Tag Archives: lactate

Hyperglycaemia & mortality in sepsis – lactate dependent?

I like this paper for introducing a new concept to me. For years the critical care community has recognised the link between hyperglycaemia and mortality, leading to early recommendations of intensive insulin regimens subsequently shown not to be of benefit. Now it appears that the association between hyperglycaemia and mortality may be less relevant in patients with a normal lactate.

In a study of adult nondiabetic critically ill patients, hyperglycaemia had a significant association with increased mortality risk using simple univariate analysis. When they adjusted for concurrent hyperlactataemia however, hyperglycaemia was not significantly associated with increased mortality risk.

The authors discuss several known or postulated aspects of interplay between lactate and glucose in sepsis:

  • Hyperlactataemia appears to inhibit glucose uptake by muscle cells and decrease activity of the GLUT-4 transporters
  • Hyperlactataemia has also been shown to increase insulin resistance directly
  • Glucose and lactate levels tend to be elevated simultaneously in severe sepsis at baseline.
  • Experimentally it has been estimated that 45% of infused (radiolabelled) lactate is either converted into glucose via gluconeogenesis or is transformed into glycogen via the Cori cycle, representing a higher proportion of glucose formation from lactate than in nonseptic controls.
  • It is possible that elevated glucose and lactate levels in sepsis both may be measures of the same phenomenon: glucose accumulates due to the sympathomimetic response to a systemic infection with increased catecholamine levels leading to increased activity of the Na+K+-ATPase, resulting in accumulation of adenosine diphosphate (ADP). Increased levels of ADP in turn augment glycogenolysis.
  • Mitochondrial metabolism cannot meet the increased cellular energy needs of sepsis, resulting in accumulation of ADP and leading to cytosolic glycolysis and lactate production, even in an aerobic environment.

The augmented glycolysis of sepsis (and during adrenergic therapy such as epinephrine/adrenaline or albuterol/salbutamol) is one of the causes of a raised lactate to consider when applying the LACTATES mnemonic I like to use.

Hyperlactatemia affects the association of hyperglycemia with mortality in nondiabetic adults with sepsis
Acad Emerg Med. 2012 Nov;19(11):1268-75

BACKGROUND: Admission hyperglycemia has been reported as a mortality risk factor for septic nondiabetic patients; however, hyperglycemia’s known association with hyperlactatemia was not addressed in these analyses.

OBJECTIVES: The objective was to determine whether the association of hyperglycemia with mortality remains significant when adjusted for concurrent hyperlactatemia.

METHODS: This was a post hoc, nested analysis of a retrospective cohort study performed at a single center. Providers had identified study subjects during their emergency department (ED) encounters; all data were collected from the electronic medical record (EMR). Nondiabetic adult ED patients hospitalized for suspected infection, two or more systemic inflammatory response syndrome (SIRS) criteria, and simultaneous lactate and glucose testing in the ED were enrolled. The setting was the ED of an urban teaching hospital from 2007 to 2009. To evaluate the association of hyperglycemia (glucose > 200 mg/dL) with hyperlactatemia (lactate ≥ 4.0 mmol/L), a logistic regression model was created. The outcome was a diagnosis of hyperlactatemia, and the primary variable of interest was hyperglycemia. A second model was created to determine if coexisting hyperlactatemia affects hyperglycemia’s association with mortality; the main outcome was 28-day mortality, and the primary risk variable was hyperglycemia with an interaction term for simultaneous hyperlactatemia. Both models were adjusted for demographics; comorbidities; presenting infectious source; and objective evidence of renal, respiratory, hematologic, or cardiovascular dysfunction.

RESULTS: A total of 1,236 ED patients were included, and the median age was 77 years (interquartile range [IQR] = 60 to 87 years). A total of 115 (9.3%) subjects were hyperglycemic, 162 (13%) were hyperlactatemic, and 214 (17%) died within 28 days of their initial ED visits. After adjustment, hyperglycemia was significantly associated with simultaneous hyperlactatemia (odds ratio [OR] = 4.14, 95% confidence interval [CI] = 2.65 to 6.45). Hyperglycemia and concurrent hyperlactatemia were associated with increased mortality risk (OR = 3.96, 95% CI = 2.01 to 7.79), but hyperglycemia in the absence of simultaneous hyperlactatemia was not (OR = 0.78, 95% CI = 0.39 to 1.57).

CONCLUSIONS: In this cohort of septic adult nondiabetic patients, mortality risk did not increase with hyperglycemia unless associated with simultaneous hyperlactatemia. The previously reported association of hyperglycemia with mortality in nondiabetic sepsis may be due to the association of hyperglycemia with hyperlactatemia.

More on the meaning of lactate values

A newly published study(1) reminds us that we need to do better than just identify a raised lactate in patients with sepsis; we need to make sure it’s not increasing when they leave the ED (if we can). An incremental rise is associated with mortality.

The authors comment:

We found that the prognostic value of lactate continues to rise across a wide range of values, from 0 to 20 mmol/L…. These data suggest that grouping patients into less granular and larger groups, such as low, intermediate, and high, potentially underutilizes the prognostic value of the test. Furthermore, we did not find any value of lactate, up to a maximum value of 20 mmol/L, where mortality failed to increase with an increase in lactate concentration.

The paper does not state whether the lactate was arterial or venous, although either can be used. The Surviving Sepsis Campaign provides this comment:

In the course of the Campaign the question has been raised many times as to whether an arterial or venous lactate sample is appropriate. While there is no consensus of settled literature on this question, an elevated lactate of any variety is typically abnormal, although this may be influenced by other conditions..

This relationship between lactate trend and mortality has also been demonstrated in a study of all patients admitted to hospital (with or without sepsis), which also showed good correlation between arterial and venous lactate(2).

Lactate clearance has been shown to be an acceptable alternative to central venous oxygen saturation as a goal for therapy in ED severe sepsis patients(3), which is good because it provides one less reason for a central line.

Always remember the good emergency physician / critical care practitioner will consider other causes of a raised lactate, particularly when things don’t add up. I invented the ‘LACTATES’ acronym to help me remember them(4), and it’s come in handy several times.

Craving more info on lactate? Check out the EMCrit site with its great lactate reference sheet.

1. Prognostic Value of Incremental Lactate Elevations in Emergency Department Patients With Suspected Infection
Acad Emerg Med. 2012 Aug;19(8):983-5

Objectives:  Previous studies have confirmed the prognostic significance of lactate concentrations categorized into groups (low, intermediate, high) among emergency department (ED) patients with suspected infection. Although the relationship between lactate concentrations categorized into groups and mortality appears to be linear, the relationship between lactate as a continuous measurement and mortality is uncertain. This study sought to evaluate the association between blood lactate concentrations along an incremental continuum up to a maximum value of 20 mmol/L and mortality.

Methods:  This was a retrospective cohort analysis of adult ED patients with suspected infection from a large urban ED during 2007–2010. Inclusion criteria were suspected infection evidenced by administration of antibiotics in the ED and measurement of whole blood lactate in the ED. The primary outcome was in-hospital mortality. Logistic and polynomial regression were used to model the relationship between lactate concentration and mortality.

Results:  A total of 2,596 patients met inclusion criteria and were analyzed. The initial median lactate concentration was 2.1 mmol/L (interquartile range [IQR] = 1.3 to 3.3 mmol/L) and the overall mortality rate was 14.4%. In the cohort, 459 patients (17.6%) had initial lactate levels >4 mmol/L. Mortality continued to rise across the continuum of incremental elevations, from 6% for lactate <1.0 mmol/L up to 39% for lactate 19–20 mmol/L. Polynomial regression analysis showed a strong curvilinear correlation between lactate and mortality (R = 0.72, p < 0.0001).

Conclusions:  In ED patients with suspected infection, we found a curvilinear relationship between incremental elevations in lactate concentration and mortality. These data support the use of lactate as a continuous variable rather than a categorical variable for prognostic purposes.

2. Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review
Scand J Trauma Resusc Emerg Med. 2011 Dec 28;19:74 Free Full Text

BACKGROUND: Using blood lactate monitoring for risk assessment in the critically ill patient remains controversial. Some of the discrepancy is due to uncertainty regarding the appropriate reference interval, and whether to perform a single lactate measurement as a screening method at admission to the hospital, or serial lactate measurements. Furthermore there is no consensus whether the sample should be drawn from arterial, peripheral venous, or capillary blood. The aim of this review was: 1) To examine whether blood lactate levels are predictive for in-hospital mortality in patients in the acute setting, i.e. patients assessed pre-hospitally, in the trauma centre, emergency department, or intensive care unit. 2) To examine the agreement between arterial, peripheral venous, and capillary blood lactate levels in patients in the acute setting.

METHODS: We performed a systematic search using PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL up to April 2011. 66 articles were considered potentially relevant and evaluated in full text, of these ultimately 33 articles were selected.

RESULTS AND CONCLUSION: The literature reviewed supported blood lactate monitoring as being useful for risk assessment in patients admitted acutely to hospital, and especially the trend, achieved by serial lactate sampling, is valuable in predicting in-hospital mortality. All patients with a lactate at admission above 2.5 mM should be closely monitored for signs of deterioration, but patients with even lower lactate levels should be considered for serial lactate monitoring. The correlation between lactate levels in arterial and venous blood was found to be acceptable, and venous sampling should therefore be encouraged, as the risk and inconvenience for this procedure is minimal for the patient. The relevance of lactate guided therapy has to be supported by more studies.

3. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial
JAMA. 2010 Feb 24;303(8):739-46

CONTEXT: Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department.

OBJECTIVE: To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation (ScvO2) as goals of early sepsis resuscitation.

DESIGN, SETTING, AND PATIENTS: Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals.

INTERVENTIONS: We randomly assigned patients to 1 of 2 resuscitation protocols. The ScvO2 group was resuscitated to normalize central venous pressure, mean arterial pressure, and ScvO2 of at least 70%; and the lactate clearance group was resuscitated to normalize central venous pressure, mean arterial pressure, and lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to 6 hours. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment.

MAIN OUTCOME MEASURE: The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at Delta equal to -10%.

RESULTS: Of the 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographic, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalization. Thirty-four patients (23%) in the ScvO2 group died while in the hospital (95% confidence interval [CI], 17%-30%) compared with 25 (17%; 95% CI, 11%-24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined -10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, -3% to 15%). There were no differences in treatment-related adverse events between the groups.

CONCLUSION: Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality.

4. Non-septic hyperlactataemia in the emergency department
Emerg Med J. 2010 May;27(5):411-2

Some causes of a raised lactate

A high serum lactate does not necessarily mean a bad prognosis: it all depends on the cause.

I made this diagram as a mnemonic for the causes of high lactates:

Additional information added 1st June 2011
: One cause of an elevated lactate may be artefactual, secondary to interference with the assay (used on ABG machines) by ethylene glycol. The assay may also be subject to interference from certain drugs at toxic levels such as isoniazid, acetaminophen and thiocyanate. This information is from the Renal Fellow Network.