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Synovial fluid lactic acid. a diagnostic aid in septic arthritis

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774
SYNOVIAL FLUID LACTIC ACID
A DIAGNOSTIC AID IN SEPTIC ARTHRITIS
ITZHAK BROOK, MICHAEL J . REZA, KENNETH S. BRICKNELL, RODNEY BLUESTONE,
and SYDNEY M . FINEGOLD
Lactic acid concentrations in the synovial fluid of
84 patients with acute monoarticular arthritis were determined by gas liquid chromatography. Lactic acid values in
27 cases of nongonococcal septic arthritis were strikingly
higher (mean 1170 mg/100 ml) than in 45 cases of inflammatory or degenerative arthritis (mean 34 mg/100 ml), as
well as in 12 cases of gonococcal arthritis (mean 27 mg/
100 ml). With the proper equipment, determination of
lactic acid can be a relatively rapid, reliable procedure.
Synovial fluid lactic acid concentrations therefore can be
used as a rapid, supplemental diagnostic aid in differentiating nongonococcal septic arthritis from both gonococcal
and nonseptic acute arthritis.
From the Infectious Disease and Rheumatology Sections.
Wadsworth VA Hospital and Department of Medicine, UCLA Medical Center. Los Angeles, California.
Presented in part at the Annual Meeting o f the American
Society for Microbiology, New Orleans, May 13, 1977, and at the XIV
International Congress of Rheumatology, San Francisco, June 29,
1977.
Itzhak Brook, M.D., M.S.: Assistant Professor of Child
Health and Development, George Washington University, Washington D.C.; Michael J . Reza, M.D.: Assistant Professor of Medicine and R heumatology, UCLA School o f Medicine; Kenneth Bricknell, M.S.C.: Research Associate, Infectious Disease; Rodney Bluestone, M.B., M.R.C.P.: Chief, Department of Rheumatology,
Wadsworth VA Hospital, Professor of Medicine, UCLA School of
Medicine; Sydney M. Finegold, M.D.: Chief, Infectious Diseases
Section, Wadsworth VA Hospital, Professor of Medicine, UCLA
School of Medicine.
Address reprint requests to Dr. Sydney Finegold. Infectious
Disease, 691/11 IF. Wadsworth VA Hospital. Wilshire and Sawtelle
Blvds.. Los Angeles CA 90073.
Submitted for publication March 28. 1978: accepted April 24.
1978.
Arthritis and Rheumatism, Vol. 21, No. 7 (September-October 1978)
The early and accurate diagnosis of septic arthritis is of great clinical importance. Without treatment,
bacterial infections can cause complete destruction of
joints with surprising rapidity. Differentiation of an infectious arthritis from a noninfectious inflammatory
synovitis is a frequent diagnostic problem for physicians. I n particular, patients who present with an acute,
monoarticular arthritis, with or without a history of a
chronic polyarthritis, should always be suspected of
having a septic arthritis. The gram stain of a smear of
synovial fluid, as well as a synovial fluid white blood cell
count, is often diagnostic of an infection and can be
done rapidly. Synovial fluid culture results, however,
usually are not available for 24 to 48 hours, and analysis
of these results may fail to yield a diagnosis despite
careful bacteriologic examination. This is particularly
true in cases of gonococcal arthritis and in patients who
have been partially or inadequately treated with antibiotics. I n addition to the sharp increase in the incidence
of gonococcal arthritis, we have recently seen several
patients with acute gouty and septic arthritis coexisting.
Although most physicians including ourselves
would start antibiotic therapy in a patient suspected of
having septic arthritis, an additional diagnostic test, if
sufficiently rapid, reliable, and simple to perform, could
be a clinical asset in the rapid diagnosis and treatment
of acute monoarticular arthritis.
Measurement of synovial fluid lactic acid concentrations in various pathologic conditions has been attempted in the past (1). However, almost all of the data
775
SYNOVIAL FLUID LACTIC ACID
collected were related to patients suffering from noninfectious inflammatory processes (2). A small increase
in the amount of lactic acid was noted in patients with
rheumatoid arthritis (when measured under low oxygen
tension) (3). Also, in vitro studies revealed that bacterial
endotoxins could cause an increase in the amount of
synovial fluid lactate (4).
Recent work done by various investigators has
demonstrated that elevations of lactic acid in cerebrospinal fluid indicated the presence of bacterial meningitis
(5-7). This test was proved to be very reliable in the
differentiation between aseptic meningitis and bacterial
meningitis, even in partially treated cases. W e were thus
stimulated to study synovial fluid lactic acid concentrations in 84 cases of acute, monoarticular arthritis to see
if this test could be of value in the rapid diagnosis of
septic arthritis.
MATERIALS AND METHODS
Patients with a diagnosis of untreated, acute monoarticular arthritis (8) were admitted to Wadsworth Hospital
Center, Veterans Administration Hospital, and the University
of California, Los Angeles Medical Center between August 1,
1976 and March 1, 1977. On admission and before any therapy
was given, the inflamed joints were aspirated. Repeated aspiration during the course of therapy was performed in several
Table 1. Diagnosis in 84 Patients with Acute
Monoarticular Arthritis
Diagnosis
Septic (39 cases)
Gonococcus
Staphylococcus aureus
Pseudomonas A eruginosa
Other gram-negative bacilli
(Klebsiella-2; Proteus mirabilis-2
Enterobacter-1; H influenza-I;
E coli-I)
Anaerobic streptococcus
Pneumococcus
Candida A lbicans
Inf7ammatory (32 cases)
Rheumatoid arthritis
Acute gout or pseudogout
Chronic inflammatory bowel disease
Reiter’s syndrome
Psoriatic arthritis
Systemic lupus erythematosus
Degenerative (13 cases)
Osteoarthritis
Traumatic
Total study group
Number of Patients
12
I1
6
I
1
1
1
16
9
4
1
1
I
8
5
84
cases as indicated by the clinical course. The patients were
divided into three major subgroups (Table I): A) septic, B)
inflammatory, and C ) degenerative arthritis; each of which
was further subdivided into specific diagnostic entities.
Group A: Septic Arthritis. In addition to positive synovial fluid bacterial cultures, patients in this group tended to
have depressed synovial fluid glucose in the presence of elevated W BC (especially polymorphonuclear leukocytes)
counts. Of the 12 patients with gonococcal arthritis, 8 had
positive synovial cultures for gonococci, while 4 had the diagnosis established on the basis of positive urethral cultures for
gonococci, tenosynovitis, pustular skin rash, and rapid response to intravenous penicillin.
Groups B and C: Inflammatory and Degenerative Arthritis. Patients with the following diagnoses presented with an
acute exacerbation of arthritis, negative bacterial cultures, and
clinical and biochemical evidence of the conditions listed below:
1. Rheumatoid arthritis (8) (16 patients in group B)
2. Osteoarthritis (degenerative joint disease) (8 in
group C)
3. Acute gout and pseudogout (crystal proven) (9 in
group B)
4. Traumatic arthritis. Patients with this diagnosis had
acute trauma to their joints within 48 hours and
presented with joint effusions, usually bloody (5 in
group C)
5. Chronic inflammatory bowel disease (4 in group B)
6. Reiter’s syndrome (HLA-B27 antigen positive) ( 1 in
group B)
7. Psoriatic arthritis ( 1 in group B)
8. Systemic lupus erythematosus ( 1 in group B)
The synovial fluid was obtained by direct puncture of
the affected joints using aseptic technique. Fluids that were
grossly bloody were not included in the study. One-tenth milliliter of 50% sulfuric acid was added to 0.9 ml of the synovial
fluid immediately after collection. Specimens were placed in a
sterile tube and frozen immediately at -20°C until analyzed.
Lactic acid measurement was done as previously described using gas liquid chromatography (GLC) (9). After
methylation, 10 M I of the chloroform extract was injected into
a 6 foot X ‘/s inch (outside diameter) stainless steel Resoflex
column (Gurrell Company, Pittsburgh, Pennsylvania), using a
thermal conductivity detector (Varian Aerograph, Sunnyvale,
California). Helium carrier gas at 60 ml/minute was used.
Injector block temperature was 1550C, the column was 145OC,
and the detector block 160°C.
RESULTS
Eighty-four patients were studied (Table 1). Seventy-two of t h e patients were males, and 12 were females. Their ages ranged from 23 to 66 years; the average age was 45 years. There were 39 patients in the septic
arthritis group, including 12 with gonococcal arthritis,
and 45 in the nonseptic arthritis group.
All patients with gonococcal arthritis had lactic
acid concentrations in the synovial fluid of less than 50
776
BROOK ET AL
Table 2. Synovial Fluid Lactic Acid Concentration in Acute Monoarticular Arthritis
~~
Diagnosis
Average Lactic
Acid Level (mg%)
No. of Patients
Septic (39 cases)
Gram-negative rod infections
Gram-positive coccal infections
Gonococcal infections
Candida albicans infection
Inflammatory (32 cases)
Rheumatoid arthritis
Gouty arthritis and pseudogout
Inflammatory bowel disease
Reiter's syndrome
Psoriatic arthritis
Systemic lupus erythematosus
Degenerative (13 cases)
Osteoarthritis (DJD)
Traumatic arthritis
Total patients
mg/100 ml (average 27 mg/100 ml + 11.3) (Table 2). All
patients with Pseudomonas and other gram-negative bacillary infection had lactic acid concentrations greater
than 130 mg/100 ml (average 1,587 mg/100 ml f 998.6);
in one case of Pseudomonas arthritis where followup
aspirations were done, lactic acid values decreased after
intraarticular aminoglycoside therapy from 135 mg/ 100
ml to 19 mg/100 ml (Figure I). There were 13 patients
with gram-positive coccal infection (1 1 Staphylococcus
uureus, 1 pneumococcal, and 1 due to an anaerobic
streptococcus). In all of these, lactic acid concentrations
were higher than 48 mg/100 ml (average 555 k 830). In
the group of patients with nonseptic effusions, synovial
lactate concentrations were all below 62 mg/100 ml
(mean 29.4 f 14.45).
Statistical analysis using the Student's t test
showed that synovial lactate concentrations from patients with gram-negative rod and gram-positive coccal
septic arthritis were significantly higher than those from
both the gonococcal septic arthritis group and the nonseptic inflammatory and degenerative arthritis groups ( P
< 0.001) (Table 3).
The distribution of the individual lactate values is
shown in Figure 2. It is obvious that there is no overlap
between lactic acid values in the gram-negative bacillary, gram-positive coccal, and fungal septic arthritides, as contrasted to the patients with gonococcal arthritis in whom lactic acid concentrations were
uniformly below 50 mg/100 ml. When only lactic acid
measurements were used, patients with gonococcal arthritis could not be differentiated from the patients with
13
Range of Lactic
Acid (rngW)
13
12
1
1587
555
27
2100
16
9
4
I
1
1
47
27
46
18
18
18
8-62
8-45
42-50
18
18
18
8
5
17
14
5-28
8-18
130-2500
48-2000
18-50
2100
84
inflammatory and noninflammatory arthritis. In the 2
cases of Staphylococcus aureus arthritis with low concentrations of lactic acid (48 and 52 mg/100 ml) (Figure 2)
it was discovered that both patients had received partial
antibiotic therapy prior to admission. Both were treated
orally with dicloxacillin for 5 and 6 days.
I6O1
THE CHANGES IN SYNOVIM FLUID LACTIC ACID IN A PATIENT
WITH PSEUDOMONAS ARTHRITIS WRING THERAPY
804
---
60.
40-
20-
1
3
5
-
1
4
I1
13
I5
17
1'9
+
)
x)
DAYS
Figure 1. These data were obtained from a 39-year-oldfemale with a
serious Pseudomonas aeruginosa septic arthritis of the knee. Synovial
fluid cultures were positive through day 9, transiently negative days 1013, then positive again on days 14-18. Recovery was temporally related
As can be seen,
to intraarticular therapy with I5 mg of tobramycin (T).
the synovial fluid lactic acid level remained elevated until infection was
completely eradicated with intraartimlar tobramycin. (G & C = gentamicin and carbenicillin intravenously: G = intraarticular gentamicin;
A = afebrile.)
SYNOVIAL FLUID LACTIC ACID
777
Table 3. Joint Fluid Characteristics in 84 Cases
No. of
Cases
Diagnosis
Septic arthritis (nongonococcal)
27
Gonococcal arthritis
12
Inflammatory
32
Degenerative
13
~~~~~~~
Mean
Total Protein
gm%
(Range)
5.5
(4.0-7.0)
4.7
(3.0-5.6)
3.2
(2.1-5.4)
2.5
(0.9-4.3)
Mean
Glucose
(Range)
Mean
WBC/mm8
(Range)
Mean
90 Polys
(Range)
20
(3-36)
30
(2-69)
83
(27- 125)
93
(81-109)
103,261
(3 1,240-202,000)
26,800
(1 020-74,OOO)
4845
(1 50-33,500)
787
(1 11-14,582)
97
(86-99)
85
(70-94)
51
(4-86)
27
(0-40)
mg%
Mean
Lactic Acid
(Range)
I l70*
(48-2500)
27
( I 8-50)
39
(8-62)
16
(5-28)
~
* P value between septic arthritis and gonococcal arthritis is << 0.001; P value between septic arthritis
Synovial fluid glucose concentrations varied
greatly in the noninfectious groups (mean 82.2 f 31.3)
with exceedingly low concentrations being found in
some rheumatoid effusions. The synovial fluid white
blood count was much lower in nonseptic arthritis
and inflammatory arthritis is
(mean 4,393 f 6,069) as compared with septic arthritis
(mean 103,261 i= 42,398 per cubic millimeter). However,
there was considerable overlap in the synovial white
blood cell count between the nonseptic inflammatory,
gonococcal, and septic groups.
...f
..
I50
ACID MG%
I
.
SEPTIC ARTH.
<< 0.001.
INFLAMMATORY ARTH.
OA
....
1 TRAUMA
NON- INFLAMM
ARTH
Figure 2. Synovial fluid lactic acid concentrations in 82 patients with septic, inflammatory, and noninflammatory arthritis. Gm (+) cocci = gram-positive cocci: CC = gonococcal; G m (-) Bac. = gramnegative bacilli; fung = fungal; gout = acute crystal synovitis; R A = rheumatoid arthritis; colitis = inflammatory bowel disease; OA = osteoarthritis. Not shown here are 2 patients (cases 83 and 84) with sterile.
post-traumatic arthritis, in whom lactit acid values were 18 and 16 mg/lOO ml.
778
BROOK ET AL
DISCUSSION
The data presented suggest that lactic acid measurements can be used as an additional valuable diagnostic tool in differentiation between gonococcal and
nongonococcal septic arthritis, especially in cases where
other diagnostic data are overlapping and not clear-cut.
Lactic acid measurement can clearly differentiate between septic arthritis other than gonococcal and other
sterile inflammatory and noninflammatory conditions in
the joints and can alert the physician to the presence of
bacterial infection in patients suffering from any of the
types of chronic polyarthritis. Of importance are the 2
patients with partially treated staphylococcal arthritis in
whom the synovial fluid lactate levels were normal. It is
not clear why their cultures were positive yet their lactate levels were within the normal range. Because this is
a common clinical situation, the authors would stress
that joint fluid lactate levels can be misleading in those
patients who have been partially or inadequately treated
with antibiotics and should not be used as a basis for
withholding necessary antibiotic therapy.
The mechanism of lactic acid formation in the
joints has been studied in the past. Studies of synovial
membrane metabolism as reflected by oxygen and bicarbonate’tension, pH and lactic acid formation showed
that decrements in oxygen partial pressures in rheumatoid arthritis joint fluids were accompanied by decrease
in pH and in increase in Pcoz and lactic acid concentration (1). These changes signified the changeover of local
tissues from mainly aerobic to largely anaerobic (glycolytic) metabolism. Other investigators found an inverse
relationship between lactic acid synovial levels and glucose (10). Glucose is metabolized to pyruvic acid which
is converted to lactic acid-a “metabolic blind alley”
under anaerobic conditions. Other studies, mainly in
rheumatoid arthritis, confirmed the above findings
showing that low pH values and high Pcoz and lactic
values correlated with low oxygen partial pressures ( 1 1).
Lactic acid concentrations in these studies of patients
with rheumatoid arthritis were usually in the range of 15
to 55mg/100 ml. Lactic acid concentrations in bacterial
inflammatory arthritis have not been hitherto studied.
In vitro experiments studying the effects of bacterial products on selected synovial fibroblast functions
have been teported (4).Extracts of gram-negative bacteria applied to fibroblast cultures markedly increased
hyaluronic acid production, glucose utilization, and lactate production. On the other hand, extracts of grampositive cocci (staphylococci and streptococci) and Neisseria gonorrhoeue had no stimulating capabilities. The
“activation phenomenon” caused by materials from
bacteria may participate with the known action of connective tissue activating peptide (CTAP), which is postulated to be a mediator in the inflammatory reaction
(12). These data correlate with the elevated lactic acid
concentrations in patients with gram-negative bacillary
arthritis reported here. They do not, however, explain
the elevated synovial lactate noted here in staphylococcal and other gram-positive coccal infections. Since,
however, only bacterial products were used in the above
experiments, the participation of other constituents of
the whole bacteria may contribute by the additional
stimulus of other unidentified bioactive materials that
produce the increase in lactic acid.
The lack of significant lactic acid elevation in
gonococcal arthritis may signify, therefore, the inability
of bacterial products of this organism to cause the metabolic changes capable of producing excess lactate. Interestingly, synovial lactates were similar in joint fluid culture-positive and negative gonococcal arthritis, the
latter thought by some to be a-hypersensitivity or immunologic phenomenon.
Lactic acid measurement therefore appears to be
a valuable additional diagnostic tool in the early differentiation between gonococcal and nongonococcal septic
arthritis, and between nongonococcal septic arthritis
and nonseptic arthritis before bacterial cultures are
available. Although gas liquid chromatography apparati
are not routinely available in all hospitals, determination of synovial fluid lactic acid concentration in centers
where gas liquid Chromatography is available can be a
relatively simple, rapid, and reproducible test.
ACKNOWLEDGMENTS
The authors would like to thank Ms Linda Prince and
Ms Wendy Barend for secretarial assistance, and Mr.David
M. Reza for assistance in preparing the joint fluid specimens.
REFERENCES
I . Treuhalt PS, McCarty DJ: Synovial fluid pH, lactate,
oxygen and carbon dioxide partial pressure in various
joint diseases. Arthritis Rheum 14475-484, 1971
2. Roberts JE, McLess BD, Werley G P Pathways of glucose
metabolism in rheumatic and non-rheumatic synovial
membrane. J Lab Clin Med 70503-511, 1967
3. Goetzl E, Rynes RI, Stillman S: Abnormalities of respiratory gases in synovial fluid of patients with juvenile
rheumatoid arthritis. Arthritis Rheum 17:450-454, 1974
4. Buckingham RB, Custer CV, Hoag P F The effect of
SYNOVIAL FLUID LACTIC ACID
bacterial products on synovial fibroblast function: hypermetabolic changes induced by endotoxin. J Clin Invest
5 1 : 1 186-1 194, 1972
Bland RD, Lester RD, Ries, J P Cerebrospinal fluid lactic
acid and pH in meningitis. Am J Dis Child 128:151-156,
I974
Controni G, Rodriguez WJ, Dean C, et al: Rapid diagnosis of meningitis by gas liquid chromatographic analysis of
cerebrospinal fluid lactic acid. CI Proc Child Hosp Nat
Med Ctr 31:194-201, 1975
Brook I, Bricknell KS, Overturf G, et al: Spinal fluid lactic
acid, a diagnostic acid in bacterial meningitis. Pediatr Res
10:396, 1975 (abstract)
Ropes MW, Bennett GA, Cobb S, et al: 1958 Revision of
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Bricknell KS, Sugihara PT, Brook I: Optimizing methylation conditions for gas-liquid chromatography assay of
lactic acid in biological samples. Abstr of Annual Meeting, Amer SOCMicrobiology, 1976 p 44
Lund-Olsen K: Oxygen tension in synovial fluids. Arthritis
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Falchuk KH, Goetzl El, Kulka JR:. Respiratory gases of
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metabolic imbalance in rheumatoid arthritis. Am J Med
49~223-231, 1970
Castor CW: Connective tissue activation. I. The nature,
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time activation peptide. Arthritis Rheum 14:41-54, 1971
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