Feb 092020

Jon-Emile S. Kenny MD [@heart_lung]

Sich regen bringt Segen

-German proverb


It is an overcast day in Bern, Switzerland.  I have recently left Zermatt, having had the honour and pleasure of speaking at ‘The Big Sick’ conference.  I spent the day roaming the narrowed passages of this old, beautiful city.  In the midst of my meanderings I visited the flat of Albert Einstein and the museum dedicated to his impactful life; he was a non-conformist, no doubt, and he changed the world.

After this eventful day, I stumbled over some cobblestones into a café and read a manuscript written by a trio of sepsis non-conformists.  Drs. Spiegel, Gordon and Marik have coined a new reflex in critical care medicine – the ‘Lacto-Bolo Reflex.’  Their treatise, found here, is well-worth reading.

The Lacto-Bolo Reflex

Appropriately, Drs. Spiegel, Gordon and Marik begin their manuscript with a definition:

The Lacto-Bolo reflex: a well-known pathological reflex observed in the majority of house staff and a large portion of attending physicians. It involves the reflexive administration of IV crystalloid in response to a serum lactate above what is considered normal.”

While the authors do not specify the underlying mechanism(s) of this reflex, they do suggest some hypotheses in their brief historical overview of lactate in resuscitation.  The origins of the reflex likely date back to 1992 when Bone and colleagues first published consensus definitions for sepsis and organ failure in which they proclaimed that serum lactate elevation be considered a marker of inadequate tissue oxygenation.

Lactate and Tissue Perfusion

In succinct fashion, the authors summarize data casting doubt on the entrenched belief that lactate signifies dysfunctional oxidative phosphorylation in sepsis and septic shock.  Lactate rises when adrenergic stress rises; indeed, epinephrine increases oxygen delivery but also lactate [see lecture 2].  By contrast, esmolol and dexmedetomidine tend to decrease oxygen delivery but also lactate!  I have previously argued that the differential diagnosis for lactate elevation should mirror that of sinus tachycardia as the underlying mechanisms are very similar.

Lactate-Guided Resuscitation: pro

Spiegel and colleagues relay that perhaps the best evidence supporting lactate to guide resuscitation is that of Jansen and colleagues, published in 2010.  In this trial, 348 ICU patients [roughly 40% of whom had severe sepsis or septic shock] with an elevated lactate were randomized to 20% lactate reduction every 2 hours or ‘usual care.’  In the end, there was no significant difference between the two groups prior to statistical adjustment.  Unusually, however, the authors corrected for baseline dissimilarities and only then found that those randomized to lactate guidance had improved mortality.  Note that post-hoc statistical transformation is highly unusual in an RCT because randomization is assumed to assure balance pre-intervention.

Lactate-Guided Resuscitation: con

The recently published ANDROMEDA-SHOCK study randomized 424 patients with septic shock [i.e. lactate ≥ 2.0 mmol/L, requiring vasopressors to maintain a MAP of 65 mm Hg after a fluid bolus of at least 20 mL/kg] to an 8-hour resuscitation protocol.  Note that this is over 3-times more septic patients than Jansen and colleagues above.

As discussed in depth previously, patients in ANDROMEDA-SHOCK were randomized to resuscitation based on either lactate reduction or improved capillary refill time.  Those who were resuscitated by lactate reduction had an 8.5% absolute increase in mortality [hazard ratio, 0.75 (95% CI, 0.55 to 1.02); p = 0.06].  Unlike Jansen and colleagues, the authors of ANDROMEDA-SHOCK did not perform statistical adjustments with this finding.  While it is true that the 95% confidence interval crossed 1.0, the balance of the signal suggests that if there was greater statistical power, true harm may have been identified; importantly, this cannot be known.

Clinical Implications

I wholeheartedly agree with Drs. Spiegel, Gordon and Marik when they note that lactate may be useful.  Lactate elevation in sepsis is a marker of stress and its persistence should trigger the clinician not to thoughtlessly give intravenous fluids, but rather consider cryptic sources of impending death.  Is there inadequate source control?  Are the antibiotics correct?  Is there a hidden, massive pulmonary embolus?

I do not believe that the suggestion of harm in the lactate arm of ANDROMEDA-SHOCK was due to excessive intravenous fluids, however.  The lactate group only received 400 mL more than the capillary refill group.  To compare, in the PRoCESS trial, the non-EGDT protocol group received 1.1 to 1.5 more litres of crystalloid, but had a similar mortality rate to the usual care group.  Additionally, in ANDROMEDA, both the capillary refill arm and lactate arms had nearly identical numbers of patients pushed to the flat portion of their Starling curves; another mechanism, I think, must be invoked.

Where does this leave us?  If I had to derive an algorithm for sepsis resuscitation, it would be guided by mean arterial blood pressure [MAP] and capillary refill time [CRT].  Thereafter, if MAP and CRT are not normalized with rational selection of vasoactive medications and the clinician opts to administer intravenous fluids, then sensible use of bedside ultrasound is employed to assess the lungs, heart, visceral organs and brain for volume tolerance.  I covered this topic at the inaugural Hospitalist and Resuscitationist Conference in Montreal [see lecture 3].  Such an approach, I think, might extinguish the neuronal arc involved in the “Lacto-Bolo Reflex.”



Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he also the creator and author of a free hemodynamic curriculum at heart-lung.org

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The ‘Lacto-Bolo Reflex’