mixedmetabolicandrespiratoryacid-base disturbances ... · disturbances vomiting ngsuction...

Dr. MeCurdy

35S

Mixed Metabolic and RespiratoryAcid-BaseDisturbances:Diagnosisand Treatment -

Donna Kern McCurdy, M.D.

patients with primary ventilatory disturbancesoften have associated with their respiratory

alkalosis or acidosis complicating metabolic acid-base disorders which profoundly affect their re-sponse to the respiratory disturbance. Physicianscaring for them must be able to recognize thesemixed disturbances if treatment is to be successful.Some day, computer terminals for diagnosis of acid-base problems will be standard equipment in mosthospitals,i but until such electronic consultation isreadily available, clinicians must rely on their ownability to analyze acid-base data correctly. Basic tocorrect analysis of mixed acid-base disturbances isan understanding of normal compensatory pro-cesses in the four simple acid-base disorders. Else-where in this issne, Rastegar and Thier havereviewed the normal physiologic responses to acuteand chronic hyper- and hypocapnia. This paperreviews the compensatory changes which - occur inmetabolic acid-base disturbances and tries to showhow these disorders affect the diagnosis and man-agement of patients with ventilatory abnormalities.

GENERAL PATrERNS OF COMPENSATORY PROCESSES

The Henderson-Hasselbalch equation states:

FJCO:� HCO�pHpK-l-log H2C03 orpH=pK+Iog .O3xPcoz

Since pK is a ccrnstant, what the equation reallysays is that p11 is determined not by the totalamount of HCOa or H�CO:� present, but the ratio ofbicarbonate to carbonic acid. In a simple acid-basedisturbance, the initial insult changes the normalconcentration of either the numerator (the metabol-ic component) or the denominator (the respiratorycomponent) of this ratio. Compensatory processes

�Assoeiate Professor of Medicine, Renal-Electrolyte Section,Dep-artint-nt of Medicine, University of PennsylvaniaSchool of Medicine, Philadelphia.

Reprint reqne.xtx� Dr McGordy, 3400 Sprnee Street, Phi1�-deIphk� 19104

are secondary reactions by buffers, lungs and kid-neys which return this ratio (and therefore pH)back toward normal. As discussed by Rastegar andThier, in respiratory acidosis, renal and buffermechanisms secondarily raise bicarbonate concen-tration, and in respiratory alkalosis they lowerbicarbonate concentration. But since patients withmetabolic acid-base disturbances have by definitiona primary defect in the regulation of bicarbonateconcentration, how can they compensate normallyfor a complicating primary respiratory disturbance?Similarly, hyperventilation is a major compensatorymechanism in metabolic acidosis, and hypoventila-tion occurs in metabolic alkalosis. Respiratory dis-turbances, therefore, prevent normal compensationfor metabolic disturbances. And so begin the prob-lems for the patient with combined respiratory andmetabolic acid-base disorders.

\Ve currently believe that the stimulus for com-pensation in a simple acid-base disturbance is thechange in pH produced by the initial shift in Pco2or HC03. If abnormal pH is the stimulus, normalcompensation should not “over-correct” pH. Itshould not even return pH completely to controlvalues.2 That does not mean that patients with asimple acid-base disturbance cannot have a normalpH. Since normal pH values occur over the range of7.35-7.45, a mild disturbance, once compensated,might return pH to the range of normal. In chronicrespiratory acidosis, for example, the likelihood ofcompensation returning pH to normal is inverselyproportional to the level of Pco7. At a Pco2 of 50mm Hg, 75 percent of patients might still have pHvalues in the normal range. At a Pco2 of 60 mm Hg,that likelihood would drop to 15 percent, and at aPcoa of 70 mm Hg, fewer than 1 percent of patientswould be expected to compensate well enough toreturn arterial pH even to low normal.3

From this, we can make two important general-izations which are helpful in recognizing whether or

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ACID-BASE MAP

PH

36S DONNA KERN MCCURDY

CHEST, VOL. 62, NO. 2, AUGUST 1972 SUPPLEMENT

not a given patient has a mixed acid-base distur-bance. First, the more significant the stress of aprimary acid base disorder, the less likely that pHwill be normal and the more likely that a normalpH indicates the presence of a mixed acid-basedisturbance. Second, a pH opposite to that predictedby the initial disturbance at a time when acid-basestatus is fairly stable makes a diagnosis of mixeddisturbance mandatory.

Goldberg and colleagues,’ in developing a com-puter program for diagnosis of clinical acid-basedisorders, have compiled the published informationon normal compensation in simple acid-base dis-orders and depicted them graphically in the acid-base map shown in Figure 1. Shaded areas encom-pass with 95 percent confidence the range of Pco2,pH and HCO3- you would expect to find in patientswho have only one acid-base disturbance. If apatient’s values fall outside these shaded areas, it isvery unlikely that the patient has just one acid-basedisturbance. If values fall inside the confidencebands for a simple acid-base disturbance, that factalone does not prove a simple disturbance but just

Table 1-A Syuemotie Approoeh so And.Bo�e Di.ignoth

I) Search the history for potential processes.

2) Are there acid-ba.se clues on physical examination?

3) In the routine electrolytes, what area) CO�bi Undetermined anione� K

4) Scan other laboratory data for acid-base clues.

5) Explain the pH, Pco� and H(’O,

that the data are compatible with one disturbance.How then do you make an acid-base diagnosis

with assurance if blood gases and the acid-basemap together can’t tell you for sure? The answer isthat you must interpret them in light of the clinicalpicture.

A Sysm��nc APPROACH m ACID-BASE DIAGNosIs

In teaching the diagnosis and treatment of clini-cal acid-base disturbances, we have tried to use asystematic approach which is complete enough toscreen all the possibilities but quick and easy

n�n�Fic.unz 1. Acid-base map to show the normal compensatory range of pH, Pco2 and HCOr insimple acid-base disorders. Values on the ordinate represent blood H± concentration (left) innanamnles/L or PH (right). Abscissa is Pco2 in mm Hg. Diagonal lines represent isopleths forblood HCO:j� concentration in mEq/L. Clear area in the c-enter of the graph is the range of nor-mal. See text for details and interpretation of plotting patient data. Graph taken from the work ofGoldberg and associate,.’


Table 2-Co.nn.on Causes of �mple Acid.BaseDisturbances

vomitingNG Suctionchloruretic diureticsalkali Rxglucocortieoid Rxmineralocorticoid excesssevere K depletionIV SO�, P0,Cl restriction

9ia a Na depleted patient

Resin�Lo�y Alk�ilozispsychogenic hyperventilationprimary CNS diseaseGram negative sepsissalicylate intoxicationpulmonary edemaast.hn�arestrictive lung diseasemechanical overventilationpneumoniahepatic failurehigh altitudesevere anemia

METABOLIC AND RESPIRATORYACID-BASE DISTURBANCES 37S


Me1�thoii�, A�,idosi,s Me�oboh,� Atko1o�i.sHyperehloremic

diarrheaacetazolainideNH,Cl, Arginine HCIureterosigmoidostomyinterstitial renal diseaserenal tubular acidosis

Increased undetermined aniongeneralized renal failurediabetic ketoacidosislactic aeidosismethanol intoxicationsalicylate intoxicationethylene glycol

intoxication

Respiratory A cidosisobstructive lung diseasechest wall diseasemechanical andervent.ilationCNS depressionsevere pulmonary edemastatus asthmatieusprimary hypoventilationpneumot horaxabdominal distention

enough to be useful at the bedside. The five basicsteps are outlined in Table 1.

Since simple acid-base disturbances are definedas disease processes which, if otherwise unopposed,would tend to change pH in the predicteddirection,4 the first step is to screen the history forpotential causes of those disorders. Table 2 lists thecommon causes of the four simple acid-base dis-turbances. Look not only for clinical diagnoses suchas renal disease or emphysema, but also for drugingestion, therapeutic maneuvers such as ventilatoryassistance or salt restriction, and so on. The historywill give you possible disturbances which can beevaluated in subsequent steps.

Second, are there any findings on physical exam-ination which might confirm a diagnosis suspectedin the history or suggest new Ones? Such findingsmight include cyanosis, characteristic changes ofobstructive lung disease on examination of thechest, hypotension, jaundice, high fever, or even anasogastric tube in place. A positive Trousseau’ssign may indicate alkalemia.

Third, examine the routine serum electrolytes andget all the information you can from them. Remem-ber that the serum COz content in mM/L is almostentirely bicarbonate, the contribution of H2CO,and dissolved CO2 being equal only to .03 x Pcoz inmm Fig. Thus, the serum CO2 tells you only ifHCO� is high, low or normal and not if Pco2 or pH

are abnormal.Next, calculate the undetermined anions by sub-

tracting the sum of CO2 and chloride from theserum sodium concentration. This undeterminedanion fraction (or anion gap or delta) is normallyless than 12-14 mEq/L. It comprises anionic pro-teins, phosphates, sulfates and anions of variousorganic acids. Minor elevations in undeterminedanion to 15 or 16 mEq/L are occasionally seen inrespiratory alkalosis, and of course, erroneous eleva-tion may occur if one of the three determinationsused to calculate it are in error. A true elevation inundetermined anion, however, always indicatesmetabolic acidosis. (The converse is not true sincesome causes of metabolic acidosis are hyper-chloremic with no increase in delta, Table 2). Thehigher the delta, the more one should suspectincreased production of some organic acid. Deltasabove 25 mEq/L are usually seen only in diabeticketoacidosis, methanol or ethylene glycol poisoning,salicylate intoxication and lactic acidosis.

The third point to note in the routine electrolytesis the level of the serum potassium. Since importantbuffer systems exist inside cells, H + shifts intracel-lularly in acidosis and moves from intracellular toextracellular fluid in alkalosis. These shifts of H+across cells are in exchange for sodium and potas-sium, Since serum sodium concentration is highrelative to the magnitude of the shift, pH changesin arterial blood have little noticeable effect onserum sodium concentration. For potassium, how-ever, arterial pH is even more important than totalbody potassium in determining serum potassiumconcentration.5 The pH effects on potassium levelsin blood are less obvious in respiratory than inmetabolic acid-base disturbances, and there areexceptions to the rule. Nevertheless, serum potas-sium level can be a very useful indicator of arterialpH, particularly in a mixed acid-base disturbance.Acidemia usually begets hyperkalemia unlessacidosis developed in an already potassium de-peleted patient or the acidosis itself was due to theloss of KHCOa. This occurs in diarrhea, acetazol.amide (Diamox) therapy and renal tubular acidosis.Alkalemia is usually associated with hypokalemia,but occasionally potassium loading either by in-creased intake or increased tissue breakdown canoverwhelm the tendency for the rise in pH to lowerserum potassium concentrations.

The fourth step in the systematic approach toacid-base diagnosis is to check other laboratory datafor clues. These might include elevated blood sugar,ammonia or urea nitrogen, positive blood culture,abnormal spirogram, marked polycythemia, and soon. Other abnormal laboratory tests are easily




suggested by looking over the causes of the primaryacid-base disturbances shown in Table 2.

One of the most common questions we are askedis, “Do you really need to get blood gases on everypatient?” The answer is no. If, after goingthroughsteps 1 through 4, no acid-base diagnosis is ap-parent, then you don’t need a pH. If the stepssuggest a single disturbance of mild degree andnothing in the routine electrolytes or other labora-tory studies contradicts the diagnosis, then againthere is probably no need to get a pH. But if yoususpect a mixed disturbance, or if any one of thesteps so far turns up a surprise, then blood gases arein order. When you get them, explain them. Arethey what you expected? If not, did you overempha-size a potential process in the history which turnsout not to be clinically significant, or did you misssomething? Most important, make sure that thechanges in Pco2, pH and HCOi which you areattributing to ‘�compensation” are physiologicallypossible. Plotting data on the acid-base map mayhelp answer the question.

Pui� MEl nouc AcrnosisThe disease processes listed in Table 2 which

produce metabolic acidosis do so either through lossof HCO� from the body or retention of non-volatileacids, that is, acids other than carbonic acid whichis excreted by the lungs. As pH falls and H+concentration rises, the excess H + is buffered im-mediately by extracellular fluid HCO3 in the fol-lowing reaction

H� + HCO3- H2CO3 H20 + CO,�

The CO2 formed is blown off by the lungs, allowingthe reaction to move to the right and preventaccumulation of H + in body fluids, but unfortu-nately HCO� is consumed in the process. Were thereno means for regenerating that HCO3 (and otherbody buffers), man would have very little toleranceto an acid load. Quantitatively, total extracellularfluid HCO� amounts to about 450 mEq. If oneconsiders nonbicarbonate buffer systems of hemo-globin, plasma proteins and intracellular fluid pro-teins, total body buffering capacity is only twicethat contributed by HCO� or about 12-15 mEq/kgbody weight acutely. In chronic acid loading, thevalue is somewhat higher due apparently to theslow titration of less readily available buffer storesin bone.6

Although total buffering capacity is limited, ifyou remember that the extremes of free H + con-centration which man can survive are only betweenMOO! and .001 mEq/L, the importance of theimmediate response of buflers to the slightest in-

crease in H� concentration is quite apparent.Protection of body buffer stores is the province of

the kidney. HCOa consumed and excreted by thelungs in the reaction above must be regenerated bythe renal secretion of H�. A more detailed discus-sion of both this and the chemistry of body buffersappears in the paper by Rastegar and Thier (this is-sue). Briefly, renal regeneration of bicarbonatestores depends upon three processes: the completereabsorption of filtered bicarbonate, the secretionof IF onto urinary buffers resulting in a loweringof urinary pH, and the excretion of IF by ionictrapping of NH3 as NHi� in the acid tubularurine! By these mechanisms, the kidney is able toexcrete several hundred milliequiva!ents of IF aday and regenerate an equivalent amount ofHCO� and return it to the body buffer pool.

An important compensatory mechanism defend-ing body pH in metabolic acidosis is hyperven-tilation which lowers the denominator of theHCO�/H2CO3 ratio. Change in minute ventilationbegins almost immediately after induction ofmetabolic acidosis. If acidosis develops slowly, fullcompensatory hyperventilation develops simulta-neously and can lower Pco2 to as low as 10 mm Hgin severe acidemia, thereby allowing virtually com-plete titration of body buffer stores before fatalacidemia ensues.8

Of all of the normal compensatory mechanisms insimple acid-base disturbances, the ventilatorv re-sponse to metabolic acidosis is probably the mostpredictable. Albert, Dell and Winters0 studied therelationship between Pco� and HCO3- in 60 patientswith simple metabolic acidosis. Their studiesshowed that the degree of compensatory- hypocap-nia that could be expected at any level of HCO�in pure metabolic acidosis could be calculated bythe following formula:

Pco2 =1.54 X HCO� + 8.36 ± 1.1

This is simply a mathematical expression of theconfidence band for metabolic acidosis shown inFigure 1. Given the values for pH. Pco2 and HCO3in any patient with metabolic acidosis, if measuredPcoz is significantly higher than Pco2 predicted bythe formula, then he has a complicating respiratoryacidosis. Conversely, if his Pco2 is significantlylower than that predicted by the formula, hyper-ventilation is out of proportion to the acidosis andindicates a primary respiratory alkalosis.

A word of caution is in order in using either theacid-base map or Winter’s formula. When metabol-ic acidosis develops rapidly, there may be a variablelag phase before maximum ventilatory responseoccurs. If there is rapid correction of metabolic


BLOOD

HCO3

Na’

Frcuni� 2. A diagrammatic representation of processes whichaffect renal HCO3- reabsorption. Straight solid line arrowsrepresent active reabsorption of Na+. Dashed arrows implypassive reabsorption of Cl and CO,2. Reabsorbed CO,2 ishydroxylated in the tubular cell and returns HCO� to blood.Dashed arrows for H� and K� imply active or passive move-ment of these ions into tubular lumen. Bouncing arrowfor HPO4 =and SO4 =indicate these anions are relativelyimpermeant and therefore contribute to electrical negativityof the lummal side of the membrane and facilitating to theoutward movement of Th and Kt See text for details.



acidosis with bicarbonate therapy, there may be asimilar lag phase of 24 hours or more beforehyperventilation stops)#{176}That means don’t jump toconclusions about a second primary disturbance ifthe acid-base picture is changing rapidly.

The primary mechanism which stimulates respi-ration in metabolic acidosis involves chemorecep-tors in the aortic arch which sense a fall in arterialpH. There also appear to be central receptorssensitive to a change in pH of cerebrospinal fluid(CSF) and perhaps also medullary intracellular pHand pH of blood perfusing that region of thebrain.””2 The lag phase in turning off hyperven-tilation following rapid correction of metabolicacidosis may be due to differential permeability ofPco2 and HCO� across the blood brain barrier, Pco2equilibrating freely between blood and cerebro-spinal fluid while HCO3- is transiently excluded.

PURE METABOLIC ALKALOSIS

The primary defect in metabolic alkalosis is, bydefinition, an increase in serum HCO3- concentration.Since serum HC03 levels are normally controlledby the kidney, you have to understand somethingabout those mechanisms to know why factors listedin Table 2 produce metabolic alkalosis. Some of theprocesses affecting renal HC05 reabsorption areshown in Figure 2.

Sodium is actively reabsorbed as ionic Na +. Howmuch sodium is reabsorbed is a function of effectivearterial blood volume, filtration fraction, aldos-terone and all the factors that regulate sodiumbalance. How much sodium is reabsorbed as NaCIand how much is reabsorbed in exchange for H� orK depends in large measure on the availability ofchloride, the only permeant anion in glomerdarfiltrate and therefore the only anion as such that canbe reabsorbed with sodium. When chloride is notavailable for reabsorption, either because ofchloride depletion or dilution of available chlorideby infusion of impermeant anions such as sulfate orphosphate the percentage of sodium reabsorbed inexchange for IF and K� increases. Every mEq ofH secreted into urine adds a mEq of HCO� toblood, either by the somewhat indirect reabsorptionof HCO� (Fig 2) or through generation of a newHCO� ion in the tubular cell. If abnormal volumeregulation obligates complete sodium reabsorption,then associated chloride depletion will obligateexcessive Na�:H and Na:K� exchange andlead to hvpokalemic metabolic alkalosis.

In the absence of stimuli for excessive sodiumreabsorption, the kidney will selectively reject so-dium bicarbonate and correct the alkalemia. Thesemechanisms are so efficient that it is almost impos-

sible to make a normal man alkalotic by feedinghim HCO3- unless you add stimuli for increasedsodium reabsorption such as preceding sodium de-pletion or mineralocorticoid therapy.

In clinical disease, any potential cause ofmetabolic alkalosis will have more profound effectson acid-base balance if they occur in a patient whois sodium depleted, has a sodium retaining state andgeneralized edema or who has excessive mineralo-corticism.

Potassium depletion in metabolic alkalosis iscommon and results from increased renal Na:Kexchange. Of itself, potassium depletion is usuallynot the cause of the alkalosis, although severedepletion may contribute to metabolic alkalosis bycausing a renal chloride leak. The predominantmechanism underlying alkalosis in a given patientcan be determined by measuring urinary chlorideconcentraion off diuretic therapy.’� If chloridedepletion is the problem, virtually no chlorideappears in the urine. Urinary chloride concentra-tions above 10 mEq/L suggest that potassiumdepletion is also contributing to the alkalosis. Logi-cal therapy in either case is potassium chloride.

Since pH is determined by the ratio of




HCO�fH2CO� and the primary insult in metabolicalkalosis is a rise in HCO3 concentration, one wouldexpect hypoventilation to be a normal compen-satory mechanism and it is. But if you look at thewidth and shape of the normal range of compensa-tion in metabolic alkalosis and compare it with oth-er simple acid-base disorders in Figure 1, you willsee that the band for metabolic alkalosis is bothwider and less linear than any other. Graphically,this tells you that it is hard to predict the degree ofhypoventilation for any given level of alkalosis. Italso says that, beyond a certain point, no furtherventilatory compensation can be expected no mat-ter how high the serum HCO3- rises. It is probablyhypoxia that limits any further respiratory com-pensation since hypoventilation to a Pco2 of 65 mmHg, for example, would lower Po�z to 60 mm Hg, alevel of hypoxia which in itself would stimulaterespiration. That means that Pco2 values above 65mm Hg must indicate primary respiratory acidosis.

Studies in which metabolic alkalosis has beeninduced in normal volunteers have not shownrespiratory compensation to produce Pcoz valuesabove 55 mm Hg,’5’6although clinical studiessuggest some patients can raise Pco2 to the mid 60’sby compensatory hypoventilation.17 Given a pa-tient with no history of pulmonary disease and noapparent cause of primary hypoventilation whohas a high HCOi, an alkaline pH and a Pco2 in thegray zone of 55-65 mm Hg, how can you tell if thehypercapnia represents compensation for metabolicalkalosis or primary respiratory acidosis in a patientwho also has metabolic alkalosis? Two maneuvershave been suggested to differentiate between thetwo possibilities. One is to examine the patient’s re-sponse to breathing 100 percent oxygen for 12minutes.18 Patients with primary respiratory aci-dosis develop increasing hypercapnia and frankacidosis on oxygen, while those with compensatoryhypoventilation and pure metabolic alkalosis donot. It is interesting that in the series in which thistest was originally proposed, six of seven patientswith initial Pco2 values above 54 mm Hg developedrespiratory acidosis while breathing oxygen, sug-

gesting that patients with pure metabolic alkalosisrarely compensate to Pco2 levels above 55 mmHg.

A second maneuver which is theoretically reason-able but still needs to be proved clinically is tocalculate the alveolar-arterial (Aa) oxygen gradientusing Campbell’s simplified gas equation. This es-timates alveolar Po� as equal to the partial pressureof oxygen in inspired air minus 1.25 X Pco2 ofarterial blood. At normal atmospheric pressure.while breathing room air, this formula can hesimplified to

alveolar Po2 = 150 - 1.25 X Pco�

To get the Aa gradient, simply subtract measuredarterial Po� from calculated alveolar Po2. The nor-mal Aa gradient is 10 mm Hg or less, Values above15 mm Hg indicate either a ventilation/perfusiondefect or significant shunting of blood through thelungs, findings you would hope should not occur innormal compensatory hypoventilation. Using thisformula, you will find that some of the reportedpatients thought to have compensatory hypoventila-tion with Pa� values above 60 mm Hg in supposedpure metabolic alkalosis have high Aa gradients andmay actually have had a mixed disturbance.

Obviously, more study is required before weunderstand fully the limits of respiratory compen-sation in metabolic alkalosis. Until we do, it seemsreasonable to suspect a complicating respiratoryacidosis if the Pco2 is much above 55 mm Hg,particularly if the Aa gradient is above 15. Onemight also suspect that no rise in Pco-.1 mightindicate primary respiratory alkalosis. �Vhile thatmay occur, potassium depleted patients character-istically do not develop hypercapnia, apparentlybecause of paradoxic intracellular aciclosis whichprevents hypoventilation.u9

REcOGNITIoN OF MIXED METABOLIC AN�)RESPLBATOnY DIsoRDERs

There are two pitfalls in correctly assessing theclinical significance of a mixed metabolic and re-spiratory acid-base disturbance. One is to assume

T�bIe 3-Mi�d R�pir�ry .,.�.d M�tobo�k �4dd-B�e Dia�.,born,e�

Resp

Additive E ifeet on pH

Resp

Opposite Eff ects on pH

MetMetalkalosis a1kalo�is Reap acid Met acid alkalo�is Met acid alkalos,,u Resp ac,d

�H 1 1 I ICO, content I I I I I IComb1ned pH 11 II pH ± ±BloodPicture CO, content ± ± (‘Os content IT




that a normal CO2 content means there is no acid-base emergency. The other is to assume a grosslyabnormal CO2 is an indication for immediate ther-apy. Neither is the case. As a matter of fact, theexact opposite is true. Table 3 gives the possiblecombinations of double acid-base disturbances in-volving a metabolic and a respiratory disorder. No-tice that when two disturbances move pH in thesame direction, they move HCOs (and thereforeCO2 content) in opposite directions. That meanspatients with severe acidemia or alkalemia can beexpected to have relatively normal CO2 contents. Iftwo disturbances move pH in opposite directionsand therefore cancel out the separate effects, theymove HC03 in the same direction. That meanspatients with extremely high or low serum CO2values characteristically do not have a widely ab-berrant pH. These are just a few of the reasons whywe urge a systematic approach to acid-base diag-nosis such as the one outlined in Table 1. Thefollowing example demonstrates how such an ap-proach avoids the pitfalls in evaluating clinicalsituations.

A patient with known chronic obstructive lungdisease and stable chronic hypereapnia was ad-mitted because of a urinary tract infection. Exceptfor fever and flank pain, physical examination wasunchanged from his last office visit. Admissionblood studies showed Na 135, K 4.2, Cl 90, CO2 36,BUN 20, FBS 78, pH 7.30, Pco2 68, HC03 35.Treatment included his usual regimen of broncho.dilators and IPPB and also a potentially nephro-toxic antibiotic. Fever subsided but he becameincreasingly restless and on the fifth day com-plained of nausea. Routine blood studies that morn-ing were Na 135, K 6.3, Cl 93, CO2 23. At this pointyou are asked to evaluate the situation.

A quick review of the history certainly wouldshow the potential for chronic respiratory acidosis.You might also recognize the additional potentialfor nephrotoxic antibiotics to produce unsuspectedpolyuric acute renal failure and metabolic acidosis.Physical examination is disturbing in that youcannot explain his restlessness on apparent worsen-ing of. his pulmonary disease. The routine electro-lytes tell you what has happened. His now normalCO2 le, HCO� is clearly inappropriate to purecompensated respiratory acidosis. The increasedundetermined anion, now 19 versus 9 on admission,indicates a complicating metabolic acidosis, al-though proof of the cause (acute renal failure)must await a repeat BUN (which was 75.) Thehvperkalemia alerts you to increased acidemia sincethe history eliminated potassium-blocking diuretics,mineralocorticoid deficiency or potassium loading.

Blood gases only confirm what you know must havehappened. They showed pH 7.09, PCO2 69, HCO�22. Notice that the complete analysis of the elec-trolyte pattern picked up the new problem evenbefore you recognized the development oi acute re-nal failure.

COMMON CUNICAL SETrINGS OF MIXEDDIS1-UIRBANCES

If you look over the causes of simple acid-basedisorders listed in Table 2, you will see that severalclinical situations must commonly be associatedwith mixed metabolic and respiratory acid-basedisturbances, for example: cardiac arrest (respira-tory and metabolic acidosis), septic shock, salicylateintoxication, and hepatorenal syndrome (respira-tory alkalosis and metabolic acidosis). Of all thepossible mixed acid-base disturbances, however, theassociation of metabolic alkalosis and respiratoryacidosis is so common that it deserves specialcomment.

Renal compensation for respiratory acidosis isincreased reabsorption of HCO3- and renal chloridewasting, producing the typical blood picture ofhypochloremia and an increase in CO2 content.While both Pco2 and HCO� are elevated, theHCO�/ H2C03 ratio is not quite back to the normal20/1. When treatment of the ventilatory distur-bance lowers Pcoe, a transient alkalemia will de-velop until previously retained bicarbonate is ex-creted. Prolonged alkalemia, however, commonlyoccurs in patients with apparently stable chronicrespiratory acidosis.2#{176}In some series, as high asof patients with chronic respiratory acidosis havehad a complicating metabolic alkalosis. The causemay be therapy which of itself could cause meta-bolic alkalosis such as antacid or alkali ingestion forassociated peptic ulcer disease or diuretics for corpulmonale. A more important factor in most pa-tients, however, is the chloride depletion incurredduring the phase of compensatory bicarbonateretention. As long as the patient has a stimulus toreabsorb sodium, and chloride depletion is per-petuated by a low sodium diet without chloridesupplements, obligate renal bicarbonate reabsorp-tion will maintain high serum bicarbonate levelseven when arterial pH is frankly alkale,nic.’3

TREATMENT OF Mix�n Acm-BASE D�s’ruI�a�xcF.sObviously, one cannot discuss or even imagine all

possible combinations of clinical diseases whichcould give rise to mixed acid-base disturbances.Rather, the purpose of this section is to go over thegeneral principles upon which rational therapy isbased in the four possible combinations of mixed




metabolic and respiratory acid-base disorders.

Respiratory Acidosis and Metabolic AlkalosisThe clinical settings which give rise to this mixed

disturbance have been reviewed above. The typicalelectrolyte pattern is one of hypochioremia, hypo-kalemia, high CO2 content and a near normal ormoderately elevated pH. Since both the numeratorand denominator of the HCOa/H2C03 ratio areincreased, therapy must be directed at loweringboth Pco2 and HC03 levels simultaneously. If onlythe ventilatory abnormality is treated, previouslyretained HCO� can result in severe alkalemia andhypokalemia, clearly a hazard in patients receivingdigitalis. This sudden alkalemia may be dangerousfor another reason.2’ The high blood pH maydepress respiration and lead to a secondary rise inPcoz. Since HCO� moves slowly into the brain whilePco2 equilibrates quickly, one may create theparadox of a falling CSF pH in the presence offrank alkalemia in blood. Whichever mechanismpredominates, the danger of rapidly inducingalkalemia in respiratory failure is clear from thedata of Asmundson and Kilburn2’ who attributed12 deaths among 146 patients to this therapeuticerror.

Both hypokalemia and alkalemia can be avoidedif chloride deficits are repaired at the same timetherapy attempts to improve ventilation. This maybe given as NaCl if the patient is sodium depleted,KC1 in hypokalemic patients and those with edema,and arginine HCI in patients with both sodiumexcess and initially elevated levels of serum potas-sium. The appropriate treatment of respiratoryacidosis is reviewed elsewhere in this symposium.

Respiratory Acidosis and Metabolic Acid osisThis combination represents an acid-base emer-

gency. In terms of the HCO3-/H2C03 ratio, thenumerator is falling while the denominator is rising.In terms of compensatory mechanisms, metabolicacidosis prevents both buffer and renal compensa-tion for respiratory acidosis which in turn blocksventilatory compensation for the metabolic dis-order. The result is rapidly progressive acidemia.Serum CO2 content may be normal if metabolicacidosis develops in a patient with previously com-pensated respiratory acidosis. If respiratory acidosisdevelops iii a patient with pre-existing metabolicacidosis, CO2 content will be low. The level ofundetermined anion depends on the cause of themetabolic disturbance, but the potassium is almostalways high.

Treatment must be aggressive and directed atboth problems simultaneously. Precise managementof the respiratory disturbance, of course, depends

upon its cause. If the patient is hypotensive or thePo2 is less than 50 mm Hg,2� tissue hypoxia andincreased lactate production may sveil be contribut-ing to metabolic acidosis, and every effort must beexpended to reverse the hypoxic hvpoperfusedstate. Since hvpoxic hypercapneic patients oftenincrease arterial Pco2 when given oxygen,2� andpatients with mixed respiratory and metabolicacidosis can ill afford increasing hvpercapnia, oxy-gen should probably be given only with intubationand artificial ventilatorv support. If Po2 is 60 mmHg or higher and the patient is not hvpotensive.then it usually is safe to assume that tissue oxygendelivery is adequate enough to prevent excesslactate production. Whatever the cause of the met-abolic acidosis, NaHCO� should be administeredwhile the above measures are instituted to improveoxygenation and lower Pcoe. Remember that theaim of therapy is to return pH (not CO2 content) toa safe range. An approximation of immediate HCO.�requirements can be made by plotting blood gasvalues on the acid-base map (Fig 1). Lay a rulerperpendicular to the Pco2 scale to give you theisopleth for any given level of Pco2. Find the HCO�isopleth that intersects with the patient’s currentPco2. Then move down the Pco2 isopleth until youreach a HC03 value where pH is in a safer range.Multiply this increment in HCO�(mEq/L) h theextracel]ular fluid (ECF) volume, it’, 20 percent ofbody weight in kilograms to get the dose of HCO:�.For example, if initial values are pH 7.02, Pco2 80.and HCO� 21 in a 70 kg man, raising the HCO� levelacutely to 30 would raise pH to 7.2. Thus 9 mEq/LX 14L or 126 mEq of HC03 would be a reasonabledose to give acutely. Appreciate that the alkali dosecalculated is an under estimation since intracellularbuffer stores must also he regenerated. Neverthe-less, it gives you a “ball park” figure for acute ECFdistribution and buys time for ventilator therapyto begin lowering Pco-�.

Alkali is also the emergency treatment for hvper-kalemia. Oral and rectal ion exchange resins shouldbe started as well if hyperkalemia is associated withECG changes and the patient is in renal failure. Iflarge amounts of alkali are required as normallyoccurs in lactic acidosis, and the patient is unable tohandle the sodium load either because of congestiveheart failure or renal failure, dialysis may berequired to allow continued administration of alkaliby providing a port of exit for the sodium load.Respiratory Atka!o.s-Lsand Metabolic Acidosis

As noted previously, this combination of distur-bances is not rare in seriously ill patients. It occursmost commonly in combined hepatic and renalfailure and in septic shock and consequently de-




velops in a patient who already has a serious,complex disease. Of all of the mixed disturl,ances,this is the easiest one to miss. Usually metabolicacidosis is recognized because of the apparent renalfailure. Then without systematically reviewing theacid-base data each time, a common error is toignore a falling serum potassium concentration andattribute a low Pco2 to compensatory hyperventila-tion unless the patient is clearly alkalemic. This is asituation when calculating the appropriate Pcoz orplotting data on the nomogram can tell you ifhyperventilation is excessive even before pH be-comes frankly alkalemic. In seeing a great manypatients with renal failure, we have noticed thatpatients will often begin to show a complicatingrespiratory alkalosis a day or so before they developfever, hypotension and the full blown picture ofseptic shock. The reason for this is not clear, but theclinical value of advance warning in impendingseptic shock is obvious.

The typical blood picture in mixed respiratoryalkalosis and metabolic acidosis is moderate hypo-kalemia, a pH near normal or slightly alkaline, anda severe depression of CO2 content. The danger ofmisinterpreting the situation as simple metabolicacidosis and treating the “CO2’� by giving HCO� isobvious. Since pH is usually almost normal, noimmediate acid-base therapy is required. Therapyinstead should be directed at primary disease statesproducing the acid-base disturbances.Respirator?/ Alkalosis and Metabolic Alkalosis

Of all the possible mLxed disturbances, this is therarest, usually occurring only when a fortuitous (ornot so fortuitous) association of primary diseasesmakes it possible. There is one clinical situation,however, in which one might predict this mixeddisorder. This is in the wake of aggressive and suc-cessful correction of respiratory acidosis in a patientwho had previously undergone renal compensationby increasing plasma bicarbonate concentration. Theover-correction of Pco2 retention by too successfulventilatory assistance coupled with high serumbicarbonate concentration before the kidneys havehad a chance to excrete it can produce severealkalemia and hypokalemia, the major hazard ofthis dlisturbance, Treatment is to cut back onventilator�’ assistance and allow Pco2 to rise at leastto normal, and treat both the metabolic alkalosisand hvpokalemia b� giving potassium chloride.

in patients in whom the respiratory alkalosis isnot due to mechanical over-ventilation, it is muchmore difikult to return Pco� safely to normal. Usualmanagement must depend on treatment of thedisease process leading to primary hyperventilation.If pH reaches dangerously high levels in this mixed

disturbance, it is usually safer to give arginine HCIintravenously to reduce the metabolic component,than to increase the concentration of Pco2 ininspired air and directly treat the respiratory dis-turbance.

SUMMARY

Acid-base disturbances are disease processeswhich, if otherwise unopposed, affect blood levelsof Pco2, HCO3 and pH in characteristic ways.Anything that affects a patient’s ability to defendbody fluid pH is a significant clinical problem andmust be recognized by the physicians treating him.That is why it is no more “roundsmanship” todiagnose a triple acid-base disturbance than it is torecognize a simple acid-base disorder. For example,consider the patient with acute renal failure(metabolic acidosis), nasogastric suction ( metabol-ic alkalosis) and bilateral pleural effusions (respi-ratory acidosis).

Because a mixed disturbance is the result ofseveral primary and compensatory processes allaffecting the same blood gas values, it is necessaryto be able to recognize the limits of normal compen-sation to a given acid-base stress. Nomograms arehelpful, but they cannot be used alone. Somehow�the clinician must be able to organize what heknows about acid-base balance and put it togetherwith what he knows about the patient. The follow-ing system for diagnosing clinical acid-base disor-ders is easy to use and avoids most of the pitfalls ofquick decisions based only on blood gas values andnomograms. The system has five steps: 1) scan thehistory for potential processes which lead to simpleacid-base disorders; 2) note findings on physicalexamination which suggest an acid-base distur-bance; 3) check the routine electrolytes for a)serum CO2 content (which tells you HCO� concen-tration), b) undetermined anion (values significant-ly higher than 14 mean metabolic acidosis) and c)serum potassium (which usually moves opposite toarterial pH); 4) scan other lab data for diseaseprocesses associated with acid-base disturbances; 5)when you get blood gas values, explain them. Inparticular, he sure that a change in Pco2 or HCOswhich you are attributing to compensation is in thephysiologically possible range.

REFERENCES

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