Indices of Tissue Perfusion: Triggers of Targets of Resuscitation?

Daniel De Backer; Marie Van Hove; Pierre Foulon; Joe Kadou; Gregoire Michiels; Simone Giglioli

doi:10.4103/jtccm.jtccm_1_20

REVIEW ARTICLE

Year : 2020 | Volume : 2 | Issue : 1 | Page : 1-9

Indices of Tissue Perfusion: Triggers of Targets of Resuscitation?

Daniel De Backer¹, Marie Van Hove², Pierre Foulon³, Joe Kadou³, Gregoire Michiels³, Simone Giglioli³
¹ Department of Intensive Care; Department of Emergency Medicine, CHIREC Hospitals, Université Libre De Bruxelles, Brussels, Belgium
² Department of Emergency Medicine, CHIREC Hospitals, Université Libre De Bruxelles, Brussels, Belgium
³ Department of Intensive Care, CHIREC Hospitals, Université Libre De Bruxelles, Brussels, Belgium

Date of Submission	21-Mar-2020
Date of Acceptance	20-Aug-2020
Date of Web Publication	31-Dec-2020

Correspondence Address:
Prof. Daniel De Backer
Department of Intensive Care, CHIREC Hospitals, Boulevard du Triomphe 201, B-1160, Brussels
Belgium

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jtccm.jtccm_1_20

Abstract

Circulatory shock is characterized by a decrease in oxygen delivery to the tissues associated with impairment in oxygen metabolism and tissue hypoxia. Clinical and biological signs of impaired tissue perfusion and tissue hypoxia are used as bedside to detect circulatory failure and trigger resuscitation procedures. The most popular signs of tissue hypoperfusion include mean arterial pressure, capillary refill time and mottling score, central venous oxygen saturation (ScvO₂), veno-arterial difference in PCO₂ (PvaCO₂), microcirculation assessment, and lactate. Both the severity and duration of the alterations in any of these variables are associated with a poor outcome so that it sounds logical to trigger therapy based on these. Using these variables as target for therapy is much more complex. Some of the limits for using some of these variables as targets include an incertitude about the target to reach (should we aim at normalizing or improving the variable, and by how much?) and the time lag between resolution of impaired tissue perfusion/hypoxia and normalization of the variable. The ideal target variable should have a well-defined end point and a rapid response time. Interestingly, hemodynamic resuscitation targeting these variables gave variable results. In this review, we will discuss the interest and limitations of the above-mentioned indices of tissue perfusion and hypoxia as trigger as well as end point of resuscitation in critically ill patients.

Keywords: Capillary refill time, central venous oxygen saturation, lactate, microcirculation, skin perfusion, veno.arterial difference in PCO₂

How to cite this article:
De Backer D, Van Hove M, Foulon P, Kadou J, Michiels G, Giglioli S. Indices of Tissue Perfusion: Triggers of Targets of Resuscitation?. J Transl Crit Care Med 2020;2:1-9

How to cite this URL:
De Backer D, Van Hove M, Foulon P, Kadou J, Michiels G, Giglioli S. Indices of Tissue Perfusion: Triggers of Targets of Resuscitation?. J Transl Crit Care Med [serial online] 2020 [cited 2023 Mar 31];2:1-9. Available from: http://www.tccmjournal.com/text.asp?2020/2/1/1/305783

Introduction

Shock is characterized by an impaired perfusion to the organs, leading to an oxygen delivery (DO₂) insufficient to sustain basal metabolism of the tissues.^[1],[2] While best evaluated by the analysis of the relationship between oxygen consumption (VO₂) and DO₂,^[3] surrogates of tissue perfusion are often used at bedside to identify circulatory failure.^[1] When identified, hemodynamic monitoring,^[4] from noninvasive,^[5] including echocardiography,^[2] to more advanced,^[6],[7] is often warranted in patients with circulatory failure to measure cardiac output and its determinants, and to optimize DO₂ and tissue perfusion. Perfusion indices can be used in two ways. Perfusion indices are mostly used to assess severity of the disease,^{[8],[9],[10],[11]} and thus to identify patients who may benefit from hemodynamic interventions aimed at improving tissue perfusion (Trigger). Several randomized trials have tested the value of signs to tissue perfusion for guiding resuscitation,^{[12],[13],[14],[15]} evaluating the response to therapy and sometimes indicating further interventions (target or end point of resuscitation). In this review, we will discuss to which extend clinical and biological indices of tissue perfusion can be used not only to trigger but also to guide hemodynamic resuscitation.

Arterial Pressure

Arterial pressure is a key determinant of organ perfusion. Many trials have demonstrated that the severity and duration of hypotension are associated with a poor outcome.^[11],[16] Importantly, a shorter time is required for severe hypotension than for less severe hypotension to be associated with impaired organ function and increased risk of death.^[11] In addition, a low mean arterial pressure (MAP)^[11] and low diastolic arterial pressure (DAP)^[17] are both associated with a poor outcome so that one may question whether resuscitation should be targeted to MAP, DAP, or both? Most of the trials have investigated the impact of correcting MAP, which is considered to reflect tissue perfusion.

While nobody contests the relevance of hypotension, to which extent should it be corrected? Correction of severe hypotension is associated with improved organ perfusion,^[18] however targeting higher levels of blood pressure was not associated with improved tissue perfusion.^[19] In some selected patients without other signs of tissue hypoperfusion, not correcting mild hypotension was not associated with adverse events.^[20]

Several trials compared a low and higher targets of MAP, usually 65-70-80-85 mmHg, and none found any survival advantage for either level of blood pressure.^[21],[22] Interestingly, in Asfar et al.'s trial^[21] targeting a higher MAP was associated with less impairment in renal function, especially in the group of previously hypertensive patients, but at the expense of a higher rate of arrhythmias and a trend to higher incidence of acute myocardial infarction. This was not confirmed in the subsequent trial by Lamontagne et al.^[22] who failed to demonstrate any difference in survival as well as in renal function or in any of the measured potential adverse outcome. Accordingly, it seems that blood pressure target should be personalized.^[23],[24]

Obviously, the personalization of blood pressure target should be based on other measurements than blood pressure itself. In addition, tissue perfusion may remain altered even when perfusion pressure is restored. Accordingly, other markers of tissue hypoperfusion are important to consider.

Skin Perfusion

Skin perfusion is one of the most accessible markers of tissue perfusion. It can be assessed using mottling score, capillary refill time (CRT), or evaluation of skin temperature.^[25]

The mottling score reflects local perfusion at knee level^[26] and is associated with outcome.^[9],[27] Interestingly, even though often further impaired by vasopressors, the mottling score retains its predictive value on outcome independently of doses of vasopressor agents.^[28] While easy to perform, data using this variable as a guide to therapy remain scarce and descriptive.^[20]

The CRT is a clinical measure of tissue perfusion that rapidly respond to an intervention.^[29] A prolonged CRT is associated with a poor outcome,^[27],[30] even though some confounding factors may also play a role.^[31]

Even though looking simple, there are nevertheless several issues with CRT measurements. First, the interobserver variability is moderate with Kappa values around 0.40–0.56,^[32],[33] with limits of agreement between two observers as high as 1.9 s.^[34] Second, CRT normal values depend on age and sex.^[32],[35] It also depends on the site where it is investigated (finger tip vs. knee or sternum) and on the duration of the pressure.^[32] Standardization of the procedure including the use of a chronometer is thus required to minimize interrater variability as it is performed in randomized trials.^[36] One may nevertheless that this may be achieved in clinical practice. Some devices are now also proposed to limit this variability,^[37] but these are not yet broadly available at bedside.

Taking into account these limitations, CRT can be used to track the evolution of patients with shock.^{[12],[29],[38],[39]} Lima et al.^[29] were the first to report that CRT rapidly respond to vasodilator agents administration. In the ANDROMEDA-SHOCK trial, CRT was assessed every 30 min for 8 h, triggering various hemodynamic interventions (fluids–vasopressors–inotropes) when abnormal.^[12] The response to the first fluid bolus in the emergency department (ED) may also help to identify septic shock patients with poor outcome, as patients failing to normalize their CRT after the first fluid bolus had a mortality of 67% for a mortality of only 9% in patients with normal or normalized CRT.^[39] These data may appear slightly caricatural, and contrast somewhat with the multicentric date of the ANDROMEDA-SHOCK trial, as 75% of these patients had an abnormal CRT (the 25^th percentile was 3.0 so that 75% of the patients had an abnormal CRT at baseline) were included only after a first bolus of fluid and had a mortality of 35%.^[12]

Skin Temperature

Differences between core and toe can be used to assess peripheral tissue perfusion. Low peripheral temperature is associated with impaired outcome.^[40] This measurement is relatively complex and is markedly influenced by ambient temperature. This may perhaps explain its lack of popularity despite being around for >50 years.^[41]

Central (ScvO₂) and Mixed-Venous (SvO₂) Oxygen Saturations

ScvO₂ and SvO₂ are excellent indices of impaired cardiac output, and hence tissue perfusion. In sepsis, microcirculatory and mitochondrial alterations may comparatively increase ScvO₂/SvO₂, even when cardiac output is impaired, leading to a pseudo-normal ScvO₂/SvO₂.

Several studies have shown that a low ScvO₂, which occurs in 25%–30% of patients with septic shock, is associated with a poor outcome.^[42],[43] Time spent with a low SvO₂ is also associated with a poor outcome.^[16] Even though ScvO₂ is not equivalent to SvO₂, it can be accepted as surrogate in the absence of pulmonary artery catheter. ScvO₂ can be used to track the response to hemodynamic targeted therapies already in the ED, as soon as a central line is inserted.^[43]

Targeting SvO₂ and ScvO₂ has been the topic of multiple randomized trials. The first trial to be published was the a multicentric Italian trial targeting SvO₂ (and also cardiac index) and demonstrating no impact of this strategy.^[44] Of note, SvO₂ was normal in most patients at inclusion, probably as patients could be admitted up to 48 h after intensive care unit (ICU) admission. Timing of the intervention is likely a crucial issue. The concept of early goal directed therapy (EGDT) was then developed by Rivers et al.^[14] These authors suggested that resuscitation based on ScvO₂ (target 70%) on top of usual care consisting on targets for MAP and central venous pressure and urine output) may improve outcome. In their landmark study, these authors observed a remarkable decrease in mortality rates in the intervention group.^[14] The results of this trial were unfortunately not confirmed in three large-scale randomized trials.^[15] Does this mean that this approach should be abandoned? Probably not. There were several striking differences between the positive and the negative trials.^[45] ScvO₂ was low in the River's trial while it was already on target in the three negative trials so that there was limited room for improvement in the recent trials. In addition, 20% of the patients in the control group of the three negative trials were not admitted to the ICU at the end of the 6 h of EGDT; this sounds unrealistic for patients included for shock not responding to fluids and requiring vasopressors or lactate levels higher than 4 mmol/L. This suggests that less severe patients were admitted in the recent trials, even though meeting at least transiently the inclusion criteria. Hence, it is likely that the concept remains valid but that patient selection is crucial.

Another point that should not be neglected is that ScvO₂ provides important information. Abnormal ScvO₂, especially after institution of initial resuscitation measures, is associated with increased risk of death.^[46] This is why we should not neglect to measure ScvO₂ as it helps to guide therapy, even at later stages, even if it doesn't need to be always corrected.^[47]

Lactate

Lactate is considered to reflect the onset of anaerobic metabolism. In experimental conditions, lactate increases sharply once oxygen consumption (VO₂) begins to decrease in response to a decrease oxygen delivery (DO₂).^[48],[49] Critically ill patients demonstrating VO₂/DO₂ dependence also present hyperlactatemia.^[50] Nevertheless, lactate can also be produced in other conditions than tissue hypoxia, especially inflammatory processes, and during beta-adrenergic stimulation, leading to an accelerated glycolysis and aerobic production of lactate.^{[51],[52],[53],[54]} Measurements of pyruvate may help to identify a hypoxic source of lactate. Rimachi et al. demonstrated in patients with cardiogenic or septic shock that hyperlactatemia is predominantly of hypoxic origin at admission and during the next few hours while at 24 h hyperlactatemia was mostly related to a decreased clearance and/or aerobic production.^[55]

Multiple studies have shown that elevated lactate levels are associated with a poor outcome, independently of its cause.^[10],[56] Lactate is hence often used as triage in the ED. It is also used in the current definitions of septic shock.^[57]

Lactate can be used to trigger resuscitation. In particular, the Surviving Sepsis Campaign guidelines recommend the measurement of lactate at recognition of sepsis, to initiate fluid resuscitation in patients with hyperlactatemia and to reevaluate the effects of resuscitation by repeating lactate measurements.^[58] Lactate-guided resuscitation has emerged after the observation that the higher the decrease in lactate levels, the best the outcome. Targeting lactate decreases of 10%–20% every 2 h for 6–8 h have been investigated in several trials.^{[12],[13],[59]} In one trial, lactate-guided therapy (targeting lactate decrease by 10% every 2 h for 6 h) shown no superiority over EGDT.^[59] Another trial reported that lactate-guided therapy (targeting a 20% decrease every 2 h for 8 h) added to EGDT improved outcome compared to EGDT alone.^[13]

Hence, lactate-guided therapy is feasible and seems beneficial when added to EGDT. Lactate-guided therapy is nevertheless limited by the relatively slow decrease in lactate levels in response to therapy.^[60]

Veno-Arterial Differences in PCO₂ (PvaCO₂)

According to the Fick principle applied to CO₂ production, VCO₂ = cardiac output times veno-arterial difference in CO₂ content. As CO₂ content is quite difficult to measure (it can be estimated by complex formulas), most physicians use the veno-arterial difference in PCO₂, or PvaCO₂, even If the relationship between CO₂ content and PCO₂ may be influence by the Haldane effect.

In experimental conditions, PvaCO₂ rises sharply when VO₂ becomes dependent on DO₂, close to the point at which lactate rises.^[49] In critically ill patients, PvaCO₂ has been found to be associated with indices of tissue hypoperfusion and seems particularly attractive when ScvO₂ is close to target.^[61] In addition, the presence of an increased PvaCO₂ may reflect microcirculatory alterations when ScvO₂ is normalized.^[62] Algorithms have been proposed to interpret increased PvaCO₂ gradients together with ScvO₂, separating the systemic and microcirculatory flow components.^[63]

Multiple studies have reported the prognostic value of PvaCO₂, and persistent increases in PvaCO₂ is associated with poor outcome.^{[64],[65],[66]}

Interestingly, PvaCO₂ provides additional information to lactate and may be useful to interpret hyperlactatemia [Figure 1]. As PvaCO₂ improves more rapidly than lactate, normal PvaCO₂/high lactate represents a state in which tissue perfusion is adequate and lactate elevated either as a consequence of a resolved hypoxic event (lactate clearance is slow) or due to nonanaerobic production (adrenergic stimulation or inflammatory processes). On the other hand, an elevated PvaCO₂ with normal lactate suggest an impaired tissue perfusion non yet leading to tissue hypoxia. Finally, dividing PvaCO₂ by arterio-venous difference in O₂ (AVDO₂) reflects respiratory quotient, and an elevated respiratory quotient is present in tissue hypoxia. In patients with septic shock receiving fluid administration, an increased PvaCO₂/AVDO₂ was associated with an increase in VO₂ so that it can be used to detect tissue hypoxia and VO₂/DO₂ dependency.^[67] In septic shock patients, elevated PvaCO₂/AVDO₂ was associated with a poor outcome and provided additional information compared to lactate.^[68]

Figure 1: Interpretation of PvaCO₂ and lactate levels

Click here to view

To which extent PvaCO₂ can be used as a target of resuscitation? PvaCO₂ is a dynamic measurement, rapidly responding to therapeutic interventions. PvaCO₂ usually decreases in response to dobutamine administration, up to a point where VO₂ increases due to excessive metabolic effects of the beta-adrenergic agent.^[69],[70] PvaCO₂ as well as CRT normalizes before normalization of lactate in adequately resuscitated patients with septic shock.^[38] A randomized trial found no benefit of a PvaCO₂-targeted therapy compared to EGDT in sepsis.^[71] However, the interest of PvaCO₂ becomes more obvious when combining these measurements with ScvO₂ rather than instead of ScvO₂. At this stage, no large-scale randomized trial has tested the impact of a PvaCO₂-targeted resuscitation on the top of EGDT on outcome.

Microcirculation

The microcirculation is the key determinant of tissue perfusion. De Backer et al. first demonstrated in 2002 that the microcirculation is altered in patients with septic shock.^[72] These alterations were characterized by a decrease in capillary perfusion, with huge heterogeneity within the sampled area (stopped flow capillaries are present in close vicinity of adequately perfused vessels). These results have now been replicated in more than thirty studies by various teams throughout the world. Importantly, microvascular alterations are associated with poor outcome.^{[72],[73],[74],[75]}

Importantly, these alterations were dissociated from central hemodynamics and could thus not be predicted from classical hemodynamic tools. Nevertheless, there was a good relationship between PvaCO₂ and microvascular perfusion so that PvaCO₂ can be used to detect microvascular alterations.^[62]

While there is no doubt that microcirculatory alterations are contributing to impaired outcome and that microvascular perfusion improves in patients with favorable outcome,^[75] microcirculatory targeted resuscitation is not yet feasible. We need first to and to better report which drugs should be used to improve the microvascular perfusion. Fluids, dobutamine, and vasoactive agents have variable effects with beneficial effects in some but not all patients.^{[76],[77],[78],[79],[80]} Some agents modulating endothelial function demonstrated interesting results in experimental models^[81],[82] but these need to be replicated in critically ill patients. We need also to define what would be the microcirculatory target value (normalization vs. improvement by xx%?).

Lactate Versus Capillary Refill Time Versus ScvO₂ Versus an Integrative Approach? Lessons from the ANDROMEDA-SHOCK Trial

In a multicentric randomized trial including 424 patients with septic shock, CRT-guided therapy was compared to lactate-guided therapy.^[36] The goals were to normalize CRT (<3 s) in the CRT group and to normalize or to decrease lactate levels by 20% every 2 h in the lactate group. Mortality by day 28 was 34.9% in the CRT group and 43.4% in the lactate group, but this difference failed to reach statistical significance (P = 0.06). In a Bayesian analysis, the mortality difference was found to be significant.^[83]

What may explain the differences between lactate-guided and CRT-guided therapy? As CRT and lactate were used to guide therapy, differences in therapy likely explain the differences in outcome. As in the CRT group lactate decreased more rapidly than in the lactate-guided group, this suggest that the interventions were implemented more efficiently when triggered by CRT compared with lactate. Differences in the amount of fluid administered are unlikely to explain differences in outcome even though significant (around 400 mL lower in CRT than in lactate group). On the other hand, vasopressors tests were more frequently performed in the lactate group than in the CRT group (used in 40% of the patients in lactate group and in 29% in CRT group). If anything, this would suggest that CRT assessment prevented the implementation rather than triggering additional interventions. The alternative explanation is that the interventions may have been implemented in a more timely fashion in the CRT group. Indeed, CRT was assessed every 30 min while lactate was assessed every 2 h so that there was a possibility to implement or to stop therapies more frequently.

This study should not be misinterpreted. It does not mean that lactate should not be measured anymore and that resuscitation should be guided on CRT only. In a recent observational study, CRT and clinical sings predicted very poorly the occurrence of acute kidney injury, but the addition of lactate in the model allowed to reach satisfactory predictive value.^[84] In the ANDROMEDA-SHOCK trial, patients were included as they presented with hyperlactatemia (≥2.0 mmol/L was mandated as an inclusion criteria), so the study does not evaluate whether CRT-guided therapy is safe in patients without hyperlactatemia. In patients with normal lactate levels and impaired CRT, there is a risk of overtreating patients in whom the impaired tissue perfusion has no major consequences on metabolism. Lactate also decreased more rapidly in the CRT than lactate group, confirming the intrinsic value of this measurement in reflecting the adequacy of the resuscitation in the CRT.

Accordingly, it sounds wise to integrate several variables such as CRT, lactate, but also ScvO₂ and PvaCO₂ and not to rely only on one marker, taking into account the limitations of each marker [Table 1]. The different time course of these variables should be taken into account, as these demonstrate different normalization rates in septic shock survivors, with usually an initial rapid improvement, followed by a much slower trend thereafter.^[38] One should continue to try to improve tissue perfusion when several of these variables remain altered but should refrain to intervene when most variables are normalized.^[60]

Table 1: Advantage and limits of the various indices of tissue perfusion

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Conclusions

Multiple indices can be used to detect impaired tissue perfusion and most are associated with outcome. While these indices can be used to detect which patients may potentially benefit from additional interventions, the lack of clear definition of what is the best value to trigger for some markers and the reaction time of others make some indices less suitable for being used as targets. Nevertheless, given the additive information of the various indices, it is advisable to use several markers in combination than using one in isolation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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