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OPINION Lactate and microcirculation as suitable targets
for hemodynamic optimization in resuscitation
of circulatory shock
Michael E. Kiyatkin a and Jan Bakker b,c,d,e

Purpose of review
A discussion of recent research exploring the feasibility of perfusion-guided resuscitation of acute
circulatory failure with a focus on lactate and microcirculation.
Recent findings
Upon diagnosis of shock, hyperlactemia is associated with poor outcome and, under appropriate clinical
circumstances, may reflect inadequate tissue perfusion. Persistent hyperlactemia despite resuscitation is
even more strongly correlated with morbidity and mortality. Importantly, there is minimal coherence
between lactate trends and static hemodynamic measures such as blood pressure, especially after the
initial, hypovolemic phase of shock. During this early period, lactate guided-resuscitation is effective and
possibly superior to hemodynamic-guided resuscitation. Similar to hyperlactemia, impaired microcirculation
is ubiquitous in shock and is evident even in the setting of hemodynamic compensation (i.e., occult shock).
Moreover, persistent microcirculatory derangement is associated with poor outcome and may reflect
ongoing shock and/or long-lasting damage. Although the wait continues for a microcirculation-guided
resuscitation trial, there is progress toward this goal.
Although questions remain, a multimodal perfusion-based approach to resuscitation is emerging with
lactate and microcirculation as core measures. In this model, hyperlactemia and microcirculatory
derangement support the diagnosis of shock, may help guide resuscitation during the initial period, and
may reflect resuscitation efficacy and iatrogenic harm (e.g., fluid overload).
lactate, microcirculation, shock

INTRODUCTION compensation. Second, resuscitation aimed at nor-

In spite of decades of research, treatment of acute malization of MAP, CO, and central venous pressure
circulatory failure remains challenging. This is due (CVP) is increasingly recognized as contributory to

in large part to the inability to clearly monitor tissue harmful fluid overload [3 ]. In place of these
perfusion. As inadequate perfusion is pathogno-
monic of shock, this limitation is a major obstacle a
Department of Anesthesiology, bDivision of Pulmonary, Allergy, and
in patient care. Traditionally, therapeutic interven-
Critical Care Medicine, Department of Medicine, Columbia University
tions such as fluid resuscitation were targeted to Medical Center, NewYork-Presbyterian Hospital, cDepartment of Pul-
improve static, global hemodynamic parameters monary and Critical Care, Langone Medical Center-Bellevue Hospital,
such as mean arterial pressure (MAP) and cardiac New York University, New York, New York, USA, dDepartment of Intensive
output (CO). These parameters are relatively easy to Care Adults, Erasmus MC University Medical Center, Rotterdam, The
Netherlands and eFacultad de Medicina, Pontificia Universidad Catolica
measure with good accuracy and precision and were
de Chile, Santiago, Chile
considered the primary determinants, and therefore
Correspondence to Jan Bakker, Division of Pulmonary, Allergy, and
good surrogates, of organ perfusion. This reliance on Critical Care Medicine, Department of Medicine, Columbia University
MAP and CO continues to this day [1 ]. There is a Medical Center, NewYork-Presbyterian Hospital, 622 West 168th St.,
growing consensus; however, that macrohemody- Room PH 8109, New York, NY 10032, USA. Tel: +1 917 208 7648;
namic parameters are in fact poorly reflective of e-mail:
tissue perfusion [2]. First, changes in hemodynamic Curr Opin Crit Care 2017, 23:000000
values may be masked by catecholamine-driven DOI:10.1097/MCC.0000000000000423

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mortality with an admission lactate more than

KEY POINTS 2 mmol/l only in univariate but not multivariate
 Persistent hyperlactemia and microcirculatory analysis, with a clear association between mortality
derangement are characteristic of acute circulatory and persistent hyperlactemia for more than 72 h
failure and are associated with poor outcome. [16 ]. A meta-analysis of various forms of circulatory
shock similarly demonstrated a survival benefit of
 During resuscitation of shock and especially after the &
improved hyperlactemia over 624 h [17 ]. These
initial, hypovolemic phase, there is minimal coherence
between static hemodynamic measures such as blood and previous studies have contributed to the incorp-
pressure and serum lactate or oration of hyperlactemia more than 2 mmol/l
peripheral microcirculation. despite adequate fluid resuscitation into the
Sepsis-3 diagnostic criteria [18].
 Studies continue to demonstrate efficacy of lactate
guided-resuscitation during the initial 68-h period after
diagnosis of shock.
 Although the wait continues for a microcirculation- WITH ABNORMAL HEMODYNAMIC
guided resuscitation trial, there is progress toward PARAMETERS ONLY DURING THE INITIAL
this goal. PHASE OF SHOCK
The relationship between lactate and systemic
hemodynamic parameters during circulatory shock
traditional parameters, there is growing interest in is puzzling. On the one hand, they appear to be
more direct measures of tissue perfusion such serum incoherent. For example, whereas a reduction in
lactate and peripheral tissue microcirculation. In lactate during treatment of septic shock is associated
this review, we highlight recent studies that support with improved mortality, an elevation in MAP, CVP,
multimodal perfusion-guided resuscitation of acute and ScvO2 are not [10]. In fact, secondary analysis of
circulatory failure, with a focus on lactate and the ARISE trial for the treatment of septic shock
microcirculation monitoring. revealed that isolated hyperlactemia more than
4.0 mmol/l without hypotension, but not vice versa,
was associated with increased morbidity and
mortality [19 ]. Moreover, there was no difference
ASSOCIATED WITH POOR OUTCOME AND in lactate concentrations in septic shock patients
MAY REFLECT INADEQUATE TISSUE resuscitated to either normodynamic or hyperdy-
PERFUSION namic states [14]. On the other hand, others have
There continues to be no question that hyperlacte- noted that both hyperlactemia more than
mia more than 2 and especially more than 4 mmol/l 2.0 mmol/l and MAP less than 65 mmHg at the onset
at the time of shock diagnosis is associated with of septic shock and after 24 h of resuscitation were
increased morbidity and mortality [49]. This independent predictors of mortality, although cor-
association may reflect inadequate perfusion. This relation between the two was not explored [4].
also supports hyperlactemia as an important warn- Several explanations have been put forth for
ing sign of shock that should prompt expanded
& && && &
these discrepancies [20 ,21 ,22 ,23 ]. It appears
resuscitation. that during the initial, hypovolemic phase of shock,
Persistent hyperlactemia, despite several hours hyperlactemia does indeed parallel poor systemic
of resuscitation, is even more strongly associated hemodynamics. In these circumstances, fluid resus-
with poor outcome. Many groups have demon- citation improves both. However, this hemody-
strated in septic and cardiogenic shock that persist- namic coherence and fluid sensitivity rapidly
ent hyperlactemia more than 2 mmol/l after 624 h disappears, severely limiting the utility of hemody-
of resuscitation, rather than initial hyperlactatemia,
namic-based resuscitation protocols [23 ].
was associated with elevated morbidity and
mortality. During resuscitation of either form of
shock, a reduction in lactate levels of more than RESUSCITATION OF SHOCK TARGETING
2060% by 624 h predicted lower mortality [10 AN INCREMENTAL DECREASE IN LACTATE
15]. Even in studies in which admission hyperlacte- IS EFFECTIVE, AT LEAST DURING THE
mia more than 24 mmol/l was indeed associated EARLY PHASE
with higher mortality, persistent hyperlactemia Given the above, it is clear why lactate is an attrac-
beyond 24 h had an even stronger association with tive clinical parameter for guiding resuscitation.
poor outcome [4,8]. Exploring this further, a post- Randomized control trials incorporating lactate
hoc analysis of the FINNAKI trial revealed greater are continuing with encouraging results. One such

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Lactate and microcirculation as suitable targets Kiyatkin and Bakker

trial in septic shock patients compared early goal- hemorrhagic shock, sublingual microcirculatory
directed therapy with a modified protocol replacing abnormalities developed rapidly and were associ-
ScvO2 monitoring with a graded venous lactate ated with low CO and MAP as well as elevated
reduction protocol (10% by 2 h, 20% by 4 h, and lactate. Over a 3-h resuscitation course, however,
30% by 6 h). Although patients in the lactate-guided CO and MAP gradually normalized despite the
group received more fluid, they experienced lower persistence of aberrant microcirculation and
morbidity and mortality over 60 days [24 ]. This hyperlactemia [33]. In summary, microcirculatory
parallels the findings of previous lactate-guided derangement may parallel abnormal hemodynam-
&& &&
resuscitation trials [25 ,26 ]. Studies have so far ics in the initial period, is an exquisitely sensitive
limited lactate-guided resuscitation to the initial, marker of acute circulatory failure, and should lower
acute phase of shock, typically 68 h after diagnosis. the threshold for expanding resuscitation.
The reasons for this are multiple. As discussed above,
the correlation between persistent hyperlactemia
and mortality is strongest during the initial period. PERSISTENT MICROCIRCULATORY
As clarified later in this article, in the subacute phase DERANGEMENT IN SHOCK IS
of shock, lactate normalization slows and becomes ASSOCIATED WITH POOR OUTCOME
multifactorial, with continued lactate-guided resus- As with persistent hyperlactemia, evidence contin-
citation potentially leading to fluid overload ues to mount that persistent microcirculatory
& && && &
[20 ,21 ,22 ,23 ]. derangement is associated with increased morbidity
and mortality. In septic shock patients, for example,
persistent abnormalities in capillary perfusion of
IMPAIRED MICROCIRCULATION IS skin and sublingual mucosa 2472 h after the
UNIVERSAL IN SHOCK AND IS PRESENT initiation of resuscitation was found to be associated
EVEN WHEN GLOBAL HEMODYNAMICS with elevated sequntial organ failure (SOFA) scores,
ARE COMPENSATED a more positive fluid balance, greater vasopressor
With the onset of shock, the microcirculation shows use, higher lactate concentrations, and increased
clear evidence of dysfunction even in the absence of mortality [14,34]. This is consistent with an earlier
any changes in static hemodynamic parameters (i.e., study in pediatric septic shock patients that revealed
occult shock). For example, during the first 6 h of equally impaired microcirculation in survivors
septic shock resuscitation, it was noted that the and nonsurvivors after 24 h of resuscitation but
severity of sublingual microcirculatory impairment improved microcirculation only in survivors by
was not correlated with any decreases in MAP, CO, Day 2 and especially by Day 3, with nonsurvivors
or mixed venous oxygen saturation (SmvO2) [27]. exhibiting persistent impairments in their micro-
Furthermore, after 24 h of resuscitation, patients circulation [35]. Comparing lactate and microcircu-
with normodynamic septic shock were found to lation, both of which are excellent prognostic
have equivalent, abnormal microcirculation as markers, a recent study in septic shock patients
patients in a hyperdynamic state [14]. In an animal revealed that combined hyperlactemia more than
model of septic shock, a dobutamine infusion 4 mmol/l and hypoperfusion after 24 h was associ-
during the first 2 h of resuscitation significantly ated greater morbidity and mortality than equival-
improved sublingual and small bowel mucosal ent hyperlactemia but normal peripheral perfusion
microcirculation with a parallel decrease in lactate [36 ]. In adult cardiogenic shock patients, abnormal
but had no change in CO, MAP, CVP, or SmvO2 [28]. sublingual microcirculation at the initiation of
In patients with hemorrhagic shock, blood trans- veno-arterial Extra Corporeal Membrane Oxygen-
fusion within 12 h likewise improved microcircula- ation support was likewise found to be a strong
tory parameters without affecting MAP, CO, or predictor of mortality [30]. This further supports
lactate [29]. In cardiogenic shock, there were no the value of microcirculation monitoring.
significant differences in hemodynamics or lactate
at the time of initiation of mechanical support
between survivors and nonsurvivors despite signifi- PERSISTENT MICROCIRCULATORY
cant differences in their microcirculatory profiles ABNORMALITIES DESPITE EFFECTIVE
[30]. In certain circumstances, however, hemody- RESUSCITATION MAY REFLECT
namic coherence is indeed observed. For example, it LONG-LASTING INJURY
was demonstrated that fluid challenge in septic Although microcirculatory derangement is ubiqui-
shock patients improved microcirculation together tous, ominous, and may on occasion mirror abnor-
with CO and hyperlactemia but only within the first mal hemodynamics during the initial hypovolemic
24 h of resuscitation [31,32]. In an animal model of phase of shock, the microcirculation becomes more

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difficult to interpret in the subacute period (>24 h). hemorrhagic shock patients presenting to the emer-
Systemic hemodynamics typically normalize, gency room [41 ]. Although not utilizing dark field
whereas microcirculatory parameters either normal- microscopy, other measures of peripheral perfusion
ize concurrently reflecting shock resolution [37] or such as capillary refill time (CRT) were recently
persist for several days indicating long-lasting ische- compared against traditional hemodynamics in a
mic damage, continued shock, or iatrogenic injury goal-directed trial for septic shock. Less morbidity
& &&
(e.g., fluid overload) [23 ,38,39 ]. For example, in was noted when fluid resuscitation was guided by a
one study in septic shock, abnormal skin micro- combination of peripheral perfusion measures
circulation was correlated with elevated lactate [42 ].
but only at the time of diagnosis, losing correlation
2472 h after initiation of resuscitation with lactate
largely normalizing, suggesting shock resolution, CAVEATS TO LACTATE-GUIDED AND
whereas microcirculation remained abnormal [34]. MICROCIRCULATION-GUIDED
Conversely, in another group of septic shock RESUSCITATION
patients with persistent hyperlactemia despite With respect to monitoring serum lactate, studies
48 h of treatment, fluid loading improved hemody- continue to highlight the complexity of lactate
namic parameters but had no effect either on lactate metabolism and the need to interpret hyperlactemia
levels or the microcirculation, suggesting continued with caution. In a septic shock sheep model, for
shock [32]. Some have argued that this late, fluid- example, esmolol and dexmedetomidine infusions
insensitive state makes microcirculation better during resuscitation lowered endogenous lactate
suited for evaluating organ dysfunction than guid- levels and enhanced clearance of exogenous lactate
ing resuscitation [39 ]. Others have countered that without affecting CO [43]. This agrees with a previous
because microcirculation monitoring is uniquely clinical study showing lower admission lactate con-
able to distinguish patterns of shock such as gener- centrations in septic shock patients on -blocker
alized low flow state or heterogeneous capillary therapy [44 ]. This cautions against the common
blood flow, this technique may caution against misconception that lactate is simply a metabolic
further fluid administration and suggest more tar- byproduct of glycolysis, and thus a marker of dysoxia.
geted therapies such as nitroglycerin and inotropes In reality, hyperlactemia is not clearly associated with
[38,40]. Moreover, as noted above, when microcir- decreased delivery of oxygen; rather, it is a key glu-
culation is paired with other perfusion parameters coneogenic precursor whose production is enhanced
such as lactate, this fluid-insensitivity may in fact by adrenergic drive and exogenous catecholamines,
argue against any further fluid administration, and its serum concentration may be elevated from
which may only improve vital signs while causing reduced hepatic clearance due to ischemia or even
harmful fluid overload. In other words, microcircu- the sepsis toxicosis itself [45].
latory monitoring can help diagnose occult shock Although a clearer picture of microcirculatory
and both guide and limit resuscitation in the acute changes during shock is emerging, there remain a
as well as subacute periods. number of concerns. Perhaps the Achilles Heel of this
technique, rapid and reliable quantification of dark
field microscopy, the most modern technique for
CONTINUED WAIT FOR A measuring microcirculation, remains challenging.
MICROCIRCULATION-GUIDED The latest generation of automated algorithms for
RESUSCITATION TRIAL analyzing data remain unreliable and inaccurate
Although lactate-guided resuscitation has already compared with traditional, manual evaluation
been evaluated in multiple randomized controlled [46,47]. However, this will surely improve as the
trials, we are still waiting for an equivalent study algorithms are developed further. Another possibility
incorporating microcirculation. Without such a is the development of a simpler grading system, for
study, postulating about grand resuscitation strat- example, the 5-point point of care microcirculation
egies will remain in the realm of research rather than score, which requires only 2 min for calculation
at the bedside in which it desperately belongs. A with good interrater consistency and agreement with
traditional 45-min-long analysis [48 ]. Conversely,
microcirculation trial is inevitable as dark field
microscopes become more widespread and auto- this may prove irrelevant and microcirculation
mated analyses improve. Although we eagerly await monitoring may evolve into a multipurpose tech-
this trial, progress continues toward this goal. One nique akin to echocardiography, with minimally
promising, ongoing study is the MICROSHOCK skilled operators deducing basic yet important infor-
trial, which recently demonstrated the feasibility mation and highly skilled able to obtain more
and safety of sublingual imaging in traumatic detailed data. Another continued concern is the

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Lactate and microcirculation as suitable targets Kiyatkin and Bakker

treatment. Microcirculation monitoring may

additionally provide information about the mechan-
ism of shock. This, of course, must be paired with
treatment of the underlying cause. Moreover, no
protocol, however well supported, can fully replace
the judgement and repeated re-evaluation of an
experienced and skeptical clinician.


Financial support and sponsorship

FIGURE 1. A putative triangular basis of circulatory shock. None.
As hypothesized by Vincent et al. in their tribute to Prof Max
Harry Weil [55], the full clinical picture of shock includes Conflicts of interest
three features: hypotension, altered tissue perfusion, and There are no conflicts of interest.
hyperlactatemia, all of which originate from underlying
microcirculatory disturbances. However, this presentation is
often incomplete. Adapted from [55].
Papers of particular interest, published within the annual period of review, have
relevance of the most common monitoring site the been highlighted as:
& of special interest
sublingual region. This is commonly monitored && of outstanding interest

because it is readily accessible and the bulk of data,

including recent studies [49,50], support a close cor- 1. Cecconi M, Hofer C, Teboul JL, et al. Fluid challenges in intensive care: the
FENICE study: a global inception cohort study. Intensive Care Med 2015;
relation of sublingual, intestinal mucosal, and con- &

junctival microcirculation, suggesting a common This is a multinational, prospective observational cohort study in over 2000 mixed
diagnosis critically ill patients examining the use of fluid boluses during resuscita-
sympathetic vasoconstrictor mechanism. tion. Hypotension was the primary indication (60%) for fluid challenge followed
Other concerns that should be addressed before by oliguria (20%). Hyperlactemia and skin mottling were triggers of fluid
challenging in only 6 and 2% of cases, respectively. Alarmingly, the absence
adopting lactate-guided and/or microcirculation- of a response to fluid challenge was not significantly associated with a decision to
guided resuscitation include significant study hetero- halt further fluid therapy. This important and revealing study highlights the need for
re-evaluation of current resuscitation strategies.
geneity and the relationship of these promising strat- 2. Dunser MW, Takala J, Brunauer A, Bakker J. Re-thinking resuscitation: leaving
egies with other perfusion-based techniques such as blood pressure cosmetics behind and moving forward to permissive hypoten-
sion and a tissue perfusion-based approach. Crit Care 2013; 17:326.
CRT. As illustrated above, the literature is unfortu- 3. Byrne L, Van Haren F. Fluid resuscitation in human sepsis: time to rewrite
nately riddled with heterogeneity, including failure && history? Ann Intensive Care 2017; 7:4.
This is an excellent review of the history and danger of excessive fluid challenge in
to distinguish hyperdynamic from normodynamic the treatment of septic shock. This article highlights major gaps in our under-
septic shock, evaluation of shock at different stages of standing of sepsis pathophysiology as well as the need for more clinically relevant
hyperdynamic septic shock animal models. It also supports the importance of
resuscitation, use of different animal models, and use exploring minimal or even no fluid strategies for sepsis resuscitation.
of nonstandardized diagnoses and resuscitation pro- 4. Houwink AP, Rijkenberg S, Bosman RJ, van der Voort PH. The association
between lactate, mean arterial pressure, central venous oxygen saturation and
tocols [51]. Moreover, there are other promising, peripheral temperature and mortality in severe sepsis: a retrospective cohort
technically simpler perfusion parameters, including analysis. Crit Care 2016; 20:56.
5. Oedorf K, Day DE, Lior Y, et al. Serum lactate predicts adverse outcomes in
CRT and tissue Pv-aCO2, a combination of which emergency department patients with and without infection. West J Emerg
& &&
may prove highly informative [36 ,42 ,5254]. Med 2017; 18:258266.
6. Filho RR, Rocha LL, Correa TD, et al. Blood lactate levels cutoff and mortality
prediction in sepsis-time for a reappraisal? A Retrospective Cohort Study.
Shock 2016; 46:480485.
CONCLUSION 7. Gale SC, Kocik JF, Creath R, et al. A comparison of initial lactate and initial
base deficit as predictors of mortality after severe blunt trauma. J Surg Res
Acute circulatory failure remains difficult to treat [18]. 2016; 205:446455.
8. Lee WC, Fang CY, Chen HC, et al. Associations with 30-day survival
Because shock is defined by inadequate tissue per- following extracorporeal membrane oxygenation in patients with acute ST
fusion, lactate and microcirculation hold great segment elevation myocardial infarction and profound cardiogenic shock.
Heart Lung 2016; 45:532537.
promise as resuscitation monitors. Progress continues 9. van Donkelaar CE, Dijkland SA, van den Bergh WM, et al. Early circulating
in this direction, and an era of perfusion-guided lactate and glucose levels after aneurysmal subarachnoid hemorrhage corre-
late with poor outcome and delayed cerebral ischemia: a two-center cohort
resuscitation may be near (Fig. 1). Specifically, hyper- study. Crit Care Med 2016; 44:966972.
lactemia and microcirculatory derangement may 10. Zhou J, Song J, Gong S, et al. Persistent hyperlactatemia-high central
venousarterial carbon dioxide to arterialvenous oxygen content ratio is
support the diagnosis of shock and guide resuscita- associated with poor outcomes in early resuscitation of septic shock Am J
tion during the initial period. By 24 h, persistent Emerg Med 2017. [Epub ahead of print]
11. Haas SA, Lange T, Saugel B, et al. Severe hyperlactatemia, lactate clearance
hyperlactemia and abnormal microcirculation may and mortality in unselected critically ill patients. Intensive Care Med 2016;
indicate continued shock and prompt expanded 42:202210.

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Cardiovascular system

12. Chertoff J, Chisum M, Simmons L, et al. Prognostic utility of plasma lactate 26. Jansen TC, van Bommel J, Schoonderbeek FJ, et al. Early lactate-guided
measured between 24 and 48 h after initiation of early goal-directed therapy in && therapy in intensive care unit patients a multicenter, open-label, randomized
the management of sepsis, severe sepsis, and septic shock. J Intensive Care controlled trial. Am J Respir Crit Care Med 2010; 182:752761.
2016; 4:13. This is an early and important lactate-guided resuscitation trial in a mixed cohort of
13. Lokhandwala S, Andersen LW, Nair S, et al. Absolute lactate value vs relative circulatory shock patients. Morbidity and mortality were significantly lower when
reduction as a predictor of mortality in severe sepsis and septic shock. J Crit the therapeutic algorithm targeted a reduction in lactate versus an improvement in
Care 2017; 37:179184. static hemodynamic parameters.
14. Edul VS, Ince C, Vazquez AR, et al. Similar microcirculatory alterations in 27. Ospina-Tascon GA, Umana M, Bermudez WF, et al. Can venous-to-arterial
patients with normodynamic and hyperdynamic septic shock. Ann Am Thorac carbon dioxide differences reflect microcirculatory alterations in patients with
Soc 2016; 13:240247. septic shock? Intensive Care Med 2016; 42:211221.
15. Lavrentieva A, Voutsas V, Konoglou M, et al. Determinants of outcome in burn 28. Ospina-Tascon GA, Garcia Marin AF, Echeverri GJ, et al. Effects of dobutamine
ICU patients with septic shock. J Burn Care Res 2017; 38:e172e179. on intestinal microvascular blood flow heterogeneity and oxygen extraction
16. Varis E, Pettila V, Poukkanen M, et al. Evolution of blood lactate and 90-day during septic shock. J Appl Physiol (1985) 2017. [Epub ahead of print]
& mortality in septic shock. A post hoc analysis of the FINNAKI study. Shock 29. Tanaka S, Escudier E, Hamada S, et al. Effect of RBC transfusion on
2017; 47:574581. sublingual microcirculation in hemorrhagic shock patients: a pilot study. Crit
This is a post-hoc analysis of the multicenter FINNAKI trial evaluating outcomes in Care Med 2017; 45:e154e160.
septic shock patients. Consistent with other studies, there was a clear association 30. Kara A, Akin S, Dos Reis Miranda D, et al. Microcirculatory assessment of
between mortality and persistent hyperlactemia more than 2 mmol/l after 72 h of patients under VA-ECMO. Crit Care 2016; 20:344.
resuscitation. Although univariate analysis also suggested an association between 31. Pottecher J, Deruddre S, Teboul JL, et al. Both passive leg raising and intravas-
admission hyperlactemia and mortality, multivariate analysis did not demonstrate cular volume expansion improve sublingual microcirculatory perfusion in severe
any significance. This suggests that, in spite of its complicated metabolic function, sepsis and septic shock patients. Intensive Care Med 2010; 36:18671874.
persistent hyperlactemia much more so than admission hyperlactemia is clearly 32. Ospina-Tascon G, Neves AP, Occhipinti G, et al. Effects of fluids on
associated with poor outcomes. microvascular perfusion in patients with severe sepsis. Intensive Care Med
17. Vincent JL, Quintairos ESA, Couto L Jr, Taccone FS. The value of blood 2010; 36:949955.
& lactate kinetics in critically ill patients: a systematic review. Crit Care 2016; 33. Hutchings SD, Naumann DN, Watts S, et al. Microcirculatory perfusion shows
20:257. wide inter-individual variation and is important in determining shock reversal
This is a meta-analysis of 96 different studies in a diverse cohort of critically ill during resuscitation in a porcine experimental model of complex traumatic
patients with all forms of shock. Consistent with the extensive sepsis literature, all hemorrhagic shock. Intensive Care Med Exp 2016; 4:17.
other forms of shock exhibit an association between mortality rate and persistent 34. Sturm T, Leiblein J, Schneider-Lindner V, et al. Association of microcirculation,
hyperlactemia despite 624 h of resuscitation. This supports the importance of so- macrocirculation, and severity of illness in septic shock: a prospective observa-
called lactate clearance in monitoring resuscitation of acute circulatory failure, tional study to identify microcirculatory targets potentially suitable for guidance
regardless of shock cause. of hemodynamic therapy. J Intensive Care Med 2016. [Epub ahead of print]
18. Shankar-Hari M, Phillips GS, Levy ML, et al. Developing a new definition and 35. Top AP, Ince C, de Meij N, et al. Persistent low microcirculatory vessel density in
assessing new clinical criteria for septic shock: for the Third International nonsurvivors of sepsis in pediatric intensive care. Crit Care Med 2011; 39:813.
Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 36. Alegria L, Vera M, Dreyse J, et al. A hypoperfusion context may aid to interpret
315:775787. & hyperlactatemia in sepsis-3 septic shock patients: a proof-of-concept study.
19. Gotmaker R, Peake SL, Forbes A, Bellomo R. Mortality is greater in septic Ann Intensive Care 2017; 7:29.
& patients with hyperlactatemia than with refractory hypotension. Shock 2017. This is a very informative retrospective study in septic shock patients comparing
[Epub ahead of print] the prognostic ability of hyperlactemia with and without hypoperfusion defined by
This is a post-hoc analysis of the multicenter ARISE trial comparing outcomes in ScvO2 less than 70% or Pc(v-a)CO2 at least 6 mmHg. The presence of hypo-
septic shock patients with isolated, significant hyperlactemia (>4 mmol/l) versus perfusion in addition to hyperlactemia predicted greater vasopressor requirement,
isolated, fluid-refractory hypotension. Isolated hyperlactemia was associated with prolonged mechanical ventilation, longer ICU stay, more rescue therapies, and
higher morbidity and mortality. This emphasizes the greater clinical relevance of greater mortality. This study highlights both the complexities of interpreting
significant hyperlactemia compared with static hemodynamic parameters in the hyperlactemia in isolation and the utility of additional perfusion monitors, possibly
setting of septic shock resuscitation. together as a multimodal monitoring strategy.
20. Bakker J, de Backer D, Hernandez G. Lactate-guided resuscitation saves 37. Hernandez G, Luengo C, Bruhn A, et al. When to stop septic shock resuscita-
& lives: we are not sure. Intensive Care Med 2016; 42:472474. tion: clues from a dynamic perfusion monitoring. Ann Intensive Care 2014; 4:30.
One of three excellent editorials on the current state of lactate-guided resuscita- 38. Ince C, Guerci P. Why and when the microcirculation becomes disassociated
tion. This article emphasizes the complicated physiology of lactate metabolism and from the macrocirculation. Intensive Care Med 2016; 42:16451646.
the need to take this into account when interpreting study results. The authors 39. Hernandez G, Teboul JL. Is the macrocirculation really dissociated from the
recommend a multimodal perfusion monitoring strategy to best treat circulatory && microcirculation in septic shock? Intensive Care Med 2016; 42:16211624.
failure, whereas minimizing the impact of confounders of any one strategy. This is a thought-provoking editorial questioning the clinical relevance of micro-
21. Bloos F, Zhang Z, Boulain T. Lactate-guided resuscitation saves lives: yes. circulatory abnormalities. The authors argue that in the acute phase of shock,
&& Intensive Care Med 2016; 42:466469. microcirculatory changes frequently parallel and are redundant to standard of care
One of three excellent editorials on the current state of lactate-guided resuscita- macrohemodynamic parameters. In the subacute phase, however, persistent
tion. This article summarizes evidence supporting hyperlactemia and particularly its microcirculatory changes are often resistant to fluid administration. The authors
persistence as a predictor of morbidity and mortality. argue that these observations call into question the utility of microcirculation
22. Monnet X, Delaney A, Barnato A. Lactate-guided resuscitation saves lives: no. monitoring in everyday clinical practice. These valid concerns are addressed by an
&& Intensive Care Med 2016; 42:470471. excellent response [38].
One of three excellent editorials on the current state of lactate-guided resuscita- 40. Ince C. Hemodynamic coherence and the rationale for monitoring the micro-
tion. This article emphasizes the complicated metabolic role of lactate and the circulation. Crit Care 2015; 19 (Suppl 3):S8.
current scarcity of randomized controlled trials, evaluating lactate reduction as a 41. Naumann DN, Mellis C, Smith IM, et al. Safety and feasibility of sublingual
resuscitation guide. & microcirculation assessment in the emergency department for civilian and
23. Bakker J. Lactate levels and hemodynamic coherence in acute circulatory military patients with traumatic haemorrhagic shock: a prospective cohort
& failure. Best Pract Res Clin Anaesthesiol 2016; 30:523530. study. BMJ Open 2016; 6:e014162.
An excellent review of the current state of lactate-guided resuscitation with an This is a preliminary report on the feasibility of a major ongoing clinical trial
emphasis on the utility of multimodal perfusion monitoring strategies to better evaluating the utility of microcirculation monitoring in the resuscitation of traumatic
evaluate resuscitation and limit the impact of weaknesses inherent to each tool. hemorrhagic shock. Sublingual monitoring of microcirculation was shown to be
24. Zhou X, Liu D, Su L, et al. Use of stepwise lactate kinetics-oriented hemo- safe and practical even in an emergency situation.
&& dynamic therapy could improve the clinical outcomes of patients with sepsis- 42. van Genderen ME, Engels N, van der Valk RJ, et al. Early peripheral perfusion-
associated hyperlactatemia. Crit Care 2017; 21:33. && guided fluid therapy in patients with septic shock. Am J Respir Crit Care Med
This is a single-center, randomized controlled trial in septic shock patients 2015; 191:477480.
comparing outcomes with early goal-directed therapy versus a modified This is a very important proof-of-concept clinical trial in septic shock patients
protocol incorporating graded venous lactate reduction (i.e., 10% by 2 h, comparing standard hemodynamic-directed therapy with a multimodal perfusion
20% by 4 h, and 30% by 6 h) in place of the SvO 2 and transfusion arms. This evaluation-directed protocol incorporating capillary refill time, peripheral perfusion
builds on earlier lactate-guided resuscitation trials [25 &&,26&&] and likewise index, forearm-to-fingertip body temperature gradient, and tissue oxygenation
demonstrates reduced morbidity and mortality when lactate is used to direct saturation. Patients who were resuscitated according to peripheral perfusion
resuscitation. markers received less fluid and had shorter hospital stays and lower SOFA scores.
25. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous Although not evaluating the more advanced and informative sublingual microcir-
&& oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. culation dark-field microscopy technique, this study supports the utility of perfusion
JAMA 2010; 303:739746. monitoring and provides a framework for future microcirculation studies.
This is an early and important randomized controlled trial that demonstrated 43. Hernandez G, Tapia P, Alegria L, et al. Effects of dexmedetomidine and
noninferiority of lactate-guided compared with hemodynamically guided treatment esmolol on systemic hemodynamics and exogenous lactate clearance in early
of septic shock. experimental septic shock. Crit Care 2016; 20:234.

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Lactate and microcirculation as suitable targets Kiyatkin and Bakker

44. Contenti J, Occelli C, Corraze H, et al. Long-term beta-blocker therapy 49. Yin L, Yang Z, Yu H, et al. Changes in sublingual microcirculation is closely
& decreases blood lactate concentration in severely septic patients. Crit Care related with that of bulbar conjunctival microcirculation in a rat model of
Med 2015; 43:26162622. cardiac arrest. Shock 2016; 45:428433.
This very interesting retrospective study in septic shock patients revealed an 50. de Bruin AF, Kornmann VN, van der Sloot K, et al. Sidestream dark field
association between lower blood lactate concentration and -blocker therapy imaging of the serosal microcirculation during gastrointestinal surgery. Color-
regardless of a particular patients SOFA score. Although there was heterogeneity ectal Dis 2016; 18:O103O110.
between the two patient groups (e.g., less heart failure in the -blocker group), this 51. Kavanagh BP, Nurok M. Standardized intensive care. Protocol misalign-
study clearly highlights the important metabolic role of lactate and the danger of ment and impact misattribution. Am J Respir Crit Care Med 2016;
simplistically associating hyperlactemia with dysoxia. 193:1722.
45. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. 52. Ospina-Tascon GA, Bautista-Rincon DF, Umana M, et al. Persistently
Crit Care 2014; 18:503. high venous-to-arterial carbon dioxide differences during early resusci-
46. Arnemann PH, Hessler M, Kampmeier T, et al. Comparison of an automatic tation are associated with poor outcomes in septic shock. Crit Care
analysis and a manual analysis of conjunctival microcirculation in a sheep 2013; 17:R294.
model of haemorrhagic shock. Intensive Care Med Exp 2016; 4:37. 53. Jakob SM, Groeneveld AB, Teboul JL. Venousarterial CO2 to arterial
47. Carsetti A, Aya HD, Pierantozzi S, et al. Ability and efficiency of an automatic venous O2 difference ratio as a resuscitation target in shock states? Intensive
analysis software to measure microvascular parameters. J Clin Monit Comput Care Med 2015; 41:936938.
2016. [Epub ahead of print] 54. Mesquida J, Saludes P, Gruartmoner G, et al. Central venous-to-arterial
48. Naumann DN, Mellis C, Husheer SL, et al. Real-time point of care micro- carbon dioxide difference combined with arterial-to-venous oxygen
& circulatory assessment of shock: design, rationale and application of the point content difference is associated with lactate evolution in the hemody-
of care microcirculation (POEM) tool. Crit Care 2016; 20:310. namic resuscitation process in early septic shock. Crit Care 2015;
This is an interesting article addressing one of the major limitations of microcirculation 19:126.
monitoring the labor-intensive interpretation of microscopy videos. This is often cited 55. Vincent JL, Ince C, Bakker J. Clinical review: circulatory shock an update: a
as the major hindrance to the incorporation of this technique into everyday clinical tribute to Professor Max Harry Weil. Crit Care 2012; 16:239.
practice. Although one approach is to automate this process [46,47], another approach
is to develop faster and simpler data interpretation tools, as explored in this article.

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