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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 -base physiology. 2. Know the differential diagnosis of metabolic associated with high and plan for initial management. Author Disclosure 3. Know the differential diagnosis of normal anion gap . Drs Nitu, 4. Describe pulmonary compensatory changes in metabolic acidosis and . Montgomery, and 5. Understand how various can lead to acid-base imbalance. Eigen have disclosed 6. Describe renal compensatory changes in 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 , , , chills, diarrhea, leg contain a discussion cramps, abdominal pain, and . 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 of 165 beats/min, respiratory rate of 28 breaths/min, pressure commercial product/ 65/30 mm Hg, and saturation of 100% on 4 L/min of oxygen. The most likely diag- device. nosis for this patient is toxic syndrome, which was later confirmed with a positive test. The initial gas (ABG) values are: ● pH, 7.24 ● Abbreviations Partial pressure of oxygen (PO2), 138 mm Hg ● Partial pressure of (PCO2), 19 mm Hg ABG: arterial blood gas ● Ϫ (HCO3 ), 8 mEq/L (8 mmol/L) AG: anion gap ● (BE), Ϫ18 mEq/L (18 mmol/L) BE: base excess BUN: blood nitrogen Such findings are suggestive of metabolic acidosis with respi- .Ca2؉: ratory compensation :Cl؊: Further laboratory results are CNS: ● (Naϩ), 133 mEq/L (133 mmol/L) DKA: diabetic ● (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 ● (BUN), 49 mg/dL (17.5 mmol/L) 2؉ Mg : magnesium ● , 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 , the adjusted AG is 17 mEq/L PO2: partial pressure of oxygen RTA: (17 mmol/L). Lactic acidemia due to shock, one of the likely causes for

*Associate Professor of Clinical , Section of Pediatric , Critical Care and ; 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 (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- 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 can lead to alterations in systemic pH and arterial PCO2. Systemic pH unraveling of the tertiary structure, thereby caus- is monitored by central on the ventro- ing enzyme dysfunction, enzyme loss, and 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 involves the , 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. -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 (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. is associated 3 2 3 Ϫ ()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. 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.

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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 , organic and inorganic the alkalosis range, reflecting the concept that overcompen- , and . In addition, 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 ’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 of sulfur- measure the pH and the PCO2 directly. The HCO3 containing amino . 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 , primarily via hydrogen blood in vitro to restore the pH to 7.40 while the PCO2 is ϩ 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 . 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 (re- follows: Na K Mg (magnesium) Ca (cal- ϩ ϩϭ Ϫϩ Ϫϩ Ϫϩ 3Ϫ ferred to and measured as titratable acidity). The kidneys cium) H Cl HCO3 protein PO4 (phos- ϩ ϩ Ϫϩ 2Ϫ ϩ 2Ϫϩ synthesize and excrete NH3, which combines with H phate) OH SO4 (sulfate) CO3 conjugate ϩ Ϫ Ϫ excreted by the collecting duct cells to form NH4 : base . Sodium, chloride, and HCO3 are measured ϩϩ ϭ ϩ H NH3 NH4 .NH3 diffuses freely across mem- easily in the serum. Therefore, the AG is calculated by the ϩ ϭ ϩ Ϫ Ϫϩ Ϫ branes; NH4 does not. Failure to produce and excrete formula AG {Na } {Cl HCO3 }. A normal AG is ϩ Ϯ sufficient NH4 , therefore, leads to the development of 12 2 mEq/L (12 mmol/L). Some clinicians and some metabolic acidosis. published reports include potassium as a measured cation in the calculation of AG, which raises the normal value by Extracellular and Intracellular Buffers in 4 mEq/L (4 mmol/L). Acid-Base Balance The AG is defined as the difference between the The most important buffer in the extracellular fluid is unmeasured plasma anions and the unmeasured plasma Ϫ HCO3 , due both to its relatively high concentration cations. Clinically, an elevated AG is believed to reflect an and its ability to vary PCO2 via changes in alveolar venti- increase of unmeasured anions and, therefore, a meta- lation. analysis of arterial pH and PCO2 bolic acidosis. This concept is explained by the fact that allows for centrally mediated adjustments in minute ven- unmeasured cations (Mg2ϩ ϩ Ca2ϩ ϩ Hϩ) are more

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tightly controlled and the unmeasured anions have a greater tendency to fluctuate. Theoretically, the AG also Table 1. Causes of Normal Anion can increase following a decrease in serum Kϩ,Ca2ϩ,or ϩ Gap Metabolic Acidosis Mg2 , but the normal concentration of these cations is so low that a reduction does not have a significant clinical Disorders of the Gastrointestinal (GI) Tract Leading To impact on the AG. Excessive Bicarbonate Loss In general, these principles hold true for the previ- • Diarrhea: the leading cause of normal anion gap ously healthy individual who develops an acute illness. metabolic acidosis in children However, for the critically ill host whose plasma protein • Surgical procedures that lead to an anastomosis of the are greatly reduced, the low protein val- ureter with the GI tract, such as ureteroenterostomy/ ureterosigmoidostomy, due to bicarbonate loss in the ues hide an associated increase in unmeasured anions. intestine Without the correction for hypoalbuminemia, it is possi- • Pancreatic fistula ble to overlook a true high AG acidosis, mistakenly Iatrogenic Hyperchloremic Metabolic Acidosis assuming it to be a normal AG acidosis. According to the Figge formula, each 1-g/dL reduc- • Result of excessive fluid with 0.9% tion in the concentration is expected to or excessive use of 3% sodium chloride to correct reduce the AG by 2.5 mEq/L: Renal Loss of Bicarbonate Adjusted AGϭobserved AG ϩ (2.5 ϫ • Renal tubular acidosis type II (proximal) [normal albumin Ϫ observed albumin] • Iatrogenic: carbonic anhydrase inhibitor (acetazolamide) Metabolic Acid-Base Disturbance • Hyperparathyroidism Metabolic Acidosis •Medications Metabolic acidosis is defined as an acid-base imbalance • Acidifying agents: sodium chloride, potassium Ϫ chloride, enteral supplements that leads to anion excess (low HCO3 concentration) and subsequently to an arterial pH below 7.35. Several • Magnesium chloride • Cholestyramine mechanisms can lead to metabolic acidosis: excess acid • Spironolactone production, increased acid intake, decreased renal acid ex- Ϫ cretion, increased HCO3 loss from the gastrointestinal Ϫ (GI) tract, and excess HCO3 excretion in the kidney. For a patient who has intact respiratory function, developing metabolic acidosis leads to respiratory com- frequent conditions leading to normal AG metabolic pensation by . Each 1-mEq/L reduction acidosis. Ϫ in plasma HCO3 concentration prompts a 1.2-mm Hg Of particular note is renal tubular acidosis (RTA), a compensatory fall in the PCO2. Clinically, the patient’s complex set of disorders of the kidney that can lead to respiratory rate increases within the first hour of the onset normal AG metabolic acidosis. One disorder is the inabil- of metabolic acidosis, and respiratory compensation is ity to excrete the daily acid load (type 1 RTA), leading to ϩ Ϫ achieved within 24 hours. Failure of the respiratory sys- progressive H ion retention and low plasma HCO3 tem to compensate for metabolic acidosis is an ominous concentration (Ͻ10 mEq/L [10 mmol/L]). Another Ϫ sign that should trigger careful evaluation of the patient’s disorder arises from the inability to reabsorb HCO3 mental status and cardiorespiratory function. normally in the (proximal RTA or type 2 Ϫ Calculating the AG is a very useful initial step in RTA). HCO3 is lost in the urine despite some reabsorp- diagnosing various causes of metabolic acidosis. tion in the distal nephron, leading to metabolic acidosis and alkaline urine. Metabolic Acidosis With Normal Anion Gap Normal AG metabolic acidosis caused by excessive Ϫ Metabolic acidosis with normal AG reflects an imbalance HCO3 losses may be corrected by slow infusion of of the measured plasma anions and cations. According to -containing intravenous fluids. ϭ ϩ Ϫ Ϫ ϩ Ϫ the formula: AG Na (Cl HCO3 ), metabolic acidosis with normal AG can be explained by excessive Elevated Anion Gap Metabolic Acidosis Ϫ loss of HCO3 (in the stool or in the urine) or by Elevated AG metabolic acidosis results from an excess of inability to excrete hydrogen ions. Table 1 lists the most unmeasured anions. Various conditions that cause an

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accumulation of unmeasured anions, leading to high AG The earliest symptoms of DKA are related to hyper- metabolic acidosis, are listed in Table 2. glycemia. Older children and adolescents typically pres- When faced with an elevated AG metabolic acidosis, ent with polyuria (due to the -induced osmotic calculating the osmotic gap may help determine the ), (due to the increased urinary losses), underlying condition. Similar to the AG, the osmotic gap , and weight loss. Hypovolemia may be severe if is the difference between the measured serum osmolality urinary losses are not replaced, with the presentation and the calculated value. The calculated serum osmo- of very dry mucous membranes and prolonged lality is: 2 ϫ [Naϩ] ϩ glucose/18 ϩ BUN/2.8. A refill time. As a result of worsening metabolic acidosis, normal osmotic gap should be 12Ϯ2 mOsm/L. A high the patient develops hyperventilation and deep (Kuss- osmotic gap is a sign of an excess of an unmeasured maul) respirations, representing respiratory compensa- osmotic active substance such as ethylene glycol (anti- tion for metabolic acidosis. Hyperpnea develops from an freeze), (wood alcohol), or paraldehyde. increase in minute volume (rate ϫ tidal volume) or from increased tidal volume alone without an increase in respi- Ketoacidosis ratory rate. When DKA is being managed, the patient’s Ketoacidosis describes accumulation of bodies chest excursion and respiratory rate should be observed (beta-hydroxybutyrate and ) following carefully to determine if hyperpnea is present. In infants, excessive intracellular use of lipids as a metabolic sub- hyperpnea may be manifested only by tachypnea. strate. This metabolic shift occurs during or Without prompt medical attention, DKA can prog- fasting or as a reflection of a lack of appropriate metabolic ress to and cardiorespiratory arrest. substrate for energy production (during specific diets Neurologic findings, ranging from drowsiness, lethargy, where carbohydrates are replaced with lipids). Hyper- and obtundation to , are related to the severity of ketotic diets sometimes are employed for intractable hyperosmolality or to the degree of acidosis. Treatment epilepsy in an effort to decrease the threshold. of DKA includes sensitive correction of the underlying (DKA) results from a decrease , volume, and deficiencies. in insulin production that leads to an inability to trans- port glucose into the cell. The cell shifts to lipid metab- Lactic acidosis, another cause of an elevated AG, occurs olism, despite the surrounding (also de- when cells shift to anaerobic pathways for energy pro- scribed as “starvation in the middle of the plenty”). The duction as a result of due to inappro- diagnosis of DKA is confirmed by the findings of hyper- priate tissue , inappropriate oxygen supply, or glycemia, a high AG acidosis, ketonuria, and ketonemia. mitochondrial dysfunction (as seen in inborn errors of metabolism or ingestion of drugs or toxins). The clinical presentation may involve or symptoms consis- Table 2. Causes of Elevated Anion tent with the initial disorder that led to lactic acidosis, Gap Metabolic Acidosis such as cyanosis, suggestive of tissue hypoperfusion, and . As lactic acidosis wors- Ketoacidosis ens, further hemodynamic compromise occurs. Manage- • Starvation or fasting ment should be targeted to restoring adequate tissue • Diabetic ketoacidosis perfusion and oxygen supply by treating the underlying Lactic Acidosis cause of the lactic acidosis. • Tissue hypoxia Inborn Errors of Metabolism • Excessive muscular activity Several inborn errors of metabolism can present with • Inborn errors of metabolism high AG metabolic acidosis. Based on the affected met- Ingestions abolic pathway, the increased AG is caused by a different • Methanol chemical substance: defects present with hy- • Ethylene glycol perammonemia; or inborn errors of amino acids, carbo- • Salicylates hydrate, or organic acid metabolism present either with • Paraldehyde ketoacidosis, lactic acidosis (as in Krebs cycle defects), or Renal Failure increased organic acids production. Symptoms often are • nonspecific and include poor feeding, failure to thrive, seizures, and vomiting.

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Managing inborn errors of metabolism involves iden- Massive ingestions of creams containing propylene tifying the defective or deficient enzyme and limiting the glycol (eg, silver sulfadiazine) also can lead to increased intake of the metabolic substrate that requires the use of AG metabolic acidosis. that particular enzyme. In selected cases, may be the appropriate tool for removing the excess anion. Renal Failure Renal failure causes an increased AG metabolic acidosis due to the failure to excrete Hϩ. Normally, elimination Ingestions of the serum acid load is achieved by urinary excretion of ϩ ϩ Ingestions of various chemical substances are another H , both as titratable acidity and as NH4 . Titratable cause of metabolic acidosis with an elevated AG. Sali- acid is a term used to describe acids such as phosphoric cylate overdose is well known to cause increased AG acid and sulfuric acid present in the urine. The term ϩ metabolic acidosis by interfering with cellular metabo- explicitly excludes NH4 as a source of acid and is part of lism (uncoupling of oxidative phosphorylation). Early the calculation for net acid excretion. The term titratable symptoms of salicylate overdose include tinnitus, fever, acid was chosen based on the chemical reaction of titra- vertigo, nausea, vomiting, and diarrhea. More severe tion (neutralization) of those acids in reaction with so- intoxication can cause altered mental status, coma, non- dium hydroxide. cardiac pulmonary edema, and death. Most patients As the number of functioning declines in show signs of intoxication when the plasma salicylate and the glomerular filtration rate concentration exceeds 40 mg/dL. Treatment of salicy- decreases to below 25% of normal, the patient develops late ingestion involves promoting alkaline diuresis to progressive high AG metabolic acidosis ( enhance renal salicylate excretion. In severe cases, dialysis may occur transiently in the initial phases of renal failure). In addition to the decrease in NH ϩ excretion, decreased may be required (generally considered when plasma sa- 4 titratable acidity (primarily as phosphate) may play a role licylate concentrations exceed 80 mg/dL in acute intox- in the pathogenesis of metabolic acidosis in patients who ication and 60 mg/dL in chronic ingestions). experience advanced kidney disease. Of course, dialysis Toluene inhalation also can lead to metabolic acidosis often is employed to correct the severe fluid and electro- with an increased AG. In patients who experience tolu- lyte imbalances generated by renal failure. ene ingestion (glue sniffing), the overproduced hippu- rate is both filtered and secreted by the kidneys, leading Management of Metabolic Acidosis to rapid elimination in the urine. As a result, the AG may Regardless of the cause, acidemia, if untreated, can lead be near-normal or normal at the time of presentation and to significant adverse consequences (Table 3). the patient might be diagnosed mistakenly as having a Ϫ Use of HCO3 to adjust the pH for pa- normal AG acidosis. tients who have metabolic acidosis is controversial. Slow Ethylene glycol (antifreeze), methanol, and paralde- infusion of sodium bicarbonate-containing intravenous hyde ingestion lead to an increased AG metabolic acido- fluids can be used in cases of normal AG metabolic sis and an increased osmotic gap. Both the AG and the Ϫ acidosis to replenish excessive HCO3 losses (eg, as a acidosis due to methanol and ethylene glycol ingestions result of excessive diarrhea). However, infusing sodium result from metabolism of the parent compound. Nei- bicarbonate-containing fluids for increased AG meta- ther may be seen in patients early in the course of bolic acidosis has questionable benefit and should not be ingestion or when there is concurrent ingestion of etha- used clinically. nol. Ethanol combines competitively with alcohol dehy- Ϫ ϩ As discussed, HCO3 combines with H , leading to drogenase, thereby slowing the metabolism of methanol H2CO3 that subsequently dissociates to CO2 and H2O. or ethylene glycol to their toxic metabolites and slowing Ϫ Infusing HCO3 decreases serum pH and raises CO2 and the appearance of both the acidosis and the high AG. H2O. Neither the cell membranes nor the blood-brain Ϫ This effect explains why ethanol administration is used in barrier is very permeable to HCO3 ;CO2 diffuses freely to the medical management of methanol and ethylene gly- the intracellular space, where it combines with H2O, lead- col ingestions, along with fomepizole (alcohol dehydro- ing to H2CO3 and worsening of the intracellular pH. genase inhibitor). Management of ethylene glycol and Administering intravenous sodium bicarbonate to a patient also involves hemodialysis, which re- who has an increased AG metabolic acidosis can lead to a moves both the ingested substance and the metabolic false sense of security because the underlying problem is byproducts from the serum. hidden by an artificially improved serum pH.

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Metabolic Alkalosis Table 3. Consequences of Metabolic alkalosis is defined as an acid-base imbalance Ϫ Metabolic Acidosis leading to increased plasma HCO3 and an arterial pH above 7.45. Several mechanisms can lead to the elevation Ϫ Cerebral in the plasma HCO3 : excessive hydrogen loss, func- Ϫ • Inhibition of metabolism tional addition of new HCO3 , and • Cerebral edema around a relatively constant amount of extracellular • Obtundation and coma Ϫ HCO3 (called a “”). The kidneys Ϫ Cardiovascular are extremely efficient in eliminating excess HCO3 in • Decreased cardiac contractility the urine. A confounding factor is required for serum Ϫ • Decreased cardiovascular responsiveness to HCO3 to accumulate, such as impaired renal function, catecholamine Kϩ depletion, or volume depletion. • Decreased threshold for In general, a patient compensates for a metabolic • Reduction of cardiac output, blood pressure, and end-organ perfusion alkalosis by decreasing ventilation. Respiratory compen- • Pulmonary vasoconstriction sation by raises PCO2 by 0.7 mm Hg for Ϫ Respiratory every 1 mEq/L (1 mmol/L) of serum HCO3 increase. Excessive Hϩ losses can occur either in the urine or GI • Hyperventilation as a result of respiratory Ϫ compensation tract and lead to HCO3 accumulation as the result of • Decreased respiratory muscle strength the following reactions: • Increased work of 7 ϩϩ Ϫ H2O H HO Hematologic Ϫϩ 7 Ϫ • Oxyhemoglobin dissociation curve shifts to the right HO CO2 HCO3 (the oxygen is more easily released at the tissue level Increased loss of gastric content, which has high con- due to a lower pH) centrations of hydrogen chloride, as a result of persistent Metabolic vomiting (eg, self-induced, ) or high • Inhibition of anaerobic nasogastric tube drainage leads to metabolic alkalosis. If • Insulin resistance fluid losses continue unreplaced, and lactic • Decreased adenosine triphosphate synthesis • acidosis ultimately develop. Of note, infants of mothers • Increased protein degradation who have bulimia have metabolic alkalosis at birth. High Hϩ loss in the urine can occur in the distal nephron. Increased secretion of stimulates ϩ Sodium bicarbonate once held a prominent position the secretory H-ATPase pump, increasing Na reabsorp- tion, thereby making the lumen more electronegative in the management of . Reversing the aci- ϩ ϩ dosis caused by global hypoperfusion made physiologic and causing more H and K excretion, which results in sense because severe acidemia may worsen tissue perfu- concurrent metabolic alkalosis and . Patients sion by decreasing cardiac contractility. However, the who have primary mineralocorticoid excess present with most effective means of correcting the acidosis in cardiac hypokalemia and . In contrast, secondary arrest is to restore adequate oxygenation, ventilation, due to congestive or and tissue perfusion. Because most pediatric cardiac ar- cirrhosis usually does not present with metabolic alkalosis rests are due to , support of ventilation or hypokalemia because the above-mentioned mecha- ϩ through early intubation is the primary treatment, fol- nism is blunted by decreased distal nephron Na deliv- lowed by support of the circulation with fluids and ery. Iatrogenic metabolic alkalosis along with volume inotropic agents. Currently, the American Heart Associ- contraction can occur in patients treated with loop or Ϫ ation recommends that sodium bicarbonate administra- diuretics, which cause Cl depletion and in- ϩ tion be considered only in children who suffer prolonged creased delivery of Na to the collecting duct, which ϩ ϩ cardiac arrest and documented severe metabolic acidosis enhances K and H secretion. and who fail to respond to oxygenation, ventilation, Bartter and Gitelman syndromes present with meta- intravenous fluids, and chest compressions combined bolic alkalosis and hypokalemia due to a genetic defect in with epinephrine in recommended doses. the transporters in the loop of Henle and distal tubule,

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respectively, the same locations as those inhibited by of large administrations of citrate are infusion of more loop and thiazide diuretics. than 8 units of banked blood or fresh frozen plasma In addition to Hϩ loss, metabolic alkalosis also can be or administration of citrate as an anticoagulant during induced by the shift of Hϩ into the cells. dialysis. As discussed previously, hypokalemia is a frequent find- ing in patients who have metabolic alkalosis. Hypokalemia Contraction Alkalosis by itself causes intracellular acidosis and increased serum Contraction alkalosis occurs when relatively large vol- ϩ Ϫ alkalosis by the following mechanism: intracellular K umes of HCO3 -free fluid are lost, a situation frequently shifts into the serum to replete the extracellular stores, and seen with administration of intravenous loop diuretics. to maintain electroneutrality, Hϩ enters the cells. Hydro- Contraction alkalosis also may occur in other disorders in Ϫ Ϫ gen movement into the cells lowers the intracellular pH which a high-Cl , low-HCO3 solution is lost, such as Ϫ and leaves unbuffered excess HCO3 in the serum. The sweat losses in cystic fibrosis, loss of gastric in intracellular acidosis in renal tubular cells promotes Hϩ patients who have achlorhydria, and fluid loss from fre- Ϫ secretion and, therefore, HCO3 reabsorption. quent stooling by patients who have congenital chlori- Metabolic alkalosis due to functional addition of dorrhea, a rare congenital secretory diarrhea. Ϫ “new” HCO3 can occur by several mechanisms: de- Regardless of the cause, alkalosis, if untreated, can Ϫ creased renal excretion of HCO3 , posthypercapnic lead to significant adverse consequences (Table 4). alkalosis, or excessive intake or administration of alkali. Management of Metabolic Alkalosis Decreased Renal Bicarbonate Excretion Three general principles apply to the therapy of meta- Renal failure can lead to metabolic alkalosis because the bolic alkalosis: correct true volume depletion, correct Kϩ Ϫ Ϫ Ϫ kidneys fail to excrete excess HCO3 . depletion, and correct Cl depletion (in Cl -responsive metabolic alkalosis). For patients who have true volume Posthypercapnic Alkalosis

Chronic respiratory acidosis (retention of CO2) leads to a compensatory increase in hydrogen secretion and an Ϫ Table 4. Consequences of ensuing increase in the plasma HCO3 concentration to correct the pH. When the PCO2 is decreased rapidly by Untreated Alkalosis of a patient who has chronic respiratory acidosis, the ensuing metabolic alkalosis is Cerebral slow to disappear. Because ClϪ loss often is present in • Cerebral vasoconstriction with reduction of cerebral posthypercapnic alkalosis, repleting the ClϪ deficit may blood flow be essential to correct the alkalosis. • , seizures, lethargy, , and stupor

Furthermore, the acute fall in PCO2 in a person who Cardiovascular has chronic respiratory acidosis raises the cerebral intra- • Vasoconstriction of the small , including cellular pH acutely, a change that can induce serious coronary • Decreased threshold for arrhythmias neurologic abnormalities and death because CO2 can diffuse freely across the blood-brain barrier out of the Respiratory intracellular space, leading to severe alkalosis. Accord- • Compensatory hypoventilation with possible ingly, the PCO2 must be reduced gradually in mechani- subsequent hypoxemia and hypercarbia (respiratory cally ventilated patients who present initially with chronic failure) . Hematologic • Oxyhemoglobin dissociation curve shifts to the left Excessive Intake or Administration of Alkali (the oxygen is bound more tightly to the Alkali administration does not induce metabolic alkalosis oxyhemoglobin) in healthy people because the healthy kidney can excrete Ϫ Metabolic and Electrolyte Imbalances HCO3 rapidly in the urine. However, metabolic alka- Ϫ • Stimulation of anaerobic glycolysis losis can occur if very large quantities of HCO3 are Ϫ • Hypokalemia administered acutely or if the ability to excrete HCO 3 • Decreased plasma ionized calcium is impaired. The administration of large quantities of • Hypomagnesemia and citrate is known to lead to metabolic alkalosis. Examples

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depletion, fluid administration of normal saline replaces with other metabolic acid-base disturbances, often mak- the ClϪ and free water deficits. Potassium chloride ad- ing accurate diagnosis and treatment of the underlying ministration for patients who have concurrent hypokale- disease difficult to achieve. mia is an important component of treatment. This agent becomes particularly helpful in patients who are edema- Respiratory Acidosis tous due to heart failure or cirrhosis and cannot receive Respiratory acidosis occurs when arterial PCO2 increases sodium chloride because an infusion can increase the and arterial pH decreases due to a reduction in alveolar degree of edema. Another method for treating metabolic minute ventilation or, less commonly, an excessive in- alkalosis in an edematous patient is to administer acet- crease in CO2 production. Acute respiratory acidosis azolamide, a carbonic anhydrase inhibitor, which causes occurs with an acute elevation in PCO2 as a result of a mild increase in production of urine that has high sudden limitation or failure of the respiratory system. Ϫ HCO3 content, thus reacidifying the blood. Chronic respiratory acidosis is due to more indolent Correcting metabolic alkalosis (usually - increases in PCO2 as a consequence of systemic disease induced) may be particularly important for intubated over the course of several days. Reduction in minute patients who have chronic respiratory acidosis. The ventilation can result from depression of central nervous higher pH caused by the metabolic alkalosis subse- system (CNS) respiratory drive, anatomic obstruction of quently impairs the respiratory drive and leads to hypo- the respiratory tract, or intrinsic or acquired impairments ventilation that exacerbates hypoxemia, delaying wean- of normal thoracic excursion (Table 5). ing and extubation. In these patients, metabolic alkalosis usually is corrected by enteral supplements of potassium chloride or sodium chloride. Very rarely, in the intensive Table 5. Common Causes of care unit setting, the metabolic alkalosis can be so severe Respiratory Acidosis in that it impairs weaning from mechanical ventilation. In these circumstances, intravenous infusion of hydrogen Children chloride can correct the alkalosis. Measuring the urinary ClϪ is the preferred method for Central Nervous System Depression assessing the renal response to ClϪ therapy. For patients • Medication effects experiencing ClϪ depletion (urinary ClϪ Ͻ10 mEq/L – Sedative: benzodiazepines, barbiturates – Analgesic: narcotics [10 mmol/L]) (eg, GI losses, diuretic therapy, and sweat – Anesthetic agents: propofol losses in cystic fibrosis), every attempt should be made to • Central nervous system disorders correct . Conditions that cause metabolic – Head trauma alkalosis due to high aldosterone concentrations are un- – Infection responsive to ClϪ and are associated with high urine ClϪ – Tumor – Congenital central hypoventilation concentrations. Minimizing continuing acid and chloride losses by Impairments of Thoracic Excursion or Ventilatory Efficiency excessive nasogastric fluid drainage with a histamine2 blocker or proton pump inhibitor also may be helpful. • Chest wall/lung disorders – Asphyxiating thoracic dystrophy – Progressive thoracic scoliosis Respiratory Acid-Base Disturbances – Thoracic trauma As noted, chemoreceptor analysis of arterial pH and – Acute lung injury/ PCO2 allows for centrally mediated adjustments in min- – /parapneumonic effusion ute ventilation to maintain arterial PCO2 near 40 mm Hg. – Severe obesity Primary respiratory disturbances in acid-base equilibrium • Nerve/muscle disorders – Congenital myopathies may result from different pathologic scenarios. Arterial – Spinal cord injury PCO2 rises abnormally (respiratory acidosis) if systemic – Toxin exposure: organophosphates, botulism CO2 production exceeds the ventilatory capacity or when – Guillain-Barre´ syndrome efficient ventilation is inhibited by intrinsic or acquired Respiratory Tract Obstruction conditions. Conversely, arterial PCO decreases abnor- 2 • Upper airway obstruction mally (respiratory alkalosis) in response to physiologic – Adenotonsillar hypertrophy disorders that result in excessive ventilation. Both respi- • Status asthmaticus ratory acidosis and alkalosis may appear in association

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The body’s compensatory changes in response to acute respiratory acidosis initially are limited to buffering Table 6. Common Causes of Ϫ via systemically available cellular HCO3 stores. Because Ϫ Respiratory Alkalosis in of this limitation, serum HCO3 concentrations rise acutely by only 1 mEq/L (1 mmol/L) for every 10-mm Children

Hg elevation in arterial PCO2. In response to chronic Ϫ Medication Toxicity respiratory acidosis, the kidney retains HCO3 and secretes acid, an alteration in function that takes sev- • Salicylate overdose eral (3 to 5) days to have a noticeable physiologic ef- • Central nervous system stimulants – Xanthines (eg, caffeine) fect. Eventually, in chronic respiratory acidosis, serum Ϫ – Analeptics (eg, doxapram) HCO3 concentrations ultimately rise by approximately 3.5 mEq/L (3.5 mmol/L) for every 10-mm Hg eleva- Central Nervous System Disorders tion in arterial PCO2. • Central nervous system tumor Respiratory acidosis can affect both the CNS and • / • Hyperventilation syndrome: stress/anxiety cardiovascular system adversely. CNS effects include in- creased cerebral blood flow and increased intracranial Respiratory Disorders pressure, which can present clinically as disorientation, • Pneumonia acute confusion, , and mental obtundation. • Status asthmaticus Cardiovascular effects include peripheral • Pulmonary edema • Excessive mechanical or noninvasive ventilation and tachycardia. Severe hypoventilation leads to higher • Hypoxia/high altitude arterial PCO2 and more severe hypoxemia. Hypoxemia may be partially compensated by improved tissue extrac- tion of oxygen via an acute acidosis-mediated rightward tory acidosis, improves as the disor- Ϫ shift in the oxyhemoglobin dissociation curve and release der persists. Serum HCO3 concentrations decline by of oxygen to the tissues. However, as respiratory acidosis 2 mEq/L (2 mmol/L) for every 10-mm Hg decrease in persists, a reduction in red blood cell 2,3 diphospho- arterial PCO2 in acute respiratory alkalosis. In chronic Ϫ glycerate (an organophosphate created in erythrocytes respiratory alkalosis, serum HCO3 concentrations de- during glycolysis) results in a shift of the curve to the left cline by 4 mEq/L (4 mmol/L) for every 10-mm Hg and an increase of hemoglobin affinity for oxygen. decrease in arterial PCO2.

Management of Respiratory Acidosis Adverse Effects of Respiratory Alkalosis Treatment of respiratory acidosis usually focuses on cor- Adverse systemic effects of respiratory alkalosis include recting the primary disturbance. Immediate discontinu- CNS and cardiovascular disturbances. Respiratory alka- ation of medications that suppress central respiratory losis often provokes increased neuromuscular irritability, drive or administration of appropriate reversal agents manifested as or carpopedal spasms. In ad- should be considered. Noninvasive ventilation or intuba- dition, cerebral blood vessels vasoconstrict acutely and tion with mechanical ventilation may be necessary to impede adequate cerebral blood flow. Myocardial con- achieve adequate alveolar ventilation and appropriate tractility may be diminished and cardiac arrhythmias may reduction in arterial PCO2. As arterial PCO2 is corrected, occur. The oxyhemoglobin dissociation curve shifts to individuals who experience excessive ClϪ depletion may the left in response to acute respiratory alkalosis, impair- Ϫ subsequently suffer poor renal of HCO3 , ing peripheral oxygen delivery. leading to a concomitant state of metabolic alkalosis. Management of Respiratory Alkalosis Respiratory Alkalosis Treatment of respiratory alkalosis centers on correcting Respiratory alkalosis occurs when there is reduction in the underlying systemic cause or disorder. Close assess- arterial PCO2 and elevation in arterial pH due to excessive ment of oxygenation status and correction of hypoxemia alveolar ventilation. Causes of excessive alveolar ventila- via oxygen administration is paramount. Acute hyper- tion include medication toxicity, CNS disease, intrinsic ventilation syndrome often is treated simply by having lung diseases, and hypoxia (Table 6). the patient breathe into a paper bag. To prevent high Compensatory changes in response to respiratory al- altitude-associated respiratory alkalosis, slow ascent to kalosis involve renal excretion of HCO3. As in respira- allow for acclimatization is recommended; administra-

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tion of acetazolamide before ascent should be consid- Summary ered. The only cure for acute mountain sickness, once it • A wide array of conditions ultimately can lead to has developed, is either acclimatization or descent. How- acid-base imbalance, and interpretation of acid-base ever, symptoms of acute mountain sickness can be re- disorders always involves a mix of art, knowledge, duced with acetazolamide and pain medications for and clinical experience. headaches. • Solving the puzzle of acid–base disorders begins with accurate diagnosis, a process requiring two tasks. First, acid-base variables in the blood must be Suggested Reading reliably measured to determine the effect of multiple Brandis K. Acid-Base Physiology. Accessed March 2011 at: http:// ions and buffers. Second, the data must be www.anaesthesiamcq.com/AcidBaseBook/ABindex.php interpreted in relation to human disease to define Carrillo-Lopez H, Chavez A, Jarillo A, Olivar V. Acid-base disor- the patient’s acid–base status. ders. In: Fuhrman B, Zimmerman J, eds. Pediatric Critical • History, physical examination, and additional Care. 3rd ed. Philadelphia, PA: Mosby Elsevier; 2005:958–989 laboratory testing and imaging help the clinician to Grogono AW. Acid-Base Tutorial. 2010. Accessed March 2011 at: identify the specific cause of the acid-base http://www.acid-base.com disturbance and to undertake appropriate Kraut JA, Madias NE. Approach to patients with acid-base disor- intervention. ders. Respiratory Care. 2001;46:392–403

PIR Quiz Quiz also available online at: http://www.pedsinreview.aappublications.org.

9. Which of the following statements best describes the roles of the different nephron segments in maintaining acid-base balance? A. The proximal and distal tubules are equally responsible for acid excretion. B. The proximal tubule is the primary segment responsible for bicarbonate reabsorption and acid excretion. C. The distal tubule is the primary segment responsible for bicarbonate reabsorption and acid excretion. D. The proximal tubule is the primary segment responsible for bicarbonate reabsorption, and the distal nephron principally promotes acid excretion. E. The proximal tubule and loop of Henle are primarily responsible for both bicarbonate reabsorption and acid excretion.

10. Which of the following constellation of choices best describes sequelae of metabolic acidosis? Oxyhemoglobin Adenosine Cardiac Respiratory Dissociation Triphosphate Output Rate Curve Shift Synthesis A. Increased Decreased To the left Increased B. Decreased Increased To the right Decreased C. Increased Increased To the left Increased D. Increased Decreased To the right Increased E. Decreased Decreased To the right Decreased

250 Pediatrics in Review Vol.32 No.6 June 2011 fluids and electrolytes acid-base disorders

11. Among the following, the most common mechanism leading to metabolic alkalosis is: A. Chronic diarrhea. B. Secondary hypoaldosteronism. C. Hypokalemia. D. Hypoventilation. E. Primary hyperaldosteronism.

12. The most common sequelae of early acute respiratory acidosis are: Oxyhemoglobin Intracranial Dissociation Renal Bicarbonate Pressure Heart Rate Curve Shift Reabsorption A. Increased Decreased To the right Increased B. Decreased Increased To the right Decreased C. Increased Increased To the left Increased D. Increased Increased To the right Increased E. Decreased Decreased To the left Decreased

13. The most accurate statement about respiratory alkalosis is that: A. Cardiac arrhythmias are never observed. B. It occurs when there is a reduction in PCO2. C. It results in decreased renal excretion of alkali. D. It results in vasodilation of cerebral blood vessels. E. Oxygen delivery is generally unaffected.

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