891CHAPTER 72 Acid Base Disorders has traditionally been separated into three main categories (1) proximal RTA, or type 2; (2) distal RTA, or type 1; and (3) hyperkalemic RTA, or type 4 Sometimes, a f[.]
CHAPTER 72 Acid-Base Disorders has traditionally been separated into three main categories: (1) proximal RTA, or type 2; (2) distal RTA, or type 1; and (3) hyperkalemic RTA, or type Sometimes, a fourth kind is added: combined proximal and distal RTA (mixed RTA), or type 3.127 RTA results in metabolic acidosis due to the lack of urinary excretion of hydrogen ions or an excessive loss of bicarbonate due to a variety of tubular disorders.127 Molecular studies have identified genetic or acquired defects in transporters of protons and bicarbonate in most varieties of RTA.127,128 The underlying defect in all RTA types is an inability to excrete chloride in proportion to sodium, although the transporter involved dictates the specific type of RTA.127,129 In the ICU, the presence of RTA may complicate management of patients, particularly regarding the provision of resuscitative fluids.129 Undiagnosed RTA must be suspected whenever a patient’s clinical condition does not improve as expected with the proper therapeutic interventions Urinary AG (uGAP [uNa1 uK1] [uCl2]) can be used to evaluate for RTA in a patient with hyperchloremic acidosis If it is negative (uCl2 uNa1 uK1), it suggests GI bicarbonate loss, acute infusion of a high volume of saline isotonic fluid (NaCl 0.9%), or a proximal RTA On the other hand, if the uGAP is positive (uCl2 , uNa1 uK1), it suggests the presence of a distal renal tubular defect Type RTA is of special interest in the critical care setting, as it can triggered by genitourinary disruptions (e.g., urinary tract infections, bladder obstruction) as well as drugs used in ICUs, such as heparin, trimethoprim, a-adrenergic agonists, b-adrenergic antagonists, and digoxin Other medications can also cause RTA.130 Topiramate, one of the new anticonvulsant drugs, causes hyperchloremic metabolic acidosis through inhibition of the enzyme carbonic anhydrase, resulting in a type or mixed RTA.131 Another rare cause of normal AG metabolic acidosis is acetazolamide, a carbonic anhydrase inhibitor used to decrease cerebral spinal fluid production or to stimulate renal bicarbonate wasting in respiratory acidosis This drug decreases hydrolysis of H2CO3, resulting in a decrease of renal HCO32 reabsorption.132 Urinary Reconstruction Using Bowel Segments Children with lower urinary tract dysfunction due to developmental abnormalities may require urologic surgical procedures for their management that, depending on the clinical situation, may include urinary diversion Various techniques using a variety of conduits may be used depending on the clinical situation The GI tract, which is occasionally used, is a poor substitute for urothelium Its semipermeability often results in abnormal fluid and electrolyte absorption, leading to metabolic abnormalities.133 Urinary reconstructions often result in hyponatremic and hypochloremic hyperkalemic acidosis, clinically manifested by nausea, vomiting, anorexia, and muscular weakness.133 In less severe cases, a chronic metabolic acidosis may go undetected, resulting in growth failure and short stature Treating Metabolic Acidosis Treatment of metabolic acidosis should focus on the underlying cause Certain forms of acidosis have specific therapies, such as insulin and fluids for the patient with DKA, bicarbonate and citrate for patients with distal RTA, and fomepizole for methanol or ethylene glycol intoxication The following discussion focuses on lactic acidosis unless otherwise specified 891 Sodium Bicarbonate Sodium bicarbonate administration has long been the standard for management of metabolic acidosis, including lactic acidosis.64,108 In AG acidosis, especially lactic acidosis (in shock and cardiopulmonary resuscitation) and diabetic acidosis, there is a dearth of evidence regarding the safety and efficacy of bicarbonate Despite this, the use of bicarbonate continues to be common in the setting of critical illness.3,64,108,134,135 Sodium bicarbonate may increase arterial pH if, and only if, alveolar ventilation is adequate.24,134,136-138 The ultimate effect of sodium bicarbonate on intracellular pH depends on changes in Pco2, which is influenced by the extracellular nonbicarbonate buffering capacity.136 Additionally, bicarbonate may increase lactic acid production, which may worsen acidosis.136 While the mechanism for this change remains unclear, it may be due to a combination of factors, including a shift in the oxyhemoglobin-saturation relationship, enhanced anaerobic glycolysis, or changes in hepatic blood flow or lactate uptake.64,123 Arterial pH can be raised and even normalized with sodium bicarbonate.64,108,138 However, while sodium bicarbonate reliably elevates the arterial pH, at the tissue and cellular levels, its effect can be erratic In most animal models and in most organs studied to date, including the brain in healthy human volunteers, intracellular pH decreases with bicarbonate administration.71,137,139 This intracellular acidosis does not appear to damage cells, however.137 Studies that assessed the impact of bicarbonate administration during cardiopulmonary resuscitation showed no benefit in survival and hemodynamic recovery.64,71,140 Hence, routine use of sodium bicarbonate during resuscitation is no longer recommended by the American Heart Association It should be considered only after effective ventilation, chest compressions, and epinephrine administration have occurred or in situations in which bicarbonate is a specific therapeutic intervention (e.g., hyperkalemia or tricyclic antidepressant poisoning).141 Adverse effects of sodium bicarbonate are related to fluid and sodium load and include hypervolemia, hyperosmolarity, and hypernatremia.134 Intravenous bicarbonate administration can cause sudden shifts of several cations; while this may be used in the treatment of hyperkalemia, it also must be noted that bicarbonate administration lowers ionized calcium.64 Given as a bolus, sodium bicarbonate can decrease arterial blood pressure and a transient rise in intracranial pressure, probably owing to its hypertonicity.138 Overshoot alkalosis can result from overly aggressive bicarbonate correction.138,141 Dose of sodium bicarbonate is best estimated using either the SBE or the bicarbonate level derived from Pco2 measured by the blood gas analyzer: Total body base deficit SBE body weight (kg ) 0.3 (Eq 72.14) HCO3 deficit (mEq) 0.3 body weight (kg) HCO3 expected HCO3 observed (Eq 72.15) Current consensus recommendations suggest giving bicarbonate correction using a 0.3 distribution multiplier (“half correction”) in most cases to avoid unnecessary risks from an excessive load of solutes and fluid as well as overshoot alkalemia.134,138 Alternative Alkalinizing Agents Concern about the CO2-producing effect of bicarbonate led to the development of other agents to provide alkalinization through 892 S E C T I O N V I I Pediatric Critical Care: Renal different mechanisms One of these is carbicarb, which consists of equimolar concentrations of sodium bicarbonate (NaHCO3) and sodium carbonate (Na2CO3).142 Carbicarb increases the pH far more than bicarbonate While its effect on intracellular pH is more consistent, studies of its effects on hemodynamics have yielded conflicting results.135 It is not currently available for clinical use pending further clinical research Tris(hydroxymethyl) aminomethane (THAM) is an amino alcohol that behaves as a weak base (pKa 7.8) and raises both intracellular and central nervous system pH In addition, THAM’s buffering action occurs without producing CO2; thus, it is not dependent on pulmonary function.143 Even though THAM has been commercially available for several decades, there are few studies establishing its clinical efficacy A small adult ICU study showed that THAM had an equivalent but shorter-lasting alkalinizing effect in comparison with that of bicarbonate.143 However, minimal clinical utilization and serious side effects—including hyperkalemia, hypoglycemia, local extravasation injury, and hepatic necrosis in neonates—have limited its widespread clinical use.143 Of particular relevance for lactic acidosis is dichloroacetate (DCA), which stimulates pyruvate dehydrogenase, increasing the oxidation of pyruvate to acetylcoenzyme A (CoA) and facilitating its entry into the Krebs cycle This decreases lactate production and promotes the clearance of accumulated lactate.144 While initial data from both children and adults were promising, a large clinical trial in adults with severe lactic acidosis showed that DCA treatment resulted in statistically significant but clinically unimportant changes in arterial blood lactate concentrations and pH.144 Renewed interest in DCA has arisen from its potential applications for attenuating lactic acidosis in certain congenital errors of metabolism.145 Dialysis Management of Metabolic Acidosis Dialysis therapy may be indicated in cases of metabolic acidosis that are refractory to bicarbonate or in cases in which there are limitations in the amount of fluid or sodium load that can be administered to the patient, a common situation in the pediatric critical care unit Uncompensated metabolic acidosis (pH ,7.1) remains one of the acknowledged criteria for the initiation of renal replacement therapy in the pediatric ICU.135 Peritoneal dialysis is often not the best choice, particularly in states of lactic acidosis, shock, and hypoperfusion In this setting, the peritoneal membranes may not be efficient to support enough peritoneal flux, and the increase in intraabdominal pressure may contribute to a further drop in cardiac output Acute renal replacement therapy with continuous hemofiltration and hemodiafiltration are often better options for critically ill patients with metabolic acidosis that is multifactorial in origin Once continuous hemofiltration is started, rapid changes in metabolic acid-base status can be achieved Hemofiltration techniques replace plasma water, which is low in bicarbonate concentration, with a solution that contains an above-normal sodium bicarbonate (or lactate or acetate) concentration Such weak anions buffer hydrogen ions and then are transformed into CO2 (lactate and acetate must convert first to bicarbonate in the liver), which is removed by ventilation.57 The result is the progressive resolution of acidemia and acidosis, with lowering concentrations of phosphate and unmeasured anions Metabolic Alkalosis Primary metabolic alkalosis is defined as an elevation of arterial pH above 7.45 or a reduction in [H1] with an increase in plasma HCO32 and compensatory hypoventilation, resulting in a rise in Pco2 However, a high HCO32 concentration alone is not enough to diagnose metabolic alkalosis, as this can represent compensation by the kidney for respiratory acidosis Metabolic alkalosis is generated by net gain of base (primarily bicarbonate) or loss of nonvolatile acid from the extracellular fluid.146,147 This excess base may be gained through oral or parenteral bicarbonate administration or by the administration of other weak anions—such as lactate, acetate, or citrate—with the gain of strong cations (mainly sodium) The acid deficit may be due to hydrochloric acid loss by vomiting or enhanced renal acid excretion promoted by diuretics or aldosterone excess and is often accompanied by hypochloremia and hypokalemia.146–148 There can also be contraction of the extracellular fluid volume (known as contraction alkalosis) due to chloride loss Alkalemia can be classified as mild (pH 7.45–7.50), moderate (pH 7.50–7.55), or severe (pH 7.55).147,148 Metabolic alkalosis involves a generation stage during which the concentration of alkali within the body increases and a maintenance stage during which the kidneys fail to compensate for this change.148 In most situations, when volume and potassium are normalized, metabolic alkalosis self-corrects Metabolic alkalosis is common in critically ill pediatric patients A study of children after cardiac surgery found that 72% of children younger than 12 months old developed metabolic alkalosis in contrast with 30% of those older than 12 months.148 Studies in adults suggest that metabolic alkalosis may be associated with increased risk of mortality.147 Metabolic alkalosis in patients with severe sepsis and trauma may be due to a number of factors—including fluid administration to address shock, hypotension, and acidosis—with large quantities of citrated blood or lactated Ringer solution given as well as the administration of bicarbonate itself (eBox 72.5).147 Other patients may present with preexisting metabolic alkalosis due to chronic diuretic use, excessive steroids, high-dose antacids, elevated GI fluid losses (emesis, suction, or chloride-rich diarrhea), and a posthypercapnic state.148 Alkalemia may lead to neuromuscular excitability due to decreased ionized calcium concentration and potassium shifts and can cause altered mental status, increased seizure activity, cardiac arrhythmias, decreased oxygen release to tissue from hemoglobin, and, in some instances, depression of ventilatory drive Metabolic alkalosis can be classified by response to therapy using serum chloride concentration as the variable.3,29 Often, the loss of Cl2 is temporary and can be treated with replacement; this type of metabolic alkalosis is known as chloride responsive Chloride-responsive metabolic alkalosis is the most frequently encountered metabolic alkalosis in the pediatric critical care unit and can also be the most severe.146–148 In other cases, hormonal mechanisms leading to an excess of mineralocorticoid activity directly produce ongoing losses of K1 and Cl2, or genetic renal tubular defects lead to abnormalities in electrolyte transport, mainly in chloride reabsorption In this setting, the Cl2 deficit can be offset only temporarily at best by Cl2 administration Therefore, this form of metabolic alkalosis is said to be chloride resistant (see eBox 72.5).146–148 The hallmark of this group of disorders is an increased urine Cl2 concentration, more than 20 mEq/L (usually 40 mEq/L).62,146,148 The etiology of metabolic alkalosis can often be ascertained from the history If there is no pertinent history, the most likely diagnoses are surreptitious vomiting or diuretic use, or a cause of mineralocorticoid excess Random urine chloride determination may useful: uCl2 less than 20 mEq/L is consistent with chlorideresponsive metabolic alkalosis; uCl2 greater than 20 mEq/L is 892.e1 • eBox 72.5 Causes of Metabolic Alkalosis in Critically Ill Patients Chloride-Responsive (Decreased Urine [Cl2])a Gastrointestinal losses of Cl2 • Gastric drainage or persisting vomiting • Chloride-wasting acute diarrheas Renal Losses of Cl2 and K1 • Diuretics (mainly acute use) • High dose of certain penicillin-derivative antibiotics • Posthypercapnia Chloride-Resistant (Increased Urine [Cl2])b Excess mineralocorticoid activity: ongoing losses of K1 and Cl2 • Primary and secondary hyperaldosteronism • Congenital adrenal hyperplasia (17a-hydroxylase or 11b-hydroxylase deficiency) • Cushing syndrome • Primary renin-secreting tumors • Steroid treatment Genetic renal tubular defects of electrolyte transport • Problem in chloride reabsorption • Bartter and Gitelman syndromes • Defective epithelial sodium channel (decreased sodium elimination) • Liddle syndrome Drug-induced hypokalemic alkalosis • Diuretics administered for prolonged time • High-dose glucocorticoids • Fludrocortisone • Aminoglycosides • Toxic effects of licorice (Glycyrrhiza glabra) • Ion exchange resin Excess cation (alkali) gain • Massive blood transfusion • Massive infusion of lactated Ringer solution • Parenteral hyperalimentation with excessive sodium acetate • Alkali ingestion/treatment and milk-alkali syndrome • Magnesium depletion Miscellaneous Group (Variable Urine [Cl2])b Hypoproteinemia Cystic fibrosis Congenital chloride diarrhea Salt-losing nephropathy a ,20 mEq/L, usually ,15 mEq/L .20 mEq/L, usually 40 mEq/L b CHAPTER 72 Acid-Base Disorders consistent with chloride-unresponsive metabolic alkalosis.146,148 Metabolic alkalosis is one of the few clinical settings in which urine chloride concentration is a more accurate estimate of volume status than urine [Na1].149 The most common clinical situation in the critical care setting is the intravenous administration of strong cations without strong anions, such as occurs with a massive blood transfusion In this case, sodium is administered predominantly with citrate (a weak anion) instead of chloride A similar mechanism of metabolic alkalosis occurs when the parenteral nutrition contains excess sodium acetate (another weak anion) and insufficient chloride to balance the sodium The excessive infusion of plasma volume expanders and sodium lactate (such as in lactated Ringer solution) can also cause metabolic alkalosis Treating Metabolic Alkalosis Regardless of the type of metabolic alkalosis, the first step is to attenuate or stop the process that generated the imbalance in the first place.147 As mortality is especially high when a pH in excess of 7.6 develops, intervention at a pH of 7.55 and greater is recommended.136,147 Up to 10% of the total bicarbonate filtered is reabsorbed or lost to urine in the distal renal tubule In most patients with metabolic alkalosis, extracellular fluid—together with chloride, potassium, and magnesium concentrations—is decreased As potassium, chloride, and magnesium concentrations limit bicarbonate excretion, their low concentrations will make metabolic alkalosis refractory to correction Treatment of metabolic alkalosis should focus on the restoration of circulating volume and electrolyte composition to allow renal excretion of bicarbonate and the correction of alkalosis.147 Respiratory Acid-Base Derangements Although the pathology that results in respiratory acid-base abnormalities depends on the clinical situation, respiratory acidbase derangements always have the same mechanism: alveolar ventilation is altered (either increased or decreased) out of proportion to CO2 production Normal CO2 production by the body is robust: about 220 mL/min or about 317 L/day in a 70-kg adult, which is equivalent to 15,000 mmol of carbonic acid per day, 30 times that handled by the kidneys and GI tract.29 CO2 is produced through cellular metabolism or HCO32 is produced through metabolic acids Paco2 levels of 35 to 45 mm Hg at sea level are maintained by a match of alveolar minute ventilation to CO2 production This central control creates a responsive system that allows adjustment of Pao2 to compensate for metabolic alterations in pH in predictable patterns (see eTable 72.1 and eBox 72.2).29 Pulmonary ventilation is adjusted by the brainstem’s respiratory center in response to changes in Paco2 and pH Respiratory drive can also be influenced by other neural (anxiety, wakefulness) and nonneural factors (e.g., exercise, muscle strength) and can be altered in pathologic situations (cystic fibrosis, asthma, and congenital central hypoventilation syndrome).150 When this normal respiratory balance is disrupted, Paco2 deviates from normal and respiratory acid-base disturbances can occur Respiratory acidosis is caused by CO2 retention and hypercapnia (Paco2 elevation), while respiratory alkalosis results from hyperventilation, leading to a drop in Paco2 Buffers in the body result in a metabolic response to alterations in CO2, with the response depending on the degree and chronicity of the alteration in CO2 The initial response to Paco2 change is almost instantaneous, 893 leading to adequate compensation within 30 minutes If the alteration in Paco2 is sustained for more than hours, mechanisms within the kidney induce changes in bicarbonate concentration, reaching maximal impact within to days These renal effects lead to a new steady state for the pH.22,51 Respiratory Acidosis Respiratory acidosis results when CO2 elimination by the lungs is not sufficient to match CO2 production by the tissues, with an increase in Paco2 to a new equilibrium.29,151 The increase in Paco2 immediately increases both the hydrogen ion and bicarbonate concentrations in blood (see Eq 72.6).15,18,21 If the Paco2 remains increased, compensatory mechanisms are activated to restore [H1] toward normal When Pco2 acutely rises above 70 mmHg, loss of consciousness and seizures can be seen due to the decrease of intracellular pH.152 However, in patients with ARDS, hypercapnic acidosis may provide beneficial effects on pulmonary function through complex interactions with reactive oxygen species, alveolar-capillary barrier, and the immune system.68 Primarily, compensation is accomplished by removal of Cl2 from the plasma space Because movement of Cl2 into the tissues or red blood cells results in a drop of intracellular pH, Cl2 must be removed from the body to achieve a lasting effect on pH The kidneys play a key role in Cl2 removal by using ammonium as a cation for the excretion of Cl2 without losing Na1 or K.21,61 Thus, when kidney function is intact, Cl2 is eliminated in the urine After a few days, blood pH returns to near 7.35 Compensation results in an increased pH for any degree of hypercarbia According to the Henderson-Hasselbalch equation (see Eqs 72.7 and 72.8), the increased pH will result in an increased HCO32 concentration for a given Pco2.24 Acute respiratory acidosis develops as a consequence of the impaired function of one or more of the respiratory “compartments” that are essential to ventilatory function: central nervous system; neuronal, muscular (skeletal, including the diaphragm); and lung parenchyma (airway and alveoli; eTable 72.3) Conditions that cause the failure of the lungs to eliminate CO2 can also be grouped by anatomic area in which the abnormality occurs.71,151,153 The most common causes of acute CO2 retention in critical illness are airway and parenchymal lung disease It is important to note that acute CO2 retention can also produce primary hypoxemia, which poses the principal threat to life While there are numerous pathophysiologic mechanisms and many clinical examples, two account for the majority of cases of respiratory acidosis in critical illness The first is “pure” hypoventilation due to brainstem, neuromuscular dysfunction, or restrictive lung disease In this situation, the lungs fail to exchange CO2 and oxygen, resulting in a fall in Pao2 and a proportional rise in Paco2 In the second and more common situation, alveolar hypoventilation results from an imbalance between perfusion and hypoventilation in damaged lung (i.e., ventilation-perfusion [V/Q] mismatch) In this case, a fall in Pao2 often precedes hypercapnia When hypercapnia finally develops, the reduction in Pao2 is proportionally greater than the rise in Paco2.29 Chronic respiratory acidosis occurs typically in the setting of chronic pulmonary disease, whether it be from parenchymal abnormalities (e.g., bronchopulmonary dysplasia), altered chest wall mechanics (chest congenital deformities, kyphoscoliosis), upper 893.e1 eTABLE Etiology of Respiratory Acid-Base 72.3 Derangements Respiratory Acidosis (Increased Paco)2 Central Nervous System Depression Severe head trauma Cerebral edema Metabolic diseases Infectious diseases, sedation Pharmacologic effect of drugs Neural (Peripheral), Muscular, and Skeletal Structures Electrolyte Disturbances Hypophosphatemia Hypokalemia Specific Diseases Myasthenia gravis Guillain-Barré syndrome Spinal cord injury Muscular dystrophy Other Ventilatory Restriction Skeletal dysplasias Rib fractures and flail chest Intraabdominal hypertension from ascites, closure of congenital abdominal wall defects, etc Lungs (Airway and Alveoli) Respiratory Obstructive Disease, Either Acute or Chronic Croup Asthma Bronchiolitis Bronchopulmonary dysplasia Alveolar Injury Pneumonia Acute lung injury Acute respiratory distress syndrome Cardiogenic pulmonary edema Respiratory Alkalosis (Decreased Paco)2 Hypoxemia High altitudes Pulmonary disease Pulmonary Disorders Pneumonia, Interstitial pneumonitis Fibrosis Edema Pulmonary embolism Vascular disease Bronchial asthma Pneumothorax Cardiovascular Disorders Congestive heart failure Hypotension Metabolic Disorders Acidosis (diabetic, renal, or lactic) Hepatic failure Central Nervous System Disorders Psychogenic or anxiety-induced hyperventilation Central nervous system infection Central nervous system tumors Drugs Salicylates Methylxanthines b-Adrenergic agonists Progesterone Miscellaneous Fever Sepsis Pain Pregnancy ... compensation within 30 minutes If the alteration in Paco2 is sustained for more than hours, mechanisms within the kidney induce changes in bicarbonate concentration, reaching maximal impact within to... transport, mainly in chloride reabsorption In this setting, the Cl2 deficit can be offset only temporarily at best by Cl2 administration Therefore, this form of metabolic alkalosis is said to be... stage during which the concentration of alkali within the body increases and a maintenance stage during which the kidneys fail to compensate for this change.148 In most situations, when volume