A certain mystique exists in medicine today regarding the subject of acid-base balance. Research conducted among several test group physicians at teaching hospitals revealed that arterial blood gas (ABG) interpretations are correct only 40% of the time. More distressingly, management error occurred 33% of the time because of incorrect interpretation. As many as 90% of intensive care patients have an acid-base disorder; thus, understanding acid-base balance is an essential component in the clinical management of critically ill patients. NORMAL ACID-BASE METABOLISM In general, the body attempts to maintain the pH of its fluids between 7.35 and 7.45, a pH that is associated with a H+ ion concentration of 40â•¯nmol/L. To put this concentration in perspective, the Na or K concentration in the body, which is expressed in mmol/L, is one million times more concentrated than the simple hydrogen ion H+. Despite this minute concentration, H+ is carefully regulated, as it has far-reaching effects and reacts readily with proteins and enzymes, which significantly alters the rates of reactions for which they are responsible. Most of the daily acid production comes from the metabolism of fats and carbohydrates. This produces carbon dioxide that, when combined with water, produces carbonic acid, which is in equilibrium with hydrogen and bicarbonate: 1. CO2 + H2O = H2CO3 2. H2CO3 = H+ and HCO3 In addition, proteins and phosphates that are eaten contribute a small amount to this acid load. The body maintains acid-base homeostasis in a variety of ways, but an important mechanism is the direct buffering of H+ via intracellular and extracellular proteins, bone, and serum HCO3. The kidneys also play a major role, specifically compensating for acidosis through the absorption of HCO3 – in the proximal tubule and through H+ excretion in the distal tubule. By far, however, the most effective manner of maintenance of appropriate pH is through ventilation, with modulation of the elimination of CO2 production. This is immediately apparent on viewing the Henderson-Hasselbalch equation, which points out the importance of partial pressure of CO2 (pCO2) and HCO3 – as they relate to pH: pH HCO3 pCO = 6.10 + log( )/0.03 2 One can see that pH is inversely related to pCO2 and, of course, directly related to serum HCO3 –. Although normally minute ventilation is between 5 and 7â•¯L, this can be increased by a factor of 10, thereby eliminating even a significantly abnormal quantity of CO2 production through the lungs. Arterial Blood Gas Interpretation Most commonly, blood pH is measured with an arterial blood gas. In this type of analysis, the pH, pCO2, and partial pressure of oxygen (pO2) are directly measured. For the purposes of this chapter, a normal arterial blood gas has a pH of 7.40, a pCO2 of 40, and a pO2 of 100. For fluency in the discussion of acid-base issues, acidemia is the term used by convention when the pH is less than 7.4, and alkalemia is used when the pH is greater than 7.4 (e.g., the patient’s condition is acidemic in the former case and alkalemic in the latter). But the measured pH, whether normal, acidemic, or alkalemic, is invariably the result of two or more processes that raise or lower the H ion concentration (e.g., hyperventilation, which lowers the H concentration, and uremia, which raises it). These individual processes are referred to as alkaloses and acidoses; depending on which is dominant, the patient experiences alkalemia or acidemia. An unknown wag wrote that “human survival is a constant battle against the hydrogen ion,” which emphasizes the point that death is invariably preceded by an acidosis. But to the extent that the process is caught early, intervention and reversal of the acidosis may be possible, and thus, a life may be saved. The key lies in early recognition. What follows is a useful way to interpret a blood gas at the bedside, with the intent that the caregiver will have ample warning of an impending problem. To this end, the only two important values in a blood gas are the pH and the pCO2. One needs to know both to determine the acid-base status of a patient. pO2 has no relevance in this analysis. Hypoxia may be a cause of a metabolic acidosis, but knowledge of the patient’s pO2 does not help with determination of the presence or the degree of the acidosis (Figure 1). On the basis of the Henderson-Hasselbalch equation, if the pCO2 acutely drops 10â•¯mm Hg, the pH rises 0.08 units, and vice versa. This assumes that there is no metabolic component to the patient’s acidbase disorder. The serum bicarbonate concentration does change when the pCO2 changes, because a change in dissolved CO2 changes the HCO3 concentration, but the change is only minimal. (To be perfectly accurate, if the pCO2 changes 10â•¯mm Hg, the HCO3 concentration changes 2â•¯mEq/L, in the same direction.) Thus, if one assumes no metabolic component to the acid-base disturbance, when faced with the results of an ABG, immediately on looking at the pCO2, one can predict what the pH should be. The rule of thumb is that when the pCO2 drops 10â•¯mm Hg, the pH rises 0.08 units. However, if the measured pH is higher than that which was predicted based on the pCO2 alone, the patient has a metabolic alkalosis on top of the respiratory disturbance. If the pH is lower than what would have been predicted based on the pCO2 alone, the patient has a metabolic acidosis. One can take this analysis a step further and become more quantitative regarding the degree of the metabolic disturbance. The difference between the predicted pH, based on the pCO2 alone, and the measured pH (multiply the predicted and actual pH by 100 to work with a whole number) gives one a measure of the degree of the metabolic acidosis or alkalosis present. Furthermore, multiplication of that difference by 2/3 yields a variable called the base excess (if the pH was higher than predicted) or the base deficit (if the pH was lower than predicted). In reality, the base deficit quantifies the absolute deficit (or excess) of total body bicarbonate, expressed in mEq/L. In general, the bicarbonate space can be assumed to be roughly 1/3 the body weight. Consequently, a 90-kg person has a bicarbonate space of 30â•¯L. A base deficit of 6 in such a person represents a total body bicarbonate deficit of 180â•¯mEq (30â•¯L bicarbonate space × base deficit of 6). By following the base deficit, one can determine the effectiveness of one’s treatment of a metabolic disturbance (e.g., a lactic acidosis from cardiogenic shock). Successful therapy with improved cardiac output and oxygen delivery is associated with a decrease in anaerobic metabolism and a progressive amelioration of the base deficit. METABOLIC ACIDOSIS Metabolic acidosis is the most common acid-base disorder in medicine, a state characterized by excessive acid production (e.g., lactic acid), reduced acid excretion (e.g., renal failure), or the loss of whole body alkali (e.g., diarrhea). Many life-threatening conditions are associated with metabolic acidosis, thus raising the importance of its prompt diagnosis and treatment. A metabolic acidosis is diagnosed when the serum HCO3 concentration is less than 22â•¯mEq/L, which roughly corresponds to a base deficit of more than 2. To determine the cause of metabolic acidosis, first determine the presence or absence of an anion gap, which is the calculated difference between the serum cations and anions obtained at the same time that the arterial blood gas was drawn. In serum, the sum of the commonly measured cations (e.g., sodium) outnumber the anions (e.g., HCO3 and chloride), which is the “gap.” The normal anion gap is between 8 and 12â•¯mEq/L and is made up of unmeasured and therefore “hidden” anions. When these unmeasured gap anions are added to the Cl– and HCO3 –, the sum equals the Na+ concentration, in keeping with the fact that the body maintains electrical neutrality. In normal conditions, these unmeasured anions consist mainly of albumin, phosphate, and sulfate. In the intensive care unit (ICU), where albumin concentrations are frequently low, an appropriate correction should be taken into account. Albumin is negatively charged, and when its concentration diminishes, CL– and HCO3 – concentration increases to compensate, thus lowering the acceptable gap. Roughly, for every 1.0â•¯g/dL decrease in serum albumin below 4.4â•¯g/dL, the measured anion gap should decrease by 3â•¯mmol/L. Gap Acidosis A large anion gap indicates the loss of HCO3 ions without a concurrent increase in chloride. Electroneutrality is maintained by elevated levels of unmeasured anions, such as lactate, beta-hydroxybutyrate, acetoacetate, or abnormal quantities of PO4, and SO4, anions that do not normally make up the gap. A search for conditions that lead to these excess hidden anions and a widened gap should be undertaken (Box 1). Methanol or Ethylene Glycol Toxicity Both alcohols are toxic but are sweet and therefore are often ingested. Methanol is metabolized to formic acid, which inhibits oxidative phosphorylation-producing lactate, and ethylene glycol is converted to oxalic acid. In both cases, there is a widened osmolar gap (different from the anion gap) and an anion gap. Diabetic Ketoacidosis In uncontrolled diabetes, the increase in ketoacids is buffered by bicarbonate, diminishing its concentration, with a resultant gap acidosis. Once effective treatment with insulin has begun, the production of ketoacids ceases and the bicarbonate concentration rapidly normalizes. Propylene Glycol This substance is an additive for antifreeze, a solvent, and a moisturizer, among other uses. When ingested, it is converted to pyruvic acid, acetic acid, and then lactic acid, all of which cause an increased anion gap. Isoniazid Isoniazid (INH) is an antibiotic that is used in the treatment of Mycobacterium tuberculosis. In some cases, it can cause a significant diminution in gamma-aminobutyric acid, leading to seizures, and a lactic acidosis on that basis. Lactic Acidosis Although most commonly seen in hypoperfusion syndromes in which cells undergo anaerobic metabolism producing significant lactate, a lactic acidosis may also arise from defects in lactate clearance, pyruvate dehydrogenase, or thiamine deficiency. Renal Failure A drastic decrease in glomerular filtration leads to a decrease in the excretion of sulfates, phosphates, urate, and hippurate (all unmeasured anions), along with a decrease in HCO3 reabsorption. Ethylene Glycol As stated previously, this sweet alcohol, prone to abuse, leads to formation of the unmeasured anions, glycolate and oxalate, which cause a gap acidosis. Both are primary renal toxins. Rhabdomyolysis Crush injuries or other causes of myocyte cell death release organic acids into the blood stream, leading to an increase in unmeasured anions. Salicylate Aspirin overingestion initially causes a respiratory alkalosis with a compensatory metabolic acidosis. However, at high concentrations, salicylates inhibit key enzymes in the Kreb’s cycle, uncoupling oxidative phosphorylation and causing a lactic acidosis. A useful mnemonic used to recall the causes of a gap metabolic acidosis is MUDPILERS (see Box 1). In all acidoses, when a net retention of hydrogen ion occurs, the body activates three compensatory responses, namely: (1) buffering; (2) increased ventilation; and (3) increased renal absorption and regeneration of HCO3. In the face of a metabolic acidosis, the drop in pH immediately stimulates the ventilatory drive, enhancing CO2 elimination with a concomitant rise in the pH toward normal. Treatment of a Gap Acidosis Immediate recognition and treatment of a metabolic acidosis can be lifesaving. In all cases, the underlying cause must be addressed with simultaneous support of the patient. In the ICU, severe metabolic acidoses is frequently treated with bicarbonate. However, its use does not come without a price: fluid overload, hypernatremia, hypocalcemia, impairment of hemoglobin/oxygen dissociation, and an acute lowering of cerebrospinal fluid (CSF) pH, which can cause mental status changes. Nevertheless, although the etiology for the acidosis is being addressed, maintenance of pH above 7.3 with hyperventilation and bicarbonate administration provides a margin of safety. Interestingly, a low pH itself does not independently lead to the hemodynamic collapse seen in the acidemic, critically ill patient. In fact, there is a striking discordance between the clinical course and the outcome of acidemias caused by respiratory failure as opposed to those that are metabolic in origin. As an example, lactate may play
BOX 1:â•‡Anion gap metabolic acidosis M Methanol (osmol gap, >10) U Uremia D Diabetic ketoacidosis P Propylene glycol (radiator fluid and preservative in diazepam and lorazepam) I Isoniazid L Lactic acid (sepsis, ischemia, propofol, short gut) E Ethylene glycol (osmol gap, >10) R Rhabdomyolysis S Salicylates
a key role in circulatory collapse, apart from the associated increase in H+ concentration. Thus, although hemodynamic improvements are commonly observed after bicarbonate administration, given to buffer the acidosis, the truly pathologic molecule may not be addressed. Nongap Acidosis The causes of anion gap acidoses differ significantly from those of nongapped acidoses, most particularly in that none of the latter is primarily lethal. A nongap acidosis occurs when loss of HCO3 is completely compensated for by an increase in Cl– concentration and is perhaps better described as a hyperchloremic nongap acidosis. The two organs capable of contributing to this process are the gut and the kidney. A useful pneumonic for remembering its causes is FUSEDCARS (Box 2). Gastrointestinal loss of HCO3, as occurs in diarrhea, and renal losses, as seen in renal tubular acidoses, often part of longstanding diabetes, are typically seen in the ICU setting. When faced with a nongap hyperchloremic acidosis, the first step, therefore, is to determine whether the intestine or the kidney is the culprit. Urine pH is high or alkaline if the kidney is responsible but low if the intestine is the cause of bicarbonate loss. Physiologically, the normal kidney compensates for an acidosis both by reabsorbing bicarbonate in the proximal tubule and thick ascending limb, increasing proton secretion in the distal tubule, and by collecting duct and excreting protons as ammonium chloride (NH4Cl). This process causes the urine pH to be low (<5) and implicates the intestine as the cause. When the etiology is renal, the differential diagnosis can be narrowed down to a renal tubular acidosis, use of carbonic anhydrous inhibitors, spironolactone, early renal failure, or ureteral diversions. The loss of HCO3 and impairment of H+ secretion from the kidneys constitutes the renal tubular acidoses (RTA). With a proximal renal tubular acidosis, there is also a loss of HCO3 absorption proximally, as opposed to a distal renal tubular acidosis in which there is dysfunction of the distal tubule and an inability to secrete protons. Although the kidney and the intestine should be viewed as the primary causes, hyperchloremic acidosis is iatrogenically seen with the rapid administration of 0.9% NaCl resuscitation solution, a process that results in the loss of HCO3, fully replaced by Cl–. RESPIRATORY ACIDOSIS Respiratory acidosis (Box 3) occurs when ventilation fails to remove all of the CO2 produced by the body’s metabolism, with a resultant rise in pCO2 above 40. Causes include loss of pulmonary elasticity as seen in idiopathic pulmonary fibrosis or sarcoid and long-standing chronic obstructive pulmonary disease (COPD) with gradual inability to eliminate CO2. Both lead to a slow increase in CO2 compensated for by the kidneys, which increase bicarbonate reabsorption. However, an exacerbation of COPD and bronchiolar spasm as seen in an allergic reaction or asthma are acute causes of a respiratory acidosis frequently encountered in the surgical setting. But the most common cause is central nervous system (CNS) depression from narcotics; benzodiazepines; stroke, which can cause either hypoventilation or hyperventilation; and chest wall muscle weakness from residual muscular paralysis after surgery. Treatment In all situations, the aim of the provider is to facilitate ventilation. In the case of bronchospasm, bronchodilators with beta agonists, anticholinergics, or steroids may be appropriate. For muscular weakness or even CNS depression, noninvasive pressure ventilation with pressure support and continuous positive airway pressure may obviate the need for intubation. It is important to address the adequate reversal of residual effects of neuromuscular blockade, with the administration of neostigmine, or the effects of narcotics or benzodiazepines, which can be neutralized with naloxone or flumazinal. However, if the rise in pCO2 is poorly tolerated and associated with a change in mental status or hypoxia, then intubation and mechanical support are necessary. To a large degree, whenever a question exists regarding the effectiveness of noninvasive support, intubation is always appropriate. Hypoventilation is effectively treated with mechanical support, and given the ability to intubate atraumatically, allowing a patient to become hemodynamically compromised from hypoventilation, hypoxemia, and severe respiratory acidemia should almost never occur in the monitored setting.
BOX 2:â•‡ Nongapped acidoses F Fistula, pancreatic U Ureteroenterostomy S Saline administration E Endocrine (hyperparathyroidism) D Diarrhea C Carbonic anhydrase inhibitors A Ammonium chloride R Renal tubular acidosis S Spironolactone
BOX 3:â•‡ Respiratory acidosis CNS depressants (sedatives, CNS disease, obesity hypoventilation syndrome) Lung disease (COPD, bronchospasm) Kyphoscoliosis Guillain-Barré syndrome Myasthenia gravis CNS, Central nervous system; COPD, chronic obstructive pulmonary disease.
BOX 4:â•‡ Metabolic alkalosis Volume contraction (vomiting, overdiuresis, ascites) Hypokalemia Mechanical ventilation in a hypercapneic condition Alkali ingestion (bicarbonate) Excess glucocorticoids or mineralocorticoids
BOX 5:â•‡ Respiratory alkalosis Catastrophic CNS event (CNS hemorrhage) Drugs (salicylates, progesterone) Pregnancy (especially the third trimester) Decreased lung compliance (interstitial lung disease) Liver cirrhosis Anxiety CNS, Central nervous system.
METABOLIC ALKALOSES In the ICU setting, a metabolic alkalosis (Box 4) is almost always the result of upper gastrointestinal losses or diuretic therapy. To occur, however, the alkalosis must be to some degree associated with intravascular volume depletion or hypokalemia; if not, the kidney simply excretes the excess bicarbonate. Gastrointestinal Hydrogen Loss As pointed out in the section on metabolic acidosis, loss of lower gastrointestinal secretions, as in diarrhea, causes an acidosis because these fluids are high in bicarbonate concentration. However, gastric secretions are high in hydrogen concentration, and gastric suctioning or vomiting leads to its loss and a concomitant alkalosis. In general, gastric acid, on entering the duodenum, causes pancreatic bicarbonate secretion, and the event is pH neutral. However, gastric suctioning prevents the secreted H+ from reaching the duodenum, and consequently, no stimulation to pancreatic bicarbonate secretion occurs. Diuretic Therapy In the surgical setting, postoperative patients experience hyperaldosteronism, the result of stress-induced stimulation of the reninangiotensin system. In this setting, when loop diuretics are used, increased Na+ delivery to the distal tubule occurs. This increased Na delivery in the face of aldosterone leads to increased Na absorption in exchange for K+ and H+. The H+ loss is exacerbated by hypokalemia which invariably occurs in this situation. To a degree, a shift of intracellular K+ to the extracellular space to compensate, but to maintain electrical neutrality, H+ ion enters the cell. This increased H+ concentration in the distal tubular cell leads to its preferential secretion in exchange for Na+, exacerbating the resulting alkalosis. Similarly, any cause in an increased circulating mineralocorticoid can lead to an alkalosis, and it always is associated with hypokalemia, for the reasons stated previously. Contraction Alkalosis Significant losses of predominantly bicarbonate-free fluid cause a contraction alkalosis. This is most commonly seen in the edematous patient treated with diuretics who has a significant, rapid fluid loss. In this situation, loss of free water around a fixed quantity of bicarbonate leads to its increased concentration. Similarly, significant dehydration or sweating with free water and NaCl loss leads to a rise in bicarbonate concentration. But by far, in the hospital, diuretic therapy is the most common cause of this metabolic derangement. Hypercapneic Alkalosis Chronic hypercapnea and its associated respiratory acidosis lead to increased H+ secretion by the kidney. The ensuing rise in bicarbonate concentration can compensate to a large degree for the primary respiratory acidosis. However, if in this setting, the pCO2 is rapidly lowered, as might be the case with overzealous mechanical ventilation, the respiratory acidosis vanishes in the face of the ongoing metabolic alkalosis. This can be dangerous if the rise in pH is significant and sudden, as acute intracerebral alkalosis can lead to delirium, seizures, and even death. Therapy Most metabolic alkaloses are volume responsive. Adequate volume expansion inhibits the production of renin and decreases any hyperaldosterone effect that may be contributing. Furthermore, NaCl administration replenishes the Cl– ion, which is necessary for the adequate excretion of HCO3 – in the collecting duct of the kidney. Finally, as mentioned previously, K+ repletion is essential, or the kidney continue to excrete H+ in exchange for Na+ absorption, maintaining the alkalosis. Occasionally, acetazolamide is helpful to inhibit the carbonic anhydrase in the proximal tubular cells, preventing the absorption of bicarbonate in that portion of the kidney and allowing it to be excreted. However, this increases Na delivery to the distal tubule, which in the face of aldosterone activity leads to its resorption in exchange for K+. Profound hypokalemia can result if this ion is not aggressively supplemented. Finally, if hypokalemia is allowed to continue in the face of acetazolamide therapy, Na reabsorption in exchange for hydrogen maintains the alkalosis, despite the prevention of bicarbonate resorption proximally. RESPIRATORY ALKALOSIS As discussed in the beginning of this chapter, a fall in CO2 leads to a rise in pH. Clinically, this is the result of hyperventilation. Although frequently the result of anxiety or pain, the most important causes are primary CNS stimulation, hypoxemia, sepsis, and pulmonary embolus. In the critically ill, CNS stimulation can be the result of a stroke or an acute rise in intracranial pressure, hypoxemia from heart failure or an acute lung injury, or sepsis from a gram-negative organism. Pulmonary embolus causes hyperventilation from primary stimulation of lung receptors. An acute respiratory alkalosis, of course, can be the result of hyperventilation from overaggressive mechanical ventilation. Hyperventilation with its resultant alkalemia causes cerebral vasoconstriction, with a decrease in cerebral blood flow. Neurologic symptoms, such as dizziness, confusion, and paresthesias, classically numbness around the mouth, can result. This is in distinct contrast to a metabolic alkalosis, which rarely causes CNS changes, as the increase in serum bicarbonate concentration is reflected in the brain much more slowly because of the blood–brain barrier, and the pH change associated with a decrease in pCO2 occurs immediately (Box 5). Treatment Apart from overzealous ventilation, which is easily and immediately correctable, the clinical settings associated with respiratory alkalosis can be life threatening. Considering that stroke, brain tumor, sepsis, and pulmonary embolism are diagnoses that must be entertained, this acid-base disturbance should create a sense of urgency on the part of the provider to make a diagnosis and provide treatment. Attributing hyperventilation to anxiety, stress, or pain should be a diagnosis by default. SUGGESTED READINGS Adrogué HJ, Madias NE: Management of life-threatening acid-base disorders, N Engl J Med 338:26–34, 1998. Forsythe SM, Schmidt GA: Sodium bicarbonate for the treatment of lactic acidosis, Chest 117(1):260–267, 2000. Gluck SL: Acid-base, Lancet 352(9126):474–479, 1998.
One needs to know only the pH and the partial pressure of CO2 (pCO2) to determine the acid-base status of a patient; partial pressureof oxygen (pO2) has no relevance in this analysis.