The p H of Sclerosing Agents*
A Determinant of Pleural Symphysis
Steven
and
A. Sahn, M.D., F.C.C.P.;
Daniel
E. Potts,
James
T. Good,
Jr.,
M.D.;
M.D.
The rate of success in producing pleural symphysis with
showed little change when diluted by pleural fluid. A 0.5
intrapleural
percent solution of sodium hydroxide had the highest
instillation of sclerosing
agents has been
variable. Differences in the designs of studies probably
pH (13.0). The remainder of the sclerosing
account for some of the variability, but the reasons for
showed a range of pH from 4 . 3 to 8.7. Experimental and
solutions
the remainder are not clear. Since a low pH of the
clinical experience suggests that tetracycline consistent-
pleural fluid is associated with pleural adhesions and
ly has the highest rate of success in producing pleural
loculations, the pH of the commonly used solutions of
symphysis. It appears that when proper technique is em-
sclerosing agents was determined, both in their usual
ployed, the pH of the solution of the sclerosing agent is
concentrations and when diluted with large quantities
an important determinant of the production of pleural
of exudative pleural fluid. The buffered solution of tetra-
symphysis.
cycline hydrochloride had the most acidic pH (2.0) and
"ITarious neoplastic, radioisotopic, and antimicro*
bial agents have been instilled into the pleural
space for the purpose of promoting pleural symphysis, primarily in the setting of a malignant pleural
effusion. The success of this procedure has varied
from less than 30 percent to 100 percent. "
1
6
Besides
the designs of the studies, the reasons for this variability are not clear. The response may be related to
dosage, as has been shown for both quinacrine
7
and
tetracycline, but adverse effects can limit the dos8
age
with
employed.
a
low
tuberculous
Since
pH
exudative
(empyemas,
effusions,
and
pleural
effusions
carcinomatous
rheumatoid
and
effusions)
tend to be associated with pleural adhesions and
loculations, the pH of the solution of the sclerosing
agent could be an important factor in determining
the production of pleural symphysis.
M A T E R I A L S AND METHODS
T h e following agents were studied: tetracycline hydrochloride (buffered [Panamycin] and unbuffered solutions);
mechlorethamine ( M u s t a r g e n ) ; quinacrine (Atabrine) dihydrochloride; bleomycin sulfate ( B l e n o x a n e ) ; 5-fmorouracil;
cephradine ( V e l o s e f ) ; and sodium hydroxide. T h e clinically
used dosage of each sclerosing agent was employed as for a
70-kg ( 1 5 4 - l b ) man. E a c h sclerosing agent was diluted in
1 0 0 ml (commonly used volume to administer the drug) of
" F r o m t h e Pleural Space Laboratory, W e b b - W a r i n g L u n g
Institute, Division of Pulmonary Sciences, Department of
Medicine, University of Colorado Medical Center, Denver.
Manuscript received November 1 ; revision accepted December 5 .
Reprint requests: Dr. Sahn, 4200 East Ninth Avenue,
Denver
80262
198
bacteriostatic water to give the final concentration (Table 1 ) .
Measurements of p H were performed in duplicate using an
analyzing system (Radiometer) in conjunction with a glass
microelectrode.
Since it has been suggested that lidocaine be instilled into
the pleural space with tetracycline in order to reduce the
pleuritic pain that may result from this procedure, the p H of
a 1 percent solution of lidocaine with both buffered and
unbuffered tetracycline was measured. The clinically used
dose of tetracycline was diluted in 7 0 ml of bacteriostatic
water and 3 0 ml of the 1 percent solution of lidocaine, and
the p H was measured in duplicate.
8
Because drainage of the pleural space prior to instillation
of a sclerosing agent frequently is not complete, the effect of
large quantities of pleural fluid on the p H of the sclerosing
solution was determined. T h e previously employed dosages
of unbuffered and buffered tetracycline were diluted with an
exudative pleural fluid with a protein concentration of 4 , 0
g m / 1 0 0 ml and a p H of 7 . 3 5 as if the final volume were 5 0 0
ml and 1 , 0 0 0 ml. T h e p H of the resultant solutions was
measured in duplicate.
Three groups of five New Zealand white rabbits had either
a buffered solution of tetracycline hydrochloride ( 1 5 mg/kg
of body w e i g h t ) , quinacrine dihydrochloride ( 7 m g / k g ) , or
mechlorethamine ( 0 . 2 m g / k g ) instilled into the right pleural
space percutaneously using a technique that previously has
been described in detail. Thoracocenteses were attempted
daily in all animals. Rabbits were killed 3 0 days after the
instillation of the sclerosing agent, and the right pleural space
was examined for pleural symphysis.
8
Fifteen patients had malignant pleural effusions (lung, six;
breast, five; lymphoma, two; stomach, one; and cervix, one)
diagnosed either b y cytologic examination of pleural fluid or
by pleural biopsy. The effusions were refractory to thoracocentesis, chemotherapy, or radiotherapy. These 15 patients
were treated according to the following protocol: ( 1 ) drainage via a chest tube until the chest x-ray film was free of fluid
and until drainage from the tube was less than 1 0 0 ml/24 hr;
SAHN, GOOD, POTTS
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21056/ on 06/16/2017
CHEST, 76: 2, AUGUST, 1979
Table 1—Solutions of Sclerosing Agents in Order of
Ascending pH
Final
Sclerosing Agent
Dosage,
Concentration,
mg/kg
mg/ml
pH
Tetracycline hydrochloride
Buffered
Buffered
15
20
Unbuffered
15
20
Unbuffered
10
2.0
14
10
2.0
2.5
14
2.5
Mechlorethamine
0.2
0.14
4.3
Quinaerine dihydroehloride
7
5
•15
Bleomycin
1.5
1
4.7
5-Fluorouracil
36
25
8.5
Cephradine
15
10
8.7
Cephradine
20
14
8.7
7
5
13.0
Sodium hydroxide (0.5
percent solution)
( 2 ) instillation of a buffered solution of tetracycline hydrochloride ( 1 5 m g / k g ) ;
umes of the same exudative pleural fluid resulted in
values for pH of 6.40 and 6.70, respectively. Values
for pH were 0.1 to 0.3 units lower with the dosage of
tetracycline hydrochloride of 20 mg/kg.
In the experimental studies, intrapleural instillation of tetracycline produced a polymorphonuclearpredominant, exudative pleural effusion without a
low pH or glucose level; postmortem examination
showed essentially complete pleural symphysis in
four animals and partial pleurodesis in one. Neither
quinaerine nor mechlorethamine produced enough
fluid to be sampled by thoracocentesis, and the
pleural spaces appeared essentially normal at 30
days.
Thirteen of the 15 patients treated with intrapleural instillation of tetracycline had total pleural
symphysis clinically and did not develop subsequent
pleural fluid. Two of the 15 patients had partial
pleural symphysis requiring additional thoracocenteses. Both had extensive tumor involving the visceral pleura at postmortem examination.
( 3 ) clamping of the chest tube for two
DISCUSSION
hours with the patient rotated in the supine, prone, and right
and left lateral decubitus positions; and ( 4 ) removal of the
chest tube when drainage was
less than
100
ml/24
hr.
Patients were followed-up until the time of death, which
ranged from 1 to 2 0 months after treatment, in order to determine clinical pleural symphysis and control of the effusion.
RESULTS
The pH of the sclerosing agents are shown in
ascending order in Table 1. Of the acidic sclerosing
agents, solutions of tetracycline, both buffered and
unbuffered, had the lowest pH; increasing the concentration 1.4 times had no effect on the pH of the
solution. The pH of solutions of 5-fluorouracil and
cephradine, a newer cephalosporin, were mildly
alkaline; and the 0.5 percent solution of sodium
hydroxide had the highest pH.
The pH of the 1 percent solution of lidocaine was
6.3. The solution of lidocaine plus buffered tetracycline hydrochloride at a concentration of 10 mg/
ml had a pH of 2.3, and the solution of lidocaine plus
buffered tetracycline hydrochloride at a concentration of 14 mg/ml had a pH of 2.1. The pH of the
solution of lidocaine plus unbuffered tetracycline
hydrochloride at a concentration of 10 mg/ml was
3.0, and the pH of the solution of lidocaine plus
unbuffered tetracycline hydrochloride at a concentration of 14 mg/ml was 2.8.
When the buffered solution of tetracycline hydrochloride (15 mg/kg) was diluted in 500 and 1,000
ml of an exudative pleural fluid with a pH of 7.35,
the resulting values for pH were 3.8 and 4.0, respectively. The unbuffered solution of tetracycline hydrochloride (15 mg/kg) diluted in the same volCHEST, 76: 2, AUGUST, 1979
While the rate of success in producing pleural
symphysis with sclerosing agents has been variable,
the assessment of the efficacy of these agents is
difficult because of differences in the concentrations
used, the selection of patients, the type of malignant
neoplasm, the follow-up period, the method of evaluating patients, and the technique employed.
Intrapleural instillation of tetracycline has been
reported to be effective in 83 to 100 percent of the
patients with malignant pleural effusions. - Previous and present experimental studies also have
confirmed the effectiveness of instillation of tetracycline in producing pleural symphysis and have
suggested that the response is related to dosage; it
appears that a dose of at least 15 mg/kg is required
to produce a high rate of pleural symphysis. Our
series demonstrating an 87 percent rate of complete
response agrees with previously published clinical
data. 6
10
8
8
6
10
A commercially available solution of tetracycline
(Panmycin) is buffered with ascorbic acid, and the
solution maintains a pH of less than 4.1 when diluted with up to 1,000 ml of exudative pleural fluid.
In contrast, the pH of an unbuffered solution of
tetracycline rose to greater than 6.0 when diluted
with pleural fluid. These findings may be one explanation for the failure of the development of pleural symphysis when an unbuffered solution of tetracycline or other agents are used and the pleural
space is not drained adequately.
Mechlorethamine (nitrogen mustard) has been
the antineoplastic agent most frequently used in the
THE pH OF SCLEROSING AGENTS
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21056/ on 06/16/2017
199
treatment of malignant pleural effusions. Rates of
success from 25 to 87 percent have been reported,
with the higher rates reported from those groups
who used drainage with a chest tube prior to instillation.
Experimental data from our laboratory
have not demonstrated pleural symphysis in rabbits
treated with intrapleural instillation of mechlorethamine (0.2 mg/kg).
Quinacrine (Atabrine) dihydrochloride has been
reported to be successful in 43 to 100 percent of the
cases.
Investigators have used varying dosages
ranging from 100 to 200 mg in repeated doses to a
dosage of 1.5 gm in a single dose. Pain and fever are
common adverse effects, and hypotension, hallucinations, and even death have been reported with therapy with a single high dose, The pH of quinacrine
is similar to mechlorethamine, and studies from our
laboratory have failed to show pleural symphysis in
rabbits after a dose of 7 mg/kg.
1,11
5,12
7
Therapy with bleomycin has been reported to
produce remissions in approximately 60 percent of
the patients with malignant effusions. The rate of
success with administration of bleomycin is similar
to that of quinacrine and mechlorethamine; and, in
fact, their values for pH fall into a narrow range
between 4.30 and 4.70.
3
Intracavitary instillation of a single dose of 5fluorouracil produced improvement in 38 percent of
patients with different types of tumors. Despite its
antineoplastic effect in experimental neoplasms, the
mildly alkaline pH probably explains the low yield
in producing pleural symphysis.
2
Since cephalosporins have been known to produce
peripheral thromboplilebitis, the pH of a solution of
a new cephalosporin, cephradine, was measured and
found to be mildly basic. To our knowledge, no
studies have been reported on the use of cephalosporins as sclerosing agents in the pleural space,
but based on the pH, one would not expect a high
yield with cephradine.
In a single report from Chile, a rate of success of 93
percent (14/15) in the treatment of malignant pleural effusions from breast cancer has been achieved
with the use of a 0.5 percent solution of sodium
hydroxide. The strongly basic pH of this solution
would be compatible with the reported rate of
success.
With the literature replete with uncontrolled studies, it is difficult to clearly define the reasons for
success or failure with instillation of these various
agents; however, certain factors appear to be important in determining the rate of successful pleural
symphysis. These are the pH of the sclerosing agent,
the dosage of the sclerosing agent, the completeness
of drainage of the pleural space, the condition of the
13
200
underlying lung and visceral pleura, and the technique of drainage of the pleural space and of instillation of the sclerosing agent. If the pleural space is
not drained completely, exudative pleural fluid will
dilute the sclerosing agent and raise the final pH. If
the patient has a visceral pleural "peel," pleural
symphysis can never be produced, short of decortication.
Despite the relatively small number of patients
studied, solutions of tetracycline and sodium hydroxide, the agents with the most abnormal pH,
appear to be most effective in producing pleural
symphysis; while the drug with the most neutral pH,
5-fluorouracil, has resulted in the poorest yield. It
appears that the pH of the sclerosing solution is an
important determinant in the production of pleural
symphysis.
ACKNOWLEDGMENT:
The buffered tetracycline hydrochloride ( P a n m y c i n ) was supplied by the LTpjohn Co.,
Kalamazoo, Mich; the bleomycin sulfate (Bienoxane) was
supplied by Bristol Laboratories, Syracuse, NY; and the
cephradine (Velosef) was supplied by E. R. Squibb and
Sons, Princeton, NJ.
REFERENCES
1 Fracchia AA, Knapper W H , Carey J T , et al: Intrapleural
chemotherapy for effusion from metastatic breast carcinoma. Cancer 2 6 : 6 2 6 - 6 2 9 , 1970
2 Suhrland L G , Weisberger AS: Intracavitary 5-fluorouracil
in malignant effusions. Arch Intern Med 1 1 6 : 4 3 1 - 4 3 3 ,
1965
3 Paladine W , Cunningham T J , Sponzo R, et al: Intracavitary bleomycin in the management of malignant effusions.
Cancer 3 8 : 1 9 0 3 - 1 9 0 8 , 1 9 7 6
4 Card RY, Cole DR, Henschk U K : Summary of ten years
of the use of radioactive colloids in intracavitary therapy.
J NucI Med 1 : 1 9 5 - 1 9 8 , 1960
5 Hickman JA, Jones M C : Treatment of neoplastic pleural
effusions with local instillations of quinacrine
(Mepacrine) hydrochloride. Thorax 2 5 : 2 2 6 - 2 2 9 , 1970
6 Rubinson RM, Bolooki H: Intrapleural tetracycline
control of malignant pleural effusion: a preliminary
port. South Med J 6 5 : 8 4 7 - 8 4 9 , 1972
for
re-
7 Borja E R , Pugh RP: Single dose quinacrine (Atabrine)
and thoracostomy in the control of pleural effusions in
patients with neoplastic diseases. Cancer
31:899-901,
1973
8 Sahn SA, Potts D E : The effect of tetracycline on rabbit
pleura. Am Rev Respir Dis 1 1 7 : 4 9 3 - 4 9 9 , 1978
9 Wallach H W : Intrapleural therapy with tetracycline and
lidocaine for malignant pleural effusions (letter to edit o r ) . Chest 7 3 : 2 4 6 , 1978
10 W'allach H W : Intrapleural tetracycline
pleural effusions. Chest 6 8 : 5 1 0 - 5 1 2 , 1975
for
malignant
11 Kinsey D L , Carter K, Klassen KP: Simplified management of malignant pleural effusion. Arch Surg 8 9 : 3 8 9 392, 1964
12 Rochlin D B , Smart CR, Wagner D E , et al: Control of
recurrent malignant effusions using quinacrine hydrochloride. Surg Gynecol Obstet 1 1 8 : 9 9 1 - 9 9 4 , 1964
13 Bezanilla AR: Treatment for malignant pleural
(letter to editor). Chest 7 0 : 4 0 8 - 4 0 9 , 1976
SAHN, GOOD, POTTS
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21056/ on 06/16/2017
effusions
CHEST, 76: 2, AUGUST, 1979