INTRODUCTION
The resuscitation of patients in sepsis is a challenge for many reasons. One of the
important questions is: Who needs what kind of resuscitation? In the present
guidelines, resuscitation is mostly directed at patients with a high risk of
mortality. In this review, I will discuss the value of using lactate levels to
identify patients who might benefit from treatment and how to use sequential lactate
levels in the process.
THE CLINICAL SCENARIO
Although lactate has been advocated as a marker of tissue hypoperfusion by the
Surviving Sepsis Campaign guidelines when it rises above 1.0mmol/L,(1) aggressive
fluid resuscitation is
only recommended for patients with a lactate level above 4.0mmol/L, due to its
association with high mortality.(2)
However, the origin of hyperlactatemia and its treatment might be more complex.
First, it is important to realize that tissue hypoperfusion does not cause a rise
in
lactate until the decrease in oxygen delivery to the tissues (as an effect of
hypoperfusion) reaches a critical point, where it is insufficient to meet the oxygen
demand of the tissues, causing cellular dysoxia to occur and lactate levels to
increase.(3) Second, as the
clearance capacity of the liver almost disappears in sepsis,(4) persistently increased
lactate
levels may not be related to tissue dysoxia. Finally, other factors in sepsis might
contribute to increased lactate levels in the presence of adequate tissue oxygen
delivery.(5) Nevertheless,
lactate is an important marker of the patient's response to the initiated therapy.
In ALL forms of acute circulatory failure, a decrease in lactate levels is
associated with a more favorable outcome.(6) Thus, from this we can form our first
conclusion: If
lactate levels DO NOT decrease following the initiation of treatment, something is
wrong.
Although there are many reasons why patients with sepsis might have increased lactate
levels, in the early presentation of these patients, inadequate oxygen delivery is
the most likely cause. It is also the only cause we can effectively treat when we
exclude intoxications, inborn errors of metabolism and other metabolic causes of
increased lactate levels.(5) The
initial treatment of hyperlactatemia in patients with sepsis should be directed at
improving tissue oxygen delivery. This is most effectively accomplished by improving
global blood flow, which aims to improve microcirculatory perfusion. Other measures
that could be used simultaneously are improving arterial oxygen saturation,
improving hemoglobin levels and decreasing oxygen demand. When started immediately
upon admission to the ICU, this package will not only effectively decrease lactate
levels; it will also improve survival by 20%.(7) Although patients in afore mentioned
study(7) had a lactate concentration at or
above 3.0mmol/L, it is conceivable that patients with lower concentration levels
might also benefit, as lactate levels between 2.0 - 3.9mmol/L in patients with
suspected infection are associated with significant mortality, even in the absence
of hypotension.(8) The concept of
using the treatment package from the study by Jansen et al.(7) only in the early resuscitation
period (first 8 hours of ICU admission) was recently confirmed in a study on septic
shock survivors. Hernandez et al.(9) assessed the normalization ratio of lactate and
showed that a
biphasic curve existed. In the early hours (first 6 hours), lactate levels
normalized rapidly following the initiation of therapy. In the second phase (up to
24 hours), the normalization was much slower. In the end, 50% of the patients (all
survivors) had increased lactate levels at 24 hours after the initiation of
treatment. The authors speculated that, early in the course of sepsis, the increased
lactate levels quickly responded to improvements in tissue oxygen delivery (the main
effect of increasing cardiac output by fluid resuscitation and improving perfusion
pressure by using vasopressors). This phase might thus represent a flow-dependent
phase of hyperlactatemia whereas, in the later phase, the increased lactate levels
are probably more related to other factors. This allows a second conclusion on the
use of lactate levels in patients with sepsis: Increased lactate levels should be
seen as the consequence of inadequate tissue oxygenation for only a limited time in
the early course of sepsis. In addition, driving the patient to normal lactate
levels with the continued resuscitation of tissue perfusion/oxygenation might not
be
effective any longer.
The ultimate goal of resuscitation is to restore microcirculatory perfusion, not
macro hemodynamics.(10) However,
current guidelines/protocols are still mostly directed towards macrocirculatory
parameters, such as blood pressure, using aggressive fluid resuscitation. Although
recent trials on the use of early goal directed therapy (EGDT) have shown no benefit
over usual care,(11) we should
recognize that the resuscitation of sepsis patients has already changed
significantly. In the recent EGDT studies, fluid resuscitation was already done in
the majority of patients. Even in the lactate study by Jansen et al.,(7) lactate levels
had the exact same
trajectory in the control group patients compared to the protocol patients, despite
the fact that the treatment team was unaware of the actual levels. This brings up
a
relevant question: If the lactate levels were not different between the two groups,
why did the patients in the lactate oriented group have better survival? There were
few differences in the variables collected in the study that could explain this
effect. On average, the patients in the protocol group were treated with
approximately 500mL more fluids in the treatment period and over 1L less fluids in
the observation period (8 - 72 hours after initiation of treatment). In addition,
the use of nitroglycerin to improve microcirculatory perfusion (as demanded by
protocol in the protocol group) was more present in the protocol group than the
control group (43% versus 20% of the patients, respectively).
Although this did not result in differences in lactate levels, this adjustment in
therapy might have had a significant effect in the patients who really needed the
extra fluids and vasodilators when their lactate levels did not decrease as
projected (20% decrease per 2 hours in the protocol group). Second, the use of less
fluids in the observation period might have resulted in less morbidity associated
with fluid overload.(12-14)
One aspect, related to a comment made earlier, was not captured in the study. The
goal in the protocol group was to decrease lactate by at least 20% per 2 hours; upon
failure to meet this goal, a reassessment of the current treatment was initiated
and, in some patients, additional diagnostic procedures (CT-scan, echo, etc.) were
initiated and therapy was adjusted (laparotomy, change of antibiotic regimen,
etc.).
Therefore, given the above arguments, we can conclude that, in patients with sepsis,
early resuscitation of the circulation aimed to improve the balance between oxygen
delivery and oxygen demand, thereby restoring tissue oxygenation using a multimodal
approach that is effective in improving survival. Several important factors should
be taken into account when using this approach. First, this approach should be used
for a limited time (current evidence suggests 6 - 8 hours). Although the original
study(7) used a lactate
level above 3.0mmol/L, studies suggest that this regimen might be effective in all
sepsis patients with increased lactate levels (above 2.0mmol/L). Following the start
of resuscitation, lactate levels should decrease rapidly if the balance between
oxygen demand and oxygen delivery indeed improves (Figure 1). Therefore, frequent
measurements (at least every 2 hours)
should be part of the resuscitation protocol. If the therapeutic measures do not
result in a rapid decrease in lactate levels, then RETHINK, REASSESS and
RESOLVE.
Figure 1
How to use lactate in resuscitating sepsis associated circulatory
dysfunction.