Editorial Commentary

Lactate guided resuscitation—nothing is more dangerous than

Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
Correspondence to: Paul E. Marik, MD, FCCM, FCCP. Professor of Medicine, Chief, Pulmonary and Critical Care Medicine, Eastern Virginia
Medical School, 825 Fairfax Ave., Suite 410, Norfolk, VA 23507, USA. Email: [email protected].
Provenance: This is an invited article commissioned by the Section Editor Xue-Zhong Xing [National Cancer Center (NCC)/Cancer Hospital,
Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China].
Comment on: Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs
Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA
2019;321:654-64.

Submitted May 31, 2019. Accepted for publication Jul 16, 2019.
doi: 10.21037/jtd.2019.07.67
View this article at: http://dx.doi.org/10.21037/jtd.2019.07.67

Sodium chloride is a poison to all people when given in large doses, repeated measurement of blood lactate every 2 to 4 hours
and occasionally very toxic in small doses to a certain class of cases until normalization (3). The goal of lactate guided
(sepsis) (1). resuscitation is to normalize or decrease lactate levels by
——Trout (1913) 20% every 2 hours. This goal is supposedly achieved by
repeated boluses of crystalloids to achieve the desired
In the ANDROMEDA-SHOCK study, Hernández et al., decline in blood lactate levels. Surprisingly, this approach
randomized 424 patients presenting with septic shock to is devoid of any pathophysiologic basis, has no scientific
one of two resuscitation strategies—the peripheral perfusion underpinning and is based on myths which have been
group and the lactate-guided group—for the first eight clearly debunked. Furthermore, as evidenced by the
hours of management (2). End-organ perfusion was assessed ANDROMEDA-SHOCK study, this approach will lead to
using capillary refill time or “lactate clearance” respectively. volume overload with an increased risk of organ dysfunction
If perfusion was deemed to be inadequate, the patients and death (4). Lactate guided resuscitation in patients with
received fluid boluses until they were considered to be fluid severe sepsis and septic shock is based on the cascading
non-responsive at which point they received vasopressor myths that an elevated blood lactate level is a consequence
agents. The lactate-guided strategy led to a higher volume of organ hypoperfusion with inadequate oxygen delivery
of fluid administered and the greater use of vasopressor and with the consequent anaerobic production of lactate.
agents, however this approach failed to improve patient It follows from this reasoning that hyperlactemia must
outcomes. The 28-day mortality was 34.9 percent in the be treated by aggressive fluid resuscitation with the
peripheral perfusion group and 43.4 percent in the lactate goal of increasing cardiac output and oxygen delivery,
group (95% CI, 0.55 to 1.02; P=0.06). There was less organ and that this process must be intensified until the blood
dysfunction at 72 hours in the peripheral perfusion group lactate level has normalized. However, numerous clinical
as evidenced by a mean72-hour Sequential Organ Failure and experimental investigations have been unable to
Assessment (SOFA) score of 5.6 vs. 6.6 (95% CI, −1.97 to demonstrate an association between an increased blood
−0.02; P=0.045). lactate concentration and evidence of tissue hypoxia (5).
The ANDROMEDA-SHOCK study (2) was modeled It seems like clinicians, researchers and the authors
according to the Surviving Sepsis Campaign Guidelines of clinical guidelines don’t learn from the mistakes of
which propose guiding hemodynamic resuscitation by the past, as we have been down this road before. In the

© Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2019;11(Suppl 15):S1969-S1972 | http://dx.doi.org/10.21037/jtd.2019.07.67
S1970 Marik. Lactate guided resuscitation

1980’s, based on observational studies in surgical patients, together with mitochondrial dysfunction with multiple
William Shoemaker and colleagues (6), popularized the abnormalities of the Krebs cycle enzymes and electron
idea of driving up oxygen delivery (to supranormal levels) transport chain underlie this bioenergetic failure (16,17).
in critically ill patients including those with sepsis. Studies This process is further driven by β2 adrenergic mediated
in trauma patients demonstrated that this strategy did not glycogenolysis with increased production of glucose and
improve overall outcome (7). Similarly, in a study published pyruvate. These observations likely explains the lack of
over 20 years ago, Gattinoni et al. demonstrated that a trial ischemic necrosis found at autopsy in patients who have
of goal-orientated hemodynamic therapy did not improve died from sepsis (18). Furthermore, it explains the finding
the outcome of critically ill patients (8). Hayes et al. of acute kidney injury in patients with sepsis despite
performed a randomized controlled trial in which critically maintained renal blood flow (18). The proximal convoluted
ill medical patients were randomized to “supranormal tubule has amongst the highest number of mitochondrion
oxygen delivery” or usual care (9). While there was a per cell and is therefore highly vulnerable to biogenetic
significant increase in oxygen delivery in the supranormal failure (17).
group, oxygen consumption remained unchanged with a It is important to emphasize that severe sepsis and septic
substantial increase in mortality in this group of patients. shock are primarily not volume depleted states (19), and that
Ronco et al. demonstrated that increasing oxygen delivery titrating fluids to a blood lactate level or markers or peripheral
in septic patients with an increased blood lactate level perfusion (i.e., both arms of the ANDROMEDA-SHOCK
neither increased oxygen consumption nor decreased lactate study) will result in iatrogenic salt water drowning (20).
levels (10). Similarly, in a group of patients with sepsis The description of iatrogenic crystalloid induced multiple
and hyperlactemia, Marik and Sibbald demonstrated that organ failure is not new (21). In an editorial published in
blood transfusion failed to increase oxygen consumption 1967, Moore and Shires made a plea for “moderation”
nor result in a decline in blood lactate concentration (11). regarding fluid resuscitation requirements. In addition to
In an elegant analysis of data from the ALBIOS study, altering cell structure and function and potentiating the
Gattinoni et al. demonstrated that hyperlactatemia in sepsis inflammatory response (22), clinicians may not be cognizant
is “caused more frequently by impaired tissue oxygen of the adverse hemodynamic effects of crystalloids in patients
utilization, rather than by impaired oxygen transport” (12). with sepsis. Paradoxically in the setting of sepsis crystalloids
Furthermore, these authors state that “the current strategy act as vasodilators, decrease adrenergic responsiveness and
of fluid resuscitation could be modified according to the increase capillary leakiness (23). Recently He and colleagues
origin of excess lactate”. Morelli and coworkers randomized demonstrated that lung microcirculatory flow was reduced
patients with refractory septic shock to an esmolol infusion with fluid loading, with a significant increase in septal
(selective β1 antagonist) or placebo (13). Oxygen delivery thickness (24).
fell in the esmolol as compared to control patients, yet The primary hemodynamic goal in patients with sepsis is
“paradoxically” the decline in the lactate levels was greater to achieve a mean arterial pressure (MAP) >65–70 mmHg.
in the patients treated with esmolol. These studies provide This is best achieved by a physiologically guided,
strong evidence that hyperlactemia in sepsis is unlikely to conservative fluid strategy followed by the early use of
be associated with inadequate oxygen delivery and that norepinephrine (25). Norepinephrine is a potent veno-
attempts at increasing oxygen delivery may be harmful. constrictor, which increases the stressed blood volume,
Remarkably, the first author of the ANDROMEDA- thereby increasing venous return and cardiac output.
SHOCK study has previously stated that “seeking to lower Apart from increasing venous return and arterial tone,
lactate levels (by whatever means given the multiple events unlike crystalloids, norepinephrine has been demonstrated
that regulate its blood levels) has no credibility and no to increase microcirculatory flow (26). Furthermore, we
logic in terms of hemodynamics, bioenergetics, or tissue advocate for the early use of appropriate antibiotics and the
protection” (14). early application of metabolic resuscitation (hydrocortisone,
These data suggest that an alternative explantation ascorbic acid and thiamine) (25). This revised approach to
must exist for the hyperlactemia of sepsis (15,16). Indeed, the early management of sepsis is summarized in Figure 1.
a growing body of evidence suggests that sepsis is In summary, current evidence suggests that most of the
characterized by bioenergetic failure rather than inadequate increase in blood lactate in patients with severe sepsis is
oxygen delivery. Abnormalities of energy metabolism, unrelated to poor tissue perfusion and is therefore unlikely

© Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2019;11(Suppl 15):S1969-S1972 | http://dx.doi.org/10.21037/jtd.2019.07.67
Journal of Thoracic Disease, Vol 11, Suppl 15 September 2019 S1971

Traditional approach

Antibiotics

Fluid
Norepinephrine
Vasopressin
Epinephrine
Stress-dose steroids

Revised approach
Antibiotics

Fluid

Norepinephrine
Epinephrine1
Vasopressin2
Metabolic resuscitation (Hydrocortisone/Ascorbate/Thiamine)

Time

Figure 1 Paradigm change in the management of sepsis and septic shock. Reproduced with permission from Society of Critical Care Medicine
and Wolters Kluwer Health, Inc. (25).

to respond to iatrogenic attempts to increase oxygen Mortality Among Patients With Septic Shock: The
delivery. Driving up oxygen delivery in septic patients with ANDROMEDA-SHOCK Randomized Clinical Trial.
an increased blood lactate concentration will not increase JAMA 2019;321:654-64.
oxygen consumption and is likely to increase the morbidity 3. Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis
and mortality of these patients. Campaign: International Guidelines for Management
of Sepsis and Septic Shock:2016. Crit Care Med
2017;45:486-552.
Acknowledgments
4. Marik PE, Linde-Zwirble WT, Bittner EA, et al. Fluid
None. administration in severe sepsis and septic shock, patterns
and outcomes. An analysis of a large national database.
Intensive Care Med 2017;43:625-32.
Footnote
5. Marik PE. SEP-1: The Lactate Myth and Other Fairytales.
Conflicts of Interest: The author has no conflicts of interest to Crit Care Med 2018;46:1689-90.
declare. 6. Shoemaker WC, Appel PL, Waxman K, et al. Clinical
trial of survivors cardiorespiratory patterns as therapeutic
Ethical Statement: The author is accountable for all goals in critically ill postoperative patients. Crit Care Med
aspects of the work in ensuring that questions related 1982;10:398-403.
to the accuracy or integrity of any part of the work are 7. McKinley BA, Kozar RA, Cocanour CS, et al. Normal
appropriately investigated and resolved. versus supranormal oxygen delivery goals in shock
resuscitation: the response is the same. J Trauma
2002;53:825-32.
References
8. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-
1. Trout HM. Proctoclysis – An experimental study. Surg oriented hemodynamic therapy in critically ill patients. N
Gynecol Obstet 1913;16:560-2. Engl J Med 1995;333:1025-32.
2. Hernández G, Ospina-Tascón GA, Damiani LP, et al. 9. Hayes MA, Timmins AC, Yau E, et al. Elevation of
Effect of a Resuscitation Strategy Targeting Peripheral systemic oxygen delivery in the treatment of critically ill
Perfusion Status vs Serum Lactate Levels on 28-Day patients. N Engl J Med 1994;330:1717-22.

© Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2019;11(Suppl 15):S1969-S1972 | http://dx.doi.org/10.21037/jtd.2019.07.67
S1972 Marik. Lactate guided resuscitation

10. Ronco JJ, Fenwick JC, Wiggs BR, et al. Oxygen Am J Respir Crit Care Med 2013;187:509-17.
consumption is independent of increases in oxygen 19. Marik P, Bellomo R. A rational apprach to fluid therapy in
delivery by dobutamine in septic patients who have sepsis. Br J Anaesth 2016;116:339-49.
normal or increased plasma lactate. Am Rev Respir Dis 20. Marik PE. Iatrogenic salt water drowning and the hazards
1993;147:25-31. of a high central venous pressure. Ann Intensive Care
11. Marik PE, Sibbald WJ. Effect of stored-blood transfusion 2014;4:21.
on oxygen delivery in patients with sepsis. JAMA 21. Bascom JU, Burgess M. Crystalloids: An Iatrogenic source
1993;269:3024-29. of multiple organ failure? Infection 2001;29:180.
12. Gattinoni L, Vasques F, Camporota L, et al. Understanding 22. Cotton BA, Guy JS, Morris JA, et al. The cellular,
lactatemia in human sepsis: potential impact for early metabolic, and systemic consequences of aggressive fluid
management. Am J Respir Crit Care Med 2019;(5):582-9. resuscitation strategies. Shock 2006;26:115-21.
13. Morelli A, Ertmer C, Westphal M, et al. Effect of heat 23. Byrne L, Obonyo NG, Diab SD, et al. Unintended
rate control with esmolol on hemodynamic and clinical consequences; fluid resuscitation worsens shock in an
outcomes in patients with septic shock. A randomized ovine model of endotoxemia. Am J Respir Crit Care Med
clinical trial. JAMA 2013;310:1683-91. 2018;198:1043-54.
14. Hernandez G, Bellomo R, Bakker J. The ten pitfalls 24. He H, Hu Q, Long Y, et al. Effects of high PEEP and
of lactate clearance in sepsis. Intensive Care Med fluid administration on systemic circulation and pulmonary
2019;45:82-5. microcirculation and alveoli in a canine model. J Appl
15. Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated Physiol 2019;127:40-6.
hyperlactatemia. Crit Care 2014;18:503. 25. Marik PE, Farkas JD. The Changing Paradigm of Sepsis:
16. Marik PE. Patterns of Death in Patients with Sepsis Early Diagnosis, Early Antibiotics, Early Pressors, and Early
and the Use of Hydrocortisone, Ascorbic Acid, and Adjuvant Treatment. Crit Care Med 2018;46:1690-2.
Thiamine to Prevent These Deaths. Surg Infect (Larchmt) 26. Fiorese Coimbra KT, de Freitas FGR, Bafi AT, et al.
2018;19:812-20. Effect of Increasing Blood Pressure With Noradrenaline
17. Sun J, Zhang J, Tian J, et al. Mitochondria in sepsis- on the Microcirculation of Patients With Septic Shock
induced AKI. J Am Soc Nephrol 2019;30:1151-61. and Previous Arterial Hypertension. Crit Care Med
18. Takasu O, Gaut JP, Watanabe E, et al. Mechanisms of 2019;47:1033-40.
cardiac and renal dysfunction in patients dying of sepsis.

Cite this article as: Marik PE. Lactate guided resuscitation—

© Journal of Thoracic Disease. All rights reserved. J Thorac Dis 2019;11(Suppl 15):S1969-S1972 | http://dx.doi.org/10.21037/jtd.2019.07.67