Systematic assessment of fluid responsiveness during early septic shock resuscitation: secondary analysis of the ANDROMEDA-SHOCK trial

BACKGROUND: Fluid boluses are administered to septic shock patients with the purpose of increasing cardiac output as a means to restore tissue perfusion. Unfortunately, fluid therapy has a narrow therapeutic index, and therefore, several approaches to increase safety have been proposed. Fluid responsiveness (FR) assessment might predict which patients will effectively increase cardiac output after a fluid bolus (FR+), thus preventing potentially harmful fluid administration in non-fluid responsive (FR-) patients. However, there are scarce data on the impact of assessing FR on major outcomes. The recent ANDROMEDA-SHOCK trial included systematic per-protocol assessment of FR. We performed a post hoc analysis of the study dataset with the aim of exploring the relationship between FR status at baseline, attainment of specific targets, and clinically relevant outcomes. METHODS: ANDROMEDA-SHOCK compared the effect of peripheral perfusion- vs. lactate-targeted resuscitation on 28-day mortality. FR was assessed before each fluid bolus and periodically thereafter. FR+ and FR- subgroups, independent of the original randomization, were compared for fluid administration, achievement of resuscitation targets, vasoactive agents use, and major outcomes such as organ dysfunction and support, length of stay, and 28-day mortality. RESULTS: FR could be determined in 348 patients at baseline. Two hundred and forty-two patients (70%) were categorized as fluid responders

A hypoperfusion context may aid to interpret hyperlactatemia in sepsis-3 septic shock patients: a proof-of-concept study

__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. __Results:__ We 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%). __Conclusions:__ Two 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

Impairment of exogenous lactate clearance in experimental hyperdynamic septic shock is not related to total liver hypoperfusion

Introduction: Although 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. Methods: After 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. Results: Significant 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). Conclusions: Endotoxemia induces an early and severe impairment in lactate clearance that is not related to total liver hypoperfusion

A lactate-targeted resuscitation strategy may be associated with higher mortality in patients with septic shock and normal capillary refill time: a post hoc analysis of the ANDROMEDA-SHOCK study

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

Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients

The aims of this study are to determine the general relationship of perfused vessel density (PVD) to mortality and organ dysfunctions and to explore if patients in the lowest quartile of distribution for this parameter present a higher risk of bad outcome and to identify systemic hemodynamic and perfusion variables that enhances the probability of finding a severe underlying microvascular dysfunction. This is a retrospective multicenter study including 122 septic shock patients participating in 7 prospective clinical trials on which at least 1 sublingual microcirculatory assessment was performed during early resuscitation. Perfused vessel density was significantly related to organ dysfunctions and mortality, but this effect was largely explained by patients in the lowest quartile of distribution for PVD (P = .037 [odds ratio {OR}, 8.7; 95% confidence interval {CI}, 1.14-66.78] for mortality). Hyperlactatemia (P < .026 [OR, 1.23; 95% CI, 1.03-1.47]) and high norepinephrine requirements (P < .019 [OR, 7.04; 95% CI, 1.38-35.89]) increased the odds of finding a severe microvascular dysfunction. Perfused vessel density is significantly related to organ dysfunctions and mortality in septic shock patients, particularly in patients exhibiting more severe abnormalities as represented by the lowest quartile of distribution for this parameter. The presence of hyperlactatemia and high norepinephrine requirements increases the odds of finding a severe underlying microvascular dysfunction during a sublingual microcirculatory assessmen

When to stop septic shock resuscitation: clues from a dynamic perfusion monitoring

Methods: We designed a prospective, observational clinical study. One hundred and four septic shock patients with hyperlactatemia were included and followed until hospital discharge. The 84 hospital-survivors were kept for final analysis. A multimodal perfusion assessment was performed at baseline, 2, 6, and 24 h of ICU treatment.Results: Some variables such as central venous oxygen saturation, central venous-arterial pCO2 gradient, and capillary refill time were already normal in more than 70% of survivors at 6 h. La

Development and validation of a prediction model for early diagnosis of SCN1A-related epilepsies

Background and Objectives: Pathogenic variants in the neuronal sodium-channel α1-subunit gene (SCN1A) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum including the severe childhood epilepsy, Dravet syndrome, characterized by drug-resistant seizures, intellectual disability and high mortality, and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome versus GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of SCN1A-related epilepsies. Methods: Retrospective multicenter cohort study comprising data from SCN1A-positive Dravet syndrome and GEFS+ patients consecutively referred for genetic testing (March 2001-June 2020) including age of seizure onset and a newly-developed SCN1A genetic score. A training cohort was used to develop multiple prediction models that were validated using two independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome versus other GEFS+ phenotypes. Results: 1018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1 and 60/72 (83%) in validation cohort 2. A high SCN1A genetic score 133.4 (SD, 78.5) versus 52.0 (SD, 57.5; p &lt; 0.001) and young age of onset 6.0 (SD, 3.0) months versus 14.8 (SD, 11.8; p &lt; 0.001) months, were each associated with Dravet syndrome versus GEFS+. A combined 'SCN1A genetic score and seizure onset' model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC], 0.89 [95% CI, 0.86-0.92]) and outperformed all other models (AUC, 0.79-0.85; p &lt; 0.001). Model performance was replicated in both validation cohorts 1 (AUC, 0.94 [95% CI, 0.91-0.97]) and 2 (AUC, 0.92 [95% CI, 0.82-1.00]). Discussion: The prediction model allows objective estimation at disease onset whether a child will develop Dravet syndrome versus GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (http://scn1a-prediction-model.broadinstitute.org/). Classification of Evidence: This study provides Class II evidence that a combined 'SCN1A genetic score and seizure onset' model distinguishes Dravet syndrome from other GEFS+ phenotypes

Current practice and evolving concepts in septic shock resuscitation

International audienceClinical and pathophysiological understanding of septic shock has progressed exponentially in the previous decades, translating into a steady decrease in septic shock-related morbidity and mortality. Even though large randomized, controlled trials have addressed fundamental aspects of septic shock resuscitation, many questions still exist. In this review, we will describe the current standards of septic shock resuscitation, but the emphasis will be placed on evolving concepts in different domains such as clinical resuscitation targets, adequate use of fluids and vasoactive drugs, refractory shock, and the use of extracorporeal therapies. Multiple research opportunities remain open, and collaborative endeavors should be performed to fill in these gaps

Consensus and Diversity in the Management of Varicocele for Male Infertility: Results of a Global Practice Survey and Comparison with Guidelines and Recommendations

Varicocele is a common problem among infertile men. Varicocele repair (VR) is frequently performed to improve semen parameters and the chances of pregnancy. However, there is a lack of consensus about the diagnosis, indications for VR and its outcomes. The aim of this study was to explore global practice patterns on the management of varicocele in the context of male infertility