Pending Publication

Background Microcirculatory dysfunction may persist despite restoration of conventional macrocirculatory targets in sepsis, reflecting loss of hemodynamic coherence. This review synthesizes current microcirculatory monitoring approaches according to the physiological information they provide and examines how complementary modalities may be integrated to characterize persistent or regional tissue hypoperfusion. Main body A narrative review of PubMed-indexed literature was conducted, with emphasis on bedside peripheral perfusion assessment, tissue oxygenation and superficial perfusion imaging, direct microvascular visualization, and organ- or tissue-specific monitoring. Recent studies were prioritized together with landmark methodological and validation studies. Available techniques interrogate distinct but overlapping components of the circulation. Bedside peripheral measures provide rapid information on skin reperfusion and vascular tone; spectroscopic and optical techniques characterize tissue oxygenation, reactivity, and spatial perfusion heterogeneity; direct microvascular imaging enables assessment of microvascular density and flow; and organ-specific approaches provide information on renal, cerebral, or retinal perfusion and oxygenation. Discordance between these domains may persist despite improvement in blood pressure or cardiac output, supporting serial multimodal rather than single-variable interpretation. However, substantial heterogeneity in acquisition protocols, measurement sites, devices, analytical methods, and proposed thresholds limits comparability and clinical implementation. Conclusion Microcirculatory monitoring should currently be viewed as a complementary framework for identifying persistent or heterogeneous tissue hypoperfusion beyond conventional macrocirculatory targets. Its integration into individualized resuscitation remains promising but requires standardized methodology, external validation, and prospective interventional evidence before any single modality or multimodal strategy can be adopted as a validated resuscitation endpoint.

Pending Publication

Norepinephrine is the first-line vasopressor in septic shock, yet prolonged catecholamine exposure is associated with adverse effects that have prompted growing interest in catecholamine-sparing strategies. This review highlights current evidence on the rationale for catecholamine use, the burden of sustained adrenergic exposure, and current and emerging sparing strategies. Early norepinephrine initiation, including via peripheral access, shortens hypotension duration and reduces fluid requirements. However, catecholamine exposure can carry dose-dependent cardiac, metabolic, and immunological consequences. Perfusion-guided strategies, including individualization of blood pressure targets and titration of vasopressor use based on capillary refill time, represent the cornerstone of reduction of catecholamines. Among alternative non-adrenergic vasopressors, vasopressin reduces catecholamine exposure and the risk of atrial fibrillation, with potential renal benefits. Angiotensin II represents an option in catecholamine-refractory shock, with post-hoc evidence suggesting benefit in patients with acute kidney injury or elevated renin concentrations. Inhibition of circulating dipeptidyl peptidase 3, which degrades angiotensin II, is an emerging therapeutic strategy. Corticosteroids restore vasopressor sensitivity and accelerate catecholamine weaning. Short-acting β1-blockers have shown hemodynamic promise but inconsistent outcomes, underscoring the need for better patient selection. Methylene blue, targeting the vasodilatory nitric oxide pathway, represents another strategy. Finally, emerging immunomodulatory approaches, including extracellular histone neutralization and polymyxin B hemoperfusion in endotoxin phenotypes, aim to attenuate the dysregulated host response driving vasopressor dependency. A personalized and multimodal approach, including perfusion-guided targets, non-adrenergic vasopressors, and phenotype-based patient selection, represents the most promising strategy to reduce potential consequences of adrenergic burden while maintaining tissue perfusion.

Background To support hemodynamic management in vasoplegic shock, we previously developed a closed-loop automated infusion system of norepinephrine (NE) and fluid to automatically restore arterial pressure (AP) and cardiac output (CO). To enhance the practical feasibility and efficacy of the system, we integrated a minimally invasive CO monitor and a closed-loop control of vasopressin (AVP) infusion to the system and validated the integrated system in dogs with endotoxin-induced shock. Methods Based on the circulatory equilibrium framework, the system directly controls systemic vascular resistance and stressed blood volume by titrating NE and Ringer’s acetate solution (RiA), respectively, thereby restoring AP and CO. AVP is automatically initiated once infusion rate of NE is increased higher than 1 μg·kg⁻1·min⁻1. The minimally invasive CO monitor estimates CO (COes) by a machine-learning analysis of the peripheral AP contour. In eight anesthetized dogs, the system was implemented, and reference CO (COref) was measured using an aortic flow probe to calibrate COes and track reference hemodynamics. Endotoxin shock was induced via intravenous lipopolysaccharide infusions. After the target AP and COes were set to 70 mmHg and 132 (132–133) mL·min−1·kg−1, respectively, the system was activated. Results The lipopolysaccharide infusion significantly reduced AP from 82 (80–85) to 52 (50–56) mmHg and COref from 132 (125–146) to 90 (80–103) mL·min−1·kg−1, and increased the blood lactate level (LAC) from 21 (21–23) to 36 (32–38) mg·dL−1. Once the system was activated, infusions of NE and RiA were automatically initiated. Infusion of AVP initiated during the system control was associated with significant reduction in NE dose while maintaining AP. Within 5 min after system activation, AP and COes were recovered to >65 mmHg and >122 (122–123) ml·min−1·kg−1, respectively. The median absolute performance errors for AP and COes were <5%. At 60 min after system activation, AP and COref significantly increased to 72 (68–75) mmHg and 130 (127–137) ml·min−1·kg−1 and LAC significantly decreased to 26 (25–28) mg·dL−1 relative to the values observed at endotoxin shock. COes tracked directional changes in COref reasonably well. Conclusions This proof-of-concept study validates the feasibility and physiological performance of the system for the hemodynamic management of vasoplegic shock.

Background To support hemodynamic management in vasoplegic shock, we previously developed a closed-loop automated infusion system of norepinephrine (NE) and fluid to automatically restore arterial pressure (AP) and cardiac output (CO). To enhance the practical feasibility and efficacy of the system, we integrated a minimally invasive CO monitor and a closed-loop control of vasopressin (AVP) infusion to the system and validated the integrated system in dogs with endotoxin-induced shock. Methods Based on the circulatory equilibrium framework, the system directly controls systemic vascular resistance and stressed blood volume by titrating NE and Ringer’s acetate solution (RiA), respectively, thereby restoring AP and CO. AVP is automatically initiated once infusion rate of NE is increased higher than 1 μg·kg⁻1·min⁻1. The minimally invasive CO monitor estimates CO (COes) by a machine-learning analysis of the peripheral AP contour. In eight anesthetized dogs, the system was implemented, and reference CO (COref) was measured using an aortic flow probe to calibrate COes and track reference hemodynamics. Endotoxin shock was induced via intravenous lipopolysaccharide infusions. After the target AP and COes were set to 70 mmHg and 132 (132–133) mL·min−1·kg−1, respectively, the system was activated. Results The lipopolysaccharide infusion significantly reduced AP from 82 (80–85) to 52 (50–56) mmHg and COref from 132 (125–146) to 90 (80–103) mL·min−1·kg−1, and increased the blood lactate level (LAC) from 21 (21–23) to 36 (32–38) mg·dL−1. Once the system was activated, infusions of NE and RiA were automatically initiated. Infusion of AVP initiated during the system control was associated with significant reduction in NE dose while maintaining AP. Within 5 min after system activation, AP and COes were recovered to >65 mmHg and >122 (122–123) ml·min−1·kg−1, respectively. The median absolute performance errors for AP and COes were <5%. At 60 min after system activation, AP and COref significantly increased to 72 (68–75) mmHg and 130 (127–137) ml·min−1·kg−1 and LAC significantly decreased to 26 (25–28) mg·dL−1 relative to the values observed at endotoxin shock. COes tracked directional changes in COref reasonably well. Conclusions This proof-of-concept study validates the feasibility and physiological performance of the system for the hemodynamic management of vasoplegic shock.

Norepinephrine is the first-line vasopressor in septic shock, yet prolonged catecholamine exposure is associated with adverse effects that have prompted growing interest in catecholamine-sparing strategies. This review highlights current evidence on the rationale for catecholamine use, the burden of sustained adrenergic exposure, and current and emerging sparing strategies. Early norepinephrine initiation, including via peripheral access, shortens hypotension duration and reduces fluid requirements. However, catecholamine exposure can carry dose-dependent cardiac, metabolic, and immunological consequences. Perfusion-guided strategies, including individualization of blood pressure targets and titration of vasopressor use based on capillary refill time, represent the cornerstone of reduction of catecholamines. Among alternative non-adrenergic vasopressors, vasopressin reduces catecholamine exposure and the risk of atrial fibrillation, with potential renal benefits. Angiotensin II represents an option in catecholamine-refractory shock, with post-hoc evidence suggesting benefit in patients with acute kidney injury or elevated renin concentrations. Inhibition of circulating dipeptidyl peptidase 3, which degrades angiotensin II, is an emerging therapeutic strategy. Corticosteroids restore vasopressor sensitivity and accelerate catecholamine weaning. Short-acting β1-blockers have shown hemodynamic promise but inconsistent outcomes, underscoring the need for better patient selection. Methylene blue, targeting the vasodilatory nitric oxide pathway, represents another strategy. Finally, emerging immunomodulatory approaches, including extracellular histone neutralization and polymyxin B hemoperfusion in endotoxin phenotypes, aim to attenuate the dysregulated host response driving vasopressor dependency. A personalized and multimodal approach, including perfusion-guided targets, non-adrenergic vasopressors, and phenotype-based patient selection, represents the most promising strategy to reduce potential consequences of adrenergic burden while maintaining tissue perfusion.

Background Current recommendations for intraoperative blood pressure management suggest maintaining mean arterial pressure (MAP) at ≥ 60–65 mmHg to avoid hypotension. However, controversy remains regarding whether higher or individualized MAP targets improve clinically important outcomes in surgical patients. We aimed to determine whether intensive intraoperative blood pressure management, defined as higher fixed or individualized MAP targets, reduces major postoperative morbidity compared with standard management (MAP ≥ 60–65 mmHg). Methods We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science for randomized controlled trials (RCTs) comparing intensive and standard intraoperative blood pressure management in adults undergoing noncardiac surgery. The primary outcomes were postoperative myocardial injury, postoperative delirium (POD), and acute kidney injury (AKI). Secondary outcomes included postoperative mortality, stroke, heart failure, acute respiratory distress syndrome (ARDS), pneumonia, intensive care unit (ICU) admission, surgical site infection (SSI), and hospital length of stay (LOS). Data were pooled using a random-effects model with the Hartung–Knapp adjustment. Risk ratios (RR) were calculated for dichotomous outcomes, and mean differences (MD) were calculated for continuous outcomes. Trial sequential analysis (TSA) was performed to control for random error and assess the conclusiveness of the available evidence. Results Eighteen RCTs involving 16,573 patients were included. Compared with standard management, intensive management was associated with lower risks of POD (10 studies; RR = 0.72, 95% CI [0.55, 0.93]; P = 0.019; moderate-certainty evidence) and SSI (5 studies; RR = 0.64, 95% CI [0.53, 0.76]; P = 0.002; moderate-certainty evidence). However, no significant between-group differences were observed in postoperative myocardial injury (9 studies; RR = 1.02, 95% CI [0.92, 1.13]), AKI (13 studies; RR = 0.92, 95% CI [0.79, 1.06]), or mortality (13 studies; RR = 0.99, 95% CI [0.83, 1.17]). TSA supported a beneficial effect of intensive management on POD, and indicated that a clinically meaningful benefit of the prespecified magnitude was unlikely for myocardial injury and AKI. No significant between-group differences were observed in postoperative stroke, pneumonia, heart failure, ICU admission, or hospital LOS. Conclusions In this systematic review and meta-analysis, intensive intraoperative blood pressure management may reduce the risks of POD and SSI in adults undergoing noncardiac surgery. However, it was not associated with significant differences in postoperative myocardial injury, AKI or mortality. Protocol registration PROSPERO: CRD420261323873.

Background Current recommendations for intraoperative blood pressure management suggest maintaining mean arterial pressure (MAP) at ≥ 60–65 mmHg to avoid hypotension. However, controversy remains regarding whether higher or individualized MAP targets improve clinically important outcomes in surgical patients. We aimed to determine whether intensive intraoperative blood pressure management, defined as higher fixed or individualized MAP targets, reduces major postoperative morbidity compared with standard management (MAP ≥ 60–65 mmHg). Methods We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science for randomized controlled trials (RCTs) comparing intensive and standard intraoperative blood pressure management in adults undergoing noncardiac surgery. The primary outcomes were postoperative myocardial injury, postoperative delirium (POD), and acute kidney injury (AKI). Secondary outcomes included postoperative mortality, stroke, heart failure, acute respiratory distress syndrome (ARDS), pneumonia, intensive care unit (ICU) admission, surgical site infection (SSI), and hospital length of stay (LOS). Data were pooled using a random-effects model with the Hartung–Knapp adjustment. Risk ratios (RR) were calculated for dichotomous outcomes, and mean differences (MD) were calculated for continuous outcomes. Trial sequential analysis (TSA) was performed to control for random error and assess the conclusiveness of the available evidence. Results Eighteen RCTs involving 16,573 patients were included. Compared with standard management, intensive management was associated with lower risks of POD (10 studies; RR = 0.72, 95% CI [0.55, 0.93]; P = 0.019; moderate-certainty evidence) and SSI (5 studies; RR = 0.64, 95% CI [0.53, 0.76]; P = 0.002; moderate-certainty evidence). However, no significant between-group differences were observed in postoperative myocardial injury (9 studies; RR = 1.02, 95% CI [0.92, 1.13]), AKI (13 studies; RR = 0.92, 95% CI [0.79, 1.06]), or mortality (13 studies; RR = 0.99, 95% CI [0.83, 1.17]). TSA supported a beneficial effect of intensive management on POD, and indicated that a clinically meaningful benefit of the prespecified magnitude was unlikely for myocardial injury and AKI. No significant between-group differences were observed in postoperative stroke, pneumonia, heart failure, ICU admission, or hospital LOS. Conclusions In this systematic review and meta-analysis, intensive intraoperative blood pressure management may reduce the risks of POD and SSI in adults undergoing noncardiac surgery. However, it was not associated with significant differences in postoperative myocardial injury, AKI or mortality. Protocol registration PROSPERO: CRD420261323873.

Hemodynamic stabilization and preservation of organ perfusion are central elements in the management of septic shock. This is achieved by fluid...