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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.

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OBJECTIVE: To identify the first symptoms and signs of patients with suspected infection or sepsis and their association with the composite outcome of admission to the Intensive Care Unit (ICU) or mortality. DESIGN: Prospective cohort study between June 2019 and March 2020. SETTING: Hospital Universitario San Vicente Fundación, Colombia. PATIENTS: Over 18 years of age with suspicion or confirmation of sepsis, which required hospitalization. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Symptoms and signs associated with infection, with their time of evolution, specified in the study. RESULTS: From 1005 eligible patients, 261 were included. After multivariable adjustment with a logistic regression model, the main factors for ICU admission or mortality were heart rate (OR 1.04 with 95% CI 1.04-3.7), respiratory rate (OR 1.19 with 95% CI 1.0-1.4) and capillary refill time (OR 3.4 with 95% CI 1.9-6.1). CONCLUSIONS: Heart rate, respiratory rate, and capillary refill may behave as early predictors of ICU admission and mortality in cases of sepsis.

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Capillary Refill Time (CRT) assesses peripheral perfusion in resource-limited settings. However, the repeatability and reproducibility of CRT measurements are limited for individuals with darker skin. This paper presents quantitative CRT measurements demonstrating good performance and repeatability across all Fitzpatrick skin phototypes. The study involved 22 volunteers and utilized controlled compression at 7 kPa, an RGB video camera, and cocircular polarized white LED light. CRT was determined by calculating the time constant of an exponential regression applied to the mean pixel intensity of the green (G) channel. An adaptive algorithm identifies the optimal regression region for noise reduction, and flags inappropriate readings. The results indicate that 80% of the CRT readings fell within a 20% range of the expected CRT value. The repetition standard deviation was 17%. These findings suggest the potential for developing reliable and reproducible quantitative CRT methods for robust measurements in patient triage, monitoring, and telehealth applications.

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Multiple tissue perfusion markers are described to guide therapy in critically ill pediatric patients undergoing congenital heart surgery. Given the advantages of capillary refill time, our goal is to determine its predictive capacity for mortality and postoperative extracorporeal oxygenation requirements in congenital heart surgery and compare it to serum lactate. We conducted a prospective cohort observational study in a single high-complexity university hospital. Serum lactate and capillary refill time were measured at five predetermined time points: preoperative, immediate postoperative, 6, 12, and 24 h after the surgery. Prolonged immediate postoperative, 6 h, and 12 h capillary refill time measurements turned out to be independent risk factors for both outcomes. The capillary refill time area under the curve ranged between 0.70 and 0.80, while the serum lactate resulted between 0.79 and 0.92 for both outcomes. Both tissue perfusion markers resulted in mortality and extracorporeal oxygenation requirement predictors. Given the advantages of capillary refill time over serum lactate, a monitoring strategy including these two perfusion markers should be considered for congenital heart surgeries.

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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.

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RESUMO Introdução: A reversão precoce da hipoperfusão tecidual induzida é essencial para a sobrevida no choque séptico. No entanto, falta consenso sobre a melhor estratégia de ressuscitação inicial, uma vez que intervenções destinadas a toda a população com choque séptico podem produzir administração desnecessária de líquidos. Este artigo relata a justificativa, o delineamento e o plano de análise do estudo ANDROMEDA-2, que visa determinar se uma estratégia guiada por perfusão periférica, que consiste na ressuscitação guiada pelo tempo de enchimento capilar com base em fenótipos clínicos e hemodinâmicos, está associada a uma diminuição no desfecho composto de mortalidade, tempo até a interrupção ao suporte de órgãos e tempo de internação em comparação com o atendimento padrão em pacientes com choque séptico precoce (< 4 horas do diagnóstico). Metódos: O estudo ANDROMEDA-2 é um ensaio clínico randomizado controlado multinacional e multicêntrico. No grupo de intervenção, o tempo de enchimento capilar será medido a cada hora, durante 6 horas. Se estiver anormal, os pacientes serão alocados em um algoritmo, começando com a avaliação da pressão de pulso. Pacientes com pressão de pulso inferior a 40mmHg serão testados quanto à capacidade de resposta a líquidos e receberão líquidos de acordo. Em pacientes com pressão de pulso > 40mmHg, norepinefrina será titulada para manter a pressão arterial diastólica > 50mmHg. Os pacientes que não normalizarem o tempo de enchimento capilar após as etapas anteriores serão submetidos à ecocardiografia de cuidados intensivos para avaliação da disfunção cardíaca e posterior manejo. Por fim, serão realizados testes com vasopressores e inodilatadores para otimizar ainda mais a perfusão. Um tamanho de amostra de 1.500 pacientes fornecerá 88% de poder para demonstrar a superioridade da estratégia direcionada ao tempo de enchimento capilar. Conclusão: Se for demonstrado que o direcionamento ao tempo de enchimento capilar é uma estratégia melhor, os processos de atendimento na ressuscitação do choque séptico podem ser otimizados com ferramentas usadas à beira do leito.

ABSTRACT Background: Early reversion of sepsis-induced tissue hypoperfusion is essential for survival in septic shock. However, consensus regarding the best initial resuscitation strategy is lacking given that interventions designed for the entire population with septic shock might produce unnecessary fluid administration. This article reports the rationale, study design and analysis plan of the ANDROMEDA-2 study, which aims to determine whether a peripheral perfusion-guided strategy consisting of capillary refill time-targeted resuscitation based on clinical and hemodynamic phenotypes is associated with a decrease in a composite outcome of mortality, time to organ support cessation, and hospital length of stay compared to standard care in patients with early (< 4 hours of diagnosis) septic shock. Methods: The ANDROMEDA-2 study is a multicenter, multinational randomized controlled trial. In the intervention group, capillary refill time will be measured hourly for 6 hours. If abnormal, patients will enter an algorithm starting with pulse pressure assessment. Patients with pulse pressure less than 40mmHg will be tested for fluid responsiveness and receive fluids accordingly. In patients with pulse pressure > 40mmHg, norepinephrine will be titrated to maintain diastolic arterial pressure > 50mmHg. Patients who fail to normalize capillary refill time after the previous steps will be subjected to critical care echocardiography for cardiac dysfunction evaluation and subsequent management. Finally, vasopressor and inodilator tests will be performed to further optimize perfusion. A sample size of 1,500 patients will provide 88% power to demonstrate superiority of the capillary refill time-targeted strategy. Conclusions: If hemodynamic phenotype-based, capillary refill time-targeted resuscitation demonstrates to be a superior strategy, care processes in septic shock resuscitation can be optimized with bedside tools.

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Septic shock leads to progressive hypoperfusion and tissue hypoxia. Unfortunately, numerous uncertainties exist around the best monitoring strategy, as available techniques are mere surrogates for these phenomena. Nevertheless, central venous oxygen saturation (ScvO2), venous-to-arterial CO2 gap, and lactate normalization have been fostered as resuscitation targets for septic shock. Moreover, recent evidence has challenged the central role of lactate. Following the ANDROMEDA-SHOCK trial, capillary refill time (CRT) has become a promissory target, considering the observed benefits in mortality, treatment intensity, and organ dysfunction. Interpretation of CRT within a multimodal approach may aid clinicians in guiding resuscitative interventions and stop resuscitation earlier, thus avoiding the risk of morbid fluid overload. Integrative assessment of a patient's perfusion status can be easily performed using bedside clinical tools. Based on its fast kinetics and recent supporting evidence, targeting CRT (within a holistic assessment of perfusion) may improve outcomes in septic shock resuscitation.

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PURPOSE: To assess the presence of sublingual microcirculatory and skin perfusion alterations in COVID-19 pneumonia. MATERIALS AND METHODS: This is a preliminary report of a prospective observational study performed in four teaching intensive care units. We studied 27 mechanically ventilated patients with acute respiratory distress syndrome secondary to COVID-19. Sublingual microcirculation was assessed by hand-held videomicroscopy. A software-assisted analysis of videos was performed. We also measured capillary refill time. RESULTS: Patients were hemodynamically stable with normal lactate (1.8 [1.6-2.5] mmol/L) and high D-dimer (1.30 [0.58-2.93] µg/mL). Capillary refill time was prolonged (3.5 [3.0-5.0] s). Compared to previously reported normal values, total and perfused vascular density (21.9 ± 3.9 and 21.0 ± 3.5 mm/mm2) and heterogeneity flow index (0.91 ± 0.24) were high; and the proportion of perfused vessels (0.96 ± 0.03), microvascular flow index (2.79 ± 0.10), and red blood cell velocity (1124 ± 161 µm/s) were reduced. The proportion of perfused vessels was inversely correlated with total vascular density (Pearson r = -0.41, P = 0.03). CONCLUSIONS: COVID-19 patients showed an altered tissue perfusion. Sublingual microcirculation was characterized by decreases in the proportion of perfused vessel and flow velocity along with high vascular densities. This last finding might be related to enhanced angiogenesis or hypoxia-induced capillary recruitment.

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BACKGROUND: Persistent hyperlactatemia has been considered as a signal of tissue hypoperfusion in septic shock patients, but multiple non-hypoperfusion-related pathogenic mechanisms could be involved. Therefore, pursuing lactate normalization may lead to the risk of fluid overload. Peripheral perfusion, assessed by the capillary refill time (CRT), could be an effective alternative resuscitation target as recently demonstrated by the ANDROMEDA-SHOCK trial. We designed the present randomized controlled trial to address the impact of a CRT-targeted (CRT-T) vs. a lactate-targeted (LAC-T) fluid resuscitation strategy on fluid balances within 24 h of septic shock diagnosis. In addition, we compared the effects of both strategies on organ dysfunction, regional and microcirculatory flow, and tissue hypoxia surrogates. RESULTS: Forty-two fluid-responsive septic shock patients were randomized into CRT-T or LAC-T groups. Fluids were administered until target achievement during the 6 h intervention period, or until safety criteria were met. CRT-T was aimed at CRT normalization (≤ 3 s), whereas in LAC-T the goal was lactate normalization (≤ 2 mmol/L) or a 20% decrease every 2 h. Multimodal perfusion monitoring included sublingual microcirculatory assessment; plasma-disappearance rate of indocyanine green; muscle oxygen saturation; central venous-arterial pCO2 gradient/ arterial-venous O2 content difference ratio; and lactate/pyruvate ratio. There was no difference between CRT-T vs. LAC-T in 6 h-fluid boluses (875 [375-2625] vs. 1500 [1000-2000], p = 0.3), or balances (982[249-2833] vs. 15,800 [740-6587, p = 0.2]). CRT-T was associated with a higher achievement of the predefined perfusion target (62 vs. 24, p = 0.03). No significant differences in perfusion-related variables or hypoxia surrogates were observed. CONCLUSIONS: CRT-targeted fluid resuscitation was not superior to a lactate-targeted one on fluid administration or balances. However, it was associated with comparable effects on regional and microcirculatory flow parameters and hypoxia surrogates, and a faster achievement of the predefined resuscitation target. Our data suggest that stopping fluids in patients with CRT ≤ 3 s appears as safe in terms of tissue perfusion. Clinical Trials: ClinicalTrials.gov Identifier: NCT03762005 (Retrospectively registered on December 3rd 2018).

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