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Physiologic Consequences and Bodily Adaptations to Hyper- and Hypocapnia
PhysiologicConsequencesand Bodily Adaptationsto Hyper- and Hypocapnia* Asglmar Rastegar, M.D.
and Samuel 0. Th er, A1.D.t
Dr. Rastegar
his article reviews the mechanisms by which man compensates for hypo- and hypercapnia and presents the extent of the expected responses to acute and chronic changes in Pco2. Primary respiratory acid-base disturbances and the compensatory mechanisms for dealing with those disturbances have been well described; however, the question of how much compensation is enough has been more difficult to answer. The answer to that question is critical since more than one primary acid-base disturbance may exist in the same patient at the same time. When such a “mixed disturbance” exists, the patient’s acid-base status will reflect the contribution of all primary disturbances. The presence of a mixed disturbance is best appreciated on the basis of the clinical history and physical findings. However, there will be circumstances when the presence of a mixed disturbance ‘ill only be suspected from the evaluation of blood gases and serum electrolytes. For example, if it is possible to predict the response to hypo- or hypercapnia, observation of an excessive or inadequate response vill alert the physician to the presence of a mixed disturbance. Confidence bands defining the adequacy of compensation for hypo. and hyper. capnia have been constructed. The use and limitations of these confidence bands in defining mixed disturbances and predicting complications of therapv will be mentioned in this paper and discussed in detail by Dr. McCurdy (this issue). Mechani. ms for the Regulation of Hydrogen Ion Concentration Man is able to maintain a fairly stable extracellular hydrogen ion concentration (pH 7.4). This vital capability depends upon a multicomponent buffering system which prevents marked changes in From the Renal and Electrolyte Section, Department of Medicine, University of Pennsylvania School of Medicine. Postclcwtoral Renal Fellow. t.Associate Professor of Medicine. Reprint req,,evts Dr. Thfer, Department of .Vedkine, 3400 Spruce Street, Philadel;,hki 19104
extracellular pH. The characteristics of buffer solutions will be defined first as a basis for understanding of the total body response to changes in CO2 tensions resulting from variations in alveolar ventilation. Buffers A physiologic buffer solution is the solution of a weak acid and its salt. By de nition, it resists marked changes in H’ ion concentration following the addition of moderate amounts of acid or base. An important characteristic of any buffer system is the dissociation constant (Ka) of its acid. Ka is (H-)(A-) defined as: Ka Strong acids tend to have higher Ka’s than weak acids. From this simple equation one can derive the following equation which defines the relationship between H- ion concentration and components of the buffer solution: pH
=
A-(base) pKa + Log HA (acid)
where pH and pKa are by definition -Log F!’ and -Log Ka respectively. This is the well known Henderson-Hasselbalch equation. This equation has several important implications. First, the pKa of any acid can be de ned as the pH at which the acid is half ionized because at this pH the ratio of A/HA is unity and the log of one is zero. Second, when this ratio is unity, addition of a given amount of base or acid will cause less change in the ratio (and, therefore, pH) than if this ratio is not unity. #{149} Therefore, any buffer solution will be most effective at a pH close to its pka. Buffering capacity will also depend on the absolute concentration of the components of the buffering system. The body contains many buffer systems including plasma proteins, cellular proteins, hemoglobin, bicarbonate carbonic add, etc. The Henderson-Hasseihaich equation can he written for each buffer See appendix.
28S
HYPER- AND HYPOCARNIA pair separately, but changes in W ion concentration in the intact organisms will reflect a change in all buffer systems. Components of Cellular and Extracellular Fluid Buffers Proteins plasma and cellular proteins, including hemoglobin, are important buffers due to availability of titratable groups within these molecules. The buffering capacity oi hemoglobin is almost entirely due to the imidazole groups of histidine (pKa close to 7). Plasma proteins have several titratable groups with a wide range of piCa’s. A number of these pKa’s fall within the physiologic pH range and account for the buffer capacity of these proteins. Hemoglobin by virtue of a more favorable apparent pKa and higher concentration is approximately six times as effective as are plasma proteins over the physiologic pH range. For example, in one liter of blood containing 150 grams of hemoglobin and 38.5 grams of plasma protein, hemoglobin can buffer 27.5 mEq of H’ ion, whereas plasma protein can only buffer 4.25 mEq when pH is titrated from 7.5 to 6.5.1 Other tissue proteins and organic phosphate complexes including bone and cartilage are also involved in regulation and defense of extracellular H’ ion concentration. Bicarbonate carbonic acid system. There are two characteristics of this system which make it the most important buffer system in the body: a) this is quantitatively the most abundant buffer system of the extracellular fluid; b) the pKa of this system is 6.1. Therefore, at the normal extracellular p1-I of 7.4, it is theoretically far from an ideal buffer. The discussion of buffers in the preceding section was based on a closed system in which the components of the buffer varied dependently. The bicarbonate carbonic acid system is an open system. The bicarbonate concentration is regulated primarily by the kidney while carbonic acid is in equilibrium with the CO2 tension and therefore is regulated h the lung. In subsequent discussion we will deal with circumstances in which the primary alteration is in the carbonic acid component. Now we will examine the means by which the bicarbonate component is regulated. Regulation the Plasma Bicarbonate Concentration by the Kidnetj Extracellelar bicarbonate concentration is primarily regulated by the kidney. Bicarbonate is freely filtered at the glomerulus and is about 90 percent reabsorhed in the proximal tubule. Bicarbonate reabsorption accompanies active H ion secretion: each time an H’ ion is produced for
29S secretion, a bicarbonate ion is produced for return to the plasma. The bicarbonate which escapes reabsorption in the proximal tubule is reabsorbed in the distal tubule by a similar mechanism (Fig la). The urine is normally essentially free of bicarbonate. Under normal circumstances the kidney reab. sorbs more than 4,000 mEq of bicarbonate daily. However, in order to maintain normal acid-base balance, the kidney must also be able to generate approximately 60 to 80 mEq of new bicarbonate daily. The newly generated bicarbonate replaces the bicarbonate used daily to buffer non.volatile acids produced by the diet. This is accomplished by excretion of 60-80 mEq of H ion by the kidney as ammonium ions (NH ) and titratable acids. The buffering of secreted H ions by ammonia (NH ) or other buffers (primarily phosphate) allows for the excretion of large quantities of H’ ion without lowering urine pH below 4.5 which is the lowest urinary pH attainable by the normal kidney (Fig ib, ic). If it is necessary to excrete more than 60-80 mEq of H’ ions per day, the kidney is able to increase the excretion of ammonium ions amid, to a lesser Cdl
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bonate by formation of tiftatable
CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
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RASTEGARAND THIER
extent, titratable acids. Ammonia is produced by the deamination of glutamine and, to a lesser extent, of other amino acids. The processes by which ammonia production is increased require the induction of enzymes. Though ammonia production is quantitatively the most important process by which H ion is secreted in response to acidosis, there is a lag of two to three days before ammonia excretion becomes maximally effective. In normal man with a serum bicarbonate of 24-26 mEqI L, all filtered bicarbonate is reabsorbed. If the serum bicarbonate concentration is increased by infusion of bicarbonate, the maximum tubular reabsorptive capacity for bicarbonate (Tm bicarbonate) is exceeded and all excess bicarbonate (normally that amount above 26 mEq/ L) appears in the urine. Several factors control the maximum tubular reabsorption of bicarbonate. These factors are often interrelated; however, for the sake of clarity, they will be discussed separately: a) Extracellular volume: The kidney regulates extracellular volume by controlling sodium reabsorption. Sodium is primarily reabsorbed in the proximal tubule along with chloride and bicarbonate. Chloride reabsorption is thought to be passive while bicarbonate reabsorption is coupled to active H’ ion secretion. Contraction of extracellular volume is associated with an increase in Tm bicarbonate while expansion of the extracellular volume tends to depress bicarbonate reabsorption. The increase or decrease in Tm bicarbonate is probably secondary to parallel changes in sodium reabsorption in the proximal tubule. b) Pkzsina CO2 letel: There is a direct linear relationship between plasma CO2 tension (Pco2) and renal bicarbonate reabsorption. This relationship is independent of extracellular pH.2 Therefore, during hypercapnia the Tm bicarbonate is increased, allowing for a gradual increase in serum bicarbonate; and conversely, during hypocapnia the Tm bicarbonate is decreased, resulting in bicarbonate excretion in the urine and a decrease in serum bicarbonate. This important relationship can best be explained by changes in intracellular pH. Pco readily crosses all cell barriers. A rise in Pco2 increases the carbonic acid concentration of renal tubular cells making more F!- ion available for secretion into the tubular lumen. As discussed above, this process of increased H ion secretion results in an increased bicarbonate reabsorption. c) Plasma chloride concentration: Chloride is the major anion reabsorbed with Na’ in the proximal tubule. In hvpochloremia due to chloride depletion, Tm bicarbonate is increased so that bicarbonate is actively reabsorbed in a larger proportion with Na’ in an attempt to maintain
extracellular fluid volume. This fact max’ play an important role in prolonging the recovery phase of chronic hypercapnia in which the patient is hypochioremic. As long as there is a stimulus to retain sodium and hypochloremia persists, the patient will be unable to excrete excess biocarbonate. d) Body k stores: An inverse relationship exists between Tin bicarbonate and total body K- stores. Potassium depletion is associated with an increase, and K loading with a decrease, in bicarbonate reabsorp. tion. The mechanisms by which K alters the Tm bicarbonate is the subject of some controversy and is not yet well defined. e) Steroids: The role of steroids in regulation of bicarbonate is far from clear. Steroid administration is associated with an increase in serum bicarbonate, and patients with an endogenous increase of mineralocorticoids tend to have metabolic alkalosis. Although this phenomenon may be secondary to K* depletion associated with steroid administration or hypermineralocorticoidism, a direct role of steroids is not ruled out. Defense of H’ Ion Concentration in Acute Hypcrcapnia and Hypocapnki It is clear that in order to defend the H ion concentration in the face of changing serum carbon dioxide tension, the body must be able to vary serum bicarbonate appropriately. The cellular buffers play the primary role in the response to acute changes in carbonic acid concentration.3 Though the bicarbonate carbonic acid buffer system plays a key role in the defense against metabolic acidosis and alkalosis, and though this system is important in the response to chronic respiratory aeid.base disturbance, it is not critical in acute respiratory disturbance. Acute changes in Pco2 are buffered primarily by cellular buffers (97 percent of the buffering of acute respiratory acidosis and 99 percent of the buffering of acute respiratory alkalo. sis occurs by cellular mechanisms). Increase in Pco. increases the carbonic acid concentration and therefore W ion activity. The F!’ ion thus created enters the cell in exchange for Na’ and K’, and is buffered by cellular proteins leaving a bicarbonate ion in the extracellular fluid.
CO2+ H20 H2CO3 H+ HCOremains inextracellular fluid Buffered byproteins f-H (Na’+ K’) intracellular
This cellular buffering accounts for approximately half of the acute increase in serum bicarbonate. At the same time, some CO2 enters the red blood cell (RBC) where it is hydrated in the presence of RBC carbonic anhydrase forming carbonic acid which is dissociated, releasing H ion and bicar-
CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
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HYPER- AND HYPOCAPNIA bonate:
I
CO2
H’ ion is then buffered
40
Cl- Extracellular
HCO
Fluid
by hemoglobin, and bicarbonate enters extracellular fluid in exchange for Cl. This accounts for approximately 30 percent of the acute increase in plasma bicarbonate. Plasma proteins are poor buffers and contribute minimally. In man the magnitude of the increase in bicarbonate concentration is small, amounting to less than 5 mEq as the Pco2 increases acutely from 40 to 8Omm Hg.5 During acute hypocapnia the reverse situation occurs, resulting in the release of H ion from intracellular buffers and the exchange of Ci- and bicarbonate in the opposite direction across RBC membrane. These processes result in a decrease in extnicellular bicarbonate concentration which usually amounts to a reduction of 7 to 8 mEq/L as the Pco2 is reduced from 40 to 15 mm Hg.6 Acute steady State studies in dogs kept in environmental chambers show that at each Pc level over the range of 30-130 mm Hg the serum bicarbonate level responds rapidly, reaching a plateau in approximately one hour.4 A similar response has been documented in man over a more limited range of 40-80 mm Hg Pco2 in approximately ten minutes.5 Serum bicarbonate response to increasing hvpercapnia is curvilinear with smaller increments at higher Pco2 levels. The change in H’ ion concentration per change in Pco2, however, is linear (Fig 2a,b). The . H’/ Pm is the slope of this curve and was found to be 0.77 n molefL per mm Hg at all levels of Pco2. Therefore, in acute hypercapnia the defense of W ion concentration is constant over a wide range of Pco2. This defense is, however, incomplete since H’ ion concentration is never returned tO baseline level.-5 In studies of acute hypocapnia in man6 steady state is achieved in approximately ten minutes at each Pco2 level over the range of 15.40 mm Hg. As in the studies of acute hypercapnia, H ion concentration varies directly with Pco2 and HI Pco2 is 0.74 n mole/L per mm Hg change in Pco . Therefore, the slope of this curve is similar to that during acute hypercapnia (Fig 3). In summary, from studies of acute hypo- and hypcrcapnia it can be seen that in normal man there is a linear response of hydrogen ion concen. tration over the range of Pco from 15-80 mm Hg (0.74-0.77 n mole W/mm Hg Pco ). Over this
.
44
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Fa JnE 2A (upper). Steady-state relationship between plasma bicarbonate concentration and Pco2 and ZB (lower). It ion concentration and Pc.2 during acute hypercapnia (dashed lines) and chronic hypereapnia (solid lines) in dog. The formula de nes the relationship between H’ ion concentration amid Pco in chronic hypereapnia. Reproduced by permission of the poblishers and authors J Clin Invest 44:291.301. 1965.
same range of Pco2 the bicarbonate response, which occurs within ten minutes, is curvilinear falling off at the highest Pco2 levels. Despite the rapidity of the bicarbonate response to variations in Pcim, the magnitude of this response is quite limited. In man increasing Pco2 from 40 to 80 mm Hg increases serum bicarbonate from 24 mEq/L to only 27 mEq/L. Studies in the dog over the range of Pco2 from 30 to 130 mm Hg are remarkably similar to those in man. This similarity has been used to extrapolate to man the data derived from dogs at levels of Pco2 not safely attainable in man. Defense of W Ion Concentration in Chronic Hypercapnia and Hypocapnia The increase in the serum bicarbonate level during acute hypercapnia is almost exclusively due to buffering by already available buffers. If hvpercapnia continues, this buffering capacity will be exhausted rapidly. Therefore, during chronic hy-
CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
32S
RASTEGARAND THIER 110
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Ficunt 3. Combined significance band for acute hypocapnia and acute hypercapnia in man. The significance band for H ion concentration is in the upper section of the figure and for bicarbonate concentration in the lower portion. Reproduced by permission of the publisher and authors, New Eng J Med 280:117-123, 1969.
percapnia the body must increase excretion of H ion and increase bicarbonate production and reabsorption by the kidney to compensate for a decreased CO2 excretion through the lung. Chronic stable hypercapnia has been studied by Schwartz and his colleagues 8 utilizing an environmental chamber. Dogs were exposed to CO2 levels between 35 to 135 mm Hg until chronic steady state was achieved and total body titration was then determined. During the first 24 hours of exposure, there was a rapid increase in plasma bicarbonate concentration which was not associated with an increase in urinary H’ ion excretion and therefore was secondary to H’ ion buffering by cellular and extracellular buffers. This initial rapid rise accounted for 50 percent of the total increase during steady state chronic hypercapnia. This steady state was achieved over the next three to six days and the serum bicarbonate level continued to rise steadily and finally reached a new stable level. This latter increase was associated with an increase in urinary H’ ion excretion in the form of urinary ammonium. In fact the increase in urinary H’ ion excretion during this period was adequate to account for the total increase in plasma bicarbonate; therefore, during this phase the kidney was able to replenish the cellular and extracellular buffers used during the acute phase of adjustment. As indicated above. in the discussion of mechanism of H’ ion homeostasis, the elevation of serum Pco2 is associated with an increase th H’ ion excretion by the kidney and thus with the addition of newly gen-
crated bicarbonate to extracellular fluid. At the same time, the elevated Pco2 level raises the Tm for bicarbonate and enables the kidney to maintain the bicarbonate concentration at a new higher level. Despite these mechanisms, the defense of extracellular pH is incomplete, just as it was in acute hypercapnia. W ion concentration increases in a linear fashion as a function of Pco2. but the slope of the curve for chronic hypercapnia is only 0.32 n mole/L per mm Hg rise in Pco2 level compared to 0.74 n mole/L per mm Hg rise in Pco2 in acute studies. The serum bicarbonate concentration still increases in a curvilinear fashion, but the steady state bicarbonate concentration for a given level of chronic Pco2 elevation is significantly greater than in acute studies (Fig 2a.b). Similar studies cannot be carried out in man for obvious reasons. Most reported studies in patients with chronic hypercapnia are difficult to interpret since other independent metabolic and respiratory disturbances were not completely ruled out. However, the data obtained by Brackett and his colleagues9 and Engle and his colleagues1#{176} are important, since in their patients studied during steady state hypercapnia other metabolic or respiratory problems were excluded. Qualitatively the response of man to chronic hypercapnia is similar to that in the dog, with a linear relationship between Pco2 and H’ ion concentration and curvilinear relationship between Pco2 and bicarbonate concentrations. The slopes (. H’/Pcm) obtained were different in the two studies (0.24 vs 0.126) and may reflect the patient populations studied. It should he emphasized that chronic hypercapnic man is not able to fully compensate for an increase in Pco2. and his defense of extracellular pH falls short of a complete return of H’ ion concentration to the baseline (Fig 4b). Of special interest is the effect of acute changes in Pco2 superimposed on chronic stable hypereap. nia. Goldstein et al” studied the effect of acute hypercapnia in dogs adapted to six different levels of chronic hypercapnia. They found that the ability of the animal to prevent marked changes in H’ ion concentration in response to superimposed acute hypercapnia increases as a direct function of the level of underlying hypercapnia. In other words, dogs with higher levels of chronic hypercapnia were better equipped to defend pH against acute elevations of Pco2. The authors point out that this is not due to a greater contribution of intracellular and extracellular buffers. Part of this interesting observation can be explained mathematically by examining the Henderson-Hassclhalch equation. The pH is a function of the HCOa/ Pco ratio. If the HCOa
CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
HYPER- AND HYPOCAPNIA
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F e.urn 4a (upper). Steady-state relationship between H ion concentratIon and Pro-, in acute hypercapnia and 4b (lower), chronic hypercapnia in man. Note that H- ion concentration increases as a direct function of Pcoo in both situations; however, the rate of increase is significantly greater in acute hypercapnia compared to chronic hypercapnia. Figure 4a from New Eng J Med 272:6-12, 1965, Figure 4b from New Eng J Med 280:124-130, 1969, by permission of the authors and publisher.
concentration is greater to start with (as a response to chronic hypercapnia), it takes a greater change in Pco acutely to cause a given change in pH. Bole of liripoxemia Most of our present understanding of the control of extracellular pH during changes in Pco2 is the result of studies in which changes in Pcoz were not associated with an appropriate change in Po2 level. Clinically, most patients with acute and chronic hvpercapnia are hypoxemic as well. Therefore the role of hypoxemia in the body’s adjustment to Pco2 changes has important clinical signifleance. The renal response to chronic hypercapnia in dogs with Po of 45-56 mm Hg is similar to the response in dogs with normal Po2)2 Therefore, moderate hypoxemia does not interfere with normal response to chronic hvpercapnia. However, if Po2 decreases below 40 mm Hg, there is a significant decrease in plasma bicarbonate associated with a marked increase in plasma lactic acid level. This is due to marked tissue hypoxia)3 Studies on chronic hvpocapnia are difficult to
perform. In general, as discussed above, a decrease in serum carbon dioxide tension is associated with a decrease in Tm bicarbonate. Studies in acdimatization to high altitude show that initial plasma bicarbonate concentration decreases rapidly, probably secondary to cellular buffering. Then there is a second more gradual decrease in plasma bicarbonate concentration associated with stabilization of pH still at a significantly higher level than baseline.14 Tm bicarbonate measured in natives living at high altitude is significantly decreased compared to measurements in other subjects at sea level)5 There are no careful studies at different levels of stable hypocapnia, and the only data used in constructing significance bands have been generated by calculating the expected bicarbonate response for each level of Pcoz assuming complete compensation to normal pH)6 So far we have been discussing the in vivo total body titration curves for Pco2. This is clearly different from whole blood titration curves in vitro, where a tube of blood is equilibrated with a known Pco2 and the buffering capacity of blood is measured. Figure 5 shows whole blood and acute whole body titration curves over similar Pco2 ranges. As can be seen, the whole blood titration with CO2 in eitro produces a greater increase in the plasma bicarbonate. This would suggest that during acute hypercapnia the cellular contribution of bicarbonate is insufficient to raise the bicarbonate level of the interstitial fluid to the same extent that the buffers of whole blood elevate the plasma concentration, and as a result, there is a loss of some of the bicarbonate generated by the blood buffers into the interstitial space by equilibration. 34
32-
I
30 WL
\w
oY
24
20 40
90
90
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Ficuns 5. Comparison of carbon whole blood and whole body. The are significantly different (p.(O.Ol) of 70 mm Hg and above. (From 1964 by permission of the authors
CF-lEST,VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
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dioxide titration cone for bicarbonate concentrations at carbon dioxide tension 3 Clin Invest 43:777-786, and publisher.)
RASTEGARAND THIER
34$ Thus, the in vitro blood titration studies may yield information which varies significantly from the actual in vivo responses. Since the therapy of acid base disorders is the correction of abnormal physiology, the physician should utilize physiologic data whenever possible and avoid isolated nonphysiologic measurements. To manage the patient with acute or chronic hyper- or hypocapnia, it is useful to take into account confidence bands defining the expected response of H ion concentration and bicarbonate concentration to alterations in Pco2. Confidence bands, as illustrated in Figure 3, deane the range of response expected at the 95 percent probability level. The use of the confidence bands provides the physician with a powerful tool for evaluating acid-base disturbances if he keeps several points in mind: 1. The confidence bands have been generated with the assumption that altered Pcoz is the only abnormality. 2. If the patient s response falls outside the confidence band, there is a high likelihood that he has at least a second independent primary acid base disturbance, that is, there is a mixed disturbance. 3. If the patient’s response falls within the confidence band, he may still have a mixed disturbance with the sum of his primary disturbances leading to the picture of an apparent normal compensation. An evaluation of the clinical history and physical findings will be critical in anticipating this difficulty. 4. In treating the patient with a primary or mixed disturbance, it is critical that the physician understand the basic compensatory mechanisms which are operating. With the correction of the primary disturbance, the prior metabolic compensation may persist and appear as a new primary disturbance. For example, with rapid correction of respiratory acidosis, an apparent primary metabolic alkalosis may emerge. APPENDIX
lfKaisdeflnedas Then H-
(H )(A-) (HA)
=
By taking log of both sides we will have: log (H) = log Ka + log (HA) log (A-) Now multiply both sides by -1: -log (H ) = -log Ka - log (HA) + log (A-) -log (H’) = pH and log Ka = pKa by definition. Therefore: pH = pKa log (HA) + log (A) or: pH = pKa + log (A-) (HA) -
-
-
For example, let us compare the effect of addi-
tion of 10 mEq of strong acid to the buffer system when
HA
(therefore unity) and when
=
A-
90
HA = 10 (Or 9). In the first circumstance addition of 10 mEq of strong acid will change A1 HA ratio from unity to 40/60 or 0.66 (a 30 percent decrease), while in the second circumstance the ratio will change to 80/20 or 4 (approximating a 60 percent decrease). REFERENCES 1 Pitts R: Physiology of the Kidney and Body Fluids. Chicago, Year Book Medical Publishers, 1968 2 Relman AS, Etsteo B, Schwartz VB: The regulation of renal bicarbonate reabsorption by plasma carbon dioxide tensiofl. 3 Clin Invest 32:972-978, 1953 3 Ciebiseb C. Berger L, Pitts H: The extrarenal response to acute acid base dishirhanc-es of respiratory origin. 3 Clin Invest 34:231-245, 1955 4 Cohen 33, Brackett NC, Schwath WB: The nature of carlx,n dioxide titration curve in the normal dog. 3 din Invest 43:777-786, 1964 5 Brackett NC, Jr. Cohen JJ, Schwartz WB: Carbon dioxide titration in man. New Eng J Med 272:6-12, 1965 6 Arbus CS. Herbert LA, Levesque PR, et al: Characterization and clinical application of the ‘significant hand” for acute respirators alkalosis. New Eng 3 Med 280:117123, 1969 7 Polas A, Havnie CD. I-lays RM, et al: Effect of chronic hypercapnia on electrolyte and acid base equilibrium. 1. Adaptation. J Clin Invest 40:1223-1237, 1961 8 Sch vartz \VB, Brackett NC, Cohen JJ The response of extracellular hydrogen ion concentration ti, graded degree of chronic hypercapnia: The physiologic limit of the defense of H. 3 Clin Invest 4-4:291-301. 196.5 9 Brackett NC. Wingo CF. \turan 0, Ct al. Acid base response to chronic hypercapnia in nun. New Eng J Nied 280:124-130, 1989 10 Engel K, Dell RB, Rahill WJ, et al: Quantitative dix. placement of acid base equilibrium in chronic respiratory acidosis. J Appl l’hy iol 24:288-295. 1968 11 Goldstein \ID, Gennari FJ, Schwartz WB: Influence of graded degree of chronic hypercapnia on the acute carbon dioxide titration curve. J Clin Invest 50:208-216, 1971 12 Sapir DC, Levine DZ. Schwartz WB: The effect of hypoxeniia on electrolyte and acid base equilibririm: An exaniination of norrnocapneic hvpoxeniia and of the influence of hypoxeinia on the adaptation to chn,nie hvpercapnia. I Clin Invest 46:369-377. 1967 13 Mitho*-fer JC, Karetzky MS. Porter \VF: The in eico carbon dioxide titration cone in the presence of hypoxia. Resp Physiol 4:1.5-23, 1968 14 Forwand SA, Lanclowne M, Follanshee JN, et a!: Effect of acetazolamide on acute mountain sickness .N ew Eng Med 279:839-845, 1968 15 Monge C, Lozano R, Careel#{233}n A: Renal excretion of bicarbonate in high altitude natives and in natives with chronic mountain sickness. 3 Clin Invest 43:2303, 1964 16 Winters RW, Engel K, Dell RB-Acid Base Physiology in Medicine. A Self Instruction Program. The London Co. (West Lake, Ohio) and Radiometer A/S (Copenhagen, Denmark) 1967, p 258
CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
and Samuel 0. Th er, A1.D.t
Dr. Rastegar
his article reviews the mechanisms by which man compensates for hypo- and hypercapnia and presents the extent of the expected responses to acute and chronic changes in Pco2. Primary respiratory acid-base disturbances and the compensatory mechanisms for dealing with those disturbances have been well described; however, the question of how much compensation is enough has been more difficult to answer. The answer to that question is critical since more than one primary acid-base disturbance may exist in the same patient at the same time. When such a “mixed disturbance” exists, the patient’s acid-base status will reflect the contribution of all primary disturbances. The presence of a mixed disturbance is best appreciated on the basis of the clinical history and physical findings. However, there will be circumstances when the presence of a mixed disturbance ‘ill only be suspected from the evaluation of blood gases and serum electrolytes. For example, if it is possible to predict the response to hypo- or hypercapnia, observation of an excessive or inadequate response vill alert the physician to the presence of a mixed disturbance. Confidence bands defining the adequacy of compensation for hypo. and hyper. capnia have been constructed. The use and limitations of these confidence bands in defining mixed disturbances and predicting complications of therapv will be mentioned in this paper and discussed in detail by Dr. McCurdy (this issue). Mechani. ms for the Regulation of Hydrogen Ion Concentration Man is able to maintain a fairly stable extracellular hydrogen ion concentration (pH 7.4). This vital capability depends upon a multicomponent buffering system which prevents marked changes in From the Renal and Electrolyte Section, Department of Medicine, University of Pennsylvania School of Medicine. Postclcwtoral Renal Fellow. t.Associate Professor of Medicine. Reprint req,,evts Dr. Thfer, Department of .Vedkine, 3400 Spruce Street, Philadel;,hki 19104
extracellular pH. The characteristics of buffer solutions will be defined first as a basis for understanding of the total body response to changes in CO2 tensions resulting from variations in alveolar ventilation. Buffers A physiologic buffer solution is the solution of a weak acid and its salt. By de nition, it resists marked changes in H’ ion concentration following the addition of moderate amounts of acid or base. An important characteristic of any buffer system is the dissociation constant (Ka) of its acid. Ka is (H-)(A-) defined as: Ka Strong acids tend to have higher Ka’s than weak acids. From this simple equation one can derive the following equation which defines the relationship between H- ion concentration and components of the buffer solution: pH
=
A-(base) pKa + Log HA (acid)
where pH and pKa are by definition -Log F!’ and -Log Ka respectively. This is the well known Henderson-Hasselbalch equation. This equation has several important implications. First, the pKa of any acid can be de ned as the pH at which the acid is half ionized because at this pH the ratio of A/HA is unity and the log of one is zero. Second, when this ratio is unity, addition of a given amount of base or acid will cause less change in the ratio (and, therefore, pH) than if this ratio is not unity. #{149} Therefore, any buffer solution will be most effective at a pH close to its pka. Buffering capacity will also depend on the absolute concentration of the components of the buffering system. The body contains many buffer systems including plasma proteins, cellular proteins, hemoglobin, bicarbonate carbonic add, etc. The Henderson-Hasseihaich equation can he written for each buffer See appendix.
28S
HYPER- AND HYPOCARNIA pair separately, but changes in W ion concentration in the intact organisms will reflect a change in all buffer systems. Components of Cellular and Extracellular Fluid Buffers Proteins plasma and cellular proteins, including hemoglobin, are important buffers due to availability of titratable groups within these molecules. The buffering capacity oi hemoglobin is almost entirely due to the imidazole groups of histidine (pKa close to 7). Plasma proteins have several titratable groups with a wide range of piCa’s. A number of these pKa’s fall within the physiologic pH range and account for the buffer capacity of these proteins. Hemoglobin by virtue of a more favorable apparent pKa and higher concentration is approximately six times as effective as are plasma proteins over the physiologic pH range. For example, in one liter of blood containing 150 grams of hemoglobin and 38.5 grams of plasma protein, hemoglobin can buffer 27.5 mEq of H’ ion, whereas plasma protein can only buffer 4.25 mEq when pH is titrated from 7.5 to 6.5.1 Other tissue proteins and organic phosphate complexes including bone and cartilage are also involved in regulation and defense of extracellular H’ ion concentration. Bicarbonate carbonic acid system. There are two characteristics of this system which make it the most important buffer system in the body: a) this is quantitatively the most abundant buffer system of the extracellular fluid; b) the pKa of this system is 6.1. Therefore, at the normal extracellular p1-I of 7.4, it is theoretically far from an ideal buffer. The discussion of buffers in the preceding section was based on a closed system in which the components of the buffer varied dependently. The bicarbonate carbonic acid system is an open system. The bicarbonate concentration is regulated primarily by the kidney while carbonic acid is in equilibrium with the CO2 tension and therefore is regulated h the lung. In subsequent discussion we will deal with circumstances in which the primary alteration is in the carbonic acid component. Now we will examine the means by which the bicarbonate component is regulated. Regulation the Plasma Bicarbonate Concentration by the Kidnetj Extracellelar bicarbonate concentration is primarily regulated by the kidney. Bicarbonate is freely filtered at the glomerulus and is about 90 percent reabsorhed in the proximal tubule. Bicarbonate reabsorption accompanies active H ion secretion: each time an H’ ion is produced for
29S secretion, a bicarbonate ion is produced for return to the plasma. The bicarbonate which escapes reabsorption in the proximal tubule is reabsorbed in the distal tubule by a similar mechanism (Fig la). The urine is normally essentially free of bicarbonate. Under normal circumstances the kidney reab. sorbs more than 4,000 mEq of bicarbonate daily. However, in order to maintain normal acid-base balance, the kidney must also be able to generate approximately 60 to 80 mEq of new bicarbonate daily. The newly generated bicarbonate replaces the bicarbonate used daily to buffer non.volatile acids produced by the diet. This is accomplished by excretion of 60-80 mEq of H ion by the kidney as ammonium ions (NH ) and titratable acids. The buffering of secreted H ions by ammonia (NH ) or other buffers (primarily phosphate) allows for the excretion of large quantities of H’ ion without lowering urine pH below 4.5 which is the lowest urinary pH attainable by the normal kidney (Fig ib, ic). If it is necessary to excrete more than 60-80 mEq of H’ ions per day, the kidney is able to increase the excretion of ammonium ions amid, to a lesser Cdl
-.
N.’
RecI.inted
Hco;
.
LOInCIt
N.’
.__
*
*
HCO
uco -
Co.
b
o
N ’.HCO
-
r
N’
N ’ * [HCO
r
N wHCOi 1
Fzcu.ir
Cdl
lood
_____________ N.H,PO Cdi
mood .‘
#{149}
HCo;*H
-
u ..
-
[Hco
1. Mechanisms
#{149}
Hco*HJ ,
involved
I
in regulations
of plasma
bicarbonate concentration by the kidney. a) mechanismsfor bicarbonate
reclamation; b and c) generation of new bicaracid and ammomum ion, Reproduced by permission of the publisher, Clinical Pharmacology, Basic Principles in Therapeutics. Nielmon KL and Mo,-relli HF Eds. New York, The Macmillan C0., 1972.
bonate by formation of tiftatable
CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
30S
RASTEGARAND THIER
extent, titratable acids. Ammonia is produced by the deamination of glutamine and, to a lesser extent, of other amino acids. The processes by which ammonia production is increased require the induction of enzymes. Though ammonia production is quantitatively the most important process by which H ion is secreted in response to acidosis, there is a lag of two to three days before ammonia excretion becomes maximally effective. In normal man with a serum bicarbonate of 24-26 mEqI L, all filtered bicarbonate is reabsorbed. If the serum bicarbonate concentration is increased by infusion of bicarbonate, the maximum tubular reabsorptive capacity for bicarbonate (Tm bicarbonate) is exceeded and all excess bicarbonate (normally that amount above 26 mEq/ L) appears in the urine. Several factors control the maximum tubular reabsorption of bicarbonate. These factors are often interrelated; however, for the sake of clarity, they will be discussed separately: a) Extracellular volume: The kidney regulates extracellular volume by controlling sodium reabsorption. Sodium is primarily reabsorbed in the proximal tubule along with chloride and bicarbonate. Chloride reabsorption is thought to be passive while bicarbonate reabsorption is coupled to active H’ ion secretion. Contraction of extracellular volume is associated with an increase in Tm bicarbonate while expansion of the extracellular volume tends to depress bicarbonate reabsorption. The increase or decrease in Tm bicarbonate is probably secondary to parallel changes in sodium reabsorption in the proximal tubule. b) Pkzsina CO2 letel: There is a direct linear relationship between plasma CO2 tension (Pco2) and renal bicarbonate reabsorption. This relationship is independent of extracellular pH.2 Therefore, during hypercapnia the Tm bicarbonate is increased, allowing for a gradual increase in serum bicarbonate; and conversely, during hypocapnia the Tm bicarbonate is decreased, resulting in bicarbonate excretion in the urine and a decrease in serum bicarbonate. This important relationship can best be explained by changes in intracellular pH. Pco readily crosses all cell barriers. A rise in Pco2 increases the carbonic acid concentration of renal tubular cells making more F!- ion available for secretion into the tubular lumen. As discussed above, this process of increased H ion secretion results in an increased bicarbonate reabsorption. c) Plasma chloride concentration: Chloride is the major anion reabsorbed with Na’ in the proximal tubule. In hvpochloremia due to chloride depletion, Tm bicarbonate is increased so that bicarbonate is actively reabsorbed in a larger proportion with Na’ in an attempt to maintain
extracellular fluid volume. This fact max’ play an important role in prolonging the recovery phase of chronic hypercapnia in which the patient is hypochioremic. As long as there is a stimulus to retain sodium and hypochloremia persists, the patient will be unable to excrete excess biocarbonate. d) Body k stores: An inverse relationship exists between Tin bicarbonate and total body K- stores. Potassium depletion is associated with an increase, and K loading with a decrease, in bicarbonate reabsorp. tion. The mechanisms by which K alters the Tm bicarbonate is the subject of some controversy and is not yet well defined. e) Steroids: The role of steroids in regulation of bicarbonate is far from clear. Steroid administration is associated with an increase in serum bicarbonate, and patients with an endogenous increase of mineralocorticoids tend to have metabolic alkalosis. Although this phenomenon may be secondary to K* depletion associated with steroid administration or hypermineralocorticoidism, a direct role of steroids is not ruled out. Defense of H’ Ion Concentration in Acute Hypcrcapnia and Hypocapnki It is clear that in order to defend the H ion concentration in the face of changing serum carbon dioxide tension, the body must be able to vary serum bicarbonate appropriately. The cellular buffers play the primary role in the response to acute changes in carbonic acid concentration.3 Though the bicarbonate carbonic acid buffer system plays a key role in the defense against metabolic acidosis and alkalosis, and though this system is important in the response to chronic respiratory aeid.base disturbance, it is not critical in acute respiratory disturbance. Acute changes in Pco2 are buffered primarily by cellular buffers (97 percent of the buffering of acute respiratory acidosis and 99 percent of the buffering of acute respiratory alkalo. sis occurs by cellular mechanisms). Increase in Pco. increases the carbonic acid concentration and therefore W ion activity. The F!’ ion thus created enters the cell in exchange for Na’ and K’, and is buffered by cellular proteins leaving a bicarbonate ion in the extracellular fluid.
CO2+ H20 H2CO3 H+ HCOremains inextracellular fluid Buffered byproteins f-H (Na’+ K’) intracellular
This cellular buffering accounts for approximately half of the acute increase in serum bicarbonate. At the same time, some CO2 enters the red blood cell (RBC) where it is hydrated in the presence of RBC carbonic anhydrase forming carbonic acid which is dissociated, releasing H ion and bicar-
CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
31 S
HYPER- AND HYPOCAPNIA bonate:
I
CO2
H’ ion is then buffered
40
Cl- Extracellular
HCO
Fluid
by hemoglobin, and bicarbonate enters extracellular fluid in exchange for Cl. This accounts for approximately 30 percent of the acute increase in plasma bicarbonate. Plasma proteins are poor buffers and contribute minimally. In man the magnitude of the increase in bicarbonate concentration is small, amounting to less than 5 mEq as the Pco2 increases acutely from 40 to 8Omm Hg.5 During acute hypocapnia the reverse situation occurs, resulting in the release of H ion from intracellular buffers and the exchange of Ci- and bicarbonate in the opposite direction across RBC membrane. These processes result in a decrease in extnicellular bicarbonate concentration which usually amounts to a reduction of 7 to 8 mEq/L as the Pco2 is reduced from 40 to 15 mm Hg.6 Acute steady State studies in dogs kept in environmental chambers show that at each Pc level over the range of 30-130 mm Hg the serum bicarbonate level responds rapidly, reaching a plateau in approximately one hour.4 A similar response has been documented in man over a more limited range of 40-80 mm Hg Pco2 in approximately ten minutes.5 Serum bicarbonate response to increasing hvpercapnia is curvilinear with smaller increments at higher Pco2 levels. The change in H’ ion concentration per change in Pco2, however, is linear (Fig 2a,b). The . H’/ Pm is the slope of this curve and was found to be 0.77 n molefL per mm Hg at all levels of Pco2. Therefore, in acute hypercapnia the defense of W ion concentration is constant over a wide range of Pco2. This defense is, however, incomplete since H’ ion concentration is never returned tO baseline level.-5 In studies of acute hypocapnia in man6 steady state is achieved in approximately ten minutes at each Pco2 level over the range of 15.40 mm Hg. As in the studies of acute hypercapnia, H ion concentration varies directly with Pco2 and HI Pco2 is 0.74 n mole/L per mm Hg change in Pco . Therefore, the slope of this curve is similar to that during acute hypercapnia (Fig 3). In summary, from studies of acute hypo- and hypcrcapnia it can be seen that in normal man there is a linear response of hydrogen ion concen. tration over the range of Pco from 15-80 mm Hg (0.74-0.77 n mole W/mm Hg Pco ). Over this
.
44
CO2+ H2O H2CO3 H’ ± HCO3Intracellular (RBC)
mEq/L
36 32
-
28
-
24
-
20
-
20
40
I
t
100
p O, ,nv Hg
120
140
100.
7D0
e .
7.10
pH
Z30
:.1.40
as2pC4#269
40.
40
pCO. H,
I
7.!O
140
Fa JnE 2A (upper). Steady-state relationship between plasma bicarbonate concentration and Pco2 and ZB (lower). It ion concentration and Pc.2 during acute hypercapnia (dashed lines) and chronic hypereapnia (solid lines) in dog. The formula de nes the relationship between H’ ion concentration amid Pco in chronic hypereapnia. Reproduced by permission of the poblishers and authors J Clin Invest 44:291.301. 1965.
same range of Pco2 the bicarbonate response, which occurs within ten minutes, is curvilinear falling off at the highest Pco2 levels. Despite the rapidity of the bicarbonate response to variations in Pcim, the magnitude of this response is quite limited. In man increasing Pco2 from 40 to 80 mm Hg increases serum bicarbonate from 24 mEq/L to only 27 mEq/L. Studies in the dog over the range of Pco2 from 30 to 130 mm Hg are remarkably similar to those in man. This similarity has been used to extrapolate to man the data derived from dogs at levels of Pco2 not safely attainable in man. Defense of W Ion Concentration in Chronic Hypercapnia and Hypocapnia The increase in the serum bicarbonate level during acute hypercapnia is almost exclusively due to buffering by already available buffers. If hvpercapnia continues, this buffering capacity will be exhausted rapidly. Therefore, during chronic hy-
CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
32S
RASTEGARAND THIER 110
80
H 6#{176} 40
720 730
nM/I.
750 770
20
pH
30
HC025 mEq/L
20 Is
10
30
50
70
FOCO,,u miHg
Ficunt 3. Combined significance band for acute hypocapnia and acute hypercapnia in man. The significance band for H ion concentration is in the upper section of the figure and for bicarbonate concentration in the lower portion. Reproduced by permission of the publisher and authors, New Eng J Med 280:117-123, 1969.
percapnia the body must increase excretion of H ion and increase bicarbonate production and reabsorption by the kidney to compensate for a decreased CO2 excretion through the lung. Chronic stable hypercapnia has been studied by Schwartz and his colleagues 8 utilizing an environmental chamber. Dogs were exposed to CO2 levels between 35 to 135 mm Hg until chronic steady state was achieved and total body titration was then determined. During the first 24 hours of exposure, there was a rapid increase in plasma bicarbonate concentration which was not associated with an increase in urinary H’ ion excretion and therefore was secondary to H’ ion buffering by cellular and extracellular buffers. This initial rapid rise accounted for 50 percent of the total increase during steady state chronic hypercapnia. This steady state was achieved over the next three to six days and the serum bicarbonate level continued to rise steadily and finally reached a new stable level. This latter increase was associated with an increase in urinary H’ ion excretion in the form of urinary ammonium. In fact the increase in urinary H’ ion excretion during this period was adequate to account for the total increase in plasma bicarbonate; therefore, during this phase the kidney was able to replenish the cellular and extracellular buffers used during the acute phase of adjustment. As indicated above. in the discussion of mechanism of H’ ion homeostasis, the elevation of serum Pco2 is associated with an increase th H’ ion excretion by the kidney and thus with the addition of newly gen-
crated bicarbonate to extracellular fluid. At the same time, the elevated Pco2 level raises the Tm for bicarbonate and enables the kidney to maintain the bicarbonate concentration at a new higher level. Despite these mechanisms, the defense of extracellular pH is incomplete, just as it was in acute hypercapnia. W ion concentration increases in a linear fashion as a function of Pco2. but the slope of the curve for chronic hypercapnia is only 0.32 n mole/L per mm Hg rise in Pco2 level compared to 0.74 n mole/L per mm Hg rise in Pco2 in acute studies. The serum bicarbonate concentration still increases in a curvilinear fashion, but the steady state bicarbonate concentration for a given level of chronic Pco2 elevation is significantly greater than in acute studies (Fig 2a.b). Similar studies cannot be carried out in man for obvious reasons. Most reported studies in patients with chronic hypercapnia are difficult to interpret since other independent metabolic and respiratory disturbances were not completely ruled out. However, the data obtained by Brackett and his colleagues9 and Engle and his colleagues1#{176} are important, since in their patients studied during steady state hypercapnia other metabolic or respiratory problems were excluded. Qualitatively the response of man to chronic hypercapnia is similar to that in the dog, with a linear relationship between Pco2 and H’ ion concentration and curvilinear relationship between Pco2 and bicarbonate concentrations. The slopes (. H’/Pcm) obtained were different in the two studies (0.24 vs 0.126) and may reflect the patient populations studied. It should he emphasized that chronic hypercapnic man is not able to fully compensate for an increase in Pco2. and his defense of extracellular pH falls short of a complete return of H’ ion concentration to the baseline (Fig 4b). Of special interest is the effect of acute changes in Pco2 superimposed on chronic stable hypereap. nia. Goldstein et al” studied the effect of acute hypercapnia in dogs adapted to six different levels of chronic hypercapnia. They found that the ability of the animal to prevent marked changes in H’ ion concentration in response to superimposed acute hypercapnia increases as a direct function of the level of underlying hypercapnia. In other words, dogs with higher levels of chronic hypercapnia were better equipped to defend pH against acute elevations of Pco2. The authors point out that this is not due to a greater contribution of intracellular and extracellular buffers. Part of this interesting observation can be explained mathematically by examining the Henderson-Hassclhalch equation. The pH is a function of the HCOa/ Pco ratio. If the HCOa
CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
HYPER- AND HYPOCAPNIA
33$
Sc
7.10
H70 nM/L
6050-
730
4030
-
40
50
70
pCO., n.n I4
80
90
90
70 0$.
0
PM 730
40 30
740 0#{149}#{149}#{149}#{149}0 pc..,n.z 24
-
I 40
50
60
I 70
90
I 90
I 00
PlO
F e.urn 4a (upper). Steady-state relationship between H ion concentratIon and Pro-, in acute hypercapnia and 4b (lower), chronic hypercapnia in man. Note that H- ion concentration increases as a direct function of Pcoo in both situations; however, the rate of increase is significantly greater in acute hypercapnia compared to chronic hypercapnia. Figure 4a from New Eng J Med 272:6-12, 1965, Figure 4b from New Eng J Med 280:124-130, 1969, by permission of the authors and publisher.
concentration is greater to start with (as a response to chronic hypercapnia), it takes a greater change in Pco acutely to cause a given change in pH. Bole of liripoxemia Most of our present understanding of the control of extracellular pH during changes in Pco2 is the result of studies in which changes in Pcoz were not associated with an appropriate change in Po2 level. Clinically, most patients with acute and chronic hvpercapnia are hypoxemic as well. Therefore the role of hypoxemia in the body’s adjustment to Pco2 changes has important clinical signifleance. The renal response to chronic hypercapnia in dogs with Po of 45-56 mm Hg is similar to the response in dogs with normal Po2)2 Therefore, moderate hypoxemia does not interfere with normal response to chronic hvpercapnia. However, if Po2 decreases below 40 mm Hg, there is a significant decrease in plasma bicarbonate associated with a marked increase in plasma lactic acid level. This is due to marked tissue hypoxia)3 Studies on chronic hvpocapnia are difficult to
perform. In general, as discussed above, a decrease in serum carbon dioxide tension is associated with a decrease in Tm bicarbonate. Studies in acdimatization to high altitude show that initial plasma bicarbonate concentration decreases rapidly, probably secondary to cellular buffering. Then there is a second more gradual decrease in plasma bicarbonate concentration associated with stabilization of pH still at a significantly higher level than baseline.14 Tm bicarbonate measured in natives living at high altitude is significantly decreased compared to measurements in other subjects at sea level)5 There are no careful studies at different levels of stable hypocapnia, and the only data used in constructing significance bands have been generated by calculating the expected bicarbonate response for each level of Pcoz assuming complete compensation to normal pH)6 So far we have been discussing the in vivo total body titration curves for Pco2. This is clearly different from whole blood titration curves in vitro, where a tube of blood is equilibrated with a known Pco2 and the buffering capacity of blood is measured. Figure 5 shows whole blood and acute whole body titration curves over similar Pco2 ranges. As can be seen, the whole blood titration with CO2 in eitro produces a greater increase in the plasma bicarbonate. This would suggest that during acute hypercapnia the cellular contribution of bicarbonate is insufficient to raise the bicarbonate level of the interstitial fluid to the same extent that the buffers of whole blood elevate the plasma concentration, and as a result, there is a loss of some of the bicarbonate generated by the blood buffers into the interstitial space by equilibration. 34
32-
I
30 WL
\w
oY
24
20 40
90
90
p O Hu
Ficuns 5. Comparison of carbon whole blood and whole body. The are significantly different (p.(O.Ol) of 70 mm Hg and above. (From 1964 by permission of the authors
CF-lEST,VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT
90
dioxide titration cone for bicarbonate concentrations at carbon dioxide tension 3 Clin Invest 43:777-786, and publisher.)
RASTEGARAND THIER
34$ Thus, the in vitro blood titration studies may yield information which varies significantly from the actual in vivo responses. Since the therapy of acid base disorders is the correction of abnormal physiology, the physician should utilize physiologic data whenever possible and avoid isolated nonphysiologic measurements. To manage the patient with acute or chronic hyper- or hypocapnia, it is useful to take into account confidence bands defining the expected response of H ion concentration and bicarbonate concentration to alterations in Pco2. Confidence bands, as illustrated in Figure 3, deane the range of response expected at the 95 percent probability level. The use of the confidence bands provides the physician with a powerful tool for evaluating acid-base disturbances if he keeps several points in mind: 1. The confidence bands have been generated with the assumption that altered Pcoz is the only abnormality. 2. If the patient s response falls outside the confidence band, there is a high likelihood that he has at least a second independent primary acid base disturbance, that is, there is a mixed disturbance. 3. If the patient’s response falls within the confidence band, he may still have a mixed disturbance with the sum of his primary disturbances leading to the picture of an apparent normal compensation. An evaluation of the clinical history and physical findings will be critical in anticipating this difficulty. 4. In treating the patient with a primary or mixed disturbance, it is critical that the physician understand the basic compensatory mechanisms which are operating. With the correction of the primary disturbance, the prior metabolic compensation may persist and appear as a new primary disturbance. For example, with rapid correction of respiratory acidosis, an apparent primary metabolic alkalosis may emerge. APPENDIX
lfKaisdeflnedas Then H-
(H )(A-) (HA)
=
By taking log of both sides we will have: log (H) = log Ka + log (HA) log (A-) Now multiply both sides by -1: -log (H ) = -log Ka - log (HA) + log (A-) -log (H’) = pH and log Ka = pKa by definition. Therefore: pH = pKa log (HA) + log (A) or: pH = pKa + log (A-) (HA) -
-
-
For example, let us compare the effect of addi-
tion of 10 mEq of strong acid to the buffer system when
HA
(therefore unity) and when
=
A-
90
HA = 10 (Or 9). In the first circumstance addition of 10 mEq of strong acid will change A1 HA ratio from unity to 40/60 or 0.66 (a 30 percent decrease), while in the second circumstance the ratio will change to 80/20 or 4 (approximating a 60 percent decrease). REFERENCES 1 Pitts R: Physiology of the Kidney and Body Fluids. Chicago, Year Book Medical Publishers, 1968 2 Relman AS, Etsteo B, Schwartz VB: The regulation of renal bicarbonate reabsorption by plasma carbon dioxide tensiofl. 3 Clin Invest 32:972-978, 1953 3 Ciebiseb C. Berger L, Pitts H: The extrarenal response to acute acid base dishirhanc-es of respiratory origin. 3 Clin Invest 34:231-245, 1955 4 Cohen 33, Brackett NC, Schwath WB: The nature of carlx,n dioxide titration curve in the normal dog. 3 din Invest 43:777-786, 1964 5 Brackett NC, Jr. Cohen JJ, Schwartz WB: Carbon dioxide titration in man. New Eng J Med 272:6-12, 1965 6 Arbus CS. Herbert LA, Levesque PR, et al: Characterization and clinical application of the ‘significant hand” for acute respirators alkalosis. New Eng 3 Med 280:117123, 1969 7 Polas A, Havnie CD. I-lays RM, et al: Effect of chronic hypercapnia on electrolyte and acid base equilibrium. 1. Adaptation. J Clin Invest 40:1223-1237, 1961 8 Sch vartz \VB, Brackett NC, Cohen JJ The response of extracellular hydrogen ion concentration ti, graded degree of chronic hypercapnia: The physiologic limit of the defense of H. 3 Clin Invest 4-4:291-301. 196.5 9 Brackett NC. Wingo CF. \turan 0, Ct al. Acid base response to chronic hypercapnia in nun. New Eng J Nied 280:124-130, 1989 10 Engel K, Dell RB, Rahill WJ, et al: Quantitative dix. placement of acid base equilibrium in chronic respiratory acidosis. J Appl l’hy iol 24:288-295. 1968 11 Goldstein \ID, Gennari FJ, Schwartz WB: Influence of graded degree of chronic hypercapnia on the acute carbon dioxide titration curve. J Clin Invest 50:208-216, 1971 12 Sapir DC, Levine DZ. Schwartz WB: The effect of hypoxeniia on electrolyte and acid base equilibririm: An exaniination of norrnocapneic hvpoxeniia and of the influence of hypoxeinia on the adaptation to chn,nie hvpercapnia. I Clin Invest 46:369-377. 1967 13 Mitho*-fer JC, Karetzky MS. Porter \VF: The in eico carbon dioxide titration cone in the presence of hypoxia. Resp Physiol 4:1.5-23, 1968 14 Forwand SA, Lanclowne M, Follanshee JN, et a!: Effect of acetazolamide on acute mountain sickness .N ew Eng Med 279:839-845, 1968 15 Monge C, Lozano R, Careel#{233}n A: Renal excretion of bicarbonate in high altitude natives and in natives with chronic mountain sickness. 3 Clin Invest 43:2303, 1964 16 Winters RW, Engel K, Dell RB-Acid Base Physiology in Medicine. A Self Instruction Program. The London Co. (West Lake, Ohio) and Radiometer A/S (Copenhagen, Denmark) 1967, p 258
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