Jan 172016

15419185_sJon-Emile S. Kenny [@heart_lung]

On this snowy, Stockholm Sunday, I look out from my quarters on the Mälardrottningen across the still, icy waters and I think about a cirrhotic patient for whom I recently cared.  She presented with significant dyspnea as she had stopped taking her diuretics.  Instead, she was using excessive doses of her friend’s albuterol inhaler to treat her shortness of breath.  Additionally, she had been drinking alcohol heavily for seven days prior to admission.  Her venous pH was 7.38, and her lactate concentration was over 7.0 mmol/L – a sepsis alert was called.


In a very recent and fantastic review by Suetrong and Walley, the mechanisms of lactate formation are revisited.  Notably, a distinction is made between hyperlactatemia – an elevated concentration of lactate in the blood – and lactic acidosis, which is comprised of both hyperlactatemia and systemic acidosis.

The authors discuss the mechanisms by which lactate is formed and aptly detail that many of these processes do not result in acid formation.  Notably, while the generation of pyruvate from glucose does generate [H+], the conversion of pyruvate to lactate consumes an equimolar amount of [H+] such that the production of lactate does not result in a net gain of protons [i.e. acidosis].  So where does the acidosis – with which we are so familiar – come from?  The excess protons are the result of an impaired Kreb’s Cycle.  In states of true tissue oxygen debt, intracellular protons can no longer be consumed during the Kreb’s Cycle; consequently, intracellular acidosis and acidemia ensue.  It is this latter means of hyperlactatemia to which we attach the label ‘type A’ or lactic acidosis with clinical evidence of tissue hypoxia.

However, as described 40 years ago, excessive lactate may come from clinical states where there is no evidence of tissue hypoxia – the so-called B-type lactate.  As clearly and concisely surveyed in their review, Suetrong and Walley explain that increased glycolytic flux [e.g. from sepsis itself, from beta-agonists, from increased muscle activity], a poisoned pyruvate dehydrogenase complex [e.g. from thiamine deficiency or other toxins/medications], an elevated NADH/NAD+ ratio [e.g. from ethanol intoxication] and impaired lactate clearance [e.g. from severe hepatic or even renal insufficiency] may all result in hyperlactatemia.  Within this litany of causes, to the extent that mitochondrial, and therefore the Kreb’s Cycle function remains intact, there can be little-or-no acidosis despite elevations in serum lactate.

Lactate concentration in sepsis

The authors go on to explain the underlying reasons for hyperlactatemia and lactic acidosis in sepsis which include impaired oxygen delivery in early, under-resuscitated sepsis [a mechanism common to all types of shock], but also regional cytopathic tissue hypoxia.  This latter entity occurs due to microcirculatory unrest and embarrassed mitochondrial function.  While tissue can maximally extract up to 70% of its received oxygen supply, in sepsis, this ability may be diminished to 50% extraction or less.  Thus, when total body – or even organ – oxygen delivery is optimized [or exceeded], localized oxygen debt can occur.  In addition to the aforementioned states of A-type lactate, increased B-type lactate is a common entity within the sphere of severe sepsis and septic shock.  B-type lactate can and will occur because resting adrenergic state is increased, exogenous catecholamines are administered and lactate clearance is impaired.  Importantly, the provision of beta-agonists such as epinephrine are known to raise serum lactate levels secondary to hepatic stimulation of glycogenolysis/glycolysis [i.e. increased B-type lactate]; ostensibly, this effect is counterbalanced by epinephrine’s ability to augment cardiac output and, therefore, tissue oxygen delivery [i.e. attenuated A-type lactate].

Clinical implications of lactate measurement

Whether obtained from an arterial or venous sample, if measured quickly following phlebotomy, serum lactate elevation is a strong prognosticator in sepsis.  Significantly, this is irrespective of the underlying pathophysiology of lactate elevation [i.e. A versus B-type above].  Thus, regardless of the reason for lactate elevation, it speaks to tissues and organs under hemodynamic and/or metabolic duress; whatever its underpinnings, hyperlactatemia should be heeded.  Arguably, this is why there is no true inflection point in the relationship between lactate level and prognosis in septic patients.

While elevated lactate predicts untoward clinical outcomes, using its clearance as a marker of successful resuscitation has revealed mixed results.  As the authors highlight, this may be the result of the aforementioned competing effects of beta-agonists such as epinephrine on serum lactate concentrations.  Indeed, in the CATS trial, epinephrine infusion significantly increased serum lactate, but did not impair clinical outcome in severely septic patients.  Conversely, the use of esmolol in a similar patient population reduced oxygen delivery, and serum lactate levels, but improved clinical end-points.  The use of lactate clearance is equivalent, or perhaps superior, to central venous oxygen saturation; however, this debate is nuanced and muddied.  In summary, changes in lactate concentration, alone, cannot solely and definitively be used as a resuscitative end-point, but must be integrated into a clinical gestalt which should include other indices of hemodynamic success such as improved urine output, mentation, etc.

Treating lactic acidosis in sepsis

As described in this excellent post, hyperlactatemia, like sinus tachycardia, may be an adaptive response to sepsis.  Therefore, treatment should focus on the underlying fire rather than the smoke.  Source control and timely, appropriate antibiotics are clearly paramount.  Beyond these interventions, expeditious restoration of global hemodynamic parameters without excessive fluid administration is indicated.  If lactate levels continue to rise, the clinician must consider impaired organ perfusion [e.g. gut or limb ischemia] and microcirculatory dysfunction as underlying etiologies.  Excessive beta-agonists should be avoided and hepatic insults such as medications or venous congestion should be appreciated and rectified in an attempt to augment lactate clearance.  Finally, there is little or no role for the use of sodium bicarbonate in lactic acidosis.  As well, renal replacement therapy and dichloroacetate provision have both been shown to treat lactic acidosis, but without clear improvement in survival.

*For an in-depth discussion on lactate metabolism, please see this post; additional reading on sodium bicarbonate can be found here.  Finally, capillary refill may be a better resuscitation end-point than lactate - reviewed here.

Happy New Year and belated-birthday, Mum!


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Review: Lactate & Sepsis