IMPORTANCE Abnormal peripheral perfusion after septic shock resuscitation has been associated with organ dysfunction and mortality. The potential role of the clinical assessment of peripheral perfusion as a target during resuscitation in early septic shock has not been established. OBJECTIVE To determine if a peripheral perfusion-targeted resuscitation during early septic shock in adults is more effective than a lactate level-targeted resuscitation for reducing mortality. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized trial conducted at 28 intensive care units in 5 countries. Four-hundred twenty-four patients with septic shock were included between March 2017 and March 2018. The last date of follow-up was June 12, 2018. INTERVENTIONS Patients were randomized to a step-by-step resuscitation protocol aimed at either normalizing capillary refill time (n = 212) or normalizing or decreasing lactate levels at rates greater than 20% per 2 hours (n = 212), during an 8-hour intervention period. MAIN OUTCOMES AND MEASURES The primary outcome was all-cause mortality at 28 days. Secondary outcomes were organ dysfunction at 72 hours after randomization, as assessed by Sequential Organ Failure Assessment (SOFA) score (range, 0 [best] to 24 [worst]); death within 90 days; mechanical ventilation-, renal replacement therapy-, and vasopressor-free days within 28 days; intensive care unit and hospital length of stay. RESULTS Among 424 patients randomized (mean age, 63 years; 226 [53%] women), 416 (98%) completed the trial. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06; risk difference, −8.5% [95% CI, −18.2% to 1.2%]). Peripheral perfusion-targeted resuscitation was associated with less organ dysfunction at 72 hours (mean SOFA score, 5.6 [SD, 4.3] vs 6.6 [SD, 4.7]; mean difference, −1.00 [95% CI, −1.97 to −0.02]; P = .045). There were no significant differences in the other 6 secondary outcomes. No protocol-related serious adverse reactions were confirmed. CONCLUSIONS AND RELEVANCE Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting serum lactate levels, did not reduce all-cause 28-day mortality.

In an ARDS model supported with ECMO, near-apneic ventilation decreased histologic lung injury and matrix-metalloproteinase activity, and prevented the expression of myofibroblast markers.

BackgroundSeptic shock is a highly lethal condition. Early recognition of tissue hypoperfusion and its reversion are key factors for limiting progression to multiple organ dysfunction and death. Lactate-targeted resuscitation is the gold-standard under current guidelines, although it has several pitfalls including that non-hypoxic sources of lactate might predominate in an unknown proportion of patients. Peripheral perfusion-targeted resuscitation might provide a real-time response to increases in flow that could lead to a more timely decision to stop resuscitation, thus avoiding fluid overload and the risks of over-resuscitation. This article reports the rationale, study design and analysis plan of the ANDROMEDA-SHOCK Study.MethodsANDROMEDA-SHOCK is a randomized controlled trial which aims to determine if a peripheral perfusion-targeted resuscitation is associated with lower 28-day mortality compared to a lactate-targeted resuscitation in patients with septic shock with less than 4 h of diagnosis. Both groups will be treated with the same sequential approach during the 8-hour study period pursuing normalization of capillary refill time versus normalization or a decrease of more than 20% of lactate every 2 h. The common protocol starts with fluid responsiveness assessment and fluid loading in responders, followed by a vasopressor and an inodilator test if necessary. The primary outcome is 28-day mortality, and the secondary outcomes are: free days of mechanical ventilation, renal replacement therapy and vasopressor support during the first 28 days after randomization; multiple organ dysfunction during the first 72 h after randomization; intensive care unit and hospital lengths of stay; and all-cause mortality at 90-day. A sample size of 422 patients was calculated to detect a 15% absolute reduction in mortality in the peripheral perfusion group with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle.ConclusionsIf peripheral perfusion-targeted resuscitation improves 28-day mortality, this could lead to simplified algorithms, assessing almost in real-time the reperfusion process, and pursuing more physiologically sound objectives. At the end, it might prevent the risk of over-resuscitation and lead to a better utilization of intensive care unit resources.Trial registration ClinicalTrials.gov Identifier: NCT03078712 (registered retrospectively March 13th, 2017)

Background Persistent hyperlactatemia is particularly difficult to interpret in septic shock. Besides hypoperfusion, adrenergic-driven lactate production and impaired lactate clearance are important contributors. However, clinical recognition of different sources of hyperlactatemia is unfortunately not a common practice and patients are treated with the same strategy despite the risk of over-resuscitation in some. Indeed, pursuing additional resuscitation in non-hypoperfusion-related cases might lead to the toxicity of fluid overload and vasoactive drugs. We hypothesized that two different clinical patterns can be recognized in septic shock patients through a multimodal perfusion monitoring. Hyperlactatemic patients with a hypoperfusion context probably represent a more severe acute circulatory dysfunction, and the absence of a hypoperfusion context is eventually associated with a good outcome. We performed a retrospective analysis of a database of septic shock patients with persistent hyperlactatemia after initial resuscitation.ResultsWe defined hypoperfusion context by the presence of a ScvO2 < 70%, or a P(cv-a)CO2 ≥6 mmHg, or a CRT ≥4 s together with hyperlactatemia. Ninety patients were included, of whom seventy exhibited a hypoperfusion-related pattern and 20 did not. Although lactate values were comparable at baseline (4.8 ± 2.8 vs. 4.7 ± 3.7 mmol/L), patients with a hypoperfusion context exhibited a more severe circulatory dysfunction with higher vasopressor requirements, and a trend to longer mechanical ventilation days, ICU stay, and more rescue therapies. Only one of the 20 hyperlactatemic patients without a hypoperfusion context died (5%) compared to 11 of the 70 with hypoperfusion-related hyperlactatemia (16%).ConclusionsTwo different clinical patterns among hyperlactatemic septic shock patients may be identified according to hypoperfusion context. Patients with hyperlactatemia plus low ScvO2, or high P(cv-a)CO2, or high CRT values exhibited a more severe circulatory dysfunction. This provides a starting point to launch further prospective studies to confirm if this approach can lead to a more selective resuscitation strategy. Electronic supplementary materialThe online version of this article (doi:10.1186/s13613-017-0253-x) contains supplementary material, which is available to authorized users.

IntroductionAlthough the prognostic value of persistent hyperlactatemia in septic shock is unequivocal, its physiological determinants are controversial. Particularly, the role of impaired hepatic clearance has been underestimated and is only considered relevant in patients with liver ischemia or cirrhosis. Our objectives were to establish whether endotoxemia impairs whole body net lactate clearance, and to explore a potential role for total liver hypoperfusion during the early phase of septic shock.MethodsAfter anesthesia, 12 sheep were subjected to hemodynamic/perfusion monitoring including hepatic and portal catheterization, and a hepatic ultrasound flow probe. After stabilization (point A), sheep were alternatively assigned to lipopolysaccharide (LPS) (5 mcg/kg bolus followed by 4 mcg/kg/h) or sham for a three-hour study period. After 60 minutes of shock, animals were fluid resuscitated to normalize mean arterial pressure. Repeated series of measurements were performed immediately after fluid resuscitation (point B), and one (point C) and two hours later (point D). Monitoring included systemic and regional hemodynamics, blood gases and lactate measurements, and ex-vivo hepatic mitochondrial respiration at point D. Parallel exogenous lactate and sorbitol clearances were performed at points B and D. Both groups included an intravenous bolus followed by serial blood sampling to draw a curve using the least squares method.ResultsSignificant hyperlactatemia was already present in LPS as compared to sham animals at point B (4.7 (3.1 to 6.7) versus 1.8 (1.5 to 3.7) mmol/L), increasing to 10.2 (7.8 to 12.3) mmol/L at point D. A significant increase in portal and hepatic lactate levels in LPS animals was also observed. No within-group difference in hepatic DO2, VO2 or O2 extraction, total hepatic blood flow (point D: 915 (773 to 1,046) versus 655 (593 to 1,175) ml/min), mitochondrial respiration, liver enzymes or sorbitol clearance was found. However, there was a highly significant decrease in lactate clearance in LPS animals (point B: 46 (30 to 180) versus 1,212 (743 to 2,116) ml/min, P <0.01; point D: 113 (65 to 322) versus 944 (363 to 1,235) ml/min, P <0.01).ConclusionsEndotoxemia induces an early and severe impairment in lactate clearance that is not related to total liver hypoperfusion.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-015-0928-3) contains supplementary material, which is available to authorized users.

This multinational study shows major concerns in the delivery of critical care across Latin America, particularly in human resources. Technology was suboptimal, especially in public hospitals. A 24/7 availability of supporting specialists and of key procedures was inadequate. Mortality was high in comparison to high-income countries.

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)

BackgroundPersistent hyperlactatemia during septic shock is multifactorial. Hypoperfusion-related anaerobic production and adrenergic-driven aerobic generation together with impaired lactate clearance have been implicated. An excessive adrenergic response could contribute to persistent hyperlactatemia and adrenergic modulation might be beneficial. We assessed the effects of dexmedetomidine and esmolol on hemodynamics, lactate generation, and exogenous lactate clearance during endotoxin-induced septic shock.MethodsEighteen anesthetized and mechanically ventilated sheep were subjected to a multimodal hemodynamic/perfusion assessment including hepatic and portal vein catheterizations, total hepatic blood flow, and muscle microdialysis. After monitoring, all received a bolus and continuous infusion of endotoxin. After 1 h they were volume resuscitated, and then randomized to endotoxin-control, endotoxin-dexmedetomidine (sequential doses of 0.5 and 1.0 μg/k/h) or endotoxin-esmolol (titrated to decrease basal heart rate by 20 %) groups. Samples were taken at four time points, and exogenous lactate clearance using an intravenous administration of sodium L-lactate (1 mmol/kg) was performed at the end of the experiments.ResultsDexmedetomidine and esmolol were hemodynamically well tolerated. The dexmedetomidine group exhibited lower epinephrine levels, but no difference in muscle lactate. Despite progressive hypotension in all groups, both dexmedetomidine and esmolol were associated with lower arterial and portal vein lactate levels. Exogenous lactate clearance was significantly higher in the dexmedetomidine and esmolol groups.ConclusionsDexmedetomidine and esmolol were associated with lower arterial and portal lactate levels, and less impairment of exogenous lactate clearance in a model of septic shock. The use of dexmedetomidine and esmolol appears to be associated with beneficial effects on gut lactate generation and lactate clearance and exhibits no negative impact on systemic hemodynamics.