Article fluids and electrolytes Acid-Base Disorders Mara Nitu, MD,* Greg Objectives After completing this article, readers should be able to: Montgomery, MD,† Howard Eigen, MD§ 1. Understand the mechanisms for regulating acid-base physiology. 2. Know the differential diagnosis of metabolic acidosis associated with high anion gap and plan for initial management. Author Disclosure 3. Know the differential diagnosis of normal anion gap metabolic acidosis. Drs Nitu, 4. Describe pulmonary compensatory changes in metabolic acidosis and alkalosis. Montgomery, and 5. Understand how various diuretics can lead to acid-base imbalance. Eigen have disclosed 6. Describe renal compensatory changes in respiratory acidosis and alkalosis. no financial relationships relevant to this article. This Case Study commentary does not A 16-year-old girl who has no significant previous medical history presents to the emer- gency department with a 4-day history of nausea, vomiting, fever, chills, diarrhea, leg contain a discussion cramps, abdominal pain, and headaches. She is finishing her menstrual period and ar- of an unapproved/ rives with a tampon in place, which she reports that she inserted yesterday. Her vital signs investigative use of a include a heart rate of 165 beats/min, respiratory rate of 28 breaths/min, blood pressure commercial product/ 65/30 mm Hg, and oxygen saturation of 100% on 4 L/min of oxygen. The most likely diag- device. nosis for this patient is toxic shock syndrome, which was later confirmed with a positive antibody test. The initial arterial blood gas (ABG) values are: ● pH, 7.24 ● Abbreviations Partial pressure of oxygen (PO2), 138 mm Hg ● Partial pressure of carbon dioxide (PCO2), 19 mm Hg ABG: arterial blood gas ● Ϫ Bicarbonate (HCO3 ), 8 mEq/L (8 mmol/L) AG: anion gap ● Base excess (BE), Ϫ18 mEq/L (18 mmol/L) BE: base excess BUN: blood urea nitrogen Such findings are suggestive of metabolic acidosis with respi- .Ca2؉: calcium ratory compensation :Cl؊: chloride Further laboratory results are CNS: central nervous system ● Serum sodium (Naϩ), 133 mEq/L (133 mmol/L) DKA: diabetic ketoacidosis ● Potassium (Kϩ), 4.2 mEq/L (4.2 mmol/L) GI: gastrointestinal ● Chloride (ClϪ), 109 mEq/L (109 mmol/L) ؉ H : hydrogen ● HCO Ϫ, 12 mEq/L (12 mmol/L) ؊ 3 HCO3 : bicarbonate ● Anion gap (AG), 12 mEq/L (12 mmol/L) ؉ K : potassium ● Blood urea nitrogen (BUN), 49 mg/dL (17.5 mmol/L) 2؉ Mg : magnesium ● Creatinine, 3.96 mg/dL (350 ␮mol/L) ؉ Na : sodium ● Calcium, 5.2 mg/dL (1.3 mmol/L) NH3: ammonia ● Albumin, 2.0 g/dL (20 g/L) NH4: ammonium The apparently normal AG is misleading. After correcting PCO2: partial pressure of carbon dioxide the AG for hypoalbuminemia, the adjusted AG is 17 mEq/L PO2: partial pressure of oxygen RTA: renal tubular acidosis (17 mmol/L). Lactic acidemia due to shock, one of the likely causes for *Associate Professor of Clinical Pediatrics, Section of Pediatric Pulmonology, Critical Care and Allergy; Medical Director, PICU/ Riley Hospital for Children; Medical Co-Director of Lifeline Transport Team, Indianapolis, IN. †Assistant Professor of Clinical Pediatrics, Section of Pulmonology, Critical Care and Allergy; Medical Director, Pediatric Bronchoscopy Laboratory, James Whitcomb Riley Hospital for Children, Indianapolis, IN. §Billie Lou Wood Professor of Pediatrics, Associate Chairman for Clinical Affairs; Director, Section of Pediatric Pulmonology, Critical Care and Allergy, James Whitcomb Riley Hospital for Children, Indianapolis, IN. 240 Pediatrics in Review Vol.32 No.6 June 2011 fluids and electrolytes acid-base disorders increased AG metabolic acidosis, is confirmed by a high Each acid-base disorder leads to countering respira- serum lactate value of 6.9 mg/dL (0.8 mmol/L). One hour tory or renal compensatory responses that attempt to later, the ABG values are: normalize the pH. In metabolic acidosis, for example, ventilation is increased, resulting in a decrease in PCO , ● pH, 7.06 2 ● which tends to raise the pH toward normal. These com- PO2,63mmHg ● pensatory attempts never overshoot correcting the pH PCO2,47mmHg ● Ϫ (Figs. 2 and 3).The process of acid-base regulation in- HCO3 , 13.2 mEq/L (13.2 mmol/L) volves the respiratory system (controls PCO2), kidneys ● BE, Ϫ16 mEq/L (16 mmol/L) Ϫ (regulates plasma HCO3 by changes in acid excretion), This ABG panel reveals metabolic acidosis without and a very complex system of extracellular and intra- respiratory compensation due to developing respiratory cellular buffers. failure. The Respiratory System in Acid-Base Balance Introduction The respiratory system contributes to acid-base balance The loss of acid-base balance is an expression of various via timely adjustments in alveolar minute ventilation that conditions encountered frequently in clinical practice. maintain systemic acid-base equilibrium in response to Changes in hydrogen ion concentration can lead to alterations in systemic pH and arterial PCO2. Systemic pH unraveling of the protein tertiary structure, thereby caus- is monitored by central chemoreceptors on the ventro- ing enzyme dysfunction, enzyme loss, and cell death. lateral surface of the medulla oblongata and arterial PCO2 Understanding the physiology behind various distur- (as well as arterial PO2) by peripheral chemoreceptors bances in acid-base balance is necessary for determining a located at the carotid and aortic bodies. These chemore- correct diagnosis and management plan. ceptors act through central respiratory control centers in Maintaining acid-base homeostasis involves the lungs, the pons and medulla to coordinate the respiratory mus- kidneys, and a very complex system of buffers, all aiming cle efforts of inhalation and exhalation, leading to adjust- to maintain the normal pH (7.35 to 7.45) of the arterial ments in both components of minute ventilation: tidal blood. Lowering the arterial pH below 7.35 is termed volume and respiratory cycle frequency. Lung-mediated acidosis, and an increase of the arterial pH above 7.45 changes in arterial PCO2 can lead to rapid alteration in ϩ constitutes alkalosis. systemic hydrogen ions (H ) because CO2 is lipid- Metabolic acidosis is associated with a low pH and low soluble and may readily cross cell membranes according Ϫ to the following equation: Hϩ ϩ HCO Ϫ7H CO HCO3 concentration. Metabolic alkalosis is associated 3 2 3 Ϫ (carbonic acid)7CO ϩ H O (water). Under normal with a high pH and high HCO3 concentration. Respi- 2 2 physiologic conditions, this process allows for tight con- ratory acidosis is associated with a low pH and high PCO2. Respiratory alkalosis is associated with a high pH and low trol of arterial PCO2 near 40 mm Hg. PCO2 (Fig. 1). Figure 2. Primary metabolic acidosis with subsequent respi- ratory alkalosis compensation. The red arrow does not cross Figure 1. Acid-base changes in metabolic versus respiratory into the alkalosis range, reflecting the concept that overcom- disorders. pensation never occurs. Pediatrics in Review Vol.32 No.6 June 2011 241 fluids and electrolytes acid-base disorders Ϫ tilation to maintain arterial PCO2. The HCO3 interacts with Hϩ, as demonstrated in the following formula: ϩ ϩ Ϫ 7 7 ϩ H HCO3 H2CO3 CO2 H2O. This reaction serves as the basis for the Henderson-Hasselbalch equa- ϭ ϩ Ϫ ϫ tion: pH 6.1 log (HCO3 /0.03 PCO2). Although this equation describes a patient’s acid-base status, it does not provide insight into the mechanism of the acid-base disorder. The Henderson-Hasselbalch equation lists PCO2 and Ϫ HCO3 as independent predictors of acid-base balance, but in reality they are interdependent (as suggested by ϩ ϩ Ϫ the chemical reaction H HCO3 described previ- ously). Furthermore, the Henderson-Hasselbalch equa- tion does not account for other important nonbicarbon- ate buffers present in the body, such as the primary Figure 3. Primary respiratory acidosis with subsequent meta- bolic alkalosis compensation. The red arrow does not cross into intracellular buffers of proteins, organic and inorganic the alkalosis range, reflecting the concept that overcompen- phosphates, and hemoglobin. In addition, bone is an sation never occurs. important site for buffering of acid and base loads. Laboratory Assessment of Acid-Base Balance The Kidneys in Acid-Base Balance Acid-base balance is assessed by blood gas analysis and The kidney’s role in acid-base balance consists of reab- serum measurement of several important electrolytes, Ϫ sorbing filtered HCO3 and excreting the daily acid load leading to the calculation of the AG. Blood gas analyzers Ϫ derived principally from the metabolism of sulfur- measure the pH and the PCO2 directly. The HCO3 containing amino acids. Ninety percent of filtered value is calculated from the Henderson-Hasselbalch Ϫ HCO3 is reabsorbed in the proximal tubules, primarily equation. The BE value also is calculated as the amount by Naϩ-Hϩ exchange, and the remaining 10% is reab- of base/acid that should be added to a sample of whole sorbed in the distal nephron, primarily via hydrogen blood in vitro to restore the pH to 7.40 while the PCO2 is ϩ secretion by a proton pump (H -ATPase). Under nor- held at 40 mm Hg. The PCO2 not only points to the type Ϫ mal conditions, no HCO3 is present in the final urine. of disorder (respiratory or metabolic) but also corre- The excretion of the daily Hϩ load occurs in the distal sponds to the magnitude of the disorder. tubule. Once excreted in the urine, the Hϩ must be The AG method was developed to include other bound to a buffer to avoid excessive urine acidification nonbicarbonate buffers in the analysis. Based on the and promote further excretion. The two primary buffers principle of electroneutrality, the sum of the positive in the urine are ammonia (NH3), which is excreted and charges should equal the sum of the negative charges as ϩ ϩϩ ϩϩ 2ϩ ϩ 2ϩ measured as ammonium (NH4 ) and phosphate (re- follows: Na K Mg (magnesium) Ca (cal- ϩ ϩϭ Ϫϩ Ϫϩ Ϫϩ 3Ϫ ferred to and measured as titratable acidity).