Lactic acidosis: Clinical implications and management strategies

HOW TO APPROACH AN ELEVATED LACTATE LEVEL

An elevated lactate level should prompt an evaluation for causes of decreased oxygen delivery, due either to a systemic low-flow state (as a result of decreased cardiac output) or severe anemia, or to regionally decreased perfusion, (eg, limb or mesenteric ischemia). If tissue hypoxia is ruled out after an exhaustive workup, consideration should be given to causes of hyperlactatemia without concomitant tissue hypoxia (type B acidosis).

Treatment differs depending on the underlying mechanism of the lactate elevation; nevertheless, treatment is mostly related to optimizing oxygen delivery by giving fluids, packed red blood cells, and vasopressors or inotropic agents, or both (Figure 2). The specific treatment differs based on the shock state, but there are similarities that can guide the clinician.

FLUID SUPPORT

Giving fluids, with a goal of improving cardiac output, remains a cornerstone of initial therapy for most shock states.^22,23

How much fluid?

Fluids should be given until the patient is no longer preload-dependent, although there is much debate about which assessment strategy should be used to determine if cardiac output will improve with more fluid (ie, fluid-responsiveness).²⁴ In many cases, fluid resuscitation alone may be enough to restore hemodynamic stability, improve tissue perfusion, and reduce elevated lactate concentrations.²⁵

The decision to give more fluids should not be made lightly, though, as a more positive fluid balance early in the course of septic shock and over 4 days has been associated with a higher mortality rate.²⁶ Additionally, pushing fluids in patients with cardiogenic shock due to impaired left ventricular systolic function may lead to or worsen pulmonary edema. Therefore, the indiscriminate use of fluids should be avoided.

Which fluids?

Despite years of research, controversy persists about whether crystalloids or colloids are better for resuscitation. Randomized trials in heterogeneous intensive care unit patients have not detected differences in 28-day mortality rates between those allocated to crystalloids or 4% albumin²⁷ and those allocated to crystalloids or hydroxyethyl starch.²⁸

Hydroxyethyl starch may not be best. In a study of patients with severe sepsis, those randomized to receive hydroxyethyl starch had a higher 90-day mortality rate than patients randomized to crystalloids (51% vs 43%, P = .03).²⁹ A sequential prospective before-and-after study did not detect a difference in the time to normalization (< 2.2 mmol/L) of lactate (P = .68) or cessation of vasopressors (P = .11) in patients with severe sepsis who received fluid resuscitation with crystalloids, gelatin, or hydroxyethyl starch. More patients who received hydroxyethyl starch in these studies developed acute kidney injury than those receiving crystalloids.^28–30

Taken together, these data strongly suggest hydroxyethyl starch should not be used for fluid resuscitation in the intensive care unit.

Normal saline or albumin? Although some data suggest that albumin may be preferable to 0.9% sodium chloride in patients with severe sepsis,^31,32 these analyses should be viewed as hypothesis-generating. There do not seem to be differences between fluid types in terms of subsequent serum lactate concentrations or achievement of lactate clearance goals.^28–30 Until further studies are completed, both albumin and crystalloids are reasonable for resuscitation.

Give fluids until the patient is no longer preload-dependent, but excessive fluids may be deleterious

Caironi et al³³ performed an open-label study comparing albumin replacement (with a goal serum albumin concentration of 3 g/dL) plus a crystalloid solution vs a crystalloid solution alone in patients with severe sepsis or septic shock. They detected no difference between the albumin and crystalloid groups in mortality rates at 28 days (31.8% vs 32.0%, P = .94) or 90 days (41.1% vs 43.6%, P = .29). However, patients in the albumin group had a shorter time to cessation of vasoactive agents (median 3 vs 4 days, P = .007) and lower cardiovascular Sequential Organ Failure Assessment subscores (median 1.20 vs 1.42, P = .03), and more frequently achieved a mean arterial pressure of at least 65 mm Hg within 6 hours of randomization (86.0% vs 82.5%, P = .04).

Although serum lactate levels were lower in the albumin group at baseline (1.7 mmol/L vs 1.8 mmol/L, P = .05), inspection of the data appears to show a similar daily lactate clearance rate between groups over the first 7 study days (although these data were not analyzed by the authors). Achievement of a lactate level lower than 2 mmol/L on the first day of therapy was not significantly different between groups (73.4% vs 72.5%, P = .11).³³

In a post hoc subgroup analysis, patients with septic shock at baseline randomized to albumin had a lower 90-day mortality rate than patients randomized to crystalloid solutions (RR 0.87, 95% CI 0.77–0.99). There was no difference in the 90-day mortality rate in patients without septic shock (RR 1.13, 95% CI 0.92–1.39, P = .03 for heterogeneity).³³

These data suggest that albumin replacement may not improve outcomes in patients with severe sepsis, but may have advantages in terms of hemodynamic variables (and potentially mortality) in patients with septic shock. The role of albumin replacement in patients with septic shock warrants further study.

VASOPRESSORS

Vasopressors, inotropes, or both should be given to patients who have signs of hypoperfusion (including elevated lactate levels) despite preload optimization or ongoing fluid administration. The most appropriate drug depends on the goal: vasopressors are used to increase systemic vascular resistance, while inotropes are used to improve cardiac output and oxygen delivery.

Blood pressure target

The Surviving Sepsis Campaign guidelines recommend a mean arterial blood pressure target of at least 65 mm Hg during initial resuscitation and when vasopressors are applied for patients with septic shock.²² This recommendation is based on small studies that did not show differences in serum lactate levels or regional blood flow when the mean arterial pressure was elevated above 65 mm Hg with norepinephrine.^34,35 However, the campaign guidelines note that the mean arterial pressure goal must be individualized in order to achieve optimal perfusion.

A large, open-label trial³⁶ detected no difference in 28-day mortality rates in patients with septic shock between those allocated to a mean arterial pressure goal of 80 to 85 mm Hg or 65 to 70 mm Hg (36.6% vs 34.0%, P = .57). Although lactate levels did not differ between groups, the incidence of new-onset atrial fibrillation was higher in the higher-target group (6.7% vs 2.8%, P = .02). Fewer patients with chronic hypertension needed renal replacement therapy in the higher pressure group, further emphasizing the need to individualize the mean arterial pressure goal for patients in shock.³⁶

Which vasopressor agent?

Dopamine and norepinephrine have traditionally been the preferred initial vasopressors for patients with shock. Until recently there were few data to guide selection between the two, but this is changing.

In a 2010 study of 1,679 patients with shock requiring vasopressors, there was no difference in the 28-day mortality rate between patients randomized to dopamine or norepinephrine (53% vs 49%, P = .10).³⁷ Patients allocated to dopamine, though, had a higher incidence of arrhythmias (24% vs 12%, P < .001) and more frequently required open-label norepinephrine (26% vs 20%, P < .001). Although lactate levels and the time to achievement of a mean arterial pressure of 65 mm Hg were similar between groups, patients allocated to norepinephrine had more vasopressor-free days through day 28.

Norepinephrine, not dopamine, should be the initial vasopressor in most types of shock

An a priori-planned subgroup analysis evaluated the influence of the type of shock on patient outcome. Patients with cardiogenic shock randomized to dopamine had a higher mortality rate than those randomized to norepinephrine (P = .03). However, the overall effect of treatment did not differ among the shock subgroups (interaction P = .87), suggesting that the reported differences in mortality according to subgroup may be spurious.

In a 2012 meta-analysis of patients with septic shock, dopamine use was associated with a higher mortality rate than norepinephrine use.³⁸

In light of these data, norepinephrine should be preferred over dopamine as the initial vasopressor in most types of shock.

Epinephrine does not offer an outcome advantage over norepinephrine and may be associated with a higher incidence of adverse events.^39–42 Indeed, in a study of patients with septic shock, lactate concentrations on the first day after randomization were significantly higher in patients allocated to epinephrine than in patients allocated to norepinephrine plus dobutamine.³⁹ Similar effects on lactate concentrations with epinephrine were seen in patients with various types of shock⁴⁰ and in those with cardiogenic shock.⁴²

These differences in lactate concentrations may be directly attributable to epinephrine. Epinephrine can increase lactate concentrations through glycolysis and pyruvate dehydrogenase activation by stimulation of sodium-potassium ATPase activity via beta-2 adrenergic receptors in skeletal muscles,⁴³ as well as decrease splanchnic perfusion.^42,44,45 These effects may preclude using lactate clearance as a resuscitation goal in patients receiving epinephrine. Epinephrine is likely best reserved for patients with refractory shock,²² particularly those in whom cardiac output is known to be low.

Phenylephrine, essentially a pure vasoconstrictor, should be avoided in low cardiac output states and is best reserved for patients who develop a tachyarrhythmia on norepinephrine.²²

Vasopressin, also a pure vasoconstrictor that should be avoided in low cardiac output states, has been best studied in patients with vasodilatory shock. Although controversy exists on the mortality benefits of vasopressin in vasodilatory shock, it is a relatively safe drug with consistent norepinephrine-sparing effects when added to existing norepinephrine therapy.^46,47 In patients with less severe septic shock, including those with low lactate concentrations, adding vasopressin to norepinephrine instead of continuing norepinephrine alone may confer a mortality advantage.⁴⁸