Introduction with a case
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Once upon a time a 60-year-old man was transferred from the oncology ward to the ICU for treatment of neutropenic septic shock. Over the course of the morning he started rigoring and dropped his blood pressure from 140/70 to 70/40 within a few hours, refractory to four liters of crystalloid.
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In the ICU his blood pressure didn't improve with vasopressin and norepinephrine titrated to 40 mcg/min. His MAP remained in the high 40s, he was mottled up to the knees, and he wasn't making any urine. Echocardiography suggested a moderately reduced left ventricle ejection fraction, not terrible but perhaps inadequate for his current condition.
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Dobutamine has usually been our choice of inotrope in septic shock. However, this patient was so unstable that we chose epinephrine instead. On an epinephrine infusion titrated to 10 mcg/min his blood pressure improved immediately, his mottling disappeared, and he started having excellent urine output.
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However, his lactate level began to rise. He was improving clinically, so we suspected that the lactate was due to the epinephrine infusion. We continued the epinephrine, he continued to improve, and his lactate continued to rise. His lactate level increased as high as 15 mM, at which point the epinephrine infusion was being titrated off anyway. Once the epinephrine was stopped his lactate rapidly normalized. He continued to improve briskly. By the next morning he was off vasopressors and ready for transfer back to the ward.
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This was eye-opening. It seemed that the epinephrine infusion was the pivotal intervention which helped him stabilize. However, while clinically improving him, the epinephrine infusion was also driving his lactate to very high levels. How could this be? Isn't lactate evil? Isn't the entire point of sepsis resuscitation to normalize the lactate?
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Basic science: Understanding lactate in sepsis
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The classical understanding of lactate in sepsis is flawed. The following is a brief overview of newer ideas about lactate. For a more complete discussion please see articles by Paul Marik listed below in the references.
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(1) Elevated lactate in septic shock is not due to anaerobic metabolism
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Traditionally it was believed that elevated lactate is due to anaerobic metabolism, as a consequence of inadequate perfusion with low oxygen delivery to the tissues. This has largely been debunked. Most patients with sepsis and elevated lactate have hyperdynamic circulation with very adequate delivery of oxygen to the tissues. Studies have generally failed to find a relationship between lactate levels and systemic oxygen delivery or mixed venous oxygen saturation. There is little evidence of frank tissue hypoxemia in sepsis. Moreover, the lungs have been shown to produce lactate during sepsis, which couldn't possibly be due to hypoxemia (Marik 2014).
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This has significant implications for sepsis treatment. Traditional belief in inadequate oxygen delivery led to multiple interventions to improve oxygen delivery (e.g. blood transfusion to target a hemoglobin of 10 mg/dL, use of inotropes to increased mixed venous oxygen saturation >70%, and nitroglycerine infusion for hypertensive patients). Lack of oxygen deficiency may explain why these interventions have not proven to be beneficial.
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(2) Elevated lactate in septic shock is mostly due to stimulation of beta-2 adrenergic receptors
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Lactate elevation in sepsis seems to be due to endogenous epinephrine stimulating beta-2 receptors (figure below). Particularly in skeletal muscle cells, this stimulation up-regulates glycolysis, generating more pyruvate than can be used by the cell's mitochondria via the TCA cycle. Excess pyruvate is converted into lactate.
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This process is entirely aerobic, occurring despite adequate oxygen delivery. Lactate generation doesn't occur because the mitochondria are unable to function in the absence of oxygen. Instead, lactate generation occurs because the TCA cycle simply isn't able to keep up with a very rapid rate of glycolysis.
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(3) Elevated lactate in shock might be a beneficial compensatory response
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Lactate serves as a metabolic fuel for the heart and brain in conditions of stress. In a rat sepsis model, depletion of lactate caused cardiovascular collapse, which could be reversed by infusing sodium lactate (Levy 2007). This study also found that selective blockade of beta-2 receptors decreased lactate levels and reduced survival duration. In humans, RCTs have shown that concentrated sodium lactate improves cardiac output among post-CABG patients and heart failure patients (Nalos 2014, Leverve 2008)(1).
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Lactate correlates with illness severity, generally being a sign of badness. This may lead to the misconception that lactate itself is harmful. However, like sinus tachycardia, although elevated lactate is an ominous sign it still may function as a beneficial compensatory mechanism.
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Clinical applications: Using lactate to our advantage
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This alternative understanding of lactate has some implications for bedside patient management.
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(1) Identification of occult shock: Lactate still works.
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The autonomic nervous system and endogenous catecholamines are mysterious and confounding. When exposed to the same infection, some patients have a weak endogenous catecholamine response and immediately develop hypotension. Other patients have a robust release of endogenous catecholamines which supports their blood pressure, preventing hypotension (these are often younger patients who may look deceptively well).
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Lactate is a marker of endogenous catecholamine release (2). This makes lactate useful for detecting patients who have occult shock: patients who are maintaining their blood pressure due to a vigorous endogenous catecholamine response. These patients may have deceptively reassuring vital signs, masking the fact that they are in a catecholamine-dependent shock state (simply using their own catecholamines rather than, for example, a norepinephrine infusion). Elevated lactate identifies these patients as having an increased risk of death or decompensation, thus requiring more aggressive management. Although most often associated with sepsis, occult shock with elevated lactate may be seen with any cause of shock.
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(2) Serial lactate levels to monitor a patient in septic shock? Unknown utility.
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In 2010 Jones et al. demonstrated that trending serial lactate levels was non-inferior to using mixed venous oxygen saturation as a guide to sepsis resuscitation. However, more recently the PROCESS, ARISE, and PROMISE trials have demonstrated that trending mixed venous oxygen saturation is unnecessary to begin with. In hindsight, both interventions may be equally unnecessary.
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Currently it is unknown whether adding lactate to other resuscitation endpoints is beneficial. For example, suppose a patient is doing well clinically (e.g. with an adequate blood pressure, good urine output, and down-titrating vasopressors) but has a persistently elevated lactate level. Will escalating the resuscitation based on the lactate level be beneficial, or harmful due to over-resuscitation (e.g. volume overload, arrhythmic complications from vasopressors)?
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There is no clear evidence about how lactate might guide treatment intensity within the context of a modern sepsis resuscitation. Many approaches are reasonable. However, lactate is not an indicator of inadequate oxygen delivery, so an elevated lactate should not be blindly used as a trigger to increase oxygen delivery.
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(3) Lactated Ringer's (LR): Still a physiologically sensible choice.
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The common fear of administering lactate reveals a misunderstanding of LR and the role of lactate in shock states. First, LR contains sodium lactate (not lactic acid), and is therefore not acidotic. Second, lactate probably has a beneficial role as discussed above (although it is very rapidly metabolized). Occasional concern has been raised about the effect of LR on trending lactate levels, but this effect is minimal and the utility of precisely trending lactate levels is unclear.
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Unfortunately, Plasmalyte and Normosol were designed decades ago specifically to avoid the administration of lactate. Their design was misguided, as discussed in further detail here. For most critically ill patients, LR may be the best crystalloid.
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(4) Epinephrine in septic shock: Underutilized due to fear of lactate?
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Epinephrine has been recommended as a second-line vasopressor by many authors including the Surviving Sepsis guideline. Although popular abroad, it is rarely used in the US. One common reason for avoiding epinephrine is concern that it may cause elevated lactate levels which could be harmful or confound serial trending of lactate.
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Improved understanding of lactate may allow us to utilize epinephrine more often. As discussed above, serial trending of lactate is of unknown value and should not dissuade us from using epinephrine if this is the best drug. Elevated lactate levels might be beneficial and provide a dual action of epinephrine on the heart, rather than representing an undesirable “side-effect:”
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In 2010 Wutrich examined the prognostic value of changes in lactate following initiation of epinephrine infusion in patients with shock (mostly septic shock). Survivors had significantly greater increases in lactate over the first four hours of epinephrine therapy compared to nonsurvivors (figure below). Thus, an epinephrine-induced rise in lactate may be a good prognostic sign, indicating that the epinephrine is working.
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Epinephrine's properties may make it ideal for patients who fail to respond well to norepinephrine (+/- low-dose vasopressin). Such patients often have adequate afterload, but need some additional inotropy. At low doses (e.g. 0-10 micrograms/min), epinephrine functions as an inotrope (Moran 1993). For patients who fail to respond to inotropic doses of epinephrine, higher doses of epinephrine will provide inotropy and vasoconstriction as well. Thus, an epinephrine titration may be a simple approach to rapidly trial inotropic support and then provide additional vasoconstriction if needed.
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There is only one RCT comparing epinephrine vs. dobutamine as a second-line agent for patients with septic shock on norepinephrine (Mahmoud 2012). These authors found that compared to dobutamine, epinephrine led to faster hemodynamic stabilization, greater urine output, higher lactate levels, and no mortality difference. Unfortunately this study is very limited by the use of low doses of norepinephrine (0.1 mcg/Kg/min).
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One advantage of the norepinephrine-epinephrine combination is that it is difficult to screw up. Epinephrine alone is generally adequate for septic shock (Myburgh 2008). Therefore, any combination of norepinephrine and epinephrine is probably fine. Alternatively, when patients end up on norepinephrine combined with dobutamine, it is easier to make significant titration errors (e.g. titrating off norepinephrine before dobutamine).
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- Lactate production in septic shock is not due to anaerobic metabolism or low oxygen delivery. It is largely driven by endogenous epinephrine stimulating aerobic glycolysis via beta-2 adrenergic receptors.
- Lactate may have a protective effect, serving as a metabolic fuel for the heart and brain under conditions of stress.
- Elevated lactate is useful to identify occult shock (patients who are being maintained by a robust endogenous catecholamine release). These patients are at increased risk for deterioration and require more aggressive care.
- There is no clear evidence about what lactate adds to other resuscitation targets (e.g. blood pressure and urine output). If lactate is trended during sepsis resuscitation, it should be interpreted carefully in clinical context.
- Administration of sodium lactate is safe and potentially beneficial. This supports the use of lactated ringers as a resuscitative fluid.
- Epinephrine has often been avoided in the past due to concerns regarding lactate generation. Given that lactate is potentially beneficial, epinephrine should be re-considered as a second-line vasopressor. At low doses it works primarily as an inotrope, whereas at higher doses it also functions as a vasoconstrictor.
Stay tuned for another post about septic shock next week.
Notes
(1) In fairness it is also possible that some of these hemodynamic effects may be due to the alkalinizing effect of hypertonic sodium lactate.
(2) Of course, lactate may also be elevated by a variety of other conditions including mesenteric ischemia, medications such as metformin and propofol, various intoxications, liver failure, etc. Any patient with elevated lactate requires careful consideration for these numerous causes. When no obvious cause can be found, elevated lactate is generally regarded as a sign of shock until proven otherwise.
Additional information:
Material from Paul Marik et al.
- Garcia-Alvarez M, Marik PE, Bellomo R. Sepsis-associated hyperlactatemia. Critical Care 2014; 18: 503.
- Marik PE and Bellomo R. Lactate clearance as a target of therapy in sepsis: a flawed paradigm. Open Access Critical Care 2013.
- [Lecture at SMACC Chicago – Will link to this when it becomes available]
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- Vasopressin: Renal microvascular hemodynamics & vasopressin
- Norepinephrine: Early norepinephrine to stabilize the MAP in sepsis
Josh Farkas
Josh is the creator of PulmCrit.org. He is an assistant professor of Pulmonary and Critical Care Medicine at the University of Vermont (Burlington Vermont, USA).
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Thankyou for another interesting article and references – only recently found your site and I am hooked!
Your conclusion that lactic acid cannot be the result of hypoxia because it is produced by the lungs is not logical however…
Whilst in a well oxygenated patient, the alveoli may be rich in oxygen, the lung tissue does not receive any oxygen supply from the alveoli. The lung tissue is nourished from the systemic circulation via the bronchial arteries which arise from the thoracic aorta. If there is high systemic oxygen consumption or poor systemic oxygen delivery then the lung tissue may well be hypoxic regardless of the concentration of oxygen at the alveoli.
There is some evidence to support anaerobic metabolism, but I wouldn’t qualify it as being definitive. (Compared to, for example, the observation that lactate is generated in the lung – which seems fairly definitive evidence for the aerobic generation of lactate.)
From a clinical standpoint whether or not there may be a small component of anaerobic lactate generation is irrelevant. The key point is that we cannot use lactate as an indicator of anaerobic metabolism. All of the above clinical implications remain unchanged regardless of your opinion on the matter.
Hi Josh, Hi FOAM fans 🙂
Here, in our university hospital we have started giving sodium lactate to some patients. This is under evaluation and IT IS NOT routine.
https://translate.google.fr/translate?sl=auto&tl=en&js=y&prev=_t&hl=fr&ie=UTF-8&u=http%3A%2F%2Fwww.nfkb0.com%2F2015%2F04%2F21%2Fle-lactate-de-sodium-dans-les-etats-de-chocs%2F&edit-text=&act=url
Thank you for the post. Just a minor point of order, in the Mahmoud 2012 study, they used up to 0.1 mcg/KG/min of norepi (or 7 mcg/min in a 70kg person), not 0.1 mcg/min. This dose would actually fall into the inclusion criteria of the VASST trial (> 5 mcg/min).
However, for VASST the average dose of norepi at study inclusion was around 20 mcg/min (0.26-0.28 mcg/kg/min), and I am in complete agreement that Mahmoud et al. randomized their patients too early and on too low a dose of norepi. It just wasn't THAT low.
Again, great post, thanks for writing on this topic.
"Therefore, any combination of norepinephrine and epinephrine is probably fine. Alternatively, when patients end up on norepinephrine combined with dobutamine, it is easier to make significant titration errors (e.g. titrating off norepinephrine before dobutamine)". Can you just comment on this for a new pharmacist or direct me to any articles on the importance/significance of when to titrate what?
Thanks! I fixed the units in the post.
Using a low cutoff of 0.1 mcg/kg/min probably helped them enroll more patients in their study. However, most practitioners would go substantially higher on the norepinephrine before considering a second agent.
Thanks, this is really interesting. Hypertonic sodium lactate could have a role for vasopressor-refractory shock, severe acidosis, or both.
To do a norepinephrine/dobutamine titration, would typically start with norepinephrine titrating against a MAP target. If you're having difficulty achieving the target MAP or getting enough perfusion (e.g. adequate MAP but low urine output & cold mottled skin), would look at the ejection fraction with echocardiography and add some dobutamine if the ejection fraction is low. One will often get a sense quickly if the dobutamine is helping – dobutamine seems to work best in patients with severely reduced ejection fraction and in such patients can improve both Bp and perfusion. As the patient is improving, I generally like to get the dobutamine off first. Excess beta-1 stimulation of the heart from dobutamine for too long probably isn't a great thing. I'm a bit more comfortable leaving patients on norepinephrine for longer periods of time as some patients seem to develop prolonged vasoplegia and may need low-dose norepinephrine for a while. The main danger of a dobutamine/norepinephrine titration might be that if high doses of dobutamine were used with insufficient norepinephrine it might be possible to put a lot of stress on the myocardium with inadequate preload (noting that vasoconstrictors like norepinephrine cause venoconstriction as well) and afterload.
Metabolic Theory of Septic Shock
Please do a search for the above
Yes, it is certainly possible that anaerobic metabolism may occur in some patients with septic shock for example patients with extremely low cardiac output who are very close to death. However, overall in most cases it seems that lactate is due to aerobic metabolism.
The utility of using lactate to guide resuscitation is unknown. My current practice is to usually follow it. If the lactate isn't decreasing, this may be a signal to re-evaluate the patient top to bottom – did we miss a focus of infection? Does the patient need more definitive diagnostic imaging? Are we using the wrong antibiotic? Are the hemodynamics optimized?
Excellent. I agree with your use of the lactate as a marker for recovery. The truth is we have no data for almost anything we do in sepsis management so we have to fall back on engaging the pathophysiology. I would add that the slope of the bicarb is an often missed marker. While volume expansion as a cause of a modest negative slope must always be considered, it is important to recognize that a bicarb of 19 at 5PM may be a bicarb of 12 at midnight. In such a case, the negative slope will soon be associated with death but it is important to note that the negative bicarb slope, especially in the young patient, is commonly due to quite correctable causes but only if the slope is detected and correction is provided timely. By the time the bicarb is 12 it is generally too late. When we look at unexpected mortalities from sepsis, the negative bicarb slope is one of the most commonly missed warning signs. The slope often accelerates to 1 meq/hr so it is important to obtain and look specifically at the slope of serial bicarbonate levels more often than every 12 hrs early in… Read more »
Many providers in my ICU prefer phenylephrine because many of our septic patients are tachycardic, so there is a fear of using anything with beta activity which may increase the HR, and it drives me crazy because I know phenylephrine is the pressor of the devil, although anesthesiologists love it. I was wondering if you could comment on this.
Perhaps prolonged increased HR being a sign of high sympathetic tone for too long is bad, hence esmolol drips becoming more popular though the jury is still out on whether or not they really improve outcomes.
They cannot handle the truth! I recently met with a sepsis scientist to discuss the need to move to clinical care and research which is applied as a function of the dynamic relational patterns. He did not not disagree that "there are no thresholds of unexpected hospital death, only the dynamic relational patterns of unexpected hospital death". However there is a new twist given the failure of thresholds in the trials. His argument was that the patterns are too complex to learn and that nurses and physicians need the thresholds as green and red lights because they cannot handle the complexity. In other words…. [you cannot handle the truth]. I pointed out that it is impossible to dichotomize complexity into thresholds and that he underestimates the cognitive capacity of nurses and physicians. Really, it comes down to all of you because it is your perceived limited capacity to learn which is now cited as one of the primary reasons to perpetuate threshold decision making in critical care. There are no thresholds of sepsis or unexpected hospital death, only the dynamic relational patterns of sepsis and unexpected hospital death. We look forward to the day when FOAMites say with one voice… Read more »
"Lactate production in septic shock is not due to anaerobic metabolism or low oxygen delivery." This is theory and I think every review — even Marik's – mentions that it is likely a combination of type I and II hyperlactatemia that contributes to the elevated lactate in shock stats.
Yes, that may have been slightly over-stated: Please see my reply to the first comment.
To get really technical about it, in order for something to be scientific it must be testable. If something is not testable and cannot be disproven, then it is not scientific. To say “despite evidence to the contrary, maybe some anaerobic metabolism occurs to a small extent or in some patients” is nearly impossible to disprove and therefore isn’t very scientific. Are you aware of any definitive evidence that anaerobic metabolism commonly occurs in sepsis?
My point was that it is likely multifactorial. I disagree with your statement. You quoted Marik's review as the evidence that lactate is not due to anaerobic metabolism while (on page 9 of 11 in the review) they mention that there's decent evidence that lactate elevation may be due to hypoxia as well.
I'm not familiar with an 'acidotic death'? The acidosis is not what kills patients – its the underlying pathology.
Excellent point Dr. Anderson. Let me explain relevant the pathophysiology of dynamic relational patterns of death. Acidotic death is a term applied to patients who are in a reversible state of anaerobic metabolism (such as severe sepsis, profound hypovolemia, cardiac tamponade, dynamic hyperinflation), but the state is missed (the hyperinflation, high intrapericardial pressure or low venous pressure in relation to intrathoracic pressure i.e. relative hypovolemia persists unmitigated or insufficiently mitigated relative to venous pressure.) The arterial and venous bicarbonate (total CO2) will fall due to dynamic lactic acid production due to the low pK of lactic acid (high affinity to donate hydrogen ion) eventually reaching levels which cannot be compensated by hyperventilation and this is commonly associated with dyspnea which is often discounted or mitigated by sedatives or narcotics. The respiratory effort adds to the lactate production. The fall in Ph shifts the oxyhemoglobin curve to the right accelerating arterial hypoxemia if significant V/Q mismatch or Qs/Qt elevation (shunt) is present. Death often occurs when hyperventilation cannot be maintained or when sedatives are given by an unknowing operator in an attempt to prepare for intubation. An acidotic death, like a hypoxic death, is (as you point out) due to another… Read more »
I was just thinking that maybe trending lactate can be of use but we have just been looking at it the wrong way. From what I gather in the discussion, we agree that lactate used as a marker for marker for hypoxia and anaerobic metabolism is debunked and that lactate is actually a marker for compensation. When the body is in a stressful state and epinephrine signals creation of more lactate to maintain adequate energy for myocardium and brain neurons until this compensation fails. I was wondering if and how long does it takes for a persons stores of epinephrine to deplete or when does this compensation generally fail. The trending down of lactate in a sick person could maybe be seen as a failure of this compensation? I understand that it will trend down as the need for epinephrine decreases and the person is responding well to resuscitation but in situations were clinically the person is not looking well, it could be a sign of impending compensatory failure?
You may say that elevated lactate in sepsis is not due to anaerobic metabolism, but I disagree. Yes, the patient may be in a hyperdynamic state, but the stress on the body from the overwhelming disease state means the metabolic energy requirements exceed the body’s ability to provide those energy requirements, thus hyperdynamism is the body’s attempt to deliver a higher energy substrate or oxygen per unit time to the body’s tissues. And when the tissue doesn’t get it, the anaerobic metabolism and subsequent lactate production occurs. Simple physiology. And hyperdynamism absolutely doesn’t mean that there is no peripheral localized arteriolar vasoconstriction causing the anaerobic state. You may not be able to actually MEASURE it that far out in the vascular tree.
Reading through all these great comments have been eye-opening and a great pleasure. Huge thanks to everyone and thanks for all the great references!
Excellent Points and we'll presented. I suspect that you do not mean to say that Lactate production in septic shock is NOT due to anerobic metabolism is always true. Sepsis is a dynamic state. While often hyperdynamic in its early stages patients often present late or progreess despite antibiotics. The presence of sepsis indiced mycardial depression, volume depletion and orexisting heart disease, may render cardiac output quite low. Anerobic.state can cause profound lactic acidosis and, given the low Pk of lactic acid, the bicarb can fall at rates of 1 meq per hour or more. As with all shock states, early correction of the low perfusion state is pivotal in this setting as by fluid, epi, etc.or the patient may die due to profound buffer depletion, an acidotic death. A high negative slope of bicarb is an ominous sign of impending acidotic death and correction of low intravascular volume may be pivotal when this is present. Inadequate oxygen delivery to meet demand causes lactic acidosis in extreme exercise, severe volume depletion, and low cardiac output shock states including those induced by mycardial infarction, massive pulmonary embolism, severe hyperkalemia, percardial tamponade, sepsis, dynamic hyperinflation, and many other causes. The point is… Read more »
There is a strong argument (and evidence base), that lactate is not produced by anaerobic metabolism in humans. If cellular dysfunction resulted from lack of oxygen supply, we would see necrotic tissue in septic patients but this is not the case.
There is undeniably heterogeneity in the microcirculation but this may be the result of cells not utilising oxygen and thereby causing localised arteriolar constriction, rather than a lack of oxygen supply per se.
Paul Marik gave an excellent talk on lactate at SMACC Chicago last year.
That’s awesome, thanks for embedding the lecture.