Sepsis: A Spoonful of Fluid Helps the Lactate Go Down

Myth: Lactate elevation in sepsis is caused by anaerobic metabolism. Aggressive fluid resuscitation will replete volume status, improve hypoperfusion and decrease lactate. 

Malady: While lactate is an established prognostic marker in sepsis, beware turning a spoonful of fluid into a bucket just to treat that raised lactate. As always dear reader, clinical judgement supersedes all. 

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Mirror mirror on the ward, which is the most misunderstood marker of them all? Today’s article will focus on the humble lactate. We use it ubiquitously in the assessment, monitoring and management of the critically ill, from various types of shock to trauma and even mesenteric ischaemia. It’s one of the main reasons we order a VBG. But why does the lactate rise? Is it dangerous? Is fluids the answer to a stubborn hyperlactataemia in the floridly septic patient?

Multiple spirals into rabbit holes and several throbbing headaches later, here we have it. 

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Spiral 1: Why does lactate rise?

Lactate rises due to “anaerobic metabolism”, which occurs due to global hypoperfusion in sepsis. While this explanation is born from truth, it fails to grasp the nuances and biochemical complexities of the septic state – also sometimes referred to in ICU as a “meropenem deficiency”. 

Glycolysis initially occurs in the cytosol of cells with the conversion of glucose to pyruvate. The fate of pyruvate depends on the oxygenated state of the tissue. In aerobic conditions, pyruvate enters the citric acid cycle (Kreb’s cycle) in the mitochondria to produce energy via oxidative phosphorylation. However, in anaerobic states, pyruvate is instead fermented to lactate – a smaller ATP payoff (2 ATP versus 32 in aerobic conditions), but a faster one that doesn’t require oxygen [1].

Biochemistry for beginners. Source: Etiology and Therapeutic Approach to Elevated Lactate Levels (Andersen, L.W. et al. 2013)

The slightly outdated Cohen and Woods classification (born a hefty 3 decades before your M&M authors, in 1976) simplifies the causes of hyperlactataemia into inadequate oxygen delivery (Type A) and basically everything else including medications (Type B) [2]. Phypers & Pierce (2006) offer a more informative breakdown [3]. See the original article or the Deranged Physiology reproduction [4] for more details, but to simplify:

• Increased lactate production due to increased glycolysis (from ATP shortages – we can slot hypoxia, anaemia and shock into this category – or exogenous stimuli including catecholamines, salbutamol and adrenaline), pyruvate dehydrogenase inactivity (thiamine deficiency!) and oxidative phosphorylation defects
• Decreased lactate clearance (liver disease is the common culprit here) 

Most of these mechanisms are deployed in the case of sepsis to produce an elevated lactate [5, 6]. Global hypoperfusion and tissue hypoxia due to circulatory shock is the classical mechanism behind hyperlactataemia in sepsis, and therefore is used as the justification for aggressive fluid resuscitation. However the dutiful researchers carrying the medical profession have unearthed the following:

1. Microcirculatory dysfunction: Vasodilation, microthrombi and endothelial dysfunction can cause microvascular stasis and subsequent regional tissue hypoxia. The bypassing of oxygen-rich blood from these poorly perfused areas (microvascular shunting) also worsens this [7].
2. Bacterial endotoxins and cytokines directly inhibit pyruvate dehydrogenase (thus shunting pyruvate metabolism away from aerobic glycolysis) [8].
3. Hyperdynamic circulation with excess endogenous catecholamines that upregulate glycolysis (as the Krebs cycle becomes saturated, pyruvate metabolism shifts to the lactate pathway) [9]. This is similar to why salbutamol increases lactate.
4. Liver failure (whether chronic or acute organ dysfunction in severe sepsis) impairing lactate clearance [5].

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Spiral 2: Is lactate dangerous?

Lactate is not just a beastly metabolic waste product signalling death-by-hypoxia. It is, in fact, a signalling molecule and potential energy source via gluconeogenesis or re-entry into the citric acid cycle (as it can re-form pyruvate in a process catalysed by pyruvate dehydrogenase) [10]. So lactate itself isn’t that dangerous. However, lactic acidosis (i.e. elevated lactate with a concurrent pH < 7.35) is bad. The body works incredibly hard to maintain equilibrium, so with any acid-base disturbances comes a myriad of compensatory and adverse consequences. Acidaemia can induce hyperventilation, hyperkalaemia, reduced myocardial contractility, arterial vasodilation, impaired immune response, and cellular death to name a few issues [11]. 

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The biggest spiral of all: How should lactate be interpreted and utilised in resuscitation of the septic patient?

Lactate = exists. Clinicians = “Let’s give a 1L fluid bolus stat to drop that”.

Lactate is an established prognostic marker for mortality and morbidity in sepsis – the higher the initial lactate, the more scared you should be (because it is an indicator of significant cellular and mitochondrial dysfunction). Lactate elevation may precede overt shock so ignore a raised lactate at your own peril [12]. Early lactate measurement is therefore rightfully a vital recommendation in national and international guidelines for early recognition and management of sepsis [13, 14]. Indeed, the presence of both fluid-resistant hypotension and lactate >2mmol/L predicted greater mortality risk than either criteria alone [15]. As sepsis does induce an element of intravascular depletion from leaky capillaries, early fluid resuscitation is important and appropriate [13, 14]. 

However, given we have just shown hypoperfusion is not the only cause of lactate elevation in sepsis, it can be inferred that using lactate alone to guide ongoing fluid resuscitation may be inappropriate. There are also numerous confounders that can maintain an alarming lactate despite effective patient resuscitation and resolution of hypoperfusion – like adrenaline boluses, liver dysfunction (whether acute or chronic), or other medications like metformin which should really be withheld [5]. Honing in on that lactate and getting excessive with the boluses can lead to saline overdose, fluid overload and end-organ dysfunction. And remember the reason we are giving fluids in the first place – resuscitation and clinical improvement, not lactatemia. The ANDROMEDA-SHOCK trial [15], which compared lactate-guided versus peripheral-perfusion targeted (via capillary refill time) resuscitation strategies, found a non-significant (p=0.06) trend towards reduced mortality in the latter group. Reduced end-organ dysfunction was also observed in the peripheral-perfusion group. Moreover, those with a normal capillary refill time at baseline were found to have worse end organ dysfunction and greater interventions when allocated to lactate-guided resuscitation.

The latest Surviving Sepsis Guidelines [14] acknowledge that aiming for normal lactate levels may not be possible, and that there is not enough evidence to support a restrictive versus liberal ongoing fluid administration strategy. Holistic patient assessment utilising capillary refill time, passive leg raise, blood pressure, dynamic measures of cardiac output and stroke volume may serve you better than lactate alone. 

A spoonful of fluid will indeed help the lactate go down – but as always, dear reader, clinical judgement overrides all. 

Giants’ Shoulders:
[2] Cohen, R. D., & Woods, H. F. (1976). Clinical and biochemical aspects of lactic acidosis. Blackwell Scientific ; Philadelphia : distributed by Lippincott.
[3] Phypers, B., & Pierce, T. (2006). Lactate physiology in health and disease. https://doi.org/10.1093/bjaceaccp/mkl018
[4] Classification systems of lactic acidosis and [6] Lactic acidosis in sepsis and septic shock by Deranged Physiology 
[5] An excellent overview of mechanisms fuelling lactic acidosis in sepsis by Suetrong, B., & Walley, K. R. (2016)
[15] The ANDROMEDA-SHOCK Randomized Clinical Trial (2019). JAMA, https://doi.org/10.1001/jama.2019.0071 (with a Bayesian re-analysis finding lower mortality in the peripheral perfusion group) 

Also Cited Above:
[1] Chaudhry R, Varacallo MA. Biochemistry, Glycolysis. StatPearls Publishing; 2025 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482303/ 
[7] Bateman, R. M., Sharpe, M. D., & Ellis, C. G. (2003). Bench-to-bedside review: microvascular dysfunction in sepsis–hemodynamics, oxygen transport, and nitric oxide. Critical Care (London, England), 7(5), 359–373. https://doi.org/10.1186/cc2353 
[8] Crouser E. D. (2004). Mitochondrial dysfunction in septic shock and multiple organ dysfunction syndrome. Mitochondrion, 4(5-6), 729–741. https://doi.org/10.1016/j.mito.2004.07.023 
[9] Levy, B., Desebbe, O., Montemont, C., & Gibot, S. (2008). Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock (Augusta, Ga.), 30(4), 417–421. https://doi.org/10.1097/SHK.0b013e318167378f
[10] Rabinowitz, J. D., & Enerbäck, S. (2020). Lactate: the ugly duckling of energy metabolism. Nature Metabolism, 2(7), 566–571. https://doi.org/10.1038/s42255-020-0243-4
[11] Kraut, J. A., & Madias, N. E. (2010). Metabolic acidosis: pathophysiology, diagnosis and management. Nature Reviews Nephrology, 6(5), 274–285. https://doi.org/10.1038/nrneph.2010.33
[12] Casserly, B., Phillips, G. S., Schorr, C., Dellinger, R. P., Townsend, S. R., Osborn, T. M., Reinhart, K., Selvakumar, N., & Levy, M. M. (2015). Lactate measurements in sepsis-induced tissue hypoperfusion: results from the Surviving Sepsis Campaign database. Critical care medicine, 43(3), 567–573. https://doi.org/10.1097/CCM.0000000000000742
[13] Sepsis Clinical Care Standard – Australian Commission on Safety and Quality in Health Care
[14] Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. https://doi.org/10.1007/s00134-021-06506-y