Clinical Review & Education

JAMA Diagnostic Test Interpretation

Lactate in Sepsis
Hernando Gomez, MD; John A. Kellum, MD

A 67-year-old man with a medical history of coronary artery disease, hypertension, and
cirrhosis presented to the emergency department reporting 5 days of cough, fever, anorexia, and malaise. He was found to be tachycardic, hypotensive, in severe respiratory distress, and oliguric, and he had peripheral cyanosis and a lactate level of 3.1 mmol/L (reference range, 0.6-1.7 mmol/L) (27.9 mg/dL; reference range, 5.0-15 mg/dL). He was intubated,
given empirical antibiotics for suspected community-acquired pneumonia, resuscitated with
3 L of Ringer lactate solution, and admitted to the intensive care unit. Following admission,
the patients lactate level decreased to 1.2 mmol/L (10.8 mg/dL). However, blood pressure
declined progressively through the night despite further fluid resuscitation and the addition of vasopressors (norepinephrine, vasopressin, and epinephrine) and hydrocortisone.
The following morning, his central venous pressure was 13, stroke volume variation was 7%,
and lactate was 3.0 mmol/L (27.0 mg/dL). Mean arterial pressure of 60 to 65 mm Hg was
achieved but lactate continued to increase to 4.2 mmol/L (37.8 mg/dL).

HOW DO YOU INTERPRET THESE TEST

RESULTS?

A. The patient has epinephrineinduced 2-adrenergic stimulation

driving his hyperlactatemia.
B. The patient likely has sepsis, possibly with an uncontrolled infectious
source, that requires further workup.
C. The patient has decreased lactate
clearance due to liver dysfunction
and complicated by Ringer lactate
solution.
D. The patient is hypoperfused and
requires further fluid and pressor
resuscitation.

Answer
B. The patient likely has sepsis, possibly with an uncontrolled infectious source, that requires further workup.

Test Characteristics
Studies in hypoxia, low flow states, and early septic shock1 have
provided grounds to conceptualize hyperlactatemia (arterial or
venous blood lactate >2 mmol/L [>18.0 mg/dL]), as the manifestation of inadequate oxygen delivery and anaerobic metabolism. Hypoxia impairs oxidative
Quiz at jama.com
phosphorylation, which inhibits adenosine triphosphate (ATP) production and nicotinamide
adenine dinucleotide (NADH) reoxidation, promoting pyruvate
accumulation. The conversion of pyruvate to lactate reoxidizes
NADH into NAD + and increases the lactate:pyruvate ratio to
greater than 10:1.1 However, in sepsis, nonhypoxemic causes such
as inflammation and catecholamine-driven accelerated glycolytic
flux, stimulation of sodium-potassium ATPase pump activity, and
inhibition of pyruvate dehydrogenase in specific compartments
such as striated muscle and the lung,2 as well as decreased lactate
metabolism by the liver, may be more important contributors to
hyperlactatemia. Hence, categorization of lactic acidosis by the
presence (type A) or absence (type B) of signs of tissue hypoxia
can be misleading as lactate is neither sensitive nor specific for
hypoxia.
Lactate testing is inexpensive (mean Medicare reimbursement, $13.92) and predicts hospital mortality (likelihood ratio,
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1.4-2 for 2.5 mmol/L [22.5 mg/dL]-cutoff; or 2.6-6.3 for 4

mmol/L [36.0 mg/dL]-cutoff).3,4 Furthermore, early lactate normalization and clearance of greater than 50% are robust predictors
of survival (odds ratios, 5.2 for lactate normalization and 4.0 for lactate
clearance)5 and targeting resuscitation to lactate clearance resulted in
improved survival in one study.6 Accordingly, guidelines for the Surviving Sepsis Campaign recommend lactate normalization as a target of
resuscitation.7 However, targeting fluid resuscitation and pressors to
lactate clearance may be detrimental if hyperlactatemia is driven by
high glycolytic flux (common in resuscitated septic shock) and not by
hypoperfusion. In the ProCESS (Protocol-based Care for Early Septic
Shock)trial,protocolizedcarethatdeliveredmorefluidtopatientswith
septic shock did not improve outcome for patients with or without
hyperlactatemia.8

Application of Test Results to This Patient

On admission, a lactate level of 3.1 mmol/L (27.9 mg/dL) should
alert the clinician to the high severity of illness. However,
response to volume resuscitation and ventilatory support with
complete lactate clearance is a positive prognostic sign and
further suggests that systemic and respiratory muscle hypoperfusion may have been driving hyperlactatemia. Subsequent worsening of lactate, despite achieving goals of resuscitation, suggested a different scenario. First, the patient was no longer fluid
responsivehis central venous oxygen saturation was 76% and
ongoing fluid administration is likely to produce fluid overload.
Second, other confounders were present including possible liver dysfunction and the use of epinephrine. Additionally, suspicion of an

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JAMA Diagnostic Test Interpretation Clinical Review & Education

uncontrolled infectious source perpetuating a hypermetabolic

state with increased glycolytic flux and activation of sodiumpotassium ATPase membrane pumps should prompt further
investigation (eg, empyema). Lactate was used for prognosis, to
drive therapy, and to understand the course of the disease.
Although sustained undetected hypoperfusion at the microcirculatory level could have contributed to the patients deterioration,
only adequate control of the infectious source and supportive
care, but not more fluids or pressors, allowed the patient to
improve.

Other Diagnostic Testing Approaches

Perhaps the main reason that lactate is used, despite the challenges to interpretation discussed previously, is that alternatives are
quite limited. Central venous oxygen saturation9 and venoarterial
CO2 difference/arteriovenous oxygen content ratio10 may provide
similar information but are more invasive and expensive. However,
more than alternatives, these tests may prove complementary

ARTICLE INFORMATION
Author Affiliations: Center for Critical Care
Nephrology and The CRISMA Center, Department
of Critical Care Medicine, University of Pittsburgh,
Pittsburgh, Pennsylvania.
Corresponding Author: John A. Kellum, MD,
Center for Critical Care Nephrology, Department of
Critical Care Medicine, University of Pittsburgh,
3550 Terrace St, Pittsburgh, PA 15261 (kellumja
@ccm.upmc.edu).
Section Editor: Mary McGrae McDermott, MD,
Senior Editor.
Conflict of Interest Disclosures: Both authors
have completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. Dr
Kellum reports no disclosures. Dr Gomez reports
receipt of grants from the National Institutes of
Health/National Heart, Lung, and Blood Institute
(1K12HL109068-02).
Correction: This article was corrected online on
January 21, 2015, to reflect consistent units of
measure.

to lactate because they can suggest the presence or absence of hypoxia as a cause of hyperlactatemia.

Patient Outcome
The patients sepsis ultimately responded to antibiotics. He recovered fully and was discharged home 1 week later.

Clinical Bottom Line

Hyperlactatemia must be interpreted in the context of the patients clinical condition, relevant history, other biomarkers, and response to ongoing therapy and should never be used in isolation.
Although it is important to consider hypoperfusion in the differential, it is essential to recognize hyperlactatemia as a manifestation
of metabolic stress and severity of the disease process.
As the case illustrates, while the admission lactate suggested hypoperfusion, the subsequent pattern suggested a more complicated pathophysiology and required care tailored to overall clinical context.

2. Kellum JA, Kramer DJ, Lee K, Mankad S, Bellomo

R, Pinsky MR. Release of lactate by the lung in acute
lung injury. Chest. 1997;111(5):1301-1305.

international guidelines for management of severe

sepsis and septic shock: 2012. Crit Care Med.
2013;41(2):580-637.

3. Shapiro NI, Howell MD, Talmor D, et al. Serum

lactate as a predictor of mortality in emergency
department patients with infection. Ann Emerg Med.
2005;45(5):524-528.

8. Yealy DM, Kellum JA, Huang DT, et al; ProCESS

Investigators. A randomized trial of protocol-based
care for early septic shock. N Engl J Med. 2014;370
(18):1683-1693.

4. Trzeciak S, Dellinger RP, Chansky ME, et al.

Serum lactate as a predictor of mortality in patients
with infection. Intensive Care Med. 2007;33(6):
970-977.

9. Jones AE, Shapiro NI, Trzeciak S, Arnold RC,

Claremont HA, Kline JA; Emergency Medicine
Shock Research Network (EMShockNet)
Investigators. Lactate clearance vs central venous
oxygen saturation as goals of early sepsis therapy:
a randomized clinical trial. JAMA. 2010;303(8):739746.

5. Puskarich MA, Illich BM, Jones AE. Prognosis of

emergency department patients with suspected
infection and intermediate lactate levels:
a systematic review. J Crit Care. 2014;29(3):334-339.
6. Jansen TC, van Bommel J, Schoonderbeek FJ,
et al; LACTATE study group. Early lactate-guided
therapy in intensive care unit patients:
a multicenter, open-label, randomized controlled
trial. Am J Respir Crit Care Med. 2010;182(6):752-761.

10. Monnet X, Julien F, Ait-Hamou N, et al. Lactate

and venoarterial carbon dioxide difference/arterialvenous oxygen difference ratio, but not central
venous oxygen saturation, predict increase in
oxygen consumption in fluid responders. Crit Care
Med. 2013;41(6):1412-1420.

7. Dellinger RP, Levy MM, Rhodes A, et al; Surviving

Sepsis Campaign Guidelines Committee including
the Pediatric Subgroup. Surviving sepsis campaign:

REFERENCES
1. Levy B, Sadoune LO, Gelot AM, Bollaert PE,
Nabet P, Larcan A. Evolution of lactate/pyruvate
and arterial ketone body ratios in the early course
of catecholamine-treated septic shock. Crit Care Med.
2000;28(1):114-119.

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