Journal of Critical Care 29 (2014) 334–339

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Journal of Critical Care

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Prognosis of emergency department patients with suspected infection

and intermediate lactate levels: A systematic review
Michael A. Puskarich, MD, Benjamin M. Illich, Alan E. Jones, MD ⁎
Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, MS

a r t i c l e i n f o a b s t r a c t

Keywords: Purpose: Previous studies have shown a correlation between blood lactate greater than 4.0 mmol/L and
Infection mortality in patients with suspected infection in the emergency department (ED), but data are more limited
Lactate regarding the prognosis of intermediate blood lactate (2.0-3.9 mmol/L), particularly in the absence of
Prognosis hemodynamic instability. We sought to quantify the prognostic significance of intermediate blood lactate
Review
levels in ED patients with suspected infection, emphasizing patients without hypotension.
Methods: A systematic review of 4 databases was conducted to identify studies using a comprehensive search
strategy. All studies performed on adult ED patients with suspected infection and available data on
hemodynamics, intermediate lactate levels, and mortality rates were included.
Results: We identified 20 potential publications, 8 of which were included. Intermediate lactate elevation was
found in 11062 patients with suspected or confirmed infection, 1672 (15.1%) of whom died. Subgroup
analysis of normotensive patients demonstrated a mortality of 1561 (14.9%) of 10 442, with rates from
individual studies between 3.2% and 16.4%.
Conclusion: This systematic review found that among ED patients with suspected infection, intermediate
lactate elevation is associated with a moderate to high risk of mortality, even among patients without
hypotension. Physicians should consider close monitoring and aggressive treatment for such patients.
© 2014 Elsevier Inc. All rights reserved.

1. Purpose identification of at-risk patients for whom bundled care is appropriate

In the United States, emergency departments (EDs) treat approxi-
mately 570 000 patients with sepsis yearly [1]. In addition, there are 200
000 US deaths attributed to sepsis annually [2], with estimated mortality
rates ranging from 15% to 30% based on administrative databases [3].
Despite active research in the field, early administration of bundled care
and quantitative resuscitation protocols remains the most consistently
beneficial therapy for the treatment of severe sepsis available in the ED.
Despite success in the literature, adoption of such protocols has been
slow for numerous reasons, including lack of nursing expertise, inability
to measure a central venous pressure [4], and inclusion in early goal-
directed therapy based on lactate criteria (rather than hypotension) [5].
Furthermore, the placement of central venous lines is accompanied by
certain risks including pneumothorax, arterial injury [6], and exposure
to the risk of catheter-related blood stream infections [7], a major target
of quality improvement initiatives. Furthermore, such protocols increase
medical cost per patient, and although such protocols appear to be cost-
effective in terms of life years gained when considering all patients with
septic shock [8,9], it is expected that as the risk of death decreases, cost-
effectiveness will decrease as well. Thus, it is evident that specific
⁎ Corresponding author. Department of Emergency Medicine, University of Mississippi
Medical Center, 2500 N State St, Jackson, MS 39216.
E-mail address: aejones@umc.edu (A.E. Jones).
should be balanced against the unnecessary risks and expense that
accompanies the overtreatment for low-risk individuals.
The prognostic value of lactate in ED patients with suspected
infection and septic shock is well known [10,11], and increasing levels
have been demonstrated to have a curvilinear relationship with
mortality [12,13] with no clear stepwise “break” to separate low,
moderate, or high risk of death, making proscriptive assessment and
treatment guidelines based on these criteria difficult. Based on the
original study of early goal-directed therapy [14], the current threshold
for initiating early goal directed therapy in the absence of hypotension
is a serum lactate greater than 4.0 mmol/L [15]. This number appears to
have been selected arbitrarily to define “high” serum lactate, though
these patients are clearly at a high risk of death. Observations suggest
that patients with a lactate in this range (N 4.0 mmol/L) without
hypotension that undergo quantitative resuscitation have a mortality
rate not significantly different from those patients requiring vasopres-
sor requirement [16]. What remains unclear, however, is whether
patients with an intermediate range lactate, particularly in the absence
of hypotension, might similarly benefit from initiation of some type of
quantitative resuscitation protocol. As a first step to address this
question, we conducted a systematic review to determine the risk
associated with a lactate of 2.0 to 3.9 mmol/L (intermediate range),
with an emphasis on the subgroup of patients without hypotension, in
order to determine the risk of death in this patient population.

0883-9441/$ – see front matter © 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jcrc.2013.12.017
 M.A. Puskarich et al. / Journal of Critical Care 29 (2014) 334–339
2. Materials and methods
2.1. Search strategy for identification of studies
We followed a written protocol that was designed in accordance
with recommended guidelines and finalized prior to beginning the
study [17]. A preliminary search strategy was developed using
exploded Medical Subject Heading terms and keywords involving
sepsis, systemic inflammatory response syndrome (SIRS), lactate, and
outcome. This strategy was revised and improved upon by a medical
librarian. We searched MEDLINE (1950–July 2013), SCOPUS (1996–
July 2013), Cochrane Library (2005–July 2013), and CINAHL Plus
(1937–July 2013) using a search strategy outlined in Appendix 1.
Briefly, our final search strategy included the search terms lactates or
acidosis, lactic, and bacterial infections or brain abscess or central
nervous system infections or infections, or systemic inflammatory
response syndrome and was limited to human studies that reported
either prognosis or an outcome assessment (health care). All results
were supplemented with a review of their related articles [18].
2.2. Inclusion criteria
We considered studies eligible for review, regardless of language
or publication type, if they were observational studies of human
adults (age N17 years) admitted through the ED, with a diagnosis of
SIRS, sepsis, or infection-related diagnosis with available lactate and
hemodynamic data. Reviews, correspondence, editorials, and nonhu-
man studies were excluded; however, their reference lists were
screened if relevant to identify further studies for inclusion. We
attempted to contact corresponding authors for clarification of
missing or incomplete data.
2.3. Study selection and data abstraction
Two reviewers (B.M.I. and A.E.J.) independently screened the titles
and abstracts of identified studies for potential eligibility. Cases of
disagreement were resolved by conference between the reviewers. If
agreement could not be reached, the full manuscript was obtained for
review. The full manuscript of each study that passed the relevance
screen was reviewed by one of the investigators (B.M.I.). Study data
were abstracted independently by each reviewer using a standardized
data collection form. In cases of disagreement in abstracted data, a
third reviewer abstracted the data and consensus was reached by
conference between the 3 reviewers.
Fig. 1. Search, inclusion, and exclusion flow diagram.
335
2.4. Outcome measurements
The primary outcome of interest was 28-day mortality. Other
mortality data were also accepted, such as in-hospital mortality and
30-day mortality. To assess the prognostic significance of an
intermediate lactate in the setting of normotension on morbidity,
we report the rates of progression to either shock or Sequential Organ
Failure Assessment (SOFA) score increase of more than 1 if available.
2.5. Subgroup analysis
A predefined subgroup of patients with an intermediate lactate
and no evidence of hypotension was examined to describe the
mortality in this group of patients and compared with those patients
with an intermediate lactate and hypotension, when specified. If
hemodynamic data were unavailable, we attempted to contact the
authors to obtain these data. If the data were unavailable or we failed
to receive a response, these patients were excluded from the
subgroup analysis. To assess if our choice of outcome measure
affected our results, we compare the summary 28- and 30-day
mortality rates with the summary in-hospital mortality rate.
2.6. Data analysis
Given significant methodological differences between studies,
combining the data using meta-analytic techniques was deemed
inappropriate. Therefore, we used simple descriptive statistics to
present mortality rates as percentages, with accompanying ranges,
when appropriate. Summary mortality rates for various groups are
reported as a raw sum of total number of deaths divided by total
number of patients.
3. Results
3.1. Study selection
Searching the databases identified 302 potential publications for
review (Fig. 1). Reviewing reference lists and related articles found 5
other potential studies. After removing duplicates and screening titles
and abstracts, 287 articles were excluded as irrelevant and 20 articles
were found to be appropriate for further review. The 20 relevant
articles were retrieved in full text. A single reviewer examined all of
the references obtained. Twelve of these articles were excluded
for failing to meet inclusion criteria. Reasons for exclusion include
using a main diagnosis other than sepsis in patient cohorts, lack of
336 M.A. Puskarich et al. / Journal of Critical Care 29 (2014) 334–339

intermediate lactate data (in some cases, authors were contacted for
these data), and the use of a patient database from an already included
study. Overall, 8 studies were identified for inclusion [12,18-24].
3.2. Description of included studies
Table 1 summarizes the characteristics of the included studies. Five
of the studies were prospective cohorts, and 3 were retrospective.
Seven were performed in the United States, and 1 was performed in
South Korea. Intermediate lactate elevation was variably defined as
2.0 to 3.9, 2.0 to 4.0, 2.1 to 3.9, and 2.5 to 4.0. Reported mortality rates
included 3-, 28-, and 30-day mortality, as well as in-hospital
mortality. All studies reporting 3-day mortality also reported 28-day
or in-hospital mortality, which was preferentially used for summary
descriptive analysis as defined a priori. Six of the 8 studies either
reported data to allow for specific subgroup analyses, or authors were
able to provide these data upon being contacted.
3.3. Summary of individual included studies
Four studies were identified and included in our analysis that
evaluated the prognostic value of lactate and included groups of
patients with intermediate lactate levels with or without hypotension.
Shapiro et al [19] performed a prospective cohort study regarding
using serum lactate as a biomarker for predicted sepsis outcome.
Inclusion criteria were adults admitted through the ED with an
infection-related diagnosis and serum venous lactate obtained. Out-
comes reported were 3- and 28-day hospital mortality. A total of
1278 patients were enrolled. Lactate was divided into low (0-2.5
mmol/L), intermediate (2.5-4.0 mmol/L), and high (N4.0 mmol/L)
groups. The intermediate group had a mortality rate of 24 (9.0%) of
267 at 28 days. Hemodynamic data were not available for subgroup
analysis. Howell et al [21] published a prospective observational
cohort study determined to identify the relationship between early
serum venous lactate and 28-day mortality in patients with clinically
suspected infection. Lactate was similarly divided into low (0-2.5
mmol/L), intermediate (2.5-4.0 mmol/L), and high (N4.0 mmol/L)
groups. Author contact was necessary to derive the complete data
reported below and in Table 1. Overall mortality was 18 (7.3%) of 246
at 28 days in the intermediate lactate group. Among our predefined
subgroup of patients without hypotension, the intermediate lactate
group had 12 (5.2%) of 229 deaths at 28 days. Comparatively, those
with hypotension (defined as lowest blood pressure in the ED,
without details regarding whether this represented transient or
refractory hypotension) and intermediate lactate had a mortality of
35.3% (6/17 patients).
Trzeciak et al [20] published post hoc analysis of a prospectively
gathered data set in order to determine the usefulness of initial serum
lactate as a predictor of hospital mortality. Inclusion criteria were age
N 18 years, primary or secondary diagnosis of infection, hospital
admission, and a measurement of lactate. In-hospital mortality rate
was 25% in the intermediate lactate groups. Intermediate lactate was
defined as 2.1 to 3.9 and had a total of 59 (24.8%) of 238 deaths.
Specific hemodynamic data were not recorded in this patient registry
for further subgroup analysis. Mikkelsen et al [12] published a
retrospective cohort study to determine if lactate was an independent
predictor of mortality in patients with infection. Patients with severe
sepsis were placed into a shock (persistent hypotension despite
adequate crystalloid bolus) or nonshock group, based on accepted
consensus definitions [25]. Intermediate lactate was defined as 2.0 to
3.9 mmol/L, and the 28-day mortality rates were 16.4% for the
intermediate lactate normotension group and 37.3% in patients with
intermediate lactate levels and shock.
Four further studies were identified that excluded patients with
hypotension with the specific goal of documenting the incidence and
determining risk factors for the progression to shock among ED
patients with suspected infection. Glickman et al [22] published a
multicenter prospective cohort study with the goal of identifying risk
factors among hemodynamically stable septic patients in order to
predict those patients who would progress to shock. Inclusion criteria
were patients presenting to the ED with 2 or more SIRS criteria,
confirmed infection, and normotension at presentation. The author
was contacted directly for information regarding the intermediate
lactate group. In patients with a lactate from 2.0 to 3.9 mmol/L, the
30-day mortality was 13 (9.4%) of 138. Song et al [23] published a
retrospective cohort study in 2012 specifically addressing patients
with sepsis and intermediate lactate level (2.0-4.0 mmol/L). The
study was designed to identify risk factors associated with clinical
deterioration. Inclusion criteria were patients admitted through the
ED with stable hemodynamics and intermediate lactate levels. Of 474
patients enrolled, 48 (10.1%) died in-hospital. Of further interest, 108
(22.7%) of 474 of these progressed to shock with 72 hours of ED
arrival. Arnold et al [24] published a multicenter prospective
observational study aimed at identifying demographic and physio-
logic parameters associated with progressive organ failure in patients
with “preshock” sepsis, defined as normotension with a lactate of
between 2.0 and 3.9 mmol/L. This study used a modified SOFA score
as a secondary outcome assessment. The in-hospital mortality rate
reported in this study was significantly lower than the others, with
only 3 deaths (3.2% mortality). The primary outcome in this study
was the composition outcome of a rise in SOFA of more than 1,
initiation of vasopressors or mechanical ventilation within 72h of

Table 1
Summary of studies reporting mortality data in patients with an intermediately elevated lactate

Author Study design Intermediate definitiona Outcomeb Overall Normotensive subgroupc Hypotensive subgroupd

Shapiro et al [19] Prospective 2.5-4.0 28-d 24/267 (9.0%) No hemodynamic data available
3-d 12/267 (4.5%)
Howell et al [21] Prospective 2.5-4.0 28-d 18/246 (7.3%) 12/229 (5.2%) 6/17 (35.3%)
Trzeciak et al [20] Prospective 2.1-3.9 In-hospital 59/238 (24.8%) No hemodynamic data available
3-d 20/238 (8.4%)
Mikkelsen et al [12] Retrospective 2.0-3.9 28-d 74/415 (17.8%) 52/317 (16.4%) 22/59 (37.3%)
Glickman et al [22] Prospective 2.0-3.9 30-d 13/138 (5.8%) 13/138 (5.8%) Excluded by study design
Song et al [23] Retrospective 2.0-4.0 In-hospital 48/474 (10.1%) 48/474 (10.1%) Excluded by study design
Progression to shock 108/474 (22.7%) 108/474 (22.7%)
Arnold et al [24] Prospective 2.0-3.9 In-hospital 3/94 (3.2%) 3/94 (3.2%) Excluded by study design
Progression to SOFA N1 24/94 (26%) 24/94 (26%)
Liu et al [18] Retrospective 2.0-3.9 In-hospital 947/9190 (10.3%) 947/9190 (10.3%) Excluded by study design
30-d 1433/9190 (15.6%) 1433/9190 (15.6%)
a
Intermediate lactate as defined by study, mmol/L.
b
Mortality unless otherwise specified.
c
Patients with an intermediate lactate without hypotension: deaths (n)/total (n) (%).
d
Patients with an intermediate lactate with hypotension: deaths (n)/total (n) (%).
 M.A. Puskarich et al. / Journal of Critical Care 29 (2014) 334–339
enrollment, or in-hospital death from any cause. Of the 94 patients
enrolled, 24 (26%) met the composite outcome.
The largest patient cohort responsible for most patients was
recently published by Liu et al [18], who reported a retrospective
study that included 9190 patients with a diagnosis of sepsis on
admission and an initial lactate between 2.0 and 3.9 mmol/L. The aim
of this study was to evaluate the association between initial
intermediate lactate levels, lactate clearance, fluid resuscitation, and
mortality. Outcomes included in-hospital and 30-day mortality, with
947 (10.3%) and 1433 (15.6%) deaths, respectively. Furthermore, this
study subdivided the cohort into those with and without lactate
clearance. Most patients (79.5%) showed some improvement in
lactate levels by 12 hours. The 30-day mortality rate for this group
was 13.3%, whereas it was 24.7% in patients without lactate clearance,
consistent with other literature suggesting a favorable prognosis
associated with early lactate clearance [26,27].
3.4. Summary mortality, subgroup mortality, and progression to
shock rates
Collectively, 11 062 patients were found to meet the inclusion
criteria in 8 patient cohorts. Of these 11 062 patients, 1672 (15.1%)
had a final outcome of death (in-hospital, 28-day, or 30-day
mortality). Further analysis of patients with known normotension
(via exclusion of patients with unknown hemodynamics or those
patients with known hypotension) left 10 442 patients with inter-
mediate lactate values without hypotension. There were 1561 deaths
in this subgroup, for an overall mortality rate of 14.9%, with an
individual study range from 3.2% to 16.4%. Although not a primary
goal of the study, our review identified a minority of patients with
both intermediate lactate levels and hemodynamic instability.
Mortality rates in this group of patients were only explicitly described
by 2 studies, 35% [21] and 37% [12], respectively. Undoubtedly, there
were more hemodynamically unstable patients in 2 other studies
[19,20], but lack of hemodynamic data made further analysis
impossible. Mortality was similar between those studies reported
28- to 30-day and in-hospital mortality rates (15.3% [1510/9874] vs
10.2% [998/9758]). Hospital length of stay of these patients was only
reported in 2 studies, with a median of 4 (intraquartile range, 2-7)
[24] and a mean (SD) of 6.1 (7.8) days [18]. Only 1 study reported ICU
length of stay, a median of 0 days (intraquartile range, 0-1) [24].
Considering prospective vs retrospective studies, mortality results
were similar (11.9% [117/983] vs 10.6% [1069/10 079]), suggesting
against significant bias within the retrospective studies and against all
of the effects being driven by the single large retrospective cohort.
Patients with an intermediate lactate and hypotension had a 28-day
mortality that was approximately double (24.3% [28/115 patients])
that of those with normotension. For comparison, studies reporting
mortality rates for the high lactate group (N4.0 mmol/L) with
normotension observed mortality rates ranging from 26.5% to 31.8%.
Finally, the overall rate of progression to shock or SOFA greater than 1
was 23.2% (132/568).
4. Discussion
In this systematic review, we used standardized methodology to
identify and report the prognostic value of intermediately elevated
lactate values in ED patients with suspected infection but without
hemodynamic instability and found an overall summary rate of 15%,
indicating a nontrivial risk of either in-hospital or 28- to 30-day
mortality. This is compared with mortality rates for other acute
emergency care conditions such as myocardial infarction (~ 5%) [28],
nonmassive pulmonary embolism (15%) [29], and ischemic (12%)
stroke [30]. We believe that these data highlight the poor prognosis
associated with even a slightly elevated lactate level in the setting of
337
suspected infection and should prompt clinicians to consider more
aggressive monitoring and/or therapy for these patients.
In the ED, the goal of a physician is to rapidly and accurately assess
the severity of a person's illness in order to appropriately choose
therapy. Serum lactate has become standard in the assessment of
patients with suspected infection [15]. However, despite the data
regarding the prognosis associated with intermediate lactate levels
(2.0-3.9 mmol/L), a consensus regarding what constitutes appropri-
ately aggressive treatment in this group of patients has yet to emerge.
Rivers et al [14] and the Surviving Sepsis Campaign [15] guidelines
defined the use of early goal-directed therapy for patients with lactate
greater than 4.0 mmol/L even in the absence of persistent hypoten-
sion. The data in this review suggest that restricting aggressive
resuscitation therapy to only this cohort of patients could potentially
miss further at-risk patients in the intermediately elevated lactate
group, and we would advocate for more aggressive identification,
monitoring, and treatment for these patients.
There is no current consensus regarding the therapeutic plan for
this group of patients. It would be easy to suggest that merely
extending early goal-directed therapy and quantitative resuscitation
protocols to these patients is indicated given their similar pathophys-
iology and relatively high mortality rates. However, such a strategy
would require placement of a large number of central venous
catheters with all of their attendant risks, in a group of patients that
may or may not require them. Although the subgroup of patients with
both hypotension and an intermediately elevated lactate would
qualify for quantitative resuscitation strategies [15] and may require
vasopressors if unresponsive to fluid resuscitation, most patients
included in this review had no clinical indication for vasopressors (ie,
refractory hypotension), at least not initially in the ED. Placement of
central venous catheters in this group of patients would therefore be
solely for the purposes of monitoring central venous pressure, the
value of which has been questioned [31]; monitoring central venous
oxygen saturation, which is of unproven value in this group of
patients; or “prophylactically” in the event that the patient might later
deteriorate and require vasopressors.
Therefore, therapeutic options for these patients at high risk of
clinical deterioration remain of uncertain benefit at this time. At a
minimum, given data suggesting a high rate of progression to shock
[23,24], close monitoring would seem indicated in these patients so
that appropriate therapy can be initiated immediately if the patient
progresses to septic shock. Based on data suggesting the association
between administration of antibiotics and time of shock onset
[32-34], it would also seem reasonable to continue to advocate for
aggressive, early antibiotic administration as soon as feasible in this
group of patients with a high risk of death, although we are aware of
no data that clearly demonstrate the time sensitivity of antibiotic
administration in patients without hemodynamic shock. Intravenous
fluid resuscitation, given its cornerstone place in the resuscitation of
septic shock, would seem to be another reasonable therapeutic
option, although it remains of unproven benefit in this situation.
Finally, in the setting of normotension where resuscitation to specific
physiologic end points such as blood pressure is not an option, lactate
clearance (decrease in lactate levels over time) may prove to be a
reasonable therapeutic target, given its prognostic value [10,35] and
use in the setting of septic shock [15]. This issue is of particular
relevance and may be an area for future research, as the most recent
Surviving Sepsis Campaign guidelines now given a 2C recommenda-
tion for the use of lactate normalization (the decrease of an abnormal
lactate to a subsequent normal lactate) as a therapeutic target during
the first 6 hours of resuscitation. Although 2 randomized clinical trials
have demonstrated the use of lactate clearance as a resuscitation
parameter, the 2C recommendation results partly due to the fact
that these studies used different lactate clearance goals (10% and
20%, respectively) and that no interventional trial to date has
evaluated the use of lactate normalization as a therapeutic target.
338 M.A. Puskarich et al. / Journal of Critical Care 29 (2014) 334–339
Since the publication of these guidelines, one observational study
has demonstrated the prognostic but not therapeutic value of lactate
normalization [36]. As with the other aforementioned therapies,
targeting lactate normalization remains unstudied among patients
with intermediate lactate levels and normotension and requires
further study.
4.1. Strengths and limitations
Using standardized predetermined methodology, we performed a
comprehensive literature review, more than 11 000 with an interme-
diate lactate level and more than 10 000 with stable hemodynamics.
These data give us insight into the prognostic value of intermediate
lactate values in the setting of suspected infection. Although our
search was broad and encompassed numerous medical libraries, it is
possible that conference abstracts and other unpublished data from
the “gray” literature were not identified, limiting our results.
Furthermore, given the significant methodologic differences between
studies, it would not have been appropriate to perform a meta-
analysis in this setting, which limits the interpretation of any pooled
data. Finally, a systematic review is limited by the quality of the
published literature, and any selection bias or differential treatment
for these patients for whom no clear standard of care exists may have
affected our results and reported mortality rates.
5. Conclusion
In this systematic review, we found that among ED patients with
suspected infection, intermediate lactate elevation is associated with
a moderate to high risk of mortality compared with many other acute
care diseases, even among patients without hypotension. Physicians
should be aware of the poor prognosis of this group of patients, should
monitor them closely, and give consideration to more aggressive
treatment in order to prevent further progression to shock or death.
Acknowledgments
Dr Jones has received salary support from the National Institute of
General Medical Sciences (R01 GM103799). Dr Puskarich received
salary support from a Career Development Grant from the Emergency
Medicine Foundation.
Appendix 1. Representative search strategy for the
Medline database
b1950 to JULY 2013N
1. Lactates/(55420)
2. Acidosis, Lactic/(6720)
3. (((bacterial infections) OR brain abscess) OR central nervous
system infections) OR infections (1875648)
4. Systemic Inflammatory Response Syndrome (92052)
5. (Lactates) OR Acidosis, Lactic/(59597)
6. (((((bacterial infections) OR brain abscess) OR central nervous
system infections) OR infections)) OR Systemic Inflammatory
Response Syndrome (1881924)
7. Prognosis/(11211486)
8. Outcome Assessment (Health Care)/(130252)
9. (Prognosis) OR Outcome Assessment (Health Care) (1186218)
10. (((((Lactates) OR Acidosis, Lactic/)) AND ((((((bacterial infec-
tions) OR brain abscess) OR central nervous system infections) OR
infections)) OR Systemic Inflammatory Response Syndrome)))
AND (((Prognosis) OR Outcome Assessment (Health Care)) (310)
11. Limit (#10) to HUMANS, AGE 19 + (193)
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