- Email: [email protected]
Effects of the menstrual cycle, pregnancy, hysterectomy, and other operative procedures upon urinary mucopolysaccharide excretion: A preliminary report
Effects of the menstrual hysterectomy,
cycle, pregnancy,
and other operative procedures
upon urinary mucopolysaccharide A preliminary WILLIAM GEORGE S. Ann
J. R.
LOUISE Arbor,
LEDGER,
report M.D.
THOMPSON, GROBELNY,
excretion:
M.D. M.S.
Michigan
Mucopolysaccharide (MPS) determinations were performed on 174 24 hr. urine specimens from 57 patients. Urinary MPS were increased on the fifteenth and twentieth days of the menstrual cycle. Normal pregnancy was associated with a rise in urinary MPS excretion that persisted in the early postgartum fleriod. At least a portion of the elevated MPS of the postpartum period seems to be contributed by the involuting uterus, for MPS excretion was lower in patients undergoing cesarean hysterectomy than in those women who had cesarean section. Urinary MPS were increased following hysterectomy and other operative procedures. Generally, the more major procedures were accompanied with the highest levels of MPS excretion. Significant pelvic infection postoperatively was associated with rises in MPS excretion. The significance of these findings is discussed.
hysterectomy was stimulated by the knowledge that the laying down of ground substance was a predictable biochemical event in the formation of connective tissue as healing after major operative trauma. progresses This turnover of MPS should be reflected in the postoperative urinary excretion. In addition, plasma MPS are increased in patients with inflammatory conditions, including those secondary to bacterial infections.6 The clinical evaluation of postoperative infection is imprecise with no consistent laboratory tests available to aid in the diagnosis. Evaluation of urinary MPS in normal patients and in those with postoperative infectious morbidity might clarify the nature of the infectious and provide precise biochemical process measurements in such patients. For comparison, we made a number of MPS determinations in nonpregnant women at various times during the menstrual cycle, in pregnant
MLJCOPOLYSACCHARIDES (MPS), or glycosaminoglycans, are long-chain polymers, composed of alternating hexosamine and hexuronic acid moieties. These compounds form the basis for the anionic character of the ground substance of connective tissue. Because of this integral relationship with connective tissue, MPS excretion has been studied in a number of clinical conditions. An increase in the urinary excretion of MPS has been found in patients with diseases that primarily affect connective tissue1m4 and in patients with diverse pathologic conditions.5 Our interest in MPS excretion following From the Department of Obstetrics and Gynecology and the Department of Internal Medicine, The University of Michigan, and Wayne County General Hospital. This work was supported by United States Public Health Service Grant AM 09796 (Dr. Thompson).
494
Volume Number
110 4
Urinary
women at different and in postpartum Materials
and
intervals patients.
ante
partum,
*Furadantin,
Eaton
methods
Labs.,
Inc.,
__I_
Table I. Patient
Norwich,
New
York.
_____-----~..1 i No. of patients
Nonpregnant Pregnant-ante partum Pregnant-post partum Nonpregnant hysterectomy Other operative pr.lcedures
,1; 11 i
I- 8
MPS cycle
excretion (expressed Excretion
R. L. C. R.
19
1:: -y; $-
57
menstrual
Subject
MPS determinations
4 6 18 21
Totals
Table II.
-Day
T. B. T. P.
6.0 2.8 2.3 ___7.1
Totals Mean
18.2 4.6
495
population
GKHlfl
Twenty-four-hour urine samples were collected from patients from the Obstetric and Gynecology Service of the University of Michigan Medical Center and Wayne County General Hospital. One hundred seventy-four MPS determinations were performed on the 24 hr. urine samples of 57 patients. The clinical categories of the patients studied and the numbers of urine samples evaluated are noted in Table I. The most detailed studies were done in Groups 1 and 4 designated in Table I. The 4 nonpregnant volunteers, who were not taking oral contraceptives, collected urine samples at regular intervals during the menstrual cycle. The largest single group of patients studied in detail underwent elective hysterectomy. There were one hundred thirteen 24 hr. urine samples collected from 21 patients. These patients ranged from 27 to 67 years of age. Nine had abdominal hysterectomies and 12 had vaginal hysterectomies. Of these 21 patients, 7 had no infectious morbidity following operation. Ten patients had minor morbidity, i.e., 9 had lower urinary tract infections requiring either sulfa or l[ (5-nitrofurfurylidene) amino] hydantoin”, and one patient developed atelectasis and was treated with intermittent positive pressure breathing without antibiotics. Four patients had more serious infectious morbidity. Two had a pelvic cellulitis requiring systemic antibiotics, ,lnd 2 had postoperatve adnexal infections requiring a second operation. Less detailed studies were done in Groups 2, 3, and 5 (Table I). Antepartum MPS determinations were made on 6 normal women at various stages of pregnancy and on 18 women on the first or second postpartum day. Eight of the latter group had vaginal deliveries; 6 had cesarean sections; and 4 had cesarean hysterectomies. In addition, 8 patients having operative procedures other
excretion
mucopolysaccharide
5 1Day
IO 1Day
6.6 3.7 ‘1.0 5.6 -17.9 4.5
during the as milligrams) --.~----.-~~ ~..-~-. (mg.) _----~15 1Day
-..-20 1 Day 25
7.9 6.0 2.6 --10.1
5.6 6.0 4.3 7.8 --..
6.0 2.1 -6.6
26.6 6.7
"3.7 5.9
I:!:.+ 4.9
than hysterectomy were evaluated. These operations varied in magnitude from dilatation and curettage plus a conization to a cholecystectomy. MPS were precipitated from 24 hr. urine specimens with cetylpyridinium chloride with the use of the method previously described from our laboratory.” FolIowing reprecipitation, MPS was measured as uranic acid, with the use of the carbazole reaction.’ With this method” normal 24 hr. excretion for women is 6.8 k 2.2 mg. The creatinine content of each urine specimen was also determined, with the use of a modification of thr Jaffe renction.q Results
Nonpregnant patients. Four wortlen of childbearing age were evaluated as outpatients at various intervals during thl- menstrual cycle (Table II). All subjects were of proved fertility, had menses at regular intervals, every 28-32 days, and none was taking oral contraceptives, All had a medical background, being either physician’;; wives or hospital personnel, and were well oriented toward achieving a complete 24 hr. collection. A consistent increase of 30 to 50 per cent in MPS excretion was observecl on the
496
Ledger,
Thompson,
and
Grobelny Amer.
June 15, 1971 J. Obstet. Gynec.
Temperature =M Bars = Mean
2
20
I
= Standard
Error
P E” 63 15 e b r 8 HI0 5 8 2 -5
99O 98.6’
g” r 3 1 Mean Urinary Creatinine Grams/Whr. Number Patients
‘re )P
Op Day
0
1.03
1.12
I.13
1.07
1.08
I.15
1.07
I2
9
13
I5
I4
IO
8
i;;
3IY
6
7
Day 8
1.07
.98
1.08
II
9
5
af
Fig. 1. Urinary mucopolysaccharide elevations are superimposed upon collections in patients more than
excretion following hysterectomy. the mucopolysaccharide determinations. 8 days postoperative are not included
fifteenth and twentieth days of the menstrual cycle. Although the mean values were not statistically significant (p > 0.05), this no doubt reflects the small sample size. Pregnant patients. Twenty-four-hour urinary MPS determinations were obtained ante partum and on the first or second postpartum day following vaginal delivery, cesarean section, and cesarean hysterectomy (Table III), The mean values in each instance were higher than those obtained from nonpregnant patients (6.8 mg. per 24 hr.), and the highest values of all were obtained in post-cesarean section patients. Postoperative studies. Mean MPS determinations with standard errors of the mean in patients undergoing hysterectomy are graphically portrayed in Fig. 1. The average temperature elevations of these patients in the postoperative period have been superimposed upon this bar graph, and mean urinary creatinine is noted. The urinary MPS of the day of operation and each of Days 1 to 8 of the postoperative period were consistently greater than the control values obtained preoperatively. The patients with more serious infectious
Table III. Urinary
Mean temperature Seven 24 hour urine in this diagram.
MPS
No. of determinations
GTOUP Normal-ante Vaginal post
partum
deliverypartum
Cesarean sectionpost partum Cesarean -post Normal
hysterectomy partum =
in pregnant
6.8 + 2.2 mg. per
women
Mean (mg./24
6
18.0
8
13.5
6
36.4
4
19.0
hr.)
24 hr.
morbidity following hysterectomy are discussed individually. Fig. 2 depicts the clinical course and MPS determinations of a patient with pelvic cellulitis in the immediate postoperative period. This patient did not become afebrile until she had received systemic antibiotics for 4 days. The severity of the infection clinically paralled an increased level of MPS in the urine. Each of the MPS determinations of this patient on postoperative Days 4, 5, 6, and 7 were greater than the mean plus 2 standard deviations of the mean. These are highly significant increases. The other 3 patients developed morbidity
Volume 110 Number
Urinary
mucopolysaccharide
excretion
497
4
Table IV. MPS m
MEAN
VALUES
in other
operative
procedures
Procedure
Preoperative values (mg./24 hr.)
Postoperative values (mg./24 hr.)
Tubal
ligation
5.6
8.8
Tubal
ligation
6.6
8.1
Dilatation tage,
and curetconization
i.!) 6.4 8..2
Hysterotomy at 18 weeks’ gestation
Herniorrhaphy
16.9
Herniorrhaphy
17 .I
Insertion Nail
30 ‘5
of Badgley (Hip)
Cholecystectomy op Day
poet op I
0’ 0 !
3
4
5
6
64-- 3__
7
Fig. 2. Urinary mucopolysaccharide excretion in a patient with pelvic cellulitis in the postoperative period. The mucopolysaccharide values are superimposed upon the mean values obtained in this study. Clinical@, this patient did not become afebrile until the fourth day of antibiotic therapy. *Clinical diagnosis was pelvic cellulitis. The patient was given systemic antibiotics.
iatc in the postoperative course, and all were discharged from the hospital after the original operation, only to be readmitted with a serious pelvic infection. MPS determinations were obtained from one patient readmitted on the sixteenth postoperative day with a diagnosis of pelvic cellulitis. Her MPS values were elevated but to a much lesser degree than that found in the other patients with pelvic cellulitis, and she responded rapidly to systemic antibiotics, becoming afebrile within 24 hr. Fig. 3 depicts the in-patient course of 2 patients, each hospitalized with an adnexal abscess. E. S. is unique for we have MPS determinations available from the initial hospitalization, and these were within the range of normal values as determined in this study (Fig. 1) . The MPS obtained after removal of the adnexal abscess was much lower than preoperative values. The fourth patient, 0. M.,
had no MPS determinations from her initial hospitalization. She was readmitted, and MPS were obtained 2 days prior to laparotomy and removal of the adnexal abscesses. These determinations are also depicted in Fig. 3. The 53.8 mg. per 24 hr. represents the highest value for MPS obtained in all of the women undergoing hysterectomy evaluated in this study. Table IV lists the urinary MPS in patients having operations other than hysterectomy. All patients evidenced some increase in MPS excretion in the postoperative period over expected values. In general, the more major operative procedures were associated with the highest values of MPS. Comment
A review of our data suggests that various segments of the life cycles of women may affect the levels of MPS excreted in the urine. The 4 nonpregnant women each had an increase in MPS excretion on the fifteenth and twentieth days, which corresponds with the earIy secretory phase of the menstrua1 cycle. Previous data from this laboratory suggest that the level of MPS excretion in the urine is not estrogen dependent, for normal values in women age 60 or older are
498
Ledger,
Thompson,
and
Grobelny
ES. OM
-
Fig. 3. Urinary mucopolysaccharide determinations from patients with postoperative adnexal abscesses confirmed by laparotomy. Patient E. S. is unique for we have mucopoly accharide values from the initial hospitalization and following operative removal of the absc d.
similar to those of women of childbearing age.g Normal pregnancy seems to be associated with an increased MPS excretion. This might be expected, for pregnancy is an anabolic phenomenon characterized by nitrogen retention with an increased production of ground substance and collagen within the maternal uterus and the fetus with the continued growth of each.lO The increase in MPS excretion associated with pregnancy persists in the postpartum period (Table III). At least a portion of this must be contributed by the involuting postpartum uterus, for this is the only occasion in OUI data where the more major operative procedure (cesarean hysterectomy) yielded lower MPS values than the lesser one (cesarean section). An obvious factor would seem to be removal of the involuting uterus as a source of urinary MPS in those patients undergoing cesarean hysterectomy.
Total abdominal hysterectomy and vaginal hysterectomy were associated with an increase in urinary MPS excretion in the postoperative period. This seems to be a physiologic response to the operative trauma of hysterectomy, for the increased levels of MPS were found in all patients, including those without morbidity. The rise in MPS postoperatively roughly parallels the temperature elevations found (Fig. 1) , but the increased levels of MPS diminished at a slower rate than the temperature elevations. Other operative procedures also induced mucopolysacchariduria. However, those patients with less extensive operative procedures demonstrated a smaller rise in MPS excretion than those undergoing a more major procedure (Table IV). The postoperative urinary MPS excretion results do not parallel the pattern of collagen synthesis in incisional wounds. His-
Urinary
tochemical and biochemical studies have delineated a lag phase until the fourth to sixth day of wounding, when collagen synthesis begins and continues until about the fifrise in urinary teenth day. I1 The immediate MPS in patients following hysterectomy thus precedes collagen synthesis. There are a number of possible explanations for this phenomenon. It may reflect the early laying down of ground substance in the connective tissue scars, occurring in the phase of reparative inflammation, prior to the formation of collagen fibers.l” Another factor may be the metabolic status of postoperative patients following major operations, for it has been demonstrated that fasting consistently increases urinary hydroxyproline, one of the constituents of collagen fibers.13 The severity of pelvic infections following hysterectomy was paralleled by markedly elevated urinary mucopolysaccharides. Three of the 4 patients with postoperative pelvic inSection had the highest MPS determinations obtained in those women undergoing hysterectomy. These patients required a long treatment course with antibiotics, and, in two instances, operative removal of an abscess. The fourth patient, with less elevated MPS, had a dramatic clinical response to antibiotics and was afebrile within 24 hr. The patients with adnexal abscess following hysterectomy fit the clinical pattern that has been described in a previous pub1ication.l’ They were premenopausal women, undergoing elective vaginal hysterectomy, and their infectious complications were noted late in the postoperative period. Two of the 3 patients requiring readmission had MPS determinations during their original hospitalization, and these were not elevated above the levels found in other patients following hysterectomy. Elevated urinary MPS in the immediate postoperative period did not serve as a marker to detect the patient who would later develop an adnexal abscess. This is an interesting observation, for, ciinicaily, there had been no evidence of pelvic infection in these women at the time of discharge examination. This suggests to us that the post-
mucopolysaccharide
excretion
499
operative adnexal infection is either a very low-grade inflammatory process at this point or, alternatively, the infection is acquired later outside of the hospital. In those patients requiring operative intervention for postoperative adnexal abscesses, the MPS values obtained prior to operative removal of the abscesses were well above the range seen in postoperative hysterectomy patients and were much higher than those obtained in the patient readmitted with pelvic cellulitis. Removal of the adnexal abscess caused a dramatic drop in MPS, suggesting this infection, and the pelvic reaction to it: were major sources of the elevated MPS excreted in the urine. The finding of elevated urinary MPS in patients with bacterial infections supports the previous observation of eievated plasma MPS in similar circurnst;mces.6 The mechanism for the increased excretion of MPS in postoperative patients is not known. Urinary MPS excretion probably reflects both synthesis and breakdown of connective tissue. The early rise in MPS excretion following hysterectomy? other surgical procedures, parturition, and particularly the tremendous elevations in patients with severe infectious morbidity suggest tllat tissue breakdown is an important factor. Alternatively, the rise in MPS cxcretitln during pregnancy suggests that new formation Iof connective tissue in the absence ol’ infection can also increase MPS in thtx urine. Because of the complexity of this test, both in time and technique, it is lmlikely that it could be used as a routine et-nluation for all postoperative patients. Also: in this series of patients, it did not prove tc> be an indicator for those women who wotild later develop serious infection. It is of interest to note in Fig. 2 that elevated urina1.y MPS occurred 2 days before the clinical diagnosis of a prlvic cellulitis was made and a;ltibiotic therapy was begun. The urinary excretion of MPS seems to reflect the extent and degree of pelvic inflammation and infection in patients with postoperative morbid&. Prospective studies in the future will )Ilore accurately delineate the practical valuers of this laboratory procedure.
500
Ledger, Thompson,
and Grobelny
Amer.
June 15, 1971 J. Obstet. Gynec.
REFERENCES
1. Dorfman, A., and Matalon, R.: Amer. J. Med. 47: 691, 1969. 2. Di Ferrante, N.: J. Clin. Invest. 36: 1516, 1957. 3. Di Ferrante, N., Robbins, W. C., and Rich, C.: J. Lab. Clin. Med. 50: 897, 1957. 4. Be&son, G. S., and Dalferes, E. R., Jr.: Clin. Res. 11: 57. 1963. G. R.: Castor, C. W., Ballantyne, 5. Thompson, L. M., and Prince, R. K.: J. Lab. Clin. Med. 68: 617, 1966. 6. Kerby, G. P.: J. Clin. Invest. 37: 962, 1958. 7. Bitter, T., and Muir, H. M.: Anal. Biochem. 4: 330, 1962.
8. 9. 10. 11. 12. 13. 14.
Bonsnes, R. W., and Taussky, H. H.: J. Biol. Chem. 158: 581, 1945. Thompson, G. R.: Unpublished data. Zusvan, F. P.. and Goodrich. S.: AMER. ”T. OR&ET. GY&c. 100: 7, 1968: Dunphy, J. E., and Udupa, K. N.: New Eng. J. Med. 233: 847, 1955. Bole, G. G., and Robinson, W. D.: J. Lab. Clin. Med. 59: 713, 1962. Bell, N. H.: J. Clin. Endocr. 29: 338, 1969. Ledger, W. J., Campbell, C., Taylor, D., and Willson, J. R.: Surg. Gynec. Obstet. 129: 973, 1969.
cycle, pregnancy,
and other operative procedures
upon urinary mucopolysaccharide A preliminary WILLIAM GEORGE S. Ann
J. R.
LOUISE Arbor,
LEDGER,
report M.D.
THOMPSON, GROBELNY,
excretion:
M.D. M.S.
Michigan
Mucopolysaccharide (MPS) determinations were performed on 174 24 hr. urine specimens from 57 patients. Urinary MPS were increased on the fifteenth and twentieth days of the menstrual cycle. Normal pregnancy was associated with a rise in urinary MPS excretion that persisted in the early postgartum fleriod. At least a portion of the elevated MPS of the postpartum period seems to be contributed by the involuting uterus, for MPS excretion was lower in patients undergoing cesarean hysterectomy than in those women who had cesarean section. Urinary MPS were increased following hysterectomy and other operative procedures. Generally, the more major procedures were accompanied with the highest levels of MPS excretion. Significant pelvic infection postoperatively was associated with rises in MPS excretion. The significance of these findings is discussed.
hysterectomy was stimulated by the knowledge that the laying down of ground substance was a predictable biochemical event in the formation of connective tissue as healing after major operative trauma. progresses This turnover of MPS should be reflected in the postoperative urinary excretion. In addition, plasma MPS are increased in patients with inflammatory conditions, including those secondary to bacterial infections.6 The clinical evaluation of postoperative infection is imprecise with no consistent laboratory tests available to aid in the diagnosis. Evaluation of urinary MPS in normal patients and in those with postoperative infectious morbidity might clarify the nature of the infectious and provide precise biochemical process measurements in such patients. For comparison, we made a number of MPS determinations in nonpregnant women at various times during the menstrual cycle, in pregnant
MLJCOPOLYSACCHARIDES (MPS), or glycosaminoglycans, are long-chain polymers, composed of alternating hexosamine and hexuronic acid moieties. These compounds form the basis for the anionic character of the ground substance of connective tissue. Because of this integral relationship with connective tissue, MPS excretion has been studied in a number of clinical conditions. An increase in the urinary excretion of MPS has been found in patients with diseases that primarily affect connective tissue1m4 and in patients with diverse pathologic conditions.5 Our interest in MPS excretion following From the Department of Obstetrics and Gynecology and the Department of Internal Medicine, The University of Michigan, and Wayne County General Hospital. This work was supported by United States Public Health Service Grant AM 09796 (Dr. Thompson).
494
Volume Number
110 4
Urinary
women at different and in postpartum Materials
and
intervals patients.
ante
partum,
*Furadantin,
Eaton
methods
Labs.,
Inc.,
__I_
Table I. Patient
Norwich,
New
York.
_____-----~..1 i No. of patients
Nonpregnant Pregnant-ante partum Pregnant-post partum Nonpregnant hysterectomy Other operative pr.lcedures
,1; 11 i
I- 8
MPS cycle
excretion (expressed Excretion
R. L. C. R.
19
1:: -y; $-
57
menstrual
Subject
MPS determinations
4 6 18 21
Totals
Table II.
-Day
T. B. T. P.
6.0 2.8 2.3 ___7.1
Totals Mean
18.2 4.6
495
population
GKHlfl
Twenty-four-hour urine samples were collected from patients from the Obstetric and Gynecology Service of the University of Michigan Medical Center and Wayne County General Hospital. One hundred seventy-four MPS determinations were performed on the 24 hr. urine samples of 57 patients. The clinical categories of the patients studied and the numbers of urine samples evaluated are noted in Table I. The most detailed studies were done in Groups 1 and 4 designated in Table I. The 4 nonpregnant volunteers, who were not taking oral contraceptives, collected urine samples at regular intervals during the menstrual cycle. The largest single group of patients studied in detail underwent elective hysterectomy. There were one hundred thirteen 24 hr. urine samples collected from 21 patients. These patients ranged from 27 to 67 years of age. Nine had abdominal hysterectomies and 12 had vaginal hysterectomies. Of these 21 patients, 7 had no infectious morbidity following operation. Ten patients had minor morbidity, i.e., 9 had lower urinary tract infections requiring either sulfa or l[ (5-nitrofurfurylidene) amino] hydantoin”, and one patient developed atelectasis and was treated with intermittent positive pressure breathing without antibiotics. Four patients had more serious infectious morbidity. Two had a pelvic cellulitis requiring systemic antibiotics, ,lnd 2 had postoperatve adnexal infections requiring a second operation. Less detailed studies were done in Groups 2, 3, and 5 (Table I). Antepartum MPS determinations were made on 6 normal women at various stages of pregnancy and on 18 women on the first or second postpartum day. Eight of the latter group had vaginal deliveries; 6 had cesarean sections; and 4 had cesarean hysterectomies. In addition, 8 patients having operative procedures other
excretion
mucopolysaccharide
5 1Day
IO 1Day
6.6 3.7 ‘1.0 5.6 -17.9 4.5
during the as milligrams) --.~----.-~~ ~..-~-. (mg.) _----~15 1Day
-..-20 1 Day 25
7.9 6.0 2.6 --10.1
5.6 6.0 4.3 7.8 --..
6.0 2.1 -6.6
26.6 6.7
"3.7 5.9
I:!:.+ 4.9
than hysterectomy were evaluated. These operations varied in magnitude from dilatation and curettage plus a conization to a cholecystectomy. MPS were precipitated from 24 hr. urine specimens with cetylpyridinium chloride with the use of the method previously described from our laboratory.” FolIowing reprecipitation, MPS was measured as uranic acid, with the use of the carbazole reaction.’ With this method” normal 24 hr. excretion for women is 6.8 k 2.2 mg. The creatinine content of each urine specimen was also determined, with the use of a modification of thr Jaffe renction.q Results
Nonpregnant patients. Four wortlen of childbearing age were evaluated as outpatients at various intervals during thl- menstrual cycle (Table II). All subjects were of proved fertility, had menses at regular intervals, every 28-32 days, and none was taking oral contraceptives, All had a medical background, being either physician’;; wives or hospital personnel, and were well oriented toward achieving a complete 24 hr. collection. A consistent increase of 30 to 50 per cent in MPS excretion was observecl on the
496
Ledger,
Thompson,
and
Grobelny Amer.
June 15, 1971 J. Obstet. Gynec.
Temperature =M Bars = Mean
2
20
I
= Standard
Error
P E” 63 15 e b r 8 HI0 5 8 2 -5
99O 98.6’
g” r 3 1 Mean Urinary Creatinine Grams/Whr. Number Patients
‘re )P
Op Day
0
1.03
1.12
I.13
1.07
1.08
I.15
1.07
I2
9
13
I5
I4
IO
8
i;;
3IY
6
7
Day 8
1.07
.98
1.08
II
9
5
af
Fig. 1. Urinary mucopolysaccharide elevations are superimposed upon collections in patients more than
excretion following hysterectomy. the mucopolysaccharide determinations. 8 days postoperative are not included
fifteenth and twentieth days of the menstrual cycle. Although the mean values were not statistically significant (p > 0.05), this no doubt reflects the small sample size. Pregnant patients. Twenty-four-hour urinary MPS determinations were obtained ante partum and on the first or second postpartum day following vaginal delivery, cesarean section, and cesarean hysterectomy (Table III), The mean values in each instance were higher than those obtained from nonpregnant patients (6.8 mg. per 24 hr.), and the highest values of all were obtained in post-cesarean section patients. Postoperative studies. Mean MPS determinations with standard errors of the mean in patients undergoing hysterectomy are graphically portrayed in Fig. 1. The average temperature elevations of these patients in the postoperative period have been superimposed upon this bar graph, and mean urinary creatinine is noted. The urinary MPS of the day of operation and each of Days 1 to 8 of the postoperative period were consistently greater than the control values obtained preoperatively. The patients with more serious infectious
Table III. Urinary
Mean temperature Seven 24 hour urine in this diagram.
MPS
No. of determinations
GTOUP Normal-ante Vaginal post
partum
deliverypartum
Cesarean sectionpost partum Cesarean -post Normal
hysterectomy partum =
in pregnant
6.8 + 2.2 mg. per
women
Mean (mg./24
6
18.0
8
13.5
6
36.4
4
19.0
hr.)
24 hr.
morbidity following hysterectomy are discussed individually. Fig. 2 depicts the clinical course and MPS determinations of a patient with pelvic cellulitis in the immediate postoperative period. This patient did not become afebrile until she had received systemic antibiotics for 4 days. The severity of the infection clinically paralled an increased level of MPS in the urine. Each of the MPS determinations of this patient on postoperative Days 4, 5, 6, and 7 were greater than the mean plus 2 standard deviations of the mean. These are highly significant increases. The other 3 patients developed morbidity
Volume 110 Number
Urinary
mucopolysaccharide
excretion
497
4
Table IV. MPS m
MEAN
VALUES
in other
operative
procedures
Procedure
Preoperative values (mg./24 hr.)
Postoperative values (mg./24 hr.)
Tubal
ligation
5.6
8.8
Tubal
ligation
6.6
8.1
Dilatation tage,
and curetconization
i.!) 6.4 8..2
Hysterotomy at 18 weeks’ gestation
Herniorrhaphy
16.9
Herniorrhaphy
17 .I
Insertion Nail
30 ‘5
of Badgley (Hip)
Cholecystectomy op Day
poet op I
0’ 0 !
3
4
5
6
64-- 3__
7
Fig. 2. Urinary mucopolysaccharide excretion in a patient with pelvic cellulitis in the postoperative period. The mucopolysaccharide values are superimposed upon the mean values obtained in this study. Clinical@, this patient did not become afebrile until the fourth day of antibiotic therapy. *Clinical diagnosis was pelvic cellulitis. The patient was given systemic antibiotics.
iatc in the postoperative course, and all were discharged from the hospital after the original operation, only to be readmitted with a serious pelvic infection. MPS determinations were obtained from one patient readmitted on the sixteenth postoperative day with a diagnosis of pelvic cellulitis. Her MPS values were elevated but to a much lesser degree than that found in the other patients with pelvic cellulitis, and she responded rapidly to systemic antibiotics, becoming afebrile within 24 hr. Fig. 3 depicts the in-patient course of 2 patients, each hospitalized with an adnexal abscess. E. S. is unique for we have MPS determinations available from the initial hospitalization, and these were within the range of normal values as determined in this study (Fig. 1) . The MPS obtained after removal of the adnexal abscess was much lower than preoperative values. The fourth patient, 0. M.,
had no MPS determinations from her initial hospitalization. She was readmitted, and MPS were obtained 2 days prior to laparotomy and removal of the adnexal abscesses. These determinations are also depicted in Fig. 3. The 53.8 mg. per 24 hr. represents the highest value for MPS obtained in all of the women undergoing hysterectomy evaluated in this study. Table IV lists the urinary MPS in patients having operations other than hysterectomy. All patients evidenced some increase in MPS excretion in the postoperative period over expected values. In general, the more major operative procedures were associated with the highest values of MPS. Comment
A review of our data suggests that various segments of the life cycles of women may affect the levels of MPS excreted in the urine. The 4 nonpregnant women each had an increase in MPS excretion on the fifteenth and twentieth days, which corresponds with the earIy secretory phase of the menstrua1 cycle. Previous data from this laboratory suggest that the level of MPS excretion in the urine is not estrogen dependent, for normal values in women age 60 or older are
498
Ledger,
Thompson,
and
Grobelny
ES. OM
-
Fig. 3. Urinary mucopolysaccharide determinations from patients with postoperative adnexal abscesses confirmed by laparotomy. Patient E. S. is unique for we have mucopoly accharide values from the initial hospitalization and following operative removal of the absc d.
similar to those of women of childbearing age.g Normal pregnancy seems to be associated with an increased MPS excretion. This might be expected, for pregnancy is an anabolic phenomenon characterized by nitrogen retention with an increased production of ground substance and collagen within the maternal uterus and the fetus with the continued growth of each.lO The increase in MPS excretion associated with pregnancy persists in the postpartum period (Table III). At least a portion of this must be contributed by the involuting postpartum uterus, for this is the only occasion in OUI data where the more major operative procedure (cesarean hysterectomy) yielded lower MPS values than the lesser one (cesarean section). An obvious factor would seem to be removal of the involuting uterus as a source of urinary MPS in those patients undergoing cesarean hysterectomy.
Total abdominal hysterectomy and vaginal hysterectomy were associated with an increase in urinary MPS excretion in the postoperative period. This seems to be a physiologic response to the operative trauma of hysterectomy, for the increased levels of MPS were found in all patients, including those without morbidity. The rise in MPS postoperatively roughly parallels the temperature elevations found (Fig. 1) , but the increased levels of MPS diminished at a slower rate than the temperature elevations. Other operative procedures also induced mucopolysacchariduria. However, those patients with less extensive operative procedures demonstrated a smaller rise in MPS excretion than those undergoing a more major procedure (Table IV). The postoperative urinary MPS excretion results do not parallel the pattern of collagen synthesis in incisional wounds. His-
Urinary
tochemical and biochemical studies have delineated a lag phase until the fourth to sixth day of wounding, when collagen synthesis begins and continues until about the fifrise in urinary teenth day. I1 The immediate MPS in patients following hysterectomy thus precedes collagen synthesis. There are a number of possible explanations for this phenomenon. It may reflect the early laying down of ground substance in the connective tissue scars, occurring in the phase of reparative inflammation, prior to the formation of collagen fibers.l” Another factor may be the metabolic status of postoperative patients following major operations, for it has been demonstrated that fasting consistently increases urinary hydroxyproline, one of the constituents of collagen fibers.13 The severity of pelvic infections following hysterectomy was paralleled by markedly elevated urinary mucopolysaccharides. Three of the 4 patients with postoperative pelvic inSection had the highest MPS determinations obtained in those women undergoing hysterectomy. These patients required a long treatment course with antibiotics, and, in two instances, operative removal of an abscess. The fourth patient, with less elevated MPS, had a dramatic clinical response to antibiotics and was afebrile within 24 hr. The patients with adnexal abscess following hysterectomy fit the clinical pattern that has been described in a previous pub1ication.l’ They were premenopausal women, undergoing elective vaginal hysterectomy, and their infectious complications were noted late in the postoperative period. Two of the 3 patients requiring readmission had MPS determinations during their original hospitalization, and these were not elevated above the levels found in other patients following hysterectomy. Elevated urinary MPS in the immediate postoperative period did not serve as a marker to detect the patient who would later develop an adnexal abscess. This is an interesting observation, for, ciinicaily, there had been no evidence of pelvic infection in these women at the time of discharge examination. This suggests to us that the post-
mucopolysaccharide
excretion
499
operative adnexal infection is either a very low-grade inflammatory process at this point or, alternatively, the infection is acquired later outside of the hospital. In those patients requiring operative intervention for postoperative adnexal abscesses, the MPS values obtained prior to operative removal of the abscesses were well above the range seen in postoperative hysterectomy patients and were much higher than those obtained in the patient readmitted with pelvic cellulitis. Removal of the adnexal abscess caused a dramatic drop in MPS, suggesting this infection, and the pelvic reaction to it: were major sources of the elevated MPS excreted in the urine. The finding of elevated urinary MPS in patients with bacterial infections supports the previous observation of eievated plasma MPS in similar circurnst;mces.6 The mechanism for the increased excretion of MPS in postoperative patients is not known. Urinary MPS excretion probably reflects both synthesis and breakdown of connective tissue. The early rise in MPS excretion following hysterectomy? other surgical procedures, parturition, and particularly the tremendous elevations in patients with severe infectious morbidity suggest tllat tissue breakdown is an important factor. Alternatively, the rise in MPS cxcretitln during pregnancy suggests that new formation Iof connective tissue in the absence ol’ infection can also increase MPS in thtx urine. Because of the complexity of this test, both in time and technique, it is lmlikely that it could be used as a routine et-nluation for all postoperative patients. Also: in this series of patients, it did not prove tc> be an indicator for those women who wotild later develop serious infection. It is of interest to note in Fig. 2 that elevated urina1.y MPS occurred 2 days before the clinical diagnosis of a prlvic cellulitis was made and a;ltibiotic therapy was begun. The urinary excretion of MPS seems to reflect the extent and degree of pelvic inflammation and infection in patients with postoperative morbid&. Prospective studies in the future will )Ilore accurately delineate the practical valuers of this laboratory procedure.
500
Ledger, Thompson,
and Grobelny
Amer.
June 15, 1971 J. Obstet. Gynec.
REFERENCES
1. Dorfman, A., and Matalon, R.: Amer. J. Med. 47: 691, 1969. 2. Di Ferrante, N.: J. Clin. Invest. 36: 1516, 1957. 3. Di Ferrante, N., Robbins, W. C., and Rich, C.: J. Lab. Clin. Med. 50: 897, 1957. 4. Be&son, G. S., and Dalferes, E. R., Jr.: Clin. Res. 11: 57. 1963. G. R.: Castor, C. W., Ballantyne, 5. Thompson, L. M., and Prince, R. K.: J. Lab. Clin. Med. 68: 617, 1966. 6. Kerby, G. P.: J. Clin. Invest. 37: 962, 1958. 7. Bitter, T., and Muir, H. M.: Anal. Biochem. 4: 330, 1962.
8. 9. 10. 11. 12. 13. 14.
Bonsnes, R. W., and Taussky, H. H.: J. Biol. Chem. 158: 581, 1945. Thompson, G. R.: Unpublished data. Zusvan, F. P.. and Goodrich. S.: AMER. ”T. OR&ET. GY&c. 100: 7, 1968: Dunphy, J. E., and Udupa, K. N.: New Eng. J. Med. 233: 847, 1955. Bole, G. G., and Robinson, W. D.: J. Lab. Clin. Med. 59: 713, 1962. Bell, N. H.: J. Clin. Endocr. 29: 338, 1969. Ledger, W. J., Campbell, C., Taylor, D., and Willson, J. R.: Surg. Gynec. Obstet. 129: 973, 1969.