Definition of Clinically Relevant Lactic Acidosis in Patients with Internal Diseases

Transcription

1 Defiitio of Cliically Relevat Lactic Acidosis i Patiets with Iteral Diseases DIETER LUFT, PRIV. Doz., DR. MED., GUNTRAM DEICHSEL, DR. RER. NAT., REINHOLD-M. SCHMULLING, PROF. DR. MED., WOLFGANG STEIN, DR. RER. NAT., DR. MED., AND MANFRED EGGSTEIN, PROF. DR. MED. I order to defie cliically relevat lactic acidosis, 12 biochemical variables, eight cliical symptoms ad sigs, leadig diagoses, ad mortality were evaluated prospectively i approximately 2,000 uselected patiets with iteral diseases, cosecutively admitted to the hospital. Patiets with icomplete data sets were ot cosidered. Of those patiets who repeatedly were admitted to the hospital durig the time of the study, oly the first admissio was icluded for statistical aalysis. I additio to 11 defiitios of lactic acidosis give i the literature, sequetial cluster aalyses of the biochemical variables were used to estimate the icidece of lactic acidosis i 1,467 patiets. Depedig upo which defiitio was used, % of all patiets were classified as sufferig from lactic acidosis, with a mortality rate ragig from 30-88%. From this study it is cocluded that a limit of.::;7.35 for ph ad of >5-6 mmol/l for the cocetratio of lactate i whole blood will miimize false-egative or false-positive classificatios.. (Key words: Defiitio of lactic acidosis; Icidece of lactic acidosis; Mortality rate of lactic acidosis; Cluster aalysis) Am J Cli Pathol 1983; 80: SINCE THE CLINICAL INVESTIGATIONS ofhuckabee12 13 ad the wide-spread itroductio of rapid methods for the estimatio of the cocetratio of lactate i whole blood, it is well kow that iteral diseases ca be accompaied by clearly. elevated cocetratios of lactate. The progostic sigificace of the cocetratio of lactate has to be determied separately for each disease, e.g., shock of differet aetiology, myocardial ifarctio, or biguaide itoxicatio. 2 It is ot justified to use the term "lactic acidosis" i every case of elevatio of the cocetratio of lactate that exceeds the upper limit of the ormal rage. Therefore, a rage of hyperlactatemia has bee iterposed to separate the uequivocally ormal rage from pathologic lactic acidosis. To the preset, the upper limit of hyperlactatemia is still uder discussio. From 1963 to 1978, at least 15 differet defiitios of lactic acidosis have bee proposed The cocetratios of lactate rage from 1.3 mmolfl1 9 to 9.0 mmol/l, 23 ad the limits of ph vary from to Received December 22, 1982;.received revised mauscript ad accepted for publicatio March 30, Address reprit requests to Dr. Luft: Mediziische Uiversitatskliik, Abt. I. Med. IV, Otfried-Muller, Str. 10, D-7400 Tubige 1, Federal Republic of Germay. Medical Cliic, Departmet of Iteral Medicie IV, Uiversity of Tubige, ad Istitute for Medical Biometrics, Uiversity of Tubige, Tubige, Federal Republic of Germay I this study, the attempt was made first to relate the cosequeces of these differet defiitios to the absolute umber of patiets classified as sufferig from lactic acidosis, to the relative portios of progostically favorable symptoms ad sigs, ad to the outcome mortality rate, ad secod to deduce a coveiet defiitio of cliically relevat lactic acidosis, i.e., a cliical coditio with bad progosis due to a serious iteral disease requirig treatmet i a itesive care uit, urget diagostic procedures, ad therapeutic measures (e.g., admiistratio of bicarboate). A commoly accepted defiitio of cliically relevat lactic acidosis would facilitate the compariso of the efficiecy of differet therapeutic protocols i serious diseases ad allow a estimatio of the icidece of lactic acidosis i differet iteral diseases. Methods The followig 12 biochemical ad eight cliical variables were collected i a cotiuous series of approximately 2,000 uselected iterally ill patiets o their admissio to the hospital. I the followig list of variables, the laboratory methods ad cliical criteria used are give i paretheses: Biochemical Variables ph, Pco 2, stadard bicarboate, p02 (A VL-Gas-Check, Bad Homburg, FRG), blood glucose (Techico-1- chael-auto-aalyzer; Techico, Bad Vilbel, FRG), ad lactate (modified ezymatic method 7 22 ; aca Du Pot, Bad Nauheim, FRG) were determied i capillary whole blood. Capillary whole blood was used for lactate estimatio, because i a previous ivestigatio, 16 it was foud that there is a strog correlatio betwee the arterial ad the capillary cocetratios of lactate (~ = 0.98, = 103, P < 0.01). The cocetratios of /83/1000/0484 $01.10 Americ~ Society of Cliical Pathologists 484

2 Vol. 80 No. 4 creatiie (SMA 6/60 ad 12/60, respectively; Techico, Bad Vilbel, FRG), urea (SMA 6/60 ad 12/60, respectively), sodium ad potassium (SMA 6/60 ad flame photometry, respectively), ad chloride (SMA 6/60, 12/60, ad potetiometry, respectively) were evaluated i serum. The differet methods yielded comparable results. The aio gap was calculated accordig to [Na+] + [K+] - [HC0 3 -] ~ [Ci-]. 8 Cliical Variables Iformatio was collected o the cause of admissio (plaed-emergecy), type of ward (geeral ward-itesive care uit), geeral cliical aspect (good, moderate-poor), cosciousess (ormal-impaired), ski perfusio (ormal-pathologic), respiratio rate (below or over 20/mi), shock (abset-preset), ad urie excretio (over or below 40 ml/h). Additioally, the cliically leadig diagosis, up to te more diagoses, ad the mortality were recorded i a protocol. Statistical Methods Out of 15 kow defiitios of lactic acidosis, those 11 defiitios 8 10 i with exact biochemical criteria were used to calculate the icidece of lactic acidosis. Oly the first of possibly multiple admissios of idividual patiets durig the time of the study ad. oly complete sets of biochemical data were icluded, thus leavig 1,467 out of 1,988 admissios for evaluatio. I additio, the sequetial cluster program, 5 usig either the origial data sets of stadardized data 'sets, was applied to Search for patiets with lactic acidosis. The clusterig algorithm used is based o McQuee's sigle-pass method ad outlied i Deichsel. 5 Give a data set, the algbrithm suggests a umber of disjoit clusters that are to be iterpreted by the user. No sigificace test of cluster validity is performed. The algorithm is regarded as a aid for data soopig. "Origial data'' are the data as they were measured~ whereas "ormalized data" meas that the vallles of each variable were trasformed to zero mea ad uity variace. The results obtaied with either the origial data set or the ormalized data set (umber of clusters, members of each cluster) were compared i order to fid out whether the widely differig variaces of the differet biochemical variables used i the sequetial cluster program would ifluece search procedures. Differeces betwee the various sets of criteria used for classificatio with regard to the absolute umbers of patiej?.ts classified, the frequecies of alterative cliical variables withi the differet groups of patiets, ad the mortality rates were. tested for statistical sigificace usig a liear logistic model. 9 Fittig a liear logistic model (or logit model) is a method for aalyzig a DEFINITION OF LACTIC ACIDOSIS 485 Table 1. Icidece of Lactic Acidosis i Iterally Ill Ipatiets ( = 1,467) o Admissio to the Hospital Accordig to Differet Sets of Criteria of Classificatio Criteria lactate ~ Author(s) ph.:; (mmol/l) P. B. Oliva D. Depperma ad coauthors D. I. Peretz ad associates E. Ritz ad colleagues H. A. Krebs ad associates M. Haslbeck ad colleagues R. I. Misbi ad co-authors Cluster aalysis (Co)t (7.36)t (4.3)t Cluster a(llysis (Cs)t (7.36)t (6.4)t K. G. M. M. Alberti ad associates R. E. Traquada ad colleagues H. Ftirster P. H. Wise ad co-authors Mortality* Icidece % % The cotiuous icrease of the mortality rate has bee prove to be statistically sigificat (P < O.QI, liear logistic model). t Origial dala used for cluster aalysis (CO); stadardized data used for cluster aalysis (CS). l Values i paretheses were ot used as cutotfvalues but represet the least deviatio from the ormal rage, which has bee icluded by the cluster program. 2 X k (or higher dimesioal) cotigecy table. The respose variable is biomial, a.d a test of sigificace is based o a compariso of a sample of k biomial distributios: for each distributio the probability of success P is estimated, to be specific: log (P/( 1 - P)) is estimated. Uder the ull hypothesis all Ps are equal. I our case, the hypothesis of equal mortality had to be rejected. Results Icidece of Lactic Acidosis Accordig to Differet Defiitios The ici(iece of lactic aeidosis accordig to 11. differet sets of criteria i 1,467 uselected hospital patiets o admissio is show i Table 1. Takig ito accciu~t all sets of classificatio criteria used, a total umber of 62 patiets was classified as sufferig from lactic acidosis. The highest umber icluded by oe sigle set of criteria was 56 beig obtaied with the criteria of Oliva. 18 The lowest umber was obtaied usig the criteria of Wise. 23 The icidece of lactic acidosis scatters from % of all patiets. Though the absolute umbers of patiets selected by diweret sets of criteria do ot scatter widely, eve whe oly small absolute umbers are obtaied, the selectio of idividual patiets differ cosiderably (Fig. 1).

3 486 LUFT ET AL. A.J.C.P. October 1983 paretheses i Table do ot represet cutoff values determied before performig clustl;!r aalysis i order to discrimiate patiets with lactic acidosis. These values merely show the least pathologic coditios i the clusters of lactic acidotic patiets. Cosiderig these biochemical results, the cliical symptoms ad sigs, ad the leadig diagoses, it is justified to classify all these patiets as havig lactic acidosis. These combied clusters of patiets ( = 13 ad = 12, respectively), ot selected by empirical criteria, correspod very closely with certai groups defied by empirical criteria (Table l, Fig. 1). The relative cotributios of differet diseases to the developmet of lactic acidosis do ot chage with differet defiitios. The most frequet causes are cardiopulmoary diseases ad itoxicatios. Diseases of the cetral ervous system, the gastroitestial tract (liver, !COi ICSI Ill FIG. 1. Scattergram showig the differig selectio of patiets sufferig from lactic acidosis by differet selectio criteria. The compositios of groups of patiets chage cosiderably, eve whe criteria are used with which oly small absolute umbers of patiets are selected. Each horizotal bar represets oe idividual patiet. The umbers below each vertical colum of bars refer to the respective referece from which the defiitio criteria were take. CO = cluster aalysis of the origial data set; CS= cluster aalysis of the ormalized data set. Cluster aalyses of either the origial or the ormalized data sets of the 12 biochemical variables reveal 17 or 18 groups of patiets, respectively. Three or four groups of these patiets were characterized by high idividual cocetratios of lactate (Fig. 2). As show i Figure 2, groups of patiets foud by cluster aalysis are characterized by high_ blood lactate cocetratios; a metabolic acidosis with a varyig degree of respiratory compesatio; slight to excessive hyperglycemia; geerally ormal cocetratios of sodium, potassium, ad chlorides; mostly a icrease of the cocetratios of urea ad creatiie; ad a raised aio gap. Although the compositio ad the umbers of clusters differ accordig to the data set used, the et result is almost idetical. Cluster aalysis of origial data revealed 13 patiets, whereas aalysis of ormalized data revealed I. 12 patiets, 11 of these patiets beig idetical. Therefore,. we ca coclude that differig variaces of the origial data did ot ifluece aalysis procedure. Values for ph ad for the cocetratio of lactate give i FIG. 2. Profiles of 12 biochemical variables i 13 patiets classified by a cluster aalysis of the origial data set as sufferig from lactic acidosis. The ormal rage of all biochemical variables, i.e., 1. ph ( ); 2. pc02 (35-45 mmhg); 3. stadard bicarboate (22-26 mmol/l); 4. p02 ( mmhg); 5. lactate ( mmol/l); 6. aio gap ( mmol/l); 7. creatiie ( mg/dl); 8. urea (12-46 mg/dl); 9. blood glucose (postpradial mg/dl); JO. sodium ( mmol/l); 11. potassium ( mmol/l); ad 12. chlorides ( mmol/l), have bee ormalized ad are represeted by the dotted 'area. Idividual measuremets are give as multiples of the respectiye ormal rage.

4 Vol. 80 No. 4 DEFINITION OF LACTIC ACIDOSIS 48? Table 2. Mea Biochemical Variables (±SEM) i Groups of Patiets Classified as Havig Acidosis by Differet Criteria Ref. Bicarboate Blood Glucose Lactate Creatiie Urea Sodium Potassium Aio Gap Nr. () ph mmol/l mg/dl mmol/l mg/c!l mg/dl mmol/l mmol/l mmol/l 18 (56) 7.28 ± ± ± ± ± ± ± ± ± (49) 7.26 ± ± ± ± ± ± ± ± ± (33) 7.21 ± l ± ± ± ± ± ± ± ± (27) 7.20 ± ± ± ± ± ± ± ± ± (18) 7.19 ± ± ± ± ± ± ± ± ± (15) 7.18 ± ± ± ± ± ± ± ± ± (14) 7.16 ± ± ± ± ± ± ± ± ± 2.6 co (13) 7.17 ± ± ± ± ± ± ± ± ± 2.5 cs (12) 7.16 ± I ± ± ± ± ± ± ± ± (12) 7.14 ± ± ± ± ± ± ± ± ± (10) 7.15 ± ± ± ± ± ± ± ± ± (8) 7.11 ± ± ± ± ± ± ± ± ± (7) 7.10 ± ± ± ± ± ± ± ± ± 4.1 Coversio from covetioal uits to SI uits: blood glucose: mg/dl X ~ mmol/l: creatiie: mg/dl X 88.1,418 ~ µmol/l; urea: mg/dl X ~ mmolfl. pacreas, bowel), ad edocrie disturbaces ca be detected as uderlyig causes oly by usig broad defiitios Applyig the broadest defiitios, 6 8 oe patiet without ay orgaic iteral disease is icluded i the group of patiets with lactic acidosis. Biochemical Variables Iheret chages are evidet whe the differet groups of patiets, foud by differet sets of criteria, are arraged accordig to the absolute umber of patiets classified. This is because of the icreasigly restrictive defiitios of lactic acidosis (Table 2). The mea ph ad the mea cocetratio of stadard bicarboate steadily decrease, whereas the mea cocetratios of lactate ad the aio gap are augmeted. The mea values of Pco 2 (rage of the meas mmhg), p 02 (rage of the meas mmhg), ad chloride (rage of the meas mmol/l) do ot chage systematically. With the more restrictive defiitios, slight icreases of the mea cocetratios of sodium ad potassium ca be demostrated. The mea cocetratios of blood glucose, creatiie, ad urea icrease cotiuously, thus idicatig that, with most restricted defiitios, oly patiets with multiple orga impairmets are icluded. Patiets with lesser deviatios from the ormal rage ad therefore better progosis whe classified with the more restrictive criteria are excluded. Cliical Variables The relative frequecies of most of the cliical variables idicatig a good progosis 16 decrease sigificatly (P < 0.01) from the broadest to the most restricted defiitio (Fig. 3). With broad defiitios, a large umber is selected of patiets who are ot sufferig from a serious disease, thus lackig the respective cliical symptoms ad sigs, i.e., treatmet i a itesive care uit, bad geeral coditio, impaired cosciousess, pathologic ski perfusio, low urie excretio, ad shock. With more restricted defiitios, the portio of alterative cliical variables (which idicates a favorable progosis) decreases cosiderably ad eve approaches zero. The reductio of the absolute umber of patiets classified (Fig. 3), the icreasig deviatio from the ormal rage of the biochemical variables (Table 2), ad the icrease of the relative portio of bad cliical variables (Fig. 3) is accompaied by a icrease of mortality from 30 to 88% (Fig. 3). Discussio A thorough review of the respective literature reveals that the proposed defiitios of lactic acidosis are based o quite differet deductios such as the observatio of biguaide-iduced lactic acidosis i patiets with diabetes, theoretic cosideratios (Hederso-Hasselbalch equatio), or geeral cliical experiece. So far oe of these defiitios based o retrospective studies has bee ivestigated i a prospective study for its suitability. Furthermore, o prospective compariso is available that idicates 1) whether ay sigificat differece of cliical relevace exists betwee oly slightly differet. defiitios, ad 2) how importat such possible differeces would be. The icidece of lactic acidosis had bee determied by 11 defiitios of lactic acidosis ad two additioal cluster aalyses i 1,467 iterally ill patiets o admissio to the hospital. The icidece rages from % of all patiets. Usig broad defiitios, the pqrtio of patiets ot sufferig from a severe disease ad cosequetly with low mortality rate is high (3Q-36%). Whereas, usig the most restricted defii-

5 488 LUFT ET AL A.J.C.P. October 198J '50 40 IT] CO CS I co cs FIG. 3. Absolute frequecies of progostically favorable ad ufavorable variables ad mortality respectively i groups of patiets sufferig from lactic acidosis defied by differet criteria. I.) ward; 2.) geeral cliical coditio; 3.) cosciousess; 4.) ski perfusio; 5.) respiratio rate; 6.) shock; 7.) urie excretio; 8.) outcome mortality rate. Cause of admissio (plaed-emergecy) is ot show, because oly very small differeces are demostrable. The umbers below the colums refer to the respective referece from which the defiitio criteria were take. CO = Cluster aalysis of the origial data set. CS = Cluster aalysis of the ormalized data set. The shaded area of each colum represets the part either of patiets with ufavorable cliical variables (I-7) or of patiets who died (8).

6 Vol. 80 No. 4 tios, oly patiets i the worst cliical coditios are icluded ad the resultat mortality rate i these. patiets is high (80-88% ). O the other had, usig more restricted defiitios, it is obvious that a certai umber of patiets with a bad progosis is excluded (Fig. 3). Statistical aalysis of the total sample of patiets 16 showed sigificat coti'elatios of the lactate cocetratios i whole blood with: 1) the cocetratios of all biochemical variables except Pco 2, 2) the relative portios of progostically bad cliical variables, ad 3) the mortality rate. It has to be accepted that a cotiuum exists, begiig with ormal values of all biochemical parameters ad favorable cliical variables, ad, therefore, a very low mortality rate, ad edig with extreme deviatios of all biochemical variables (icludig lactate), bad cliical coditios, ad, therefore, very high mortality. It is ot possible to determie cutoff values of iheret biologic importace because o acute chages are detectable: first, i the cotiuous rage of biochemical values, secod, the percetage of alterative cliical criteria, or, third, the mortality rate. Cliically relevat lactic acidosis has to be defied pragmatically i order to miimize the umber of false classificatios. Takig ito accout the cliical ad biochemical variables ad the mortality rate, oly margial chages i. all these criteria ca be detected startig with the defiitio of Haslbeck ad co-workersll (Table 1). Comparig the absolute umber of patiets classified with their defiitio, about twice as may patiets are selected as with the defiitio of Wise ad co-workers. 23 The suggestio to use criteria i this rage, which has bee used by Haslbeck ad associates, 11 i.e., ph s 7.35 ad cocetratios of lactate i whole blood >5-6 mmol/l is supported further by the fact that, usig the ubiased cluster aalysis, a group of patiets is defied that meets these criteria. The presece of cliical symptoms ad sigs of ufavorable progostic sigificace ad the sigificat elevatios of the cocetratios of blood glucose, creatiie, ad urea are essetial precoditios for the diagosis of cliically relevat lactic acidosis. DEFINITION OF LACTIC ACIDOSIS Refereces 489 I. Alberti KGMM, Nattrass M: Lactic acidosis. Lacet 1977; 2: Cohe RD, Woods HF: Cliical ad biochemical aspects of lactic acidosis. Oxford, Blackwell, Colay LA, Loewestei JE: Pheformi ad hyperamylasemia i lactic acidosis. A Iter Med 1977; 87: Daowski TS, Forsham PH, Golder MG, et al: Lactic acidosis i diabetes mellitus, JAMA 1963; 184:47 5. Deichsel G: Radom walk clusterig i large data sets, Compstat 1980-Proceedigs i computatioal statistics. Edited by MM Barritt, D Wishart. Wie, Physica, 1980, pp Depperma D, Heidlad A, Ritz E, Hori W: Lactat-Azidose Eie miigliche Komplikatio der Buformi-Therapie. Kli Wocheschr 1978; 56: Du Pot Istrumets: Lactic acid test methodology aca-dupot Automatic Cliical Aalyzer. Wilmigto, Du Pot Co., Istrumet Products Automatic Cliical Aalysis Divisio, Emmett M, Naris RG: Cliical use of the aio gap. Medicie (Baltimore) 1977; 56: Fieberg SE: The aalysis of cross-classified categorical data. Cambridge, Lodo, MIT Press, Forster H: Die Bedeutug der Laktat-Azidose als miigliche Nebewirkug bei Biguaid-Therapie. Fortschr Med 1976; 94: Haslbeck M, Wittma P, Bachma W, Mehert H: Verlauf, Therapie ud diagostische Probleme bei Diabetiker mit Laktatazidose ach Biguaidbehadlug. Ifusiostherapie 1978; 5: Huckabee WE: Abormal restig blood lactate. I. The sigificace of hyperlactatemia i hospitalized patiets. Am J Med 1961; 30: Huckabee WE: Abormal restig blood lactate. II. Lactic acidosis. Am J Med 1961; 30: Huckabee WE: Lactic acidosis. Am J Cardiol 1963; 12: Krebs HA, Woods HF, Alberti KGMM: Hyperlactataemia ad lactic acidosis. Essays Med Biochem 1975; 1: Luft D: Kliische Bedeutug der Hyperlaktatamie. Stuttgart: Thieme, Misbi RI: Pheformi-associated lactic acidosis: Pathogeesis ad treatmet. A Iter Med 1977; 87: Oliva PB: Lactic acidosis. Am J Med 1970; 48: Peretz DI, McGregor M, Dossetor JB: Lacticacidosis: A cliically sigificat aspect of shock. Ca Med Assoc J 1964; 90: Ritz E, Heidlad A: Lactic acidosis. Cli Nephrol 1977; 7: Traquada RE, Grat WJ, Peterso CR: Lactic acidosis. Arch Iter Med 1966; 117: Varley H: Practical cliical biochemistry. Lodo, W. Heiema, 1967, pp Wise PH, Chapma M, Thomas DW, Clarkso AR, Hardig PE, Edwards JB: Pheformi ad lactic acidosis. Br Med J 1976; 1:70-72