome was mean arterial pressure after 1-h of treatment. Additional clinical outcomes included mean arterial pressure and norepinephrine equivalent dose requirements over time, and study-drug dose over time. Biological outcomes included baseline RAS biomarkers (renin, angiotensin-I, angiotensin-II, and angiotensin-I/angiotensin-II ratio), and the change in renin from 0 to 3 h. RESULTS: We included n = 321 patients, of whom, 270 were ACEi and ARB-unexposed, 29 were ACEi-exposed and 22 ARB-exposed. In ACEi/ARB-unexposed patients, angiotensin-treated patients, compared to placebo, had higher hour-1 mean arterial pressure (9.1 mmHg [95% CI 7.6-10.1], p < 0.0001), lower norepinephrine equivalent dose over 48-h (p = 0.0037), and lower study-drug dose over 48-h (p < 0.0001). ACEi-exposed patients treated with angiotensin-II showed similarly higher hour-1 mean arterial pressure compared to ACEi/ARB-unexposed (difference in treatment-effect: - 2.2 mmHg [95% CI - 7.0-2.6], pinteraction = 0.38), but a greater reduction in norepinephrine equivalent dose (pinteraction = 0.0031) and study-drug dose (pinteraction < 0.0001) over 48-h. In contrast, ARB-exposed patients showed an attenuated effect of angiotensin-II on hour-1 mean arterial pressure versus ACEi/ARB-unexposed (difference in treatment-effect: - 6.0 mmHg [95% CI - 11.5 to - 0.6], pinteraction = 0.0299), norepinephrine equivalent dose (pinteraction < 0.0001), and study-drug dose (pinteraction = 0.0008). Baseline renin levels and angiotensin-I/angiotensin-II ratios were highest in ACEi-exposed patients. Finally, angiotensin-II treatment reduced hour-3 renin in ACEi/ARB-unexposed and ACEi-exposed patients but not in ARB-exposed patients. CONCLUSIONS: In vasodilatory shock patients, the cardiovascular and biological RAS response to angiotensin-II differed based upon prior exposure to ACEi and ARB medications. ACEi-exposure was associated with increased angiotensin II responsiveness, whereas ARB-exposure was associated with decreased responsiveness. These findings have clinical implications for patient selection and dosage of angiotensin II in vasodilatory shock. Trial Registration ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Association of Active Renin Content With Mortality in Critically Ill Patients: A Post hoc Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) Trial.

OBJECTIVE: Sepsis is a leading cause of mortality. Predicting outcomes is challenging and few biomarkers perform well. Defects in the renin-angiotensin system (RAS) can predict clinical outcomes in sepsis and may outperform traditional biomarkers. We postulated that RAS dysfunction (elevated active renin, angiotensin 1-7 [Ang-(1-7)], and angiotensin-converting enzyme 2 (ACE2) activity with depressed Ang-II and ACE activity) would be associated with mortality in a cohort of septic patients. DESIGN: Post hoc analysis of patients enrolled in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized controlled trial. SETTING: Forty-three hospitals across the United States. PATIENTS: Biorepository samples of 103 patients. INTERVENTIONS: We analyzed day 0 (within 24 hr of respiratory failure, septic shock, or both) and day 3 samples ( n = 103 and 95, respectively) for assessment of the RAS. The association of RAS values with 30-day mortality was determined using Cox proportional hazards regression with multivariable adjustments for age, sex, VICTAS treatment arm, systolic blood pressure, Sequential Organ Failure Assessment Score, and vasopressor use. MEASUREMENTS AND MAIN RESULTS: High baseline active renin values were associated with higher 30-day mortality when dichotomized to the median of 188.7 pg/mL (hazard ratio [HR] = 2.84 [95% CI, 1.10-7.33], p = 0.031) or stratified into quartiles (Q1 = ref, HR Q2 = 2.01 [0.37-11.04], HR Q3 = 3.22 [0.64-16.28], HR Q4 = 5.58 [1.18-26.32], p for linear trend = 0.023). A 1- sd (593.6 pg/mL) increase in renin from day 0 to day 3 was associated with increased mortality (HR = 3.75 [95% CI, 1.94-7.22], p < 0.001), and patients whose renin decreased had improved survival compared with those whose renin increased (HR 0.22 [95% CI, 0.08-0.60], p = 0.003). Ang-(1-7), ACE2 activity, Ang-II and ACE activity did not show this association. Mortality was attenuated in patients with renin over the median on day 0 who received the VICTAS intervention, but not on day 3 ( p interaction 0.020 and 0.137, respectively). There were no additional consistent patterns of mortality on the RAS from the VICTAS intervention. CONCLUSIONS: Baseline serum active renin levels were strongly associated with mortality in critically ill patients with sepsis. Furthermore, a greater relative activation in circulating renin from day 0 to day 3 was associated with a higher risk of death.

Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock.

BACKGROUND: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. METHODS: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. RESULTS: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2-161.5], p = 0.0028). Similarly, oxygenation index decreased by - 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus - 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI - 8.6 to - 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5-47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. CONCLUSIONS: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. TRIAL REGISTRATION: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

A novel diagnostic method for a rare fungus: FcMBL facilitates Wickerhamomyces anomalus identification in an immunocompromised neonate.

Fungemia negatively impacts patient outcomes, current diagnostics lack sensitivity to identify emerging rare mycoses, and fungal infections are increasing in prevalence, variety, and resistance. We report a case of Wickerhamomyces anomalus in an immunocompromised neonate in which FcMBL bead-based matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) resulted in species identification roughly 30 hours before standard pathogen identification methods. Deploying FcMBL bead-based MALDI-TOF MS may improve the speed and accuracy of identification, and therefore treatment, of rare pathogens.

Sepsis Management in the Cardiac Intensive Care Unit.

Septic shock management in the cardiac intensive care unit (CICU) is challenging due to the complex interaction of pathophysiology between vasodilatory and cardiogenic shock, complicating how to optimally deploy fluid resuscitation, vasopressors, and mechanical circulatory support devices. Because mixed shock portends high mortality and morbidity, familiarity with quality, contemporary clinical evidence surrounding available therapeutic tools is needed to address the resultant wide range of complications that can arise. This review integrates pathophysiology principles and clinical recommendations to provide an organized, topic-based review of the nuanced intricacies of managing sepsis in the CICU.

Pulmonary Co-Infections Detected Premortem Underestimate Postmortem Findings in a COVID-19 Autopsy Case Series.

Bacterial and fungal co-infections are reported complications of coronavirus disease 2019 (COVID-19) in critically ill patients but may go unrecognized premortem due to diagnostic limitations. We compared the premortem with the postmortem detection of pulmonary co-infections in 55 fatal COVID-19 cases from March 2020 to March 2021. The concordance in the premortem versus the postmortem diagnoses and the pathogen identification were evaluated. Premortem pulmonary co-infections were extracted from medical charts while applying standard diagnostic definitions. Postmortem co-infection was defined by compatible lung histopathology with or without the detection of an organism in tissue by bacterial or fungal staining, or polymerase chain reaction (PCR) with broad-range bacterial and fungal primers. Pulmonary co-infection was detected premortem in significantly fewer cases (15/55, 27%) than were detected postmortem (36/55, 65%; p < 0.0001). Among cases in which co-infection was detected postmortem by histopathology, an organism was identified in 27/36 (75%) of cases. Pseudomonas, Enterobacterales, and Staphylococcus aureus were the most frequently identified bacteria both premortem and postmortem. Invasive pulmonary fungal infection was detected in five cases postmortem, but in no cases premortem. According to the univariate analyses, the patients with undiagnosed pulmonary co-infection had significantly shorter hospital (p = 0.0012) and intensive care unit (p = 0.0006) stays and significantly fewer extra-pulmonary infections (p = 0.0021). Bacterial and fungal pulmonary co-infection are under-recognized complications in critically ill patients with COVID-19.

Sustainable surgical resource initiative for Haiti: the SSRI-Haiti project.

In response to the 2010 earthquake and subsequent cholera epidemic, St Luke's Medical Center was established in Port-au-Prince, Haiti. Here, we describe its inception and evolution to include an intensive care unit and two operating rooms, as well as the staffing, training and experiential learning activities, which helped St Luke's become a sustainable surgical resource. We describe a three-phase model for establishing a sustainable surgical centre in Haiti (build facility and acquire equipment; train staff and perform surgeries; provide continued education and expansion including regular specialist trips) and we report a progressive increase in the number and complexity of cases performed by all-Haitian staff from 2012 to 2022. The results are generalised in the context of the 'delay framework' to global health along with a discussion of the application of this three-phase model to resource-limited environments. We conclude with a brief description of the formation of a remote surgical centre in Port-Salut, an unforeseen benefit of local competence and independence. Establishing sustainable and collaborative surgery centres operated by local staff accelerates the ability of resource-limited countries to meet high surgical burdens.

SHock-INduced Endotheliopathy (SHINE): A mechanistic justification for viscoelastography-guided resuscitation of traumatic and non-traumatic shock.

Irrespective of the reason for hypoperfusion, hypocoagulable and/or hyperfibrinolytic hemostatic aberrancies afflict up to one-quarter of critically ill patients in shock. Intensivists and traumatologists have embraced the concept of SHock-INduced Endotheliopathy (SHINE) as a foundational derangement in progressive shock wherein sympatho-adrenal activation may cause systemic endothelial injury. The pro-thrombotic endothelium lends to micro-thrombosis, enacting a cycle of worsening perfusion and increasing catecholamines, endothelial injury, de-endothelialization, and multiple organ failure. The hypocoagulable/hyperfibrinolytic hemostatic phenotype is thought to be driven by endothelial release of anti-thrombogenic mediators to the bloodstream and perivascular sympathetic nerve release of tissue plasminogen activator directly into the microvasculature. In the shock state, this hemostatic phenotype may be a counterbalancing, yet maladaptive, attempt to restore blood flow against a systemically pro-thrombotic endothelium and increased blood viscosity. We therefore review endothelial physiology with emphasis on glycocalyx function, unique biomarkers, and coagulofibrinolytic mediators, setting the stage for understanding the pathophysiology and hemostatic phenotypes of SHINE in various etiologies of shock. We propose that the hyperfibrinolytic phenotype is exemplified in progressive shock whether related to trauma-induced coagulopathy, sepsis-induced coagulopathy, or post-cardiac arrest syndrome-associated coagulopathy. Regardless of the initial insult, SHINE appears to be a catecholamine-driven entity which early in the disease course may manifest as hyper- or hypocoagulopathic and hyper- or hypofibrinolytic hemostatic imbalance. Moreover, these hemostatic derangements may rapidly evolve along the thrombohemorrhagic spectrum depending on the etiology, timing, and methods of resuscitation. Given the intricate hemochemical makeup and changes during these shock states, macroscopic whole blood tests of coagulative kinetics and clot strength serve as clinically useful and simple means for hemostasis phenotyping. We suggest that viscoelastic hemostatic assays such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are currently the most applicable clinical tools for assaying global hemostatic function-including fibrinolysis-to enable dynamic resuscitation with blood products and hemostatic adjuncts for those patients with thrombotic and/or hemorrhagic complications in shock states.

Resonant Acoustic Rheometry to Measure Coagulation Kinetics in Hemophilia A and Healthy Plasma: A Novel Viscoelastic Method.

Compared with conventional coagulation tests and factor-specific assays, viscoelastic hemostatic assays (VHAs) can provide a more thorough evaluation of clot formation and lysis but have several limitations including clot deformation. In this proof-of-concept study, we test a noncontact technique, termed resonant acoustic rheometry (RAR), for measuring the kinetics of human plasma coagulation. Specifically, RAR utilizes a dual-mode ultrasound technique to induce and detect surface oscillation of blood samples without direct physical contact and measures the resonant frequency of the surface oscillation over time, which is reflective of the viscoelasticity of the sample. Analysis of RAR results of normal plasma allowed defining a set of parameters for quantifying coagulation. RAR detected a flat-line tracing of resonant frequency in hemophilia A plasma that was corrected with the addition of tissue factor. Our RAR results captured the kinetics of plasma coagulation and the newly defined RAR parameters correlated with increasing tissue factor concentration in both healthy and hemophilia A plasma. These findings demonstrate the feasibility of RAR as a novel approach for VHA, providing the foundation for future studies to compare RAR parameters to conventional coagulation tests, factor-specific assays, and VHA parameters.

SARS-CoV-2 infection and persistence in the human body and brain at autopsy.

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6-14. Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

FcMBL magnetic bead-based MALDI-TOF MS rapidly identifies paediatric blood stream infections from positive blood cultures.

Rapid identification of potentially life-threatening blood stream infections (BSI) improves clinical outcomes, yet conventional blood culture (BC) identification methods require ~24-72 hours of liquid culture, plus 24-48 hours to generate single colonies on solid media suitable for identification by mass spectrometry (MS). Newer rapid centrifugation techniques, such as the Bruker MBT-Sepsityper® IVD, replace culturing on solid media and expedite the diagnosis of BCs but frequently demonstrate reduced sensitivity for identifying clinically significant Gram-positive bacterial or fungal infections. This study introduces a protocol that utilises the broad-range binding properties of an engineered version of mannose-binding lectin linked to the Fc portion of immunoglobulin (FcMBL) to capture and enrich pathogens combined with matrix-assisted laser desorption-ionisation time-of-flight (MALDI-TOF) MS for enhanced infection identification in BCs. The FcMBL method identified 94.1% (64 of 68) of clinical BCs processed, with a high sensitivity for both Gram-negative and Gram-positive bacteria (94.7 and 93.2%, respectively). The FcMBL method identified more patient positive BCs than the Sepsityper® (25 of 25 vs 17 of 25), notably with 100% (3/3) sensitivity for clinical candidemia, compared to only 33% (1/3) for the Sepsityper®. Additionally, during inoculation experiments, the FcMBL method demonstrated a greater sensitivity, identifying 100% (24/24) of candida to genus level and 9/24 (37.5%) top species level compared to 70.8% (17/24) to genus and 6/24 to species (25%) using the Sepsityper®. This study demonstrates that capture and enrichment of samples using magnetic FcMBL-conjugated beads is superior to rapid centrifugation methods for identification of BCs by MALDI-TOF MS. Deploying the FcMBL method therefore offers potential clinical benefits in sensitivity and reduced turnaround times for BC diagnosis compared to the standard Sepsityper® kit, especially for fungal diagnosis.

Lowering platelet count threshold to 10,000/µL for peripherally inserted central catheter placement safely conserves blood products.

Despite the low risk of peripherally inserted central catheter (PICC) insertion-related bleeding, the practice of administering prophylactic platelets varies greatly. Limiting unnecessary blood product transfusions reduces transfusion-related adverse events, financial cost, and delays in care. We assessed the impact of lowering prophylactic platelet administration threshold on blood product utilization patterns and bleeding events. This quasi-experimental study was conducted in an urban academic tertiary medical center. The study population included patients with platelet counts ≥ 10,000/µL and < 50,000/µL undergoing PICC placement in 2018 and 2019 when the minimum platelet thresholds were 50,000/µL and 10,000/µL, respectively. The primary outcome was blood product utilization and the secondary outcome was PICC insertion-related bleeding complications. Thirty-five patients using the 10,000/µL (10 K) platelet threshold and 46 patients using the 50,000/µL (50 K) platelet threshold were enrolled. The 50 K group received more platelets before PICC insertion (0.870 ± 0.885 and 0.143 ± 0.430 pools of platelets-per-person, p < 0.001). No patients experienced clinically significant bleeding. Immediately following PICC insertion, minor bleeding occurred in five patients (two [4.3%] and three [8.6%] in the 50 K and 10 K groups, respectively). Bleeding rates between the two cohorts did not differ (p = 0.647). Lowering the minimum platelet threshold from 50,000/µL to 10,000/µL resulted in less prophylactic platelet and total blood product administration with no appreciable difference in PICC insertion-related bleeding.

Feasibility of Tele-Training to Acquire Sublingual Microcirculatory Images.

Background: Recent advances in device technology and image analysis software used to assess the sublingual microcirculation have expanded clinicians' understanding of hemodynamics beyond assessments of blood pressure and end-organ function to provide unique insight into blood flow at the tissue level. Similarly, significant advances in virtual education and telemedicine have transpired recently, especially during the coronavirus disease (COVID-19) pandemic. However, the training of clinicians to acquire microcirculation images continues to rely on in-person instruction, which can be limited by available local expertise and resources, as well as geographic access to instructors. Objective: Our project aimed to test the feasibility of deploying an online curriculum in combination with tele-guidance versus an in-person guided approach to instruct novices to understand basic principle of microcirculatory function and to acquire sublingual microcirculatory images. Methods: After participating in brief didactics, 14 participants were divided into two groups to acquire microcirculatory images on a healthy volunteer. Each participant either 1) obtained images after an in-person demonstration or 2) obtained images with tele-guidance by using FaceTime technology. We recorded individual microcirculation quality scores, necessary time to acquire each image, percentage of correct theoretical questions on assessments, participant satisfaction with the curriculum, and participants' degree of confidence with image acquisition. Results: Participants' image quality scores (14.7 vs. 23.6, P = 0.3) and time to acquire images (191.2 vs. 199.4 s) did not significantly differ. In addition, participants' scores on theoretical knowledge assessments improved over the course of training (19.0% vs. 54.8%, P < 0.05). Conclusion: This feasibility study provides a novel framework for how to successfully deploy asynchronous education and telemedicine to direct novices to acquire sublingual microcirculatory images. Using technological advances to teach microcirculation may enhance wide-scale adoption of a promising clinical monitoring tool for critically ill patients.

Effects of a single bolus of hydroxocobalamin on hemodynamics in vasodilatory shock.

PURPOSE: Hydroxocobalamin has been observed to cause transient hypertension in healthy subjects, but rigorous studies examining its efficacy are lacking. MATERIALS AND METHODS: Adults in shock who received hydroxocobalamin from 2017 to 2021 were analyzed retrospectively. Hourly hemodynamics from 24 h before and after treatment were collected, and the difference and hourly change of mean arterial pressure (MAP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and norepinephrine-equivalent dose (NED) were examined in mixed-effects models. RESULTS: This study included 3992 hemodynamic data points from 35 patients and is the largest case series to date. In the mixed effects model, there was no difference in MAP 24-h after hydroxocobalamin administration (estimated fixed effect [EFE] -0.2 mmHg, p = 0.89). A two-piecewise mixed model found that the hourly change in MAP was not different from zero in either the pre-administration (EFE 0.0 mmHg/h, p = 0.80) or post-administration segments (EFE 0.0 mmHg/h, p = 0.55). Analysis of the SBP, DBP, and NED also found similar insignificant results. CONCLUSIONS: Although hydroxocobalamin has been observed to cause hypertension in healthy subjects, our results suggest that in patients with shock, hydroxocobalamin may not be effective in improving hemodynamics at 24 h after administration.

A Multicenter Observational Cohort Study of Angiotensin II in Shock.

INTRODUCTION: Angiotensin II (Ang-2) is a non-catecholamine vasopressor that targets the renin-angiotensin-aldosterone system by agonism of the angiotensin type 1 receptor. Its utility as a vasopressor and a catecholamine-sparing agent was demonstrated in the pivotal ATHOS-3 trial, and numerous post-hoc analyses have shown reduced mortality in certain subsets of the population. METHODS: Consecutive adult patients at 5 centers who received Ang-2 from 2017-2020 were included in this multicenter, retrospective observational cohort study. Patient demographics, hemodynamics, and adverse events were collected. The primary outcomes of the study were the mean difference in MAP and norepinephrine (NEpi)-equivalent dose at hours 0 and 3 following initiation of Ang-2 therapy. RESULTS: One hundred and sixty-two patients were included in this study. The primary outcomes of an increase in MAP (mean difference 9.3 mmHg, 95% CI 6.4-12.1, p < 0.001) and a reduction in NEpi equivalent dose (mean difference 0.16 µg/kg/min, 95% CI 0.10-0.22, p < 0.001) between hours 0 and 3 were statistically significant. The median time to reach a MAP ≥65 was 16 minutes (IQR 5-60 min). After stratifying patients by the NED dose and number of vasopressors administered prior to the initiation of Ang-2, those with a NED dose < 0.2 µg/kg/min, NED dose < 0.3 µg/kg/min, or those on ≤ 3 vasopressors had a significantly greater reduction in NED by hour 3 than those patients above these thresholds. CONCLUSION: Ang-2 is an effective vasopressor and reduces catecholamine dose significantly. Its effect is rapid, with target MAP obtained within 30 minutes in most patients. Given the critical importance of adequate blood pressure to organ perfusion, Ang-2 should be considered when target MAP cannot be achieved with conventional vasopressors. Ang-2 should be utilized early in the course of shock, before the NED dose exceeds 0.2-0.3 µg/kg/min and before the initiation of the fourth-line vasopressor.

Renin Kinetics Are Superior to Lactate Kinetics for Predicting In-Hospital Mortality in Hypotensive Critically Ill Patients.

OBJECTIVES: Whole blood lactate concentration is widely used in shock states to assess perfusion. We aimed to determine if the change in plasma renin concentration over time would be superior to the change in lactate concentration for predicting in-hospital mortality in hypotensive patients on vasopressors. DESIGN: Prospective, observational cohort study. SETTING: Tertiary academic ICU. PATIENTS: Adult patients on vasopressors for greater than 6 hours to maintain a mean arterial pressure greater than or equal to 65 mm Hg during January 2020. INTERVENTIONS: Plasma renin concentrations were measured at enrollment and at 24, 48, and 72 hours. Whole blood lactate measurements were performed according to normal standard of care. Logistic regression was performed to evaluate whether the change in renin or lactate concentration could predict in-hospital mortality. Generalized estimating equations were used to analyze the association between renin and lactate concentration and in-hospital mortality. The area under the receiver operating characteristics curve was performed to measure the discriminative ability of initial and peak renin and lactate concentration to predict mortality. The association between renin and lactate concentration above the upper limit of normal at each timepoint with in-hospital mortality was also examined. MEASUREMENTS AND MAIN RESULTS: The study included 197 renin and 148 lactate samples obtained from 53 patients. The slope of the natural log (ln) of renin concentration was independently associated with mortality (adjusted odds ratio, 10.35; 95% CI, 1.40-76.34; p = 0.022), but the slope of ln-lactate concentration was not (adjusted odds ratio, 4.78; 95% CI, 0.03-772.64; p = 0.55). The generalized estimating equation models found that both ln-renin (adjusted odds ratio, 1.18; 95% CI, 1.02-1.37; p = 0.025) and ln-lactate (adjusted odds ratio, 2.38; 95% CI, 1.05-5.37; p = 0.037) were associated with mortality. Area under the receiver operating characteristics curve analysis demonstrated that initial renin could predict in-hospital mortality with fair discrimination (area under the receiver operating characteristics curve, 0.682; 95% CI, 0.503-0.836; p = 0.05), but initial lactate could not (area under the receiver operating characteristics curve, 0.615; 95% CI, 0.413-0.803; p = 0.27). Peak renin (area under the receiver operating characteristics curve, 0.728; 95% CI, 0.547-0.888; p = 0.01) and peak lactate (area under the receiver operating characteristics curve, 0.746; 95% CI, 0.584-0.876; p = 0.01) demonstrated moderate discrimination. There was no significant difference in discriminative ability between initial or peak renin and lactate concentration. At each study time point, a higher proportion of renin values exceeded the threshold of normal (40 pg/mL) in nonsurvivors than in survivors, but this association was not significant for lactate. CONCLUSIONS: Although there was no significant difference in the performance of renin and lactate when examining the absolute values of each laboratory, a positive rate of change in renin concentration, but not lactate concentration, over 72 hours was associated with in-hospital mortality. For each one-unit increase in the slope of ln-renin, the odds of mortality increased 10-fold. Renin levels greater than 40 pg/mL, but not lactate levels greater than 2 mmol/L, were associated with in-hospital mortality. These findings suggest that plasma renin kinetics may be superior to lactate kinetics in predicting mortality of hypotensive, critically ill patients.

Assessing calorie and protein recommendations for survivors of critical illness weaning from prolonged mechanical ventilation - can we find a proper balance?

BACKGROUND & AIMS: Survivors of critical illness requiring prolonged mechanical ventilation (PMV) are predisposed to malnutrition, muscle wasting, and weakness. There is a lack of data regarding nutrition adequacy among these patients, and although nitrogen balance has been studied as a marker of adequate protein intake in healthy individuals and acutely critically ill patients, it has not been well studied in critically ill patients with PMV. The purpose of this study was to determine if patients requiring PMV admitted to a long-term acute care hospital (LTACH) achieved registered dietitian (RD) recommended goals for energy and protein intake and if the recommendations were adequate to avoid negative nitrogen balance. METHODS: Using a retrospective, cohort study design, patients requiring PMV who had orders for 24-h urine collections for urea nitrogen (24hrUUN) were included. Energy and protein intake was calculated from chart documentation of dietary intake for the 24-h period during which patients underwent a 24hrUUN. Nitrogen intake was estimated from protein intake. Dietary intake was compared to RD-recommendations to determine the percentage of RD-recommendations achieved. Nitrogen balance was calculated as nitrogen intake minus nitrogen loss, with negative balance categorized as less than -1. RESULTS: Subjects (n = 16) were 38% male and 75% African American (mean age 61.5 ± 3.2 years; mean BMI 27.5 ± 2.5 kg/m2). Duration of LTACH hospitalization was 26.5 (6-221) days. Mean energy and protein intake was 21.7 ± 2.9 kcal/kg/d and 1.1 ± 0.1 g/kg/d, respectively, which corresponded to 86% of both RD energy and protein recommendations. Ten patients achieved a positive nitrogen balance (mean 0.9 ± 1.1 g). In addition, there was a positive linear relationship between protein intake and nitrogen balance (r = 0.59, p = 0.016). CONCLUSION: Survivors of critical illness requiring PMV achieved a high percentage of RD-recommended protein and calories, and prevented a negative nitrogen balance in a majority of patients. Increasing protein intake can prevent a negative nitrogen balance. Future studies should evaluate whether these patients are able to maintain a steady state of nitrogen intake and excretion over time and how this affects time to and/or success of weaning.