The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients.

BACKGROUND: Norepinephrine (NE) is a cornerstone drug in the management of septic shock, with its dose being used clinically as a marker of disease severity and as mortality predictor. However, variations in NE dose reporting either as salt formulations or base molecule may lead to misinterpretation of mortality risks and hinder the process of care. METHODS: We conducted a retrospective analysis of the MIMIC-IV database to assess the impact of NE dose reporting heterogeneity on mortality prediction in a cohort of septic shock patients. NE doses were converted from the base molecule to equivalent salt doses, and their ability to predict 28-day mortality at common severity dose cut-offs was compared. RESULTS: 4086 eligible patients with septic shock were identified, with a median age of 68 [57-78] years, an admission SOFA score of 7 [6-10], and lactate at diagnosis of 3.2 [2.4-5.1] mmol/L. Median peak NE dose at day 1 was 0.24 [0.12-0.42] µg/kg/min, with a 28-day mortality of 39.3%. The NE dose showed significant heterogeneity in mortality prediction depending on which formulation was reported, with doses reported as bitartrate and tartrate presenting 65 (95% CI 79-43)% and 67 (95% CI 80-47)% lower ORs than base molecule, respectively. This divergence in prediction widened at increasing NE doses. When using a 1 µg/kg/min threshold, predicted mortality was 54 (95% CI 52-56)% and 83 (95% CI 80-87)% for tartrate formulation and base molecule, respectively. CONCLUSIONS: Heterogeneous reporting of NE doses significantly affects mortality prediction in septic shock. Standardizing NE dose reporting as base molecule could enhance risk stratification and improve processes of care. These findings underscore the importance of consistent NE dose reporting practices in critical care settings.

Prospective, randomized, controlled trial assessing the effects of a driving pressure-limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan.

BACKGROUND: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. OBJECTIVE: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. METHODS: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. OUTCOMES: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. CONCLUSION: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

Capillary refill time response to a fluid challenge or a vasopressor test: an observational, proof-of-concept study.

BACKGROUND: Several studies have validated capillary refill time (CRT) as a marker of tissue hypoperfusion, and recent guidelines recommend CRT monitoring during septic shock resuscitation. Therefore, it is relevant to further explore its kinetics of response to short-term hemodynamic interventions with fluids or vasopressors. A couple of previous studies explored the impact of a fluid bolus on CRT, but little is known about the impact of norepinephrine on CRT when aiming at a higher mean arterial pressure (MAP) target in septic shock. We designed this observational study to further evaluate the effect of a fluid challenge (FC) and a vasopressor test (VPT) on CRT in septic shock patients with abnormal CRT after initial resuscitation. Our purpose was to determine the effects of a FC in fluid-responsive patients, and of a VPT aimed at a higher MAP target in chronically hypertensive fluid-unresponsive patients on the direction and magnitude of CRT response. METHODS: Thirty-four septic shock patients were included. Fluid responsiveness was assessed at baseline, and a FC (500 ml/30 mins) was administered in 9 fluid-responsive patients. A VPT was performed in 25 patients by increasing norepinephrine dose to reach a MAP to 80-85 mmHg for 30 min. Patients shared a multimodal perfusion and hemodynamic monitoring protocol with assessments at at least two time-points (baseline, and at the end of interventions). RESULTS: CRT decreased significantly with both tests (from 5 [3.5-7.6] to 4 [2.4-5.1] sec, p = 0.008 after the FC; and from 4.0 [3.3-5.6] to 3 [2.6 -5] sec, p = 0.03 after the VPT. A CRT-response was observed in 7/9 patients after the FC, and in 14/25 pts after the VPT, but CRT deteriorated in 4 patients on this latter group, all of them receiving a concomitant low-dose vasopressin. CONCLUSIONS: Our findings support that fluid boluses may improve CRT or produce neutral effects in fluid-responsive septic shock patients with persistent hypoperfusion. Conversely, raising NE doses to target a higher MAP in previously hypertensive patients elicits a more heterogeneous response, improving CRT in the majority, but deteriorating skin perfusion in some patients, a fact that deserves further research.

Consistency of data reporting in fluid responsiveness studies in the critically ill setting: the CODEFIRE consensus from the Cardiovascular Dynamic section of the European Society of Intensive Care Medicine.

PURPOSE: To provide consensus recommendations regarding hemodynamic data reporting in studies investigating fluid responsiveness and fluid challenge (FC) use in the intensive care unit (ICU). METHODS: The Executive Committee of the European Society of Intensive Care Medicine (ESICM) commissioned and supervised the project. A panel of 18 international experts and a methodologist identified main domains and items from a systematic literature, plus 2 ancillary domains. A three-step Delphi process based on an iterative approach was used to obtain the final consensus. In the Delphi 1 and 2, the items were selected with strong (≥ 80% of votes) or week agreement (70-80% of votes), while the Delphi 3 generated recommended (≥ 90% of votes) or suggested (80-90% of votes) items (RI and SI, respectively). RESULTS: We identified 5 main domains initially including 117 items and the consensus finally resulted in 52 recommendations or suggestions: 18 RIs and 2 SIs statements were obtained for the domain "ICU admission", 11 RIs and 1 SI for the domain "mechanical ventilation", 5 RIs for the domain "reason for giving a FC", 8 RIs for the domain pre- and post-FC "hemodynamic data", and 7 RIs for the domain "pre-FC infused drugs". We had no consensus on the use of echocardiography, strong agreement regarding the volume (4 ml/kg) and the reference variable (cardiac output), while weak on administration rate (within 10 min) of FC in this setting. CONCLUSION: This consensus found 5 main domains and provided 52 recommendations for data reporting in studies investigating fluid responsiveness in ICU patients.

Coexistence of a fluid responsive state and venous congestion signals in critically ill patients: a multicenter observational proof-of-concept study.

BACKGROUND: Current recommendations support guiding fluid resuscitation through the assessment of fluid responsiveness. Recently, the concept of fluid tolerance and the prevention of venous congestion (VC) have emerged as relevant aspects to be considered to avoid potentially deleterious side effects of fluid resuscitation. However, there is paucity of data on the relationship of fluid responsiveness and VC. This study aims to compare the prevalence of venous congestion in fluid responsive and fluid unresponsive critically ill patients after intensive care (ICU) admission. METHODS: Multicenter, prospective cross-sectional observational study conducted in three medical-surgical ICUs in Chile. Consecutive mechanically ventilated patients that required vasopressors and admitted < 24 h to ICU were included between November 2022 and June 2023. Patients were assessed simultaneously for fluid responsiveness and VC at a single timepoint. Fluid responsiveness status, VC signals such as central venous pressure, estimation of left ventricular filling pressures, lung, and abdominal ultrasound congestion indexes and relevant clinical data were collected. RESULTS: Ninety patients were included. Median age was 63 [45-71] years old, and median SOFA score was 9 [7-11]. Thirty-eight percent of the patients were fluid responsive (FR+), while 62% were fluid unresponsive (FR-). The most prevalent diagnosis was sepsis (41%) followed by respiratory failure (22%). The prevalence of at least one VC signal was not significantly different between FR+ and FR- groups (53% vs. 57%, p = 0.69), as well as the proportion of patients with 2 or 3 VC signals (15% vs. 21%, p = 0.4). We found no association between fluid balance, CRT status, or diagnostic group and the presence of VC signals. CONCLUSIONS: Venous congestion signals were prevalent in both fluid responsive and unresponsive critically ill patients. The presence of venous congestion was not associated with fluid balance or diagnostic group. Further studies should assess the clinical relevance of these results and their potential impact on resuscitation and monitoring practices.

Efectos del reto de líquidos sobre el acople ventrículo arterial en un biomodelo porcino de choque endotóxico / The effect of fluid challenge on ventriculo-arterial coupling in an endotoxic shock swine bio-model

Introducción: el reto de líquidos es una prueba que consiste en administrarlos y medir la respuesta hemodinámica mediante el cambio del gasto cardíaco (GC), aunque solo medir el GC resulta insuficiente. El acople ventrículo-arterial (AVA) (elastancia arterial efectiva/ elastancia telesistólica: Eae/Ets) aparece como una variable que evalúa el estado cardiocirculatorio en forma integral. Objetivo: evaluar el AVA en un biomodelo de choque endotóxico y durante retos de líquidos. Materiales y métodos: biomodelo de choque endotóxico (9 porcinos). Se midieron variables hemodinámicas cada hora desde un tiempo 0 (T0) hasta T6. Se realizaron 5 retos de líquidos entre T0 y T4. El tiempo de hipotensión se denominó TH0. Se calcularon diferencias de medianas de variables entre T0-T4. Se clasificaron los retos en dos grupos según el delta del AVA (AVA posreto-AVA prerreto), en ΔAVA≤0 o >0, se midieron variables antes y después de cada reto. Se determinó la relación lactato/piruvato (L/P) en T0, T3 y T6, se establecieron correlaciones entre la diferencia LP T6-T0 y de variables hemodinámicas. Resultados: el AVA aumentó (1.58 a 2,02, p=0.042) por incremento en la Eae (1.74 a 2,55; p=0.017). El grupo ΔAVA≤0 elevó el GC (4.32 a 5,46, p=0.032) y el poder cardíaco (PC) (0.61 a 0,77, p=0,028). El Δ L/P se correlacionó con el Δ del índice de choque sistólico y diastólico (r=0.73), pero no con el del AVA. Conclusión: durante el choque endotóxico el AVA aumentó de manera significativa. Durante el reto de líquidos el grupo Δ AVA≤0, elevó el GC y PC. El Δ L/P no se correlacionó con variables del AVA.

Introduction: fluid challenges (FCs) consist of measuring hemodynamic response through changes in cardiac output (CO) after fluid administration, although only measuring CO proves insufficient. Ventriculo-arterial coupling (V-A) (effective arterial elastance / tele-systolic elastance: E(a)/Ets) are variables used for a comprehensive cardiac and circulatory status appraisal. Objective: to evaluate V-A in an endotoxic shock bio-model by FCs. Materials and methods: an endotoxic shock bio-model (9 pigs). Hemodynamic variables were measured every hour from time 0 (T0) to T6. Five FCs were performed between T0 and T4. Hypotension time was referred to as HT. The median differences in variables between T0-T4 were calculated. Challenges were classified into two groups according to V-A delta (post-challenge V-A - pre-challenge V-A). In ΔV-A≤0 o>0, variables were measured before and after each FC. The lactate to pyruvate (L/P) ratio was determined at T0, T3 and T6. Correlations between the LP T6-T0 difference and hemodynamic variables, were established. Results: V-A increased (1.58 to 2,02, p=0.042) as Eae increased (1.74 to 2.55; p=0.017). CO (4.32 to 5.46, p=0.032) and cardiac power (CP) (0.61 to 0.77, p=0,028) increased, in the ΔV-AC≤0 group. The ΔLP correlated with the systolic and diastolic shock index (r=0.73), but not with V-A. Conclusion: V-A increased significantly during endotoxic shock. The ΔAVA≤0 group, showed elevated CO and CP during FC. ΔLP did not correlate with any of the V-A variables.

Prospective, randomized, controlled trial assessing the effects of a driving pressure-limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan / Estudo randomizado prospectivo e controlado de avaliação dos efeitos de uma estratégia de limitação da driving pressure em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade (estudo STAMINA): protocolo e plano de análise estatística

ABSTRACT Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

RESUMO Contexto: Em estudos observacionais sobre a síndrome do desconforto respiratório agudo, sugeriu-se que a driving pressure é o principal fator de lesão pulmonar induzida por ventilador e de mortalidade. Não está claro se uma estratégia de limitação da driving pressure pode melhorar os desfechos clínicos. Objetivo: Descrever o protocolo e o plano de análise estatística que serão usados para testar se uma estratégia de limitação da driving pressure envolvendo a titulação da pressão positiva expiratória final de acordo com a melhor complacência respiratória e a redução do volume corrente é superior a uma estratégia padrão envolvendo o uso da tabela de pressão positiva expiratória final baixa do protocolo ARDSNet, em termos de aumento do número de dias sem ventilador em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade. Métodos: O estudo STAMINA (ventilator STrAtegy for coMmunIty acquired pNeumoniA) é randomizado, multicêntrico e aberto e compara uma estratégia de limitação da driving pressure com a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet em pacientes com síndrome do desconforto respiratório agudo moderada a grave devido à pneumonia adquirida na comunidade internados em unidades de terapia intensiva. Esperamos recrutar 500 pacientes de 20 unidades de terapia intensiva brasileiras e duas colombianas. Eles serão randomizados para um grupo da estratégia de limitação da driving pressure ou para um grupo de estratégia padrão usando a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet. No grupo da estratégia de limitação da driving pressure, a pressão positiva expiratória final será titulada de acordo com a melhor complacência do sistema respiratório. Desfechos: O desfecho primário é o número de dias sem ventilador em 28 dias. Os desfechos secundários são a mortalidade hospitalar e na unidade de terapia intensiva e a necessidade de terapias de resgate, como suporte de vida extracorpóreo, manobras de recrutamento e óxido nítrico inalado. Conclusão: O STAMINA foi projetado para fornecer evidências sobre se uma estratégia de limitação da driving pressure é superior à estratégia da tabela de pressão positiva expiratória final baixa do protocolo ARDSnet para aumentar o número de dias sem ventilador em 28 dias em pacientes com síndrome do desconforto respiratório agudo moderada a grave. Aqui, descrevemos a justificativa, o desenho e o status do estudo.

Cost Analysis of High-Flow Oxygen Therapy Compared with Conventional Oxygen Therapy in Severe COVID-19 in Colombia: Data from a Randomized Clinical Trial.

Background: A randomized clinical trial (HiFlo-COVID-19 Trial) showed that among patients with severe COVID-19, treatment with high-flow oxygen therapy (HFOT) significantly reduced the need for invasive mechanical ventilation support and time for clinical recovery compared with conventional oxygen therapy (COT). However, the cost of this strategy is unknown. Objective: We examined total cost of HFOT treatment compared with COT in real-world setting. Methods: We conducted a post-trial-based cost analysis from the perspective of a managed competition healthcare system, using actual records of billed costs. Cost categories include general ward, intensive care unit, procedures, imaging, laboratories, medications, supplies, and others. Results: A total of 188 participants (mean age 60, 33% female) were included. Average costs (and standard deviation) in the HFOT group were USD $7992 (7394) and in the COT group USD $ 10,190 (9402). Differences, however, did not reach statistical significance (P=0.093). However, resource use was always less costly for the HNFO group, with an overall percentage decrease of 27%. Two categories make up 72% of all savings: medications (41%) and intensive care unit (31%). Conclusion: For patients in ICU with severe COVID-19 the cost of treatment with HFOT as compared to COT is likely to be cost-saving due to less use of medications and length of stay in ICU.

Variables influencing the prediction of fluid responsiveness: a systematic review and meta-analysis.

INTRODUCTION: Prediction of fluid responsiveness in acutely ill patients might be influenced by a number of clinical and technical factors. We aim to identify variables potentially modifying the operative performance of fluid responsiveness predictors commonly used in clinical practice. METHODS: A sensitive strategy was conducted in the Medline and Embase databases to search for prospective studies assessing the operative performance of pulse pressure variation, stroke volume variation, passive leg raising (PLR), end-expiratory occlusion test (EEOT), mini-fluid challenge, and tidal volume challenge to predict fluid responsiveness in critically ill and acutely ill surgical patients published between January 1999 and February 2023. Adjusted diagnostic odds ratios (DORs) were calculated by subgroup analyses (inverse variance method) and meta-regression (test of moderators). Variables potentially modifying the operative performance of such predictor tests were classified as technical and clinical. RESULTS: A total of 149 studies were included in the analysis. The volume used during fluid loading, the method used to assess variations in macrovascular flow (cardiac output, stroke volume, aortic blood flow, volume‒time integral, etc.) in response to PLR/EEOT, and the apneic time selected during the EEOT were identified as technical variables modifying the operative performance of such fluid responsiveness predictor tests (p < 0.05 for all adjusted vs. unadjusted DORs). In addition, the operative performance of fluid responsiveness predictors was also influenced by clinical variables such as the positive end-expiratory pressure (in the case of EEOT) and the dose of norepinephrine used during the fluid responsiveness assessment for PLR and EEOT (for all adjusted vs. unadjusted DORs). CONCLUSION: Prediction of fluid responsiveness in critically and acutely ill patients is strongly influenced by a number of technical and clinical aspects. Such factors should be considered for individual intervention decisions.

Evidence for a personalized early start of norepinephrine in septic shock.

During septic shock, vasopressor infusion is usually started only after having corrected the hypovolaemic component of circulatory failure, even in the most severe patients. However, earlier administration of norepinephrine, simultaneously with fluid resuscitation, should be considered in some cases. Duration and depth of hypotension strongly worsen outcomes in septic shock patients. However, the response of arterial pressure to volume expansion is inconstant, delayed, and transitory. In the case of profound, life-threatening hypotension, relying only on fluids to restore blood pressure may unduly prolong hypotension and organ hypoperfusion. Conversely, norepinephrine rapidly increases and better stabilizes arterial pressure. By binding venous adrenergic receptors, it transforms part of the unstressed blood volume into stressed blood volume. It increases the mean systemic filling pressure and increases the fluid-induced increase in mean systemic filling pressure, as observed in septic shock patients. This may improve end-organ perfusion, as shown by some animal studies. Two observational studies comparing early vs. later administration of norepinephrine in septic shock patients using a propensity score showed that early administration reduced the administered fluid volume and day-28 mortality. Conversely, in another propensity score-based study, norepinephrine administration within the first hour following shock diagnosis increased day-28 mortality. The only randomized controlled study that compared the early administration of norepinephrine alone to a placebo showed that the early continuous administration of norepinephrine at a fixed dose of 0.05 µg/kg/min, with norepinephrine added in open label, showed that shock control was achieved more often than in the placebo group. The choice of starting norepinephrine administration early should be adapted to the patient's condition. Logically, it should first be addressed to patients with profound hypotension, when the arterial tone is very low, as suggested by a low diastolic blood pressure (e.g. ≤ 40 mmHg), or by a high diastolic shock index (heart rate/diastolic blood pressure) (e.g. ≥ 3). Early administration of norepinephrine should also be considered in patients in whom fluid accumulation is likely to occur or in whom fluid accumulation would be particularly deleterious (in case of acute respiratory distress syndrome or intra-abdominal hypertension for example).

Doppler identified venous congestion in septic shock: protocol for an international, multi-centre prospective cohort study (Andromeda-VEXUS).

INTRODUCTION: Venous congestion is a pathophysiological state where high venous pressures cause organ oedema and dysfunction. Venous congestion is associated with worse outcomes, particularly acute kidney injury (AKI), for critically ill patients. Venous congestion can be measured by Doppler ultrasound at the bedside through interrogation of the inferior vena cava (IVC), hepatic vein (HV), portal vein (PV) and intrarenal veins (IRV). The objective of this study is to quantify the association between Doppler identified venous congestion and the need for renal replacement therapy (RRT) or death for patients with septic shock. METHODS AND ANALYSIS: This study is a prespecified substudy of the ANDROMEDA-SHOCK 2 (AS-2) randomised control trial (RCT) assessing haemodynamic resuscitation in septic shock and will enrol at least 350 patients across multiple sites. We will include adult patients within 4 hours of fulfilling septic shock definition according to Sepsis-3 consensus conference. Using Doppler ultrasound, physicians will interrogate the IVC, HV, PV and IRV 6-12 hours after randomisation. Study investigators will provide web-based educational sessions to ultrasound operators and adjudicate image acquisition and interpretation. The primary outcome will be RRT or death within 28 days of septic shock. We will assess the hazard of RRT or death as a function of venous congestion using a Cox proportional hazards model. Sub-distribution HRs will describe the hazard of RRT given the competing risk of death. ETHICS AND DISSEMINATION: We obtained ethics approval for the AS-2 RCT, including this observational substudy, from local ethics boards at all participating sites. We will report the findings of this study through open-access publication, presentation at international conferences, a coordinated dissemination strategy by investigators through social media, and an open-access workshop series in multiple languages. TRIAL REGISTRATION NUMBER: NCT05057611.

Immediate Norepinephrine in Endotoxic Shock: Effects on Regional and Microcirculatory Flow.

OBJECTIVES: To investigate the effects of immediate start of norepinephrine versus initial fluid loading followed by norepinephrine on macro hemodynamics, regional splanchnic and intestinal microcirculatory flows in endotoxic shock. DESIGN: Animal experimental study. SETTING: University translational research laboratory. SUBJECTS: Fifteen Landrace pigs. INTERVENTIONS: Shock was induced by escalating dose of lipopolysaccharide. Animals were allocated to immediate start of norepinephrine (i-NE) ( n = 6) versus mandatory 1-hour fluid loading (30 mL/kg) followed by norepinephrine (i-FL) ( n = 6). Once mean arterial pressure greater than or equal to 75 mm Hg was, respectively, achieved, successive mini-fluid boluses of 4 mL/kg of Ringer Lactate were given whenever: a) arterial lactate greater than 2.0 mmol/L or decrease less than 10% per 30 min and b) fluid responsiveness was judged to be positive. Three additional animals were used as controls (Sham) ( n = 3). Time × group interactions were evaluated by repeated-measures analysis of variance. MEASUREMENTS AND MAIN RESULTS: Hypotension was significantly shorter in i-NE group (7.5 min [5.5-22.0 min] vs 49.3 min [29.5-60.0 min]; p < 0.001). Regional mesenteric and microcirculatory flows at jejunal mucosa and serosa were significantly higher in i-NE group at 4 and 6 hours after initiation of therapy ( p = 0.011, p = 0.032, and p = 0.017, respectively). Misdistribution of intestinal microcirculatory blood flow at the onset of shock was significantly reversed in i-NE group ( p < 0.001), which agreed with dynamic changes in mesenteric-lactate levels ( p = 0.01) and venous-to-arterial carbon dioxide differences ( p = 0.001). Animals allocated to i-NE showed significantly higher global end-diastolic volumes ( p = 0.015) and required significantly less resuscitation fluids ( p < 0.001) and lower doses of norepinephrine ( p = 0.001) at the end of the experiment. Pulmonary vascular permeability and extravascular lung water indexes were significantly lower in i-NE group ( p = 0.021 and p = 0.004, respectively). CONCLUSIONS: In endotoxemic shock, immediate start of norepinephrine significantly improved regional splanchnic and intestinal microcirculatory flows when compared with mandatory fixed-dose fluid loading preceding norepinephrine. Immediate norepinephrine strategy was related with less resuscitation fluids and lower vasopressor doses at the end of the experiment.

Risk factors for developing ventilator-associated lower respiratory tract infection in patients with severe COVID-19: a multinational, multicentre study, prospective, observational study.

Around one-third of patients diagnosed with COVID-19 develop a severe illness that requires admission to the Intensive Care Unit (ICU). In clinical practice, clinicians have learned that patients admitted to the ICU due to severe COVID-19 frequently develop ventilator-associated lower respiratory tract infections (VA-LRTI). This study aims to describe the clinical characteristics, the factors associated with VA-LRTI, and its impact on clinical outcomes in patients with severe COVID-19. This was a multicentre, observational cohort study conducted in ten countries in Latin America and Europe. We included patients with confirmed rtPCR for SARS-CoV-2 requiring ICU admission and endotracheal intubation. Only patients with a microbiological and clinical diagnosis of VA-LRTI were included. Multivariate Logistic regression analyses and Random Forest were conducted to determine the risk factors for VA-LRTI and its clinical impact in patients with severe COVID-19. In our study cohort of 3287 patients, VA-LRTI was diagnosed in 28.8% [948/3287]. The cumulative incidence of ventilator-associated pneumonia (VAP) was 18.6% [610/3287], followed by ventilator-associated tracheobronchitis (VAT) 10.3% [338/3287]. A total of 1252 bacteria species were isolated. The most frequently isolated pathogens were Pseudomonas aeruginosa (21.2% [266/1252]), followed by Klebsiella pneumoniae (19.1% [239/1252]) and Staphylococcus aureus (15.5% [194/1,252]). The factors independently associated with the development of VA-LRTI were prolonged stay under invasive mechanical ventilation, AKI during ICU stay, and the number of comorbidities. Regarding the clinical impact of VA-LRTI, patients with VAP had an increased risk of hospital mortality (OR [95% CI] of 1.81 [1.40-2.34]), while VAT was not associated with increased hospital mortality (OR [95% CI] of 1.34 [0.98-1.83]). VA-LRTI, often with difficult-to-treat bacteria, is frequent in patients admitted to the ICU due to severe COVID-19 and is associated with worse clinical outcomes, including higher mortality. Identifying risk factors for VA-LRTI might allow the early patient diagnosis to improve clinical outcomes.Trial registration: This is a prospective observational study; therefore, no health care interventions were applied to participants, and trial registration is not applicable.

How to assess tissue oxygenation?

PURPOSE OF REVIEW: To discuss the different techniques used to assess tissue oxygenation in critically ill patients. RECENT FINDINGS: While historically the analysis of oxygen consumption (VO2)/oxygen delivery (DO2) relationships has provided important information, methodological limitations prevent its use at bedside. PO2 measurements, while attractive, are unfortunately of limited value in the presence of microvascular blood flow heterogeneity which is observed in many critically ill conditions including sepsis. Surrogates of tissue oxygenation are hence used. Elevated lactate levels may suggest inadequate tissue oxygenation, but other sources than tissue hypoxia can also contribute to hyperlactatemia so that lactate measurements should be used in combination with other measurements of tissue oxygenation. Venous O2 saturation can be used to evaluate the adequacy of DO2 in respect to VO2, but it can be misleading normal or even high in sepsis. Measurements of Pv-aCO2 and computation of Pv-aCO2/CavO2 are very promising as physiologically sound, easy to measure, rapidly respond to therapy, and are associated with outcome. An elevated Pv-aCO2 reflects an impaired tissue perfusion while an increased Pv-aCO2/CavO2 ratio reflects tissue dysoxia. SUMMARY: Recent studies have highlighted the interest of surrogate measurements of tissue oxygenation and in particular PCO2 gradients.

Perspectives on peripheral perfusion assessment.

PURPOSE OF REVIEW: The ANDROMEDA-SHOCK trial positioned capillary refill time (CRT) assessment as a novel resuscitation target for septic shock.The purpose of this article is to summarize pathophysiological determinants of CRT, review new technical developments on peripheral perfusion assessment, and explore recent evidence on the role of CRT monitoring in septic shock and other critical conditions. RECENT FINDINGS: A growing body of evidence supports the role of peripheral perfusion assessment as a warning and prognostic signal in a variety of clinical conditions among severely ill patients. Recent physiological studies demonstrated a rapid improvement of CRT after a single fluid bolus or a passive leg raising maneuver, a fact which may have diagnostic and therapeutic implications. Moreover, a couple of posthoc analyses of ANDROMEDA-SHOCK trial, reinforce that a normal CRT at the start of septic shock resuscitation, or its rapid normalization, thereafter may be associated with significant better outcomes. SUMMARY: Recent data confirm the relevance of peripheral perfusion assessment in septic shock and other conditions in critically ill patients. Future studies should confirm these findings, and test the potential contribution of technological devices to assess peripheral perfusion.

Hypertonic saline infusion does not improve the chance of primary fascial closure after damage control laparotomy: a randomized controlled trial.

BACKGROUND: Previous observational studies showed higher rates of abdominal wall closure with the use of hypertonic saline in trauma patients with abdominal injuries. However, no randomized controlled trials have been performed on this matter. This double-blind randomized clinical trial assessed the effect of 3% hypertonic saline (HS) solution on primary fascial closure and the timing of abdominal wall closure among patients who underwent damage control laparotomy for bleeding control. METHODS: Double-blind randomized clinical trial. Patients with abdominal injuries requiring damage control laparotomy (DCL) were randomly allocated to receive a 72-h infusion (rate: 50 mL/h) of 3% HS or 0.9 N isotonic saline (NS) after the index DCL. The primary endpoint was the proportion of patients with abdominal wall closure in the first seven days after the index DCL. RESULTS: The study was suspended in the first interim analysis because of futility. A total of 52 patients were included. Of these, 27 and 25 were randomly allocated to NS and HS, respectively. There were no significant differences in the rates of abdominal wall closure between groups (HS: 19 [79.2%] vs. NS: 17 [70.8%]; p = 0.71). In contrast, significantly higher hypernatremia rates were observed in the HS group (HS: 11 [44%] vs. NS: 1 [3.7%]; p < 0.001). CONCLUSION: This double-blind randomized clinical trial showed no benefit of HS solution in primary fascial closure rates. Patients randomized to HS had higher sodium concentrations after the first day and were more likely to present hypernatremia. We do not recommend using HS in patients undergoing damage control laparotomy. Trial registration The trial protocol was registered in clinicaltrials.gov (identifier: NCT02542241).

Prophylactic platelet transfusion and risk of bleeding associated with ultrasound-guided central venous access in patients with severe thrombocytopenia.

BACKGROUND: Reported risk of bleeding complications after central catheter access in patients with thrombocytopenia is highly variable. Current guidelines recommend routine prophylactic platelet (PLT) transfusion before central venous catheter placement in patients with severe thrombocytopenia. Nevertheless, the strength of such recommendations is weak and supported by observational studies including few patients with very low PLT counts (<20 × 109 /L). This study aims to assess the risk of bleeding complications related to using or not using prophylactic PLT transfusion before ultrasound-guided central venous access in patients with very low PLT counts. METHODS: This was a retrospective cohort study of patients with very low PLT counts (<20 × 109 /L) subjected to ultrasound-guided central venous catheterization between January 2011 and November 2019 in a university hospital. Bleeding complications were graded according to the Common Terminology Criteria for Adverse Events. A multivariate logistic regression was conducted to assess the risk of major and minor bleeding complications comparing patients who did or did not receive prophylactic PLT transfusion for the procedure. Multiple imputation by chained equations was used to handle missing data. A two-tailed p < 0.05 was considered statistically significant. RESULTS: Among 221 patients with very low PLT counts, 72 received prophylactic PLT transfusions while 149 did not. Baseline characteristics were similar between transfused and nontransfused patients. No major bleeding events were identified, while minor bleeding events were recognized in 35.7% of patients. Multivariate logistic regression analysis showed no significant differences in bleeding complications between patients who received prophylactic PLT transfusions and those who did not (odds ratio 0.83, 95% confidence interval 0.45-1.55, p = 0.567). Additional complete case and sensitivity analyses yielded results similar to those of the main analysis. CONCLUSIONS: In this single-center retrospective cohort study of ultrasound-guided central venous access in patients with very low PLT counts, no major bleeding was identified, and prophylactic PLT transfusions did not significantly decrease minor bleeding events.

Exploring the relationship between capillary refill time, skin blood flow and microcirculatory reactivity during early resuscitation of patients with septic shock: a pilot study.

Capillary refill time (CRT), a costless and widely available tool, has emerged as a promising target to guide septic shock resuscitation. However, it has yet to gain universal acceptance due to its potential inter-observer variability. Standardization of CRT assessment may minimize this problem, but few studies have compared this approach with techniques that directly assess skin blood flow (SBF). Our objective was to determine if an abnormal CRT is associated with impaired SBF and microvascular reactivity in early septic shock patients. Twelve septic shock patients were subjected to multimodal perfusion and hemodynamic monitoring for 24 h. Three time-points (0, 1, and 24 h) were registered for each patient. SBF was measured by laser doppler. We performed a baseline SBF measurement and two microvascular reactivity tests: one with a thermal challenge at 44 °C and other with a vascular occlusion test. Ten healthy volunteers were evaluated to obtain reference values. The patients (median age 70 years) exhibited a 28-day mortality of 50%. Baseline CRT was 3.3 [2.7-7.3] seconds. In pooled data analysis, abnormal CRT presented a significantly lower SBF when compared to normal CRT [44 (13.3-80.3) vs 193.2 (99.4-285) APU, p = 0.0001]. CRT was strongly associated with SBF (R2 0.76, p < 0.0001). An abnormal CRT also was associated with impaired thermal challenge and vascular occlusion tests. Abnormal CRT values observed during early septic shock resuscitation are associated with impaired skin blood flow, and abnormal skin microvascular reactivity. Future studies should confirm these results.