Minilaparotomy versus laparoscopic cholecystectomy for elective gallstone disease : a prospective randomized stury on ultrasonic dissection, surgical stress, health status and long-term outcome after surgery

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DISSERTATIONS | SAMULI ASPINEN | MINILAPAROTOMY VERSUS LAPAROSCOPIC CHOLECYSTECTOMY... | No 366

uef.fi

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND Dissertations in Health Sciences

ISBN 978-952-61-2212-0 ISSN 1798-5706

Dissertations in Health Sciences

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND

SAMULI ASPINEN

MINILAPAROTOMY VERSUS LAPAROSCOPIC CHOLECYSTECTOMY FOR ELECTIVE GALLSTONE DISEASE

A Prospective Randomized Study on Ultrasonic Dissection, Surgical Stress, Health Status and Long-term Outcome After Surgery Gallstone disease is a common impediment

among western population and the treatment of symptomatic gallstones is generally surgical. In this thesis I evaluate the use of ultrasonic dissection in minilaparotomy versus laparoscopic cholecystectomy for the treatment

of symptomatic non-complicated gallstone disease. Besides intraoperative results and short-term outcome, I report perioperative surgical stress, health status, long-term results, postoperative residual symptoms and

patient satisfaction after minilaparotomy versus laparoscopic cholecystectomy.

SAMULI ASPINEN

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Minilaparotomy versus Laparoscopic Cholecystectomy for Elective Gallstone

Disease

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SAMULI ASPINEN

Minilaparotomy versus Laparoscopic Cholecystectomy for Elective Gallstone

Disease

A Prospective Randomized Study on Ultrasonic Dissection, Surgical Stress, Health Status and Long-term Outcome After

Surgery

To be presented by permission of the Faculty of Health Sciences, University of Eastern Finland for public examination in Kuopio University Hospital Auditorium, Kuopio, on Friday, September 9^th

2016, at 12 noon

Publications of the University of Eastern Finland Dissertations in Health Sciences

Number 366

Department of Surgery, Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland

Kuopio 2016

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Grano Oy Jyväskylä, 2016

Series Editors:

Professor Tomi Laitinen, M.D., Ph.D.

Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine Faculty of Health Sciences

Professor Hannele Turunen, Ph.D.

Department of Nursing Science Faculty of Health Sciences Associate Professor Tarja Malm, Ph.D.

A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences

Professor Kai Kaarniranta, M.D., Ph.D.

Institute of Clinical Medicine, Ophthalmology Faculty of Health Sciences

Lecturer Veli-Pekka Ranta, Ph.D. (pharmacy) School of Pharmacy

Faculty of Health Sciences Distributor:

University of Eastern Finland Kuopio Campus Library

P.O.Box 1627 FI-70211 Kuopio, Finland http://www.uef.fi/kirjasto ISBN (print): 978-952-61-2212-0

ISBN (pdf): 978-952-61-2213-7 ISSN (print): 1798-5706

ISSN (pdf): 1798-5714 ISSN-L: 1798-5706

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Author’s address: Department of Surgery Päijät-Häme Central Hospital LAHTI

FINLAND

Supervisors: Professor Matti Eskelinen, M.D., Ph.D.

Department of Surgery/ School of Medicine Kuopio University Hospital/

University of Eastern Finland KUOPIO

FINLAND

Professor Hannu Kokki, M.D., Ph.D.

Department of Anaesthesia and Operative Services/

School of Medicine

Kuopio University Hospital University of Eastern Finland KUOPIO

FINLAND

Docent Petri Juvonen, M.D., Ph.D.

Department of Surgery Kuopio University Hospital KUOPIO

FINLAND

Reviewers: Professor Ilmo Kellokumpu, M.D., Ph.D.

Department of Surgery Keski-Suomi Central Hospital University of Helsinki

JYVÄSKYLÄ FINLAND

Professor Jyrki Kössi, M.D., Ph.D.

Department of Surgery, Kanta-Häme Central Hospital University of Turku

HÄMEENLINNA FINLAND

Opponent: Docent Esko Kemppainen, M.D., Ph.D.

Department of Surgery, Helsinki University Hospital University of Helsinki

HELSINKI FINLAND

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V

Aspinen, Samuli

Minilaparotomy versus Laparoscopic Cholecystectomy for Elective Gallstone Disease. A Prospective Randomized Study on Ultrasonic Dissection, Surgical Stress, Health Status and Long-term Outcome After Surgery

University of Eastern Finland, Faculty of Health Sciences

Publications of the University of Eastern Finland. Dissertations in Health Sciences Number 366. 2016. 74 p.

ISBN (print): 978-952-61-2212-0 ISBN (pdf): 978-952-61-2213-7 ISSN (print): 1798-5706 ISSN (pdf): 1798-5714 ISSN-L: 1798-5706 ABSTRACT:

Gallstone disease is a common impediment among western population and its’ prevalence is ascending because of increased obesity and aging. The treatment of symptomatic gallstones is generally surgical.

The conventional open cholecystectomy has been widely replaced by mini-invasive surgical approaches, such as minilaparotomy cholecystectomy (MC) and, especially, laparoscopic cholecystectomy (LC). These approaches have shown to lead to less complications and shorter convalescence. Furthermore, current literature suggests that ultrasonic dissection (UsD) applied to either MC or LC leads to less postoperative pain and a shorter sick leave compared to dissection with conventional monopolar electrosurgical energy (ME).

In studies with comparable surgical data or results with irrelevant clinical significance, secondary outcome measures, such as health status, patient reported quality of life and cosmesis must be considered as important secondary measures. Moreover, several studies suggest that post-cholecystectomy abdominal symptoms are common with prevalence up to 40%. It has been evaluated that the residual symptoms could be decreased by third with a careful preoperative patient selection. Thus it seems meaningful to compare the health status, long-term outcome and quality of life after cholecystectomy with different surgical approaches.

To the best of my knowledge, there are no randomised clinical trials comparing UsD in both LC and MC procedures. Thus, the aim of this thesis was to evaluate the safety and efficacy of MC and LC procedures using UsD in both study groups. Furthermore, the aim was to assess health status with a generic, coherent, and easily administerable health survey (Rand–36). Moreover, the long-term outcome, quality of life, post-cholecystectomy symptoms and patient satisfaction after MC and LC were evaluated.

Altogether 414 patients were initially enrolled into four consecutive studies. MC was performed in 216 cases vs 198 LC cases. In follow-up studies (studies I-III), the response rate was 81-87%. In studies IV-V, two patients were excluded – one because of failed anaesthesia protocol and one with an intraoperative suspicion of a liver tumour. The final number of patients analysed in this thesis was 361 (183 MC vs 178 LC patients). The proportion of female patients was 289, vs 72 male patients, and the distribution was similar between the study groups (143 vs 146 females in MC vs LC, 40 vs 32 males in MC vs LC, respectively). The median height, weight, body mass index (BMI) or American Society of Anesthesiologist physical status (ASA) status in MC group did not differ for patients in LC group (167 cm vs 167 cm, 74 kg vs 76 kg, 27 kg/m2 vs 27 kg/m2 and ASA 2 vs ASA 2, in MC vs LC, respectively).

The baseline surgical data in terms of bleeding, conversions and complications were similar between the study groups in each study. The operative time and time at the operative theatre were longer for LC patients in study I (p-value =0.0001), but no differences were observed in studies II-IV.

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Recovery at hospital was similar regarding postoperative pain measurements, nausea and vomiting and day surgery success rate. However, after discharge, the LC patients reported lower pain scores at normal activity (p=0.05) and at quick movement/while coughing (p=0.005). Nevertheless, analgesics consumption was similar at 24 h and at 4 weeks. The length of sick leave was 17.4 days in MC versus 14.4 days in LC group (p=0.05).

The plasma concentrations of five interleukins (IL-1β, IL-1ra, IL-6, IL-8, IL-10) and hs-CRP was measured at three time points in order to assess surgical stress between MC and LC, as UsD was applied to both procedures. The patients in the MC group had greater elevation of the CRP mean values postoperatively (p=0.01). Likewise, the MC patients had greater elevation of IL-1ra mean values postoperatively, the mean pre- vs. postoperative (299 vs. 614 pg/ml in the MC group versus 379 vs. 439 pg/ml in the LC group, p=0.003). Pre- and postoperative IL-6 concentrations were similar across the study groups, but the patients in the MC group had higher IL-6 mean concentrations 6 h postoperatively (27.6 pg/ml in the MC group versus 14.8 pg/ml in the LC group, p=0.037). The mean values of IL-8, IL-10 and IL-1β did not show any statistical difference between the MC and LC groups pre- and postoperatively.

The Rand–36 survey was collected at three time points: preoperatively, 4 weeks postoperatively and at 6 months after surgery. There were no significant differences between the study groups except from the higher score in perceived health change subscale in MC group (MC score 75.0 (25.0) vs LC score 56.5 (23.2), p = 0.008) at 4 weeks postoperatively.

Based on the Rand–36 health survey results, both study groups improved from preoperative to 6 month postoperative scores in physical functioning (combined preoperative score for MC and LC 80.5 vs combined postoperative score at 6 months 86.5, p = 0.015), vitality (64.5 vs 73.5, p = 0.001), perceived health change (43.0 vs 74.6, p = 0.0001) and pain scores (57.7 vs 75.5, p = 0.001).

A phone interview was used to evaluate the long-term outcome of patients that had undergone MC or LC. Residual abdominal symptoms were common in each study and the proportion was quite similar: between 27% and 35%. The symptoms experienced were generally mild and only few had sought for medical help. Despite the fact that ongoing symptoms were common, the patients reported improved quality of life after surgery (76%–

94% of MC and 79%–96% of LC patients) with no statistically significant differences between MC and LC.

Based on this thesis, it can be concluded that, applied either to MC or LC procedure, UsD leads to less postoperative pain and shortens the convalescence time compared to conventional ME without any significant differences between MC and LC. The inflammatory response to surgical trauma caused by the procedure seems greater in MC group but without a clear clinical significance. Residual abdominal symptoms are common, but generally mild.

No significant differences between MC and LC were observed regarding health status, residual symptoms, quality of life and patient satisfaction in a long-term follow-up.

National Library of Medicine Classification: WI 750, WI 755, WI 900, WO 184

Medical Subject Headings: Cholecystectomy, Laparoscopic; Gallstones/surgery; Health Status; Interleukins;

Laparotomy; Operative Time; Patient Satisfaction; Quality of Life; Treatment Outcome; Ultrasonic Surgical Procedures

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VII

Aspinen, Samuli

Minilaparotomia vs Laparoskooppinen sappirakon poisto komplisoitumattomassa sappikivitaudissa, prospektiivinen randomoitu tutkimus ultraäänidissektiosta ja kirurgisesta stressistä sekä leikkauksen jälkeisistä pitkäaikaistuloksista.

Itä-Suomen yliopisto, terveystieteiden tiedekunta

Publications of the University of Eastern Finland. Dissertations in Health Sciences Numero 366. 2016. 74 s.

ISBN (print): 978-952-61-2212-0 ISBN (pdf): 978-952-61-2213-7 ISSN (print): 1798-5706 ISSN (pdf): 1798-5714 ISSN-L: 1798-5706 TIIVISTELMÄ:

Sappikivitauti on tavallinen maha-suolikanavan sairaus. Länsimaissa sappikivitautia sairastavia on arviolta 5–22% ja väestön ikääntyminen sekä yleisen painoindeksin kohoaminen lisäävät taudin esiintyvyyttä. Kipuoireinen tauti on kiireettömän leikkaushoidon aihe.

Perinteisen avoleikkauksen ovat laajalti korvanneet mini–invasiiviset tekniikat kuten miniviiltokolekystektomia (MC) sekä laparoskooppinen kolekystektomia (LC). Näiden vahvuuksia ovat vähäisemmät komplikaatiot ja potilaiden nopeampi toipuminen.

Ultraäänidissektion (UsD) on aiemmin todettu vähentävän postoperatiivista kipua ja toipumisaikaa sekä MC että LC toimenpiteissä monopolaarisella polttokoukulla suoritettuun leikkaukseen nähden.

Useat seurantatutkimukset osoittavat myös, että sappikivipotilaan maha-suolikanavan kliinisiä oireita ja löydöksiä on vaikea arvioida, ja jopa 40 %:lla leikatuista potilaista oireet jatkuvat kolekystektomian jälkeen. On esitetty, että huolellisella preoperatiivisella arvioinnilla voitaisiin vähentää kolmasosalla jäännösoireiden esiintyvyyttä. Tämän vuoksi on tarkoituksenmukaista seurata potilaiden toimenpiteiden jälkeistä toimintakyvyn palautumista, pitkäaikaistuloksia ja tyytyväisyyttä.

Tiettävästi, UsD:ta soveltavia MC ja LC toimenpiteitä ei aiemmin ole vertailtu. Näin ollen tämän tutkimuksen tarkoituksena on monipuolisesti kartoittaa mini-invasiivisten UsD:ta hyödyntävien, etenkin miniviiltokolekystektomian merkitystä komplisoitumattoman sappikivitaudin kirurgisessa hoidossa. Lisäksi, tämän väitöskirjan tarkoitus on verrata MC ja LC toimenpiteen läpikäyneiden potilaiden elämänlaatua, leikkaustyytyväisyyttä, sekä jäännösoireita pitkäaikaisseurannassa.

Kaikkiaan 414 potilasta satunnaistettiin neljään tutkimussarjaan, MC potilaita näistä oli 216 ja LC potilaita 198. Seurantatutkimuksissa (I-III) haastattelun vastausprosentti oli 81-87%.

Tutkimuksissa IV-V, kaksi potilasta suljettiin tutkimuksesta, toinen virheellisen anestesiaprotokollan ja toinen intraoperatiivisen maksakasvain-epäilyn vuoksi. Lopulta yhteensä 361 potilasta (183 MC ja 178 LC potilasta) analysoitiin tätä väitöstutkimusta varten.

Näistä 289 oli naisia (143 MC ja 146 LC ryhmässä) ja 72 miehiä (40 MC ja 32 LC ryhmässä).

Ryhmät vastasivat toisiaan painon, pituuden, yleisen painoindeksin sekä American society of anesthesiologists physical status -luokituksen suhteen, eikä leikkauksien aikana syntynyt ryhmien välille merkittäviä eroja, esimerkiksi leikkausajassa, -vuodossa tai komplikaatioissa.

Toipuminen sairaalassa ei niin ikään tuonut eroja ryhmien välille kipumittareilla, kipulääkityksen tai pahoinvoinnin määrässä. Kuitenkin, leikkauksen jälkeisenä aamuna MC –potilaat ilmoittivat merkitsevästi enemmän kipuoireita normaaleissa (p=0,05) ja nopeissa liikkeissä (p=0,005). Tämä ei kuitenkaan heijastunut leikkauksen jälkeisen päivän kipulääkkeiden käytöön, eikä ryhmien välillä ollut kivun tai kipulääkityksen suhteen eroa neljä viikkoa leikkauksen jälkeen. Laparoskooppisessa ryhmässä potilaiden sairauspoissaolo

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näytti kuitenkin olevan merkitsevästi lyhyempi (14,4 päivää laparoskopian jälkeen, 17,4 päivää minilaparotomian jälkeen, p=0,05).

Plasman tulehdusta välittäviä merkkiaineita (IL-1β, IL-1ra, IL-6, IL-8, IL-10) ja C- reaktiivisen proteiinin tasoa mitattiin kolmena ajanhetkenä; ennen leikkausta (PRE), heti leikkausen jälkeen (POP1) sekä kuusi tuntia leikkauksen päättymisen jälkeen (POP2).

Minilaparotomiaryhmässä nähtiin suurempi leikkauksenjälkeinen CRP-arvojen kohoaminen (p=0,01). Niin ikään, MC –potilaiden IL-1ra arvoissa (299/614 pg/ml MC -ryhmässä versus 379/439 pg/ml LC -ryhmässä, p=0,003) tapahtui suurempi nousu lähtötasoihin nähden heti leikkauksen jälkeen ja IL-6 arvoissa (27.6 pg/ml MC –ryhmässä versus 14.8 pg/ml LC - ryhmässä, p=0,037) heti leikkauksen jälkeen ja kuusi tuntia myöhemmin otetun arvon välillä.

IL-8, IL-10 and IL-1β keskiarvoissa ei havaittu eroja tutkimusryhmien välillä.

MC ja LC ryhmien välistä toiminnallista kuntoutumista kartoitettiin hyödyntäen Rand–36 tutkimuskaavaketta. Rand–36 on moniulotteinen yleinen terveydentilan profiilimittari, jonka avulla pyrimme havainnollistamaan psyykkisen ja fyysisen toimintakyvyn muutoksia leikkauksen jälkeen keräämällä Rand–36 mukaisen kyselyn tutkittavilta ennen, sekä 4 viikkoa, ja 6 kuukautta leikkauksen jälkeen. Ryhmien välillä ei havaittu tilastollisesti merkitseviä eroja lukuun ottamatta koettua terveydentilan muutosta, joka suosi MC potilaita 4 viikkoa leikkauksen jälkeen (MC 75,0 vs LC 56,5, p = 0,008). Molemmissa ryhmissä toimintakyky näytti kohentuneen 6 kuukatta leikkauksen jälkeen fyysisen toimintakyvyn (molempien ryhmien yhteenlaskettu preoperatiivinen arvo 80.5 vs molempien ryhmien yhteenlaskettu leikkauksen jälkeinen 6 kuukauden arvo 86.5, p = 0.015), tarmokkuuden (64,5 vs 73,5, p = 0,001), koetun terveyden (43,0 vs 74,6, p = 0,0001) sekä kivun (57,7 vs 75,5, p = 0,001) osa-alueilla.

Pitkäaikaistuloksia selvitettiin puhelinhaastatteluilla tutkimuksissa I-III. Vatsaoireet olivat tavallisia, mutta niiden esiintyvyys tutkimusten välillä ei juuri eronnut toisistaan (tutkimukset I-III: 27%-35%). Oireet olivat tavallisimmin lieviä ja vain osa oli myöhemmin tavannut lääkäriä vatsaoireidensa takia. Vaikka jäännösoireet olivatkin tavallisia, ilmoitti 92% (tutkimus I, MC 90% vs LC 95%, p=0,05), 88% (tutkimus II, MC 76% vs LC 96%, p=0.38), 86% (tutkimus III, MC 94% vs LC 79%, p=0,13) tutkimuspotilaista elämänlaatunsa parantuneen, eikä tutkimusryhmien välillä nähty tilastollista eroa.

Tämän väitöskirjan perusteella voidaan todeta, että UsD:ta soveltavat MC ja LC toimenpiteet näyttävät vähentävän leikkauksen jälkeistä kipua ja nopeuttavan toipumista ilman merkittäviä eroja leikkausryhmien välillä. Toimenpiteen aiheuttama inflammatorinen vaste on suurempi MC ryhmässä, ilman selvää kliinistä merkitystä. Leikkauksen jälkeiset vatsaoireet ovat tavallisia, mutta lieviä, eikä ryhmien välillä todeta eroja elämänlaadussa, leikkaustyytyväisyydessä, eikä jäännösoireissa pitkäaikaisseurannassa.

Yleinen Suomalainen asiasanasto: leikkaushoito; pitkäaikaisvaikutukset; sappikivet; sappirakko;

vatsaontelontähystys

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IX

Acknowledgements

This study was conducted at the Department of Surgery, School of Medicine, University of Eastern Finland. Clinical trials were carried out at the surgical departments of Kuopio University Hospital, Kuusankoski District Hospital (at present North Kymi Hospital), Päijät- Häme Central Hospital and Helsinki University Central Hospital, during 1998 – 2016. This study was financially supported by grants from State Research Funding and Heikki, Aarne and Aino Korhonen Foundation.

I wish to express my deepest gratitude to my supervisors, Professor Matti Eskelinen, Professor Hannu Kokki and Docent Petri Juvonen, for all the support and encouragement throughout this journey. I am grateful to Matti Eskelinen for the opportunity to work under his supervision; without his expertise and enthusiasm in clinical research this thesis would have not been possible. I acknowledge Hannu Kokki and Petri Juvonen for sharing their invaluable scientific and medical proficiency during the making of this thesis.

A humble thank you belongs to Professor Ilmo Kellokumpu and Professor Jyrki Kössi for their constructive comments and advice in reviewing this thesis.

I am most grateful to my colleague and co-author MD, PhD Jukka Harju for his enthusiastic attitude towards clinical research and invaluable advice and insight into the topic. Your work was indispensable for this thesis. I also wish to return special thank you to co-authors MSc Anu Holopainen, BM Mari Kinnunen, MD Kalevi Karjalainen, BM Jari Kärkkäinen, Professor Hannu Paajanen, Professor Kari Pulkki, MD, PhD Veikko Remes, Docent Tom Scheinin and MSc Tuomas Selander. I would also like to thank MD Martin Purdy for co-work, study nurse Petri Toroi, BM Susan Lievonen and BM Riika Korhonen for excellent groundwork and assistance in collecting data. I also thank colleagues and nursing staff at operating and recovery rooms in each participating hospital.

It is a great pleasure to acknowledge my valued friend Tommi Laaksonen, who cleared space from his own calendar to give a helping hand in creating the illustration of this thesis.

Another special thank you belongs to my dear friends and colleagues Lauri Karttunen and Annu-Riikka Säteri for their never-ending hospitality during my stays in Kuopio.

I wish to thank all my friends in Kuopio, Lahti and Helsinki, especially A-P, Jani, Jussi, Marko and Timo, for the encouragement and support throughout these busy years. Besides all the extracurricular activities, you have motivated me to drive forward with my life and career.

I would like to thank my parents-in-law, Sirpa and Jarmo, for the great support to our family over the past 5 years.

I owe my deepest gratitude to my parents, Marjo and Vesa, who have always supported me and given me a great opportunity to educate myself. I thank my brothers, Valtteri and Santeri, for the tough brotherly love and encouragement. It is a great honour to have you all in my life.

Finally, I wish to thank my family; Iris and Joel for all the joy you bring, and my wife Anna, you have been the most important and unending source of patience, support and understanding. I love you.

Helsinki, August 2016 Samuli Aspinen

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XI

List of the original publications

This dissertation is based on the following original publications:

I Harju J, Aspinen S, Juvonen P, Kokki H, Eskelinen M. Ten-year outcome after minilaparotomy versus laparoscopic cholecystectomy: a prospective randomised study. Surg Endosc 27:2512-2516, 2013.

II Aspinen S, Harju J, Juvonen P, Karjalainen K, Kokki H, Paajanen H, Eskelinen M.

A Prospective, randomized study comparing minilaparotomy and laparoscopic cholecystectomy as a day-surgery procedure: 5-year outcome. Surg Endosc 28: 827- 832, 2014.

III Aspinen S, Harju J, Juvonen P, Remes V, Scheinin T, Eskelinen M. A Prospective, randomized multicenter study comparing conventional laparoscopic cholecystectomy versus minilaparotomy cholecystectomy with ultrasonic dissection as day surgery procedure – 1-year outcome. Scand J Gastroenterol 49:

1336-1342, 2014.

IV Aspinen S, Harju J, Kinnunen M, Juvonen P, Kokki H, Eskelinen M. A randomized multicenter study of minilaparotomy cholecystectomy versus laparoscopic cholecystectomy with ultrasonic dissection in both groups. Scand J Gastroenterol 51:

354-359, 2016.

V Aspinen S, Kinnunen M, Harju J, Juvonen P, Selander T, Holopainen A, Kokki H, Pulkki K, Eskelinen M. Inflammatory response to surgical trauma in patients with minilaparotomy cholecystectomy versus laparoscopic cholecystectomy: a randomised multicentre study. Scand J Gastroenterol 51: 739-44, 2016.

VI Aspinen S, Kärkkäinen J, Harju J, Juvonen P, Kokki H, Eskelinen M. A Randomized Multicenter Trial of Health Status (RAND–36) after Minilaparotomy Cholecystectomy vs Laparoscopic Cholecystectomy. Submitted.

The publications were adapted with the permission of the copyright owners.

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4.6 Biochemical Analyses ... 30 4.7 Health Status and Long-term Outcome Assessments ... 30 4.8 Statistical Analyses ... 30 5 RESULTS ... 33 5.1 Baseline Demographic Characteristics ... 33 5.2 Intraoperative Outcome ... 33 5.3 Short-term Postoperative Outcome ... 34 5.3.1 Recovery at Hospital ... 34 5.3.2 Recovery After Discharge... 35 5.3.3 Post-hoc Analysis of Surgical and Outcome Data ... 36 5.4 Inflammatory Response to Surgical Trauma ... 38 5.4.1 Post-hoc Analysis of Inflammatory Response ... 39 5.4 Health Status ... 40 5.5 Long-term Outcome ... 44 6 DISCUSSION ... 47 6.1 Ultrasonic Dissection in Mini-invasive Cholecystectomy ... 47 6.2 Acute Phase Response After Cholecystectomy ... 48 6.3 Health Status and Long-term Outcome ... 49 6.4 Study Limitations ... 52 6.5 Future Perspectives ... 52 7 CONCLUSIONS ... 55 REFERENCES ... 57 APPENDIX ... 75

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Abbreviations

3D 3-dimension

AC Acute calcolous cholecystitis AP(P/R) Acute-phase (protein/response)

ASA American Society of Anesthesiologists physical status classification

BIQ Body image questionnaire

C Complement

CBD Common bile duct

CCK Cholecystokinine

CCL Chemokine (C-C-motif) ligand

CHD Common hepatic duct

CPSP Chronic post-surgical pain

(hs)-CRP (high sensitivity)-C-reactive protein CSQ Condition-specific questionnaire

CS Complement system

CT Computed tomography

CXCL Chemokine (C-X-C-motif) ligand DAMP Damage associated molecular pattern ELISA Enzyme-linked immunosorbent assay

ERCP Endoscopic retrograde cholangiopancreatography ESWL Extracorporeal shock wave lithotripsy

GIQLI Gastrointestinal quality of life index

gp130 Glykoprotein 130

IL Interleukin

(s/ic)IL-1Ra (secreted-/intracellular) Interleukin-1 receptor antagonist (m/s)IL-6R (membrane bound/soluble) Interleukin-6 receptor

LC Laparoscopic cholecystectomy

MC Minilaparotomy cholecystectomy

MEH Monopolar electrocauterisation hook

ME Monopolar electrosurgical energy

MLC Minilaparoscopic cholecystectomy

MRCP Magnetic resonance cholangiopancreatography

MRI Magnetic resonance imaging

NK Natural killer

NOTES Natural orifice transluminal endoscopic surgery

OC Open cholecystectomy

PAMP Pathogen associated molecular pattern

PRE Before operation

PGE2 Prostaglandin E2

POP1 Immediately after operation

POP2 6 h after operation

PTC Percutaneous transhepatic cholangiography

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QoL Quality of life

SF-36 Short Form-36

SILS Single incision laparoscopic surgery

STAT Signal transducers and activators of transcription

TH T-helper

TLR Toll-like receptor

TNF Tumor necrosis factor

UsD Ultrasonic dissection

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1 Introduction

Gallstone disease is a common impediment among western population and its prevalence is ascending because of increased obesity and aging. The incidence of gallstones in the general population is 5-22%. Albeit low mortality rates, the expenses of gallstone disease to the society are significant due its eminent prevalence (Stinton LM et al 2012).

Most gallstones are asymptomatic and the risk of developing a complication is low, thus, a prophylactic cholecystectomy is rarely recommended. On the contrary, the treatment of symptomatic gallstones is generally surgical, and frequent painful biliary colics and a complication of cholelithiasis are indications for early cholecystectomy.

The conventional open cholecystectomy (OC) has been widely replaced by mini-invasive surgical approaches, such as minilaparotomy cholecystectomy (MC) and, especially, laparoscopic cholecystectomy (LC). Soon after its’ introduction, LC revolutionised gallbladder surgery, although the popularity of the new approach was partly based on an appealing technological innovation as well as industry driven motives, not primarily a result of evidence-based science (Escarce JJ 1996). Later on, MC has been shown to be safe and effective as a surgical approach with no major outcome differences in comparative studies between MC and LC (O’Dwyer PJ et al 1990, Tyagi NS et al 1994, Majeed et al 1996, Seale AK and Ledet WP 1999, Harju J et al 2006, Rosenmüller MH et al 2013).

The standard LC is usually performed using a monopolar electrosurgical hook (MEH) for dissection and clips for occlusion of the cystic duct and cystic artery. Monopolar electrosurgical hook is known for its’ ease for securing haemostasis and cost-effectiveness.

However, some pitfalls associated with the use of the monopolar electrosurgery exist, such as the high risk of thermal injury, bile leakage and postoperative biliary complications (Amaral JF 1995, Tsimoyiannis EC et al 1998, Cengiz Y et al 2010, Sasi W 2010).

In 1995, Amaral JF et al introduced UsD in LC. Ever since, the use of UsD has been evaluated in several randomised clinical trials indicating that UsD applied to LC is a safe and effective surgical approach. Moreover, LC with UsD has shown to lead to either equal (Mattila A et al 2015) or improved intraoperative and short-term outcome. Short-time benefits of UsD in LC include a shorter mean operation time, fewer intraoperative conversions, gallbladder perforations and less blood loss, postoperative pain, nausea and vomiting, and shorter mean hospital stay (Janssen IM 2003, Cengiz Y et al 2005, Bessa SS et al 2008, El Nakeeb A et al 2010, Kandil T et al 2010, Jain SK et al 2011). However, there is no complete agreement on the clinical significance of the possible benefits of UsD vs MEH in LC (Sasi W 2010, Mattila A et al 2015).

Harju J et al (2013) applied UsD to MC and compared it to conventional LC with MEH.

This approach was shown to be safe and effective and, moreover, the patients in MC group seemed to have less postoperative pain and a shorter sick leave. In conclusion, UsD applied to either LC or MC may lead to enhanced effects in short term recovery after surgery.

However, no randomised clinical trials comparing UsD in both LC and MC procedures have been conducted.

The acute-phase response (APR), although nonspecific, is a core integrate of the innate immunity, and comprises of the physiological and biochemical responses to tissue damage, infection, inflammation, and malignant neoplasia. Furthermore, it acts to clear potential pathogens, initiate inflammatory processes, and contribute to re-establishing homeostasis and the healing process. Surgery is a unique example of planned trauma in which an increase in the plasma concentrations of acute-phase proteins (APP), as well as, cytokines - core mediators of the APR, may be observed and studied in order to assess the surgical stress, tissue trauma and healing process caused by the intervention (Alper CA 1974, Meri S and Julkunen I 2011).

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In comparing surgical treatments, perioperative and short-term outcome data must be considered as primary outcome measures. However, with comparable surgical data or results with irrelevant clinical significance, secondary outcome measures, such as health status, patient reported quality of life and cosmesis must be considered as important secondary measures. In evaluating health status after cholecystectomy, the disease-specific gastrointestinal QoL index (GIQLI) and the short form (SF–36) are recommended by evidence base (Korolija D et al, 2004). Rand–36, much like SF–36 is a widely used generic, coherent, and easily administered health survey, a questionnaire designed for measuring self-reported physical and mental health status. It contains a total of eight domains (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health) and an assessment of perceived health change. Rand-36 include the same set of items than SF-36, however, the scoring of general health and pain scales is different. The Finnish version has been validated (Aalto A-M et al 1999).

Post-cholecystectomy abdominal symptoms are common with prevalence up to 7%-41%.

The symptoms reported might be pre-existing or arise de dovo. The reviewed literature suggests that the long-term symptomatic outcome, cosmesis and quality of life (QoL) is similar whether the gallbladder is removed by conventional OC, MC or LC method (Barkun JS et al 1992, McMahon AJ et al 1995, Squirrell DM et al 1998, Jørgenssen T 2000, Ros A et al 2004, Keus F et al 2008 and 2010). However, there are no long-term outcome studies after mini-invasive cholecystectomy with UsD.

The aim of this thesis was to evaluate the use of UsD in MC vs LC in a prospective randomised study setting. The cytokine response and APR between the two techniques was further studied to assess the surgical stress and tissue trauma caused by the approach used.

Furthermore, the health status, long-term symptomatic outcome, cosmesis and patient satisfaction were studied in order to create understanding of the treatment path of a gallstone patient undergoing MC vs LC.

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3

2 Review of the Literature

2.1 ANATOMY OF THE BILIARY TREE AND GALLBLADDER

The gallbladder is a tapered, pear-shaped, sac-like, organ with hollow walls. It is approximately 8-12cm in length and 4cm in diameter with a capacity of 100ml. Anatomically, the gallbladder is divided into three sections: the fundus, body, and neck. It is attached to the liver by connective tissue and sits in its own impression beneath the right lobe the liver.

Bile canalicules arise from the liver parenchyma and form intrahepatic bile ductules in portal triads (with adjacent vein and artery). These ductules build interlobular bile ducts, which eventually construct left and right hepatic ducts. As the liver can be divided into two functional lobes, these ducts drain the bile from each, uniting at the port of the liver to form the common hepatic duct (CHD). The CHD is usually 4 to 6 cm long and it forms one edge of the Calot’s triangle (Figure 1), a crucial anatomical landmark in biliary surgery, such as the cholecystectomy. The cystic duct, another edge of the Calot’s triangle, join the gallbladder to CHD and these two ducts form the common bile duct (CBD). The CBD is later joined by the pancreatic duct to form the ampulla of Vater. This is specifically located in the major duodenal papilla, and is an opening into the duodenum.

The celiac trunk is the first major branch of the abdominal aorta. Common hepatic artery branches from the coeliac trunk, later dividing into right and left hepatic arteries. The cystic artery is a branch of the right hepatic artery and it supplies blood to the gallbladder and cystic duct.

The classic biliary anatomy appears in about 55-60%. Variants include e.g. bile system, arterial and venous anomalies (Michels NA 1966, Mortelé KJ and Ros PR 2001).

Figure 1. Anatomy of the Calot’s triangle.

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2.2 GALLSTONE DISEASE 2.2.1 Epidemiology

Gallstone disease is a common surgical condition among the Western population. The prevalence is between 10% and 15% in white adults of developed countries. Ethnic differences abound (Stinton LM et al 2012). In a Scandinavian report, gallstones exist in more than 500.000 Finns. The incidence for gallstones in Finland for women is 16% and 9% in men.

Risk factors for gallstones are genetics, obesity, significant weight loss, female gender, pregnancy, high age, fatty diet and prolonged parenteral nutrition (Mjåland O et al 1998).

Epidemiological studies show that approximately 50-70% of patients with gallstones are symptomless at the time of diagnosis and cholecystolithiasis is detected examining symptoms unrelated to gallstones. Roughly 10% of these patients develop right upper quadrant pain attacks typical for gallstones in the next 5 years and the majority remains asymptomatic. In a long time follow-up, eventually 35-40% develop symptoms and 20%

develop a complication related to cholecystolithiasis (Halldestam I et al 2004).

In Finland, cholecystectomy is the second most common operation in gastroenterological surgery after inguinal hernia repair with 8100 gallbladder operations in 2012. These patients required a total of 19290 days of hospitalization with a mean of two days, whilst the median for hospitalization was one day. The total mortality rate was 0.15% (Rautiainen H et al 2013).

2.2.2 Pathogenesis

The formation of gallstones is a complex process of environmental and genetic factors and remains yet to be fully understood. Gallstones may be divided into two main subgroups by the consistency of the stones: cholesterol stones and pigment stones.

2.2.2.1 Cholesterol Stones

Cholesterol stones are composed principally of cholesterol monohydrate crystals and the current knowledge of cholesterol stone synthesis point to three main factors: bile supersaturation, increased cholesterol crystallization and gallbladder dysmotility.

Bile supersaturation with cholesterol is theoretically caused by cholesterol hypersecretion and/or bile acid hyposecretion from the liver. Practically, bile acid hyposecretion is not regarded significant in cholesterolstone formation (Bouchier IA 1992). It is notable that most of the risk factors of gallstone disease can be explained by changes in cholesterol metabolism and 80-90% of all gallbladder stones in Western countries are cholesterol stones. Cholesterol secretion to bile is increased in obese, elderly and fasting (Stampfer MJ et al 1992). It is also well known that oestrogen increases the amount of cholesterol in the bile (Everson GT et al 1991).

While cholesterol supersaturation is essential for stone formation, not all saturated bile form cholesterol stones. It is believed that the most important factor distinguishing stone forming from non stone-forming bile is the capacity to nucleate cholesterol out of solution in the form of cholesterol monohydrate crystals. The nature of the nucleating factors remains to be determined with precision but they include mucus glycoprotein (mucin), non-mucus glycoproteins, calcium ions, immunoglobulins and possibly free fatty acids (Afdhal NH et al 1990). In addition it is recognised that there are antinucleating factors, which include apolipoproteins, lecithin and ursodeoxycholic acid. The precise balance of activity of these different factors, and how they influence stone formation remains to be determined. It is important to distinguish the nucleation of cholesterol crystals i.e. the initial formation of a crystal, from crystal growth and stone formation. It is probable that different factors determine these two processes (Bouchier IA 1992).

It has been established that gallbladder hypomotility is an important prerequisite for gallstone formation because it decreases gallbladder emptying and leaves time for nucletion of cholesterol crystals. Generally, the gallbladder releases bile after a postprandial neurohormonal stimulus. One of the most important gallbladder stimulating hormones is

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5

cholecystokinine (CCK) (Groen AK et al 1990, Schjoldager BT et al 1994). Clinical studies assessing gallbladder response to exogenous CCK have perceived gallbladder hypomotility mainly in patients with cholycystolithiasis (Behar J et al 1989, Pomeranz IS et al 1985). In addition, clinical studies have identified gallbladder motorical dysfunction in obese, diabetic, pregnant and patients with pigment stones. Thus, gallbladder hypomotility leading to improper postprandial gallbladder emptying can be accounted for a central factor in gallstone formation (Stampfer MJ et al 1992, Bouchier IA 1992, Ko CW et al 2005).

2.2.2.2 Pigment Stones

Pigment stones may be divided into “black” and “brown” stones. These stones mainly consist of acid salts of calcium hydrogen bilirubinate, which is oxidised in “black” stones, but remain unpolymerised in “brown” stones. Black stones form in sterile gallbladder, but brown stones form secondary to stasis and bacterial infection in the biliary tree.

Black pigment stones may form because of haemolysis or ineffective erythropoesis and consist mainly of calciumbilirubinate, other calcium salts, aminoglycanes and glycoproteins.

Black stones are usually X-ray positive and do not occur after cholecystectomy (Vitek L and Carey MC 2012, Trotman BW 1991).

Brown pigment stones are formed in bile infected with enteric bacteria that elaborate hydrolytic enzymes: beta-glucuronidase, phospholipase A, and conjugated bile acid hydrolase. The resulting anions of bilirubin and fatty acids form insoluble calcium salts.

Brown stones are X-ray negative and may occur after cholecystectomy. Brown stones can be located anywhere in the biliary tree, even intrahepatically (Trotman BW 1991).

2.2.2.3 Clinical Manifestations of Gallstone Disease

The most common presentation of gallstone disease is a right hypochondrium pain attack, also known as the biliary colic (Festi D et al 1999). The biliary colic is an abdominal pain, most commonly experienced in the epigastrium or in the right hypocondrium, which arises rapidly, especially after fried and/or fatty food. The pain increases quickly and will last for some minutes up to couple of hours. Nausea and/or vomiting may occur (Kraag et N al 1995).

The most common complication of gallstone disease is acute calcolous cholecystitis (AC).

Over 90% of cases of acute cholecystitis result from obstruction of the cystic duct by gallstones or by biliary sludge that has become impacted at the neck of the gallbladder.

Obstruction further increases the intraluminal pressure within the gallbladder and along with mechanical trauma caused by the gallstones triggers an acute inflammatory response.

Secondary bacterial infection occurs in 20% of AC cases and may lead to gallbladder empyema (2-3% of AC cases). Other AC complications are gangrena and perforation of the gallbladder (Indar AA and Beckingham IJ 2002).

Choledocholithiasis refers to the presence of gallstones within the CBD. Formation of primary CBD stones is uncommon as most CBD stones are secondary to the passage of gallstones from the gallbladder into the CBD. Choledocholithiasis occurs in 15 to 20 percent of patients with cholelithiasis. Some stones are small enough to pass through the CBD while larger stones are prone to cause bile obstruction. CBD stones may cause biliary colic –like pain and jaundice along with cholangitis and/or acute pancreatitis (sphincter of Oddi obstruction) (Hermann RE et al 1989).

2.3 DIAGNOSIS

2.3.1 History Taking and Questionnaires

Upper abdominal pain is a common impediment and a careful history taking is crucial when evaluating patients with gallstones. As mentioned, approximately 50-70% of patients with gallstones are symptomless at the time of diagnosis and cholecystolithiasis is detected examining symptoms unrelated to gallstones. Dyspepsia, flatulence, abdominal bloating,

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regurgitation and irregular bowel habit are common in the general population and may occur with or without cholelithiasis (Diehl AK, 1992).

In recent decades, numerous studies have tried to evaluate the typical symptoms of cholelithiasis. In the studies by Festi D et al 1999 and Mertens MC et al 2010, the most common presentation of gallstone disease was biliary colic. Furthermore, epigastric and hypochondric pain after fried or fatty food without symptoms of heartburn were associated with gallstones (Festi D et al 1999). Moreover, preoperative dyspeptic symptoms are prone to persist after cholecystectomy (Mertens MC et al 2010).

Some studies have evaluated the usefulness of standardised questionnaires in order to identify gallstone-originated symptoms. Chen TY et al (2006) used the Otago gallstones condition-specific questionnaire (CSQ) and suggested that the CSQ could be valuable in helping surgeons make priority decisions in addition to tracking subsequent outcomes.

2.3.2 Physical Examination

A normal gallbladder is not palpable and uncomplicated gallstones do not cause any pain in abdominal palpation. A palpable gallbladder is uncommon and may be caused by porcelain gallbladder or chronic obstruction in the cystic duct. Palpable gallbladder occurring with jaundice is due chronic obstruction in the biliary tree, caused either by inflammation, impacting gallstone or malignancy (Khan ZS et al 2011, Fitzgerald JE et al 2009).

Murphy’s sign refers to a clinical manoeuver in abdominal palpation. It is test designed to detect acute cholecystitis. The test is performed by palpating the right upper quadrant of the abdomen as the patient is simultaneously instructed to inspire. If the inspiration suddenly halts due increased pain, the test is considered positive. In the study by Singer AJ et al (1996), the estimated sensitivity of Murphy’s sign was 97%, and the specificity was 48%. The positive predictive value in this study was 70%, and the negative predictive value was 93%.

2.3.3 Laboratory Testing

Uncomplicated gallstone disease does not elevate basic laboratory parameters. A periodic upper right quadrant pain caused by gallstones may elevate plasma leukocyte population and cause a transient liver enzyme and amylase increase. Mirizzi syndrome, a rather rare complication, in which the CHD and the gallbladder neck is obstructed by an impacting gallstone, causes hyperbilirubinemia and obstructive icterus, along with alcalic phosphatase and gamma-glutamyle transpeptidase release. (Waisberg J et al 2005, Beltran MA 2012).

Hyperbilirubinaemia and elevated alkaline phosphatase may also refer to gallstones in the CBD. In such case, elevated aspartate aminotransferase and alanine aminotransferase levels may occur. Acute cholecystitis and cholangitis causes elevation in infection parameters (Stain SC et al 1994, Shiozawa S et al 2005).

2.3.4 Imaging Modalities

In about 15-20% of cases, gallstones are visible to radiography and is therefore not the most applicable imaging modality. Ultrasound has been the golden standard for imaging the gallbladder for the last three decades. Ultrasound offers several advantages: it is highly sensitive (>95%) and accurate, it is non-invasive without ionizing radiation, it is relatively cheap, and it has the ability to evaluate adjacent organs and calibre changes, dilatation, in the biliary tree (Bortoff GA et al 2000).

Besides ultrasound, computed tomography (CT) is a useful as an adjunctive imaging modality when ultrasound results are equivocal or the clinical setting suggests disease of adjacent organs (e.g. pancreatitis). It can demonstrate gallbladder wall thickening, gallstones (depending on composition), pericholecystic inflammation, and pericholecystic abscess.

However, not all gallstones are visible in CT (Bortoff GA et al 2000).

Cholescintigraphy is a method widely used in some countries and completely ignored in others. The principle is to show that the radiopharmaceutical fills in the gallbladder within 30 minutes in normal subjects. In case of cystic duct obstruction, gallbladder will not enhance,

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7

even after hours. (Pinto et al, 2013) In 1994, Shea et al reported a systematic review of imaging studies published between 1978 and 1990. In this review, they concluded that cholescintigraphy had the best sensitivity, 97%, and specificity, 90%, in the detection of acute cholecystitis

Magnetic resonance imaging (MRI) is suitable for indicating gallstones, however it is expensive and less available. Both conventional MRI and magnetic resonance cholangiopancreatography (MRCP) have been evaluated in the diagnosis of acute calculous cholecystitis and its complications, such as acute cholecystitis, pancreatitis, and biliary obstruction (Oh KY et al 2003, Regan F et al 1998). When compared to ultrasonography, MRCP is somewhat equivalent. However, gallstones in the CBD can be detected with much greater sensitivity compared with ultrasound (Park MS et al 1998, Bortoff GA et al 2000).

Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) are techniques used to visualize the anatomy of the biliary tract. The use of these interventions is limited for therapeutic intervention rather than a diagnostic tool (Becker CD et al 1997, Bortoff GA et al 2000).

2.4 TREATMENT

Cholecystectomy is the standard treatment for symptomatic gallbladder stones and can be performed regardless of the type, number, and size of the stones. However, patients’ current illnesses and general condition must be taken into account choosing the right treatment modality.

2.4.1 Conservative Treatment

Ursodeoxycholic acid has been used for several years for the dissolution of gallstones. Only patients with mild symptoms and small, uncalcified cholesterol gallstones in a functioning gallbladder with a patent cystic duct are considered for oral litholysis. Dissolution may also be considered if operative treatment is not possible. Treatment should continue for several months and approximately 25% of the patients develop recurrent gallstones within five years (Bellows CF et al 2005, Di Ciaula A et al 2010).

Extracorporeal shock wave lithotripsy (ESWL) was successfully used in 1985 for gallbladder stones (Sauerbruch T et al 1986). However, the risk of recurrence is high, and long-term results are unsatisfactory (Carrilho-Ribeiro L et al 2006). ESWL of bile duct stones is highly effective and can be considered in patients in whom primary endoscopic (ERCP) or surgical stone removal fails. ESWL decreases gallstone size markedly and thereby increases the speed of oral dissolution (Hoffman AF 1989, Vergunst H et al 1989).

Recent studies have raised the possibility that cholesterol-lowering agents that inhibit hepatic cholesterol synthesis (statins) or intestinal cholesterol absorption (ezetimibe) may offer, alone or in combination, additional medical therapeutic tools for treating cholesterol gallstones (Di Caula A et al 2010). For instance, in a study by Pulkkinen J et al (2014), statin treatment was associated with a shorter operation time in laparoscopic cholecystectomy, while other surgical outcome measures showed no relevant differences between no treatment and statin treatment groups. Albeit, the role of cholesterol-lowering agents in the treatment of gallstone disease still remain mainly unclear.

2.4.2 Surgical Treatment

2.4.2.1 Open, Laparoscopic and Minilaparotomy Cholecystectomy

Carl Langenbuch described the first successfull cholecysectomy in 1882 and in 1915 Edward Starr Judd published an illustrated article about cholecystectomy – technique that is very similar to the open cholecystectomy (OC) currently. As the laparoscopic approach was first introduced in 1985 by Eric Mühe (Litynski GS 1998) and further developed by a French

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surgeon, Phillipe Mouret in 1987 (Litynski GS et al 1999), OC was shortly superseded as the choice of treatment by the new laparoscopic intervention. Later on, OC was related to a prolonged hospital stay and convalescence in short-term outcome studies. However, the conventional OC is still performed mainly when laparoscopic approach fails, e.g. in case of severe inflammation and difficulties to identify anatomical structures. (Keus F et al 2006, Keus F et al 2010)

A right subcostal (Kocher) incision is the most widely used for conventional OC. For LC, a four troacar technique is the most commonly used, where an optic troacar is placed near umbilicus and three trocars are placed in the right subcostal line. In both OC and LC, either antegrade or retrograde approach to the gallbladder and Calot’s triangle may be used without a clear superiority over one (Martin IG et al 1995, Mahmud S et al 2002). In a recent prospective study by Mattila A et al (2015), no significant outcome or short-term outcome differences were observed between antegrade – approach LC using MEH vs fundus first LC using UsD.

Since the mid 1970's surgeons began shortening their incisions because of a presumed quicker convalescence (Dubois F and Berthelot B 1982, Goco IR and Chambers LG 1983).

However, soon after its’ introduction, LC revolutionised gallbladder surgery, although the popularity of the new approach was partly based on an appealing technological innovation as well as industry driven motives, not primarily a result of evidence-based science (Escarce JJ 1996). Since 1990, MC has been shown to be safe and effective as a surgical approach and later on, no major outcome differences in comparative studies between MC and LC have been observed.

Albeit MC has been evaluated in numerous studies, as highlighted by Harju J et al (2006), no clear definition for MC has been established. The various descriptions of MC are given in table 1. Most, but not all studies comparing MC and LC clearly report whether antegrade or retrograde approach to the gallbladder and the critical structures of the Calot’s triangle was used: antegrade approach is reported by; O’Dwyer PJ et al (1990), Tyagi NS et al (1994), Majeed AW et al (1996), Seale AK and Ledet WP (1999), Harju J et al (2006) and Rosenmüller MH et al (2013), whom described to have used the same technique as Seale AK and Ledet WP (1999). Furthermore, none of the studies reviewed emphasize whether the antegrade or retrograde method should be used.

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9

Table 1. The definition of minilaparotomy cholecystectomy and conversion described by different authors.

Study Definition of minilaparotomy

cholecystectomy

Considered as a

”conversion”

O’Dwyer PJ et al (1990) ”5 cm subcostal incision, division of the rectus in young patients, split in the

elderly”

”Extension of the incision (Kocher)”

Al-Tameem MM et al (1993) ”3 - 5 cm incision” Not defined

McMahon AJ et al (1993) ”5 - 7 cm incision” Not defined^A

Tyagi NS et al (1994) ”3 cm transverse high subxiphoid incision in the "minimal stress triangle”,

a vertical incision through rectus abdominis"

”Extending the existing incision

(laterally)”

McGinn FP et al (1995) ”5 - 7 cm superior right upper abdominal transverse muscle cutting

incision”

”> 8 cm incision”

Majeed AW et al (1996) ”High subxiphoid < 8 cm incision” Not defined Seale AK and Ledet WP Jr (1999) ”4 - 7 cm transverse incision 2 - 3

fingers below the xiphoid process, preserving as much of the rectus

muscle as possible”

Not defined

Ros A et al (2001) ”< 8 cm incision transverse subxiphoid or oblique incision, muscle splitting

allowed”

”> 8 cm incision”

Srivastava A et al (2001) ” A transverse rectus cutting incision with a length varying from 5 to 10 cm”

Not defined

Syrakos T et al (2004) ”An oblique right subcostal incision with partial dissection of the rectus

abdominis muscle”

Not defined

Harju J et al (2006) ”3 cm transverse high subxiphoid incision in the "minimal stress triangle”,

a vertical incision through rectus abdominis”

”> 7 cm incision or cutting the rectus

muscle”

Vagenas K et al (2006) ”An oblique, right subcostal incision (5 - 7 cm long) with partial dissection of

the rectus abdominis muscle”

Not defined

Rosenmüller MH et al (2013) ”4 - 7 cm transverse incision 2 - 3 fingers below the xiphoid process, preserving as much of the rectus

muscle as possible”

“Skin incision exceeding 8 cm”

2.4.2.2 Minilaparotomy vs Laparoscopic Cholecystectomy

Several comparative studies between MC and LC have been conducted. In the study by Barkun JS et al (1992), McMahon AJ et al (1994), McGinn FP et al (1995) and Vagenas K et al (2006) the LC patients’ mean hospital stay, convalescence time and return to normal activities was shorter compared to the MC patients. In addition, Ros A et al (2001) found that the LC patients’ hospital stay and sick leave was shorter compared to the MC patients. In contrast, in a prospective study by Majeed AW et al (1996) and Harju J et al (2006), and in a

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retrospective study by Syrakos T et al (2004), no difference in mean hospital stay or convalescence could be shown between MC and LC.

Regarding operative time, McMahon AJ et al (1994), Majeed AW et al (1996), Ros A et al (2001), Harju J et al (2006) and Vagenas K et al (2006) noticed MC to be faster compared to LC. In terms of pain measurements and analgesics use, McMahon AJ et al (1994) and McGinn FP et al (1995) found that LC patients had less pain and analgesics consumption. MC seemed less costly in the studies by McMahon AJ et al (1994), Oyogoa SO et al (2003) and Syrakos T et al (2004). McGinn FP et al (1995) and Ros A and Nilsson E (2004) and Keus F et al (2009) however evaluated that no differences in direct costs in case of high volume surgery could be observed and in contrast, Srivastava A et al (2001) noted LC to be more cost-effective than MC. Purkayastha S et al (2007) conducted a meta-analysis on randomised control trials comparing LC and MC. All published studies on the subject between 1992 and 2005 were reviewed and nine high quality randomised studies of 2032 patients were included. The conclusion of the study was that MC procedure is faster and has a similar outcome compared to LC, however, LC reduces the length of hospital stay. Later on, Keus F et al (2010) published a Cochrane database systematic review on OC, MC, or LC for patients with symptomatic cholecystolithiasis. Altogether 56 randomised studies with 5246 patients were analysed with a conclusion, that LC and MC outweights the conventional OC with no significant difference between MC and LC in recovery time. However, the operative time and cost-effectiveness favoured the MC procedure.

2.4.2.3 Other Cholecystectomy Techniques

McCloy R et al (2008), Gurusamy KS et al (2013) and Gaillard M et al (2015) reviewed the benefits, safety and feasibility of minilaparoscopic cholecystectomy (MLC). By definition, MLC is carried out with the use of smaller diameter instruments than the 5-mm instruments used for LC, a range of 1.7 to 3.5 mm being described. Some technical differences exist. In terms of surgical results no major differences could be seen, besides a modest increase in operating time after MLC compared with LC. In conclusion, MLC may be performed without exposing patients to increased occurrence of adverse events.

Other surgical approaches include single incision laparoscopicsurgery (SILS) and natural orifice transluminal endoscopic surgery (NOTES). SILS was first introduced by Navarra G et al (1997) and has later been widely studied. The procedure has not obtained a strong position compared to conventional LC and is associated with higher procedure failure rate, more blood loss, higher instrumentation costs and prolonged duration of the operation compared to conventional multiport LC (Trastulli S et al 2013). The first NOTES were performed in France in 2007 (Marescaux J et al 2007) and two years later de Sousa LH et al (2009) published the first series NOTES transvaginal cholecystectomy. This technique was recently compared to conventional LC in a meta-analysis by Xu B et al (2015), which indicated that NOTES is a safe and effective surgical approach. The patients operated transvaginally had lower postoperative pain scores, however, NOTES requires a prolonged operative time compared to conventional LC. Patients operated with NOTES cholecystectomy might benefit in terms of cosmetic result, but vaginal injury may occur (Xu B et al 2015). Furthermore, transgastric and transcolonic approaches of NOTES have been performed in animal models (Gumbs AA et al 2009, Asakuma M et al 2010, Auyang ED et al 2009) and hybrid transgastric cholecystectomy has been reported in small case series (Salinas G et al 2010), but the procedure is still technically challenging with the currently existing instrumentation.

Moreover, robotic-assisted surgery has gained a lot of interest in recent years. However, robotics has not brought any benefit in terms of perioperative and short-term postoperative data, while the costs of robotic-assisted surgery are considerably higher (Breitenstein S et al 2008).

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2.4.2.4 Indications and Timing for Surgery

As most gallstones are asymptomatic, a prophylactic cholecystectomy is rarely recommended. Such occasions are e.g. chronic haemolytic syndrome or immunosuppressive medication (Begos DG et al 1995, Curro G et al 2007). Some authors suggest a prophylactic cholecystectomy for patients in areas with higher prevalence of gallbladder carcinoma (Batra Y et al 2005).

Long-time follow-up studies show that eventually 35-40% of patients with asymptomatic gallstones develop symptoms (Halldestam I et al 2004). Patients with uncomplicated gallstone disease confirmed by imaging and experiencing biliary colics, especially after fried and/or fatty food are most likely expected to be symptomless after cholecystectomy (Attili AF et al 1995, Mertens MC et al 2010). Chronic cholecystitis and gallstone related complications are always considered as an indication for surgery unless contraindications exist. Such complications are e.g. acute calculous and acalculous cholecystits along with gallstone originated pancreatitis (Attili AF et al 1995, Laurila J et al 2004).

2.4.3 Ultrasonic Dissection

The standard LC is usually performed using a MEH for dissection and clips for occlusion of the cystic duct and cystic artery. Adequate dissection in both MC and in LC is achieved, and furthermore, MEH is known for its’ ease for securing haemostasis and cost-effectiveness.

Even though LC is considered a safe procedure, some pitfalls are associated with the use of the monopolar electrosurgery, such as the high risk of thermal injury, bile leakage and significantly more common postoperative biliary complications (Amaral JF 1995, Tsimoyiannis EC et al 1998, Cengiz Y et al 2010, Sasi W 2010).

Ultrasonic scissor is an ultrasonic surgical instrument for cutting and coagulating tissue, operating at a frequency of 55.5 kHz/second. The mechanical energy and the heat generated causes protein denaturation and formation of a coagulum that seals small blood vessels up to 2mm and 3mm, although a newer device has demonstrated the ability to coagulate blood vessels up to 7mm in diameter (Shimi SM 1995, Goldstein SL et al 2001, Heniford BT 2001).

The dissecting includes three synergistic mechanisms: cavitation, coaptation/coagulation and cutting. The lateral energy spread is minimal and the risk of distant tissue damage is lower than that of high frequency electrosurgery (Hüscher CGS et al 2003, Gelmini R et al 2010).

However, as demonstrated by an experimental animal study by Emam TA and Cuschieri A (2003), high-power ultrasonic dissection can also result in considerable heat production causing proximal collateral damage to adjacent tissues with continuous activation time exceededing 10 seconds.

Due increased life expectancy and gallstone prevalence among Western population, many surgeons are likely to encounter patients with permanent pacemakers. Use of electrocautery might inhibit or trigger the pacemaker in demand modes, damage the pacing system, or possibly cause the unit to go into its automatic safety reversion mode during surgery and can also cause thermal damage to the heart through the lead electrode (Peters RW and Gold MR 1998). Moreover, The patient return electrode should not be placed over or near a metal prosthesis, eg total hip prosthesis. As the tissue over prostheses contains scar tissue, which impedes return of the electric current, there is a theoretical risk of the heating implant to cause a tissue burn (Spruce L and Braswell MR 2012). Thus, the use of ultrasonic dissection (UsD) may increase patient-safety and its use seems justifiable especially with pacemaker patients.

Another known issue of electrosurgical energy is the surgical smoke created, which interferes with laparoscopic visibility and contains potentially carcinogenic and/or infective compounds physically small enough to be respirable and even reach the lower airways of the surgical staff (Mowbray N et al 2013). Ultrasonic dissection has its own disadvantages, as cavitation leads to the production of mist and may impair visualization, though UsD derived mist can be considered more acceptable than surgical smoke because it vanishes much more

Minilaparotomy versus laparoscopic cholecystectomy for elective gallstone disease : a prospective randomized stury on ultrasonic dissection, surgical stress, health status and long-term outcome after surgery

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Dissertations in Health Sciences

SAMULI ASPINEN

MINILAPAROTOMY VERSUS LAPAROSCOPIC CHOLECYSTECTOMY FOR ELECTIVE GALLSTONE DISEASE

SAMULI ASPINEN

Minilaparotomy versus Laparoscopic Cholecystectomy for Elective Gallstone

Disease

Minilaparotomy versus Laparoscopic Cholecystectomy for Elective Gallstone

Disease

A Prospective Randomized Study on Ultrasonic Dissection, Surgical Stress, Health Status and Long-term Outcome After

Surgery

Acknowledgements

List of the original publications

Contents

Abbreviations

1 Introduction

2 Review of the Literature