Acute hemodynamic tests to determine the status of macro-to-microcirculatory coupling during septic shock resuscitation

Dear editor

We read with great interest the recent study by Morin et al. assessing the impact of a passive leg raising (PLR) maneuver on skin blood flow (SBF) in patients with septic-related acute circulatory dysfunction [1]. The main finding was that PLR- induced changes in SBF predicted peripheral microvascular responsiveness to a subsequent fluid bolus. Similar findings were previously reported by Jacquet-Lagreze et al., when testing capillary refill time (CRT) response to a PLR in a miscellaneous cohort of critically ill patients [2]. In both studies, several patients (73% and 44%, respectively) improved peripheral perfusion during the maneuver. Interestingly, changes in peripheral perfusion were not correlated with changes in cardiac output (CO) as assessed by different techniques, suggesting a non-linear relationship between increases in systemic blood flow and tissue perfusion, as probably determined by downstream mechanisms inherent to microcirculatory regulation [3, 4].

Several aspects of this important clinical-physiological study should be highlighted. First, it explores the dynamic interaction between macrohemodynamics and a relevant microcirculatory territory such as the skin during an acute flow-directed hemodynamic intervention. The well-reproduced observation that increasing systemic blood flow does not reverse tissue hypoperfusion in some patients with septic shock, has been termed as a loss of hemodynamic coherence or macro-to-microcirculatory uncoupling [3–5]. Earlier work by Ince et al., described diverse microcirculatory alterations associated with this condition, some of them eventually related to inherent local inflammation, to the effects of over-resuscitation, or both [5]. Moreover, increasing mean arterial pressure (MAP) in patients with septic shock does not necessarily improve microcirculatory disturbances. Other potential mechanisms for macro-to-microcirculatory uncoupling are impaired microvascular reactivity, an unbalance between MAP and critical closing pressure at the microhemodynamic level, or eventually venous congestion (Fig. 1) [3]. Whatever the mechanisms, some of which can only be grossly estimated using research-restricted methods, the most important fact is that no static variable is able to predict the status of macro-to-microcirculatory coupling in a heterogeneous septic shock population that might exhibit similar clinical and macrohemodynamic profiles. This appears as relevant, since pursuing further macrohemodynamic resuscitation with fluids or vasoactive drugs in uncoupled patients may increase the hazard of fluid overload or adrenergic toxicity without any benefit in terms of reperfusion [4]. Thus, the confirmatory finding of Morin et al. that a simple PLR maneuver could identify patients with septic shock potentially benefiting from additional hemodynamic resuscitation as compared with those that could be eventually harmed, may have relevant clinical implications.

Fig. 1.

Acute hemodynamic tests to determine the status of macro-to-microcirculatory coupling during septic shock resuscitation. Bedside test including PLR, fluid challenge, MAP test, inodilator test, and diastolic arterial pressure augmentation, probe whether a macrohemodynamic response translates into improved peripheral perfusion. This downstream perfusion effect depends on the underlying microcirculatory status and on macro-micro hemodynamic interplay, including microvascular reactivity, microvascular dysfunction, the relationship among MAP, critical closing pressure, and mean systemic filling pressure, as well as venous congestion. At the bedside, CRT, a surrogate marker of microvascular blood flow, can be used to assess perfusion responsiveness. Improvement or normalization of CRT after an acute hemodynamic test suggests preserved macro-to-microcirculatory coupling, whereas persistently abnormal CRT despite a macrohemodynamic response is consistent with loss of macro-to-microcirculatory uncoupling. PLR: passive leg raising, CRT: Capillary refill time, MAP: mean arterial pressure, DAP: diastolic arterial pressure, P_CRIT: critical closing pressure, P_MSF: mean systemic filling pressure

Second, skin blood flow was assessed with Laser-doppler, a technique usually limited to research settings. Can CRT, a universally available and costless test, be used as a surrogate variable to monitor tissue perfusion? Previous studies from the same group and others, showed a good correlation between SBF and CRT suggesting this latter might be a reliable marker of skin microvascular blood flow [6, 7]. Although the intimate physiology of CRT is still not well understood, robust epidemiological data showing its prognostic value, its rapid kinetics of response to acute hemodynamic interventions [8–10], its acceptable correlation with visceral organ blood flow [11] and sublingual microcirculation [12, 13], and the results of two recent major randomized controlled trials [14, 15], support its place as a trigger but also a target for septic shock resuscitation. Thus, testing CRT response to a PLR maneuver, being both simple tests, appears as a practical bedside tool to determine the status of macro-to-microcirculatory coupling.

Third, Morin et al. operatively defined SBF response to the PLR/fluid bolus as “peripheral tissue perfusion fluid responsiveness”. It could be relevant to standardize terminology on this emerging concept, and, in our opinion, it might be better to use a broader term like “perfusion responsiveness” or “flow-responsiveness” as CRT response to other acute non-fluid related hemodynamic interventions has been recently described [8–10, 14, 15].

Fourth, and more importantly, expanding this concept led to integrate several of these acute hemodynamic tests into a physiology-grounded, personalized resuscitation strategy targeting CRT in the ANDROMEDA-SHOCK-2 (AS2) randomized trial [15]. This personalized approach consisting of sequential multilayered assessments of physiological signals to tailor fluids, vasopressors, and inotropes, aiming at CRT normalization, was superior to usual care in a hierarchical composite outcome of mortality, duration of vital support, and length of stay at day-28, primarily driven by shorter duration of organ support. Bedside hemodynamic tests in AS2 revealed a substantial heterogeneity in response to flow- and pressure-targeted interventions. Fluid challenges, administered after fluid responsiveness testing, normalized CRT in 56% of patients (234/414). Similarly, MAP and dobutamine tests achieved CRT normalization in 57% (35/62) and 40% (17/43) of patients, respectively. Diastolic arterial pressure (DAP) augmentation, a novel component of the tier 1 algorithm, normalized CRT in 18% of cases (23/127). Taken together, these findings underscore both the heterogeneity of physiological responses and the clinical utility of sequential hemodynamic testing to identify patients likely to benefit from targeted interventions, as well as those in whom further escalation may be ineffective or potentially harmful.

Finally, we acknowledge that macro-to-microcirculatory coupling is still an evolving concept with many knowledge gaps. For example, when do we consider that macrohemodynamics has been effectively optimized especially in cases of structural heart disease, septic-related cardiac dysfunction, or therapeutic intolerance? Or how could we anticipate macro-to-microcirculatory uncoupling and then, avoiding unnecessary and potentially harmful interventions, or most importantly, is macro-to-microcirculatory uncoupling reversible? Hopefully, further clinical-physiological studies will unravel this scientific conundrum.

Abbreviations

PLR

Passive leg raising

SBF

Skin blood flow

CO

Cardiac index

CRT

Capillary refill time

MAP

Mean arterial pressure

DAP

Diastolic arterial pressure

Author contributions

Conceptualization and designed the review: GH, EK. Literature search: PMand SM. Review and editing: All authors. Approved of final manuscript: All authors.

Funding

This study has been funded by FONDECYT Grant Nº 1250201.

Data availability

No datasets were generated or analyzed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent of publication

Not applicable.

Competing interests

The authors declare no competing interests.