Variation in the Size and Number of Stone Fragments After Gallbladder Lithotripsy John A. Worrell, MD,• Arthur C. Fleischer, MD,"' Alan J. Kaufman, MD,* Christopher D. Lind, MD,t William 0. Richards, MDi Leon G. Josephs, MD,* John H Arnold, MD,* Mary S. Dietrich,§ Lester F. Williams, MDi
Ninety-four gallbladder ultrasound examinations were carried out in 11 patients at intervals for the first 40 days after lithotripsy. No dissolution or other active therapy was carried out during this time. Fragment size and number were measured to determine the postlith otripsy variability. Analysis of variance (ANOV A) showed no significant changes in fragment size or number over time. The changes in fragment size and number compared to the previous measurements were then evaluated. Again, ANOVA showed no significant 9
S
ince the introduction of gallbladder lithotripsy by Sauerbruch et al in 1986, 1 intense interest has been expressed in this new modality for treating cholelithiasis. In most protocols, the primary method for monitoring gallstone fragmentation after lithotripsy has been ultrasound (US), with clinical decisions regarding additional treatment resting on the size and number of fragments present. Previous investigators, including Mathieson et al 2 and Garra et al, 3 have studied the in vitro, animal, and human models and noted the difficulties in both accurately counting and sizing gallstone fragments, especially in the pres· ence of multiple other fragments (Fig. 1). Mathieson et al reported accurate counting and sizing of fragments to within ± 1.1 mm when less than six stones were present, but noted a decrease in accuracy when the number of fragment count was more than six. Sackman Received May 9, 1990, from the Departments of •Radiology and Radiological Sciences, fGastroenterology. and tSurgery, Vanderbilt University School of Medicine, and §Vanderbilt University Computer Center, Nashville, Tennessee. Revised manuscript accepted for publication March 4, 1991. Address correspondence and reprint requests to Dr. John A. Worrell; Department of Radiology and Radiological Sciences, Van· derbilt University, Nashville, TN 37232-2675. This manuscript includes material presented at the 34th Annual Meeting of the AIUM, New Orleans, LA, March 4- 7, 1990.
changes between times. The average change in absolute size was 3.1 ± 0.6 mm, and the average change in absolute number was 1.4 ± 0.5. We conclude that fragment size and number as determined by ultrasound do not vary significantly with time during the first 40 days. The absolute size change measured to the nearest millimeter should be at least 4 mm to surpass the 95 % confidence interval. Similarly, the absolute change in number should be at least 2 to be regarded as significant.
et al reported the difficulty in estimating stone burden, especially in the postlithotripsy period,~ whereas Martin et al found the accurate assessment of fragments by US so difficult that oral cholecystography was substituted.5 This study attempts to determine the postlithotripsy variability in gallstone fragment size and number as determined by ultrasound in a clinical setting that included multiple sonologists and sonographers em· ploying a variety of equipment.
PATIENTS AND METHODS To be considered for our biliary lithotripsy protocol, a patient must have had symptoms of biliary colic and no more than three gallstones, each with a maximum diameter less than or equal to 30 mm. Exclusionary criteria included a nonfunctioning gallbladder by oral cholecystogram (OCG), pregnancy, bleeding disorder, or abdominal aortic aneurysm. Importantly, no oral dissolution therapy was permitted for 30 days before or after a lithotripsy treatment. This study is part of a multicenter study approved by the Vanderbilt Human Investigation Committee with informed consent obtained from each patient. Stone fragmentation was carried out using an investigational piezoelectric litho-
© 1991 by the American Institute of Ultrasound in Medicine• J Ultrasound Med 10:509- 512, 1991•0278-4297/91/$3.50
510
J Ultrasound Med 10:509- 512, 1991
SIZE AND NUMBER OF STONE FRAGMENTS
days 11 - 20, and days 21-40. Statistical analysis employed ANOVA, including repeated measures, calculation of the arithmetic means, and 95 % confidence limits of the grouped and pooled data using a commercial1y available statistical software package (BMDP Statistical Software, Los Angeles, CA). Results were considered significant when the P value was S 0.05.
RESULTS
Figure 1 Seven days postlithotripsy. Five fragments are noted, but note the difficulty in determining accurately the size and number of stones present.
triptor (Diasonics, Milpitas, CA) to a maximum of 12,000 pulses/treatment with an average peak pressure of 800- 900 Bars. A patient was eligible for retreatment no sooner than 2 weeks after a prior treatment for a maximum of four total treatments. If a patient failed to demonstrate a reduction in debris or fragment size or had no fragment greater than 5 mm, that patient was not eligible for additional lithotripsy.. The therapeutic end point was a stone· free gallbladder or one containing fragments less than 5 mm in maximum diameter. Stone fragments were counted and the Jargest fragment diameter determined sonographically for each patient during the postlithotripsy period. Ultrasound examinations were completed immediately after litho· tripsy and scheduled for days 3, 7, 14, 30, 90, and 180. Variations in these scheduled times were permitted to allow for patient convenience. The examinations were carried out using a variety of commercially available general purpose ultrasound units. The sonographers and sonologists were informed that the patients were part of the lithotripsy study, but they were blinded to the results of the prior sonographic studies. Standard ultrasound techniques were utilized, with additional maneuvers such as turning, coughing, and erect and multiple decubitus views em· ployed as needed to separate the fragments. The fragment with largest transverse diameter was measured to the nearest millimeter using electronic calipers. The number of fragments was counted up to six. The data were divided into five groups: day 0 (immediately post)ithotripsy), days 1- 4, days 5- 10,
A total of 12 patients (four women and eight men) underwent lithotripsy. One patient had follow -up studies performed at an outside institution and is not included in this analysis, leaving 11 patients. Twenty· six treatments were subsequently carried out. Ninety· four postlithotripsy ultrasound examinations were performed on these 11 patients (average, 8.5 studies per patient). Eight patients were retreated, including four with a total of three treatments. Results are reported as arithmetic means with the 95% confidence interval indicated. First, fragment size and number were analyzed. A total of 325 fragments were counted, an average of 3.5 ± 0.5 per study. The largest fragment size averaged 8.9 ± 1.3 mm. Fragment size and number were then considered as functions of the time interval after the treatment (Fig. 2). ANOVA with repeated measures showed no significant change in either fragment size or number between time intervals. Next, fragment size (recorded to the nearest millimeter) was compared with that reported on the immediately prior study to assess any trends in size Figure 2 The average size and number of fragments meas· ured in each of the five time intervals is plotted. ANOVA showed no s·gnjfjcant change between time intervals In either.
Size and Number of Fragments (Average values for each period)
14
Slze(mm)INumber
12
10 8
6
.. 2
0
Day o
Daya 1·4
Daya 5· 10
Daya 11- 20
Days after treatment -
Average Size
95% confidence limits
0
Average Number
Daya 21·•0
J Ultrasound Med 10:509- 512, 1991
WORRELL ET AL
Table 1: Change in Fragment Size From That of a Prior Study
Table 2: Change in Fragment Number From Test of a Prior Study
Percentage Average Size 95 % Confidence of Studies Change Limits Increase Decrease No change
35 50 15
3.7mm 3.3mm
± 1.0 mm ± 0.Bmm
change. The change here showed considerable variability: 35% of the time the diameter of the largest fragment had increased, in 50% of the cases there was a decrease, and no change was seen in 15% (Table 1). The average change was calculated with respect to both the direction of the change and the absolute value. Overall, there was a slight average change in fragment size of -0.5 ± 1.0 mm when the average was computed using signed values. When absolute values were used, the change averaged 3.1 ± 0.6 mm. The change in fragment size was then considered as a function of the time interval since the treatment (Figs. 3 and 4). ANOV A again showed no significant change in size between the time intervals. When the number of fragments was compared to the prior report, 183 revealed a decrease, 28% had an increase, and 54% showed no change in number (Table 2). Once more the data were calculated using both signed and absolute values for the change. A slight average increase in fragment number of 0.4 ± 0.6 was seen when the direction of the change was considered, and an average 1.4 ± 0.5 change in stone count occurred when absolute values were used. The change in fragment count also was considered a function of the
511
Percentage Average Change 95% Confidence of Studies in Number Limits
28
Increase Decrease No change
± 0.8 ±0.9
3.3 2.9
18 54
time interval, and once again ANOVA failed to show a significant change in count between time intervals. Finally, comparisons of the changes in fragment size and number were made between the first and subsequent treatments. Although ANOVA showed an insignificant difference in the average change in size or number of fragments with additional treatments, a significant increase in the absolute number of fragments (P < 0.001) was found between treatments. Fragment size did not vary significantly between treatments (P ;::. 0.15).
DISCUSSION Ultrasound plays the major role in determining size and number of residual gallstone fragments in most current lithotripsy protocols. Moreover, the decision to withhold or administer additional lithotripsy, medical, or even surgical treatment often hinges on these sonographic data. Theoretically it would be expected that, between lithotripsy treatments, fragment number would remain constant or decrease (allowing for possible passage of additional fragments), and that fragment size should
Figure 3 The change in size and number of fragments be· tween time intervals is plotted with respect to the sign of the change. Note that the net change in size and number of fragments between time intervals is minimized. ANOV A confirms no significant changes between time intervals.
Figure 4 The absolute value of the change in size and number of fragments is plotted. Once again, ANOV A showed no significant change in either between time intervals.
Change in Size and Number of Fragments
Change in Size and Number of Fragments
(Signed values compared to prior study)
~ze(mm)/
2
(Absolute value compared to prior study)
Slze(mm)/Number
Number
51
0 -1
-2 -3 -4'--~-'-~~~~..._~~~--L~~~~--'-~~
D•y1 1-4
D•ya 5·10
Daya 11-20
Daya 21· 40
Daye 5· 10
Days after treatment -
Change In Size
95% confidence limits
W
Change In Number
Daye 11· 20
Days after treatment -
Change In Size
95% confidence limits
Daye 21• 40
LJ Change l n Number
512
SIZE AND NUMBER OF STONE FRAGMENTS
remain the same. The results of this study show that variability in fragment size and number as reported by ultrasound is common after lithotripsy, and that size variation in this clinical setting may be greater than noted previously.2. 3 The implication of these data is that the ability of ultrasound to reveal size and number of stone fragments accurately is limited. There are several potential explanations for these difficulties. The plurality of observers probably contributes to this variation, although true inter- and intraobserver variability was not com· pared with simultaneous studies. Some stone fragments undoubtedly are passed, but a decrease in number was noted only 18% of the time. The remaining fragments are oriented differently each time to the ultrasound beam, which will affect the accuracy of the size measurement because axial is better than lateral resolution. The axial measurement is further confounded, though, by acoustic shadowing, which may obliterate the far margin of the stone. The phenomenon of increasing fragment size may also be a reflection of multiple fragments clumping together in the viscid bile, whereas an increase in fragment number may be due to unclumping and separation of fragments at a later measurement. Finally, despite physical maneuvers to separate the fragments, some stones may be obscured by the acoustic shadow of an interposed stone. The results of the ANOVA indicate that the varia· bility between the time intervals is not significant. This would suggest that the frequency of ultrasound examinations postlithotripsy may be reduced, and that timing of follow-up studies may be more elective dur· ing the first 40 days. Comparison of changes in size and number between
J Ultrasound Med 10:509- 512, 1991
multiple treatments shows that increased numbers of fragments were found, but that the size change was insignificant. Whether these measurements of fragment size and change are predicting therapeutic results, however, will require long•term follow-up. In conclusion, this study shows no significant effect of time on ultrasonically detected fragment size or count, and it confirms that variability in fragment size and number is common in the immediate postlithotripsy period. The clinical relevance of these data is that the number of postlithotripsy ultrasound studies can be markedly decreased. A change in absolute size should measure at least 4 mm to surpass the 95% confidence interval, and the absolute change in number should be at least two fragments before this change is regarded as significant.
REFERENCES 1. Sauerbruch T, Delius M, Paumgartner G, et al: Fragmen• tation of gallstones by extracorporeal shock waves. N Engl J Med 314:818, 1986 2. Mathieson JR, So CB, Malone DE, et al: Accuracy of sonography for determining the number and size of gaJlbladder stones before and after lithotripsy. AJR 153:977, 1989 3. Garra BS, Davros WJ, Lack EE, et al: Visibility of gallstone fragments at US and fluoroscopy: Implications for monitoring gallstone lithotripsy. Radiology t 74:343, 1990 4. Sackman M, Delius M, Sauerbruch T, et al: Shockwave lithotripsy of gallbladder stones: The first 175 patients. N Engl J Med 318:393, 1988 5. Martin X, Mestas JL, Cathignol D. et al: Ultrasound localJsation for shockwave lithotripsy (letter). Lancet 2:1005, 1985
Ninety-four gallbladder ultrasound examinations were carried out in 11 patients at intervals for the first 40 days after lithotripsy. No dissolution or other active therapy was carried out during this time. Fragment size and number were measured to determine the postlith otripsy variability. Analysis of variance (ANOV A) showed no significant changes in fragment size or number over time. The changes in fragment size and number compared to the previous measurements were then evaluated. Again, ANOVA showed no significant 9
S
ince the introduction of gallbladder lithotripsy by Sauerbruch et al in 1986, 1 intense interest has been expressed in this new modality for treating cholelithiasis. In most protocols, the primary method for monitoring gallstone fragmentation after lithotripsy has been ultrasound (US), with clinical decisions regarding additional treatment resting on the size and number of fragments present. Previous investigators, including Mathieson et al 2 and Garra et al, 3 have studied the in vitro, animal, and human models and noted the difficulties in both accurately counting and sizing gallstone fragments, especially in the pres· ence of multiple other fragments (Fig. 1). Mathieson et al reported accurate counting and sizing of fragments to within ± 1.1 mm when less than six stones were present, but noted a decrease in accuracy when the number of fragment count was more than six. Sackman Received May 9, 1990, from the Departments of •Radiology and Radiological Sciences, fGastroenterology. and tSurgery, Vanderbilt University School of Medicine, and §Vanderbilt University Computer Center, Nashville, Tennessee. Revised manuscript accepted for publication March 4, 1991. Address correspondence and reprint requests to Dr. John A. Worrell; Department of Radiology and Radiological Sciences, Van· derbilt University, Nashville, TN 37232-2675. This manuscript includes material presented at the 34th Annual Meeting of the AIUM, New Orleans, LA, March 4- 7, 1990.
changes between times. The average change in absolute size was 3.1 ± 0.6 mm, and the average change in absolute number was 1.4 ± 0.5. We conclude that fragment size and number as determined by ultrasound do not vary significantly with time during the first 40 days. The absolute size change measured to the nearest millimeter should be at least 4 mm to surpass the 95 % confidence interval. Similarly, the absolute change in number should be at least 2 to be regarded as significant.
et al reported the difficulty in estimating stone burden, especially in the postlithotripsy period,~ whereas Martin et al found the accurate assessment of fragments by US so difficult that oral cholecystography was substituted.5 This study attempts to determine the postlithotripsy variability in gallstone fragment size and number as determined by ultrasound in a clinical setting that included multiple sonologists and sonographers em· ploying a variety of equipment.
PATIENTS AND METHODS To be considered for our biliary lithotripsy protocol, a patient must have had symptoms of biliary colic and no more than three gallstones, each with a maximum diameter less than or equal to 30 mm. Exclusionary criteria included a nonfunctioning gallbladder by oral cholecystogram (OCG), pregnancy, bleeding disorder, or abdominal aortic aneurysm. Importantly, no oral dissolution therapy was permitted for 30 days before or after a lithotripsy treatment. This study is part of a multicenter study approved by the Vanderbilt Human Investigation Committee with informed consent obtained from each patient. Stone fragmentation was carried out using an investigational piezoelectric litho-
© 1991 by the American Institute of Ultrasound in Medicine• J Ultrasound Med 10:509- 512, 1991•0278-4297/91/$3.50
510
J Ultrasound Med 10:509- 512, 1991
SIZE AND NUMBER OF STONE FRAGMENTS
days 11 - 20, and days 21-40. Statistical analysis employed ANOVA, including repeated measures, calculation of the arithmetic means, and 95 % confidence limits of the grouped and pooled data using a commercial1y available statistical software package (BMDP Statistical Software, Los Angeles, CA). Results were considered significant when the P value was S 0.05.
RESULTS
Figure 1 Seven days postlithotripsy. Five fragments are noted, but note the difficulty in determining accurately the size and number of stones present.
triptor (Diasonics, Milpitas, CA) to a maximum of 12,000 pulses/treatment with an average peak pressure of 800- 900 Bars. A patient was eligible for retreatment no sooner than 2 weeks after a prior treatment for a maximum of four total treatments. If a patient failed to demonstrate a reduction in debris or fragment size or had no fragment greater than 5 mm, that patient was not eligible for additional lithotripsy.. The therapeutic end point was a stone· free gallbladder or one containing fragments less than 5 mm in maximum diameter. Stone fragments were counted and the Jargest fragment diameter determined sonographically for each patient during the postlithotripsy period. Ultrasound examinations were completed immediately after litho· tripsy and scheduled for days 3, 7, 14, 30, 90, and 180. Variations in these scheduled times were permitted to allow for patient convenience. The examinations were carried out using a variety of commercially available general purpose ultrasound units. The sonographers and sonologists were informed that the patients were part of the lithotripsy study, but they were blinded to the results of the prior sonographic studies. Standard ultrasound techniques were utilized, with additional maneuvers such as turning, coughing, and erect and multiple decubitus views em· ployed as needed to separate the fragments. The fragment with largest transverse diameter was measured to the nearest millimeter using electronic calipers. The number of fragments was counted up to six. The data were divided into five groups: day 0 (immediately post)ithotripsy), days 1- 4, days 5- 10,
A total of 12 patients (four women and eight men) underwent lithotripsy. One patient had follow -up studies performed at an outside institution and is not included in this analysis, leaving 11 patients. Twenty· six treatments were subsequently carried out. Ninety· four postlithotripsy ultrasound examinations were performed on these 11 patients (average, 8.5 studies per patient). Eight patients were retreated, including four with a total of three treatments. Results are reported as arithmetic means with the 95% confidence interval indicated. First, fragment size and number were analyzed. A total of 325 fragments were counted, an average of 3.5 ± 0.5 per study. The largest fragment size averaged 8.9 ± 1.3 mm. Fragment size and number were then considered as functions of the time interval after the treatment (Fig. 2). ANOVA with repeated measures showed no significant change in either fragment size or number between time intervals. Next, fragment size (recorded to the nearest millimeter) was compared with that reported on the immediately prior study to assess any trends in size Figure 2 The average size and number of fragments meas· ured in each of the five time intervals is plotted. ANOVA showed no s·gnjfjcant change between time intervals In either.
Size and Number of Fragments (Average values for each period)
14
Slze(mm)INumber
12
10 8
6
.. 2
0
Day o
Daya 1·4
Daya 5· 10
Daya 11- 20
Days after treatment -
Average Size
95% confidence limits
0
Average Number
Daya 21·•0
J Ultrasound Med 10:509- 512, 1991
WORRELL ET AL
Table 1: Change in Fragment Size From That of a Prior Study
Table 2: Change in Fragment Number From Test of a Prior Study
Percentage Average Size 95 % Confidence of Studies Change Limits Increase Decrease No change
35 50 15
3.7mm 3.3mm
± 1.0 mm ± 0.Bmm
change. The change here showed considerable variability: 35% of the time the diameter of the largest fragment had increased, in 50% of the cases there was a decrease, and no change was seen in 15% (Table 1). The average change was calculated with respect to both the direction of the change and the absolute value. Overall, there was a slight average change in fragment size of -0.5 ± 1.0 mm when the average was computed using signed values. When absolute values were used, the change averaged 3.1 ± 0.6 mm. The change in fragment size was then considered as a function of the time interval since the treatment (Figs. 3 and 4). ANOV A again showed no significant change in size between the time intervals. When the number of fragments was compared to the prior report, 183 revealed a decrease, 28% had an increase, and 54% showed no change in number (Table 2). Once more the data were calculated using both signed and absolute values for the change. A slight average increase in fragment number of 0.4 ± 0.6 was seen when the direction of the change was considered, and an average 1.4 ± 0.5 change in stone count occurred when absolute values were used. The change in fragment count also was considered a function of the
511
Percentage Average Change 95% Confidence of Studies in Number Limits
28
Increase Decrease No change
± 0.8 ±0.9
3.3 2.9
18 54
time interval, and once again ANOVA failed to show a significant change in count between time intervals. Finally, comparisons of the changes in fragment size and number were made between the first and subsequent treatments. Although ANOVA showed an insignificant difference in the average change in size or number of fragments with additional treatments, a significant increase in the absolute number of fragments (P < 0.001) was found between treatments. Fragment size did not vary significantly between treatments (P ;::. 0.15).
DISCUSSION Ultrasound plays the major role in determining size and number of residual gallstone fragments in most current lithotripsy protocols. Moreover, the decision to withhold or administer additional lithotripsy, medical, or even surgical treatment often hinges on these sonographic data. Theoretically it would be expected that, between lithotripsy treatments, fragment number would remain constant or decrease (allowing for possible passage of additional fragments), and that fragment size should
Figure 3 The change in size and number of fragments be· tween time intervals is plotted with respect to the sign of the change. Note that the net change in size and number of fragments between time intervals is minimized. ANOV A confirms no significant changes between time intervals.
Figure 4 The absolute value of the change in size and number of fragments is plotted. Once again, ANOV A showed no significant change in either between time intervals.
Change in Size and Number of Fragments
Change in Size and Number of Fragments
(Signed values compared to prior study)
~ze(mm)/
2
(Absolute value compared to prior study)
Slze(mm)/Number
Number
51
0 -1
-2 -3 -4'--~-'-~~~~..._~~~--L~~~~--'-~~
D•y1 1-4
D•ya 5·10
Daya 11-20
Daya 21· 40
Daye 5· 10
Days after treatment -
Change In Size
95% confidence limits
W
Change In Number
Daye 11· 20
Days after treatment -
Change In Size
95% confidence limits
Daye 21• 40
LJ Change l n Number
512
SIZE AND NUMBER OF STONE FRAGMENTS
remain the same. The results of this study show that variability in fragment size and number as reported by ultrasound is common after lithotripsy, and that size variation in this clinical setting may be greater than noted previously.2. 3 The implication of these data is that the ability of ultrasound to reveal size and number of stone fragments accurately is limited. There are several potential explanations for these difficulties. The plurality of observers probably contributes to this variation, although true inter- and intraobserver variability was not com· pared with simultaneous studies. Some stone fragments undoubtedly are passed, but a decrease in number was noted only 18% of the time. The remaining fragments are oriented differently each time to the ultrasound beam, which will affect the accuracy of the size measurement because axial is better than lateral resolution. The axial measurement is further confounded, though, by acoustic shadowing, which may obliterate the far margin of the stone. The phenomenon of increasing fragment size may also be a reflection of multiple fragments clumping together in the viscid bile, whereas an increase in fragment number may be due to unclumping and separation of fragments at a later measurement. Finally, despite physical maneuvers to separate the fragments, some stones may be obscured by the acoustic shadow of an interposed stone. The results of the ANOVA indicate that the varia· bility between the time intervals is not significant. This would suggest that the frequency of ultrasound examinations postlithotripsy may be reduced, and that timing of follow-up studies may be more elective dur· ing the first 40 days. Comparison of changes in size and number between
J Ultrasound Med 10:509- 512, 1991
multiple treatments shows that increased numbers of fragments were found, but that the size change was insignificant. Whether these measurements of fragment size and change are predicting therapeutic results, however, will require long•term follow-up. In conclusion, this study shows no significant effect of time on ultrasonically detected fragment size or count, and it confirms that variability in fragment size and number is common in the immediate postlithotripsy period. The clinical relevance of these data is that the number of postlithotripsy ultrasound studies can be markedly decreased. A change in absolute size should measure at least 4 mm to surpass the 95% confidence interval, and the absolute change in number should be at least two fragments before this change is regarded as significant.
REFERENCES 1. Sauerbruch T, Delius M, Paumgartner G, et al: Fragmen• tation of gallstones by extracorporeal shock waves. N Engl J Med 314:818, 1986 2. Mathieson JR, So CB, Malone DE, et al: Accuracy of sonography for determining the number and size of gaJlbladder stones before and after lithotripsy. AJR 153:977, 1989 3. Garra BS, Davros WJ, Lack EE, et al: Visibility of gallstone fragments at US and fluoroscopy: Implications for monitoring gallstone lithotripsy. Radiology t 74:343, 1990 4. Sackman M, Delius M, Sauerbruch T, et al: Shockwave lithotripsy of gallbladder stones: The first 175 patients. N Engl J Med 318:393, 1988 5. Martin X, Mestas JL, Cathignol D. et al: Ultrasound localJsation for shockwave lithotripsy (letter). Lancet 2:1005, 1985
