- Email: [email protected]
Risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy
Risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy Nigel J. Hall, Simon Eaton, Aaron Seims, Charles M. Leys, John C. Densmore, Casey M. Calkins, Daniel J. Ostlie, Shawn D. St Peter, Richard G. Azizkhan, Daniel von Allmen, Jacob C. Langer, Eveline Lapidus-Krol, Sarah Bouchard, Nelson Pich´e, Steven Bruch, Robert Drongowski, Gordon A. MacKinlay, Claire Clark, Agostino Pierro PII: DOI: Reference:
S0022-3468(13)00820-8 doi: 10.1016/j.jpedsurg.2013.10.014 YJPSU 56551
To appear in:
Journal of Pediatric Surgery
Received date: Revised date: Accepted date:
4 July 2013 7 October 2013 7 October 2013
Please cite this article as: Hall Nigel J., Eaton Simon, Seims Aaron, Leys Charles M., Densmore John C., Calkins Casey M., Ostlie Daniel J., Peter Shawn D. St, Azizkhan Richard G., von Allmen Daniel, Langer Jacob C., Lapidus-Krol Eveline, Bouchard Sarah, Pich´e Nelson, Bruch Steven, Drongowski Robert, MacKinlay Gordon A., Clark Claire, Pierro Agostino, Risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy, Journal of Pediatric Surgery (2013), doi: 10.1016/j.jpedsurg.2013.10.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy
RI P
T
Nigel J Hall1*[email protected]; Simon Eaton1; Aaron Seims2; Charles M Leys2; John C Densmore3; Casey M Calkins3; Daniel J Ostlie4; Shawn D St Peter4; Richard G Azizkhan5; Daniel von Allmen5; Jacob C Langer6; Eveline Lapidus-Krol6; Sarah Bouchard7; Nelson Piché7; Steven Bruch8; Robert Drongowski8; Gordon A MacKinlay9; Claire Clark9; Agostino Pierro1,6 1
UCL Institute of Child Health & Great Ormond Street Hospital for Children, London UK Riley Hospital for Children, Indianapolis, IN 3 The Children's Hospital of Wisconsin, Medical College ofWisconsin, Milwaukee,WI 4 Children’s Mercy Hospital, Kansas City, MO 5 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 6 Hospital for Sick Children and University of Toronto, Toronto, Canada 7 Hospital Sainte-Justine,Montreal, Canada 8 University of Michigan, Ann Arbor, MI 9 Royal Hospital for Sick Children, Edinburgh, UK
MA NU
SC
2
Corresponding author at: Surgery Unit, UCL institute of Child Health, 30 Guilford Street, LondonWC1N 1EH, UK. Tel.: +44 207 9052 641; fax: +44 207 4046 181.
ED
Abstract
PT
Background: Despite randomised controlled trials and meta-analyses, it remains unclear whether laparoscopic pyloromyotomy (LP) carries a higher risk of incomplete pyloromyotomy and mucosal perforation compared with open pyloromyotomy (OP).
CE
Methods: Multicentre study of all pyloromyotomies (May 2007 - December 2010) at 9 high volume institutions. The effect of laparoscopy on the procedure related complications of incomplete pyloromyotomy and mucosal perforation was determined using binomial logistic regression adjusting for differences among centres.
AC
Results: Data relating to 2830 pyloromyotomies (1802 [64%] LP) were analysed. There were 24 cases of incomplete pyloromyotomy; 3 in the open group (0.29%) and 21 in the laparoscopic group (1.16%). There were 18 cases of mucosal perforation; 3 in the open group (0.29%) and 15 in the laparoscopic group (0.83%). The regression model demonstrated that LP was a marginally significant predictor of incomplete pyloromyotomy (adjusted difference 0.87% [95%CI 0.0064.083]; P=0.046) but not of mucosal perforation (adjusted difference 0.56% [95%CI -0.096-3.365]; P=0.153). Trainees performed a similar proportion of each procedure (laparoscopic 82.6% vs. open 80.3%; P=0.2) and grade of primary operator did not affect the rate of either complication. Conclusions: This is one of the largest series of pyloromyotomy ever reported. Although laparoscopy is associated with a statistically significant increase in the risk of incomplete pyloromyotomy, the effect size is small and of questionable clinical relevance. Both OP and LP are associated with low rates of mucosal perforation and incomplete pyloromyotomy in specialist centres, whether trainee or consultant surgeons perform the procedure. Key words: pyloric stenosis; pyloromyotomy; minimally invasive surgery; infant
Introduction Since its introduction two decades ago, the laparoscopic approach to pyloromyotomy has gained popularity and has been implemented by many centers. During this period, a number of groups have reported comparative outcomes between the traditional open procedure and the laparoscopic
ACCEPTED MANUSCRIPT
MA NU
SC
RI P
T
procedure. Such studies initially took the form of retrospective comparative reports, but there have since been at least 5 prospective randomised controlled trials (RCTs).[1-5] Furthermore, there are 3 published systematic reviews with meta-analysis covering this topic.[6-8] The reported benefits (as defined by the attainment of statistical significance [P<0.05]) in these RCTs and meta-analyses include shorter time to achieve full feeds,[3, 6, 8] shorter post-operative time in hospital,[3, 6] less post-operative vomiting,[1] less pain,[1, 3, 4] fewer wound complications,[6] better cosmesis[2] and improved cost effectiveness.[9] Despite these benefits, there remain concerns that the laparoscopic approach may subject patients to a higher risk of the specific procedure related complications of incomplete pyloromyotomy and mucosal perforation.[4, 6, 7, 10] Although a statistically significant difference in incidence of these complications has not been demonstrated in any of the RCTs, none was large enough to detect such a difference due to the low incidence of these complications. In meta-analysis there is a trend towards higher incidence of incomplete pyloromyotomy using the laparoscopic technique that approaches statistical significance (P=0.06)[6, 7] although the validity of this figure has been questioned due to concerns over the statistical techniques used.[10, 11]
AC
CE
PT
ED
The difficulty in determining whether there is really a difference in the incidence of incomplete pyloromyotomy and mucosal perforation between laparoscopic and open pyloromyotomy lies in the sample size required to demonstrate a difference, if one truly exists. Even in published metaanalyses, the total number of patients available (due to the limited number of RCTs included and their individual sample sizes) remains limited at approximately 500.[6-8] We have previously estimated that a sample size of approximately 1250 patients would be required to demonstrate a statistically significant difference in the incidence of incomplete pyloromyotomy between laparoscopic and open procedures of 2.5% (the unadjusted difference in incidence obtained from the raw data included in meta-analysis[10]). Such a large study collecting data from individual patients has never been reported in the field of paediatric surgery to our knowledge. Therefore, we aimed to perform a study large enough to overcome the sample size limitations of previous studies with adequate power to detect small differences in the incidence of these complications between open and laparoscopic approaches.
Methods
We performed a retrospective study in 9 high volume Specialist Paediatric Surgical centres in the UK, USA and Canada. IRB/ ethical approval was obtained for each centre. Centres were invited for inclusion following a mailshot and selected only if they performed at least 15 laparoscopic pyloromyotomies per year. The study period ran from 1st May 2007 to 31st December 2010. This start date was chosen as being the date following which the last patient was randomised into a previous RCT of open versus laparoscopic pyloromyotomy[3] to exclude duplication of reporting. Data relating to all pyloromyotomies for infantile hypertrophic pyloric stenosis performed in this period were recorded including patient demographics (age, gender), operative approach (open or laparoscopic), conversion rate of laparoscopy, and grade of operating surgeon (trainee under supervision or consultant). Grade of operating surgeon was recorded because a previous RCT reported that a significantly higher proportion of laparoscopic procedures were performed by consultants than were open procedures.[3] Although grade of operating surgeon had no influence on the primary outcomes of that RCT, the effect of grade of primary operator on the primary outcomes of this study remain unknown. The primary outcomes for this study were the specific
ACCEPTED MANUSCRIPT
RI P
T
procedure related complications of (i) incomplete pyloromyotomy and (ii) mucosal perforation. A mucosal perforation was defined as breach of the mucosal barrier during pyloromyotomy which was either identified at the time of the myotomy and repaired immediately, or became apparent in the post-operative period and was re-explored and repaired. An incomplete pyloromyotomy was defined as an inadequate myotomy requiring another procedure. Redo procedures following incomplete pyloromyotomy were excluded from the analysis.
MA NU
SC
Statistical analysis A binomial multivariate logistic regression model was generated to calculate incidence of primary outcomes taking into account differences in rate of complications between different centres and grade of primary operator. Analysis of patient demographics revealed a statistically significant difference in age at surgery between open and laparoscopic groups. Furthermore an initial univariate analysis also demonstrated that age at surgery, but not gender, was a significant determinant of IP. Therefore age at surgery was included in the final multivariate model. Nonparametric data were compared using a Mann Whitney U test and proportions were compared using Chi square test. SPSS version 18 was used for all analyses.
Results
CE
PT
ED
Sample size Based on data from previous RCTs and meta-analyses we calculated that to detect statistically significant differences in the incidence of incomplete pyloromyotomy and mucosal perforation would require a total sample size of approximately 1250 and 390,000 respectively. Given the impossibility of achieving the second of these sample sizes (and therefore a near impossible chance that there is a clinically significant difference) we designed a study aiming for a sample of at least 1250 patients, and selected centres and a time scale in order to achieve this.
AC
Overall there were 2830 pyloromyotomies; 1028 were performed open and 1802 laparoscopically. The distribution of cases between the 9 centres is shown in Table 1. Patients operated laparoscopically were slightly older (difference in median age 2 days) and weighed more (difference in median weight 0.14kg); these differences were statistically significant (Table 2). Thirty-five laparoscopic procedures (1.9%) were converted to an open procedure for reasons including inability to complete the procedure laparoscopically, suspected mucosal perforation and for repair of confirmed mucosal perforation. However, not all instances of mucosal perforation in laparoscopic cases were converted to an open procedure. All such conversions were analysed in the laparoscopic group on an intention to treat basis. In total there were 24 cases of incomplete pyloromyotomy; 3 in the open group (0.29%) and 21 in the laparoscopic group (1.16%). There were 18 cases of mucosal perforation; 3 in the open group (0.29%) and 15 in the laparoscopic group (0.83%). The binomial logistic regression model demonstrated a significantly higher incidence of incomplete pyloromyotomy with laparoscopic surgery compared with open (adjusted difference 0.87% [95%CI 0.006-4.083]; P=0.046) but no significant difference in the incidence of mucosal perforation (Table 3). The distribution of mucosal perforation and incomplete pyloromyotomy amongst centres is shown in Table 4. At least one complication occurred in each centre and there was no significant relationship between
ACCEPTED MANUSCRIPT predominant procedure performed at each centre (laparoscopic or open) and distribution of complications.
SC
RI P
T
The proportion of laparoscopic and open procedures performed by trainees was similar (laparoscopic 1446/1749 [82.6%] vs. open 465/579 [80.3%]; P=0.2; data unknown for 502 procedures, 1 centre). Grade of operating surgeon had no effect on the incidence of either incomplete pyloromyotomy (adjusted difference trainee vs. consultant -0.438% [95%CI -1.1981.483]) or mucosal perforation (adjusted difference trainee vs. consultant -0.677% [95%CI -1.1830.8]).
MA NU
Discussion
AC
CE
PT
ED
Despite high quality RCTs and meta-analyses, until now it has remained unknown whether laparoscopic pyloromyotomy carries a higher incidence of incomplete pyloromyotomy or mucosal perforation than the open procedure. In this multicentre review, comprising one of the largest series of pyloromyotomy ever reported, we have identified a small (0.87%) but statistically significant (P=0.046) increase in the incidence of incomplete pyloromyotomy in the laparoscopic group compared with the open group. Although this is a statistically significant difference, we believe the size of the clinical effect it describes should be carefully considered. The difference in incidence of incomplete pyloromyotomy of 0.87% indicates that the number of children that would need to be treated laparoscopically in order for one additional episode of incomplete pyloromyotomy to occur is 115. Whilst there is a higher proportion of children in the laparoscopic group who will require a repeat procedure, this marginally higher rate of repeat procedure must be balanced against previously documented advantages of laparoscopic pyloromyotomy over the open procedure.[1, 3, 6]. Furthermore, it should be noted that previous studies reporting shorter recovery time following laparoscopy have included patients who have had an incomplete pyloromyotomy.[3, 6, 8] Thus the low incidence of an extended post-operative recovery period from incomplete pyloromyotomy does not offset the advantage of laparoscopy for the population. In agreement with previous smaller studies [1, 3, 4] we have not identified a statistically significant difference in incidence of mucosal perforation between open and laparoscopic pyloromyotomy. The reason for the higher incidence of incomplete pyloromyotomy with laparoscopic procedure is not immediately apparent. Whilst it is possible that the lack of tactile feedback during laparoscopy results in a less precise pyloromyotomy, St Peter and colleagues have impressively demonstrated in a RCT that by ensuring a pyloromyotomy of adequate length, this complication can be avoided altogether.[1] By ensuring a pyloromyotomy of minimum length 2cm (measured intra-operatively with an intracorporally placed length of string) they achieved a zero incidence of incomplete pyloromyotomy during laparoscopic procedure. These results were available to all centres prior to the first patient in this study being treated, yet still overall a higher incidence with laparoscopy was encountered. Other factors that cannot be controlled for outside the strict confines of a RCT in a ‘real world’ setting may be contributory. Our results therefore describe the rates of complication applicable to patients outside a RCT.
ACCEPTED MANUSCRIPT
MA NU
SC
RI P
T
We have also demonstrated that grade of primary operator (trainee under supervision or consultant/attending) has no significant effect on the incidence of either incomplete pyloromyotomy or mucosal perforation. A previous RCT comparing open and laparoscopic pyloromyotomy also reported no significant effect on primary outcomes attributable to grade of primary operator.[3] However, the majority of laparoscopic procedures were performed by a consultant surgeon whilst the majority of open procedures were performed by a supervised trainee. In comparison, the majority of both open and laparoscopic procedures in this series were performed by a trainee under supervision. The fact that these results are valid for procedures performed predominantly by trainees under supervision clearly has important implications for service delivery as well as for surgical training. These results demonstrate that equally good outcomes can be achieved from open and minimally invasive surgery within Paediatric Surgical training institutions where the majority of procedures are performed by trainees.
PT
ED
The main strength of this study is its size. This is one of the largest series of pyloromyotomies ever reported. This high number of cases, combined with the multicentre nature of the study, allows us to draw reliable conclusions applicable to a large number of similar centres worldwide. This study demonstrates that to detect small differences in treatment outcomes large, multicentre collaborations are essential. This study has demonstrated a statistically significant difference in incidence of incomplete pyloromyotomy when smaller RCTs have failed to do so due to sample size limitations. These data also come from a ‘real life’ setting; that is all patients were included and inclusion in the study was not limited by the eligibility criteria of a RCT.
AC
CE
A potential limitation to this study is that data were collected retrospectively. From the outset, we considered whether to perform a second, larger, multicentre randomised study as a follow-on from our previous trials [1, 3] or a retrospective review. In general terms, prospective studies are preferred as they reduce the influence of biases on the results of a study. A study in which any of the outcomes are subjective or consist of a continuous variable may be particularly prone to the influence of bias in this way. However, a study such as the current one that uses well-defined, objective, categorical endpoints is highly unlikely to be influenced by the sources of bias that exist in a typical retrospective study. In addition, the procedure related complications analysed in this study are diagnosed either during the operation or soon after it, and patients are treated in the same centre. This reduces the chance of these complications being missed from the analysis and not reported. We therefore justify this retrospective study which has the added advantage of providing data to the surgical community more rapidly than a prospective study. Interestingly, age at surgery and weight at surgery were significantly higher (by 2 days and 140g respectively) in the group undergoing laparoscopic pyloromyotomy than the group undergoing open pyloromyotomy in this study. Although this is a potential confounding factor (and source of bias), we have controlled for age at surgery in the analyses by including age in our regression model. We did not additionally control for weight in the regression analysis, as age and weight are highly correlated as expected and controlling for both age and weight would yield an over-adjusted model. A further observation is that these data were obtained from high volume, specialist Paediatric Surgical centres. Whether the results of this study are generalizable and applicable to smaller or non-specialist units is not known. There is a recognised association between patient outcomes and
ACCEPTED MANUSCRIPT
SC
RI P
T
both high volume and specialisation.[12, 13] Overall the procedural complication rates reported in this study are amongst the lowest reported for either open or laparoscopic procedures, a factor that we suspect is at least partly due to volume and specialisation. Whilst Langer and To have shown improved outcomes after open pyloromyotomy done by a Paediatric Surgeon compared with that by a general surgeon[14] and Haricharan and colleagues have shown an increased rate of complications when laparoscopic pyloromyotomy is performed by a general surgical resident rather than a paediatric surgery resident[15], it is also true that Ali and colleagues have demonstrated that laparoscopic pyloromyotomy can be safely and effectively performed by a non-specialist general surgeon in a non-specialist centre.[16]
ED
MA NU
These data may be interpreted differently by different groups of surgeons. Laparoscopic enthusiasts may regard the difference in rate of incomplete pyloromyotomy between laparoscopic and open approaches to be so small as to be of questionable clinical significance. This, combined with the previously reported benefits of laparoscopy, may be viewed as continued justification in support of the use of the laparoscopic approach. Conversely, surgeons who favour open pyloromyotomy may focus on the statistically higher incidence of incomplete pyloromyotomy with laparoscopy. We believe that this study demonstrates that the rates of incomplete pyloromyotomy and mucosal perforation at high volume Paediatric Surgical Centres are low during both open and laparoscopic procedures and justify the continued use of both procedures in such institutions. However, we would recommend that particular attention be paid to the length of the pyloromyotomy during laparoscopy especially in young or small infants.
PT
Summary
AC
CE
Open and laparoscopic pyloromyotomy have similar rates of mucosal perforation and incomplete pyloromyotomy. Both approaches to pyloromyotomy are safe and carry an acceptable rate of these complications in high volume, specialist centres.
References (1) St Peter SD, Holcomb GW, III, Calkins CM, et al: Open versus laparoscopic pyloromyotomy for pyloric stenosis: a prospective, randomized trial. Ann Surg 2006;244:363-370. (2) Siddiqui S, Heidel RE, Angel CA, et al: Pyloromyotomy: randomized control trial of laparoscopic vs open technique. J Pediatr Surg 2012;47:93-98. (3) Hall NJ, Pacilli M, Eaton S, et al: Recovery after open versus laparoscopic pyloromyotomy for pyloric stenosis: a double-blind multicentre randomised controlled trial. Lancet 2009;373:390-398. (4) Leclair MD, Plattner V, Mirallie E, et al: Laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a prospective, randomized controlled trial. J Pediatr Surg 2007;42:692-698. (5) Greason KL, Allshouse MJ, Thompson WR, et al: A prospective, randomized evaluation of laparoscopic versus open pyloromyotomy in the treatment of infantile hypertrophic pyloric stenosis. Pediatric Endosurgery & Innovative Techniques 1997;1:175-179. (6) Sola JE, Neville HL: Laparoscopic vs open pyloromyotomy: a systematic review and metaanalysis. J Pediatr Surg 2009;44:1631-1637. (7) Jia WQ, Tian JH, Yang KH, et al: Open versus laparoscopic pyloromyotomy for pyloric stenosis: a meta-analysis of randomized controlled trials. Eur J Pediatr Surg 2011;21:77-81.
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
MA NU
SC
RI P
T
(8) Oomen MW, Hoekstra LT, Bakx R, et al: Open versus laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a systematic review and meta-analysis focusing on major complications. Surg Endosc 2012;26:2104-10. (9) Carrington EV, Hall NJ, Pacilli M, et al: Cost-effectiveness of laparoscopic versus open pyloromyotomy. J Surg Res 2012;178:315-20. (10) Hall NJ, Eaton S, Pierro A: Editorial on "Open versus laparoscopic pyloromyotomy for pyloric stenosis: a meta-analysis of randomized controlled trials" by Jia et al. Eur J Pediatr Surg 2011;21:7576. (11) Eaton S, Hall NJ, Pierro A: Zero-total event trials and incomplete pyloromyotomy. J Pediatr Surg 2009;44:2434-2435. (12) Safford SD, Pietrobon R, Safford KM, et al: A study of 11,003 patients with hypertrophic pyloric stenosis and the association between surgeon and hospital volume and outcomes. J Pediatr Surg 2005;40:967-972. (13) Chowdhury MM, Dagash H, Pierro A: A systematic review of the impact of volume of surgery and specialization on patient outcome. Br J Surg 2007;94:145-161. (14) Langer JC, To T: Does pediatric surgical specialty training affect outcome after Ramstedt pyloromyotomy? A population-based study. Pediatrics 2004;113:1342-1347. (15) Haricharan RN, Aprahamian CJ, Celik A, et al: Laparoscopic pyloromyotomy: effect of resident training on complications. J Pediatr Surg 2008;43:97-101. (16) Ali A, Tripuraneni G, Velmurugan S, et al: Laparoscopic pyloromyotomy is both safe and effective in a district hospital. Surg Endosc 2008;22:151-153.
ACCEPTED MANUSCRIPT Table 1. Distribution and description of cases between centres
PT CE AC
RI P
T
male n % 350 84.5 292 83.4 329 84.6 424 84.5 140 78.2 298 79.9 83 76.9 285 82.8 146 84.9 2347 82.9
SC
weight (kg) median IQR* 3.92 3.48-4.40 3.90 3.46-4.32 3.96 3.44-4.44 3.83 3.46-4.50 4.10 3.50-4.55 4.00 3.56-4.50 3.80 3.35-4.30 4.10 3.60-4.56 3.76 3.40-4.30 3.90 3.50-4.44
ED
n
MA NU
age (days) median IQR* A 414 36 29-48 B 350 34 27-45 C 389 36 27-47 D 502 34 27-45 E 179 35 27-47 F 373 34 26-46 G 108 38 30-49 H 344 35 27-49 I 171 36 29-47 Total 2830 35 27-47 *inter-quartile range Centre
ACCEPTED MANUSCRIPT
Table 2. Demographic details of infants undergoing open or laparoscopic pyloromyotomy
AC
CE
PT
ED
MA NU
SC
RI P
T
Operative approach P Open Laparoscopic Age at surgery (days)* 34 (27-45) 36 (28-48) 0.003$ Weight at surgery (kg)* 3.85 (3.43-4.40) 3.99 (3.50-4.47) 0.002$ Males (n,%) 864 (84%) 1483 (82%) ns£ $ £ *Data are median (inter-quartile range); Mann-Whitney U test; Chi-square test
ACCEPTED MANUSCRIPT
Table 3. Rates of procedural complications of pyloromyotomy
AC
CE
PT
ED
MA NU
SC
RI P
T
Operative approach Adjusted difference^ (%, 95%CI) Open Laparoscopic Mucosal perforation (%) 0.29 0.83 0.56% (-0.096-3.365) Incomplete pyloromyotomy (%) 0.29 1.16 0.87% (0.006-4.083) ^Adjusted for centre and age; *binomial logistic regression analysis
P 0.153 0.046
ACCEPTED MANUSCRIPT
Table 4: Distribution and description of complications between centres total (n,%)
T
MP 2 (0.48%) 2 (0.57%) 1 (0.26%) 1 (0.19%) 1 (0.56%) 5 (1.34%) 4 (3.70%) 1 (0.29%) 1 (0.58%) 18 (0.64%)
AC
CE
PT
ED
MA NU
SC
RI P
open laparoscopic n MP IP n MP IP A 86 0 0 328 2 9 B 265 1 3 85 1 1 C 0 389 1 1 D 449 1 0 53 0 0 E 2 0 0 177 1 0 F 118 1 0 255 4 1 G 15 0 0 93 4 3 H 89 0 0 255 1 5 I 4 0 0 167 1 1 Total 1028 3 3 1802 15 21 MP – mucosal perforation; IP – incomplete pyloromyotomy Centre
IP 9 (2.17%) 4 (1.14%) 1 (0.26%) 0 (-) 0 (-) 1 (0.27%) 3 (2.78%) 5 (1.45%) 1 (0.58%) 24 (0.84%)
S0022-3468(13)00820-8 doi: 10.1016/j.jpedsurg.2013.10.014 YJPSU 56551
To appear in:
Journal of Pediatric Surgery
Received date: Revised date: Accepted date:
4 July 2013 7 October 2013 7 October 2013
Please cite this article as: Hall Nigel J., Eaton Simon, Seims Aaron, Leys Charles M., Densmore John C., Calkins Casey M., Ostlie Daniel J., Peter Shawn D. St, Azizkhan Richard G., von Allmen Daniel, Langer Jacob C., Lapidus-Krol Eveline, Bouchard Sarah, Pich´e Nelson, Bruch Steven, Drongowski Robert, MacKinlay Gordon A., Clark Claire, Pierro Agostino, Risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy, Journal of Pediatric Surgery (2013), doi: 10.1016/j.jpedsurg.2013.10.014
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Risk of incomplete pyloromyotomy and mucosal perforation in open and laparoscopic pyloromyotomy
RI P
T
Nigel J Hall1*
UCL Institute of Child Health & Great Ormond Street Hospital for Children, London UK Riley Hospital for Children, Indianapolis, IN 3 The Children's Hospital of Wisconsin, Medical College ofWisconsin, Milwaukee,WI 4 Children’s Mercy Hospital, Kansas City, MO 5 Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 6 Hospital for Sick Children and University of Toronto, Toronto, Canada 7 Hospital Sainte-Justine,Montreal, Canada 8 University of Michigan, Ann Arbor, MI 9 Royal Hospital for Sick Children, Edinburgh, UK
MA NU
SC
2
Corresponding author at: Surgery Unit, UCL institute of Child Health, 30 Guilford Street, LondonWC1N 1EH, UK. Tel.: +44 207 9052 641; fax: +44 207 4046 181.
ED
Abstract
PT
Background: Despite randomised controlled trials and meta-analyses, it remains unclear whether laparoscopic pyloromyotomy (LP) carries a higher risk of incomplete pyloromyotomy and mucosal perforation compared with open pyloromyotomy (OP).
CE
Methods: Multicentre study of all pyloromyotomies (May 2007 - December 2010) at 9 high volume institutions. The effect of laparoscopy on the procedure related complications of incomplete pyloromyotomy and mucosal perforation was determined using binomial logistic regression adjusting for differences among centres.
AC
Results: Data relating to 2830 pyloromyotomies (1802 [64%] LP) were analysed. There were 24 cases of incomplete pyloromyotomy; 3 in the open group (0.29%) and 21 in the laparoscopic group (1.16%). There were 18 cases of mucosal perforation; 3 in the open group (0.29%) and 15 in the laparoscopic group (0.83%). The regression model demonstrated that LP was a marginally significant predictor of incomplete pyloromyotomy (adjusted difference 0.87% [95%CI 0.0064.083]; P=0.046) but not of mucosal perforation (adjusted difference 0.56% [95%CI -0.096-3.365]; P=0.153). Trainees performed a similar proportion of each procedure (laparoscopic 82.6% vs. open 80.3%; P=0.2) and grade of primary operator did not affect the rate of either complication. Conclusions: This is one of the largest series of pyloromyotomy ever reported. Although laparoscopy is associated with a statistically significant increase in the risk of incomplete pyloromyotomy, the effect size is small and of questionable clinical relevance. Both OP and LP are associated with low rates of mucosal perforation and incomplete pyloromyotomy in specialist centres, whether trainee or consultant surgeons perform the procedure. Key words: pyloric stenosis; pyloromyotomy; minimally invasive surgery; infant
Introduction Since its introduction two decades ago, the laparoscopic approach to pyloromyotomy has gained popularity and has been implemented by many centers. During this period, a number of groups have reported comparative outcomes between the traditional open procedure and the laparoscopic
ACCEPTED MANUSCRIPT
MA NU
SC
RI P
T
procedure. Such studies initially took the form of retrospective comparative reports, but there have since been at least 5 prospective randomised controlled trials (RCTs).[1-5] Furthermore, there are 3 published systematic reviews with meta-analysis covering this topic.[6-8] The reported benefits (as defined by the attainment of statistical significance [P<0.05]) in these RCTs and meta-analyses include shorter time to achieve full feeds,[3, 6, 8] shorter post-operative time in hospital,[3, 6] less post-operative vomiting,[1] less pain,[1, 3, 4] fewer wound complications,[6] better cosmesis[2] and improved cost effectiveness.[9] Despite these benefits, there remain concerns that the laparoscopic approach may subject patients to a higher risk of the specific procedure related complications of incomplete pyloromyotomy and mucosal perforation.[4, 6, 7, 10] Although a statistically significant difference in incidence of these complications has not been demonstrated in any of the RCTs, none was large enough to detect such a difference due to the low incidence of these complications. In meta-analysis there is a trend towards higher incidence of incomplete pyloromyotomy using the laparoscopic technique that approaches statistical significance (P=0.06)[6, 7] although the validity of this figure has been questioned due to concerns over the statistical techniques used.[10, 11]
AC
CE
PT
ED
The difficulty in determining whether there is really a difference in the incidence of incomplete pyloromyotomy and mucosal perforation between laparoscopic and open pyloromyotomy lies in the sample size required to demonstrate a difference, if one truly exists. Even in published metaanalyses, the total number of patients available (due to the limited number of RCTs included and their individual sample sizes) remains limited at approximately 500.[6-8] We have previously estimated that a sample size of approximately 1250 patients would be required to demonstrate a statistically significant difference in the incidence of incomplete pyloromyotomy between laparoscopic and open procedures of 2.5% (the unadjusted difference in incidence obtained from the raw data included in meta-analysis[10]). Such a large study collecting data from individual patients has never been reported in the field of paediatric surgery to our knowledge. Therefore, we aimed to perform a study large enough to overcome the sample size limitations of previous studies with adequate power to detect small differences in the incidence of these complications between open and laparoscopic approaches.
Methods
We performed a retrospective study in 9 high volume Specialist Paediatric Surgical centres in the UK, USA and Canada. IRB/ ethical approval was obtained for each centre. Centres were invited for inclusion following a mailshot and selected only if they performed at least 15 laparoscopic pyloromyotomies per year. The study period ran from 1st May 2007 to 31st December 2010. This start date was chosen as being the date following which the last patient was randomised into a previous RCT of open versus laparoscopic pyloromyotomy[3] to exclude duplication of reporting. Data relating to all pyloromyotomies for infantile hypertrophic pyloric stenosis performed in this period were recorded including patient demographics (age, gender), operative approach (open or laparoscopic), conversion rate of laparoscopy, and grade of operating surgeon (trainee under supervision or consultant). Grade of operating surgeon was recorded because a previous RCT reported that a significantly higher proportion of laparoscopic procedures were performed by consultants than were open procedures.[3] Although grade of operating surgeon had no influence on the primary outcomes of that RCT, the effect of grade of primary operator on the primary outcomes of this study remain unknown. The primary outcomes for this study were the specific
ACCEPTED MANUSCRIPT
RI P
T
procedure related complications of (i) incomplete pyloromyotomy and (ii) mucosal perforation. A mucosal perforation was defined as breach of the mucosal barrier during pyloromyotomy which was either identified at the time of the myotomy and repaired immediately, or became apparent in the post-operative period and was re-explored and repaired. An incomplete pyloromyotomy was defined as an inadequate myotomy requiring another procedure. Redo procedures following incomplete pyloromyotomy were excluded from the analysis.
MA NU
SC
Statistical analysis A binomial multivariate logistic regression model was generated to calculate incidence of primary outcomes taking into account differences in rate of complications between different centres and grade of primary operator. Analysis of patient demographics revealed a statistically significant difference in age at surgery between open and laparoscopic groups. Furthermore an initial univariate analysis also demonstrated that age at surgery, but not gender, was a significant determinant of IP. Therefore age at surgery was included in the final multivariate model. Nonparametric data were compared using a Mann Whitney U test and proportions were compared using Chi square test. SPSS version 18 was used for all analyses.
Results
CE
PT
ED
Sample size Based on data from previous RCTs and meta-analyses we calculated that to detect statistically significant differences in the incidence of incomplete pyloromyotomy and mucosal perforation would require a total sample size of approximately 1250 and 390,000 respectively. Given the impossibility of achieving the second of these sample sizes (and therefore a near impossible chance that there is a clinically significant difference) we designed a study aiming for a sample of at least 1250 patients, and selected centres and a time scale in order to achieve this.
AC
Overall there were 2830 pyloromyotomies; 1028 were performed open and 1802 laparoscopically. The distribution of cases between the 9 centres is shown in Table 1. Patients operated laparoscopically were slightly older (difference in median age 2 days) and weighed more (difference in median weight 0.14kg); these differences were statistically significant (Table 2). Thirty-five laparoscopic procedures (1.9%) were converted to an open procedure for reasons including inability to complete the procedure laparoscopically, suspected mucosal perforation and for repair of confirmed mucosal perforation. However, not all instances of mucosal perforation in laparoscopic cases were converted to an open procedure. All such conversions were analysed in the laparoscopic group on an intention to treat basis. In total there were 24 cases of incomplete pyloromyotomy; 3 in the open group (0.29%) and 21 in the laparoscopic group (1.16%). There were 18 cases of mucosal perforation; 3 in the open group (0.29%) and 15 in the laparoscopic group (0.83%). The binomial logistic regression model demonstrated a significantly higher incidence of incomplete pyloromyotomy with laparoscopic surgery compared with open (adjusted difference 0.87% [95%CI 0.006-4.083]; P=0.046) but no significant difference in the incidence of mucosal perforation (Table 3). The distribution of mucosal perforation and incomplete pyloromyotomy amongst centres is shown in Table 4. At least one complication occurred in each centre and there was no significant relationship between
ACCEPTED MANUSCRIPT predominant procedure performed at each centre (laparoscopic or open) and distribution of complications.
SC
RI P
T
The proportion of laparoscopic and open procedures performed by trainees was similar (laparoscopic 1446/1749 [82.6%] vs. open 465/579 [80.3%]; P=0.2; data unknown for 502 procedures, 1 centre). Grade of operating surgeon had no effect on the incidence of either incomplete pyloromyotomy (adjusted difference trainee vs. consultant -0.438% [95%CI -1.1981.483]) or mucosal perforation (adjusted difference trainee vs. consultant -0.677% [95%CI -1.1830.8]).
MA NU
Discussion
AC
CE
PT
ED
Despite high quality RCTs and meta-analyses, until now it has remained unknown whether laparoscopic pyloromyotomy carries a higher incidence of incomplete pyloromyotomy or mucosal perforation than the open procedure. In this multicentre review, comprising one of the largest series of pyloromyotomy ever reported, we have identified a small (0.87%) but statistically significant (P=0.046) increase in the incidence of incomplete pyloromyotomy in the laparoscopic group compared with the open group. Although this is a statistically significant difference, we believe the size of the clinical effect it describes should be carefully considered. The difference in incidence of incomplete pyloromyotomy of 0.87% indicates that the number of children that would need to be treated laparoscopically in order for one additional episode of incomplete pyloromyotomy to occur is 115. Whilst there is a higher proportion of children in the laparoscopic group who will require a repeat procedure, this marginally higher rate of repeat procedure must be balanced against previously documented advantages of laparoscopic pyloromyotomy over the open procedure.[1, 3, 6]. Furthermore, it should be noted that previous studies reporting shorter recovery time following laparoscopy have included patients who have had an incomplete pyloromyotomy.[3, 6, 8] Thus the low incidence of an extended post-operative recovery period from incomplete pyloromyotomy does not offset the advantage of laparoscopy for the population. In agreement with previous smaller studies [1, 3, 4] we have not identified a statistically significant difference in incidence of mucosal perforation between open and laparoscopic pyloromyotomy. The reason for the higher incidence of incomplete pyloromyotomy with laparoscopic procedure is not immediately apparent. Whilst it is possible that the lack of tactile feedback during laparoscopy results in a less precise pyloromyotomy, St Peter and colleagues have impressively demonstrated in a RCT that by ensuring a pyloromyotomy of adequate length, this complication can be avoided altogether.[1] By ensuring a pyloromyotomy of minimum length 2cm (measured intra-operatively with an intracorporally placed length of string) they achieved a zero incidence of incomplete pyloromyotomy during laparoscopic procedure. These results were available to all centres prior to the first patient in this study being treated, yet still overall a higher incidence with laparoscopy was encountered. Other factors that cannot be controlled for outside the strict confines of a RCT in a ‘real world’ setting may be contributory. Our results therefore describe the rates of complication applicable to patients outside a RCT.
ACCEPTED MANUSCRIPT
MA NU
SC
RI P
T
We have also demonstrated that grade of primary operator (trainee under supervision or consultant/attending) has no significant effect on the incidence of either incomplete pyloromyotomy or mucosal perforation. A previous RCT comparing open and laparoscopic pyloromyotomy also reported no significant effect on primary outcomes attributable to grade of primary operator.[3] However, the majority of laparoscopic procedures were performed by a consultant surgeon whilst the majority of open procedures were performed by a supervised trainee. In comparison, the majority of both open and laparoscopic procedures in this series were performed by a trainee under supervision. The fact that these results are valid for procedures performed predominantly by trainees under supervision clearly has important implications for service delivery as well as for surgical training. These results demonstrate that equally good outcomes can be achieved from open and minimally invasive surgery within Paediatric Surgical training institutions where the majority of procedures are performed by trainees.
PT
ED
The main strength of this study is its size. This is one of the largest series of pyloromyotomies ever reported. This high number of cases, combined with the multicentre nature of the study, allows us to draw reliable conclusions applicable to a large number of similar centres worldwide. This study demonstrates that to detect small differences in treatment outcomes large, multicentre collaborations are essential. This study has demonstrated a statistically significant difference in incidence of incomplete pyloromyotomy when smaller RCTs have failed to do so due to sample size limitations. These data also come from a ‘real life’ setting; that is all patients were included and inclusion in the study was not limited by the eligibility criteria of a RCT.
AC
CE
A potential limitation to this study is that data were collected retrospectively. From the outset, we considered whether to perform a second, larger, multicentre randomised study as a follow-on from our previous trials [1, 3] or a retrospective review. In general terms, prospective studies are preferred as they reduce the influence of biases on the results of a study. A study in which any of the outcomes are subjective or consist of a continuous variable may be particularly prone to the influence of bias in this way. However, a study such as the current one that uses well-defined, objective, categorical endpoints is highly unlikely to be influenced by the sources of bias that exist in a typical retrospective study. In addition, the procedure related complications analysed in this study are diagnosed either during the operation or soon after it, and patients are treated in the same centre. This reduces the chance of these complications being missed from the analysis and not reported. We therefore justify this retrospective study which has the added advantage of providing data to the surgical community more rapidly than a prospective study. Interestingly, age at surgery and weight at surgery were significantly higher (by 2 days and 140g respectively) in the group undergoing laparoscopic pyloromyotomy than the group undergoing open pyloromyotomy in this study. Although this is a potential confounding factor (and source of bias), we have controlled for age at surgery in the analyses by including age in our regression model. We did not additionally control for weight in the regression analysis, as age and weight are highly correlated as expected and controlling for both age and weight would yield an over-adjusted model. A further observation is that these data were obtained from high volume, specialist Paediatric Surgical centres. Whether the results of this study are generalizable and applicable to smaller or non-specialist units is not known. There is a recognised association between patient outcomes and
ACCEPTED MANUSCRIPT
SC
RI P
T
both high volume and specialisation.[12, 13] Overall the procedural complication rates reported in this study are amongst the lowest reported for either open or laparoscopic procedures, a factor that we suspect is at least partly due to volume and specialisation. Whilst Langer and To have shown improved outcomes after open pyloromyotomy done by a Paediatric Surgeon compared with that by a general surgeon[14] and Haricharan and colleagues have shown an increased rate of complications when laparoscopic pyloromyotomy is performed by a general surgical resident rather than a paediatric surgery resident[15], it is also true that Ali and colleagues have demonstrated that laparoscopic pyloromyotomy can be safely and effectively performed by a non-specialist general surgeon in a non-specialist centre.[16]
ED
MA NU
These data may be interpreted differently by different groups of surgeons. Laparoscopic enthusiasts may regard the difference in rate of incomplete pyloromyotomy between laparoscopic and open approaches to be so small as to be of questionable clinical significance. This, combined with the previously reported benefits of laparoscopy, may be viewed as continued justification in support of the use of the laparoscopic approach. Conversely, surgeons who favour open pyloromyotomy may focus on the statistically higher incidence of incomplete pyloromyotomy with laparoscopy. We believe that this study demonstrates that the rates of incomplete pyloromyotomy and mucosal perforation at high volume Paediatric Surgical Centres are low during both open and laparoscopic procedures and justify the continued use of both procedures in such institutions. However, we would recommend that particular attention be paid to the length of the pyloromyotomy during laparoscopy especially in young or small infants.
PT
Summary
AC
CE
Open and laparoscopic pyloromyotomy have similar rates of mucosal perforation and incomplete pyloromyotomy. Both approaches to pyloromyotomy are safe and carry an acceptable rate of these complications in high volume, specialist centres.
References (1) St Peter SD, Holcomb GW, III, Calkins CM, et al: Open versus laparoscopic pyloromyotomy for pyloric stenosis: a prospective, randomized trial. Ann Surg 2006;244:363-370. (2) Siddiqui S, Heidel RE, Angel CA, et al: Pyloromyotomy: randomized control trial of laparoscopic vs open technique. J Pediatr Surg 2012;47:93-98. (3) Hall NJ, Pacilli M, Eaton S, et al: Recovery after open versus laparoscopic pyloromyotomy for pyloric stenosis: a double-blind multicentre randomised controlled trial. Lancet 2009;373:390-398. (4) Leclair MD, Plattner V, Mirallie E, et al: Laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a prospective, randomized controlled trial. J Pediatr Surg 2007;42:692-698. (5) Greason KL, Allshouse MJ, Thompson WR, et al: A prospective, randomized evaluation of laparoscopic versus open pyloromyotomy in the treatment of infantile hypertrophic pyloric stenosis. Pediatric Endosurgery & Innovative Techniques 1997;1:175-179. (6) Sola JE, Neville HL: Laparoscopic vs open pyloromyotomy: a systematic review and metaanalysis. J Pediatr Surg 2009;44:1631-1637. (7) Jia WQ, Tian JH, Yang KH, et al: Open versus laparoscopic pyloromyotomy for pyloric stenosis: a meta-analysis of randomized controlled trials. Eur J Pediatr Surg 2011;21:77-81.
ACCEPTED MANUSCRIPT
AC
CE
PT
ED
MA NU
SC
RI P
T
(8) Oomen MW, Hoekstra LT, Bakx R, et al: Open versus laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a systematic review and meta-analysis focusing on major complications. Surg Endosc 2012;26:2104-10. (9) Carrington EV, Hall NJ, Pacilli M, et al: Cost-effectiveness of laparoscopic versus open pyloromyotomy. J Surg Res 2012;178:315-20. (10) Hall NJ, Eaton S, Pierro A: Editorial on "Open versus laparoscopic pyloromyotomy for pyloric stenosis: a meta-analysis of randomized controlled trials" by Jia et al. Eur J Pediatr Surg 2011;21:7576. (11) Eaton S, Hall NJ, Pierro A: Zero-total event trials and incomplete pyloromyotomy. J Pediatr Surg 2009;44:2434-2435. (12) Safford SD, Pietrobon R, Safford KM, et al: A study of 11,003 patients with hypertrophic pyloric stenosis and the association between surgeon and hospital volume and outcomes. J Pediatr Surg 2005;40:967-972. (13) Chowdhury MM, Dagash H, Pierro A: A systematic review of the impact of volume of surgery and specialization on patient outcome. Br J Surg 2007;94:145-161. (14) Langer JC, To T: Does pediatric surgical specialty training affect outcome after Ramstedt pyloromyotomy? A population-based study. Pediatrics 2004;113:1342-1347. (15) Haricharan RN, Aprahamian CJ, Celik A, et al: Laparoscopic pyloromyotomy: effect of resident training on complications. J Pediatr Surg 2008;43:97-101. (16) Ali A, Tripuraneni G, Velmurugan S, et al: Laparoscopic pyloromyotomy is both safe and effective in a district hospital. Surg Endosc 2008;22:151-153.
ACCEPTED MANUSCRIPT Table 1. Distribution and description of cases between centres
PT CE AC
RI P
T
male n % 350 84.5 292 83.4 329 84.6 424 84.5 140 78.2 298 79.9 83 76.9 285 82.8 146 84.9 2347 82.9
SC
weight (kg) median IQR* 3.92 3.48-4.40 3.90 3.46-4.32 3.96 3.44-4.44 3.83 3.46-4.50 4.10 3.50-4.55 4.00 3.56-4.50 3.80 3.35-4.30 4.10 3.60-4.56 3.76 3.40-4.30 3.90 3.50-4.44
ED
n
MA NU
age (days) median IQR* A 414 36 29-48 B 350 34 27-45 C 389 36 27-47 D 502 34 27-45 E 179 35 27-47 F 373 34 26-46 G 108 38 30-49 H 344 35 27-49 I 171 36 29-47 Total 2830 35 27-47 *inter-quartile range Centre
ACCEPTED MANUSCRIPT
Table 2. Demographic details of infants undergoing open or laparoscopic pyloromyotomy
AC
CE
PT
ED
MA NU
SC
RI P
T
Operative approach P Open Laparoscopic Age at surgery (days)* 34 (27-45) 36 (28-48) 0.003$ Weight at surgery (kg)* 3.85 (3.43-4.40) 3.99 (3.50-4.47) 0.002$ Males (n,%) 864 (84%) 1483 (82%) ns£ $ £ *Data are median (inter-quartile range); Mann-Whitney U test; Chi-square test
ACCEPTED MANUSCRIPT
Table 3. Rates of procedural complications of pyloromyotomy
AC
CE
PT
ED
MA NU
SC
RI P
T
Operative approach Adjusted difference^ (%, 95%CI) Open Laparoscopic Mucosal perforation (%) 0.29 0.83 0.56% (-0.096-3.365) Incomplete pyloromyotomy (%) 0.29 1.16 0.87% (0.006-4.083) ^Adjusted for centre and age; *binomial logistic regression analysis
P 0.153 0.046
ACCEPTED MANUSCRIPT
Table 4: Distribution and description of complications between centres total (n,%)
T
MP 2 (0.48%) 2 (0.57%) 1 (0.26%) 1 (0.19%) 1 (0.56%) 5 (1.34%) 4 (3.70%) 1 (0.29%) 1 (0.58%) 18 (0.64%)
AC
CE
PT
ED
MA NU
SC
RI P
open laparoscopic n MP IP n MP IP A 86 0 0 328 2 9 B 265 1 3 85 1 1 C 0 389 1 1 D 449 1 0 53 0 0 E 2 0 0 177 1 0 F 118 1 0 255 4 1 G 15 0 0 93 4 3 H 89 0 0 255 1 5 I 4 0 0 167 1 1 Total 1028 3 3 1802 15 21 MP – mucosal perforation; IP – incomplete pyloromyotomy Centre
IP 9 (2.17%) 4 (1.14%) 1 (0.26%) 0 (-) 0 (-) 1 (0.27%) 3 (2.78%) 5 (1.45%) 1 (0.58%) 24 (0.84%)