Journal of Pharmacy Practice

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Mar 17, 2011 - А. Renal compensation begins approxi- mately 6 to 12 hours after an acidАbase derangement, however full compensation may take 3 to 5 ...

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A Practical Approach to Understanding Acid−Base Abnormalities in Critical Illness Amy L. Dzierba and Prasad Abraham Journal of Pharmacy Practice 2011 24: 17 DOI: 10.1177/0897190010388153

The online version of this article can be found at: http://jpp.sagepub.com/content/24/1/17

Published by: http://www.sagepublications.com

On behalf of:

New York State Council of Health-system Pharmacists

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A Practical Approach to Understanding Acid–Base Abnormalities in Critical Illness

Journal of Pharmacy Practice 24(1) 17-26 ª The Author(s) 2011 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190010388153 http://jpp.sagepub.com

Amy L. Dzierba, PharmD, BCPS1 and Prasad Abraham, PharmD, BCPS2

Abstract Acidbase disorders are common in the critically ill. Arterial blood gas (ABG) analysis is frequently used to identify and manage acidbase disturbances. Using a systematic problem-solving approach to acidbase disturbances will facilitate the identification and assess the progression and severity of the metabolic and respiratory abnormality. The intent of this review is to examine acidbase physiology and regulation, provide a method to evaluate a patient’s acidbase disorder, and provide therapeutic interventions. Keywords acidbase, arterial blood gas, critically ill, intensive care

Introduction The ability to correctly interpret acidbase abnormalities in the critically ill population is essential for recognizing and managing metabolic and/or respiratory disorders. Topics dealing with acidbase physiology are often met with great anxiety, fear, and disdain. The intent of this practical review is to assuage that anxiety, deepen understanding of acidbase disorders, and cultivate interest in this topic.

an enzyme present in the lungs and kidneys. H2CO3 weakly ionizes to produce Hþ and HCO3, whereas NaHCO3 completely ionizes to generate HCO3. When an acid is added to the system, it combines with HCO3 generating CO2 that is dissolved in the blood and subsequently eliminated via the lungs. In cases when a base is added, it combines with H2CO3 to generate HCO3, which is eliminated via the kidneys. To better quantify the relationship between pH, CO2, and HCO3 in this physiologic buffer system, Henderson and Hasselbach developed the following formula4:

Basic Physiology

pH ¼ 6:1 þ log½HCO 3 0:03  PaCO2

Precise control of hydrogen ions (Hþ) in the blood is essential for the maintenance of homeostasis. Despite the body’s large production of acids, Hþ concentrations are rather low and constant, hence are described for practical purposes as pH (negative log of Hþ concentration).1 Maintaining blood pH within a narrow range is vital to attenuate abnormal cellular functioning. The body’s complex buffer system minimizes significant alterations in pH along with the respiratory and renal systems.2,3 Buffers within the intracellular and extracellular fluid that regulate pH include sodium bicarbonate/carbonic acid (NaHCO3/H2CO3), phosphates, proteins (eg, albumin, globulin), and hemoglobin/oxyhemoglobin. The dominant buffer system of the human body is bicarbonate (HCO3)/carbonic acid. The dynamics of the system and its components are as follows:

Thus, the pH increases as the HCO3 concentration increases and decreases when the partial pressure of carbon dioxide (PaCO2) increases. Although bicarbonate is the principal buffer in the body, other variables exist contributing to the regulation of acidbase balance. The Stewart approach describes the pH in terms of the concentrations of weak acids (albumin and phosphate), PaCO2, and the strong ion difference.5,6 This approach has been validated and may offer more insight into extreme acidbase conditions observed in the critically ill patient population.5,7 The wide spread use of this method has most likely

 H2 CO3 ! H þ HCO3 þ fNa g !  NaHCO3 CO2 þ H2 O !

NewYork-Presbyterian Hospital, Columbia University, New York, NY, USA Department of Pharmacy and Drug Information, Grady Health System, Atlanta, GA, USA

Reactions within this system can flow in a bidirectional manner to maintain homeostasis depending on the concentrations of each component. The conversion of carbon dioxide (CO2) to H2CO3 is slowly catalyzed by carbonic anhydrase,

Corresponding Author: Amy L. Dzierba, Department of Pharmacy, 622 West 168th Street, New York, NY 10032, USA Email: [email protected]

þ

þ

1 2

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Table 1. Normal Values for Arterial Blood Gas Interpretation

Table 2. Primary AcidBase Disturbances

pH PaCO2 PaO2 HCO3 BE

Primary Disorder

7.35–7.45 35–45 mm Hg 80–100 mm Hg 22–26 mEq/L 2 to þ2

Abbreviations: PaCO2, partial pressure of carbon dioxide in arterial blood; PaO2, partial pressure of oxygen in arterial blood; HCO3, serum bicarbonate concentration; BE, base excess.

been dampened as a result of the mathematically cumbersome nature of the equations. The respiratory system is the second line of defense against acidbase abnormalities responding within minutes of the derangement. The largest fraction of CO2 is transported via the blood in the form of HCO3 to the lungs where it is removed from the body.1 Either an increase or decrease in the rate and depth of respirations will occur in response to aberrations in PaCO2 values. The renal response is the final line of defense in the maintenance of blood pH through the retention or excretion of HCO3. The kidneys will compensate by retaining HCO3 in the setting of a decreased systemic pH and excrete HCO3 with an elevated pH.1 In addition, the kidneys help generate ammonia (NH3) in the distal tubules, which facilitates Hþ secretion as well as generation of ‘‘new’’ HCO3. Renal compensation begins approximately 6 to 12 hours after an acidbase derangement, however full compensation may take 3 to 5 days.3

Components of Arterial Blood Gas and Normal Values Applying a structured approach to the interpretation of blood gas samples will aid in the identification of acidbase abnormalities. Components of the arterial blood gas (ABG) include the pH, partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2), bicarbonate (HCO3) concentration, and base excess. The assessment of each component will facilitate the understanding of the origin and severity of the metabolic or respiratory disorder. pH: The measurement of arterial blood pH is a way to assess the concentration of Hþ. An inverse relationship exists between pH and the concentration of Hþ such that with increased Hþ concentrations, the pH will decrease and vice versa. The pH may be within normal range in the setting of a mild acidosis, mild alkalosis, or mixed disorder. PaCO2: Evaluation of the partial pressure of CO2 in arterial blood will help characterize the adequacy of lung function in addition to the rate and depth of breathing. Hypoventilation will result in a higher PaCO2, whereas hyperventilation will result in a lower PaCO2. PaO2: The partial pressure of oxygen in arterial blood is measured to assess how well oxygen is able to move from the lungs into the blood. Hypoxemia (PaO2 45 12 mEq/L; however an AG  20 mEq/L indicates a primary metabolic acidosis regardless of pH or serum HCO3 concentration. There may be situations where concurrent metabolic disorders exist. To identify if mixed metabolic disorders are present, the delta gap should be calculated (D gap ¼ total AG minus the normal AG [12 mEq/L]). Next, add the delta gap to the measured HCO3 concentration. If the sum is greater than normal serum HCO3 (>26 mEq/L), there is an underlying metabolic alkalosis; if the sum is less than normal serum HCO3 (7.45.

Metabolic Acidosis Metabolic acidosis occurs either as a net retention of nonvolatile acids (those other than carbonic acid) or loss of HCO3. The typical laboratory abnormalities associated with this type

of primary acidosis include a low pH and low HCO3. Causes of metabolic acidosis can be categorized into 2 broad states: AG and non-AG. The utility of this information lies in the fact that there are a limited number of disease processes or drugs that produce a metabolic acidosis with an AG. An easy mnemonic used to remember these factors is MUDPILES29: Methanol, Uremia, Diabetic ketoacidosis (DKA), Paraldehyde, Isoniazid (INH) and Iron, Lactic acid, Ethylene glycol and Ethanolinduced ketoacidosis, Salicylates. While this is not an allinclusive list, it does capture the majority of the causes. The body will attempt to maintain a normal acidbase balance or compensate for the metabolic acidosis through the removal of acid. This takes place via the removal of carbonic acid as CO2. The expected compensation will be a reduction in PaCO2 manifested by an increase in respirations. Management of patients with metabolic acidosis is specific to the disease process/drug. Acidosis occurring with methanol and ethylene glycol is the result of their toxic metabolites and management includes the inhibition of further metabolite production by utilizing fomepizole, an alcohol dehydrogenase inhibitor.30,31 Chronic renal failure leads to the decreased filtration and increased reabsorption of both organic and inorganic acids; this is rectified with hemodialysis.32 DKA and alcoholic ketoacidosis (AKA) develop as a result of ketone generation due to a lack of insulin or inhibition of insulin production. Replacement of insulin stores, which is the cornerstone of DKA management, inhibits fat metabolism, the source of ketones.33 AKA corrects very easily with administration of dextrose and saline.34 INH toxicity leads to depletion of pyridoxine potentially resulting in seizures. The AG is a result of the generation of lactate from seizure activity as well as INH’s ability to inhibit the formation of nicotinamide adenine dinucleotide, which is essential for the conversion of lactate to pyruvate.35 Moreover, INH also decreases the metabolism of betahydroxybutyrate, further compounding the AG acidosis.36 Management involves administration of high doses of pyridoxine.37 Iron toxicity causes uncoupling of mitochondrial oxidative phosphorylation as well as generation of free radicals that exert direct cellular toxicity.38-40 The former leads to the

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Table 5. Evaluation of Urine Electrolytes

Table 6. Causes of Metabolic Alkalosis

Urine Solutes Cause of acidosis GI HCO3 losses Renal HCO3 losses Excess Cl intake

U Gapa

NH4þ

Cl

Naþ

# " #

" " "

# $ "

# $ "

Urinary gap ¼ sum of urine Naþ, and Kþ minus urine Cl; normal range is 10 to þ10 mEq/L. Abbreviations: HCO3, bicarbonate ion; NH4þ, ammonium ion; Cl, chloride ion; Naþ, sodium ion; ", increased; #, decreased; $, equivocal; GI, gastrointestinal. a

generation of lactic acid and subsequent AG acidosis. Treatment involves chelation. Lactic acidosis can have many etiologies but are generally divided into low delivery of oxygen or a normal delivery of oxygen along with either an increased production or decreased removal of lactate.29 Treatment involves either restoring oxygen delivery or removal of toxic agents. Historically, sodium bicarbonate (NaHCO3) was utilized in the treatment of severe metabolic acidosis. Presently, there is no clinical benefit to the administration of NaHCO3 except for toxin excretion and life-threatening hyperkalemia. There is a theoretical risk of worsening intracellular acidosis (via generation of CO2) resulting in potentially worse outcomes.41 Other complications of NaHCO3 include overcorrection alkalosis, hypokalemia, and volume overload. Tris-hydroxymethyl aminomethane (THAM), an organic amine, has been utilized as an alternative to NaHCO3 because of its lack of CO2 generation, however strong clinical data are lacking.36,42 NAG acidosis results from a loss of base, causing a low HCO3 and pH, despite a normal AG. A mnemonic for the specific etiologies of NAG acidosis is ACCRUED43: Acid infusion/Aldosterone inhibitors, Compensation for respiratory alkalosis, Carbonic anhydrase inhibitors (acetazolamide), Renal tubular acidosis (RTA), Ureteral diversion, Extra alimentation/ Hyperalimentation, Diarrhea/other gastrointestinal (GI) losses such as fistulas. In general, NAG acidosis can be broadly categorized into GI or renal losses of HCO3 or the gain of exogenous Cl. Measurement of either urinary ammonium ion (NH4þ) or calculation of the urinary AG will help differentiate between renal and nonrenal causes of HCO3 loss (Table 5). Administration of excess sodium chloride (NaCl) is a common iatrogenic cause of NAG acidosis, often termed hyperchloremic acidosis. To maintain electroneutrality, the body maintains a ratio of HCO3 to Cl of approximately 0.25 or greater.44 Excess NaCl disrupts this ratio, creating a dilutional acidosis due to a net retention of Cl. Correction of this type of acidosis requires only the removal of excess NaCl. Substituting NaCl (154 mEq of Naþ and Cl) with lactated Ringer’s (130 mEq Naþ and 110 mEq Cl), which is more isochloremic, may prevent this problem. Drugs such as aldosterone inhibitors (spironolactone) and carbonic anhydrase inhibitors (acetazolamide) will lead to

Chloride Responsive Alkalosis

Chloride Unresponsive Alkalosis

Vomiting Nasogastric (NG) suctioning Past use of loop or thiazide diuretics Posthypercapnia Cystic fibrosis

Cushing’s syndrome Exogenous steroids Increased rennin/aldosterone states Licorice ingestion Gitelman’s syndrome Bartter’s syndrome Current use of loop or thiazide diuretics Refeeding syndrome

wasting of HCO3.45 Several heterogeneous types of RTA may lead to metabolic disarray through the failure of acid secretion into the urine. Distal (type I) RTA is characterized by a defect in Hþ secretion in the distal tubule, whereas an impairment in proximal reabsorption of HCO3 exists in proximal (type II) RTA.46 Both disorders produce a urine pH that is not maximally acidified leading to a NAG acidosis with profound hypokalemia. Impairment in ammonia synthesis in the distal tubule, which is essential for Hþ secretion, is seen in type IV RTA, often presenting as a hyperkalemic and hyperchloremic acidosis. Typically, only type I RTA requires treatment with chronic alkali therapy.29 A urethral diversion is a procedure performed in patients with bladder cancer, where a section of small or large bowel is utilized to create a ‘‘neo’’bladder, after the old one has been resected. The challenge with this procedure is that the neobladder acts very much like a part of the GI tract and reabsorbs Cl in lieu of HCO3, therefore wasting HCO3 and creating a NAG acidosis, which does not correct with time.47 The small bowel is a tremendous source of HCO3 secretion; hence, in patients that develop diarrhea or small bowel fistulas, there is a wasting of HCO3 along with other cations leading to acidosis. Management includes identifying the underlying causes of diarrhea and prompt correction, whereas with fistulas bowel rest and supportive care is paramount.48

Metabolic Alkalosis Metabolic alkalosis is a pathophysiologic condition that results in the net gain of HCO3 or loss of Hþ from the extracellular fluid. In the absence of other confounding acidbase abnormalities, metabolic alkalosis clinically presents as an increase in serum pH as well as serum HCO3. Metabolic alkalosis is classically delineated into 2 types: chloride responsive and chloride unresponsive. Rarely is excessive HCO3 administration the sole cause of metabolic alkalosis, except in transient states.49 In severe cases of metabolic alkalosis, patients present with lethargy, confusion, cardiac arrhythmias, and muscle spasms.50 Some of the more common causes of metabolic alkalosis are presented in Table 6.23,44,49

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Table 7. Causes of Respiratory Acidosis

Table 8. Causes of Respiratory Alkalosis

Central respiratory depression Airway obstruction

Central stimulation Hypoxia

Respiratory disorders

Neuromuscular dysfunction

Central sleep apnea; opiates and sedatives; trauma; stroke; status epilepticus Obstructive sleep apnea; foreign body; tumor; aspiration; bronchospasm Chronic obstructive pulmonary disease; acute respiratory distress syndrome; permissive hypercapnia; pneumonia; pulmonary edema; fibrosis Guillain-Barre´ syndrome; myasthenia gravis; brain stem or cervical cord injury

In order to differentiate between the 2 general classes of metabolic alkalosis, evaluation of urine Cl is helpful. Patients that have a low urine chloride (10 mEq/L) have chloride unresponsive alkalosis.23,49 In most cases of chloride unresponsive alkalosis, urine potassium (Kþ) will also be elevated (>30 mEq/L), indicating significant renal losses of Kþ.49 In chloride responsive alkalosis, there is a depletion of Cl. Metabolic alkalosis associated with GI losses (vomiting or NG suctioning), Cl is lost in the form of hydrogen chloride.51 Diuretics, both loop and thiazide, cause a wasting of Cl via inhibition of the Naþ/Kþ/2Cl pump and the Naþ/Cl pump, respectively.52 The increased delivery of Naþ to the distal tubule promotes Kþ and Hþ secretion.53 With volume contraction, aldosterone secretion is stimulated leading to an accelerated wasting of Kþ and Hþ. Reduced glomerular filtration in combination with hypokalemia stimulates the reabsorption of HCO3 in the proximal tubule.54-58 In patients with chronic respiratory acidosis, the kidneys compensate with retention of HCO3 along with the wasting of Cl.59,60 If the respiratory acidosis is rapidly corrected, without sufficient Cl replacement, the HCO3 reabsorption persists resulting in metabolic alkalosis. Cystic fibrosis results in a defect of chloride channels, hence profound skin losses of Cl can occur resulting in metabolic alkalosis.61 The pathophysiology of chloride unresponsive metabolic alkalosis involves both the depletion of Kþ along with excessive mineralocorticoid activity. While each factor independently causes mild metabolic alkalosis, the combination leads to an additive effect.62,63 As mentioned previously, hypokalemia stimulates the reabsorption of HCO3 at the proximal tubule often observed with mineralocorticoids, licorice, and Gitelman and Bartter syndromes, leading to the development of metabolic alkalosis.48,64 Management of chloride responsive alkalosis simply requires the replacement of Cl, which can be in the form of NaCl or KCl.23,44 Hydrochloric acid or ammonium chloride can be used, if there are contraindications to NaCl or KCl, but these are very rare instances.49 Management of chloride unresponsive alkalosis includes the prompt correction of hypokalemia. In cases where excess mineralocorticoid activity is present, removal of the offending agent is

Iatrogenic

Anxiety; cirrhosis; sepsis; pregnancy; tumors; aspirin overdose; severe pain Pneumonia; congestive heart failure; high altitude; pulmonary fibrosis or edema Excessive mechanical ventilation

warranted. Addition of spironolactone, an aldosterone antagonist, may be considered in conditions of excess aldosterone such as congestive heart failure and hepatic dysfunction. With Bartter’s syndrome, angiotensin-converting enzyme inhibitors have shown some promise in reducing potassium wasting, while with Gitelman’s syndrome administration of potassium sparing diuretics such as amiloride or triamterene have beneficial effects.65,66 Refeeding syndrome requires aggressive electrolyte replacement along with slow titration of nutrition for optimal outcomes.67

Respiratory Disorders As stated earlier, the largest fraction of CO2 is transported to the lungs through plasma in the form of HCO3. In the alveoli, HCO3 combines with Hþ resulting in the release of CO2 which is then excreted through respiration, maintaining a normal pressure of 40 mm Hg. Derangements in PaCO2 will lead to alterations in pH. If the patient is suffering from a primary respiratory problem, an inverse relationship will exist between the PaCO2 and pH (as the pH decreases the PaCO2 will increase and vice versa). The severity of change will help to determine whether the patient is suffering from an acute process or if there is an underlying chronic ventilation deficit.

Respiratory Acidosis Respiratory acidosis occurs as a direct result of hypoventilation or the inability of the lungs to excrete CO2 as production continues, leading to a rise in PaCO2 (hypercapnia). Respiratory acidosis may result from a variety of acute and chronic conditions including impaired central respiratory drive, a decline in gas exchange, airway obstruction, medications, or neuromuscular dysfunction (Table 7). Acute rise in PaCO2 can be associated with neurological manifestations such as headache and confusion, potentially leading to stupor and coma if left untreated. Treatment of respiratory acidosis is focused on alleviating the underlying condition; however, treatment goals will differ depending on the chronicity of the respiratory decline. Patients presenting with acute respiratory acidosis will have an elevated PaCO2 with an acute decline in pH. Compensation occurs through a metabolic process where the kidneys begin to excrete more acid and less HCO3. This process begins approximately 6 to 12 hours after the derangement, resulting in only modest changes in serum HCO3

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usually not rising above 31 to 32 mm Hg. If compensation has occurred, but the serum HCO3 value is above or below the expected number, another acidbase abnormality is present (Table 4). In contrast, patients with chronic respiratory failure resulting from persistent conditions such as chronic obstructive pulmonary disease (COPD), neuromuscular impairment, or upper airway obstruction will have chronic, stable elevations in PaCO2; however the pH will be maintained within a near normal range as a result of renal compensation. Patients may experience an acute decline in their respiratory function (acute on chronic respiratory failure), leading to further increases in PaCO2 and a decline in pH. Adult patients suffering from acute respiratory distress syndrome are often ventilated with low tidal volumes to improve outcomes.68 This protective lung ventilation strategy is associated with some degree of hypercapnia (PaCO2 rarely exceeding 80 mm Hg) and acidemia that is tolerated by clinicians. Treatment of acute respiratory decompensation resulting in acidosis should be directed at identifying and reversing the underlying cause. Patients presenting with lifethreatening hypoxemia (PaO2