cysteine versus 10% 2-mercaptoethane sulphonate
Transcript of cysteine versus 10% 2-mercaptoethane sulphonate
Thorax (1970), 25, 737.
Clinical and physiological evaluation of mucolyticagents nebulized with isoproterenol: 10% N-acetyl-cysteine versus 10% 2-mercaptoethane sulphonate
S. R. HIRSCH, P. F. VIERNES, and R. C. KORY
Veterans' Administration Hospital, Wood, Wisconsin 53193, U.S.A.
In a controlled five-week cross-over study in 12 patients with chronic bronchitis, the effects ofnebulized 10% N-acetylcysteine pus isoproterenol were compared with a new drug, sodium2-mercaptoethane sulphonate, in 10% concentration also nebulized with isoproterenol. Bothcombinations were compared with a control aerosol of saline and a second control aerosol ofsaline plus isoproterenol. Both 10% 2-mercaptoethane sulphonate and 10% N-acetylcysteine werehighly effective in thinning mucoid, mucopurulent or purulent sputum. Subjective improvementin these patients, however, was related to the isoproterenol rather than to the mucolytic agents.When nebulized with isoproterenol, neither mucolytic agent was associated with bronchospasmin any patient. Physical findings, spirometric values, and sputum volume were unaffected bythese mucolytic agents.
One of the major problems in the treatment ofpatients with acute or chronic pulmonary diseaseis the management of thick, tenacious secretions.In recent years a number of agents designed toliquefy bronchopulmonary secretions have beenintroduced. In order to evaluate the effectivenessof such agents in an objective manner, we havedeveloped an instrument, now termed the FluidConsisto-viscosimeter (Hirsch and Kory, 1967;Hirsch, Kory, and Hamilton, 1966), which iscapable of measuring the consistency (apparentviscosity) of heterogeneous substances such assputum.
Using this instrument, we have shown in ashort-term clinical study that nebulization of 10%N-acetylsteine (N-ac) was as effective as 20%N-ac in thinning sputum. More recently, in aseven-week controlled clinical study (Kory,Hirsch, and Giraldo, 1968), we demonstrated thesputum-thinning effectiveness of 20% N-acnebulized with racemic epinephrine. Followingthese reports we received a number of enquiriesas to the effectiveness of 10% N-ac nebulizedwith isoproterenol (Iso).
In our most recent study, we described a newmethod for the in vitro measurement of thesputum-liquefying efficacy of drugs, and haveapplied the method to the evaluation of severalnew agents (Hirsch, Zastrow, and Kory, 1969).One of these agents, the sodium salt of 2-mercapto-
ethane sulphonic acid (MES), appeared to be atleast as potent as N-ac but had a less disagreeableodour.The present study was designed, therefore, to
determine: (a) whether 10% N-ac+Iso is effec-tive in liquefying sputum; (b) the comparativeeffectiveness of 10% MES+Iso in thinningsputum; (c) the effect of saline+Iso on sputumconsistency as compared to the above regimens;and (d) the clinical and physiological responsesof patients with chronic bronchitis to the aboveregimens in a controlled study.
MATERIALS AND METHODS
Twelve patients with relatively stable chronicairways obstruction and productive coughs wereadmitted to the Emphysema Study Unit of WoodVeterans' Administration Hospital. All thepatients had airway obstruction of varyingseverity and reversibility, and one also had ahistory of chronic bronchial asthma. Beforeentering the study, each patient was given appro-priate therapy with oral bronchodilators, expec-torants and, when necessary, antibiotics in orderto achieve clinical stability. The therapeuticregimen for each patient, once established, wasmaintained with virtually no change throughoutthe study.
737
S. R. Hirsch, P. F. Viernes, and R. C. Kory
TABLE IPLAN OF STUDY OF NEBULIZED DRUGS
Week Group I Group 2 Group 3 Group 4 Group 5 Group 6
1 Sal Sal Sal Sal Sal Sal2 Sal +Iso N-ac+Iso MES+Iso MES+ Iso Sal+Iso N-ac +Iso3 N-ac+Iso MES +Iso Sal+Iso N-ac +Iso MES+Iso Sal +Iso4 MES+Iso Sal +Iso N-ac+Iso Sal +Iso N-ac +Iso MES +Iso5 Sal Sal Sal Sal Sal Sal
Sal= 3-0 ml. of isotonic saline. Sal + Iso =2-5 ml. of isotonic saline plus 0-8 ml. of 1:203 isoproterenol.N-ac+lso=2-5 ml. of 10% N-acetylcysteine plus 0-8 ml. of 1:200 isoproterenol.MES+Iso=2-5 ml. of 10% 2-mercaptoethane sulphonate plus 0-8 ml. of 1:200 isoproterenol.
This investigation was designed to reduce theeffect of the natural fluctuations of the diseaseupon results of the study and the effects of oneregimen upon another. The plan of study is out-lined in Table I. The patients were divided intosix groups of two patients each. The first and last(fifth) week of the study were control periodsfor all of the six groups during which the patientsreceived nebulized isotonic saline. During thesecond, third, and fourth weeks each grouprotated through the three treatment regimens ina different order. All agents were administeredby nebulization with a Mark VII Bird IPPBrespirator at 8 a.m., 12 noon, and 6 p.m. Allsputum was collected during the control andtreatment periods from the beginning of oneIPPB nebulization to the beginning of the next.These specimens were designated the 'morning','afternoon', and 'overnight' collections.Each specimen was visually assessed as to its
type (mucoid, mucopurulent, or purulent) andplaced in a freezer at -20° C. immediately there-after. At a convenient time the sputum wasthawed, and its volume and consistency weremeasured in the Fluid Consisto-viscosimeter. Thisinstrument was developed in our laboratoriesand has been described in detail elsewhere(Hirsch and Kory, 1967; Hirsch et al., 1966;Kory et al., 1968). The principal part of the unitis a 10-ml. stainless steel syringe with a hollowplunger carefully machined to the syringe barrel(Fig. 1). At the lower end of the plunger is astainless steel disc, 1/32 in. (0O8 mm.) thick,which is held in place against the bottom of theplunger by a thin rod. This rod extends upthrough the hollow plunger and is secured by aknurled nut. Symmetrically arranged on the discare eight holes, each 1 6 mm. in diameter.Threaded into the bottom end of the syringebarrel is a Statham P-23D strain gauge pressuretransducer secured tightly in place with the aidof 0-ring seals. This assembly is mounted on amodified Harvard infusion pump which isplaced upright on a box containing the controlsfor the instrument. The tracing is recorded on a
PLUNGER CONNECTINGKNURLED SHAFTNUT
PLUNGER
PERFORATED:DISC l,
DIS [F BARREL
O RING SPACER
FLUTED NUT
TRANSDUCER
FIG. 1. Diagram of the syringe assembly showing thehollow plunger with the perforated disc at the bottom, thebarrel and the pressure transducer.
lit
FIG. 2. The Fluid Consisto-viscosimeter and the recorder.
738
0 -----Jr.AMW
!K :. 'ir.. 41
1-NNW
Clinical and physiological evaluation of mucolytic agents nebulized with isoproterenol
1-mV potentiometric strip chart recorder (Fig. 2).The sputum is placed in the barrel. The
plunger, with the perforated disc at the bottom,is driven down through the sputum by the pumpat a constant velocity (4-12 ml./ min.), therebydeveloping a pressure directly proportional to thethickness (consistency) of the specimen. Figure 3
FIG. 3. A typical record from a sputum consistencymeasurement. The heavy vertical lines mark the beginningand the end of the traversal of the plunger through thesputum. The upper tracing is a continuous record of thepressure while the lower tracing integrates the area underthe upper curve, thereby permitting calculation of the meanpressure in millimetres of mercury. The time intervalbetween the 'start' and the 'end' of the tracing is usedwith volume factor for the barrel and the velocity factorfor the plunger toprovide an accurate measurement of thesputum volume.
is a typical record from a sputum consistencymeasurement. In order to relate consistencyvalues to viscosity units in general use we havecalibrated the instrument with a series of fiveDow-Corning 210 silicones. When the pressurein millimetres of mercury is plotted against vis-cosity in centistokes of the five silicones, thestriking linearity permits the establishment of therelationship of 1 mm. Hg= 1,500 centistokes.Pressure measurements alone are meaningful onlyfor instruments with barrel and plunger dimen-sions and plunger velocity identical to those ofour own instrument. For this reason, we haveestablished 'consistency units' to relate our
measurements to conventional viscosity units.One consistency unit is equivalent to 1,500 centi-stokes. The thicker the sputum, the larger thenumber of consistency units recorded.
The forced vital capacity test was performedon the third and seventh days of each week ofthe study just before the mid-day IPPB treat-ment, and again 30 minutes thereafter. Measure-ments from the forced expiratory spirogram(Kory, Rankin and Snider, 1963) included theforced vital capacity (FVC), the one-secondforced expiratory volume (FEVL.I), the 200-1,200ml. forced expiratory flow rate (FEF2o-laoo),and the forced mid-flow (FMF).
Observations of the patient's clinical course
and side-effects were recorded daily.
RESULTS
Comparison of the treatment and the controlperiods involve four categories: sputum con-
sistency; sputum volume; spirometric measure-
ments; and the patient's clinical course.
SPUTUM CONSISTENCY The method of evaluationof sputum consistency is illustrated by Table II
which shows all the sputum-consistency valuesfor one patient (W.S.) for the entire 35 days of
TABLE II
SPUTUM CONSISTENCY IN CONSISTENCY1PATTIFNT W q-
UNITS-
Week
Day 1 2 3 4 5Saline MES+ Sal + N-ac+ SalineControl Iso Iso Iso Control
Morning specimen1 104 42 102 30 902 120 26 83 38 1443 132 15 105 50 884 120 26 82 22 I115 62 8 80 4 1366 132 8 102 10 947 104 9 74 8 112
Weekly mean 110 19 90 23 110
Afternoon specimen1 121 22 86 26 962 82 3 95 18 1323 90 12 83 19 914 118 14 67 24 525 89 2 70 7 1076 88 0 94 4 1087 87 6 68 4 137
Weekly mean 96 8 80 14 103
Overnight specimen1 102 48 112 94 962 132 44 132 78 933 139 45 121 66 1024 119 86 142 78 845 104 75 100 64 1266 126 104 107 98 1257 72 70 96 83 130
Weekly mean 113 67 116 80 108
For abbreviations see footnotes to Table I.
739
740 ~~~~~S.R. Hirsch, P. F. Viernes, and R. C. Kory
TABLE IIIWEEKLY MEAN SPUTUM CONSISTENCY IN CONSISTENCY UNITS-ALL PATIENTS
I *I~~ 1~
Sal
7240
44102
58110
Afternoon
Sal
7538
4641
20
96
Sal
7620
3453
3980
4 38 20
14 13 14
17 22 41
150 74 71
24 23 16
80 32 65
63 43 44
MES
ISO
188
N-ac
ISO
176
30 32
12 1 1
1 28
8 14
7 3
3 6
13 10
30 1 1
5 3
7 10
I1I1 13
Sal
7423
3982
46103
3812
16108
1761
52
I ~~OvernightSal MES N-acISal ± + + SalISO ISO ISO
I1II1 140 65 56 11228 45 23 26 38
75
92
28
113
48
39
21
III
35
50
63
44 44
72 48
36 1 5
116 67
26
20I
24
12
4841
2480
12
14
44 27 29
127 106 164
19 4 8
73 26 32
64 ~i 39 45
the study. The consistency values of the seven
sputum specimens collected from each patient
during one week of the study in the morning,
afternoon and overnight periods are averaged to
provide the weekly mean sputum consistency
value for that period. It is apparent from this
table that the weekly mean sputum consistency
values for week 2 (MES + Iso) and week 4 (N-ac
+ iso) are consistently lower than either of the
saline control periods (weeks and 5) or the
saline+lIso period (week 3).
The weekly mean consistency values for the
five treatment regimens for all 12 patients are
shown in Table It may be seen from this
table that those patients with relatively thin
sputum during the control periods could not
clearly demonstrate decreases in consistency to
the degree seen in those patients with thick
sputum. Eleven of the 12 patients showed distinct
lowering of sputum consistency during the
MES +Iso and the N-ac+lIso periods, but one
patient (M. S.), whose sputum was rather thin,
did not respond to either regimen. The mean
values for the five regimens for all 12 patients are
graphically presented in Figure 4. It is evident
from this figure that the mean sputum consistency
values for the MES +Iso and the N-ac +Iso
periods are lower than both the saline control
periods and the saline +Iso periods. For both the
MES +Iso and the N-ac+lIso, these differences
from the controls are highly significant for the
morning and afternoon specimens (P<0-01). The
differences are less striking for the overnight
specimens, P<0-05 for the MES +Iso and P<0-3
for the N-ac+lIso. The MES +Iso consistencyvalues are slightly lower than for N-ac+lIso, but
the difference between these two regimens is not
statistically significant. There was no significant
75-
tF 50- 45
25u
v 00
75-
,50 43
u
a 25-
0U 100
E
m 75O-Sal
MORNING
63-
AFTERNOON
52
.,-'J*:::li-
OVERNIGHT
64 ~~~~~~62
Sol+ MES-+N-ac+SalISO ISO ISO
FIG. 4. Comparison of the effect of % N-acetylcysteine(N-ac) plus isoproterenol (Iso) with that of 1000 mer-
captoethane sulphonate (MES) plus isoproterenol. For
the morning and afternoon specimens the mean sputum
consistency values for the N-ac +Iso and MES +Iso
periods are significantly lower than both the saline control
(Sal) and the saline plus isoproterenol (Sal + Iso) periods.
SalSal +
ISO
Morning
MES
I-ON-ac
IS
61 86 24 21
38 36 10 10
Patient
Group 1B.B.D.V.
Group 2G.B.W.M.
Group 3U.G.W.S.
Group 4W.E.W.H.
Group 5M.S.D.R.
Group 6J.K.E.K.
Mean
56 40
42 74
28 46
110 90
20
34 34
10 19
4 22
19 23
5 2
8 81622
10
66
13
89
24 24
53 72
45 51
16
29
6
8
14
16
40
4
10
16
5292
46108
4825
12140
1462
62
740
7I --
I
I
Clinical and physiological evaluation of inucolytic agents nebulized with isoprotenenoi
difference in sputum consistency between thesaline control and the saline+Iso periods.
Because of the possibility that different thera-peutic regimens may be more effective in lower-ing sputum consistency of a particular type ofsputum, all the sputum specimens were classifiedby visual inspection as to whether they weremucoid, mucopurulent, or purulent. Purulentsputum regularly had a significantly lower con-sistency than either mucoid or mucopurulentsputum regardless of which treatment was usedduring the collection period. Furthermore, boththe MES+ Iso and the N-ac + Iso combinationswere of equal effectiveness in lowering thesputum consistency of all three types of sputum.As might be expected because of the 14-hour col-lection period, the overnight specimen showed ahigher consistency than the morning and after-noon specimens whether the specimen wasmucoid, mucopurulent, or purulent.
SPUTUM VOLUME As illustrated in Fig. 5, theweekly mean sputum volume values did notchange significantly with any of the three drugregimens.
SPIROMETRIC TESTS None of the measurementsfrom the forced expiratory spirogram changedsignificantly with any of the three treatmentregimens.
MORNING
25E 20' 15 12-2
10-E 5-
cL
25
1S5
l0
Sol
15.5
AFTERNOON
12-8 12-5
)Vl
Sal + MES + N-acIso Iso Iso
FIG. 5. Comparison of the effect of 10% N-ac + Iso withthat of 10% MES+Iso on sputum volume. There is nosignificant change in sputum volume resulting from anyof the drug regimens compared to the volume during thecontrol periods.
CLINICAL COURSE Each patient was questioneddaily as to whether the symptoms of cough,wheezing, and dyspnoea were improved, unim-proved, or worse. The most striking subjective re-sponses were related to isoproterenol since allthree regimens containing isoproterenol providedmuch greater symptomatic improvement thaneither of the saline control regimens. However,we were unable to detect any symptomaticdifference between saline+Iso, N-ac+Iso, andMES+Iso regimens. Eight of the 12 patients feltthat N-ac+Iso allowed them to expectorate withthe least effort.The side-effects included: (1) an episode of
blood-streaked sputum in one patient during theinitial saline week, and a similar episode in asecond patient during the week he received MES+Iso; (2) nausea in one patient associated withN-ac + Iso; and (3) tightness in the chest asso-ciated with N-ac+Iso at times in three patients,and with MES+Iso in three other patients. Eightpatients considered the taste of N-ac+Iso to bethe most disagreeable; three patients consideredthe taste of MES+Iso to be more disagreeablethan N-ac+Iso; and one patient considered thetwo preparations equally distasteful. No patientin the series considered the taste of either muco-lytic agent intolerable or requiring discontinu-ance of the treatment.
Daily physical examination of the chestshowed no significant change in the breathsounds, wheezing, or crepitations attributable toany of the treatment regimens.
DISCUSSION
Our previous clinical study (Kory et al., 1968)showed that the nebulization of 20% N-acetyl-cysteine (N-ac) plus racemic epinephrine (RE)was an effective combination for loweringsputum consistency. With this combination,bronchospasm, which has occasionally beenobserved with N-ac alone (Bernstein and Ausden-moore, 1964), did not occur. In the present studynebulization of 10% N-ac combined withisoproterenol lowered sputum consistency toapproximately the same degree as 20% N-ac+RE. Figure 6 compares graphically the meansputum consistency values resulting from the twoN-ac regimens. It is apparent that the sputumconsistency values resulting from 10% N-ac+Isoare almost identical to those from 20% N-ac+RE. It is also evident that the control values arelower in the present study (Fig. 6, Study B) be-cause saline was nebulized three times daily dur-
741
S. R. Hirsch, P. F. Viernes, and R. C. Kory
ing these periods whereas, in the(Fig. 6, Study A), there was no n
ing the control periods. Our i
studies (Hirsch et al., 1969) haveaddition of 1 0 ml. of saline to 51(will result in a 34% lowering of cl
75 . 70
.c 50' 251-
0
vb
cla 100
Ul100 90
u 7550 -
25 -
control
(A)
STUDY AMORNING70=n r~~~~4
AFTER NOON
12LjJjLMRRNIGHT
47L~
20% control contrN-ac (A) (B)+RE
zIG. 6. Comparison of the mean s
during nebulization of 20% N-acetylcyepinephrine (20% N-ac+RE) and 10plus isoproterenol (100% N-ac +Iso). AN-ac + Iso lower sputum consistency todoes 20% N-ac + RE. In study A thereduring the control periods. In study Bnebulized three times daily during the c
In the same in vitr-o study,more effective than l0Q% N-,sputum. In the present clinical stiof 103% MES+Iso resulted isputum consistency values thanin all three daily specimens. TI10% MES may be more effectvitr o but also in the clinicaldifferences, however (betweenand 10% N-ac+Iso), are not st.cant.
The lack of effect of either tthe MES + Iso on the physical Ispirometric values in patientsbronchial disease again demontissue changes responsible for thpairment are not easily altered c
previous study mucolytic agents. Furthermore, the spirometric[ebulization dur- tests were performed at those times which wouldrecent in vitro specifically exclude the short-term bronchodilat-shown that the ing effects of isoproterenol. The effects of
0 ml. of sputum short-term bronchodilatation due to isoproterenolonsistency. cannot, however, be eliminated from the patient's
subjective response. Since even a small amount ofbronchodilatation results in considerable improve-
STUDY B ment in breathing comfort, it is not surprisingthat subjective improvement was related to the
63 isoproterenol rather than to the mucolytic agents.Furthermore, we have been unable to establish in
_1171 any of our studies a close correlation between_
1 w:-.1_.....sputumconsistency measurements and the easeor difficulty which the patient experiences incoughing up sputum.
52The patients were chosen for this study on the
basis of their relatively stabile clinical course and,i313 therefore, were able to provide reliable control::_l-IL.L periods with which drug regimens could be com-
pared. They were not chosen because of theirneed for mucolytic therapy although they did
62 have thick sputum. Patients who have a more_ 45 acute need for mucolytic agents (in such diseases
jjg:i:L1 Lj as laryngotracheobronchitis and post-operativeplugging of the bronchi with mucus) often are so
ol 10% control seriously ill,, have such wide fluctuations in theirN-ac (B)+ Iso course, and require so many other simultaneous
therapeutic measures that it becomes almost im-sputum consistency possible to evaluate mucolytic agents objectively.eNneplutslracstenc Nevertheless, we think that the sputum-thinning
rebulization of IO% efficacy of both N-ac and MES demonstrated inthe same degree as the present study should be applicable to acutelywas no nebulization ill patients with thick tenacious sputum.normal saline was Analysis of the three major types of sputum,
'ontrol periods. i.e., mucoid, mucopurulent and purulent, showedthat mucus is the major cause of thick, viscoussputum. This conclusion is in agreement with the
10% MES was findings of Elmes and White (1953) that mucoidac in thinning and mucopurulent sputum are significantlyudy nebulization thicker than purulent sputum.in lower mean While the data presented here and in our pre-10% N-ac + Iso vious studies substantiate the sputum-liquefying
his suggests that ability of these mucolytic agents, the precise role-ive not only in of these drugs in clinical therapy is not yet clear.situation. These It is indeed possible that in some instances the10% MES+Iso bronchial secretions which had already been pro-atistically signifi- pelled to the larger airways, mixed there with the
mucolytic agent, and so produced some of ourthe N-ac+Iso or changes. In such instances the secretions mayfindings and the well have been expectorated whether or nots with chronic mucolysis had been achieved. We think, however,strates that the that in at least some of these cases thinning ofe ventilatory im- these secretions may have facilitated expectora-even by effective tion.
742
Clinical and physiological evaluation of mucolytic agents nebulized with isoproterenol 743
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Elmes, P. C., and White, J. C. (1953). Desoxyribonuclease in thetreatment of purulent bronchitis. Thorax, 8, 295.
Hirsch, S. R., and Kory, R. C. (1967). An evaluation of the effect ofnebulized N-acetylcysteine on sputum consistency, J. Allergy,39, 265.
- and Hamilton, L. H. (1966). Evaluation of changes insputum consistency with a new instrument. Amer. Rev. resp. Dis.,94, 784.
- Zastrow, J. E., and Kory, R. C. (1969). Sputum liquefyingagents: a comparative in vitro evaluation. J. Lab. clin. Med.,74, 346.
Kory, R. C., Hirsch, S. R., and Giraldo, J. (1968). Nebulization ofN-acetylcysteine combined with a bronchodilator in patientswith chronic bronchitis. Dis. Chest., 54, 504.
-Rankin, J., and Snider, G. L. (1963). Clinical spirometry. Recom-mendations of the Section on Pulmonary Function Testing,American College of Chest Physicians. Dis. Chest, 43, 214.
3H