Article

Howell M, Donnino M, Clardy P, et al. Occult hypoperfusion and mortality in patients with suspected infection

Harvard University, Cambridge, Massachusetts, United States
Intensive Care Medicine (Impact Factor: 7.21). 12/2007; 33(11):1892-9. DOI: 10.1007/s00134-007-0680-5
Source: PubMed

ABSTRACT

To determine, in the early stages of suspected clinically significant infection, the independent relationship of the presenting venous lactate level to 28-day in-hospital mortality.
Prospective, observational cohort study.
Urban, university tertiary-care hospital.
One thousand two hundred and eighty seven adults admitted through the emergency department who had clinically suspected infection and a lactate measurement.
Seventy-three [5.7% (95% CI 4.4-6.9%)] patients died in the hospital within 28 days. Lactate level was strongly associated with 28-day in-hospital mortality in univariate analysis (p<0.0001). When stratified by blood pressure, lactate remained associated with mortality (p<0.0001). Normotensive patients with a lactate level >or=4.0 mmol/l had a mortality rate of 15.0% (6.0-24%). Patients with either septic shock or lactate >or=4.0 mmol/l had a mortality rate of 28.3% (21.3-35.3%), which was significantly higher than those who had neither [mortality of 2.5% (1.6-3.4%), p<0.0001. In a model controlling for age, blood pressure, malignancy, platelet count, and blood urea nitrogen level, lactate remained strongly associated with mortality. Patients with a lactate level of 2.5-4.0 mmol/l had adjusted odds of death of 2.2 (1.1-4.2); those with lactate >or=4.0 mmol/l had 7.1 (3.6-13.9) times the odds of death. The model had good discrimination (AUC=0.87) and was well calibrated.
In patients admitted with clinically suspected infection, the venous lactate level predicts 28-day in-hospital mortality independent of blood pressure and adds significant prognostic information to that provided by other clinical predictors.

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    • "In contrast, SpA from Staphylococcus aureus and CNF1 from E. coli promote RhoA/ROK activity[50,51]. Endogenous mediators might also contribute to Ca 2+ desensitisation: nitric oxide, kynurenine and ANP levels are elevated in septic shock[40,52], potentially promoting protein kinase G (PKG)-dependent disinhibition of MLCP and Ca 2+ desensitisation[10,53,54]. Our findings of impaired response to TxA 2 and membrane depolarisation may be of particular clinical significance for two reasons: Firstly, it is well established that restoration of normal systemic circulatory parameters is not necessarily indicative of restored regional perfusion, and indeed, ongoing regional ischaemia despite restoration of systemic blood pressure is associated with poor clinical outcome55565758. Microvascular splanchnic perfusion is not only reduced but highly heterogeneous in septic shock even within areas of uniform metabolic demand[20], indicating a failure of local vasomotor regulation. "
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    ABSTRACT: Sepsis is characterised by diminished vasopressor responsiveness. Vasoconstriction depends upon a balance: Ca(2+)-dependent myosin light-chain kinase promotes and Ca(2+)-independent myosin light-chain phosphatase (MLCP) opposes vascular smooth muscle contraction. The enzyme Rho kinase (ROK) inhibits MLCP, favouring vasoconstriction. We tested the hypothesis that ROK-dependent MLCP inhibition was attenuated in late sepsis and associated with reduced contractile responses to certain vasopressor agents. This is a prospective, controlled animal study. Sixteen-week-old C57/BL6 mice received laparotomy or laparotomy with caecal ligation and puncture (CLP). Antibiotics, fluids and analgesia were provided before sacrifice on day 5. Vasoconstriction of the femoral arteries to a range of stimuli was assessed using myography: (i) depolarisation with 87 mM K(+) assessed voltage-gated Ca(2+) channels (L-type, Cav1.2 Ca(2+) channels (LTCC)), (ii) thromboxane A2 receptor activation assessed the activation state of the LTCC and ROK/MLCP axis, (iii) direct PKC activation (phorbol-dibutyrate (PDBu), 5 μM) assessed the PKC/CPI-17 axis independent of Ca(2+) entry and (iv) α1-adrenoceptor stimulation with phenylephrine (10(-8) to 10(-4) M) and noradrenaline (10(-8) to 10(-4) M) assessed the sum of these pathways plus the role of the sarcoplasmic reticulum (SR). ROK-dependent MLCP activity was indexed by Western blot analysis of P[Thr855]MYPT. Parametric and non-parametric data were analysed using unpaired Student's t-tests and Mann-Whitney tests, respectively. ROK-dependent inhibition of MLCP activity was attenuated in both unstimulated (n = 6 to 7) and stimulated (n = 8 to 12) vessels from mice that had undergone CLP (p < 0.05). Vessels from CLP mice demonstrated reduced vasoconstriction to K(+), thromboxane A2 receptor activation and PKC activation (n = 8 to 13; p < 0.05). α1-adrenergic responses were unchanged (n = 7 to 12). In a murine model of sepsis, ROK-dependent inhibition of MLCP activity in vessels from septic mice was reduced. Responses to K(+) depolarisation, thromboxane A2 receptor activation and PKC activation were diminished in vitro whilst α1-adrenergic responses remained intact. Inhibiting MLCP may present a novel therapeutic target to manage sepsis-induced vascular dysfunction.
    No preview · Article · Dec 2015
    • "Lactate values were stratified into 3 categories. According to previous publications, cutoff values of 2.5 mmol/L [10] [14] [20] and 4 mmol/L [13] [14] [17] [18] [22], respectively, were chosen. Hyperlactatemia was defined as serum Lac concentration of at least 2.5 mmol/L. "
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    ABSTRACT: Current guidelines and most trials do not consider elevated lactate (Lac) serum concentrations when grading sepsis severity. We therefore assessed the association of different types of circulatory dysfunction regarding presence of hyperlactatemia and need for vasopressor support with clinical presentation and outcome of sepsis. In a secondary analysis of a prospective observational multicenter cohort study, 988 patients with severe sepsis were investigated regarding vasopressor support, Lac levels, and outcome. Twenty-eight-day mortality regarding shock or hyperlactatemia was as follows: hyperlactatemia more than 2.5 mmol/L and septic shock (tissue dysoxic shock): 451 patients with a mortality of 44.8%; hyperlactatemia without vasopressor need (cryptic shock): 72 patients, mortality 35.3%; no hyperlactatemia with vasopressor need (vasoplegic shock): 331 patients, mortality 27.7%; and absence of hyperlactemia or overt shock (severe sepsis): 134 patients, mortality 14.2% (P < .001). These groups showed differences in source and origin of infection. The influence of hyperlactatemia on 28-day mortality (P < .001) (odds ratio 3.0, 95% confidence interval 2.1-4.1 for Lac >4 mmol/L) was independent of vasopressor support (P < .001) (odds ratio 2.0, 95% confidence interval 1.3-3.0 for norepinephrine >0.1 μg/kg per minute) in logistic regression. Hyperlactatemia increases risk of death independent of vasopressor need resulting in different phenotypes within the classic categories of severe sepsis and septic shock. Copyright © 2014 Elsevier Inc. All rights reserved.
    No preview · Article · Oct 2014 · Journal of Critical Care
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    • "This indicates that in a group of patients with abnormal PVL, agreement with arterial lactate may be poorer than in a group with normal PVL. There are several studies that report prognostic outcomes based on PVL values taken from ED or trauma populations [6] [31] [32] [33] [37]. These data represent a strong evidence base for the use of PVL alone as a predictor of mortality. "
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    ABSTRACT: The evidence for prognostication using lactate is often based on arterial lactate (AL). Arterial sampling is painful and difficult, and carries risks. Studies comparing peripheral venous lactate (PVL) with AL showed little difference but predominantly included patients with normal lactate. The objective of this study was to measure agreement between PVL and AL in patients with elevated venous lactate. This is a retrospective cross-sectional study. Inclusion criteria: ED patients age ≥16, attending from October 2010 to June 2011 inclusive, with PVL ≥2.0mmol/L and AL taken within 1 hour. Exclusion criteria: intravenous fluid prior to or between initial venous and arterial sampling. Primary endpoint: agreement between PVL and AL defined as mean difference ±95% limits of agreement (LOA). The misclassification rate was assessed. N=232. VL median 3.50mmol/L, range 2.00 to 15.00mmol/L. AL median 2.45mmol/L, range 1.0 to 13.2mmol/L. The mean difference±SD between PVL and AL for all patients was 1.06±1.30mmol/L (95%LOA -1.53 to 3.66mmol/L). Using a cut-off of 2mmol/L and 4mmol/L, 36.2% and 17.9% of patients respectively were incorrectly classified as having elevated lactate. We report greater bias between VL and AL with broader LOA than previously documented. This may partly be due to the fact that we studied only patients with abnormal venous values, for whom close agreement would confer greatest clinical significance. The agreement between abnormal PVL and AL is poor and the high rate of misclassification may suggest that PVL is not a good substitute for AL if the venous lactate is abnormal.
    Full-text · Article · Mar 2014 · The American journal of emergency medicine
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