Ebook Marinos the CIU book (4th edition): Part 2

(BQ) Part 2 book Marinos the CIU book presents the following contents: Acid-Base disorders, renal and electrolyte disorders, the abdomen & pelvis, disorders of body temperature, nervous system disorders, nutrition & metabolism, critical care drug therapy, toxicologic emergencies, appendices.

Chapter 31

ACID-BASE ANALYSIS

Seek simplicity, and distrust it.

Alfred North Whitehead

Managing ICU patients without a working knowledge of acid-base disorders is like trying

to clap your hands when you have none; i.e., it simply can’t be done This chapterpresents a structured approach to the identification of acid-base disorders based on thetraditional relationships between the pH, PCO2, and bicarbonate (HCO3) concentration inplasma Also included is a section on the evaluation of metabolic acidosis using the aniongap and a measurement known as the “gap-gap.” Alternative approaches to acid-baseanalysis, such as the “Stewart method,” are not included here because it is unlikely, atthe present time, that these methods will replace the traditional approach to acid-baseanalysis

BASIC CONCEPTS

Hydrogen Ion Concentration and pH

The hydrogen ion concentration [H+] in aqueous solutions is traditionally expressed bythe pH, which apparently means the power of hydrogen, and is a logarithmic function ofthe [H+]; i.e.,

The physiological range of pH and corresponding [H+] is shown in Table 31.1 The normal

pH of plasma is indicated as 7.40, which corresponds to a [H+] of 40 nEq/L

Features of the pH

The relationships in Table 31.1 illustrate 3 unfortunate features of the pH: (a) it is adimensionless number, which has no relevance in chemical or physiological events, (b) itvaries in the opposite direction to changes in [H+], and (c) changes in pH are not linearlyrelated to changes in [H+] Note that as the pH decreases, the changes in [H+] becomegradually larger with each change in pH This means that changes in pH will havedifferent implications for acid-base balance at different points along the pH spectrum.Although it is unlikely that the pH will be abandoned, it is not a representative measure

of the acid-base events in the body

Table 31.1 pH and Hydrogen Ion Concentration

Hydrogen Ions as a Trace Element

Also evident in Table 31.1 is the fact that [H+] is expressed as nanoequivalents per liter(nEq/L) One nanoequivalent is one-millionth of a milliequivalent (1 nEq = 1×10-6 mEq),

so hydrogen ions are about a million times less dense than the principal ions inextracellular fluid (sodium and chloride), whose concentration is expressed in mEq/L Thisgives hydrogen ions the status of a trace element How can such a small quantity of anion have all the effects attributed to acidosis and alkalosis? Other trace elementscertainly have important biological effects, but it is also possible that changes in the [H+]are just one of several physicochemical changes that are taking place in the extracellularfluid This would explain why the same degree of acidosis is more life-threatening in lacticacidosis than in ketoacidosis (as described in the next chapter); i.e., the acidosis is notthe problem

Classification of Acid-Base Disorders

According to traditional concepts of acid-base physiology, the [H+] in extracellular fluid isdetermined by the balance between the partial pressure of carbon dioxide (PCO2) and theconcentration of bicarbonate (HCO3) in the fluid This relationship is expressed as follows(1):

The PCO2/HCO3 ratio identifies the primary acid-base disorders and secondary responses,which are shown in Table 31.2

Primary Acid-Base Disorders

According to equation 31.2, a change in either the PCO2 or the HCO3 will cause a change

in the [H+] of extracellular fluid When a change in PCO2 is responsible for a change in[H+], the condition is called a respiratory acid-base disorder: an increase in PCO2 is arespiratory acidosis, and a decrease in PCO2 is a respiratory alkalosis When a change inHCO3 is responsible for a change in [H+], the condition is called a metabolic acid-basedisorder: a decrease in HCO3 is a metabolic acidosis, and an increase in HCO3 is ametabolic alkalosis

Table 31.2 Primary Acid-Base Disorders and Secondary Responses

Secondary Responses

Secondary responses are designed to limit the change in [H+] produced by the primaryacid-base disorder, and this is accomplished by changing the other component of thePaCO2/HCO3 ratio in the same direction For example, if the primary problem is anincrease in PaCO2 (respiratory acidosis), the secondary response will involve an increase

in HCO3, and this will limit the change in [H+] produced by the increase in PaCO2.Secondary responses should not be called “compensatory responses” because they do notcompletely correct the change in [H+] produced by the primary acid-base disorder (2).The specific features of secondary responses are described next The equations described

in the next section are included in Figure 31.1

(31.4)

(31.5)

(31.6)

Responses to Metabolic Acid-Base Disorders

The response to a metabolic acid-base disorder involves a change in minute ventilationthat is mediated by peripheral chemoreceptors located in the carotid body at the carotidbifurcation in the neck

EXAMPLE: For a metabolic acidosis with a plasma HCO3 of 14 mEq/L, the ∅HCO3 is 24 –

14 = 10 mEq/L, the ∅PaCO2 is 1.2×14 = 17 mm Hg, and the expected PaCO2 is 40 – 17 =

23 mm Hg If the PaCO2 is >23 mm Hg, there is a secondary respiratory acidosis If thePaCO2 is <23 mm Hg, there is a secondary respiratory alkalosis

Metabolic Alkalosis

The secondary response to metabolic alkalosis is a decrease in minute ventilation and asubsequent increase in PaCO2 This response is not as vigorous as the response tometabolic acidosis because the peripheral chemoreceptors are not very active undernormal conditions, so they are easier to stimulate than inhibit The magnitude of theresponse to metabolic alkalosis is defined by the equation below (2)

Using a normal PaCO2 of 40 mm Hg and a normal HCO3 of 24 mEq/L, the above equationcan be rewritten as follows:

EXAMPLE: For a metabolic alkalosis with a plasma HCO3 of 40 mEq/L, the ∅HCO3 is 40 –

24 = 16 mEq/L, the ∅PaCO2 is 0.7×16 = 11 mm Hg, and the expected PaCO2 is 40 + 11

= 51 mm Hg This is only a borderline elevation in PaCO2, and it demonstrates therelative weakness of the response to metabolic alkalosis

(31.8)

Responses to Respiratory Acid-Base Disorders

The secondary response to changes in PaCO2 occurs in the kidneys, where HCO3absorption in the proximal tubes is adjusted to produce the appropriate change in plasmaHCO3 This renal response is relatively slow, and can take 2 or 3 days to reachcompletion Because of the delay in the secondary response, respiratory acid-basedisorders are separated into acute and chronic disorders

Acute Respiratory Disorders

Acute changes in PaCO2 have a small effect on the plasma HCO3, as indicated in thefollowing two equations (2)

For acute respiratory acidosis:

For acute respiratory alkalosis:

EXAMPLE: For an acute increase in PaCO2 to 60 mm Hg, the ∅HCO3 is 0.1×20 = 2 mEq/Lfor an acute respiratory acidosis, and 0.2×20 = 4 mEq/L for an acute respiratoryalkalosis Neither of these changes would be recognized as significant

FIGURE 31.1 Predictive equations for evaluating secondary responses to primary acid-base disorders All equations are

from Reference 2.

Chronic Respiratory Disorders

The renal response to an increase in PaCO2 is an increase in HCO3 reabsorption in theproximal renal tubules, which raises the plasma HCO3 concentration The response to adecrease in PaCO2 is a decrease in renal HCO3 reabsorption, which lowers the plasmaHCO3 concentration The magnitude of this response is similar, regardless of thedirectional change in PaCO2, so the equation below applies to both chronic respiratoryacidosis and alkalosis

Using a normal PaCO2 of 40 mm Hg and a normal HCO3 of 24 mEq/L, the above equationcan be rewritten as follows:

For chronic respiratory acidosis:

(31.11)

For chronic respiratory alkalosis:

EXAMPLE: For an increase in PaCO2 to 60 mm Hg that persists for at least a few days,the ∅PaCO2 is 60 – 40 = 20 mm Hg, the ∅HCO3 is 0.4×20 = 8 mEq/L, and the expectedHCO3 is 24 + 8 = 32 mEq/L

STEPWISE APPROACH TO ACID-BASE ANALYSIS

The following is a structured, rule-based approach to the diagnosis of primary, secondary,and mixed acid-base disorders using the relationships between the [H+], PCO2, and HCO3concentration described previously Several examples are included as instructional aids.The reference ranges for arterial pH, PCO2, and HCO3 are shown below

pH = 7.36–7.44PCO2 = 36–44 mm HgHCO3 = 22–26 mEq/L

Stage I: Identify the Primary Acid-Base Disorder

In the first stage of the approach, the PaCO2 and pH are used to identify the primaryacid-base disorder

2: If the PaCO2 and pH are both abnormal, compare the directional change.

2a. If the PaCO2 and pH change in the same direction, there is a primary metabolic

If only the pH or PaCO2 is abnormal, the condition is a mixed metabolic and

respiratory disorder (i.e., equal and opposite disorders)

3a.

If the PaCO2 is abnormal, the directional change in PaCO2 identifies the type of

respiratory disorder (e.g., high PaCO2 indicates a respiratory acidosis), and the

opposing metabolic disorder

3b.

If the pH is abnormal, the directional change in pH identifies the type of metabolicdisorder (e.g., low pH indicates a metabolic acidosis) and the opposing respiratorydisorder

EXAMPLE: Consider a case where the arterial pH = 7.38 and the PaCO2 = 55 mm Hg.Only the PaCO2 is abnormal, so there is a mixed metabolic and respiratory disorder ThePaCO2 is elevated, indicating a respiratory acidosis, so the metabolic disorder must be ametabolic alkalosis Therefore, this condition is a mixed respiratory acidosis andmetabolic alkalosis Both disorders are equivalent in severity because the pH is normal

Stage II: Evaluate the Secondary Responses

The second stage of the approach is for cases where a primary acid-base disorder hasbeen identified in Stage I (If a mixed acid-base disorder was identified in Stage I, godirectly to Stage III) The goal in Stage II is to determine if there is an additional acid-base disorder

Rule

4:

For a primary metabolic disorder, if the measured PaCO2 is higher than expected,there is a secondary respiratory acidosis, and if the measured PaCO2 is less thanexpected, there is a secondary respiratory alkalosis

EXAMPLE: Consider a case where the PaCO2 = 23 mm Hg, the pH = 7.32, and the HCO3

= 16 mEq/L The pH and PCO2 change in the same direction, indicating a primarymetabolic disorder, and the pH is acidemic, so the disorder is a primary metabolicacidosis Using equations 31.3 and 31.4, the ∅PaCO2 is 1.2×(24 – 16) = 10 mm Hg(rounded off), and the expected PaCO2 is 40 – 10 = 30 mm Hg The measured PaCO2 (23

mm Hg) is lower than the expected PaCO2, so there is an additional respiratory alkalosis.Therefore, this condition is a primary metabolic acidosis with a secondary respiratoryalkalosis

For a primary respiratory disorder where the HCO3 is abnormal, determine the

expected HCO3 for a chronic respiratory disorder

secondary metabolic acidosis

EXAMPLE: Consider a case where the PaCO2 = 23 mm Hg, the pH = 7.54, and the HCO3

= 38 mEq/L The PaCO2 and pH change in opposite directions, indicating a primaryrespiratory disorder, and the pH is alkaline, so the disorder is a primary respiratoryalkalosis The HCO3 is abnormal, indicating that this is not an acute respiratory alkalosis.Using Equations 31.9 and 31.11 for a chronic respiratory alkalosis, the ∅PCO2 is 40 – 23 =

17 mm Hg, the ∅HCO3 is 0.4×17 = 7 mEq/L, and the expected HCO3 is 24 + 7 = 31mEq/L The measured HCO3 is the same as expected for a chronic respiratory alkalosis,

so this condition is a chronic respiratory alkalosis with an appropriate (completed) renalresponse If the measured HCO3 was less than 31 mEq/L, this condition would be achronic respiratory alkalosis with an incomplete renal response, and if the measuredHCO3 was higher than 31 mEq/L, this would indicate a secondary metabolic alkalosis

Stage III: Use The “Gaps” to Evaluate a Metabolic Acidosis

The final stage of this approach is for patients with a metabolic acidosis, where the use ofmeasurements called gaps can help to uncover the underlying cause of the acidosis.These are described in the next section

THE GAPS

There are numerous potential sources of a metabolic acidosis in critically ill patients, andthe measurements described in this section are designed to help in the search for theculprit

(31.13)

(31.14)

(31.15)

The Anion Gap

The anion gap is a rough estimate of the relative abundance of unmeasured anions, and

is used to determine if a metabolic acidosis is due to an accumulation of non-volatileacids (e.g., lactic acid) or a primary loss of bicarbonate (e.g., diarrhea) (6,7)

Determinants

To achieve electrochemical balance, the concentration of negatively charged anions mustequal the concentration of positively charged cations This electrochemical balance isexpressed in the equation shown below using electrolytes that are routinely measured,including sodium (Na), chloride (CL), and bicarbonate (HCO3), as well as the unmeasuredcations (UC) and unmeasured anions (UA)

Rearranging the terms in this equation yields the following relationships:

The difference (UA – UC) is a measure of the relative abundance of unmeasured anions,and is called the anion gap (AG)

Reference Range: The original reference range for the AG was 12±4 mEq/L (range = 8

to 16 mEq/L) (7) With subsequent improvements in automated systems that measureserum electrolytes, the reference range for the AG has decreased to 7±4 mEq/L (range =

3 to 11 mEq/L) (8)

Influence of Albumin

The unmeasured anions and cations that normally contribute to the anion gap are shown

i n Table 31.3 Note that albumin is the principal unmeasured anion, and the principaldeterminant of the anion gap Albumin is a weak (i.e., poorly dissociated) acid thatcontributes about 3 mEq/L to the AG for each 1 g/dL of albumin in plasma (at a normalpH) (3) A low albumin level in plasma will lower the AG, and this could mask thepresence of an unmeasured anion (e.g., lactate) that is contributing to a metabolicacidosis Since hypoalbuminemia is present in as many as 90% of ICU patients (9), thefollowing formula for the “corrected AG” (AGc) has been proposed to include thecontribution of albumin:

(4.5 represents the normal concentration of albumin in plasma) For a patient with an AG

of 10 mEq/L and a plasma albumin of 2 g/dL, the AGc is 10 + (2.5×2.5) = 16 mEq/L,which represents a 60% increase in the AG

Table 31.3 Determinants of the Anion Gap

Using the Anion Gap

The AG can be used to identify the underlying mechanism of a metabolic acidosis, whichthen helps to identify the underlying clinical condition An elevated AG occurs when there

is an accumulation of fixed or non-volatile acids (e.g., lactic acidosis), while a normal AGoccurs when there is a primary loss of bicarbonate (e.g., diarrhea) (7) Table 31.4 showsthe causes of metabolic acidosis grouped according to the AG

HIGH AG: Common causes of high AG metabolic acidosis are lactic acidosis, diabeticketoacidosis, and advanced renal failure (where there is loss of H+ secretion in the distaltubules of the kidneys) Also included are toxic ingestions of methanol (which producesformic acid), ethylene glycol (which produces oxalic acid), and salicylates (which producesalicylic acid) (10)

Table 31.4 Classification of Metabolic Acidosis with the Anion Gap (AG)

NORMAL AG: Common causes of a normal AG metabolic acidosis are diarrhea, salineinfusion (see Figure 12.3), and early renal failure (where there is loss of bicarbonatereabsorption in the proximal tubules) The loss of HCO3 is counterbalanced by a gain ofchloride ions to maintain electrical charge neutrality; hence the term hyperchloremicmetabolic acidosis is used for normal AG metabolic acidoses (In high AG metabolicacidoses, the remaining anions from the dissociated acids balance the loss of HCO3, sothere is no associated hyperchloremia.)

RELIABILITY The AG has shown a limited ability to detect non-volatile acids, and thereare several reports where the AG was normal in patients with lactic acidosis (11,12) Thepoor performance of the AG may be due to the confounding influence of albumin, which

was not considered in early studies of the AG A recent study shows that the corrected AG (AGc) provides a more accurate assessment of metabolic acidosis than the

albumin-AG (13)

The Gap-Gap Ratio

In the presence of a high AG metabolic acidosis, it is possible to detect another metabolicacid-base disorder (a normal AG metabolic acidosis or a metabolic alkalosis) bycomparing the AG excess (the difference between the measured and normal AG) to theHCO3 deficit (the difference between the measured and normal HCO3 in plasma) This isaccomplished with the equation shown below, which includes 12 mEq/L for the normal AGand 24 mEq/L for the normal HCO3 in plasma

This ratio is sometimes called the gap-gap ratio because it involves two gaps (the AGexcess and the HCO3 deficit) Some applications of the gap-gap ratio are described next

Mixed Metabolic Acidoses

In metabolic acidoses caused by non-volatile acids (high AG metabolic acidosis), thedecrease in serum HCO3 is equivalent to the increase in AG, and the gap-gap (AGExcess/HCO3 deficit) ratio is unity or 1 However, if there is a second acidosis that has anormal AG, the decrease in HCO3 is greater than the increase in AG, and the gap-gapratio falls below unity (<1) Therefore, in the presence of a high AG metabolic acidosis, agap-gap ratio <1 indicates the co-existence of a normal AG (hyperchloremic) metabolicacidosis (6,14)

DIABETIC KETOACIDOSIS: A popular question on the medicine boards is a case wherethe management of a patient with diabetic ketoacidosis (DKA) is associated withimprovement in the blood glucose and the clinical condition of the patient, but theacidosis persists, and you are asked what to do (more insulin, more fluids, etc) Theanswer lies in the gap-gap ratio; i.e., DKA presents with a high AG metabolic acidosis, butthe aggressive infusion of isotonic saline during the initial management creates ahyperchloremic (normal AG) metabolic acidosis, which replaces the high AG acidosis asthe ketoacids are cleared In this situation, the serum bicarbonate remains low, but thegap-gap ratio falls below 1 as the acidosis switches from a high AG to a normal AGacidosis (15) Therefore, monitoring the serum HCO3 alone will create a false impressionthat the DKA is not resolving, while the gap-gap ratio provides an accurate measure ofthe acid-base status of the patient

Metabolic Acidosis and Alkalosis

When alkali is added in the presence of a high AG acidosis, the decrease in serumbicarbonate is less than the increase in AG, and the gap-gap is greater than unity (>1).Therefore, in the presence of a high AG metabolic acidosis, a gap-gap >1 indicates theco-existence of a metabolic alkalosis This is an important consideration becausemetabolic alkalosis is common in ICU patients (from the frequent use of nasogastricsuction and diuretics)

A FINAL WORD

For more than 100 years, the evaluation of acid-base balance has been based on a singlereaction sequence (which is shown below), and a single determinant of plasma pH (thePCO2/HCO3 ratio)

This approach is appealing because of its simplicity, but as Whitehead advises in theintroductory quote, the simplicity of this approach is also a reason for “distrust.” Thefollowing are a few reasons to distrust the traditional view of acid-base balance

1 The use of the PCO2-HCO3 relationship to identify acid-base disorders has two flaws:

a The PCO2 and HCO3 are both dependent variables, and thus it is not possible detectacid-base conditions that operate independent of these variables

b Since the CO2 in plasma is present primarily as HCO3, it is difficult to establish anindependent identity for HCO3

2 Bicarbonate does not act as a buffer in the physiological pH range (which isdemonstrated in the next chapter) The plasma [H+] is a function of the anionic chargeequivalence of plasma proteins (which act as the buffers in plasma), and is not directlyrelated to the plasma [HCO3] (16)

A novel view of acid-base balance that challenges traditional concepts was introduced byPeter Stewart (a Canadian physiologist working at Brown) about 30 years ago, and I haveincluded a textbook, and one of Stewart’s original papers on the subject (17), for yourinterest

Books

Rose BD, Post T, Stokes J Clinical Physiology of Acid-Base and Electrolyte Disorders 6th

ed New York:McGraw-Hill, 2013

Kellum JA, Elbers WG, ed Stewart’s Textbook of Acid-Base 2nd ed Amsterdam:

AcidBase.org, 2009

Gennari FJ, Adrogue HJ, Galla JH, Maddias N, eds Acid-Base Disorders and TheirTreatment Boca Raton: CRC Press, 2005

1 Adrogue HJ, Gennari J, Gala JH, Madias NE Assessing acid-base disorders Kidney Int2009; 76:1239–1247

2 Adrogue HJ, Madias NE Secondary responses to altered acid-base status: The rules

of engagement J Am Soc Nephrol 2010; 21:920–923

3 Kellum JA Disorders of acid-base balance Crit Care Med 2007; 35:2630–2636

4 Whittier WL, Rutecki GW Primer on clinical acid-base problem solving Dis Mon 2004;50:117–162

5 Fencl V, Leith DE Stewart’s quantitative acid-base chemistry: applications in biologyand medicine Respir Physiol 1993; 91:1–16

6 Narins RG, Emmett M Simple and mixed acid-base disorders: a practical approach.Medicine 1980; 59:161–187

Selected References

7 Emmet M, Narins RG Clinical use of the anion gap Medicine 1977; 56:38–54

8 Winter SD, Pearson JR, Gabow PA, et al The fall of the serum anion gap Arch InternMed 1990; 150:311–313

9 Figge J, Jabor A, Kazda A, Fencl V Anion gap and hypoalbuminemia Crit Care Med1998; 26:1807–1810

10 Judge BS Metabolic acidosis: differentiating the causes in the poisoned patient MedClin N Am 2005; 89:1107–1124

11 Iberti TS, Liebowitz AB, Papadakos PJ, et al Low sensitivity of the anion gap as ascreen to detect hyperlactatemia in critically ill patients Crit Care Med 1990;18:275–277

12 Schwartz-Goldstein B, Malik AR, Sarwar A, Brandtsetter RD Lactic acidosisassociated with a normal anion gap Heart Lung 1996; 25:79–80

13 Mallat J, Barrailler S, Lemyze M, et al Use of sodium chloride difference andcorrected anion gap as surrogates of Stewart variables in critically ill patients PLoSONE 2013; 8:e56635 (Open access jounal, accessed at www.plosone.org on4/11/2013.)

14 Haber RJ A practical approach to acid-base disorders West J Med 1991; 155:146–151

15 Paulson WD Anion gap-bicarbonate relationship in diabetic ketoacidosis Am J Med1986; 81:995–1000

16 Stewart PA Whole-body acid-base balance In :Kellum JA, Elbers PWG, eds.Stewart’s Textbook of Acid Base 2nd ed Amsterdam: AcidBase.org, 2009:181–197

17 Stewart PA Modern quantitative acid-base chemistry Can J Physiol Pharmacol 1983;61:1444–1461

LACTIC ACIDOSIS

Lactate Metabolism

Lactate is the end-product of glucose metabolism in the cytoplasm (glycolysis), and isformed by the reduction of pyruvate in a reaction catalyzed by lactate dehydrogenase(LDH) (see Figure 32.1) About 1,500 mmoles of lactate are produced daily under aerobicconditions (1,2), and the principal sites of production are skeletal muscle (25%), skin(25%), red blood cells (20%), brain (20%), and intestine (10%) Activated neutrophilsare an additional source of lactate in inflammatory conditions like acute respiratorydistress syndrome (ARDS) (3,4) The concentration of lactate in plasma is usually ″2mmol/L, with a lactate:pyruvate ratio of 10:1 (1,2) Lactate is cleared from plasma by theliver (60%), kidneys (30%), and heart (10%)

Lactate as a Fuel

The diagram in Figure 32.1 shows the energy yield from the metabolism of glucose andlactate Anaerobic glycolysis generates 32 kilocalories (kcal) per mole of glucose, which isonly 5% of the energy yield from the oxidative metabolism of glucose (673 kcal/mole)(3) The energy deficit from anaerobic lactate production can be corrected by theoxidative metabolism of lactate, which generates 326 kcal/mole (5), or 326 × 2 = 652kcal per mole of glucose (since 1 mole of glucose produces 2 moles of lactate) In fact,lactate is classified as an organic fuel, and has a caloric density (3.62 kcal/g) equivalent

to glucose (3.74 kcal/g) (5)

FIGURE 32.1 The energy yield from the oxidative metabolism of glucose and lactate, and the actions of selected factors

that promote lactic acidosis PDH = pyruvate dehydrogenase; LDH = lactate dehydrogenase.

Lactate Shuttle: Lactate is used as a fuel source during exercise (the lactate shuttle (6),and it is possible that lactate serves a similar function in critically ill patients (7) This isconsistent with the observation that lactate uptake by the myocardium is increased inpatients with septic shock (8) The possibility of a lactate shuttle in critically ill patientssuggests that the enhanced production of lactate in these patients could be an adaptiveresponse that helps to maintain energy metabolism in vital organs like the heart Thisdiffers radically from the traditional perception of lactate as a source of fatal outcomes incritically ill patients.

2 The time required for lactate levels to return to normal (lactate clearance) has agreater prognostic value than the initial lactate level Normalization of lactate levelswithin 24 hours is associated with the lowest mortality rates (see Figure 10.6 on page186).

3 The source of elevated lactate levels in severe sepsis and septic shock is a combination

of increased production of pyruvate (9) and a defect in O2 utilization in mitochondria,called cytopathic hypoxia (10) The latter phenomenon may be the result of cytokine

or bacterial toxin-induced inhibition of pyruvate dehydrogenase (11,12), the enzymeresponsible for pyruvate entry into mitochondria (see Figure 32.1) Thus, tissueoxygenation is not impaired in severe sepsis and septic shock (see Figure 14.3 on page269)

(32.2)

(32.3)

Lactate and Acidosis

The end-product of glycolysis is lactic acid, which acts like a strong acid (i.e., loses its H+)

in the physiological pH range, and exists as the negatively-charged lactate ion (1) Thelactate moiety released by cells is the lactate ion, not lactic acid So how doeshyperlactatemia produce an acidosis? This cannot be explained by the traditionalBrønsted-Lowry concept of acid base balance (i.e., an acid donates H+), but can beexplained using Peter Stewart’s concept of the strong ion difference and its role in acid-base balance (13–15)

Strong Ion Difference

The strong ion difference (SID) is the difference in the summed concentrations of strong(readily dissociated) cations and anions in extracellular fluid (13,14) The strong ions inextracellular fluid are sodium (Na), chloride (CL), potassium (K), magnesium (Mg),calcium (Ca), and lactate, so the SID is determined as follows (15):

The principle of electrical neutrality requires the following relationship between the SIDand the ions that dissociate from water (H+ + OH-):

Since OH- has a negligible influence on [H+] in the physiological pH range, the aboveequation can be simplified to:

According to this relationship, a change in SID will be accompanied by an oppositechange in [H+] and, if pH is used instead of [H+], the SID and pH will change in the samedirection (see Figure 12.4 on page 222)

Therefore, to summarize equations 32.2–32.4, an increase in the plasma lactateconcentration will decrease the SID, and this will decrease the plasma pH The SID ofplasma is normally about 40 mEq/L (14)

Causes of Hyperlactatemia

Clinical Shock Syndromes

The most notable, and most feared, sources of hyperlactatemia are the clinical shocksyndromes; i.e., hypovolemic, cardiogenic, and septic shock Although the mechanismsfor the hyperlactatemia may be different, the plasma lactate level has prognostic value inthese syndromes, as mentioned previously

Systemic Inflammatory Response Syndrome

Systemic inflammation (fever, leukocytosis, etc.) can be accompanied by mild elevations

of blood lactate (2 to 5 mEq/L) with a normal lactate:pyruvate ratio and a normal plasma

pH This condition is called stress hyperlactatemia, and is the result of an increase in theproduction of pyruvate without a defect in tissue oxygenation or oxygen utilization (10).The lactate elevation in severe sepsis and septic shock is usually associated withincreased lactate:pyruvate ratios and a decrease in plasma pH

Thiamine Deficiency

The manifestations of thiamine deficiency include high-output heart failure (wet beriberi),Wernicke’s encephalopathy, peripheral neuropathy (dry beriberi), and lactic acidosis Thelactic acidosis can be severe (17), and is caused by a deficiency in thiaminepyrophosphate, which serves as a co-factor for pyruvate dehydrogenase (see Figure32.1) Thiamine deficiency may be more common than suspected in critically ill patients,and should be considered in all cases of unexplained lactic acidosis (See Chapter 47 for amore detailed description of thiamine deficiency.)

METFORMIN: Metformin is an oral hypoglycemic agent that can produce lactic acidosisduring therapeutic dosing The mechanism for the lactic acidosis is unclear, but it occursprimarily in patients with renal insufficiency, and has a mortality rate in excess of 45%(18,19) Plasma metformin levels are not routinely available, and the diagnosis is based

on excluding other causes of lactic acidosis The preferred treatment is hemodialysis(18,19), which removes both metformin and lactate

ANTIRETROVIRAL AGENTS: Hyperlactatemia is reported in 8–18% of pa-tientsreceiving antiretroviral therapy for HIV infection (20) The responsible drugs are thenucleoside analogues (e.g., didanosine, stavudine), and the presumed mechanism isinhibition of mitochondrial DNA polymerase (21) In most cases, the hyperlactatemia ismild and not associated with acidemia, but lactate levels above 10 mmol/L have a

reported mortality rate of 33–57% (21).

LINEZOLID: Lactic acidosis has been reported during therapy with linezolid (22,23).Most cases are mild and without adverse consequences, but lactate levels as high as 10mmol/L have been reported (23) The mechanism is unknown, and lactate levelsnormalize after discontinuing the drug

Non-Pharmaceutical Toxidromes

Lactic acidosis can be the result of intoxications with cyanide, carbon monoxide, andpropylene glycol The latter agent is used as a solvent for intravenous drugs, and can beoverlooked as a cause of lactic acidosis

PROPYLENE GLYCOL: The intravenous drugs that use propylene glycol as a solventinclude lorazepam, diazepam, esmolol, nitroglycerin, and phenytoin About 55–75% ofpropylene glycol is metabolized by the liver and the primary metabolites are lactate andpyruvate (24) Propylene glycol toxicity (i.e., agitation, coma, seizures, hypotension, andlactic acidosis) has been reported in 19% to 66% of patients receiving high-doseintravenous lorazepam for more than 2 days (24,25) If suspected, the drug infusionshould be stopped and another sedative agent selected (midazolam and propofol do notuse propylene glycol as a solvent) An assay for propylene glycol in blood is available, butthe acceptable range has not been determined

Lactic Alkalosis

Severe alkalosis (respiratory or metabolic) can raise blood lactate levels as a result ofincreased activity of pH-dependent enzymes in the glycolytic pathway (26) When liverfunction is normal, the liver clears the extra lactate generated during alkalosis, and lacticalkalosis becomes evident only when the blood pH is 7.6 or higher However, in patientswith impaired liver function, hyperlactatemia can be seen with less severe degrees ofalkalemia

Other Causes

Other possible causes of hyperlactatemia in ICU patients include generalized seizures(from hypermetabolism) (27), hepatic insufficiency (from reduced lactate clearance) (28),acute asthma (from enhanced lactate production by the respiratory muscles) (29), andhematologic malignancies (rare) (30) Hyperlactatemia associated with hepaticinsufficiency is often mild (28) Hyperlactatemia that accompanies generalized seizurescan be severe (with lactate levels of 15 mmol/L) but is transient (27)

Diagnostic Considerations

The normal lactate concentration in blood is ″2 mmol/L, but increases in lactateconcentration do not have prognostic value until they reach 4 mmol/L (1), so a higherthreshold of 4 mmol/L is used to define“clinically significant” hyperlactatemia.Measurements can be obtained on arterial or venous blood samples If immediatemeasurements are unavailable, the blood should be placed on ice to retard lactateproduction by red blood cells

The anion gap (described on pages 594–596) should be elevated in lactic acidosis, butthere are numerous reports of a normal anion gap in patients with lactic acidosis (31) As

a result, the anion gap should not be used as a screening test for lactic acidosis

D-Lactic Acidosis

The lactate produced by mammalian tissues is a levo-isomer (l-lactate), whereas adextro-isomer of lactate (d-lactate) is produced by certain strains of bacteria that canpopulate the bowel (32) D-lactate generated by bacterial fermentation in the bowel cangain access to the systemic circulation and produce a metabolic acidosis, often combinedwith a metabolic encephalopathy (33) Most cases of d-lactic acidosis have been reportedafter extensive small bowel resection or after jejunoileal bypass for morbid obesity (32–34)

DIAGNOSIS: D-lactic acidosis can produce an elevated anion gap, but the standardlaboratory assay for blood lactate measures only l-lactate If d-lactic acidosis issuspected, you must request the laboratory to perform a d-lactate assay

ALKALI THERAPY

The primary goal of therapy in lactic acidosis is to correct the underlying metabolicabnormality Alkali therapy aimed at correcting the pH is of questionable value (35) Thefollowing is a brief summary of the pertinent issues regarding alkali therapy for lacticacidosis

Acidosis Is Not Harmful

The principal fear from acidosis is the risk of impaired myocardial contractility (36).However, in the intact organism, acidemia is often accompanied by an increase in cardiacoutput (37) This is explained by the ability of acidosis to stimulate catecholamine releasefrom the adrenals and to produce vasodilation Therefore, impaired contractility fromacidosis is less of a concern in the intact organism In addition, acidosis may have aprotective role in the setting of clinical shock For example, extracellular acidosis hasbeen shown to protect energy-depleted cells from cell death (38)

Bicarbonate Is Not an Effective Buffer

Sodium bicarbonate is the standard buffer used for lactic acidosis, but has limited success

in raising the serum pH (39) This can be explained by the titration curve for the carbonicacid-bicarbonate buffer system, which is shown in Figure 32.2 The HCO3 buffer pool isgenerated by the dissociation of carbonic acid (H2CO3):

The dissociation constant (pK) for carbonic acid (i.e., the pH at which the acid is 50%dissociated) is 6.1, as indicated on the titration curve Buffers are most effective within 1

pH unit on either side of the pK (40), so the effective range of the bicarbonate buffersystem should be an extracellular pH between 5.1 and 7.1 pH units (indicated by theshaded area on the titration curve) Therefore, bicarbonate is not expected to be aneffective buffer in the usual pH range of extracellular fluid Bicarbonate is not really abuffer; rather, it is a transport form of carbon dioxide in blood

Bicarbonate Can be Harmful

A number of undesirable effects are associated with sodium bicarbonate therapy One ofthese is the abilityof bicarbonate to generate CO2, which can actually lower theintracellular pH and cerebrospinal fluid pH (41,42) In fact, considering that the PCO2 is

200 mm Hg in standard bicarbonate solutions (see Table 32.1), bicarbonate is really a

CO2 burden (an acid load!) that must be removed by the lungs

Finally, bicarbonate infusions can increase blood lactate levels (42) Although this effect isattributed to alkalosis-induced augmentation of lactate production, it is not a desirableeffect for a therapy of lactic acidosis

FIGURE 32.2 The titration curve for the carbonic acid-bicarbonate buffer system The large, shaded area indicates the

effective pH range for the bicarbonate buffer system, which does not coincide with the physiological pH range of

extracellular fluid Adapted from Reference 40.

Carbicarb is a commercially available buffer solution that is a 1:1 mixture of sodiumbicarbonate and disodium carbonate As shown in Table 32.1, carbicarb has lessbicarbonate and a much lower PCO2 than the standard 7.5% sodium bicarbonate solution

As a result, carbicarb does not produce the increase in PCO2 seen with sodiumbicarbonate infusions (41)

Table 32.1 Bicarbonate-Containing Buffer Solutions

Recommendation

Alkali therapy has no role in the routine management of metabolic acidosis However,when patients are deteriorating rapidly in the setting of a severe acidemia (pH <7.0), atrial infusion of bicarbonate can be attempted as a desperation measure by administeringone-half of the estimated HCO3 deficit (42)

(where 15 mEq/L is the desired plasma [HCO3]) If cardiovascular im-provement occurs,bicarbonate therapy can be continued to maintain the plasma HCO3 at 15 mEq/L If noimprovement or further deterioration occurs, further bicarbonate administration is notwarranted

Ketogenesis

When carbohydrates are not available for metabolic energy production, there is abreakdown of triglycerides in adipose tissue (lipolysis) to generate fatty acids, which aretransported to the liver and metabolized to form 3 ketone bodies; i.e., acetoacetate, β-hydroxybutyrate, and acetone This is illustrated in Figure 32.3 These ketones arereleased from the liver and can be used as oxidative fuels by vital organs such as theheart and central nervous system The oxidative metabolism of ketones yields 4 kcal/g,which is slightly in excess of the energy yield from the oxidative metabolism of glucose(3.7 kcal/g)

FIGURE 32.3 Ketogenesis in the liver, which occurs in response to diminished availability of glucose Acetone is a ketone,

but is not a ketoacid.

Ketoacids in Blood

The normal concentration of ketones in the blood is negligible (0.1 mmol/L), but bloodketone levels increase tenfold (to 1 mmol/L) after just 3 days of starvation Acetone isnot a ketoacid, but is responsible for the “fruity” odor of breath in patients withketoacidosis Acetoacetate (AcAc) and β-hydroxybutyrate (β-OHB) are strong acids (i.e.,readily dissociate), and they promote a decrease in plasma pH when their plasmaconcentrations reach 3 mmol/L (43) The balance of AcAc and β-OHB in blood isdetermined by the following redox reaction (see Figure 32.3):

The balance of this reaction favors the formation of β-OHB In conditions of enhancedketone production, the β-OHB:AcAc ratio ranges from 3:1 in diabetic ketoacidosis, to ashigh as 8:1 in alcoholic ketoacidosis The concentration of ketoacids in the blood indiabetic and alcoholic ketoacidosis is shown in Figure 32.4 Note the preponderance of β-OHB in both conditions Because of this preponderance, ketoacidosis is more accuratelycalled β-hydroxybutyric acidosis

The Nitroprusside Reaction

The nitroprusside reaction is a colorimetric method for detecting AcAc and acetone inblood and urine The test can be performed with tablets (Acetest) or reagent strips(Ketostix, Labstix, Multistix) A detectable reaction requires a minimum AcAcconcentration of 3 mmol/L Because this reaction does not detect the predominantketoacid, β-hydroxybutyrate (43), it is an insensitive method for monitoring the severity

of ketoacidosis This is illustrated in Figure 32.4 In alcoholic ketoacidosis, the totalconcentration of ketoacids in blood is 13 mmol/L, which represents more than ahundredfold increase over the normal concentration of blood ketones, yet thenitroprusside reaction will be negative because the AcAc concentration is below 3mmol/L

ß-hydroxybutyrate Testing

There are portable “ketone meters” that can provide reliable measurements of β-OHBconcentrations in fingerstick (capillary) blood, and results are available in about 10seconds (44) (Available devices include Precision Xtra meter from Abbot Laboratoriesand Nova Max PLUS from Nova Biomedical.) The American Diabetes Association considersmeasurements of plasma β-OHB with these meters as the preferred method formonitoring patients with diabetic ketoacidosis (45)

DIABETIC KETOACIDOSIS

Diabetic ketoacidosis (DKA) is usually seen in insulin-dependent diabetic patients, butthere is no previous history of diabetes mellitus in 27–37% of cases (46) The mostcommon precipitating factors in DKA are inappropriate insulin dosing and concurrentillness (e.g., infection) The mortality rate of DKA is 1–5% (46)

FIGURE 32.4 The concentrations of acetoacetate and ß-hydroxybutyrate in the blood in diabetic ketoacidosis (DKA) and

alcoholic ketoacidosis (AKA) The horizontal hatched line represents the minimum concentration of acetoacetate required to produce a positive nitroprusside reaction.

Clinical Features

The definition of DKA proposed by the American Diabetes Association includes a bloodglucose >250 mg/dL, plasma [HCO3] <18 mEq/L, plasma pH ″7.30, an elevated aniongap, and evidence of ketones in blood or urine (45) However, there are exceptions:

1 The blood glucose is only mildly elevated (<250 mg/dL) in about 20% of cases ofDKA(47)

2 The anion gap can be normal in DKA (48) The renal excretion of ketones isaccompanied by an increase in chloride reabsorption in the renal tubules, and theresulting hyperchloremia limits the increase in the anion gap

Additional clinical features of interest in DKA are summarized below

1 Leukocytosis is not a reliable marker of infection in DKA because ketonemia produces aleukocytosis, which is proportional to the concentration of ketones in plasma (45).However, an increase in immature neutrophils (band forms) can be a reliable marker

of infection in patients with DKA (49)

2 Elevated troponin I levels without evidence of an acute coronary event has beenreported in 27% of patients with DKA (50)

3 Dehydration is almost universal in DKA, but this may not be reflected in the plasmasodium concentration because hyperglycemia has a dilutional effect on plasma sodium;i.e., the plasma sodium concentration decreases by 1.6–2 mEq/L for every 100 mg/dLincrease in the plasma glucose concentration (51,52)

Insulin therapy is started with regular insulin given intravenously, starting with a bolusdose of 0.15 units per kilogram body weight and followed with a continuous infusion at0.1 units/kg/hr Because insulin adsorbs to intravenous tubing, the initial 50 mL ofinfusate should be run through the IV setup before the insulin drip is started The bloodglucose levels should decrease by 50 to 75 mg/dL per hour (46), and the insulin infusionshould be adjusted to achieve this goal When the blood glucose level falls to 200 mg/dL,the insulin infusion should be decreased to 0.05 to 0.1 units/kg/hr, and dextrose should

be added to the intravenous fluids Thereafter, the blood glucose levels should bemaintained between 150–200 mg/dL (45,46) Achieving euglycemia is not recommendedbecause of the risk of hypoglycemia

Table 32.2 Management of Diabetic Ketoacidosis