- Email: [email protected]
Validation of Diagnostic and Performance Characteristics of the Wireless Motility Capsule in Patients With Suspected Gastroparesis
Clinical Gastroenterology and Hepatology 2019;-:-–-
1 2 3 4 5 6 7 8 9 10Q8 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
Validation of Diagnostic and Performance Characteristics of the Wireless Motility Capsule in Patients With Suspected Gastroparesis Allen A. Lee,* Satish Rao,‡ Linda A. Nguyen,§ Baharak Moshiree,k Irene Sarosiek,¶ Michael I. Schulman,# John M. Wo,** Henry P. Parkman,‡‡ Gregory E. Wilding,§§ Richard W. McCallum,¶ William L. Hasler,*,b and Braden Kuokk,b *Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan; ‡Division of Gastroenterology, Augusta University, Augusta, Georgia; §Division of Gastroenterology, Stanford University, Stanford, California; kUniversity of North Carolina, Charlotte, North Carolina; ¶Section of Gastroenterology, Texas Tech University, El Paso, Texas; #Florida Digestive Health Associate, Largo, Florida; **Division of Gastroenterology, Indiana University, Indianapolis, Indiana; ‡‡Section of Gastroenterology, Temple University, Philadelphia, Pennsylvania; §§Department of Biostatistics, University of Buffalo, Buffalo, New York; and kkDivision of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts BACKGROUND & AIMS:
It is a challenge to make a diagnosis of gastroparesis. There is good agreement in results from wireless motility capsule (WMC) analysis and gastric emptying scintigraphy (GES), but the diagnostic yield of WMC is unclear and the accuracy of this method has not been validated. We compared the performance characteristics of WMC vs GES in assessing gastric emptying in patients with suspected gastroparesis.
METHODS:
We performed a prospective study of 167 subjects with gastroparesis (53 with diabetes and 114 without) at 10 centers, from 2013 through 2016. Subjects were assessed simultaneously by GES and with a WMC to measure gastric emptying and regional transit. Delayed gastric emptying by GES was defined as more than 10% meal retention at 4 hrs whereas delayed gastric emptying by WMC was defined as more than 5 hrs for passage of the capsule into the duodenum; a severe delay in gastric emptying was defined as a gastric emptying time of more than 12 hrs by WMC or more than 35% retention at 4 hrs by GES. Rapid gastric emptying was defined as less than 38% meal retention at 1 hr based on by GES or gastric emptying times less than 1:45 hrs by WMC. We compared diagnostic and performance characteristics of GES vs WMC.
RESULTS:
Delayed gastric emptying was detected in a higher proportion of subjects by WMC (34.6%) than by GES (24.5%) (P[.009). Overall agreement in results between methods was 75.7% (kappa[0.42). In subjects without diabetes, the WMC detected a higher proportion of subjects with delayed gastric emptying (33.3%) than GES (17.1%) (P < .001). A higher proportion of subjects with diabetes had delayed gastric emptying detected by GES (41.7%) than by WMC (17.1%) (P[.002). Severe delays in gastric emptying were observed in a higher proportion of subjects by WMC (13.8%) than by GES (6.9%) (P [ .02). Rapid gastric emptying was detected in a higher proportion of subjects by GES (13.8%) than by WMC (3.3%) (P < .001). Regional and generalized transit abnormalities were observed in 61.8% subjects and only detected by WMC.
CONCLUSION:
Although there is agreement in analysis of gastric emptying by GES vs WMC, WMC provides higher diagnostic yield than GES. WMC detects delayed gastric emptying more frequently than GES and identifies extra-gastric transit abnormalities. Diabetic vs non-diabetic subjects have different results from GES vs WMC. These findings could affect management of patients with suspected gastroparesis. ClinicalTrials.gov no: NCT02022826.
Keywords: Idiopathic; Gastrointestinal Motility; Small Bowel Transit; Colonic Transit.
b
Authors share co-senior authorship.
Abbreviations used in this paper: AE, adverse event; AUC, area under the curve; CI, confidence interval; Ct, number of contractions; CTT, colonic transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; IBS, irritable bowel syndrome; MMC, migrating motor complex; SBTT, small bowel transit time; WMC, wireless motility capsule.
© 2019 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2018.11.063
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116
2
117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174
Lee et al
Clinical Gastroenterology and Hepatology Vol.
astroparesis is a chronic condition characterized by delayed gastric emptying in the absence of mechanical obstruction. Gastric emptying scintigraphy (GES) is often performed to diagnose gastroparesis but is limited by lack of standardization and radiation exposure.1 Furthermore, coexisting disorders such as irritable bowel syndrome (IBS) are commonly encountered in gastroparesis.2 These coexisting problems may be a consequence of generalized gastrointestinal dysmotility that may remain uninvestigated if scintigraphy alone is performed.3,4 It is possible that targeting specific physiological abnormalities in gastroparesis may lead to improved patient outcomes. Wireless motility capsule (WMC) is a noninvasive ambulatory test that measures transit times and pressure parameters throughout the gastrointestinal tract. Although a previous study demonstrated good agreement in gastric emptying between GES and WMC, this study was enriched with subjects who previously had an abnormal GES.5 The primary aim of this study was to prospectively evaluate the diagnostic and performance characteristics of GES and WMC in patients with unexplained upper gastrointestinal symptoms suggestive of gastroparesis. In addition, we examined the prevalence of regional and generalized transit delays as well as gastroduodenal contractile abnormalities with WMC. Finally, because prior studies have suggested physiological differences between diabetic and idiopathic gastroparesis, we also performed subgroup analyses to examine differences in test characteristics between diabetic and non-diabetic subjects.2,6
G
Methods This was a multicenter, comparative, prospective cohort study (ClinicalTrials.gov no: NCT02022826). Subjects 18 years old with 2 upper gastrointestinal symptoms for 12 weeks suggestive for gastroparesis (nausea, vomiting, upper abdominal pain, early satiation, bloating, postprandial fullness) were enrolled at 10 academic and community centers in the United States from 2013 to 2016. The protocol was approved by the Institutional Review Board at each center. Informed consent was obtained from each subject before enrollment.
-,
No.
-
What You Need to Know Background Gastric emptying scintigraphy (GES) is the most commonly ordered test for diagnosis of gastroparesis. Prior studies have shown good agreement between wireless motility capsule (WMC) and GES, but this has not been validated in patients with suspected gastroparesis. Findings Delayed gastric emptying was detected in a higher proportion of subjects by WMC than by GES. Diabetic and non-diabetic subjects showed distinct results with WMC and GES. Extragastric transit abnormalities were observed in 45% of subjects and only detected by WMC. Implications for patient care WMC provides higher diagnostic yield compared with GES, which may impact management in patients with suspected gastroparesis.
Assessment of Gastric Emptying Delayed gastric emptying time (GET) was defined as >5 hours for passage of the capsule into the duodenum, whereas abnormal GES was defined as >10% meal retention at 4 hours.7 Severe delay in gastric emptying was defined as GET >12 hours by WMC or >35% retention at 4 hours by GES.1,8 Rapid gastric emptying by GES was defined as <38% meal retention at 1 hour or GET <1:45 hours by WMC.9 All WMC studies were interpreted by a centralized, blinded reader (B.K.) to ensure data consistency.
Regional and Whole Gut Transit Delayed small bowel transit time (SBTT) was defined as >6 hours, and delayed colonic transit time (CTT) was defined as >58:45 hours.9 Generalized transit delays were defined as 2 regions with delayed transit, and global transit delays were defined as delay in all 3 regions (gastric, small bowel, and colon).
Pressure Parameters Study Protocol Subjects were asked to discontinue all substances (eg, prokinetic agents, anti-cholinergic medications, opioids, cannabinoids) that may affect gastrointestinal motility at least 72 hours before testing. After an overnight fast, subjects consumed a standardized low-fat meal. Immediately after meal ingestion, subjects swallowed the WMC while simultaneously undergoing image acquisition for scintigraphy as previously described (Supplementary Methods).5,7
Normal values for gastric and small bowel number of contractions (Ct) were defined as >29/h and >36/h, respectively, and normal gastric and small bowel area under the curve (AUC) values were set as 1359 and 1456 mm Hg/min, respectively.8
Statistical Analysis The primary outcome was analyzed as a measure of per patient device agreement for the diagnosis of delayed
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232
-
233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290
2019
Validation of Wireless Motility Capsule
gastric emptying between WMC and GES. Positive agreement is defined as the probability of a positive test by WMC given positive GES, whereas negative agreement is defined as the probability of a negative test by WMC given negative GES. Maximum likelihood estimates of positive and negative percent agreement were computed on the basis of conditional relative frequencies in addition to corresponding 95% confidence interval (CI). Additional measures including estimates of overall percent agreement and Cohen’s kappa were also calculated. Differences between groups were compared by using Wilcoxon rank-sum test for continuous measures, c2 or Fisher exact test for unpaired categorical measures, and McNemar’s tests for paired categorical data. Multiple and logistic regression models were used to assess the robustness of group comparison results and to statistically adjust for group differences in age, gender, body mass index, duration of symptoms, and marijuana and/ or opiate use. P values <.05 were considered significant. Data were analyzed by using R (version 3.4.3) and GraphPad Prism (version 7.05; GraphPad Software, La Jolla, CA). All authors had access to the study data and reviewed and approved the final manuscript.
Results Agreement in Gastric Emptying Between Wireless Motility Capsule and Gastric Emptying Scintigraphy A total of 167 subjects (53 diabetic, 114 non-diabetic) were enrolled (Table 1), and data from 154 subjects who underwent simultaneous WMC and GES were available to review (Supplementary Figure 1). GET was delayed in 53 subjects (34.6%), whereas GES showed delayed gastric emptying in 39 subjects (24.5%, P ¼ .009) (Figure 1A). Overall device agreement between WMC and GES was noted in 75.7%, 95% CI, 68.8%–82.5%, with positive agreement seen in 72.2% (n ¼ 26) and negative agreement in 76.7% (n ¼ 89). There was moderate agreement in parameters of gastric emptying by WMC and GES (kappa ¼ 0.42; 95% CI, 0.27–0.57).
Agreement in Gastric Emptying Between Diabetic vs Non-Diabetic Etiology Subgroup analyses for device agreement in diabetic vs non-diabetic subjects showed distinct results (Table 2). In diabetic subjects, GET was delayed in 37.2%, whereas delayed GES was noted in 41.7% (P ¼ .48) (Figure 1A). Overall device agreement between WMC and GES in diabetic subjects was 81.0% (n ¼ 34), with positive agreement seen in 72.2% (n ¼ 13) and negative agreement in 87.5% (n ¼ 21) (kappa ¼ 0.61; 95% CI, 0.36–0.85). In non-diabetic subjects, overall device agreement between WMC and GES was seen in 73.6% (n ¼ 81), with positive agreement in 72.2%
3
Table 1. Demographic Characteristics of Enrolled Subjects Study demographics
a
All patients Diabetics Non-diabetics P (n ¼ 167) (n ¼ 53) (n ¼ 114) valueb Age, y Female gender BMI (kg/m2) White race Diabetes subtype Type 1 Type 2 Duration of symptoms (y) GCSI total score at baseline Active marijuana usec Active opiate usec
45.1 131 28.1 144
(13.8) 51.1 (12.7) (78.4%) 36 (67.9%) (6.9) 31.0 (6.3) (87.3%) 43 (82.7%)
42.4 95 26.8 101
(13.4) (83.3%) (6.7) (89.4%)
<.01 .02 <.01 .23
6.0 (7.4)
18 (44.0%) 35 (66.0%) 6.6 (7.9)
5.8 (7.1)
.51
2.9 (1.0)
2.5 (1.0)
2.7 (1.0)
.23
14 (8.4%)
5 (9.4%)
9 (7.9%)
.74
19 (11.4%)
5 (9.4%)
14 (12.3%)
.59
BMI, body mass index; GCSI, gastroparesis cardinal symptom index. a Mean (standard deviation) unless otherwise noted. b P values are comparing diabetic vs non-diabetic subjects. c Marijuana and opiate use were active at time of baseline visit but held at least 72 hours before motility testing.
(n ¼ 13) and negative agreement in 73.9% (n ¼ 68) (kappa ¼ 0.33; 95% CI, 0.14–0.50). In non-diabetics, there was a significant increase in delayed gastric transit by WMC (33.3%, n ¼ 37) compared with GES (17.1%, n ¼ 19) (P < .001). Conversely, diabetic subjects were more likely to show delayed gastric emptying with GES vs non-diabetics (41.7% vs 17.1%, P ¼ .002) (Figure 1B). However, there were no differences in rates of delayed GET between diabetic and non-diabetic subjects.
Agreement for Severe Delay in Gastric Emptying Severely delayed gastric emptying by GES was seen in 6.9% (n ¼ 11) vs 13.8% by GET (n ¼ 21, P ¼ .02). Diabetic subjects were more likely to have severe delays in gastric emptying by GES compared with non-diabetic subjects (14.6% vs 3.6%, P ¼ .01). There were no differences in rates of severe delay by WMC between diabetic and non-diabetic subjects. There was fair agreement between severe gastric emptying delays by WMC and GES (kappa ¼ 0.38; 95% CI, 0.15–0.60).
Rapid Gastric Emptying Rapid emptying by GES was seen in 13.8% (n ¼ 22) compared with rapid GET in 3.3% (n ¼ 5, P < .001) (Figure 2). In diabetics, 18.4% of subjects showed rapid GES compared with 9.3% with rapid GET (P ¼ .16). In
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348
349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406
Lee et al
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
Figure 1. (A) Overall, there was significantly higher rate of delayed gastric emptying detected by GET (dark blue) when compared with GES (light blue) (34.6% vs 24.5%, P ¼ .009). In non-diabetic subjects, WMC detected significantly more subjects with delayed gastric transit when compared with GES (33.3% vs 17.1%, P < .001). In diabetic subjects, there were no differences in rates of delayed gastric emptying by GES and GET (37.2% vs 41.7%, P ¼ .48). (B) Diabetic subjects (light green) were more likely to have delayed gastric emptying detected by GES when compared with nondiabetic subjects (dark green) (41.7% vs 17.1%, P ¼ .002). However, there were no differences in rates of delayed gastric emptying by WMC between diabetic and nondiabetic subjects. GES, gastric emptying scintigraphy; GET, gastric emptying time; WMC, wireless motility capsule.
non-diabetic subjects, a higher proportion of subjects showed rapid GES (11.7%) compared with WMC (0.9%) (P < .001). There were no differences in the rates of rapid GES when comparing diabetic vs non-diabetic subjects (18.4% vs 11.7%, P ¼ .26). However, WMC was more likely to detect rapid gastric emptying in diabetic compared with non-diabetic subjects (9.3% vs 0.9%, P ¼ .02).
Extragastric Transit Delays by Wireless Motility Capsule Extragastric transit delays were seen in 45.6% of subjects (n ¼ 68) including delayed SBTT in 22.8% (n ¼ 34) and delayed CTT in 31.5% (n ¼ 47) (Figure 3A). Generalized transit delays were seen in 21.1% (n ¼ 32), whereas global transit delays were noted in 5.4% (n ¼ 8). Overall, 61.8% subjects (n ¼ 94) had isolated or generalized transit delays by WMC (Figure 3B). In
diabetic subjects, delayed SBTT was seen in 12.5% (n ¼ 5), delayed CTT in 32.5% (n ¼ 13), and generalized transit delays in 12.5% (n ¼ 5). In non-diabetic subjects, delayed SBTT was found in 26.6% (n ¼ 29), delayed CTT in 31.2% (n ¼ 34), and generalized transit delays in 24.8% (n ¼ 27). Non-diabetic subjects displayed a longer SBTT compared with diabetics (5.18 vs 4.34 hours, P ¼ .01). Non-diabetic subjects also showed trends toward higher rates of delayed SBTT (P ¼ .07) as well as generalized delays (P ¼ .11) compared with diabetics.
Gastric and Small Bowel Contractile Abnormalities by Wireless Motility Capsule Gastric and/or small bowel contractility abnormalities were seen in 40.4% of all subjects (n ¼ 61) (Table 2). Abnormal gastric contractility measures were noted in 26.7% with reduced antral Ct (n ¼ 40) and 18.8% with abnormal AUC (n ¼ 28). Abnormal small
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
print & web 4C=FPO
4
407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464
-
465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522
2019
Validation of Wireless Motility Capsule
5
Table 2. Prevalence of Transit Delays and Contractility Abnormalities in Patients With Suspected Gastroparesis by WMC and GES Adjusted All patients (N ¼ 167), Diabetic patients Non-diabetic n (%) or median (IQR) (N ¼ 53) patients (N ¼ 114) P valuea P valueb
Measure Delayed GES (>10% solid retention at 4 h) Severely delayed GES (>35% solid retention at 4 h) Rapid GES (<38% solid retention at 1 h) Delayed WMC GET (GET >5 h) Severely delayed WMC GET (GET >12 h) Rapid WMC GET (GET <1:45 h) WMC SBTT (h) Delayed WMC SBTTc (SBTT >6 h) WMC CTT (h) Delayed WMC CTTc (CTT >58:45 h) Transit delay in 2 regions by WMC Contractility measures Gastric Ct/h Reduced gastric Ct (<29/h) Gastric AUC Reduced gastric AUC (<1359) Small bowel Ct/h Reduced small bowel Ct (<36/h) Small bowel AUC Reduced small bowel AUC (<1456)
39/159 (24.5) 11/159 (6.9)
20/48 (41.7) 7/48 (14.6)
19/111(17.1) 4/111 (3.6)
.002 .01
.01 .07
22/160 (13.8) 53/153 (34.6) 21/153 (13.8) 5/153 (3.3) 4.6 (3.5–5.8) 34/149 (22.8) 39.3 (17.3–67.9) 47/149 (31.5) 32/152 (21.1)
9/49 (18.4) 16/43 (37.2) 9/43 (20.9) 4/43 (9.3) 4.2 (3.1–5.2) 5/40 (12.5) 43.7 (20.2–65.3) 13/40 (32.5) 5/40 (12.5)
13/111 (11.7) 37/110 (33.3) 14/110 (12.7) 1/110 (0.9) 4.8 (4.0–6.1) 29/109 (26.6) 36.9 (16.8–67.9) 34/109 (31.2) 27/109 (24.8)
.26 .67 .21 .02 .01 .07 .23 .88 .11
.94 .19 .19 .28 .21 .40 .15 .39 .62
47.5 (26–87) 40/150 (26.7) 3003 (1546–5104) 28/149 (18.8) 111 (49–180) 27/151 (17.9) 3435 (1464–5689) 38/151 (25.2)
48 (23–93) 13/43 (30.2) 2533 (1390–5626) 10/42 (23.8) 134 (66–237) 6/42 (14.3) 4440 (1533–8117) 9/42 (21.4)
47 (29–87) 27/107 (25.2) 3088 (1740–4982) 18/107 (16.8) 110 (43–166) 21/109 (19.3) 3297 (1393–5195) 29/109 (26.6)
.84 .53 .52 .32 .17 .47 .09 .51
.91 .20 .45 .22 .61 .53 .14 .60
AUC, area under the curve; Ct, number of contractions; CTT, colonic transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; IQR, interquartile range; SBTT, small bowel transit time; WMC, wireless motility capsule. a P value comparing diabetics vs non-diabetic subjects. b P value comparing diabetics vs non-diabetic subjects after adjusting for age, gender, body mass index, duration of symptoms, and history of marijuana and/or opioid use. c Small bowel and colonic transit times could not be calculated on a total of 4 subjects because of incomplete data (3 studies because of capsule retention in the stomach and 1 study related to operator error).
bowel contractility measures were seen in 17.9% with reduced Ct (n ¼ 27) and 25.2% with abnormal AUC (n ¼ 38). There were no differences in gastric or small bowel contractility measures between diabetic and nondiabetic subjects.
Association of Gastric Emptying by Wireless Motility Capsule to Other Measures There was a significantly increased rate of delayed GES in those subjects with delayed GET vs those with normal GET (49.1% vs 10.1%, P < .001) (Table 3). This association between delayed GET and delayed GES was observed in both diabetic and non-diabetic subjects. In addition, delayed SBTT was more commonly observed in those subjects with delayed GET than with normal GET (34.0% vs 17.1%, P ¼ .02). This association was observed in non-diabetic subjects (41.7% vs 19.2%, P ¼ .01) but not in diabetic subjects (14.3% vs 11.5%, P ¼ .80). Furthermore, non-diabetic subjects with delayed GET showed higher rates of small bowel contractile abnormalities, including small bowel Ct (36.1% vs 11.0%, P ¼ .004) and AUC (38.9% vs 20.5%, P ¼ .06) compared with normal GET. However, these associations were not observed in diabetic subjects.
Adverse Events A total of 37 adverse events (AEs) were reported, including 22 non-serious and 15 serious AEs (Supplementary Table 1). All serious AEs resolved. One serious AE of capsule retention was noted with WMC, which resolved after endoscopic retrieval. No serious AEs were related to GES. There were no AEs related to fasting for 8 hours after WMC ingestion.
Discussion This was a prospective multicenter study designed to critically examine the diagnostic and performance characteristics of WMC compared with the current standard of GES in patients with suspected gastroparesis. We found evidence to validate the use of WMC in evaluating these patients, including good device agreement between GES and WMC. Furthermore, WMC detected a significantly higher proportion of subjects with both delayed as well as severely delayed gastric emptying when compared with GES. Also, subgroup analyses based on the etiology for gastroparesis demonstrated important differences between GES and WMC. Specifically, we found that nondiabetic subjects who accounted for two-thirds of the study population were significantly more likely to exhibit
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580
581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638
print & web 4C=FPO
6
Lee et al
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
Figure 2. There were significantly higher rates of rapid gastric emptying with GES (light blue) when compared with GET (dark blue) in all subjects (13.8% vs 3.3%, P < .001). In non-diabetic subjects, a higher number of subjects showed rapid gastric emptying with GES compared with WMC (11.7% vs 0.9%, P < .001). In diabetic subjects, there were no differences in detection of rapid gastric emptying by GES compared with GET (18.4% vs 9.3%, P ¼ .16). WMC was more likely to detect rapid gastric emptying in diabetics compared with non-diabetic subjects (9.3% vs 0.9%, P ¼ .02). However, there were no differences in rapid gastric emptying by GES in diabetics vs non-diabetics. GES, gastric emptying scintigraphy; GET, gastric emptying time; WMC, wireless motility capsule.
delayed GET with WMC when compared with GES. In contrast, diabetic subjects were more likely to show delayed gastric emptying with GES when compared with non-diabetic subjects. Finally, WMC detected 61.8% subjects with regional and/or generalized transit delays, resulting in an additional diagnostic yield of 37.3% when compared with 24.5% of subjects with delayed GES. Our results confirm and extend previous findings by Kuo et al,5 who reported good correlation (r ¼ 0.73) between WMC and GES. However, there are important differences that merit discussion. First, this current study was performed in a cohort of patients with suspicion of but without formal diagnosis of gastroparesis. In contrast, eligibility requirements in the study by Kuo et al required a history of delayed GES that led to an enriched population of gastroparesis. Also, our study investigated extragastric transit and contractile abnormalities. Recently, Hasler et al6 also compared performance characteristics of WMC and GES. This study showed lower device agreement between WMC and GES (kappa ¼ 0.12). However, a key difference in this previous study was sequential performance of GES, followed by WMC up to 6 months later. This is in contrast to the current study where GES and WMC were performed simultaneously. The significant intra-individual variation in gastric emptying rates of up to 24% and the time difference between the 2 studies may each explain some of the differences seen between these studies.10 Second, Hasler et al also evaluated an enriched population with prior abnormal GES. Our results suggest that the level of agreement between WMC and GES is more in line with data reported by Kuo et al.
This study demonstrated that WMC was significantly more likely to detect delayed gastric emptying when compared with GES. An additional 23% of subjects with normal GES had delayed GET by WMC, which is similar to prior results.5 Although gastric emptying by WMC and GES are highly correlated, they may not be measuring identical parameters. Although both tests depend on the rate of meal emptying, WMC is measuring emptying of an indigestible object, which is facilitated by return of phase III activity of the migrating motor complex (MMC).11 Thus, WMC may have increased sensitivity for detecting gastroparesis because it measures gastric emptying time, impaired MMC, and dyscoordination of gastric and small bowel motility, whereas scintigraphy only measures meal emptying. Our study further demonstrated important differences when subtyped by etiology. Diabetic subjects were more likely to show delayed gastric emptying by GES compared with non-diabetic subjects. In contrast, non-diabetic subjects were more likely to show delayed GET compared with GES. Our results contrast with data from Hasler et al,6 who found higher rates of delayed GET but not GES in diabetics compared with idiopathic gastroparesis. Because GES was always performed first in this study, it is possible that gastric emptying had normalized in a subset of idiopathic patients by the time WMC was performed. This is supported by preliminary data from the Gastroparesis Consortium that suggests gastric emptying is more likely to normalize during a period of 48 weeks in idiopathic subjects compared with diabetic subjects with gastroparesis (41% vs 22%, P ¼ .07).12 Our results support potential phenotypic differences between diabetic
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696
697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754
print & web 4C=FPO
-
2019
Validation of Wireless Motility Capsule
7
Figure 3. (A) Delayed SBTT was noted in 22.8% of all subjects (light blue) including 12.5% of diabetic subjects (dark blue) and 26.6% of non-diabetic subjects (green) (P ¼ .07). Delayed CTT was seen in 31.5% of all subjects including 32.5% of diabetics and 31.2% of non-diabetic subjects. Generalized transit delays were found in 21.1% of subjects including 12.5% of diabetics and 24.8% of non-diabetic subjects (P ¼ .11). P values are comparing diabetics with non-diabetics. (B) Delayed GES (light blue) was seen in 24.5%, whereas delayed GET (dark blue) was detected in 34.6%. Delayed GET SBTT (light green) was found in 45.8%, GET CTT (dark green) in 52.9%, SBTT CTT (pink) in 46.3%, and overall any delay by WMC (red) was detected in 61.8%. CTT, colonic transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; SBTT, small bowel transit time; WMC, wireless motility capsule.
and non-diabetic patients. Antral hypomotility is commonly seen in patients with gastroparesis.13 This is important because emptying of digestible solids depends mainly on antral function, whereas the emptying of indigestible solids, such as WMC, depends on the antral component of phase III of MMC.14 It is possible that diabetic gastroparesis preferentially affects processes related to postprandial antral hypomotility, whereas non-diabetic subjects display abnormal interdigestive function, which is not assessed by GES. Severe delays in gastric emptying were more likely to be detected by WMC compared with GES. Few studies have looked at stratifying subjects on the basis of the degree of gastric emptying delays. Parkman et al15 demonstrated that severe delays in GES correlated with more severe overall symptoms in idiopathic gastroparesis. Meanwhile, Hejazi et al16 suggested that patients with severe delays in GES were less likely to respond to
medical therapy, which often led to placement of gastric electrical stimulators. Although these findings are intriguing, data on severe delays in gastric emptying are difficult to interpret because true cutoffs are not clearly defined. Our results indicate that rapid gastric emptying was more likely to be detected by GES compared with WMC, likely because rapid emptying is not dependent on MMC. Accelerated gastric emptying is seen in approximately 20% of patients with diabetes. Recently, hyperglycemia was found to increase the numbers of gastric interstitial cells of Cajal, leading to rapid gastric emptying in a mouse model of obesity.17 However, the definitions for accelerated gastric emptying are still not clearly defined, and the clinical significance for rapid emptying requires further validation. An intriguing finding in our study was the high rate of small bowel dysmotility, particularly in non-diabetic
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812
8
813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870
Lee et al
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
Table 3. Association of Normal vs Abnormal GET to Other Transit and Contractile Measures All subjects Delayed GET
Transit measures Delayed GES (>10% solid retention at 4 h) Delayed SBTT (>6 h) Delayed CTT (>58:45 h) Reduced gastric Ct (<29/h) Reduced gastric AUC (<1359 mm Hg/min) Reduced SB Ct (<36/h) Reduced SB AUC (<1456 mm Hg/min)
26/53 17/50 19/50 18/50 12/49 16/51 18/51
(49.1%) (34.0%) (38.0%) (36.0%) (24.5%) (31.4%) (35.3%)
Diabetic subjects Transit measures
Delayed GET Normal GET P valuea
Delayed GES (>10% solid 13/16 (81.3%) retention at 4 h) Delayed SBTT (>6 h) 2/14 (14.3%) Delayed CTT (>58:45 h) 5/14 (35.7%) Gastric Ct (<29/h) 8/16 (50.0%) Gastric AUC (<1359 mm 5/15 (33.3%) Hg/min) SB Ct (<36/h) 3/15 (20.0%) SB AUC (<1456 mm Hg/min) 4/15 (26.7%)
Normal GET
P valuea
Adjusted P valueb
10/99 (10.1%) 17/99 (17.1%) 28/99 (28.3%) 22/100 (22.0%) 16/100 (16.0%) 11/100 (11.0%) 20/100 (20.0%)
<.001 .02 .23 .07 .21 .002 .04
<.001 .11 .10 .14 .28 .01 .32
Non-diabetic subjects Adjusted Adjusted P valueb Delayed GET Normal GET P valuea P valueb
<.001
.02
13/37 (35.1%)
(11.5%) (30.8%) (18.5%) (18.5%)
.80 .75 .03 .28
.70 .26 .09 .59
15/36 (41.7%) 14/36 (38.9%) 10/34 (29.4%) 7/34 (20.6%)
3/27 (11.1%) 5/27 (18.5%)
.43 .54
.71 .67
13/36 (36.1%) 8/73 (11.0%) 14/36 (38.9%) 15/73 (20.5%)
5/26 (19.2%) 3/26 8/26 5/27 5/27
5/73 (6.8%) 14/73 20/73 17/73 11/73
(19.2%) (27.4%) (23.3%) (15.1%)
<.001
.002
.01 .22 .50 .48
.06 .08 .66 .40
.004 .06
.005 .27
AUC, area under the curve; Ct, number of contractions; CTT, colonic transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; SB, small bowel; SBTT, small bowel transit time. a P value comparing delayed GET vs normal GET. b P value comparing delayed GET vs normal GET after adjusting for age, gender, body mass index, duration of symptoms, and history of marijuana and/or prior opioid use.
subjects. We also demonstrated significant associations between delayed GET by WMC and small bowel dysmotility, including delayed SBTT and reduced small bowel contractile parameters. These abnormalities were more commonly observed in non-diabetic subjects, which suggests that altered gastric–small bowel coordination and a more diffuse gastrointestinal dysmotility may be important in this subset of patients. Although the clinical significance of delayed small bowel transit is not clearly understood, there is evidence to suggest its relevance in gastroparesis. One study demonstrated that patients with both IBS and gastroparesis commonly show small bowel dysmotility.18 Another study demonstrated that patients with chronic, unexplained gastrointestinal symptoms and presence of small intestinal bacterial overgrowth showed significant delays in SBTT.19 These results suggest that small bowel dysmotility may play an important but under-recognized pathogenic factor in gastroparesis. Prior studies have demonstrated considerable overlap between upper and lower gastrointestinal symptoms in gastroparesis.2,15 Our results confirm that 62% of subjects had transit abnormalities by WMC, and nearly one-half showed extragastric transit abnormalities, which may explain the wide range of symptoms encountered in gastroparesis. Previous studies have also documented high prevalence of extragastric transit delays, termed diagnostic gain, which influenced patient management.3,4 Similar to our results, Hasler et al6
demonstrated extragastric transit delays in >40% of subjects. Our findings support investigation of whole gut transit and motility in this population to identify important physiological abnormalities and allow for more objective therapeutic choices. There are limitations to our study. First, there was a high prevalence of patients with normal gastric emptying. However, this reflects clinical reality where symptoms do not reliably distinguish patients with gastroparesis.20 In addition, there was a predominance of white female subjects in our cohort, which mirrors the clinical population seeking care for gastroparesis.2,15 Second, a liquid meal was administered 8 hours after WMC ingestion to mitigate against concerns for hypoglycemia. This liquid meal could prolong GET and artificially increase the number of subjects with severe delays by WMC. However, only 2 subjects in this severely delayed cohort had a GET <18 hours, whereas the mean GET was >50 hours. This suggests that these findings are likely related to underlying severe motor abnormalities rather than methodologic issues. Finally, we did not correlate physiological results with symptoms or outcome data because this was outside of the scope for this specific study. This introduces the potential for bias with our study. Furthermore, our understanding of the clinical significance of detecting transit abnormalities remains incomplete because of the poor correlation between gastric emptying and/or contractile measures and symptoms.6 Other pathogenic
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928
-
929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986
2019
Validation of Wireless Motility Capsule
factors such as gastric accommodation and gastric hypersensitivity, which cannot be measured with gastric emptying tests, may also be important in some patients.20 However, transit measures may inform therapeutic response as suggested by a recent clinical trial showing that gastric motility testing may have important clinical implications that predict outcomes.21 Further transit measures often help pinpoint the location of a motility abnormality more precisely than symptoms alone.22 Information on symptom data in our study has been collected, and correlations between physiological data and symptom outcomes will be analyzed in future reports. In conclusion, we found that WMC demonstrates comparable performance characteristics as well as important differences with GES in a prospective cohort of patients with suspected gastroparesis. Overall, WMC had significantly higher diagnostic yield for delayed gastric emptying when compared with GES, suggesting greater sensitivity for detection of gastroparesis. For diabetics the yield for delayed gastric emptying was similar between the 2 devices, but in non-diabetics there was a significantly higher yield with WMC. Also, WMC identified delays in small bowel and colonic transit that will be missed if testing solely evaluates gastric emptying. Together, these findings indicate that WMC offers a more comprehensive assessment of patients with suspected gastroparesis because of increased sensitivity for detecting delayed gastric emptying as well as higher diagnostic yield. These improved diagnostic findings could impact patient management.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at https://doi.org/10.1016/j.cgh.2018.11.063.
References 1. Abell TL, Camilleri M, Donohoe K, et al. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol 2008; 103:753–763. 2. Parkman HP, Yates K, Hasler WL, et al. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol 2011;9:1056–1064, quiz 133–134. 3. Rao SSC, Mysore K, Attaluri A, et al. Diagnostic utility of wireless motility capsule in gastrointestinal dysmotility. J Clin Gastroenterol 2011;45:684–690. 4. Kuo B, Maneerattanaporn M, Lee AA, et al. Generalized transit delay on wireless motility capsule testing in patients with clinical suspicion of gastroparesis, small intestinal dysmotility, or slow transit constipation. Dig Dis Sci 2011;56:2928–2938.
9
987 988 989 990 6. Hasler WL, May KP, Wilson LA, et al. Relating gastric scintig991 raphy and symptoms to motility capsule transit and pressure 992 findings in suspected gastroparesis. Neurogastroenterol Motil Q5 993 2018;30. 994 7. Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric 995 emptying using a low fat meal: establishment of international 996 control values. Am J Gastroenterol 2000;95:1456–1462. 997 8. Kloetzer L, Chey WD, McCallum RW, et al. Motility of the 998 antroduodenum in healthy and gastroparetics characterized by 999 wireless motility capsule. Neurogastroenterol Motil 2010; 22:527–533, e117. 1000 9. Wang YT, Mohammed SD, Farmer AD, et al. Regional gastroin1001 testinal transit and pH studied in 215 healthy volunteers using the 1002 wireless motility capsule: influence of age, gender, study country 1003 and testing protocol. Aliment Pharmacol Ther 2015;42:761–772. 1004 10. Camilleri M, Iturrino J, Bharucha AE, et al. Performance char1005 acteristics of scintigraphic measurement of gastric emptying of 1006 solids in healthy participants. Neurogastroenterol Motil 2012;24: 1007 1076–e562. 1008 11. Cassilly D, Kantor S, Knight LC, et al. Gastric emptying of a non1009 digestible solid: assessment with simultaneous SmartPill pH and 1010 pressure capsule, antroduodenal manometry, gastric emptying 1011 scintigraphy. Neurogastroenterol Motil 2008;20:311–319. 1012 12. Parkman HP, Yates K, McCallum R, et al. Gastric emptying 1013 changes over time in gastroparesis: comparison of initial and 48 1014 week follow up gastric emptying tests in the Gastroparesis Registry of the Gastroparesis Consortium. Presented at Diges1015 Q6 1016 tive Disease Week, Washington, DC, 2018. 13. Stanghellini V, Ghidini C, Maccarini MR, et al. Fasting and 1017 postprandial gastrointestinal motility in ulcer and non-ulcer 1018 dyspepsia. Gut 1992;33:184–190. 1019 14. Minami H, McCallum RW. The physiology and pathophysiology 1020 of gastric emptying in humans. Gastroenterology 1984; 1021 86:1592–1610. 1022 15. Parkman HP, Yates K, Hasler WL, et al. Clinical features of 1023 idiopathic gastroparesis vary with sex, body mass, symptom 1024 onset, delay in gastric emptying, and gastroparesis severity. 1025 Gastroenterology 2011;140:101–115.e10. 1026 16. Hejazi RA, Sarosiek I, Roeser K, et al. Does grading the severity 1027 of gastroparesis based on scintigraphic gastric emptying predict 1028 the treatment outcome of patients with gastroparesis? Dig Dis 1029 Sci 2011;56:1147–1153. 1030 17. Hayashi Y, Toyomasu Y, Saravanaperumal SA, et al. Hyperglycemia increases interstitial cells of Cajal via MAPK1 and MAPK3 1031 signaling to ETV1 and KIT, leading to rapid gastric emptying. 1032 Gastroenterology 2017;153:521–535.e20. 1033 18. Evans PR, Bak YT, Shuter B, et al. Gastroparesis and small 1034 bowel dysmotility in irritable bowel syndrome. Dig Dis Sci 1997; 1035 42:2087–2093. 1036 19. Roland BC, Ciarleglio MM, Clarke JO, et al. Small intestinal 1037 transit time is delayed in small intestinal bacterial overgrowth. 1038 J Clin Gastroenterol 2015;49:571–576. 1039 20. Karamanolis G, Caenepeel P, Arts J, et al. Determinants of 1040 symptom pattern in idiopathic severely delayed gastric 1041 emptying: gastric emptying rate or proximal stomach dysfunc1042 tion? Gut 2007;56:29–36. 1043 1044 5. Kuo B, McCallum RW, Koch KL, et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther 2008;27:186–196.
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
10
1045 1046 1047 1048 1049 1050 1051 1052 1053Q1 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102
Lee et al
Clinical Gastroenterology and Hepatology Vol.
21. Talley NJ, Locke GR, Saito YA, et al. Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study. Gastroenterology 2015;149:340–349.e2. 22. Lin HC, Prather C, Fisher RS, et al. Measurement of gastrointestinal transit. Dig Dis Sci 2005;50:989–1004.
Reprint requests Address requests for reprints to: Braden Kuo, MD, Division of Gastroenterology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. e-mail: [email protected]; fax: (617)726-5895.
-,
No.
-
Acknowledgments The authors thank Dr Richard Krause for his assistance in the conduct of this study as well as Mathilde Lourde, Senior Biostatistician Medtronic, for her assistance with statistical analyses for this manuscript. Conflicts of interest These authors disclose the following: Satish Rao, Baharak Moshiree, Richard McCallum, William Hasler, and Braden Kuo received research grant support from Medtronic. Irene Sarosiek and Braden Kuo serve as consultants for Medtronic. The remaining authors disclose no conflicts. Funding Supported by a grant from Medtronic.
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
Q2 Q7
1103 1104 1105 1106 Q3 1107 1108 1109 1110 Q4 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160
-
1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218
2019
Validation of Wireless Motility Capsule
Supplementary Methods All subjects had a comprehensive evaluation, including upper endoscopy and/or gastrointestinal radiography within the past 2 years, to exclude mechanical obstruction and organic causes for their symptoms. Subjects were excluded if they had previous gastrointestinal surgery, except for appendectomy, cholecystectomy, or hysterectomy. Subjects with underlying diabetes mellitus were also excluded if they had evidence of poorly controlled disease (hemoglobin A1c >10%).
Study Protocol Subjects were asked to discontinue all medications (eg, prokinetic agents, anti-cholinergic medications, opiates, and cannabinoids) at least 72 hours before the study. All medications that affect intragastric pH were discontinued, including proton pump inhibitors for 7 days, histamine-2 receptor antagonists for 3 days, and antacids for 1 day before the study. All laxatives were discontinued at least 72 hours before testing and held for at least 4–7 days during the monitoring period. After an overnight fast, subjects reported to the study center. A standardized low-fat meal mixed with 1 mCi 99mTcsulfur colloid marker was consumed within 20 minutes. The meal contained 120 g egg substitute (Egg Beaters; Conagra Brands, Chicago, IL), 2 slices of bread, 30 g strawberry jam, and 70 mL water for a total caloric value of 255 kcal (72% carbohydrate, 24% protein, 2% fat, and 2% fiber).1 Immediately after meal completion, subjects swallowed WMC, which was activated and calibrated before ingestion. Anterior and posterior scintigraphic images were also taken in the 140 keV 99mTc peak with 20% window (140 keV 10%)
10.e1
immediately after completion of the meal. Subsequent images were obtained at 1, 2, and 4 hours. Subjects were asked to avoid solid food intake for 8 hours after capsule ingestion, followed by intake of 250 mL of a liquid meal (Ensure; Abbott Laboratories, Abbott Park, IL). Subjects were then allowed to resume a normal diet 1 hour later. A receiver to detect radiofrequency signals emitted by WMC was worn continuously for the next 5 days or until the capsule had been passed. All subjects maintained a diary to record frequency of bowel movements, stool consistency, time of meal consumption, sleep, and symptoms. The receiver and diary forms were collected after 5–7 days. GET by WMC was defined as the duration of time from capsule ingestion to pyloric passage of the capsule, characterized by an abrupt rise in pH 2 units from gastric baseline to a pH >4. SBTT by WMC was defined as the time interval between duodenal entry and ileocecal passage, which is characterized by a sudden decrease in pH 1 unit at least 30 minutes after capsule entry into the small bowel. CTT is defined as the time interval between time of ileocecal passage to anal expulsion. Numbers of contractions (Ct) >10 mm Hg in amplitude were quantified in the hour before and after GET to determine gastric and small bowel contractility, respectively.23 Areas under pressure curves (AUC) for pressure activity >10 mm Hg in the stomach and small bowel per minute were standardized to AUC per minute.
Reference 23.
Hasler WL, Saad RJ, Rao SS, et al. Heightened colon motor activity measured by a wireless capsule in patients with constipation: relation to colon transit and IBS. Am J Physiol Gastrointest Liver Physiol 2009;297:G1107–G1114.
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276
10.e2 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339
Lee et al
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
Supplementary Figure 1. Consort flow chart of participants in the study. One hundred sixtyseven subjects were enrolled in the study, with 154 subjects successfully completing the study with evaluable wireless motility capsule (WMC) data and 159 subjects for gastric emptying scintigraphy (GES). The one noncompliant subject failed to have the data receiver nearby at the time of gastric emptying.
Supplementary Table 1. Summary of Adverse Events Summary of AEs (n ¼ 167) Total of reported AEs Non-serious AEs Serious AEs SAE relationship to GES None Unlikely Possible Probable Definite relationship SAE relationship to WMC None Unlikely Possible Probable Definite relationship SAEs by action(s) taken Emergency visit Hospitalization Surgery EGD, capsule removal SAEs by outcome Resolved
37 22 15 32 2 0 0 0 13 1 0 0 1 4 9 3 1 15
NOTE. A total of 37 AEs were reported during the study including 22 nonserious AEs and 15 serious AEs. One serious AE was listed as definite relationship to WMC, which required endoscopic removal of a capsule that was retained in the stomach. No serious AEs were related to GES. All serious AEs resolved. AE, adverse event; EGD, esophagogastroduodenoscopy; GES, gastric emptying scintigraphy; WMC, wireless motility capsule.
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402
1 2 3 4 5 6 7 8 9 10Q8 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
Validation of Diagnostic and Performance Characteristics of the Wireless Motility Capsule in Patients With Suspected Gastroparesis Allen A. Lee,* Satish Rao,‡ Linda A. Nguyen,§ Baharak Moshiree,k Irene Sarosiek,¶ Michael I. Schulman,# John M. Wo,** Henry P. Parkman,‡‡ Gregory E. Wilding,§§ Richard W. McCallum,¶ William L. Hasler,*,b and Braden Kuokk,b *Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan; ‡Division of Gastroenterology, Augusta University, Augusta, Georgia; §Division of Gastroenterology, Stanford University, Stanford, California; kUniversity of North Carolina, Charlotte, North Carolina; ¶Section of Gastroenterology, Texas Tech University, El Paso, Texas; #Florida Digestive Health Associate, Largo, Florida; **Division of Gastroenterology, Indiana University, Indianapolis, Indiana; ‡‡Section of Gastroenterology, Temple University, Philadelphia, Pennsylvania; §§Department of Biostatistics, University of Buffalo, Buffalo, New York; and kkDivision of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts BACKGROUND & AIMS:
It is a challenge to make a diagnosis of gastroparesis. There is good agreement in results from wireless motility capsule (WMC) analysis and gastric emptying scintigraphy (GES), but the diagnostic yield of WMC is unclear and the accuracy of this method has not been validated. We compared the performance characteristics of WMC vs GES in assessing gastric emptying in patients with suspected gastroparesis.
METHODS:
We performed a prospective study of 167 subjects with gastroparesis (53 with diabetes and 114 without) at 10 centers, from 2013 through 2016. Subjects were assessed simultaneously by GES and with a WMC to measure gastric emptying and regional transit. Delayed gastric emptying by GES was defined as more than 10% meal retention at 4 hrs whereas delayed gastric emptying by WMC was defined as more than 5 hrs for passage of the capsule into the duodenum; a severe delay in gastric emptying was defined as a gastric emptying time of more than 12 hrs by WMC or more than 35% retention at 4 hrs by GES. Rapid gastric emptying was defined as less than 38% meal retention at 1 hr based on by GES or gastric emptying times less than 1:45 hrs by WMC. We compared diagnostic and performance characteristics of GES vs WMC.
RESULTS:
Delayed gastric emptying was detected in a higher proportion of subjects by WMC (34.6%) than by GES (24.5%) (P[.009). Overall agreement in results between methods was 75.7% (kappa[0.42). In subjects without diabetes, the WMC detected a higher proportion of subjects with delayed gastric emptying (33.3%) than GES (17.1%) (P < .001). A higher proportion of subjects with diabetes had delayed gastric emptying detected by GES (41.7%) than by WMC (17.1%) (P[.002). Severe delays in gastric emptying were observed in a higher proportion of subjects by WMC (13.8%) than by GES (6.9%) (P [ .02). Rapid gastric emptying was detected in a higher proportion of subjects by GES (13.8%) than by WMC (3.3%) (P < .001). Regional and generalized transit abnormalities were observed in 61.8% subjects and only detected by WMC.
CONCLUSION:
Although there is agreement in analysis of gastric emptying by GES vs WMC, WMC provides higher diagnostic yield than GES. WMC detects delayed gastric emptying more frequently than GES and identifies extra-gastric transit abnormalities. Diabetic vs non-diabetic subjects have different results from GES vs WMC. These findings could affect management of patients with suspected gastroparesis. ClinicalTrials.gov no: NCT02022826.
Keywords: Idiopathic; Gastrointestinal Motility; Small Bowel Transit; Colonic Transit.
b
Authors share co-senior authorship.
Abbreviations used in this paper: AE, adverse event; AUC, area under the curve; CI, confidence interval; Ct, number of contractions; CTT, colonic transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; IBS, irritable bowel syndrome; MMC, migrating motor complex; SBTT, small bowel transit time; WMC, wireless motility capsule.
© 2019 by the AGA Institute 1542-3565/$36.00 https://doi.org/10.1016/j.cgh.2018.11.063
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116
2
117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174
Lee et al
Clinical Gastroenterology and Hepatology Vol.
astroparesis is a chronic condition characterized by delayed gastric emptying in the absence of mechanical obstruction. Gastric emptying scintigraphy (GES) is often performed to diagnose gastroparesis but is limited by lack of standardization and radiation exposure.1 Furthermore, coexisting disorders such as irritable bowel syndrome (IBS) are commonly encountered in gastroparesis.2 These coexisting problems may be a consequence of generalized gastrointestinal dysmotility that may remain uninvestigated if scintigraphy alone is performed.3,4 It is possible that targeting specific physiological abnormalities in gastroparesis may lead to improved patient outcomes. Wireless motility capsule (WMC) is a noninvasive ambulatory test that measures transit times and pressure parameters throughout the gastrointestinal tract. Although a previous study demonstrated good agreement in gastric emptying between GES and WMC, this study was enriched with subjects who previously had an abnormal GES.5 The primary aim of this study was to prospectively evaluate the diagnostic and performance characteristics of GES and WMC in patients with unexplained upper gastrointestinal symptoms suggestive of gastroparesis. In addition, we examined the prevalence of regional and generalized transit delays as well as gastroduodenal contractile abnormalities with WMC. Finally, because prior studies have suggested physiological differences between diabetic and idiopathic gastroparesis, we also performed subgroup analyses to examine differences in test characteristics between diabetic and non-diabetic subjects.2,6
G
Methods This was a multicenter, comparative, prospective cohort study (ClinicalTrials.gov no: NCT02022826). Subjects 18 years old with 2 upper gastrointestinal symptoms for 12 weeks suggestive for gastroparesis (nausea, vomiting, upper abdominal pain, early satiation, bloating, postprandial fullness) were enrolled at 10 academic and community centers in the United States from 2013 to 2016. The protocol was approved by the Institutional Review Board at each center. Informed consent was obtained from each subject before enrollment.
-,
No.
-
What You Need to Know Background Gastric emptying scintigraphy (GES) is the most commonly ordered test for diagnosis of gastroparesis. Prior studies have shown good agreement between wireless motility capsule (WMC) and GES, but this has not been validated in patients with suspected gastroparesis. Findings Delayed gastric emptying was detected in a higher proportion of subjects by WMC than by GES. Diabetic and non-diabetic subjects showed distinct results with WMC and GES. Extragastric transit abnormalities were observed in 45% of subjects and only detected by WMC. Implications for patient care WMC provides higher diagnostic yield compared with GES, which may impact management in patients with suspected gastroparesis.
Assessment of Gastric Emptying Delayed gastric emptying time (GET) was defined as >5 hours for passage of the capsule into the duodenum, whereas abnormal GES was defined as >10% meal retention at 4 hours.7 Severe delay in gastric emptying was defined as GET >12 hours by WMC or >35% retention at 4 hours by GES.1,8 Rapid gastric emptying by GES was defined as <38% meal retention at 1 hour or GET <1:45 hours by WMC.9 All WMC studies were interpreted by a centralized, blinded reader (B.K.) to ensure data consistency.
Regional and Whole Gut Transit Delayed small bowel transit time (SBTT) was defined as >6 hours, and delayed colonic transit time (CTT) was defined as >58:45 hours.9 Generalized transit delays were defined as 2 regions with delayed transit, and global transit delays were defined as delay in all 3 regions (gastric, small bowel, and colon).
Pressure Parameters Study Protocol Subjects were asked to discontinue all substances (eg, prokinetic agents, anti-cholinergic medications, opioids, cannabinoids) that may affect gastrointestinal motility at least 72 hours before testing. After an overnight fast, subjects consumed a standardized low-fat meal. Immediately after meal ingestion, subjects swallowed the WMC while simultaneously undergoing image acquisition for scintigraphy as previously described (Supplementary Methods).5,7
Normal values for gastric and small bowel number of contractions (Ct) were defined as >29/h and >36/h, respectively, and normal gastric and small bowel area under the curve (AUC) values were set as 1359 and 1456 mm Hg/min, respectively.8
Statistical Analysis The primary outcome was analyzed as a measure of per patient device agreement for the diagnosis of delayed
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232
-
233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290
2019
Validation of Wireless Motility Capsule
gastric emptying between WMC and GES. Positive agreement is defined as the probability of a positive test by WMC given positive GES, whereas negative agreement is defined as the probability of a negative test by WMC given negative GES. Maximum likelihood estimates of positive and negative percent agreement were computed on the basis of conditional relative frequencies in addition to corresponding 95% confidence interval (CI). Additional measures including estimates of overall percent agreement and Cohen’s kappa were also calculated. Differences between groups were compared by using Wilcoxon rank-sum test for continuous measures, c2 or Fisher exact test for unpaired categorical measures, and McNemar’s tests for paired categorical data. Multiple and logistic regression models were used to assess the robustness of group comparison results and to statistically adjust for group differences in age, gender, body mass index, duration of symptoms, and marijuana and/ or opiate use. P values <.05 were considered significant. Data were analyzed by using R (version 3.4.3) and GraphPad Prism (version 7.05; GraphPad Software, La Jolla, CA). All authors had access to the study data and reviewed and approved the final manuscript.
Results Agreement in Gastric Emptying Between Wireless Motility Capsule and Gastric Emptying Scintigraphy A total of 167 subjects (53 diabetic, 114 non-diabetic) were enrolled (Table 1), and data from 154 subjects who underwent simultaneous WMC and GES were available to review (Supplementary Figure 1). GET was delayed in 53 subjects (34.6%), whereas GES showed delayed gastric emptying in 39 subjects (24.5%, P ¼ .009) (Figure 1A). Overall device agreement between WMC and GES was noted in 75.7%, 95% CI, 68.8%–82.5%, with positive agreement seen in 72.2% (n ¼ 26) and negative agreement in 76.7% (n ¼ 89). There was moderate agreement in parameters of gastric emptying by WMC and GES (kappa ¼ 0.42; 95% CI, 0.27–0.57).
Agreement in Gastric Emptying Between Diabetic vs Non-Diabetic Etiology Subgroup analyses for device agreement in diabetic vs non-diabetic subjects showed distinct results (Table 2). In diabetic subjects, GET was delayed in 37.2%, whereas delayed GES was noted in 41.7% (P ¼ .48) (Figure 1A). Overall device agreement between WMC and GES in diabetic subjects was 81.0% (n ¼ 34), with positive agreement seen in 72.2% (n ¼ 13) and negative agreement in 87.5% (n ¼ 21) (kappa ¼ 0.61; 95% CI, 0.36–0.85). In non-diabetic subjects, overall device agreement between WMC and GES was seen in 73.6% (n ¼ 81), with positive agreement in 72.2%
3
Table 1. Demographic Characteristics of Enrolled Subjects Study demographics
a
All patients Diabetics Non-diabetics P (n ¼ 167) (n ¼ 53) (n ¼ 114) valueb Age, y Female gender BMI (kg/m2) White race Diabetes subtype Type 1 Type 2 Duration of symptoms (y) GCSI total score at baseline Active marijuana usec Active opiate usec
45.1 131 28.1 144
(13.8) 51.1 (12.7) (78.4%) 36 (67.9%) (6.9) 31.0 (6.3) (87.3%) 43 (82.7%)
42.4 95 26.8 101
(13.4) (83.3%) (6.7) (89.4%)
<.01 .02 <.01 .23
6.0 (7.4)
18 (44.0%) 35 (66.0%) 6.6 (7.9)
5.8 (7.1)
.51
2.9 (1.0)
2.5 (1.0)
2.7 (1.0)
.23
14 (8.4%)
5 (9.4%)
9 (7.9%)
.74
19 (11.4%)
5 (9.4%)
14 (12.3%)
.59
BMI, body mass index; GCSI, gastroparesis cardinal symptom index. a Mean (standard deviation) unless otherwise noted. b P values are comparing diabetic vs non-diabetic subjects. c Marijuana and opiate use were active at time of baseline visit but held at least 72 hours before motility testing.
(n ¼ 13) and negative agreement in 73.9% (n ¼ 68) (kappa ¼ 0.33; 95% CI, 0.14–0.50). In non-diabetics, there was a significant increase in delayed gastric transit by WMC (33.3%, n ¼ 37) compared with GES (17.1%, n ¼ 19) (P < .001). Conversely, diabetic subjects were more likely to show delayed gastric emptying with GES vs non-diabetics (41.7% vs 17.1%, P ¼ .002) (Figure 1B). However, there were no differences in rates of delayed GET between diabetic and non-diabetic subjects.
Agreement for Severe Delay in Gastric Emptying Severely delayed gastric emptying by GES was seen in 6.9% (n ¼ 11) vs 13.8% by GET (n ¼ 21, P ¼ .02). Diabetic subjects were more likely to have severe delays in gastric emptying by GES compared with non-diabetic subjects (14.6% vs 3.6%, P ¼ .01). There were no differences in rates of severe delay by WMC between diabetic and non-diabetic subjects. There was fair agreement between severe gastric emptying delays by WMC and GES (kappa ¼ 0.38; 95% CI, 0.15–0.60).
Rapid Gastric Emptying Rapid emptying by GES was seen in 13.8% (n ¼ 22) compared with rapid GET in 3.3% (n ¼ 5, P < .001) (Figure 2). In diabetics, 18.4% of subjects showed rapid GES compared with 9.3% with rapid GET (P ¼ .16). In
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348
349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406
Lee et al
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
Figure 1. (A) Overall, there was significantly higher rate of delayed gastric emptying detected by GET (dark blue) when compared with GES (light blue) (34.6% vs 24.5%, P ¼ .009). In non-diabetic subjects, WMC detected significantly more subjects with delayed gastric transit when compared with GES (33.3% vs 17.1%, P < .001). In diabetic subjects, there were no differences in rates of delayed gastric emptying by GES and GET (37.2% vs 41.7%, P ¼ .48). (B) Diabetic subjects (light green) were more likely to have delayed gastric emptying detected by GES when compared with nondiabetic subjects (dark green) (41.7% vs 17.1%, P ¼ .002). However, there were no differences in rates of delayed gastric emptying by WMC between diabetic and nondiabetic subjects. GES, gastric emptying scintigraphy; GET, gastric emptying time; WMC, wireless motility capsule.
non-diabetic subjects, a higher proportion of subjects showed rapid GES (11.7%) compared with WMC (0.9%) (P < .001). There were no differences in the rates of rapid GES when comparing diabetic vs non-diabetic subjects (18.4% vs 11.7%, P ¼ .26). However, WMC was more likely to detect rapid gastric emptying in diabetic compared with non-diabetic subjects (9.3% vs 0.9%, P ¼ .02).
Extragastric Transit Delays by Wireless Motility Capsule Extragastric transit delays were seen in 45.6% of subjects (n ¼ 68) including delayed SBTT in 22.8% (n ¼ 34) and delayed CTT in 31.5% (n ¼ 47) (Figure 3A). Generalized transit delays were seen in 21.1% (n ¼ 32), whereas global transit delays were noted in 5.4% (n ¼ 8). Overall, 61.8% subjects (n ¼ 94) had isolated or generalized transit delays by WMC (Figure 3B). In
diabetic subjects, delayed SBTT was seen in 12.5% (n ¼ 5), delayed CTT in 32.5% (n ¼ 13), and generalized transit delays in 12.5% (n ¼ 5). In non-diabetic subjects, delayed SBTT was found in 26.6% (n ¼ 29), delayed CTT in 31.2% (n ¼ 34), and generalized transit delays in 24.8% (n ¼ 27). Non-diabetic subjects displayed a longer SBTT compared with diabetics (5.18 vs 4.34 hours, P ¼ .01). Non-diabetic subjects also showed trends toward higher rates of delayed SBTT (P ¼ .07) as well as generalized delays (P ¼ .11) compared with diabetics.
Gastric and Small Bowel Contractile Abnormalities by Wireless Motility Capsule Gastric and/or small bowel contractility abnormalities were seen in 40.4% of all subjects (n ¼ 61) (Table 2). Abnormal gastric contractility measures were noted in 26.7% with reduced antral Ct (n ¼ 40) and 18.8% with abnormal AUC (n ¼ 28). Abnormal small
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
print & web 4C=FPO
4
407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464
-
465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522
2019
Validation of Wireless Motility Capsule
5
Table 2. Prevalence of Transit Delays and Contractility Abnormalities in Patients With Suspected Gastroparesis by WMC and GES Adjusted All patients (N ¼ 167), Diabetic patients Non-diabetic n (%) or median (IQR) (N ¼ 53) patients (N ¼ 114) P valuea P valueb
Measure Delayed GES (>10% solid retention at 4 h) Severely delayed GES (>35% solid retention at 4 h) Rapid GES (<38% solid retention at 1 h) Delayed WMC GET (GET >5 h) Severely delayed WMC GET (GET >12 h) Rapid WMC GET (GET <1:45 h) WMC SBTT (h) Delayed WMC SBTTc (SBTT >6 h) WMC CTT (h) Delayed WMC CTTc (CTT >58:45 h) Transit delay in 2 regions by WMC Contractility measures Gastric Ct/h Reduced gastric Ct (<29/h) Gastric AUC Reduced gastric AUC (<1359) Small bowel Ct/h Reduced small bowel Ct (<36/h) Small bowel AUC Reduced small bowel AUC (<1456)
39/159 (24.5) 11/159 (6.9)
20/48 (41.7) 7/48 (14.6)
19/111(17.1) 4/111 (3.6)
.002 .01
.01 .07
22/160 (13.8) 53/153 (34.6) 21/153 (13.8) 5/153 (3.3) 4.6 (3.5–5.8) 34/149 (22.8) 39.3 (17.3–67.9) 47/149 (31.5) 32/152 (21.1)
9/49 (18.4) 16/43 (37.2) 9/43 (20.9) 4/43 (9.3) 4.2 (3.1–5.2) 5/40 (12.5) 43.7 (20.2–65.3) 13/40 (32.5) 5/40 (12.5)
13/111 (11.7) 37/110 (33.3) 14/110 (12.7) 1/110 (0.9) 4.8 (4.0–6.1) 29/109 (26.6) 36.9 (16.8–67.9) 34/109 (31.2) 27/109 (24.8)
.26 .67 .21 .02 .01 .07 .23 .88 .11
.94 .19 .19 .28 .21 .40 .15 .39 .62
47.5 (26–87) 40/150 (26.7) 3003 (1546–5104) 28/149 (18.8) 111 (49–180) 27/151 (17.9) 3435 (1464–5689) 38/151 (25.2)
48 (23–93) 13/43 (30.2) 2533 (1390–5626) 10/42 (23.8) 134 (66–237) 6/42 (14.3) 4440 (1533–8117) 9/42 (21.4)
47 (29–87) 27/107 (25.2) 3088 (1740–4982) 18/107 (16.8) 110 (43–166) 21/109 (19.3) 3297 (1393–5195) 29/109 (26.6)
.84 .53 .52 .32 .17 .47 .09 .51
.91 .20 .45 .22 .61 .53 .14 .60
AUC, area under the curve; Ct, number of contractions; CTT, colonic transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; IQR, interquartile range; SBTT, small bowel transit time; WMC, wireless motility capsule. a P value comparing diabetics vs non-diabetic subjects. b P value comparing diabetics vs non-diabetic subjects after adjusting for age, gender, body mass index, duration of symptoms, and history of marijuana and/or opioid use. c Small bowel and colonic transit times could not be calculated on a total of 4 subjects because of incomplete data (3 studies because of capsule retention in the stomach and 1 study related to operator error).
bowel contractility measures were seen in 17.9% with reduced Ct (n ¼ 27) and 25.2% with abnormal AUC (n ¼ 38). There were no differences in gastric or small bowel contractility measures between diabetic and nondiabetic subjects.
Association of Gastric Emptying by Wireless Motility Capsule to Other Measures There was a significantly increased rate of delayed GES in those subjects with delayed GET vs those with normal GET (49.1% vs 10.1%, P < .001) (Table 3). This association between delayed GET and delayed GES was observed in both diabetic and non-diabetic subjects. In addition, delayed SBTT was more commonly observed in those subjects with delayed GET than with normal GET (34.0% vs 17.1%, P ¼ .02). This association was observed in non-diabetic subjects (41.7% vs 19.2%, P ¼ .01) but not in diabetic subjects (14.3% vs 11.5%, P ¼ .80). Furthermore, non-diabetic subjects with delayed GET showed higher rates of small bowel contractile abnormalities, including small bowel Ct (36.1% vs 11.0%, P ¼ .004) and AUC (38.9% vs 20.5%, P ¼ .06) compared with normal GET. However, these associations were not observed in diabetic subjects.
Adverse Events A total of 37 adverse events (AEs) were reported, including 22 non-serious and 15 serious AEs (Supplementary Table 1). All serious AEs resolved. One serious AE of capsule retention was noted with WMC, which resolved after endoscopic retrieval. No serious AEs were related to GES. There were no AEs related to fasting for 8 hours after WMC ingestion.
Discussion This was a prospective multicenter study designed to critically examine the diagnostic and performance characteristics of WMC compared with the current standard of GES in patients with suspected gastroparesis. We found evidence to validate the use of WMC in evaluating these patients, including good device agreement between GES and WMC. Furthermore, WMC detected a significantly higher proportion of subjects with both delayed as well as severely delayed gastric emptying when compared with GES. Also, subgroup analyses based on the etiology for gastroparesis demonstrated important differences between GES and WMC. Specifically, we found that nondiabetic subjects who accounted for two-thirds of the study population were significantly more likely to exhibit
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580
581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638
print & web 4C=FPO
6
Lee et al
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
Figure 2. There were significantly higher rates of rapid gastric emptying with GES (light blue) when compared with GET (dark blue) in all subjects (13.8% vs 3.3%, P < .001). In non-diabetic subjects, a higher number of subjects showed rapid gastric emptying with GES compared with WMC (11.7% vs 0.9%, P < .001). In diabetic subjects, there were no differences in detection of rapid gastric emptying by GES compared with GET (18.4% vs 9.3%, P ¼ .16). WMC was more likely to detect rapid gastric emptying in diabetics compared with non-diabetic subjects (9.3% vs 0.9%, P ¼ .02). However, there were no differences in rapid gastric emptying by GES in diabetics vs non-diabetics. GES, gastric emptying scintigraphy; GET, gastric emptying time; WMC, wireless motility capsule.
delayed GET with WMC when compared with GES. In contrast, diabetic subjects were more likely to show delayed gastric emptying with GES when compared with non-diabetic subjects. Finally, WMC detected 61.8% subjects with regional and/or generalized transit delays, resulting in an additional diagnostic yield of 37.3% when compared with 24.5% of subjects with delayed GES. Our results confirm and extend previous findings by Kuo et al,5 who reported good correlation (r ¼ 0.73) between WMC and GES. However, there are important differences that merit discussion. First, this current study was performed in a cohort of patients with suspicion of but without formal diagnosis of gastroparesis. In contrast, eligibility requirements in the study by Kuo et al required a history of delayed GES that led to an enriched population of gastroparesis. Also, our study investigated extragastric transit and contractile abnormalities. Recently, Hasler et al6 also compared performance characteristics of WMC and GES. This study showed lower device agreement between WMC and GES (kappa ¼ 0.12). However, a key difference in this previous study was sequential performance of GES, followed by WMC up to 6 months later. This is in contrast to the current study where GES and WMC were performed simultaneously. The significant intra-individual variation in gastric emptying rates of up to 24% and the time difference between the 2 studies may each explain some of the differences seen between these studies.10 Second, Hasler et al also evaluated an enriched population with prior abnormal GES. Our results suggest that the level of agreement between WMC and GES is more in line with data reported by Kuo et al.
This study demonstrated that WMC was significantly more likely to detect delayed gastric emptying when compared with GES. An additional 23% of subjects with normal GES had delayed GET by WMC, which is similar to prior results.5 Although gastric emptying by WMC and GES are highly correlated, they may not be measuring identical parameters. Although both tests depend on the rate of meal emptying, WMC is measuring emptying of an indigestible object, which is facilitated by return of phase III activity of the migrating motor complex (MMC).11 Thus, WMC may have increased sensitivity for detecting gastroparesis because it measures gastric emptying time, impaired MMC, and dyscoordination of gastric and small bowel motility, whereas scintigraphy only measures meal emptying. Our study further demonstrated important differences when subtyped by etiology. Diabetic subjects were more likely to show delayed gastric emptying by GES compared with non-diabetic subjects. In contrast, non-diabetic subjects were more likely to show delayed GET compared with GES. Our results contrast with data from Hasler et al,6 who found higher rates of delayed GET but not GES in diabetics compared with idiopathic gastroparesis. Because GES was always performed first in this study, it is possible that gastric emptying had normalized in a subset of idiopathic patients by the time WMC was performed. This is supported by preliminary data from the Gastroparesis Consortium that suggests gastric emptying is more likely to normalize during a period of 48 weeks in idiopathic subjects compared with diabetic subjects with gastroparesis (41% vs 22%, P ¼ .07).12 Our results support potential phenotypic differences between diabetic
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696
697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754
print & web 4C=FPO
-
2019
Validation of Wireless Motility Capsule
7
Figure 3. (A) Delayed SBTT was noted in 22.8% of all subjects (light blue) including 12.5% of diabetic subjects (dark blue) and 26.6% of non-diabetic subjects (green) (P ¼ .07). Delayed CTT was seen in 31.5% of all subjects including 32.5% of diabetics and 31.2% of non-diabetic subjects. Generalized transit delays were found in 21.1% of subjects including 12.5% of diabetics and 24.8% of non-diabetic subjects (P ¼ .11). P values are comparing diabetics with non-diabetics. (B) Delayed GES (light blue) was seen in 24.5%, whereas delayed GET (dark blue) was detected in 34.6%. Delayed GET SBTT (light green) was found in 45.8%, GET CTT (dark green) in 52.9%, SBTT CTT (pink) in 46.3%, and overall any delay by WMC (red) was detected in 61.8%. CTT, colonic transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; SBTT, small bowel transit time; WMC, wireless motility capsule.
and non-diabetic patients. Antral hypomotility is commonly seen in patients with gastroparesis.13 This is important because emptying of digestible solids depends mainly on antral function, whereas the emptying of indigestible solids, such as WMC, depends on the antral component of phase III of MMC.14 It is possible that diabetic gastroparesis preferentially affects processes related to postprandial antral hypomotility, whereas non-diabetic subjects display abnormal interdigestive function, which is not assessed by GES. Severe delays in gastric emptying were more likely to be detected by WMC compared with GES. Few studies have looked at stratifying subjects on the basis of the degree of gastric emptying delays. Parkman et al15 demonstrated that severe delays in GES correlated with more severe overall symptoms in idiopathic gastroparesis. Meanwhile, Hejazi et al16 suggested that patients with severe delays in GES were less likely to respond to
medical therapy, which often led to placement of gastric electrical stimulators. Although these findings are intriguing, data on severe delays in gastric emptying are difficult to interpret because true cutoffs are not clearly defined. Our results indicate that rapid gastric emptying was more likely to be detected by GES compared with WMC, likely because rapid emptying is not dependent on MMC. Accelerated gastric emptying is seen in approximately 20% of patients with diabetes. Recently, hyperglycemia was found to increase the numbers of gastric interstitial cells of Cajal, leading to rapid gastric emptying in a mouse model of obesity.17 However, the definitions for accelerated gastric emptying are still not clearly defined, and the clinical significance for rapid emptying requires further validation. An intriguing finding in our study was the high rate of small bowel dysmotility, particularly in non-diabetic
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812
8
813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870
Lee et al
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
Table 3. Association of Normal vs Abnormal GET to Other Transit and Contractile Measures All subjects Delayed GET
Transit measures Delayed GES (>10% solid retention at 4 h) Delayed SBTT (>6 h) Delayed CTT (>58:45 h) Reduced gastric Ct (<29/h) Reduced gastric AUC (<1359 mm Hg/min) Reduced SB Ct (<36/h) Reduced SB AUC (<1456 mm Hg/min)
26/53 17/50 19/50 18/50 12/49 16/51 18/51
(49.1%) (34.0%) (38.0%) (36.0%) (24.5%) (31.4%) (35.3%)
Diabetic subjects Transit measures
Delayed GET Normal GET P valuea
Delayed GES (>10% solid 13/16 (81.3%) retention at 4 h) Delayed SBTT (>6 h) 2/14 (14.3%) Delayed CTT (>58:45 h) 5/14 (35.7%) Gastric Ct (<29/h) 8/16 (50.0%) Gastric AUC (<1359 mm 5/15 (33.3%) Hg/min) SB Ct (<36/h) 3/15 (20.0%) SB AUC (<1456 mm Hg/min) 4/15 (26.7%)
Normal GET
P valuea
Adjusted P valueb
10/99 (10.1%) 17/99 (17.1%) 28/99 (28.3%) 22/100 (22.0%) 16/100 (16.0%) 11/100 (11.0%) 20/100 (20.0%)
<.001 .02 .23 .07 .21 .002 .04
<.001 .11 .10 .14 .28 .01 .32
Non-diabetic subjects Adjusted Adjusted P valueb Delayed GET Normal GET P valuea P valueb
<.001
.02
13/37 (35.1%)
(11.5%) (30.8%) (18.5%) (18.5%)
.80 .75 .03 .28
.70 .26 .09 .59
15/36 (41.7%) 14/36 (38.9%) 10/34 (29.4%) 7/34 (20.6%)
3/27 (11.1%) 5/27 (18.5%)
.43 .54
.71 .67
13/36 (36.1%) 8/73 (11.0%) 14/36 (38.9%) 15/73 (20.5%)
5/26 (19.2%) 3/26 8/26 5/27 5/27
5/73 (6.8%) 14/73 20/73 17/73 11/73
(19.2%) (27.4%) (23.3%) (15.1%)
<.001
.002
.01 .22 .50 .48
.06 .08 .66 .40
.004 .06
.005 .27
AUC, area under the curve; Ct, number of contractions; CTT, colonic transit time; GES, gastric emptying scintigraphy; GET, gastric emptying time; SB, small bowel; SBTT, small bowel transit time. a P value comparing delayed GET vs normal GET. b P value comparing delayed GET vs normal GET after adjusting for age, gender, body mass index, duration of symptoms, and history of marijuana and/or prior opioid use.
subjects. We also demonstrated significant associations between delayed GET by WMC and small bowel dysmotility, including delayed SBTT and reduced small bowel contractile parameters. These abnormalities were more commonly observed in non-diabetic subjects, which suggests that altered gastric–small bowel coordination and a more diffuse gastrointestinal dysmotility may be important in this subset of patients. Although the clinical significance of delayed small bowel transit is not clearly understood, there is evidence to suggest its relevance in gastroparesis. One study demonstrated that patients with both IBS and gastroparesis commonly show small bowel dysmotility.18 Another study demonstrated that patients with chronic, unexplained gastrointestinal symptoms and presence of small intestinal bacterial overgrowth showed significant delays in SBTT.19 These results suggest that small bowel dysmotility may play an important but under-recognized pathogenic factor in gastroparesis. Prior studies have demonstrated considerable overlap between upper and lower gastrointestinal symptoms in gastroparesis.2,15 Our results confirm that 62% of subjects had transit abnormalities by WMC, and nearly one-half showed extragastric transit abnormalities, which may explain the wide range of symptoms encountered in gastroparesis. Previous studies have also documented high prevalence of extragastric transit delays, termed diagnostic gain, which influenced patient management.3,4 Similar to our results, Hasler et al6
demonstrated extragastric transit delays in >40% of subjects. Our findings support investigation of whole gut transit and motility in this population to identify important physiological abnormalities and allow for more objective therapeutic choices. There are limitations to our study. First, there was a high prevalence of patients with normal gastric emptying. However, this reflects clinical reality where symptoms do not reliably distinguish patients with gastroparesis.20 In addition, there was a predominance of white female subjects in our cohort, which mirrors the clinical population seeking care for gastroparesis.2,15 Second, a liquid meal was administered 8 hours after WMC ingestion to mitigate against concerns for hypoglycemia. This liquid meal could prolong GET and artificially increase the number of subjects with severe delays by WMC. However, only 2 subjects in this severely delayed cohort had a GET <18 hours, whereas the mean GET was >50 hours. This suggests that these findings are likely related to underlying severe motor abnormalities rather than methodologic issues. Finally, we did not correlate physiological results with symptoms or outcome data because this was outside of the scope for this specific study. This introduces the potential for bias with our study. Furthermore, our understanding of the clinical significance of detecting transit abnormalities remains incomplete because of the poor correlation between gastric emptying and/or contractile measures and symptoms.6 Other pathogenic
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928
-
929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 980 981 982 983 984 985 986
2019
Validation of Wireless Motility Capsule
factors such as gastric accommodation and gastric hypersensitivity, which cannot be measured with gastric emptying tests, may also be important in some patients.20 However, transit measures may inform therapeutic response as suggested by a recent clinical trial showing that gastric motility testing may have important clinical implications that predict outcomes.21 Further transit measures often help pinpoint the location of a motility abnormality more precisely than symptoms alone.22 Information on symptom data in our study has been collected, and correlations between physiological data and symptom outcomes will be analyzed in future reports. In conclusion, we found that WMC demonstrates comparable performance characteristics as well as important differences with GES in a prospective cohort of patients with suspected gastroparesis. Overall, WMC had significantly higher diagnostic yield for delayed gastric emptying when compared with GES, suggesting greater sensitivity for detection of gastroparesis. For diabetics the yield for delayed gastric emptying was similar between the 2 devices, but in non-diabetics there was a significantly higher yield with WMC. Also, WMC identified delays in small bowel and colonic transit that will be missed if testing solely evaluates gastric emptying. Together, these findings indicate that WMC offers a more comprehensive assessment of patients with suspected gastroparesis because of increased sensitivity for detecting delayed gastric emptying as well as higher diagnostic yield. These improved diagnostic findings could impact patient management.
Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at https://doi.org/10.1016/j.cgh.2018.11.063.
References 1. Abell TL, Camilleri M, Donohoe K, et al. Consensus recommendations for gastric emptying scintigraphy: a joint report of the American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine. Am J Gastroenterol 2008; 103:753–763. 2. Parkman HP, Yates K, Hasler WL, et al. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol 2011;9:1056–1064, quiz 133–134. 3. Rao SSC, Mysore K, Attaluri A, et al. Diagnostic utility of wireless motility capsule in gastrointestinal dysmotility. J Clin Gastroenterol 2011;45:684–690. 4. Kuo B, Maneerattanaporn M, Lee AA, et al. Generalized transit delay on wireless motility capsule testing in patients with clinical suspicion of gastroparesis, small intestinal dysmotility, or slow transit constipation. Dig Dis Sci 2011;56:2928–2938.
9
987 988 989 990 6. Hasler WL, May KP, Wilson LA, et al. Relating gastric scintig991 raphy and symptoms to motility capsule transit and pressure 992 findings in suspected gastroparesis. Neurogastroenterol Motil Q5 993 2018;30. 994 7. Tougas G, Eaker EY, Abell TL, et al. Assessment of gastric 995 emptying using a low fat meal: establishment of international 996 control values. Am J Gastroenterol 2000;95:1456–1462. 997 8. Kloetzer L, Chey WD, McCallum RW, et al. Motility of the 998 antroduodenum in healthy and gastroparetics characterized by 999 wireless motility capsule. Neurogastroenterol Motil 2010; 22:527–533, e117. 1000 9. Wang YT, Mohammed SD, Farmer AD, et al. Regional gastroin1001 testinal transit and pH studied in 215 healthy volunteers using the 1002 wireless motility capsule: influence of age, gender, study country 1003 and testing protocol. Aliment Pharmacol Ther 2015;42:761–772. 1004 10. Camilleri M, Iturrino J, Bharucha AE, et al. Performance char1005 acteristics of scintigraphic measurement of gastric emptying of 1006 solids in healthy participants. Neurogastroenterol Motil 2012;24: 1007 1076–e562. 1008 11. Cassilly D, Kantor S, Knight LC, et al. Gastric emptying of a non1009 digestible solid: assessment with simultaneous SmartPill pH and 1010 pressure capsule, antroduodenal manometry, gastric emptying 1011 scintigraphy. Neurogastroenterol Motil 2008;20:311–319. 1012 12. Parkman HP, Yates K, McCallum R, et al. Gastric emptying 1013 changes over time in gastroparesis: comparison of initial and 48 1014 week follow up gastric emptying tests in the Gastroparesis Registry of the Gastroparesis Consortium. Presented at Diges1015 Q6 1016 tive Disease Week, Washington, DC, 2018. 13. Stanghellini V, Ghidini C, Maccarini MR, et al. Fasting and 1017 postprandial gastrointestinal motility in ulcer and non-ulcer 1018 dyspepsia. Gut 1992;33:184–190. 1019 14. Minami H, McCallum RW. The physiology and pathophysiology 1020 of gastric emptying in humans. Gastroenterology 1984; 1021 86:1592–1610. 1022 15. Parkman HP, Yates K, Hasler WL, et al. Clinical features of 1023 idiopathic gastroparesis vary with sex, body mass, symptom 1024 onset, delay in gastric emptying, and gastroparesis severity. 1025 Gastroenterology 2011;140:101–115.e10. 1026 16. Hejazi RA, Sarosiek I, Roeser K, et al. Does grading the severity 1027 of gastroparesis based on scintigraphic gastric emptying predict 1028 the treatment outcome of patients with gastroparesis? Dig Dis 1029 Sci 2011;56:1147–1153. 1030 17. Hayashi Y, Toyomasu Y, Saravanaperumal SA, et al. Hyperglycemia increases interstitial cells of Cajal via MAPK1 and MAPK3 1031 signaling to ETV1 and KIT, leading to rapid gastric emptying. 1032 Gastroenterology 2017;153:521–535.e20. 1033 18. Evans PR, Bak YT, Shuter B, et al. Gastroparesis and small 1034 bowel dysmotility in irritable bowel syndrome. Dig Dis Sci 1997; 1035 42:2087–2093. 1036 19. Roland BC, Ciarleglio MM, Clarke JO, et al. Small intestinal 1037 transit time is delayed in small intestinal bacterial overgrowth. 1038 J Clin Gastroenterol 2015;49:571–576. 1039 20. Karamanolis G, Caenepeel P, Arts J, et al. Determinants of 1040 symptom pattern in idiopathic severely delayed gastric 1041 emptying: gastric emptying rate or proximal stomach dysfunc1042 tion? Gut 2007;56:29–36. 1043 1044 5. Kuo B, McCallum RW, Koch KL, et al. Comparison of gastric emptying of a nondigestible capsule to a radio-labelled meal in healthy and gastroparetic subjects. Aliment Pharmacol Ther 2008;27:186–196.
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
10
1045 1046 1047 1048 1049 1050 1051 1052 1053Q1 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102
Lee et al
Clinical Gastroenterology and Hepatology Vol.
21. Talley NJ, Locke GR, Saito YA, et al. Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study. Gastroenterology 2015;149:340–349.e2. 22. Lin HC, Prather C, Fisher RS, et al. Measurement of gastrointestinal transit. Dig Dis Sci 2005;50:989–1004.
Reprint requests Address requests for reprints to: Braden Kuo, MD, Division of Gastroenterology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. e-mail: [email protected]; fax: (617)726-5895.
-,
No.
-
Acknowledgments The authors thank Dr Richard Krause for his assistance in the conduct of this study as well as Mathilde Lourde, Senior Biostatistician Medtronic, for her assistance with statistical analyses for this manuscript. Conflicts of interest These authors disclose the following: Satish Rao, Baharak Moshiree, Richard McCallum, William Hasler, and Braden Kuo received research grant support from Medtronic. Irene Sarosiek and Braden Kuo serve as consultants for Medtronic. The remaining authors disclose no conflicts. Funding Supported by a grant from Medtronic.
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
Q2 Q7
1103 1104 1105 1106 Q3 1107 1108 1109 1110 Q4 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160
-
1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212 1213 1214 1215 1216 1217 1218
2019
Validation of Wireless Motility Capsule
Supplementary Methods All subjects had a comprehensive evaluation, including upper endoscopy and/or gastrointestinal radiography within the past 2 years, to exclude mechanical obstruction and organic causes for their symptoms. Subjects were excluded if they had previous gastrointestinal surgery, except for appendectomy, cholecystectomy, or hysterectomy. Subjects with underlying diabetes mellitus were also excluded if they had evidence of poorly controlled disease (hemoglobin A1c >10%).
Study Protocol Subjects were asked to discontinue all medications (eg, prokinetic agents, anti-cholinergic medications, opiates, and cannabinoids) at least 72 hours before the study. All medications that affect intragastric pH were discontinued, including proton pump inhibitors for 7 days, histamine-2 receptor antagonists for 3 days, and antacids for 1 day before the study. All laxatives were discontinued at least 72 hours before testing and held for at least 4–7 days during the monitoring period. After an overnight fast, subjects reported to the study center. A standardized low-fat meal mixed with 1 mCi 99mTcsulfur colloid marker was consumed within 20 minutes. The meal contained 120 g egg substitute (Egg Beaters; Conagra Brands, Chicago, IL), 2 slices of bread, 30 g strawberry jam, and 70 mL water for a total caloric value of 255 kcal (72% carbohydrate, 24% protein, 2% fat, and 2% fiber).1 Immediately after meal completion, subjects swallowed WMC, which was activated and calibrated before ingestion. Anterior and posterior scintigraphic images were also taken in the 140 keV 99mTc peak with 20% window (140 keV 10%)
10.e1
immediately after completion of the meal. Subsequent images were obtained at 1, 2, and 4 hours. Subjects were asked to avoid solid food intake for 8 hours after capsule ingestion, followed by intake of 250 mL of a liquid meal (Ensure; Abbott Laboratories, Abbott Park, IL). Subjects were then allowed to resume a normal diet 1 hour later. A receiver to detect radiofrequency signals emitted by WMC was worn continuously for the next 5 days or until the capsule had been passed. All subjects maintained a diary to record frequency of bowel movements, stool consistency, time of meal consumption, sleep, and symptoms. The receiver and diary forms were collected after 5–7 days. GET by WMC was defined as the duration of time from capsule ingestion to pyloric passage of the capsule, characterized by an abrupt rise in pH 2 units from gastric baseline to a pH >4. SBTT by WMC was defined as the time interval between duodenal entry and ileocecal passage, which is characterized by a sudden decrease in pH 1 unit at least 30 minutes after capsule entry into the small bowel. CTT is defined as the time interval between time of ileocecal passage to anal expulsion. Numbers of contractions (Ct) >10 mm Hg in amplitude were quantified in the hour before and after GET to determine gastric and small bowel contractility, respectively.23 Areas under pressure curves (AUC) for pressure activity >10 mm Hg in the stomach and small bowel per minute were standardized to AUC per minute.
Reference 23.
Hasler WL, Saad RJ, Rao SS, et al. Heightened colon motor activity measured by a wireless capsule in patients with constipation: relation to colon transit and IBS. Am J Physiol Gastrointest Liver Physiol 2009;297:G1107–G1114.
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 1268 1269 1270 1271 1272 1273 1274 1275 1276
10.e2 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314 1315 1316 1317 1318 1319 1320 1321 1322 1323 1324 1325 1326 1327 1328 1329 1330 1331 1332 1333 1334 1335 1336 1337 1338 1339
Lee et al
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
Supplementary Figure 1. Consort flow chart of participants in the study. One hundred sixtyseven subjects were enrolled in the study, with 154 subjects successfully completing the study with evaluable wireless motility capsule (WMC) data and 159 subjects for gastric emptying scintigraphy (GES). The one noncompliant subject failed to have the data receiver nearby at the time of gastric emptying.
Supplementary Table 1. Summary of Adverse Events Summary of AEs (n ¼ 167) Total of reported AEs Non-serious AEs Serious AEs SAE relationship to GES None Unlikely Possible Probable Definite relationship SAE relationship to WMC None Unlikely Possible Probable Definite relationship SAEs by action(s) taken Emergency visit Hospitalization Surgery EGD, capsule removal SAEs by outcome Resolved
37 22 15 32 2 0 0 0 13 1 0 0 1 4 9 3 1 15
NOTE. A total of 37 AEs were reported during the study including 22 nonserious AEs and 15 serious AEs. One serious AE was listed as definite relationship to WMC, which required endoscopic removal of a capsule that was retained in the stomach. No serious AEs were related to GES. All serious AEs resolved. AE, adverse event; EGD, esophagogastroduodenoscopy; GES, gastric emptying scintigraphy; WMC, wireless motility capsule.
FLA 5.5.0 DTD YJCGH56242_proof 4 March 2019 2:49 pm ce CLR
1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 1378 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 1401 1402