Mashhad University of Medical Sciences

(MUMS) Reviews in Clinical Medicine Clinical Research Development Center

Ghaem Hospital

Serum lactate is a useful predictor of death in severe sepsis and

septic shock
Jafar Malmir (MD)*1, Ehsan Bolvardi (MD)1, Monavar Afzal Aghaee (MD)2
1
Department of Emergency Medicine, Imam Reza hospital, School of Medicine, Mashhad University of Medical Sciences,
Mashhad, Iran
2
Department of Community Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

ARTICLE INFO ABSTRACT

Article type The severe sepsis and septic shock are as common and lethal that
Review article emergency physicians routinely confront. Actually, more than two thirds
of sepsis patients present initially to the ED. Only a few laboratory tests
Article history for markers of sepsis are currently available. The serum lactate level can
Received: 28 Jan 2014
Revised: 10 Feb 2014
help in determining prognosis and to risk-stratify patients with severe
Accepted: 24 Feb 2014 sepsis. This independent review of the literature includes 83 studies
published in all electronic-based database such as Elsevier, PubMed, and
Keywords SID during the last 18 years (40–320 patients in each). Data gathered
Lactate from English language articles and books published between 1995 and
Prognostic factor 2013. The serum lactate concentrations measured in almost all patients
Severe sepsis
with severe sepsis raised at admission and were higher in patients who
had the worst outcomes such as higher Apache-II and SOFA score. Serum
lactate was associated with mortality independent of clinically apparent
organ dysfunction and shock in patients with severe sepsis admitted to the
emergency department and intensive care unit.
This review focuses on the association between initial and serial serum
lactate level and mortality in patients presenting to the emergency
department with severe sepsis.

Please cite this paper as:

Malmir J, Bolvardi E, Afzal Aghaee M. Serum lactate is a useful predictor of death in severe sepsis and Septic
Shock. Rev Clin Med. 2014;1(3):97-104.

Introduction
Sepsis is a heterogeneous clinical microorganism. The incidence of severe
syndrome caused by any class of sepsis and the number of sepsis-related

*Corresponding author: Jafar Malmir. This is an Open Access article distributed under the
Department of Emergency Medicine, Imam Reza terms of the Creative Commons Attribution License
hospital, School of Medicine, Mashhad University (http://creativecommons.org/licenses/by/3.0),
of Medical Sciences, Mashhad, Iran which permits unrestricted use, distribution, and
E-mail: malmirj901@mums.ac.ir reproduction in any medium, provided the original
Tel: 09187075614 work is properly cited.

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Malmir J et al.

deaths is increasing (1-3). There has not Sepsis is a fatal syndrome caused by
been a scientific basis for identification of severe infection. Severe sepsis is defined as
high-risk patients or a practical standard for the presence of one or more organ system
hemodynamic optimization and adjunctive dysfunction in the context of sepsis.
pharmacological therapies in the emergency Organ dysfunction includes as pulmonary
department (ED) (4). and hematologic abnormalities, neurologic
According to several randomized, disorder, renal dysfunction, liver or cardiac
controlled trials, during the past few years, failure or hypo-perfusion with lactic acidosis.
overall mortality rate among patients with Septic shock is defined as the presence of
severe sepsis and septic shock is declining sepsis and refractory hypotension in which
(5-7). The concept of empirical therapy has intravenous fluid administration alone is
changed in order to antimicrobial resistance insufficient to maintain the hemodynamic
to several agents (8,9). of the patient.
Although there is no specific laboratory Bacteremia is found only in about 50%
test for the diagnosis of severe sepsis and of cases of severe sepsis and septic shock,
septic shock, the improvement in imaging whereas 20% to 30% of patients will have
and noninvasive interventional techniques no microbial causes identified from any
have led to new diagnostic and therapeutic source.
strategies for early source control.
Despite dramatic improvement in our Epidemiology
knowledge about severe sepsis, there is Sepsis is now the 10th most common
always a long delay in diagnosis of sepsis cause of death in the United States. A recent
and initiation of treatment, which increase study defined severe sepsis as “infection”
the incidence of organ failure and mortality. and “new-onset organ dysfunction. The
It seems that the management of severe incidence of sepsis and severe sepsis
sepsis is time-dependent suggesting a continues to increase exponentially with
“golden hour” and “silver day” giving the age. Severe sepsis occurs in 1-2% of all
ED a more important role in the care of hospitalizations. It costs an estimated 16.7
these patients. $ billion annually. Incidence and mortality
The cornerstone of treatment of severe of severe sepsis is always underestimated,
sepsis is the early diagnosis, administration however, overall hospital mortality rate was
of appropriate antibiotics, and early 28.6 % (10).
hemodynamic resuscitation.
Systemic inflammatory response syndrome Pathogenesis
(SIRS) is an inflammatory state, which There are several pathogenic events,
defines as the presence of 2 or more of the which are responsible for the transition from
following criteria: sepsis to severe sepsis/septic shock. These
1) Temperature greater than 38°C or less include a neurohumoral, generalized pro-
than 36°C and anti-inflammatory responses. The sepsis
2) Pulse rate greater than 90 beats/minutes cascade begins with a cellular activation of
3) Respiratory rate greater than 20 breaths/ monocytes, macrophages, neutrophils and
min (or PaCO2 less than 32 torr). activation of the complement that interacts
4) WBC count greater than 12,000/mm3 or with endothelial cells through numerous
less than 4,000/mm3, or greater than 10% pathogen recognition receptors (11). The
immature band forms. other mediators that may participate are

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 Malmir J et al.

tumor necrosis factors (TNF)-α, interleukins, cardinal sign of sepsis, unless patients have
caspases, proteases, leukotrienes, kinins, intrinsic cardiac disease or is taking nodal
reactive oxygen species, nitric oxide, blocking medications, tachycardia is nearly
arachidonic acid, platelet activating factor universal. Abnormalities in circulating
and eicosanoids. The vascular endothelium leukocyte count (more than 12,000 cells/
damage results in tissue ischemia and this mm3 or fewer than 4000 cells/mm3) are
diffuse endothelial disruption is responsible frequent enough to be considered important
for the various organ dysfunctions and diagnostic criteria.
global tissue hypoxia that accompanies Several serum biomarkers are purported
severe sepsis/septic shock. to have diagnostic and/or prognostic value,
but none have demonstrated acceptable
Presentation and diagnosis sensitivity and specificity for routine
Sepsis is diagnosed by history and physical clinical use.
findings, corroborated by laboratory data The serum lactate level is suggested to be
such as circulating leukocyte count, body a marker of global hypo-perfusion and tissue
fluid examination and culture. hypoxia in sepsis. According to the theory,
Detecting the syndrome in hospitalized even before patients develop frank hypoten-
patients is particularly important, as sion, tissue perfusion is impaired by myo-
nosocomial sepsis is associated with cardial depression, relative hypovolemia
longer lengths of stay and higher mortality from a leaky endothelium, increased meta-
rates compared with community-acquired bolic demands and impaired vasoregulatory
sepsis (12). Most patients will meet at mechanisms. Consequently, oxygen demand
least three SIRS criteria at intensive care exceeds supply and anaerobic production of
unit (ICU) admission (13). Fever occurs lactate ensues. Not all agreed that lactate
in approximately 60% of patients at production was a reliable marker of global
admission but may be suppressed in those hypoxia in sepsis (15).
with advanced age, renal failure or patients Animal models of polymicrobial sepsis
taking anti-inflammatory medications suggested that certain organs, particularly
(14). Hypothermia, although uncommon, the liver and small intestine, may be more
is an ominous finding associated with sensitive to impaired oxygen delivery
mortality rates of up to 60%. The lethality (16). Regardless of its exact mechanism of
of hypothermia likely is not a consequence production, patients admitted with a sepsis-
of the temperature itself but rather related diagnosis and elevated serum lactate
the relationship of hypothermia with levels (greater than 4 mmol/L) had an
underlying chronic diseases, shock and increased mortality rate (17). Furthermore,
an exaggerated inflammatory response. mortality rates have decreased in septic
Tachypnea is present in up to 80% of ICU patients with higher lactate clearance rates
patients. Although possible, the diagnosis after 6 hours of therapy (18). Serum lactate is
should be questioned in patients lacking a component of prognostic models in severe
tachypnea or gas exchange abnormalities. sepsis and septic shock and concentrations
Hypoxia is common in septic patients; more increased in these patients.
than 90% of patients will develop sufficient Procalcitonin and C-reactive protein
hypoxemia that requires supplemental (CRP), both markers of inflammation, have
oxygen, generally correlating with a PaO2/ been studied as potential diagnostic tests in
FiO2 ratio less than 300. Tachycardia is a sepsis (19-21). The reported sensitivities

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Malmir J et al.

and specificities of these tests vary widely, sepsis leading to morbidity and mortality
hence neither has achieved widespread characterized by global tissue hypoxia,
acceptance. decreased contractility and ventricular
dilatation.
Scoring systems and ability to predict In recent studies, echocardiographic
outcome findings demonstrated that in 40-50%
Most prognostic models evaluate survival of patients with severe sepsis developed
using data collected at admission or within myocardial depression and changes in
the first 24 hours in ED. There are two cardiac performances.
types including general models and disease- The responsible mechanisms for
specific models. this organ dysfunction are probably
The main categories of general prognostic mitochondrial dysfunction, myocardial cell
models include: death; however, the cardiac function is fully
1) The models for evaluating the severity reversible in the survived patients.
of illness: 2) Hematologic dysfunction
- APACHE II and III Hematologic manifestation of organ
-Simplified Acute Physiology Score dysfunction is well-recognized in severe
(SAPS) II sepsis. The most common abnormalities
- Mortality Prediction Model (MPM) II, include leukocytosis, anemia, abnormal PT
2) The models for quantifying organ and aPTT, DIC and thrombocytopenia.
dysfunction and failure: 3) Neurologic dysfunction
- Logistic Organ Dysfunction System Patients with sepsis often display
- Multiple Organ Dysfunction Score neurologic impairments manifested by
- Organ System Failure (OSF) altered mental status and lethargy, commonly
- Sequential Organ Failure Assessment referred as septic encephalopathy. The
(SOFA). incidence has been reported between 10
and 70%. The mortality rate in patients
Organ Dysfunction with septic encephalopathy is higher than
The organ dysfunction that results from that in septic patients without significant
sepsis is central to the pathogenesis of the neurologic involvement.
disease. A 3000-parient ED-based study 4) Pulmonary dysfunction
demonstrated that organ dysfunction with The lung is an early victim of the
septic shock portended increasingly worse inflammatory response to sepsis. These
outcomes. Patients with suspected infection effects are apparent irrespective of the
alone had a mortality rate of 2.1%, while primary infection that causes sepsis.
the presence of SIRS criteria and suspected Significant right-to-left shunting, arterial
infection had a mortality rate of only 1.3% hypoxemia and intractable hypoxemia
(22). However, the mortality rate was 9% occur. The resulting morbidity is high and
for those patients with severe sepsis (sepsis is a common endpoint to sepsis-related
plus organ dysfunction) and 28% for those deaths. Sepsis produces a highly catabolic
with septic shock (23). state and places significant demands on
1) Cardiovascular Insufficiency and the respiratory system. At the same time,
global tissue hypoxia airway resistance increases and muscle
The cardiovascular insufficiency is function is impaired. Irrespective of
the most important events in severe whether pneumonia is the cause of sepsis,

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 Malmir J et al.

the common pulmonary endpoint is acute Exclusion criteria

respiratory distress syndrome (ARDS). The 1) Case study
development of ARDS occurs 4 to 24 hours 2) Based on specific types of post-
after radiographic abnormalities develop. operative and chronic illnesses.
5) Endocrine dysfunction
An absolute or relative adrenal Data sources
insufficiency is common in sepsis. Studies were identified by a systematic
Depending on the balance of circulating search using PubMed, Elsevier and SID
cytokines, augmentation or suppression of up to 2013. The reference list was hand
the hypothalamic-pituitary axis is possible. searched to identify any appropriate article
Interleukin (IL-1) and IL-6 both activate that may be missed by the electronic search.
the hypothalamic-pituitary-adrenal axis. The data of each extracted study included
TNF-α and corticostatin depress pituitary 1) Demographic characteristics of participants.
function. Other factors contributed to 2) The serum lactate assessment.
adrenal insufficiency in sepsis include 3) Type of outcome.
decreased blood flow to the adrenal cortex, 4) Statistics supporting the main findings
decreased pituitary function and pituitary of the study.
secretion of adrenocorticotropic hormone To assess the quality of the included
due to severe stress. studies, methods validated for internal
validity, precision and external validity.
Methods The methodological quality and clinical
Due to lack of high quality study, relevance of each study were graded as
we decided to include all study types high, moderate, or low.
(randomized, controlled trials were
prioritized, non-randomized trials, cohort Results
and case-control studies). The case studies, The initial search included 83 abstracts,
studies with fewer than 40 patients and which were evaluated for its relationship.
abstracts which full text articles that were Twenty four articles were potentially
not available were excluded. This review associated and were assessed in full text and
was restricted to English, Persian and finally 15 articles were selected.
French languages publications. Study Sustained hyperlactatemia in patients
characteristics were defined according to in hospitalized in ICU, demonstrated by
the acute setting, which patients assessed in serial measurements, has suggested to be
the emergency department or ICU. predictive for in-hospital mortality (24-26).
Five of these studies had moderate quality
Inclusion criteria and three with a low quality, showed that
1) Blood lactate assessment in the acute high lactate levels in serial measurements
setting: emergency department, or intensive and prolonged time to normalize lactate,
care unit. predicted a higher mortality rate. The cut
2) 65 years old>age>18 years old off point of serum lactate level used in most
3) Serial lactate measured in arterial or studies was 2.0 mM. The findings of study
venous. by Nichol et al. pointed that a sustained
4) Written in English and French language lactate levels as low as 0.75-1.0 mM were
5) Human studies associated with increasing the adverse
outcomes (OR = 2.0, p < 0.0001) (27).

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Malmir J et al.

In 2004, Kliegel et al. examined usefulness of serum lactate as a prognostic

patients resuscitated for cardiac arrest and factor of 28-day mortality in patients admitted
survived at least 48 hours with sustained to the ED with clinical diagnosis of sepsis
hyperlactatemia (> 2.0 mM after 48 hours) without septic shock. They proved that
were associated with higher mortality as mortality increased in a linear way with serum
well as poor neurological outcome (28). lactate from any detectable values (35).
In a randomized controlled study by Borthwick et al. showed in their study
Jones et al. the patients with severe sepsis that there might be a role for monitoring the
in contrast to other causes of hypoperfusion normalization of serum lactate level during
were treated by two different resuscitation goal directed therapy in the ICU (36).
protocols. The first group was guided Trzeciak et al. showed in a post-hoc
by lactate levels and the other guided by analysis that serum lactate in patients with
SvO2 (29). They found that there was no possible sepsis could affect assessment of
significant difference in mortality between mortality risk, especially with an initial
two groups. lactate ≥ 4.0, increased the probability of
Two studies, suggested that the lactate acute-phase death (37). In a single-center
level greater than or equal to 4.0 mmol/L cohort study where an initial venous lactate
was 36% sensitive (95% confidence interval categorized as low (<2), intermediate, or
[CI] 27% to 45%) and 92% specific (95% high (>4), Mikkelsen et al. showed that it
CI 90% to 93%) for any death (30,31). was associated with high mortality without
Jansen et al. showed that the reduction organ dysfunction and shock in patients
of lactate level by 20% per 2 hours was with severe sepsis (38).
correlated with reduced significant mortality
in the intervention group (32). Discussion
Therefore, according to the reviewed In the population admitted to ED or ICU, it
articles, an interval between two and six seems reasonable to have close monitoring
hours seems reasonable. and perform serial lactate measurements in
Green et al. conducted an observational all patients with severe sepsis. The serial
cohort study in all patients who were lactate measurement are a useful approach
admitted to the ED with suspected infection to monitor the critically ill patient. In
during a 1-year period. Both CRP and number of studies, the role of sustained
lactate testing was done and it was shown hyperlactatemia for prediction of adverse
that increased CRP level and hyperlactemia outcomes has been shown to be undeniable.
had a higher mortality rate than patients
with abnormalities of other laboratory tests Conclusion
in isolation (33). We found that the serum lactate was a
Krishna et al. conducted a prospective useful tool for risk-stratification of the
non-interventional to ascertain the role of patients with severe sepsis, especially
serum lactate as a predictor of sepsis and the trend in serial lactate monitoring was
septic shock and showed that an increase valuable in predicting in-hospital mortality.
in lactate values followed over a period of The initial serum lactate greater than 4 was
time was highly effective in predicting the correlated with higher mortality.
impending complications or grave outcome
in patients with sepsis (34). Acknowledgement
Londono et al. aimed to determine the We would like to thank Clinical Research

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 Malmir J et al.

Development Center of Ghaem Hospital for site, and place if acquisition (community, hos-
their assistant in this manuscript. This study pital, or intensive care unit) as determinants of
workload and cost. J Crit Care. 2005;20:46-58.
was supported by a grant from the Vice 13. Alberti C, Brun-Buisson C, Burchardi H, et al.
Chancellor for Research of the Mashhad Epidemiology of sepsis and infection in ICU
University of Medical Sciences for the patients from an international multicentre cohort
research project as a medical student thesis study. Intensive Care Med. 2002;28:108-121.
14. Sprung CL, Sakr Y, Vincent JL, et al. An
with approval number of 910321. evaluation of systemic inflammatory response
syndrome signs in the Sepsis Occurrence in
Conflict of Interest Acutely ill Patients (SOAP) study. Intensive
The authors declare no conflict of interest. Care Med. 2006;32:421-427.
15. Bota DP, Ferreira FL, Melot C, et al. Body
temperature alterations in the critically ill.
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